Textbook of Epilepsy Surgery

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9781841845760-FM

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Textbook of Epilepsy Surgery

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Textbook of Epilepsy Surgery Edited by

Hans O Lüders

MD PhD

Epilepsy Center Neurological Institute University Hospitals of Cleveland Case Western Medical Center Cleveland, OH USA

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© 2008 Informa UK Ltd First published in the United Kingdom in 2008 by Informa Healthcare, Telephone House, 69-77 Paul Street, London EC2A 4LQ. Informa Healthcare is a trading division of Informa UK Ltd. Registered Office: 37/41 Mortimer Street, London W1T 3JH. Registered in England and Wales number 1072954. Tel: +44 (0)20 7017 5000 Fax: +44 (0)20 7017 6699 Website: www.informahealthcare.com All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. The Author has asserted his right under the Copyright, Designs and Patents Act 1988 to be identified as the Author of this work. A CIP record for this book is available from the British Library. Library of Congress Cataloging-in-Publication Data Data available on application ISBN-10: 1 84184 576 0 ISBN-13: 978 1 84184 576 0 Distributed in North and South America by Taylor & Francis 6000 Broken Sound Parkway, NW, (Suite 300) Boca Raton, FL 33487, USA Within Continental USA Tel: 1 (800) 272 7737; Fax: 1 (800) 374 3401 Outside Continental USA Tel: (561) 994 0555; Fax: (561) 361 6018 Email: [email protected] Book orders in the rest of the world Paul Abrahams Tel: +44 (0) 207 017 4036 Email: [email protected] Composition by Cepha Imaging Pvt. Ltd., Bangalore, India Printed and bound in India by Replika Press Pvt. Ltd. Cover illustration: © ‘An operation for stone in head’ used with kind permission from the Wellcome Trust, UK 2008.

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Dudley S Dinner MD April 17, 1947 – May 1, 2007 I dedicate this book to Dudley, my dear friend and colleague, whose contributions to epilepsy surgery will have a permanent impact on the specialty. Dudley joined the Cleveland Clinic Epilepsy Center as a fellow in clinical neurophysiology in 1979, shortly after I became the Director of the Center. This marked the beginning of a remarkable thirty years of extremely productive, daily collaboration. Throughout this period, Dudley participated in all major projects of the Center: contributing ideas, assisting in the organization of these projects, and managing their execution. Dudley’s absolute loyalty, reliability, intellectual honesty, complete dedication, exemplary modesty, and willingness to sacrifice to achieve our objectives were essential ingredients in the development of the Epilepsy Center at the Cleveland Clinic. Dudley, as an expression of his unselfishness, never demanded recognition for his contributions. Dudley was so often the driving force behind the scenes. I would like to use this opportunity to express my deepest appreciation for Dudley’s invaluable contributions, but also – and perhaps most importantly – to thank him for his friendship and unwavering support. I particularly notice his absence in my current efforts to organize an Epilepsy Center at University Hospitals. I realize now how much I relied on Dudley’s help in so many of our projects. I greatly miss him as a colleague and as a dear friend. It is a great honor to dedicate this book to Dudley.

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Contents List of Contributors

xvii

Preface

xxiv

Color plates

xxv

SECTION 1: HISTORY OF SURGERY AND RELATED FIELDS

1

1.

Epilepsy surgery in Europe before the 19th century D Schmidt and H-J Meencke

3

2.

Epilepsy surgery in Asia before the 19th century N-S Chu, T Hori, S-K Lee, Y Mayanagi, K Radhakrishnan, and H Shibasaki

12

3.

Epilepsy surgery in Latin America before the 19th century MG Campos

15

4a.

The history of epilepsy surgery in the United Kingdom CE Polkey

24

4b.

Epilepsy surgery in Ireland P Widdess-Walsh, N Delanty, and JP Phillips

32

5.

Epilepsy surgery in Germany A Ebner, H Stefan, B Pohlmann-Eden, and PA Winkler

37

6.

Epilepsy surgery in France P Kahane, A Arzimanoglou, A-L Benabid, and P Chauvel

46

7.

Epilepsy surgery in Italy G Avanzini and L Tassi

54

8a.

Epilepsy surgery in Switzerland HG Wieser and K Schindler

59

8b.

Epilepsy surgery in Austria C Baumgartner, T Czech, and O Schröttner

73

9.

Epilepsy surgery in the Nordic countries K Källén, H Høgenhaven, KO Nakken, and R Kalviäinen

77

10.

The development of epilepsy surgery in the Netherlands and Belgium W van Emde Boas and PAJM Boon

84

11.

History of epilepsy surgery in the Middle- and East-European countries and Russia P Halász

97

12.

Epilepsy surgery in Canada W Feindel

103

13.

A brief history of epilepsy surgery in the United States PJ Connolly, DD Spencer, and AA Cohen-Gadol

116

14.

Epilepsy surgery in Latin America J Godoy, AC Sakamoto, and ALF Palmini

118

15.

Epilepsy surgery in Africa MF Moodley and EL Khamlichi

125

16a.

History of epilepsy surgery in Southeast Asia S-H Lim

130

16b.

Epilepsy surgery in India DK Lachhwani and K Radhakrishnan

134

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Contents

17.

Treatment of epilepsy in Australia A Mohamed

145

18.

Epilepsy surgery in Korea BI Lee

148

19.

Epilepsy surgery in Thailand T Srikijvilaikul, C Locharernkul, and A Boongird

152

20.

History of epilepsy and seizure classification T Loddenkemper and HO Lüders

160

21.

History of electroencephalography as a presurgical evaluation tool: the pre-Berger years WT Blume

174

22.

History of neuroimaging in the presurgical evaluation B Diehl and P Ruggieri

177

23.

Epilepsy surgery in literature and film P Wolf and S Baxendale

189

24.

The future of epilepsy surgery F Andermann and W Harkness

197

SECTION 2: OVERVIEW

201

25.

Medical intractability in epilepsy DV Lardizabal

203

26.

Epidemiology of the intractable generalized epilepsies AT Berg

207

27.

Genetic factors contributing to medically intractable epilepsy JF Bautista

215

28.

Informed consent FL Vale and S Benbadis

220

29.

Epilepsy surgery: access, costs, and quality of life MG Campos and S Wiebe

223

30.

Epilepsy surgery: patient selection H Morris, I Najm, and P Kahane

230

31.

Exclusion criteria EMT Yacubian

238

SECTION 3: EPILEPSIES REMEDIABLE BY EPILEPSY SURGERY

243

32.

Classification of epileptic seizures and epilepsies HO Lüders

245

33.

Mesial temporal sclerosis HO Lüders

249

34.

Neocortical temporal lobe epilepsy A Ebner

252

35.

Premotor and central lobe epilepsy S Bauer, HM Hamer, and F Rosenow

263

36.

Mesial frontal epilepsy A Bleasel and D Dinner

274

37.

Basal frontal lobe epilepsy AV Alexopoulos and N Tandon

285

38.

Parieto-occipital lobe epilepsy V Salanova

314

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39.

Insular epilepsy J Isnard, P Ryvlin, and F Mauguière

320

40.

Cingulate epilepsy E Garzon and HO Lüders

334

41.

Hypothalamic hamartomas AS Harvey

354

42.

Rasmussen syndrome CG Bien

362

43.

The Landau–Kleffner syndrome AM Kanner, A Balabanov, TP Hoeppner, and R Byrne

369

44.

The Lennox–Gastaut syndrome: a surgically remediable epilepsy? C Dravet

384

45.

Medically intractable epilepsies not remediable by surgery NK So

394

46.

Special characteristics of surgically remediable epilepsies in infants A Gupta

400

SECTION 4: PRE-SURGICAL EVALUATION: GENERAL PRINCIPLES

407

47.

409

General principles of pre-surgical evaluation M Carreño and HO Lüders

SECTION 5: THE SYMPTOMATOGENIC ZONE

423

48.

The symptomatogenic zone – general principles C Kellinghaus and HO Lüders

425

49.

Auras: localizing and lateralizing value S Rona

432

50.

Autonomic seizures: localizing and lateralizing value V Nagaraddi and HO Lüders

443

51.

Simple motor seizures: localizing and lateralizing value S Noachtar and S Arnold

450

52.

Complex motor seizures: localizing and lateralizing value MM Bianchin and AC Sakamoto

462

53.

Dialeptic seizures: localizing and lateralizing value S Noachtar

479

54a.

Special seizures: localizing and lateralizing value SR Benbadis

488

54b.

Secondary generalized tonic-clonic seizures SD Lhatoo and HO Lüders

492

SECTION 6: THE IRRITATIVE ZONE

501

55.

The irritative zone: general principles M Eccher and D Nair

503

56.

Noninvasive electroencephalography evaluation of the irritative zone HM Hamer

512

57.

The irritative zone evaluated with invasive recordings A Palmini

521

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58.

The significance of interictal fast ripples in the evaluation of the epileptogenic zone A Bragin, RJ Staba, and J Engel Jr

530

59.

Magnetoencephalography in the evaluation of the irritative zone M Iwasaki and RC Burgess

537

60.

Magnetic resonance imaging in the evaluation of the irritative zone K Krakow, B Diehl, and JS Duncan

544

61.

Digital tools for reviewing the electroencephalogram: montage reformatting and filtering TD Lagerlund

550

62.

Average reference and Laplacian montages TD Lagerlund

558

63.

Automatic detection of epileptic spikes P LeVan and J Gotman

565

64.

Source localization of electroencephalography spikes TN Townsend and JS Ebersole

570

65.

Antiepileptic drug withdrawal in presurgical evaluation: advantages, disadvantages, and guidelines SP Claus, DN Velis, and W van Emde Boas

580

66.

Effects of sleep and sleep deprivation on seizures and the electroencephalography in epilepsy N Foldvary-Schaefer

588

SECTION 7: THE ICTAL ONSET ZONE

595

67.

The ictal onset zone: general principles, pitfalls, and caveats A Arzimanoglou and P Kahane

597

68.

Noninvasive electroencephalography in the evaluation of the ictal onset zone N Foldvary-Schaefer

603

69.

Indications for invasive electroencephalography evaluations SR Sinha, NE Crone, and RP Lesser

614

70.

Invasive electrodes in long-term monitoring GH Klem and S Nehamkin

623

71.

Foramen ovale and epidural electrodes in the definition of the seizure onset zone HG Wieser and K Schindler

629

72.

Subdural electrodes MZ Koubeissi

641

73.

Stereoelectroencephalography P Kahane and S Francione

649

74.

DC recordings to localize the ictal onset zone A Ikeda

659

75.

fMRI in the evaluation of the ictal onset zone K Hamandi and JS Duncan

667

76.

Ictal SPECT in the definition of the seizure onset zone GD Cascino and D Lachhwani

675

77.

Automatic detection of epileptic seizures FT Sun, TK Tcheng, EH Boto, BM Wingeier, TL Skarpaas, and MJ Morrell

681

78.

‘Preictal’ predictors of epileptic seizures F Mormann, K Lehnertz, and CE Elger

691

79.

Effect of anticonvulsant withdrawal on seizure semiology and ictal electroencephalography CT Skidmore and MR Sperling

702

80.

Zone of electrical stimulation induced seizures in subdural electrodes R Schulz

706

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SECTION 8: THE EPILEPTIC LESION

709

81.

The epileptogenic lesion: general principles HM Hamer and S Knake

711

82.

Magnetic resonance imaging in epilepsy: mesial temporal sclerosis GD Cascino

716

83.

Magnetic resonance imaging in neurocutaneous syndromes D Moon and A Gupta

721

84.

Magnetic resonance imaging in epileptogenic neoplasms J Tamraz and Y Comair

730

85.

Magnetic resonance spectroscopy in patients with epilepsy MA McLean, M Koepp, and FG Woermann

755

86a.

Post-processing of the magnetic resonance imaging to better define structural abnormalities S Knake, F Rosenow, and PE Grant

764

86b.

Multimodal image processing in pre-surgical planning C Vollmar, S Noachtar, and PA Winkler

771

SECTION 9: THE FUNCTIONAL DEFICIT ZONE

779

87.

The functional deficit zone: general principles C Baumgartner and E Lehner-Baumgartner

781

88.

Mesial temporal lobe epilepsy and positron emission tomography A Mohamed and MJ Fulham

792

89.

PET in neocortical epilepsies HT Chugani, C Juhász, E Asano, and S Sood

803

90.

Pre-surgical neuropsychological workup: risk factors for post-surgical deficits RM Busch and RI Naugle

817

91.

Pre-surgical psychiatric evaluations: risk factors for post-surgical deficits AM Kanner and AJ Balabanov

826

92.

Pre-surgical neuropsychological workup in children and intellectually disabled adults with epilepsy U Gleissner and C Helmstaedter

834

93.

Wada test and epileptogenic zone DS Dinner and T Loddenkemper

844

94.

Event-related potentials in patients with epilepsy K Usui and A Ikeda

858

SECTION 10: PRE-SURGICAL EVALUATION OF ELOQUENT CORTEX

869

95.

Eloquent cortex and tracts: overview and noninvasive evaluation methods J Reis and F Rosenow

871

96.

Noninvasive tests to define lateralization or localization of the motor area R Matsumoto and H Shibasaki

881

97.

Noninvasive tests to define lateralization or localization of memory EB Geller and C Santschi

889

SECTION 11: THE EPILEPTOGENIC ZONE

897

98.

The epileptogenic zone: general principles KM Klein and F Rosenow

899

99.

Future methods for the direct assessment of the epileptogenic zone J Engel Jr

902

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SECTION 12: THE PATIENT MANAGEMENT MEETING

909

100.

911

The patient management conference M Carreño and HO Lüders

SECTION 13: SURGICAL TECHNIQUES FOR PLACEMENT OF INTRACRANIAL ELECTRODES

921

101.

Anesthesia for epilepsy surgery M Lotto and A Schubert

923

102.

Placement of subdural grids F Salazar and WE Bingaman

931

103.

Placement of depth electrodes L Mulligan, K Vives, and D Spencer

938

104.

Stereoelectroencephalography D Hoffmann, GL Russo, and M Cossu

945

SECTION 14: CORTICAL MAPPING AND ELECTROCORTICOGRAPHY

961

105.

General principles of cortical mapping by electrical stimulation SU Schüle, C McIntyre, and HO Lüders

963

106.

Cortical mapping by electrical stimulation of subdural electrodes: primary somatosensory and motor areas AS Tanner and HO Lüders

107.

Cortical mapping by electric stimulation of subdural electrodes: negative motor areas P Smyth

108.

Cortical mapping by electrical stimulation of subdural electrodes: supplementary sensorimotor area in humans DS Dinner and HO Lüders

978 983

991

109.

Cortical mapping by electrical stimulation of subdural electrodes: language areas N Tandon

1001

110.

Cortical mapping by electrical stimulation: other eloquent areas M Hoppe

1016

111.

The role of electroencephalogram and magnetoencephalography synchrony in defining eloquent cortex G Kalamangalam and M Iwasaki

1026

112.

Cortical mapping using evoked potentials and Bereitschaftspotentials A Ikeda and H Shibasaki

1036

113a. Cortico-cortical evoked potentials to define eloquent cortex R Matsumoto and DR Nair

1049

113b. Cortical mapping by intra-operative optical imaging MM Haglund and DW Hochman

1060

114.

Functional localization of the cortex with depth electrodes J-P Vignal and P Chauvel

1068

115.

Intraoperative cortical mapping and intraoperative electrocorticography DR Nair and I Najm

1073

SECTION 15: RESECTIVE SURGICAL PROCEDURES FOR EPILEPSY

1081

116.

Resective surgical techniques: mesial temporal lobe epilepsy DK Binder and J Schramm

1083

117.

Resective neocortical techniques in adults EO Richter and SN Roper

1093

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xiii

118.

Epilepsy and vascular malformations: spectrum of lesions and strategies for management P Jabbour and I Awad

1098

119.

Resective neocortical techniques in children F Villarejo

1110

120.

Hemispherectomy techniques SJ Nagel, SK Elbabaa, EJ Hadar, and WE Bingaman

1121

SECTION 16: NONRESECTIVE SURGICAL PROCEDURES AND ELECTRICAL OR MAGNETIC STIMULATION FOR EPILEPSY TREATMENT

1131

121.

1133

Experimental multiple subpial transection: is it still indicated? T Tanaka, A Hodozuka, K Hashizume, M Kunimoto, and S Takebayashi

122a. Multiple subpial transections W Harkness 122b. Nonresective surgical procedures and electrical or magnetic stimulation for epilepsy treatment mutiple hippocampal transection H Shmizu 122c. Surgical disconnections of the epileptic zone as an alternative to lobectomy in pharmacoresistent epilepsy AL Benabid, S Chabardès, E Seigneuret, D Hoffmann, L Minotti, P Kahane, S Grand, and JF LeBas

1138

1149

1155

123.

Corpus callosotomy G Morrison and M Duchowny

1163

124.

Radiosurgical treatment of epilepsy I Yang and NM Barbaro

1173

125.

Vagal nerve stimulation: experimental data S Chabardès, I Najm, and HO Lüders

1179

126.

Vagal nerve stimulation: surgical technique and complications WE Bingaman

1184

127.

Vagus nerve stimulation: human studies T Loddenkemper and AV Alexopoulos

1188

128.

Experimental evidence for the involvement of the basal ganglia in the control of epilepsy C Deransart and A Depaulis

1201

129.

Repetitive transcranial magnetic stimulation F Tergau and BJ Steinhoff

1208

SECTION 17: SURGICAL OUTCOME

1221

130.

Mesial temporal lobectomy: post-surgical seizure frequency L Jehi

1223

131.

Resective surgery in children T Loddenkemper and E Wyllie

1236

132.

Hemispherectomy: post-surgical seizure frequency I Tuxhorn, H Holthausen, P Kotagal, and H Pannek

1249

133a. Psychiatric outcome of epilepsy surgery AM Kanner and AJ Balabanov

1254

133b. Sudden unexpected death in epileptic patients after epilepsy surgery D Schmidt and P Ryvlin

1263

134.

1269

Psychosocial outcome and quality of life outcome NK So and CB Dodrill

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135.

Neuropsychological outcome WB Barr

1277

136.

Temporal lobe epilepsy surgery: surgical complications D Sasaki-Adams and EJ Hadar

1288

137.

Neocortical focal epilepsy surgery: surgical complications JA González-Martínez and WE Bingaman

1300

SECTION 18: POST-SURGICAL MANAGEMENT

1307

138.

Early post-surgical management of patients with epilepsy I Melamed and AA Cohen-Gadol

1309

139.

Post-surgical pharmacotherapy: discontinuation of anticonvulsants AS Tanner and D Schmidt

1313

140.

Post-surgical rehabilitation R Thorbecke and B Hötger

1319

SECTION 19: NEUROPATHOLOGY AND RESEARCH RELATED TO EPILEPSY SURGERY

1329

141.

Neuropathology of mesial temporal sclerosis I Blümcke

1331

142.

Pathology of neocortical epilepsy M Thom and S Sisodiya

1338

143.

Pathology of malformations of cortical development R Spreafico and AJ Becker

1349

144.

Pathology of neurocutaneous abnormalities, vascular abnormalities: post-infectious and post-traumatic pathologies associated with epilepsy I Blümcke and M Hildebrandt

1359

145.

Pathology of epileptogenic neoplasms RA Prayson

1373

146.

In vitro neurophysiological studies GL Möddel and IM Najm

1384

147.

In vitro cytochemical studies in epilepsy JA González-Martínez, CQ Tilelli, and IM Najm

1397

148.

Animal models of epilepsy with special reference to models relevant for transitional research S Chabardès, I Najm, and HO Lüders

1405

SECTION 20: SURGICAL FAILURES: REOPERATION

1415

149.

Surgical failures: pre-surgical evaluation CT Skidmore and MR Sperling

1417

150.

Reoperation after failed epilepsy surgery A Boongird, JA González-Martínez, and WE Bingaman

1425

SECTION 21: CASE PRESENTATIONS

1433

151.

Lesional mesial temporal epilepsy: case discussions J Mani and IM Najm

1435

152.

A patient with nonlesional mesial temporal lobe epilepsy A Ray, G Kalamangalam, and HO Lüders

1446

153.

Patient with bitemporal lobe epilepsy AV Alexopoulos and HO Lüders

1456

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154.

Patient with lesional neocortical focal epilepsy B Abou-Khalil

1471

155.

Patient with nonlesional neocortical epilepsy L Tassi and GL Russo

1476

156.

Patient with extensive malformation of cortical development DK Lachhwani

1485

157.

Hemispherectomy in a patient with catastrophic epilepsy A Gupta

1491

158.

Case studies: Landau–Kleffner syndrome AM Kanner, MA Rossi, and MC Smith

1496

159.

Deep brain stimulation in a patient with medically intractable generalized seizures M Hodaie, C Hamani, D Zumsteg, DM Andrade, R Wennberg, and AM Lozano

1506

160.

Successful transcranial magnetic stimulation in a patient with medically intractable focal epilepsy F Fregni, G Thut, A Rotenberg, and A Pascual-Leone

1511

161.

Surgery in a patient with medically intractable gelastic seizures and a hypothalamic hamartoma S Mittal, JL Montes, J-P Farmer, and JD Atkinson

1518

162.

Surgery in a patient with focal epilepsy and dual pathology N Foldvary-Schaefer

1523

SECTION 22: APPENDICES

1535

163.

Essentials for the establishment of an epilepsy surgery program MG Campos, HB Pomata, MA Vanegas, and AC Sakamoto

1537

164.

Classification of seizure outcome following epilepsy surgery HG Wieser and K Schindler

1545

165.

Protocol for storage and processing of brain tissue for molecular studies PB Crino

1552

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Contributors B Abou-Khalil

MD

AV Alexopoulos

Department of Neurology, Vanderbilt University Medical Center, Nashville, TX, USA.

MD MPH

Department of Neurology, Section of Adult Epilepsy, The Cleveland Clinic Foundation, Cleveland, OH, USA.

F Andermann MD Montréal Neurological Hospital and Institute, McGill University; and the Hospital for Sick Children, Montréal, Quebec, Canada. DM Andrade MD Krembil Neuroscience Centre, Toronto Western Hospital; and Division of Neurology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. S Arnold

Epilepsy Center, Department of Neurology, University of Munich, Munich, Germany.

MD

A Arzimanoglou MD Child Neurology and Metabolic Disorders, University Hospital Robert Debré (AP-HP), Paris; CTRS-IDEE, Hospices Civils de Lyon, Lyon, France. E Asano

G Avanzini I Awad

Departments of Pediatrics and Neurology, Children’s Hospital of Michigan, Wayne State University, Detroit, MI, USA.

MD PhD

Department of Neurophysiology, National Neurological Institute “Carlo Besta,” Milan, Italy.

MD

MD MSc FACS FICS FAHA

Department of Neurological Surgery, Northwestern University; Feinberg School of Medicine, Chicago, IL, USA.

JD Atkinson MD Division of Pediatric Neurosurgery, Montréal Children’s Hospital; McGill University Health Centre, Montréal, Quebec, Canada. AJ Balabanov

Department of Neurological Sciences, Rush Medical College, Rush University Medical Center, Chicago, IL, USA.

MD

NM Barbaro

MD

WB Barr

Departments of Neurology and Psychiatry, New York University Medical Center, New York, NY, USA.

S Bauer

PhD

Department of Neurology, Philipps University, Marburg, Germany.

MD

C Baumgartner JF Bautista

MD

S Baxendale AJ Becker

Department of Neurological Surgery, University of California, San Francisco, CA, USA.

MD

Department of Neurology, The Cleveland Clinic Foundation, Cleveland, OH, USA.

PhD

MD

Department of Neurology, Medical University of Vienna, Vienna, Austria.

Department of Neuropsychology, National Hospital for Neurology and Neurosurgery, London, UK.

Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.

A-L Benabid

MD PhD

SR Benbadis

MD

AT Berg

Department of Biology, Northern Illinois University, DeKalb, IL, USA.

PhD

MM Bianchin C Bien

MD PhD

MD PhD

WE Bingaman A Bleasel

Departments of Neurology and Neurosurgery, University of South Florida; and Tampa General Hospital, Tampa, FL, USA.

Department of Neurological Surgery, University of California, Irvine, CA, USA. Department of Neurosurgery, The Cleveland Clinic Foundation, Cleveland, OH, USA.

MD

MBBS FRACP

I Blümcke

Department of Neurology, Psychiatry and Psychology, University of São Paulo School of Medicine, São Paulo, Brazil.

Department of Epileptology, University of Bonn, Bonn, Germany.

MD

D Binder

Department of Clinical Neurosciences, Grenoble University Hospital, Joseph Fourier University, Grenoble, France.

MD

WT Blume

Department of Neurophysiology, The Children’s Hospital at Westmead, Westmead, New South Wales, Australia.

Department of Neuropathology, University of Erlangen, Erlangen, Germany.

MD FRCPC

W van Emde Boas

London Health Sciences Centre, University Campus, London, UK.

MD PhD

Departments of EEG and EMU, Epilepsy Institutions of the Netherlands, Heemstede and Zwolle, The Netherlands.

P Boon MD PhD Department of Neurology and Laboratory for Clinical and Experimental Neurophysiology, Ghent University Hospital, Ghent, Belgium. A Boongird

MD

Neurosurgery Unit, Department of Surgery, Bangkok, Thailand.

EH Boto

PhD

Clinical Scientist, Neuropace Inc, Mountain View, CA, USA.

A Bragin

PhD

Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

RC Burgess RM Busch

MD PhD

MD PhD

MG Campos M Carreño

MD


Departments of Psychiatry and Psychology, The Cleveland Clinic Foundation, Cleveland, OH, USA.

Department of Neurosurgery, Pontifical Catholic University of Chile, Santiago de Chile, Chile.

MD PhD

Epilepsy Unit, Department of Neurology, Hospital Clínic de Barcelona, Barcelona, Spain.

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List of Contributors

GD Cascino

MD FAAN

S Chabardès

MD

Department of Neurology, Mayo Clinic, Rochester, MN, USA.


P Chauvel Laboratory of Clinical Neurophysiology and INSERM EMI La timone University Hospital, Marseille, France. PJ Connolly MD Head injury and Neurocritical Care Program, Indianapolis Neurosurgical Group, Clarian Neuroscience, Indianapolis, IN, USA. N-S Chu

Chang Gung Medical College and Memorial Hospital, Taiwan, Republic of China.

MD PhD

HT Chugani

Departments of Pediatrics, Neurology, and Radiology, Children’s Hospital of Michigan, Wayne State University, Detroit, MI, USA.

PhD

SP Claus Department of Child Neurology, Wilhelmina Children’s Hospital, University Medical Center of Utrecht, The Netherlands. AA Cohen-Gadol MD MSc Skull Base/Cerebrovascular and Epilepsy Surgery Programs, Indianapolis Neurosurgical Group, Clarian Neuroscience Institute (Methodist, Indiana University, and Riley Hospitals), Indianapolis, IN, USA. Y Comair

MD FRCSE

M Cossu

MD

PB Crino

MD PhD

NE Crone

Institute of Neurosurgery, University of Genoa, San Martino Hospital, Genoa, Italy.

MD

PhD MRCP(UK), FRCPCH

Department of Neurology, Beaumont Hospital, Dublin, Ireland.

PhD

A Depaulis

Department of Paediatric Neurology, Institute of Child Health and Great Ormond Street Hospital NHS Trust,

Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.

MD

N Delanty

Department of Neurology, The Mahoney Institute of Neurological Sciences, University of Pennsylania, Philadelphia, PA, USA.

Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.

H Cross MBChB London, UK. T Czech

Department of Surgery, Division of Neurosurgery, American University of Beirut, Beirut, Lebanon.

Grenoble Institute of Neurosciences, Joseph Fourier University, Grenoble, France.

PhD

C Deransart Grenoble Institute of Neurosciences, Joseph Fourier University, Grenoble, France. B Diehl


MD

†DS Dinner

MD

Department of Neurology, The Cleveland Clinic Foundation, Cleveland OH, USA.

C Dodrill Department of Neurology, University of Washington School of Medicine; Regional Epilepsy Center, Harborview Medical Center, Seattle, WA, USA. C Dravet Centre Saint-Paul – Hôpital Henri Gastaut, Marseille, France. MS Duchowny USA.

MD

Department of Neurology, Miami School of Medicine; Comprehensive Epilepsy Program, Miami Children’s Hospital, Miami, FL,

JS Duncan

MD

Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, UK.

JS Ebersole

MD

Department of Neurology, Adult Epilepsy Center, University of Chicago Medical Center, Chicago, IL, USA.

A Ebner

Epilepsy Centre Bethel, Bielefeld, Germany.

MD

M Eccher

MD

SK Elbabaa CE Elger

Department of Neurology, University of Pennsylvania Medical Center, Philadelphia, PA, USA. Division of Neurological Surgery, University of North Carolina, Chapel Hill, NC, USA.

MD

MD PhD FRCP


J Engel Jr MD Departments of Neurology and Neurobiology, and Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. J-P Farmer Canada. W Feindel

MD CM FRCS(C)

Division of Pediatric Neurosurgery, Montréal Children’s Hospital, McGill University Health Centre, Montréal, Quebec,

MD CM DPhil FRCSC FACS

N Foldvary-Schaefer S Francione

MD

DO

Montréal Neurological Institute, McGill University, Montréal, Quebec, Canada.

Sleep Disorders Center, The Cleveland Clinic Foundation, Cleveland, OH, USA.

Epilepsy Surgery Centre, Niguarda Hospital, Milano, Italy.

F Fregni MD PhD Center for Non-invasive Brain Stimulation, Harvard Medical School; Department of Neurology, Beth Israel Deaconess Medical Center and Boston Children’s Hospital, Boston, MA, USA. MJ Fulham

MD

PET Centre, Royal Prince Alfred Hospital, Campendown, New South Wales, Australia.

E Garzon

MD PhD

EB Geller

MD

Department of Neurology, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, Brazil.

The Institute of Neurology and Neurosurgery at Saint Barnabas, West Orange, NJ, USA.

U Gleissner

PhD

J Godoy

Department of Neurology, Pontifical Catholic University of Chile, Santiago de Chile, Chile.

MD


JA González-Martínez

MD PhD

Department of Neurological Surgery, The Cleveland Clinic Foundation, Cleveland OH, USA.

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List of Contributors J Gotman S Grand

xix

Montréal Neurological Institute, McGill University, Montréal, Quebec, Canada.

PhD


MD PhD

PE Grant

MD

Department of Radiology, Harvard Medical School, Massachusetts General Hospital, Cambridge, MA, USA.

A Gupta

MD


MM Haglund

MD PhD

P Halász

MD PhD DSc

EJ Hadar

MD

Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, NC, USA.

National Institute of Psychiatry and Neurology, Budapest, Hungary.

Division of Neurosurgery, University of North Carolina, Chapel Hill, NC, USA.

C Hamani Krembil Neuroscience Centre, Toronto Western Hospital; and Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada. K Hamandi Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, UK. HM Hamer

MD

K Hashizume

Department of Neurology, University of Marburg, Marburg, Germany. Department of Neurosurgery, Asahikawa Medical College, Asahikawa, Japan.

MD

W Harkness MD Montréal Neurological Hospital and Institute, McGill University, Montréal, Quebec, Canada; Great Ormond Street Hospital for Children, London, UK S Harvey

MD FRACP

C Helmstaedter

Children’s Epilepsy Program, Department of Neurology, Royal Children’s Hospital, Melbourne, Victoria, Australia.

MD PhD

Department of Neurophysiology, University Clinic of Epileptology, Bonn, Germany.

M Hildebrandt

MD

Department of Neuropathology, University of Erlangen, Erlangen, Germany.

DW Hochman

PhD

Department of Surgery, Duke University Medical Center, Durham, NC, USA.

M Hodaie MD MSc Ontario, Canada.

FRCS

Krembil Neuroscience Centre, Toronto Western Hospital; Division of Neurosurgery, University of Toronto, Toronto,

A Hodozuka

MD

Department of Neurosurgery, Asahikawa Medical College, Asahikawa, Japan.

D Hoffmann

MD

Department of Clinical Neurosciences, Grenoble University Hospital, Grenoble, France.

H Holthausen

MD

Neuropediatric Department, Behandlungszentrum Vogtareuth, Germany.

M Hoppe

MD

T Hor

Department of Neurosurgery, Tokyo Women’s Medical University, Tokyo, Japan.

MD

B Hötger

Department of Presurgical Evaluation, Bethel Epilepsy Centre, Bielefeld, Germany.

Department of Presurgical Evaluation, Bethel Epilepsy Center, Bielefeld, Germany.

MD

A Ikeda

MD PhD

Department of Neurology, Kyoto University Graduate School of Medicine, Shogoin, Kyoto, Japan.

J Isnard

MD PhD

Department of Functional Neurology and Epileptology, Hôpital Neurologique, Lyon, France.

M Iwasaki

MD PhD

P Jabbour

MD

L Jehi

Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA, USA.

Department of Neurosurgery, The Cleveland Clinic Foundation, Cleveland, OH, USA.

MD

C Juhász

Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan.

Departments of Pediatrics and Neurology, Children’s Hospital of Michigan, Wayne State University, Detroit, MI, USA.

MD PhD

P Kahane

Department of Neurology and INSERM, Grenoble University Hospital, Grenoble, France.

MD PhD

G Kalamangalam MD DPhil Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, UK; and The Cleveland Clinic Foundation, Cleveland, OH, USA. K Källén

Perinatal Epidemiology Research Center, Tornblad Institute, Lund University, Lund, Sweden.

MD

AM Kanner

MD

C Kellinghaus

Department of Neurological Sciences, Rush Medical College and Rush University Medical Center, Chicago, IL, USA.

MD

Department of Neurology, University Hospital Münster, Münster, Germany.

KM Klein

MD

Department of Neurology, Marburg Interdisciplinary Epilepsy Center, University Hospital Giessen, Marburg, Germany.

GH Klem

MD

Department of Neurology, Cleveland Clinic Foundation, Cleveland, OH, USA.

S Knake

MD

Clinic for Neurosurgery, Interdisciplinary Epilepsy Center, University Hospital Giessen, Marburg, Germany.

M Koepp

MD PhD

P Kotagal

MD

M Koubeissi K Krakow

M Kunimoto

Epilepsy Center, The Cleveland Clinic Foundation, Cleveland, OH, USA.

MD

MD


Department of Neurology, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, USA.

The Department of Neurology, J.W. Goethe University; Brain Imaging Center, Frankfurt, Germany. MD


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D Lachhwani

MD


TD Lagerlund

MD

Section of Electroencephalography, Mayo Clinic; Foundation Mayo Clinic College of Medicine, Rochester, MN, USA.

DV Lardizabal JF LeBas BI Lee

MD

Department of Neurobehavioral Sciences, Kirksville College of Osteopathic Medicine, Kirksville, MO, USA.

Department of Clinical Neurosciences, Neuroradiology, Grenoble University Hospital, Joseph Fourier University, Grenoble, France.

MD PhD

Department of Neurology, Yonsei University College of Medicine, Severance Hospital, Seoul, South Korea.

MD

K Lehnertz


MD

S-K Lee MD Department of Neurology, Seoul National University Hospital, Seoul National University Medical Research Institute, Seoul, South Korea. E Lehner-Baumgartner

PhD

Department of Neurology, University of Vienna, Vienna, Austria.

K Lehnertz Department of Epileptology, Helmholtz-Institute for Radiation and Nuclear Physics, University of Bonn, Bonn, Germany. RP Lesser

SD Lhatoo SH Lim

Department of Neurology and Neurosurgery, Johns Hopkins University, Baltimore, MD, USA.

MD

MBBS MD MRCP

MBBS MRCP

C Locharernkul

M Lotto

Department of Neurology, Singapore General Hospital, Outram Road, Singapore.

MD

T Loddenkemper

Department of Adult Epilepsy, The Cleveland Clinic Foundation, Cleveland, OH, USA.

Division of Neurology, Department of Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.

MD


Department of Anesthesiology, The Cleveland Clinic Foundation, Cleveland, OH, USA.

MD

A Lozano Krembil Neuroscience Centre, Toronto Western Hospital; and Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada. HO Lüders

MD PhD

Epilepsy Center, Neurological Institute, University Hospitals of Cleveland, Case Western Medical Center, Cleveland, OH, USA.

J Mani Department of Neurology, Bombay Hospital and Medical Research Center, Wockhardt Hospitals, Mumbai, India; Department of Neurology, The Cleveland Clinic Foundation, Cleveland, OH, USA. R Matsumoto F Mauguière France.

MD PhD

Kansai Regional Epilepsy Center, National Hospital Organization, Utano National Hospital, Narutaki, Ukyo-ku, Kyoto, Japan.

MD PhD DSc

Functional Neurology and Epileptology, Federative Institute of Neurosciences, Neurological Hospital P. Wertheimer, Lyon,

Y Mayanagi

MD

Department of Neurosurgery, Tokyo Police Hospital, Tokyo, Japan.

C McIntyre

PhD

Department of Biomedical Engineering, The Cleveland Clinic Foundation, Cleveland, OH, USA.

MA McLean

H-J Meencke I Melamed L Minotti S Mittal


MD

MD PhD

Division of Neurosurgery, University of Missouri-Columbia, Columbia, MO, USA.

MD

MD

Berlin-Brandenburg Epilepsy Center; Department of Epileptology, Institute of Diagnostic Epilepsy, Berlin, Germany.

Department of Clinical Neurosciences, Epilepsy Unit, Grenoble University Hospital, Joseph Fourier University, Grenoble, France.

Department of Neurosurgery, Wayne State University, Detroit, MI, USA.

MD

GL Möddel

Department of Neurology, Münster University Clinic, Münster, Germany.

MD

A Mohamed

MBBS(Hons) BSc(Maths)FRACP

J Montes

Division of Pediatric Neurosurgery, Montréal Children’s Hospital, McGill University Health Centre, Montréal, Quebec, Canada.

MD

MF Moodley D Moon


Department of Neuroradiology, The Cleveland Clinic Foundation. Cleveland, OH, USA.

MD

F Mormann

MD

Royal Prince Alfred Hospital, The University of Sydney, New South Wales, Australia.

MD


MJ Morrell MD Department of Neurology, Columbia University, College of Physicians and Surgeons; Columbia Comprehensive Epilepsy Center, New York, NY, USA. H Morris

MD

G Morrison L Mulligan


MD

MD

V Nagaraddi

Division of Neurological Surgery, University of Miami School of Medicine, Miami Children’s Hospital, Miami, FL, USA.

Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.

MD


DR Nair

MD

Section of Epilepsy, Department of Neurology, The Cleveland Clinic Foundation, Cleveland, OH, USA.

SJ Nagel

MD


I Najm,

MD

RI Naugle


PhD

Department of Psychiatry and Psychology, The Cleveland Clinic Foundation, Cleveland, OH, USA.

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xxi

S Noachtar Epilepsy Center, Department of Neurology, University of Munich, Munich, Germany. S Nehamkin R-EEG/EPT ALF Palmini

MD PhD

HW Pannek

MD

CNIM

South Euclid, OH, USA.

Department of Neurology, São Lucas Hospital, Cathólic University of Rio Grande do Sul, Porto Alegre, RS, Brazil.

Bethel Epilepsy Centre, Bielefeld, Germany.

A Pascual-Leone MD PhD Center for Noninvasive Brain Stimulation, Harvard Medical School; Departments of Neurology, Beth Israel Deaconess Medical Center and Boston Children’s Hospital, Boston, MA, USA. JP Phillips

MD

Department of Neurosurgery, Beaumont Hospital, Beaumont, Dublin, Ireland.

CE Polkey

MD FRCS

B Pohlmann-Eden HB Pomata R Prayson

Institute of Epileptology, King’s College London, London, UK. MD

Bethel Epilepsy Center, Bielefeld, Germany.

Department of Neurosurgery, Hospital de Pediatría J. P. Garrahan, University of Buenos Aires, Buenos Aires, Argentina.

MD

Department of Anatomic Pathology, The Cleveland Clinic Foundation, Cleveland, OH, USA.

MD

K Radhakrishnan Kerala, India.

DM

Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram,

A Ray

MD

Department of Neurology, Fortis Hospital, Noida, India; The Cleveland Clinic Foundation, Cleveland, OH, USA.

J Reis

MD

Department of Neurology, Interdisciplinary Epilepsy Center, Philipps-University, Marburg, Germany.

EO Richter S Rona

Department of Neurological Surgery and McKnight Brain Institute, University of Florida, Gainesville, FL, USA.

MD

MD PhD MBA

SN Roper

Department of Neurological Surgery and McKnight Brain Institute, University of Florida, Gainesville, FL, USA.

MD

F Rosenow Germany. MA Rossi IL, USA.

Department of Neurosurgery, University Hospital, Eberhard Karls University, Tübingen, Germany.

Department of Neurology, Marburg Interdisciplinary Epilepsy Center, University Hospital Giessen and Marburg GmbH, Marburg,

MD

Department of Neurological Sciences, Rush Medical College, Rush Epilepsy Center and Rush University Medical Center, Chicago,

MD

A Rotenberg MD Center for Noninvasive Brain Stimulation, Harvard Medical School; Department of Neurology, Beth Israel Deaconess Medical Center and Boston Children’s Hospital, Boston, MA, USA. P Ruggieri GL Russo P Ryvlin

Department of Diagnostic Radiology, The Cleveland Clinic Foundation, Cleveland, OH, USA.

MD

“Claudio Munari” Epilepsy Surgery Centre, Niguarda Hospital, Milan, Italy.

MD

Working Group on Epilepsy Research, Berlin, Germany.

MD PhD

AC Sakamoto MD São Paulo, Brazil. V Salanova F Salazar

MD FAAN

Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA.

The Institute of Neurology and Neurosurgery at Saint Barnabas, West Orange, NJ, USA.

MD

D Saski-Adams K Schindler

Department of Neurology, Psychiatry and Psychology, Ribeirão Preto Faculty of Medicine, University of São Paulo,


MD

C Santschi

PhD

MD

MD PhD

Division of Neurosurgery, University of North Carolina, Chapel Hill, NC, USA. Abteilung für Epileptologie & Elektroencephalographie, Neurologische Klinik, Universitätsspital, Zürich, Switzerland.

D Schmidt

MD

Epilepsy Research Group Berlin, Berlin, Germany.

J Schramm

MD

Department of Neurosurgery University of Bonn Medical Center, Bonn, Germany.

O Schröttner A Schubert R Schulz

MD

MD

Department of General Anesthesiology, The Cleveland Clinic Foundation, Cleveland, OH, USA.


MD

E Seigneuret H Shibasaki

Department of Neurosurgery, Medical University of Graz, Graz, Austria.

Department of Clinical Neurosciences, Grenoble University Hospital; Joseph Fourier University, Grenoble, France.

MD MD

Takeda General Hospital, Ishida, Fushimi-ku, Kyoto, Japan.

H Shmizu Department of Neurosurgery, Tokyo Metropolitan Neurological Hospital, Fuchu, Tokyo, Japan. SU Schüle

MD

TL Skarpaas

MD

CT Skidmore SR Sinha

The Cleveland Clinic Foundation, Cleveland, OH; Northwestern University, Chicago, IL, USA. Division of Laboratory Medicine, Sørlandet Hospital HF, Kristiansand, Norway.

MD

MD PhD

Jefferson Comprehensive Epilepsy Center, Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA. Department of Neurology, Johns Hopkins University; Sinai Hospital of Baltimore, Baltimore, MD, USA.

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S Sisodiya MD PhD Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, Queen Square, London; National Society for Epilepsy, Bucks, UK. MC Smith MD Department of Neurological Sciences, Rush Medical College, Rush Epilepsy Center and Rush University Medical Center, Chicago, IL, USA. P Smyth

Department of Political Science, University of Melbourne, Melbourne, Victoria, Australia.

PhD

NK So

MD

Oregon Comprehensive Epilepsy Program, Portland, OR, USA.

S Sood

MD

Department of Neurosurgery, Children’s Hospital of Michigan, Wayne State University, Detroit, MI, USA.

D Spencer

Department of Neurosurgery, Yale University, New Haven, CT, USA.

MD

MR Sperling R Spreafico

MD

Jefferson Comprehensive Epilepsy Center, Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA.

National Neurological Institute, “C. Besta,” Milano, Italy.

MD

T Srikijvilaikul MD Department of Neurosurgery, Chulalongkorn Comprehensive Epilepsy Program, King Chulalongkorn Memorial Hospital, Patumwan, Bangkok, Thailand. RJ Staba Department Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. H Stefan

Department of Neurology, Center of Epilepsy (ZEE), University of Erlangen-Nuremberg, Erlangen, Germany.

MD

BJ Steinhoff FT Sun

MD

Epilepsy Center Kork, Kehl-Kork, Germany.

Clinical Scientist, NeuroPace Inc, Mountain View, CA, USA.

PhD

S Takebayashi

MD


J Tamraz

MD

Department of Neurosciences and Neuroradiology, Université Saint-Joseph, Beirut, Lebanon.

T Tanaka

MD


N Tandon

MD

Department of Neurosurgery, University of Texas Medical School, Houston, TX, USA.

AS Tanner

MD

Epilepsy Program, Saint Mary's Neuroscience Program, Grand Rapids, MI, USA.

L Tassi “Claudio Munari” Epilepsy Surgery Centre, Niguarda Hospital, Milan, Italy. TK Tcheng Neuropace Inc, Mountain View, CA, USA. M Thom

Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, Queen Square, London, UK.

MD

G Thut Center for Noninvasive Brain Stimulation, Harvard Medical School; Departments of Neurology, Beth Israel Deaconess Medical Center and Boston Children’s Hospital, Boston, MA, USA. R Thorbecke

MD

F Tergau

Department of Clinical Neurophysiology, University of Göttingen, Göttingen, Germany.

MD

CQ Tilelli



MD

TN Townsend MD Department of Neurology and Neurosurgery, McGill University; McConnell Brain Imaging Center, Montréal Neurological Institute, Montréal, Quebec, Canada. I Tuxhorn K Usui

MD ChB

Bethel Epilespy Center, Bielefeld, Germany.

Human Brain Research Center, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto, Japan.

MD

FL Vale MD Department of Neurological Surgery, University of South Florida College of Medicine and Tampa General Hospital Comprehensive Epilepsy Program, Tampa, FL, USA. P LeVan

Montréal Neurological Institute, Montréal, Quebec, Canada.

MD

MA Vanegas

MD

DN Velis

Dutch Epilepsy Clinics Foundation, Heemstede, The Netherlands.

MD

Functional Neurosurgery, National Institute of Neurology and Neurosurgery, México D.F., México.

J-P Vignal

MD

Service de Neurologie, Centre Hospitalier Universitaire, Nancy, France

F Villarejo

MD

Department of Neurosurgery, Niño Jesus Hospital, Madrid, Spain.

K Vives

MD

C Vollmar

Departments of Neurology, Neurosurgery, and Pathology, Yale University School of Medicine, New Haven, CT, USA.

MD

Department of Radiology, Ludwig-Maximilians-University, Klinikum Innenstadt, Munich, Allemagne, Germany.

R Wennberg MD Krembil Neuroscience Centre, Toronto Western Hospital and Division of Neurology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. P Widdess-Walsh S Wiebe

MD

HG Wieser

MD


Department of Clinical Neurosciences, University of Calgary, Alberta, Canada. MD

Abteilung für Epileptologie & Elektroencephalographie, Neurologische Klinik, Universitätsspital, Zürich, Switzerland.

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List of Contributors PA Winkler

MD

BM Wingeier

P Wolf

MD

E Wyllie

MD

MD

Brain Sciences Institute, Swinburne University of Technology, Hawthorn, Victoria, Australia.

MD

MRI Unit, Bethel Epilepsy Center, Bielefeld, Germany.

Research Unit for Photodermatology, Department of Dermatology, Medical University Graz, Graz, Austria. Section of Pediatric Neurology, Department of Neurology, The Cleveland Clinic Foundation, Cleveland, OH, USA.

EMT Yacubian I Yang

Department of Neurosurgery, University of Munich, Munich, Allemagne, Germany.

MD

FG Woermann

xxiii

MD

Department of Neurology and Neurosurgery, University of São Paulo, São Paulo, Brazil.

Department of Neurological Surgery, University of California, San Francisco, CA, USA.

D Zumsteg MD Krembil Neuroscience Centre, Toronto Western Hospital and Division of Neurology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

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Preface It was just 7 years back, in 2001, that Dr. Youseff Comair and I edited the last book dedicated to epilepsy surgery.1 It is encouraging to note that epilepsy surgery has again made major advances, calling for a complete rewriting of essentially all the chapters of that book. Interestingly, the development of new diagnostic techniques, which certainly permit a more precise and reliable diagnosis of the epileptogenic zone, with very few exceptions, have not replaced some of the more classical diagnostic methods. In this sense, it is notorious that clinical semiology and clinical neurophysiology continue to be irreplaceable diagnostic techniques that provide a wealth of information. Moreover, modern technology, which makes recording, storage, and computer analysis of large amounts of neurophysiological data possible, gives us access to new data, such as the high-frequency oscillations or the EEG DC shifts, which promise to play important roles in the definition of the epileptogenic zone. This Textbook of Epilepsy Surgery includes over 20 chapters dedicated exclusively to the history of epilepsy surgery in different countries. I felt that it was important to collect this information on a timely basis when many of the main players who actually participated in the development of epilepsy surgery, or at least directly witnessed the developments, are still active in the field. As in our previous book on epilepsy surgery, in this book too we devote significant space to the description of the semiological seizure classification and the detailed clinical description of the epilepsies that are remediable by epilepsy surgery. In this book, we follow a systematic approach to the diagnostic evaluation of patients who are candidates for epilepsy surgery. We first discuss the general principles of epilepsy surgery, and then divide the presurgical evaluation according to the six zones (symptomatogenic zone, irritative zone, ictal onset zone, the epileptic lesion, the functional deficit zone, and the epileptogenic zone) described in the general principles chapter. These series of chapters conclude with the description of the Epilepsy Surgery Management Meeting, an essential and indispensable part of the surgical evaluation.

REFERENCES 1. Lüders H. Epilepsy Surgery, Raven Press, 1992.

xxiv

The book also incorporates detailed discussions of the cortical mapping techniques and the numerous surgical techniques that can be used to surgically treat epilepsy. This is complemented by surgical outcome, the post-surgical medical management, surgical failures, and neuropathology. Finally, selected case presentations are discussed, and proposals for the establishment of an epilepsy surgery program, classification of surgical outcome, and protocols for storage and processing of brain tissue for molecular studies are presented. I feel that epilepsy surgery is still an extremely attractive management tool for patients with medically intractable epilepsy. Unfortunately, in spite of dramatic increases in the number and mechanisms of action of modern antiepileptics, close to a third of all epileptics still suffer from uncontrolled seizures. A significant proportion of these patients are excellent surgical candidates. The extreme precision of our current presurgical evaluation methods and the recent advances in neurosurgical techniques make it imperative that all these patients get evaluated at an epilepsy center that offers epilepsy surgery. In a significant proportion of these patients, the epilepsy can be either eliminated (cured) or a significantly better seizure control can be achieved, with relatively low surgical risk. Referrals for epilepsy surgery have been continuously increasing since the pioneering efforts at the end of the 19th century. I hope that this book will contribute to making epilepsy surgery available to an even larger percentage of patients with medically intractable epilepsy.

Acknowledgments I would like to acknowledge the help of Ms. Connie Scolaro and Ms. Autumn Semsel who, throughout the editorial process, assisted me as executive secretaries, making the editorial process so much easier. Hans O Lüders

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Color plate

xxv

“Claudio Munari” Epilepsy Surgery Centre, Milano “Neuromed” Epilepsy Surgery Centre, Pozzilli

Figure 7.4

29 30 27 42

34 22 28 38

21

19

18 18

37

37

Paralimbic areas High-order (heteromodal) association areas Modality-specific (unimodal) association areas Idiotypic (primary) areas

20

Figure 34.1

VAC

VPC

i1

i2

AC-PC

i3

R

L

A

B C Figure 39.3

(a)

(b)

(c)

(d)

(e)

(f)

19


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Color plate

(a)

(b)

Figure 55.2

Figure 55.7

(a)

(b)

(c)

(d)

(f) (e)

(g)

(i)

(h)

Figure 71.2


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Color plate (a)

(b)

SPM{F7.479,288.6}

SPM{T294.5}

P2 years after surgery) was observed in only 5% of all patients and was often preceded by a specific explanatory factor such as withdrawal of antiepileptic medication. In a multivariate analysis, unitemporal MRI abnormalities, early onset of epilepsy, or the predominance of focal seizures with impaired consciousness with focal ictal EEG, were identified as predictors for successful postoperative outcome. The epilepsy unit in Helsinki University Hospital (Hospital for Children and Adolescents and Department of Neurosurgery) started in 1991 with pediatric epilepsy surgery, and since 1998 the team has also offered epilepsy surgery to adult patients in collaboration with the Department of Neurology. Between 1991 and 2005 a total of 187 therapeutic epilepsy surgery interventions had been performed in Helsinki. The program has included temporal resections (n = 72), extratemporal resections (n = 49), callosotomies (n = 34), hemispherotomies (n = 29), multiple subpial transections (n = 1), and radiotherapy of hamartomas (n = 2). During preoperative evaluation all patients were studied with video-EEG, 1.5 T MRI, and neuropsychology. When necessary ictal-SPECT, MEG (localization of interictal spikes and functional areas), FDG-PET, magnetic resonance spectroscopy, and/or invasive monitoring with subdural grids (n = 22) and strips (n = 3) is used during the presurgical work-up. Nearly all patients undergo psychiatric evaluation. The majority of the patients are children or adolescents (76%) and due to the heterogeneous population regarding syndromes and etiologies (including catastrophic epilepsies of

Table 9.2 Long-term postsurgical seizure outcome in 140 adult temporal lobe epilepsy (TLE) patients in Kuopio Epilepsy Center22 Curative group with unilateral TLE (n=103) Entire group (%)

Seizure free Persisting auras Worthwhile outcome (Engel I-II)

81

Standardized MRI protocol (%) (n=59)

Palliative TLE epilepsy group (n=37) (%)

45 12

61 11

27 3

68

74

62

9781841845760-Ch09

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Textbook of epilepsy surgery

early childhood) general outcome figures are difficult to evaluate. The team has, however, recently evaluated the two-year follow-up of cognitive outcome after pediatric epilepsy surgery.23 Altogether 38 patients, between 3–17 years of age, were evaluated before surgery and six months and 2 years postoperatively. No significant change in verbal or performance IQ was demonstrated at group level. Lateralization, type of surgery, age, sex, and presurgical IQ did not affect outcome. In conclusion, epilepsy surgery in children and adolescents did not in general have a significant impact on cognitive development in a two-year perspective. Medical intractability is defined as persistent seizures despite 2–3 maximally tolerated AED trials. In older children and adults medical intractability can be diagnosed in two years in most cases. However, the median duration of epilepsy in patients referred to presurgical evaluation at Kuopio Epilepsy Center has been 19 years.22 In the future, emphasis should be put on early prediction of medically intractable temporal lobe epilepsy in children and adolescents, since early surgery probably improves the overall outcome, especially in younger patients. Further evaluation for longterm cognitive outcome is also warranted. The epilepsy unit in Helsinki continues to focus on pediatric epilepsy surgery, accepting pediatric patients from all parts of Finland and adults within their own catchment area. Kuopio Epilepsy Center continues to treat patients with medically refractory temporal or extra-temporal focal epilepsy of all ages from the whole country, especially focusing on getting patients referred earlier.

Norway and Finland are shown in Table 9.3. Too few patients, especially children in the Scandinavian three countries, with severe, drug-resistant epilepsy, are referred to the centers for surgical evaluation, and many are referred too late, i.e., long after psychosocial problems have become irreversible. This situation is most probably not at all unique since there is a general concern that epilepsy surgery is underused. One reason for this underutilization of the resource of epilepsy surgery might be lack of knowledge about epilepsy within the medical profession24 or lack of knowledge about the favorable results of surgical treatment of epilepsy within the neurological community. In a survey concerning the provision of epilepsy services in Europe which was undertaken by the ILAE Commission on European Affairs a few years ago, all countries but six stated that they had epilepsy surgery programs.24 Lack of epilepsy surgery was more commonly reported from Eastern and Southern Europe, whereas several western ILAE chapters mentioned as a problem that epilepsy surgery was present but underused. The epilepsy surgery groups in the Scandinavian countries together with Finland recently decided to organize a meeting for collaboration and the first Nordic epilepsy surgery meeting was held in Sweden in 2004. The second will be held in Norway 2006. In the future the epilepsy surgery groups in the Nordic countries plan to meet at regular intervals to learn from each other and expand their network cooperation for the benefit of the patients.

Acknowledgment The future of epilepsy surgery in the Nordic countries? Despite increased attention in recent years, epilepsy surgery is assumed to be under-utilized in the Nordic countries. Approximate yearly numbers of procedures in Sweden,

We want to thank Kristina Malmgren, professor in neurology at Sahlgrenska University Hospital in Gothenburg, for editorial help, and Kirsten E. Stabell, neuropsychologist at the National Centre for Epilepsy in Sandvika, for providing us with the number of presurgical investigations and surgical procedures in Norway.

Table 9.3 Yearly epilepsy surgery procedures in the Nordic Countries based on an average over a 10–15 year period Sweden (9 million inhab.)

Denmark (5.3 million inhab.)

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Finland (5.2 million inhab.)

Temporal lobe resections (selective AHE included)

41

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Mixed group Multilobar resections, hemispherotomies, MST, callosotomies, hamartomas (pure lesionectomies are also included in the mixed group in Finland)

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REFERENCES 14. 1. 2. 3. 4. 5. 6. 7.

8. 9.

10.

11. 12. 13.

Expertrapport – Epilepsi – förekomst, handläggning och vårdorganisation. Stockholm, Sweden: Socialstyrelsen, 1993. Malmgren K, Sullivan M, Ekstedt G, et al. Health-related quality of life after epilepsy surgery – A Swedish multicenter study. Epilepsia 1997;38(7):830–8. Silander HC, Blom S, Malmgren K, et al. Surgical treatment for epilepsy – a retrospective Swedish multicenter study. Acta Neurol Scand 1997;95:321–30. Forsgren L Prevalence of epilepsy in adults in northern Sweden. Epilepsia 1992;33(3):450–8. Malmgren K, Rydenhag B. Temporal lobe resections for epilepsy. Data from the Swedish National Epilepsy Surgery Register 1990–95. Epilepsia 2000;41(Suppl 7):140. Rydenhag B, Silander HC, Malmgren K, Flink R. Lesionectomy for epilepsy: data from the Swedish National Epilepsy Surgery Register 1990–1999. Epilepsia 2004;45(Suppl. 3):187. Malmgren K, Rydenhag B, Olsson I, Flink R. Temporal lobe resection for epilepsy in mentally retarded patients: Data from the Swedish National Epilepsy Surgery Register 1990–1999. Epilepsia 2005;46(Suppl 6): 320. Rydenhag B, Malmgren K, Flink R. Epilepsy surgery in mentally retarded patients: pathoanatomical diagnoses. Epilepsia 2005;46(Suppl 6): 68. Olsson I, Malmgren K, Rydenhag B, Flink R. Hemispherectomies and multilobar resections: data from the Swedish National Epilepsy Surgery Register 1990–99. Epilepsia 2005;46 (Suppl 6): 162. Rydenhag B, Silander HC. Complications of epilepsy surgery after 654 procedures in Sweden, September 1990–1995: a multicenter study based on the Swedish National Epilepsy Surgery Register. Neurosurg 2001;49(1): 51–5. Behrens E, Schramm J, Konig R. Surgical and neurological complications in a series of 708 epilepsy surgery procedures. Neurosurg 1997;41(1):1–9. Flink R, Malmgren K, Åmark P, Blom S. Trends in the use of epilepsy surgery in Sweden 1991–1999. Epilepsia 2002; 43(Suppl. 8):137. Jensen I, Vaernet K. Temporal lobe epilepsy. Acta Neurochirurgica 1977;37:173–200.

15. 16. 17.

18.

19.

20.

21.

22. 23. 24.

ILAE Commision Report. Commission on Neurosurgery of the International League Against Epilepsy (ILAE) 1993–1997: recommended standards. Epilepsia 2000;41(10):1346–9. Engel J Jr. Outcome with respect to epileptic seizures. In: Engel J Jr, ed. Surgical Treatment of the Epilepsies 2nd edn. New York: Raven Press, 1993. Guldvog B, Loyning Y, Hauglie-Hanssen E, et al. Surgical versus medical treatment for epilepsy. II. Outcome related to social areas. Epilepsia 1991;32(4):477–86. Bjørnæs H, Stabell KE, Røste GK, Bakke SJ. Changes in verbal and nonverbal memory following anterior temporal lobe surgery for refractory seizures: effects of sex and laterality. Epilepsy Behav. 2005;6(1):71–84. Bjørnæs H, Stabell KE, Heminghyt E, et al. Resective surgery for intractable focal epilepsy in patients with low IQ: predictors for seizure control and outcome with respect to seizures and neuropsychological and psychosocial functioning. Epilepsia 2004;45(2):131–9. Immonen A, Jutila L, Kälviäinen R, et al. Preoperative clinical evaluation, outline of surgical technique and outcome in temporal lobe epilepsy. Advances in Technical Standards in Neurosurgery 2004;29:87–132. Lamusuo S, Pitkänen A, Jutila L, Ylinen A, Partanen K, Kälviäinen R, Ruottinen HM, Oikonen V, Nagren K, Lehikoinen P, Vaplahti M, Vainio P, Rinne JO. [11C]Flumazenil binding in the medial temporal lobe in patients with epilepsy: correlation with hippocampal MR volumetry T2 relaxometry, and neuropathology. Neurology 2000;40(2–3):155–70. Jutila L, Immonen A, Partanen K, Partanen J, Mervaala E, Ylinen A, Alafuzoff I, Paljarvi L, Karkola K, Vapalahti M, Pitkanen A. Neurobiology of epileptogenesis in the temporal lobe. Adv Tech Stand Neurosurg 2002;27:5–22. Jutila L, Immonen A, Mervaala E et al.: Long term outcome of temporal lobe epilepsy surgery: analyses of 140 consecutive patients. JNNP 2002;73:486–94. Korkman M, Granström M-L, Kantola-Sorsa E et al. Two-year follow-up of intelligence after pediatric epilepsy surgery. Pediatric Neurology 2005;33(3):173–8. Malmgren K, Flink R, Guekht AB, et al. The provision of epilepsy care across Europe. Epilepsia 2003;44(5):727–31.

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The development of epilepsy surgery in the Netherlands and Belgium W van Emde Boas and PAJM Boon

The Netherlands1 In the Netherlands, initial development of brain surgery came relatively late. In his jubilee speech on the development of surgery during the last 30 years, at the occasion of the 25th anniversary of the Nederlands Tijdschrift voor Geneeskunde (NTvG) in 1882, J.W.R. Tilanus (1829–1914), professor of surgery in Amsterdam, does not yet even mention surgery of the nervous system2 and, apart from the usual descriptions of trepanation in early general medical or surgical texts, up to 1890 no papers on surgical intervention on either the central or the peripheral nervous system had been published in the NTvG, then as now the main Dutch medical journal, nor by Dutch authors, in other medical journals or books.3,4 This changed at the initiative of Cornelis Winkler (1855–1941), the first professor in psychiatry and neurology in the Netherlands and generally considered the founding father of modern Dutch Neurology (Figure 10.1). First steps: the neurologist and the surgeon Winkler studied medicine in Utrecht where he was greatly influenced by the strict scientific approach of ophthalmologist and physiologist F.C. Donders (1818–1889). Following graduation and obtaining a PhD degree on a thesis on Virus Tuberculosum 1879; and a brief period as clinical resident in The Hague, Winkler expressed to his former teacher the desire for a more research oriented position in Utrecht. Offered the position of reader in psychiatry, Winkler initially declined, considering psychiatry too philosophical and unscientific to his liking. After some clinical work with neurological patients in the clinic for internal medicine of S. Talma (1847–1918) and following visits to T. Meynert (1833–1892) and J. Wagner von Jauregg (1857–1940) in Vienna and to numerous German protagonists of the neuropathological oriented school of psychiatry and neurology, he became convinced of the advantages of teaching both neurology and psychiatry as a whole and accepted in 1885 the lectureship of psychiatry in Utrecht, followed in 1893 by the appointment to professor in psychiatry and neurology, the first such chair to be officially created in the Netherlands.’5 Winkler was well aware of the current clinical and experimental literature on the localization of brain functions and the application of these findings to clinical neurology and early on expressed his intention to follow the example of V. Horsley (1857–1916) and others and to focus attention also 84

on brain surgery as a possible treatment for neurological disorders, notably in epilepsy patients with seizures comparable to those, induced by electrical stimulation of the cortex in animals by E. Hitzig (1838–1907) or described in humans by J. Hughlings Jackson (1835–1911).5 As luck would have it, Winkler’s appointment coincided with that of his friend and fellow student J.A. Guldenarm (1852–1905) as general surgeon in the Deaconess Hospital in Utrecht. According to Winkler, Guldenarm was a gifted and inventive surgeon, who made his own instruments, operated very neatly and with whom he felt sufficiently confident to try to remove brain tumours, ‘a great endeavour, considering that we hardly knew what we were going to do’.5 On 11 November 1889 they performed their first published surgery on a 54-year-old ex-soldier with a two year history of Jackson type seizures, beginning in the right leg and with fast neurological and mental deterioration during the last few weeks. Exploring the left frontocentral area, they partially resected an angiosarcoma from the left gyrus frontalis superior, lobus paracentralis, and gyrus centralis anterior. The patient survived the procedure and remained without seizures but with hemiplegia, aphasia, progressive loss of consciousness and increasing prolapsus cerebri before dying, three weeks after surgery.6 Between 1891 and 1893 Winkler and Guldenarm, together with A. Huysman, ENT surgeon, and H. Buringh Boekhoudt, resident to Winkler, published a series of five ‘contributions to surgery of the brain’ in the NTvG in which they provided meticulous detailed clinical histories of 15 patients (3 not operated) and discuss the value, possibilities and – often – impossibilities of surgical intervention in various neuropathological conditions.6–10 Although epilepsy was not mentioned in the title of any of these five papers it was a major symptom in five and the primary indication for surgery in a further two of the twelve operated patients. The first of the latter was a 22-year-old man with an 11 year history of Jacksonian seizures in the left hand and arm who had a right frontocentral angioma removed by Guldenarm on 4 April 18906 and changed from >40 seizures a day to multiple days without seizures with a follow up of 7 years.11 This patient was also published in a thesis 1891; by a Dutch physician, P.C. Th. Lens, defended however in Giessen and thus not really to be considered the first Dutch thesis on epilepsy surgery.12 The second patient was a 19-year-old boy with an epilepsy history of 6 years, following a skull trauma at the age of 8 years. He became free of seizures, following extirpation of a calcified lesion from the left hand area9 but died from

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central and Sylvian sulci and of the targeted cortical gyri, using just two external reference points (the glabella and the protuberantia occipitalis externa) to create a grid of triangles, projecting over skin of the skull.15 Since this system was based on comparative rather than absolute measurements it was considered to be more reliable than that of Horsley or others and the ‘triangulation according to Winkler’ (Figure 10.2) became the standard procedure for guiding the trepanation in the Netherlands for the next few decades. Such was Winkler’s enthusiasm for brain surgery that in 1895 he even published a long popular paper on the subject in De Gids, the most important cultural monthly magazine in the Netherlands. Despite the overall poor results (only 4 out of 18 operated cases still alive at the time of publication and only Ned.Tijdschr. voor Geneeskunde, 1892.DI.II.No.3. f

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Figure 10.1 Cornelis Winkler (1855–1941). Pencil drawing by Jan Veth, 1896. The portrait was made just after Winkler resigned in Utrecht and before he moved to Amsterdam. While making this portrait Veth (1864–1925) proposed to Winkler to give art lessons to medical doctors, in order to improve the quality of the illustrations in their publications. The idea however was never realized.5

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an occupational accident a few years later. Some of the early tumor cases, including one patient with Jacksonian seizures, were collected and described in the really first Dutch PhD thesis on brain surgery, defended by Winkler’s pupil R. S. Hermanides13 and again in the NTvG.14 Surgical techniques are not dealt with in detail in these papers although there is some discussion about the relative advances of a bony versus a soft tissue closing of the trepanation area in certain circumstances. Some procedures were only performed ‘after we had ascertained ourselves on the cadaver that the surgery was possible’.6 Major emphasis is given on the other hand to the problem of correct localization, prior to surgical intervention. The papers include some patients where Winkler failed to make a proper preoperative localizing diagnosis and he frankly admits that in at least one patient, in whom surgery failed, the obduction showed a right tentorium meningioma that, on correct diagnosis, could have been successfully removed.6 Winkler strongly believed that, unless surgeons had extensive knowledge of brain anatomy and physiology, brain surgery should be guided by the neurologist as the one both to make the exact diagnosis and to decide about the indication for surgical exploration and the place and extent of the necessary trepanation. For the latter he developed a new method to enable the neurologist and the surgeon to estimate the position of the

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D . C.WINKLER.–DRIEHOEKSMETING TER BAPALING DER BETREKKELIJKE LIGGING VAN WINDINGEN EN SLEUVEN DER GROOTE HERSENEN

Figure 10.2 Winklers method of triangulation. By constructing a series of triangles, based on the line between the glabella and the protuberantia occipitalis and the perpendicular dissecting line at midpoint he obtained a reasonable estimate of the position of the underlying cortical structures. The drawing is based on studies on 10 adult subjects; the darkened areas and numbers indicate cortical areas or sulci that reliably will be found within that specific triangle (lithograph illustration of Winkler’s paper15 in the NTvG, Bohn: Haarlem, 1892).

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two really cured) he argues for an aggressive approach since the patients, mostly tumor cases, have little to lose. For patients with epilepsy he considers the loss of some function to be preferred to the constant irritation of the cortex and the risks of the recurrent seizures. He discussed the use of electrical stimulation to identify the epileptic focus and the different surgical options. He preferred resection of the cortex, notably when abnormal on inspection, and did not think highly of the practice of just cutting around the suspected area in order to prevent seizure propagation. In an interesting last paragraph he commented on some early efforts on psychosurgery by Burckhart in Switzerland, which he rejected since he was of the opinion that one should treat the underlying disease in mental patients and not just the symptoms.16 In 1896, being refused a new clinic that was initially promised to him, Winkler resigned his position in Utrecht and within months accepted the newly created chair of Neurology and Psychiatry in Amsterdam where he would have ample access to clinical beds both for neurology and psychiatry and would be able to work together with J.K.A. Wertheim Salomonson (1864–1922), who already ran a clinic for neurology and electrotherapy, and in 1899 would be appointed to the first chair in neurology, electrotherapy, and radiography in the Netherlands. In Amsterdam Winkler continued his neurosurgical activities, together with the surgeons J.A. Korteweg (1851–1930) and J.A. Rotgans (1859–1948) and the professor in Internal medicine P.K. Pel (1851–1919), who also was actively interested in neurological diseases. Epilepsy initially remained a major indication. In 1897 Winkler’s pupil H.H. van Eyk (1869–1930) obtained his Ph.D. on the first (and until Brekelmans17 the last) Dutch dissertation to deal specifically with the surgical treatment of partial epilepsy18 and in that same year Winkler, in recognition of his expertise in the field, was invited to lecture on ‘Surgical intervention in the epilepsies’ at the International Congress of Psychiatry, Neurology and Hypnology In Brussels.11 In his dissertation Van Eyk described 10 cases of predominantly posttraumatic epilepsy, nine of them operated and with clear improvement in five. In addition he summarized the data from the literature, 13 cases of epilepsy due to subdural haematoma and 100 cases of posttraumatic epilepsy, including 7 of his own, and showed that the best results were obtained in patients in whom a recognizable lesion could be removed. His case #9 concerns a 20-year-old man with a 2 year history of focal seizures, beginning in the left hand. A first exploration by Rotgans and Buringh Boekhoudt showed local thickening of the dura over the hand area, identified by electrostimulation by Wertheim Salomonson. Nothing was excised and there was no improvement. Following two further surgeries with temporary improvement the patient was operated upon a fourth time on 18 June 1897, this time with Winkler performing the electrostimulation. A seizure was provoked by stimulating the finger area ‘which was photographically documented and found to be identical to the spontaneously observed seizures’, the first case of intracranial and intraoperative seizure monitoring? Following a local cortectomy the patient became paretic but also free of seizures for at least the next two months.18 At the congress in Brussels Winkler discussed 20 patients who had surgery, including two patients, successfully operated for ‘reflex-epilepsy’, due to peripheral nerve injury (one a cornea corpus alienum, the other a bullet injury of a branch of

the trigeminal nerve), a clinical entity which certainly was not epilepsy but was generally accepted at the time and considered a good indication for surgical intervention.19 In 13 patients partial epilepsy was the primary indication for surgery, in 5 the seizures were but a symptom of more serious neurological disease. According to Winkler posttraumatic cases had the best prognosis, tumor cases a varying outcome and infectious cases (Lues, TBC, otogenic abcesses) or alcoholic cases a poor prognosis. In cases without an external or internal scar and with a normal aspect of the cortex, cortectomy should only be performed if a typical seizure could be elicited from that area by electrical stimulation. For toxic epilepsies, even if manifesting with partial seizures, surgery was not indicated.11 Even at the time of the congress, however, the initial enthusiasm for epilepsy surgery (or even brain surgery in general) appeared to be lessening. In a comprehensive review of all neurosurgical interventions performed in the Netherlands between 1889 and 1900, published in the famous 3 volume series of A. Chipault (1866–1920) on the current state of neurosurgery in 1902, Winkler and Rotgans briefly refer to the earlier work but epilepsy is not mentioned anymore as a specific indication.3 This appears to be in line with developments elsewhere. In a long letter from London where he was visiting a number of hospitals, Wertheim Salomonson describes his admiration for the surgical skills of Horsley but also mentioned that at that time, in 1898, Horsley had not operated for epilepsy in the last 18 months because of disappointing results.20 Two conference reports and a review in the NTvG from the same period but citing predominantly German and Swiss sources also emphasized overall poor results of surgery for epilepsy21–23 and W.J.M Indemans (1868–1932), a general practitioner in Maastricht, reporting one patient, operated with moderate success for posttraumatic partial epilepsy, actually complained that he could not find a surgeon willing to operate on a second case.24 Winkler himself apparently lost interest and did not publish anything on epilepsy surgery afterwards although he remained involved in some cases later published by others. Also the attitude of the surgeons to surgery on the nervous system was changing. While most of the surgeons with whom Winkler had collaborated in Utrecht and, after 1896, in Amsterdam, apparently had little problems with his approach by which they had to rely completely on the diagnostic and localizing acumen of the neurologist, J.E. van Iterson (1842–1901), with whom Winkler performed some surgeries in Utrecht, was the first to challenge this approach. In a 1899 paper on the present state of surgery effectively citing Winkler himself, he stated that: The recognition and localisation of the pathology [in the brain] still is wanting and I am pleased to report that according to the first Dutch authority in this field [Winkler] this situation will not improve unless the surgeons themselves take up the diagnosis of brain disorders and stop acting only on guidance by specialists.25 With this, van Iterson started a controversy that was to continue for the next three decades and would clearly influence the further development of neurosurgery, and thus epilepsy surgery, in the Netherlands. At the time, however,

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The development of epilepsy surgery in the Netherlands and Belgium his word was hardly heeded and for some time to come the neurologist remained either the active guide of the surgeon or, by reversing the situation sketched by Winkler, actually took over the scalpel and the trephine. Intermezzo: the neurologist–neurosurgeon Louis Jacob Joseph Muskens (1872–1937)26 studied medicine in Utrecht and, significantly influenced by Donders and Winkler, early on decided for a career in physiology and neurology. After obtaining his PhD in 1896 on a thesis on the reflex mechanisms of the frog heart, supervised by T. Engelmann (1843–1909), successor [and son in law] of Donders, Muskens, on a travel grant provided by the Donders Society, spent two years in the USA where he visited and worked with C.L. Dana (1853–1935) in New York and H.P. Bowditch (1840–1911) in Boston. Stimulated by Winkler to further specialize himself he spent a next period in London in the National Hospital for the Paralysed and the Epileptic, working under W. Gowers (1845–1911) and notably, for 20 months, under Horsley in order to master the surgical skills necessary to render him independent from the general surgeon.27,28 In the USA and in London Muskens appeared to have developed his interest in epilepsy which to a large extent would mark his further career. Back in the Netherlands he instigated the founding, in 1902 in the Hague, of the ‘Dutch Society Against Falling Sickness’, which, contrary to the older 1882; ‘Christian Society for the Care of Sufferers from the Falling Sickness’, aimed to promote treatment rather than care of epilepsy. In the same year Muskens moved to Amsterdam in 1902 and took up a practice as specialist for nervous disorders, including the position (from its inception until 1918) of medical supervisor of the clinical and outpatient departments of the ‘Amsterdamse Gasthuis Tegen Vallende Ziekte’ (Amsterdam Hospital for Epilepsy), an initiative by the Amsterdam Branch of the Dutch Society and, in 1903, the first non-university-associated neurological clinic in the country. Together with the Hungarian J. Donath, Muskens, in 1908, founded the Journal Epilepsia and, in 1909, the International League Against Epilepsy (ILAE) of which he would remain active as general secretary for many years and which he helped to revive in 1937, after a long interruption of the ILAE activities following the turmoil of World War I.29 A prolific writer, Muskens published extensively about epilepsy, both from an experimental and a clinical view and with major emphasis on the social aspects and needs of persons with epilepsy. His vast clinical and experimental experience culminated in a major monograph on epilepsy, published in 1924 and translated both in German and in English.30 Other subjects included the segmental distribution of the sensory input of the cerebral cortex, the anatomo-physio-pathology of upper brain-stem connections, subject of a second major monograph on the supra-vestibular system,31 technical and clinical aspects of neurosurgery and a series of papers on the relation between neurology, neurosurgery, and psychiatry and the way those specialties should be taught to students and be practiced. In 1906 Muskens was admitted as private lecturer on nervous diseases at the municipal university of Amsterdam and in

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his official public lecture advocated the further development of organ oriented (sub) specialties in medicine, a subject highly controversial at the time32 (Muskens, 1906). In Muskens’s view specialties should focus on the anatomy, physiology, pathology, conservative treatment options and surgery of specific organs, the central nervous system representing one of the most ideal organ systems for such an approach. Psychiatry was to be separated from neurology [in the Netherlands it was not until 1974 that this separation finally was realized] and the surgical approach to the nervous system was best left to the neurologist with specific surgical training (i.e., Muskens himself). Like Winkler had done before him Muskens published a series of ‘contributions to the surgical treatment of the central nervous system’ in the NTvG, the third including a number of patients with seizures and the last dealing specifically with posttraumatic epilepsy,33–36 in addition to a large number of other papers or reports of clinical demonstrations of neurosurgical cases in Dutch or foreign journals. Unfortunately and contrary to the papers of his predecessor and teacher Muskens’s patient descriptions are often rather short and, when repeated, as is often the case, factual data (dates, type of trauma, patient initials, patient age) differ in successive publications, in part probably due to the then current poor quality of proofreading and correction in association with very fast publication, but in part apparently due to either shoddy writing or – worse – ‘massaging’ the data. Moreover Muskens had a highly contentious style of writing and presenting, emphasizing presumed diagnostic errors or failed procedures by others and exaggerating his own activities and results. Repeatedly and usually with good arguments and in terms which in today’s perspective would be considered too offensive for public discussion in print, his claims are refuted, his results doubted, his qualifications as a neurologist-surgeon denied, and his references identified as incorrect, not only by the general surgeons but notably also by his fellow neurologists and by the chief editor of the NTvG.37–44 Although Muskens apparently was considered as sufficiently an expert to be invited by the Belgian Red Cross to assist in setting up a unit for war casualties with brain or spinal injuries in Antwerp45 the chiefs of the university clinics in Amsterdam repeatedly refused to have Muskens operate in their clinics.44 Significantly, the well-known Amsterdam neurologist C. T. van Valkenburg (1872–1962), who for a number of years was the medical director of Muskens’s hospital, relied on other surgeons for his work on the sensory neuroanatomy of the human cortex, based on electrical stimulation during surgery.46–48 As far as epilepsy is concerned only few successful surgery cases eventually are listed in the chapter on posttraumatic and focal epilepsy and the surgical treatment of epilepsy in Muskens’s 1924 monograph.30 These include three of his favorite cases which he published and presented at many occasions, the first a patient with probably posttraumatic serous meningitis, operated in 1907 because of fast neurological deterioration, in whom the seizures were but a secondary symptom, and the second, a girl of 18 (cranial trauma at age 3 years) in whom Muskens, guided by sensory loss in the ulnar region of the left arm, ligated some ‘abnormal pial veins’ and claimed successful treatment of ‘seizures’ that by all his peers of the Amsterdam Neurological community, many of which previously had observed this patient, were consistently interpreted

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as psychogenic events. Only the third represents a true epilepsy surgery success story: a female patient who following trauma at age 4 and two earlier surgical interventions by Winkler and Rotgans at the age of 4 and 16, finally was rendered seizure free by Muskens by removal of two tiny bone fragments, found under the previous bone flap and, when the seizures still persisted, in a second session a small cortisectomy from the area where habitual seizures could be elicited by electrical stimulation. The remaining 7 patients in the chapter, which purports to present ‘a comprehensive report’ of a lifetime experience include one non-traumatic tumor patient (presented to illustrate the limited value of surgery in those cases), one patient operated in 1910 but without clinical information (‘all files lost’) or follow up, other than that the patient was successfully employed as a marine officer, 1 patient, operated by others with poor results, 2 patients with less than a year of follow up at the time of writing, leaving only two more reasonably well-documented cases, successfully operated for posttraumatic epilepsy in 1913 and 1918.30 In the same period that Muskens was active, occasional reports indicated that, as before, some surgical procedures for posttraumatic or other symptomatic forms of epilepsy were performed by a general surgeons, assisted by a neurologist, generally with acceptable results for posttraumatic epilepsy and poor results for all other cases. These were not part of any organized program but in number and results appear equal or even superior to Muskens’s activities. Not surprisingly Muskens academic career never progressed beyond his private readership and even as a neurosurgeon his real activities appear to have remained limited. Looking back, Muskens remains a major figure in the development of epileptology and epilepsy care, both in the Netherlands and internationally.26 For the actual development of either neurosurgery in general or epilepsy surgery in particular, however, this self proclaimed ‘self operating neurologist’ did relatively little and achieved even less. A second start: the neurosurgeon and the neuro(physio)logist Since otherwise the field remained in the hands of general surgeons with neither specific training nor interest in neurological disorders, the overall practice of neurosurgery in the Netherlands remained limited and of relatively poor quality for well into the first three decades of the 20th century. Yet increasingly the need for surgical treatment of some neurological disorders was felt and again it was a neurologist who took the initiative. In 1923 Bernard Brouwer (1881–1949), who studied medicine in Amsterdam and then trained with Winkler, was appointed to the chair of neurology, now for the first time divided from psychiatry, in the city of his Alma Mater. For his surgical cases he worked with the general surgeons O. Lanz (1865–1935) and W. Noordenbos Sr. (1875–1954) but he was well aware of the gap between their results and those reported by others. Contacts with H. Cushing (1869–1939) and W. Dandy (1886–1946) during a lecture tour in the USA in 1926 convinced him that good quality neurosurgery was only possible in a special setting and by dedicated and undivided neurosurgeons with specific and adequate training. In Amsterdam he managed to convince the municipal authorities

to have a new 100 bed clinic to be built, exclusively for neurological patients and including a fully equipped neurosurgical unit that could function independent of the general surgical clinic. While the clinic was being built Brouwer selected Ignaz Oljenick (1888–1981), a young resident surgeon, and sent him to Boston for training with Harvey Cushing. In 1929 Oljenick returned to Amsterdam and in September of that year the neurosurgical unit in the newly opened clinic started its activities.1 As far as can be ascertained from his publications Oljenick did not perform any procedures specifically for epilepsy. His first trainee, however, would. Arnaud Cornelis de Vet (1904–2001), studied medicine in Amsterdam and in 1929 applied for and obtained the position, offered by Brouwer, of resident in neurosurgery. De Vet thus became the first physician to be trained formally as a neurosurgeon in the Netherlands. After finishing his years of training with Brouwer and Oljenick and a study trip of several months to neurosurgical clinics in numerous European cities, De Vet in 1936 obtained his PhD, supported by Brouwer, on a thesis on the diagnosis of cerebral meningioma.49 His material concerns a series of 36 operated and (with one exception, histologically verified) and two unoperated cases, including 17 patients in whom seizures were the major (n = 13) or a contributing symptom. Fifteen of these had their meningeoma removed, two died within a few days following surgery, and of the remaining 13 no follow up is provided. He points to the potential value but also the risks of ventriculography for the diagnosis of these (and other) intracranial processes but also emphasizes the need for a meticulous anamnesis and clinical work up and devotes a special chapter on the epileptic symptoms, found predominantly in patients with meningeoma over the convexity or the parasaggittal areas of the brain, and their localizing significance. In the summer of 1936 De Vet left Amsterdam and moved to Wassenaar, a suburban village near The Hague where a former psychiatric clinic had been rebuild as the second non university associated hospital for psychiatric and neurological disorders, including the first non-university neurosurgical unit in the country. In the St. Ursula Clinic De Vet continued to pursue his interest in epilepsy as a possible target for surgical intervention and in 1938 he was appointed consultant neurosurgeon in the epilepsy clinic ‘Meer and Bosch’ in Heemstede. ‘Meer and Bosch’ was named after the stately mansion and the surrounding grounds, acquired in 1885 by the Christian Foundation for the care of Sufferers from the Falling Disease, founded in 1882, as living quarters for the clergyman-director. The institute, modeled after the Bodelschwing Institutions in Bielefeld, Germany, started in a small garden building at the premises of the founder, Lady A. J. M. Teding van Berkhout (1833–1909), in Haarlem but by 1938 had grown into a conglomerate of many buildings for housing, care, occupation or education, of adults and children with chronic epilepsy. Whereas care, provided by deaconess brothers and sisters, had been the original task of the foundation, the second quarter of the 20th century brought a shift towards a more medical oriented approach. In 1930 B. Ch. Ledeboer (1897–1959) was appointed as the first medical director, working together and not any more under the still prevailing clergyman director. Within a few years he managed to have a modern clinic built on the premises, with observation wards for adults and children, laboratories and even surgical facilities. In 1934 the

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The development of epilepsy surgery in the Netherlands and Belgium Queen Emma Clinic was officially opened and it was there that De Vet, starting 22 November 1938, practiced part time, in addition to his work in the St. Ursula Clinic. De Vet strongly believed in the value of ventriculography and designed a movable and translucent model of the ventricular system for better understanding of the movement of air through the ventricles and for illustrating and teaching puposes.50,51 He advocated that every patient with epilepsy should have at least one diagnostic encephalogram and from the register of surgical procedures of the Queen Emma Clinic52 it is clear that he practiced what he preached. From the 377 procedures performed between November 1938 and February 1942, less than 40 appear to have involved real neurosurgical interventions, including five resections of cortical scars or areas from which seizures could be elicited. Others concerned lesiectomies (glioma, angioma, meningioma, etc.) which De Vet himself did not consider ‘epilepsy surgery’.53 The vast majority of the procedures were suboccipital ventriculgraphies, usually performed by A. Verjaal (1910–1973), the later Professor of Neurology in Leiden but then first assistant to Ledeboer, the remainder some 20–30 bi-occipital trepanations for direct puncture of the ventricles, performed by De Vet, Verjaal assisting. In 1942 the clinics in Heemstede closed and all patients returned home in order to prevent the German occupation forces and their Dutch collaborators to take over the management of the clinics. The St. Ursula clinic remained active. Occasional surgeries for epilepsy, either as the main symptom or as a secondary phenomenon, were also performed elsewhere since neurosurgical departments by this time also had been established in other university clinics in the Netherlands. In the Valerius Clinic, associated with the Free University of Amsterdam, general surgeon C. van Gelderen actually performed some interventions, including a tumor case with seizures, guided by some of the earliest electroencephalographic (EEG) recordings performed in the Netherlands.54 These early Dutch endeavors in the field of EEG by physicist L.J. Koopman, psychiatrist L.J. Franke, and physiologist J. ten Cate were discontinued, due to war conditions (Jonkman1). After the war the neurosurgical activities in Heemstede were resumed but according to the register it was not until 1949 that some real surgical intervention, other than diagnostic procedures was performed. In that year de Vet was joined by Otto Magnus, who, due to the vicissitudes of war had worked in Zurich with W.R. Hess (1881–1973), and then trained in Neurology in London. In 1947 De Vet had suggested that Magnus, rather than starting a residency in neurosurgery, should pursue his earlier neurophysiologic interest and acquaint himself with electroencephalography (EEG). Following two more years of training in Montreal with H. Jasper (1906–1999) and W. Penfield (1891–1976), Magnus returned and introduced EEG both in Wassenaar and in Heemstede. Magnus also introduced acute electrocorticography (ACoG) as a regular procedure for epilepsy surgery and according to the register, from June 1949 to September 1954 17 cortical excisions, guided by ACoG were performed, either by P. Hanraets, pupil and later associate of De Vet or by De Vet himself, who has his last entry on 23 September 1954. After that time no neurosurgical procedures were performed in Heemstede and on arrival of A.M. Lorentz de Haas (1911–1967) as successor to Ledeboer the operating room,

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which had remained in use for minor surgeries, was closed. All epilepsy surgery activities thus were moved to Wassenaar but Magnus remained head of the EEG department, both in Wassenaar and in Heemstede, acting as a liaison between the two clinics until 1968. In an early report, specifically mentioning epilepsy, De Vet reported 80 cases of epilepsy admitted to the clinic in Wassenaar between 1936 and 1938, 63 of them being symptomatic cases. No mention was made concerning number of surgeries or outcome.55 In 1949 he reported on 105 operated patients with a good outcome (comparable to Engel I and II) in 50%. Most patients had lesions. In 15 patients he removed small areas of normal looking cortex where seizures could be elicited and from those 15 only 4 had a satisfactory outcome.53 In 1962 Magnus compared the results of the first 45 procedures with ACoG with those of the earlier series and found them to be more or less equal56. In his last paper on the subject57 De Vet however emphasised the value of ACoG in cases of non-lesional temporal lobe epilepsy. From a total series of 213 patients, operated for epilepsy in the period 1936–1969, 78 could be identified with psychomotor epilepsy, where 33 of these turned out to have a lesion. From the remaining 45, all operated with the help of ACoG by Magnus, 18 became seizure free and another 13 showed major improvement, an outcome far superior to the 1949 results.53 In 1969 De Vet retired from the St. Ursula Clinic and after his departure the interest in epilepsy surgery quickly diminished. Only a few procedures were performed in the following years and in the new Westeinde Hospital in The Hague to which the neurological and neurosurgical departments were moved in 1979 no epilepsy surgery was performed any more. By this time however the torch had already been taken over by another team, already evident in De Vet’s 1972 paper57 where he discussed the options of stereotactic intracranial EEG investigations, advocated its application in cases of bitemporal lobe EEG foci and illustrated his point by an X-ray picture of a skull with multiple intracerebral and subdural electrodes, ‘Courtesy Prof. Dr. W. Storm van Leeuwen’. Consolidation: The Dutch Collaborative Epilepsy Surgery Programme Reference to stereotactic procedures had already been made by De Vet before. Like other neurosurgeons of the period he had been actively involved in psychosurgery and, well aware of the major drawbacks of both open or closed leucotomy techniques, he recognized the potential advances of multiple and successive microcoagulations, performed through chronic indwelling micro-electrodes, but considered the technique as yet insufficiently developed.58 By the time of his retirement this had changed. Willem Storm van Leeuwen (1912–2005) studied medicine in Leiden and specialized in physiology and neurophysiology with G. J. J. Rademaker (1887–1957). In 1945 he obtained his PhD on a thesis on cardiac arrhythmia, elicited by experimental injury of the central nervous system. Supported by a Rockefeller Fellowship he then spent some years in the UK with Lord Adrian in London and with W. Gray Walter in Bristol, where he obtained his training in EEG.59 On returning to the Netherlands Storm van Leeuwen was one of the driving forces behind the further development of clinical

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neurophysiology in the Netherlands. Following alternating appointments in Leiden and Utrecht he finally settled in Utrecht in 1959 as director of the department of clinical neurophysiology and of the department of brain research of the Medical Physical Institute (MFI) of the National Dutch organization for applied physical research (TNO). The fortuitous situation of clinical neurophysiologists such as Storm van Leeuwen, Magnus, and Portugese born Fernando Lopes da Silva, whom Storm van Leeuwen had brought to Holland from the UK, collaborating with physicists as Anton Kamp in Utrecht and Henk van der Tweel (1915–1997) in Amsterdam, resulted in major advances in recording techniques and equipment, innovative early methods of computer analysis, and the development of miniaturized radiotelemetry with depth electrodes which was to be decisive for the further development of psychosurgery and, in its wake, also of epilepsy surgery in the Netherlands. Following some pioneer stereotactic coagulation procedures by a group of Dutch and Belgian neurologists and neurosurgeons, including Arthur Sonnen (1932–2000) and Jan van Manen 60 in 1971, largely through an initiative of Harry Meinardi and the Dutch National Commission for Epilepsy Research (CLEO) a working group for neuro-physio-surgery was constituted to discuss all Dutch patients for whom psychosurgical interventions were considered.61 Medical, social and ethical impact of such interventions were considered to exceed the individual responsibility of individual doctors and requiring peer review and as such the working group, although initiated by some of the core members, soon obtained formal recognition by the Dutch health authorities. Storm van Leeuwen held the chair. Members were neurologists, psychiatrists, clinical neurophysiologists, and neurosurgeons actively involved in psychosurgery and came from different clinics in the Netherlands as well as from the Dutch speaking part of Belgium. Since gross leucotomy by that time was totally discredited the method of choice was chronic stereotaxic microcogulation as originally advocated by Crow et al.62 but employing the electrodes developed originally for animal experimentation by Kamp and Lopes da Silva. Since at the onset it was clear that evaluation of epileptic patients for possible surgery would require comparable electrode types and stereotactic techniques it was decided that the activities of the working group should also include epilepsy and that epileptologists should participate.61 Special multistranded depth electrodes and subdural wire and reed multi-electrodes were developed at MFI and a method was developed for the stereotactic implantation of two to six intracerebral electrodes, aimed at the hippocampus, amygdala and mesio-frontobasal cortex, combined with 8–16 narrow subdural reeds, guided by hand and fluoroscopy over wide areas of the lateral and basal frontal, temporal and centroparietal cortex of both hemispheres, all electrodes introduced through just two small bifrontal trephine holes63 (Figure 10.3). Although reaching fewer intracerebral sites than the orthogonal stereotactic approach, developed by Taillairach and Bancaud,63 the Dutch approach performed excellently64 and had the advantage of better access to the surface cortex bilaterally with less risk for intracerebral hemorrhage and with relatively minor surgical trauma, compared to the subdural strip and grid methods, developed shortly afterwards in the USA. All procedures, including those on patients from Belgium, were performed in Utrecht by neurosurgeon C.W.M van Veelen.

Figure 10.3 (a, b) Frontal and lateral scheme, drawn after postimplantation X-ray of a patient with bilateral subdural wire and reed electrodes (continuous lines) and four depth electrodes (dotted lines) in the mesilimbic structures, all electrodes implanted through small bifrontal trephine holes according to the method, developed by the group of Storm van Leeuwen, Lopes da Silva, and Van Veelen.62

Initially psychosurgery constituted the brunt of the working group’s activities. Although at the time of Storm van Leeuwen’s retirement in 1979 the number of such cases, was dwindling, the workgroup activities continued, stimulated by the arrival of C. D. Binnie, London and Cambridge trained clinical neurophysiologist, who in 1976 had taken up the position of director of the department of clinical neurophysiology at ‘Meer and Bosch’. There he had created the first telemetric long term EEG and video monitoring unit in the country

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The development of epilepsy surgery in the Netherlands and Belgium Dutch collaborative epilepsy surgery program 160 140 120 100 80 60 40 20 0 1973

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Figure 10.4 Dutch Collaborative Epilepsy Surgery Program activities 1973–2005: all patients A total of 1656 patients has been referred and evaluated resulting in 775 resections. 160 patients had intracranial recordings (135 bilateral or unilateral depth and subdural electrodes, 25 subdural grids).

where he could accommodate even depth implanted patients, who at that time could not be monitored in Utrecht.66 The emphasis now changed from psychiatry to epilepsy, at first still at a very low pace but, following the appointments, in 1985, of A. C. van Huffelen as successor of Storm van Leeuwen and of W. van Emde Boas on the position of Binnie, who returned to the UK, the program quickly expanded (Figure 10.4). In 1989–1990 Van Emde Boas spent 5 months for additional training with F. Andermann and P. Gloor (1923–2003) in Montreal and on his return in Heemstede expanded the capacity for presurgical evaluation by creating a new ‘nonhospital but home-like’ three bed epilepsy monitoring unit, where, weather permitting, patients, including those with implanted electrodes, could be recorded, even while sitting outside in the garden. Van Huffelen, at the same time, prepared a medical technology assessment project and obtained government funding for the period 1990–1992. The final report of this project, supervised by Van Huffelen, Van Veelen, and Van Emde Boas, was offered to the Dutch health authorities in 1993 and resulted in formal acceptance – and thus formal albeit hardly sufficient third-party payment – of epilepsy surgery, including the necessary presurgical evaluation for up to an initially 50 patient maximum per year, Utrecht Academic Hospital being the only recognized hospital allowed to perform these operations in close collaboration with the three specialized Dutch epilepsy centers. By that time the constitution and procedures of the working group had drastically changed. With monitoring facilities now also available in the Epilepsy Centers Kempenhaeghe in Heeze and the Dr. Hans Berger Clinic in Breda, more clinical neurophysiologists and neurologists attended the meetings in Utrecht together with the neuropsychologists, responsible for pre- and post-surgical assessment and the Intracarotid Sodium Amytal test.67 A second monthly meeting was organized in Heemstede for the clinical neurophysiologists only for a collective review of all the seizures, video and EEG, of the patients to be discussed in the next plenary session in Utrecht, where a brief summary would be presented. Other neurosurgeons joined van Veelen and pediatric epilepsy surgery,

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Figure 10.5 Dutch Collaborative Epilepsy Surgery Program activities 1973–2005: children, up to the age of 16 years. 357 children were referred of which 133 had surgery, with one exception all since 1990. Surgical procedures range from limited lesionectomies or partial resections to structural or functional hemispherectomies and a small number of anterior callosotomies.

already practiced on a limited scale, got a major impetus when O. van Nieuwenhuizen, shortly afterwards to be appointed professor of child neurology in Utrecht, joined the group in 1991 (Figure 10.5). Special MRI protocols were developed68 and PET and occasional SPECT studies69 were performed in selected patients, the former first in collaboration with the University clinic in Liege (Belgium)’ and later in the Free University in Amsterdam, where in 1997 Magneto Encephalography (MEG) also became available. After lifting of the earlier imposed restrictions the university hospitals of Maastricht and of the Free University in Amsterdam joined the workgroup activities in 1997 and 2002. While the number of referrals and surgeries steadily increased, until levelling off around 2002 (Figure 10.5) the number of intracranial investigations sharply dropped, then started to rise again following the introduction of Grids recordings in Utrecht under the supervision of Heemstede trained F. Leijten. Initially some Belgian patients continued to be referred to the Dutch program but this came to an end following the development of epilepsy surgery in Gent and elsewhere in Belgium. Collaboration between programs on both sides of the border continued however, notably in the field of research in addition to multiple contacts between the Dutch program (since renamed ‘National Working Group for Epilepsy Surgery’ [LWEC] within the Netherlands and ‘Dutch Collaborative Epilepsy Surgery Program’ [DCESP] for international purposes) and international circles. Members of the group actively participated in many international meetings and van Emde Boas and van Nieuwenhuizen acted as commission members for the commission on epilepsy surgery and the subcommission for pediatric epilepsy surgery of the International League Against Epilepsy. Between 1973 and 2005 775 patients had been operated, the last overall results (on 338 patients operated up to 1998) published by van Veelen in 2001.70 An overview of the papers published by participating workgroup members and associated research programs (Appendix) can be obtained through Pub Med.

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Vagal nerve stimulation never was part of the activities of the LWEC although some of the member epileptologists and surgeons were or are involved in early pilot studies and in the current multicenter program for a limited number of VNS implants per year, accepted by the health authorities and coordinated by G. Hageman (Enschede) for adults and M. Majoie (Heeze) for children. Growth of patient numbers and the increased complexity of presurgical work up of individual patients and of traffic in the densely populated Netherlands have made the process of regular, now two per month, general meetings in Heemstede and Utrecht an increasing burden on the participants and some members of the LWEC have advocated the creation of local teams, leaving only the most difficult cases for broad discussion in the central group. A team consisting of neurologists, neurophysiologists, neuropsychologists, and neurosurgeons from the University of Maastricht and Epilepsy Center Kempenhaeghe has started its activities in 2005, reviewing cases from the southern part of the Netherlands; the first resective procedures have recently been performed in Maastricht. However, it takes expertise also to recognize ‘easy cases’ inasmuch as these exist and the LWEC intends, with the development of teleconferencing techniques, to continue to monitor, coordinate, and guide all epilepsy surgery activities in the Netherlands.

Belgium At the end of the 16th century Jean Baptiste van Helmont (1577–1644), the founder of the Iatrochemical School, which looked to chemical explanations of vital phenomena, from Leuven, was the first to write about the underlying mechanism of epilepsy in the Low Countries. He attributed epilepsy to a dysfunction of the orifice of the stomach where a duumvirate of stomach and spleen was thought to regulate functions of life. However, he also acknowledged that seizures could be provoked by strong emotions affecting the sensitive soul.71 In modern times, it was only after 70 years of its independence from the Netherlands in 1830 that Belgium saw some early efforts in surgical treatment of patients with epilepsy. Crocq72 mentioned 13 mostly posttraumatic cases from nine authors in his 1902 review and in that same year Lowie from Eecloo reported another patient at a major Flemish meeting.73 Yet these activities, and comparable ones in the years to follow, remained isolated cases, performed by general surgeons and not incorporated in a structured program. The interest in neurosurgery and epilepsy in Belgium dates from immediately before the World War I. In 1905, Van Gehuchten began to film neurological and psychiatric patients, among some with epileptic fits; the original nitrate movies have survived and represent in fact the first Belgian films. The Great War, with 90% of the country under German occupation, represented a period of scientific stagnation. Only in Flanders Fields did some surgeons acquire great experience in traumatology. Noteworthy is the contribution by De Page who designed a special electromagnetic device used for removing deep seated shrapnel and bullets from the brain.74 As the capacity of (neuro)surgical care on the battlefield was very limited, the Belgian Red Cross called upon the services of Muskens from The Netherlands to help setting up a unit for central nervous

system war injuries in 1914. Immediately after the World War I, Paul Martin was the first Belgian surgeon who went to the USA for training in neurosurgery with Harvey Cushing and became head of the surgical laboratory at Harvard University. He later returned to Belgium to become the first professor of neurosurgery at the University of Brussels.74 In the meantime, Van Gehuchten had joined forces with Jean Morelle, a neurosurgeon who had also trained in the USA and set up a nucleus of neurosurgery within the general surgery department at Leuven. A similar attempt was made at the University of Liège, where Christophe, who had worked with Frazier, Adson and Cushing, became lecturer in neurosurgery in 1933, probably the first of his kind in Europe.74 However, the first independent neurosurgical departments were founded only after the World War II but initially there was no special interest for epilepsy surgery. In fact, specialized epilepsy care in Belgium as such did not start until in the fifties of the 20th century. In 1955 academical neuropsychiatrists from the Universities of Gent, Brussels, Leuven, and Liège and other interested professionals founded the Belgian National League against Epilepsy. The league has survived to date but currently serves as an umbrella organization of two active regional leagues (one Flemish-speaking and one French-speaking) reflecting the federal nature of the Belgian state. According to a review by Sorel, by the end of the fifties in-patient facilities for epilepsy patients were available in neurological departments of 59 hospitals throughout the country.75 In about 10 neurosurgical units nationwide occasional epilepsy surgery procedures were performed. In the late sixties and early seventies two institutions for residential care of refractory epilepsy patients were founded in Pulderbos and in Ottignies. Pulderbos, located in the Flemish-speaking part of the country, emerged from collaboration between the University Hospital of Leuven and a major health care provider. The ‘Centre Neurologique William Lennox’ was founded in 1972 and is associated with the French-speaking ‘Université Catholique de Louvain’. The first reports in the international peer-reviewed literature of epilepsy surgery in Belgium originate from Liège where in the mid-sixties A. Waltregny, a neurosurgeon and clinical neurophysiologist, performed experimental and human studies using invasive EEG recording based on the teachings of Gastaut and Bancaud in France.64,76 Relatively few resective procedures were performed, however, without further contributions to the international epilepsy surgery literature. Many patients eligible for surgery were referred to epilepsy surgery centers in France, The Netherlands, and Western Germany. In the beginning of the eighties P. Tugendhaft and J. Brotchi at Hôpital Erasme, an academical hospital associated with the French-speaking ‘Université Libre de Bruxelles’, performed a series of invasive EEG recordings using the methodology of Wyler from the USA. and initiated the first epilepsy surgery series in Belgium.77 Neuropsychological assessment and intracarotid amytal procedures were routinely performed. In 1990, the first comprehensive epilepsy surgery center in Belgium was established at Ghent University by P. Boon, and L. Calliauw, chair of neurosurgery at Ghent University Hospital. P. Boon, a neurologist and clinical neurophysiologist, trained at Winston-Salem, NC with Penry and at

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The development of epilepsy surgery in the Netherlands and Belgium Yale University with Williamson and Spencer. Soon E. Thiery, professor of neuropsychology at Ghent University and E. Achten, neuroradiologist at Ghent University Hospital, joined the team. Their collaboration resulted in the first multidisciplinary epilepsy surgery team in Belgium, evaluating and operating increasing numbers of patients and performing clinical research.78,79 The first combined placement of depth and subdural electrodes in patients requiring invasive EEG recording, the first implantation of a vagus nerve stimulator in Belgium, and the first long-term treatment with amygdalohippocampal deep brain stimulation for temporal lobe epilepsy in Europe were all performed by their team. Over time the group in Gent came to include K. Vonck, a neurologist with special expertise in neuromodulation and D. Van Roost, a functional neurosurgeon with longstanding experience in epilepsy surgery, who trained with the neurosurgical team of Schramm at Bonn University Hospital.80,81 At about the same time, the team from the ‘Université de Liège’ headed by G. Franck and B. Sadzot, who had trained in Baltimore, USA, established a positron emission tomography unit in which patients with refractory epilepsy were systematically investigated. Most of these patients were referred from the Dutch Collaborative Epilepsy Surgery Programme in Utrecht.69,82 In the late nineties W. Van Paesschen, a neurologist who trained with Duncan and his group in London and J. Van Loon, a neurosurgeon, started with presurgical evaluation and epilepsy surgery at the ‘Katholieke Universiteit Leuven’. Their group has a strong focus on non-invasive diagnostic tools such as ictal SPECT.83 This was quickly followed by similar initiatives to establish epilepsy surgery programs at the ‘Université de Liege’ (headed by B. Sadzot and T. Grisar), the ‘Cliniques Universitaires St-Luc’ in Brussels (headed by K. Van Rijckevorsel and C. Raftopoulos), and in the ‘Centrum voor Epilepsie en Psycho-organische Stoornissen’, a private initiative in Duffel (headed by R. Hauman). The already active programme at ‘Hôpital Erasme’, Bruxelles, now directed by B. Legros and P. Van Bogaert, during the same period expanded its activities. A major breakthrough in terms of acceptance by the health authorities and funding by the national reimbursement agency was the establishment of ‘Reference Centers for Refractory Epilepsy’ in 2000. Strict criteria were defined with regard to the necessary availability of technical infrastructure, human resources and neurological and neurosurgical expertise for academical centers to be recognized as a referral center for epilepsy surgery. The main purpose was to concentrate know-how in a limited number of centers, guarantee high quality standards and limit the costs. Only patients treated in such centers got reimbursement for presurgical evaluation and surgical procedures for refractory epilepsy. After an initial phase during which six centers were recognized in 2000, presently four Reference Centers for Refractory Epilepsy are active in Belgium: in Gent (Universitair Ziekenhuis Gent), Leuven (Universitair Ziekenhuis Gasthuisberg), and two in Brussels (Hôpital Erasme, Cliniques Universitaires St-Luc). All have dedicated epilepsy surgery teams and follow a similar presugical evaluation protocol. In each center, video-EEG monitoring, 1.5T or 3T optimum MRI facilities, PET, SPECT, and neuropsychological assessment are

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available. Biannually, in each center quality and performance parameters are assessed by the national reimbursement agency. In 2003–2004, 300 patients annually underwent presurgical evaluation (including invasive video-EEG monitoring in 20 patients) resulting in 70 resective procedures and 60 implantations of a vagus nerve stimulator in patients who were not eligible for resective surgery. Presurgical evaluation and epilepsy surgery are a strong impetus for performing clinical and experimental research. Epilepsy research in Belgium has basically followed the same timelines as the clinical development of epilepsy care described above. While scientific reports on epilepsy surgery related work were scarce until the 1980s, clinical researchers from Gent, Leuven, Bruxelles, Louvain and Liège have been increasingly active. Among the most published topics in the past 15 years are EEG source localization (Gent), optimal structural magnetic resonance imaging (Gent, Leuven), functional magnetic resonance imaging (Gent), PET (Liège), ictal SPECT (Leuven), magnetoencephalography (Gent), seizure anticipation (Gent, Leuven), antiepileptic drug research (all centers), vagus nerve stimulation (Gent), and deep brain stimulation (Gent, Bruxelles).80–89 The groups from Gent and Liège have experimental animal facilities providing many relevant epilepsy animal models and they are active in the field of basic neurophysiology, neurostimulation and stem cell applications in epilepsy.90–93

Appendix: Core membersa of the Dutch Collaborative Epilepsy Surgery Program workgroup 1980–2005 Secretariat and logistic coordination E. van Wijk-Leenaars5 Clinical Neurophysiology / Epileptology C.D. Binnie,1* M. Bourez-Swart,5 G.J.F. Brekelmans,1* S. Claus1, A. Colon,3 W. van Emde Boas1 (Chair 2003–present), J. Parra Gomez1, A.C. van Huffelen5, J. Jonkman*, V. van KranenMastenbroek7, F. Leijten5, W. v.d. Meij5*, J. Overweg1* (Chair 1990–1998), L. Reebok4, H.E. Ronner6, A.E.H. Sonnen4†, W. ter Spill4*, C.J. Stam6, D.N. Velis1, E. Veltman3 (Chair 1999–2002), P.H.A. Voskuil4*, L. Wagner4, A.W. de Weerd2, A. van Wieringen1* Neurology / Epileptology J. Bruens,4† R.M.C. Debets,1 A. Elderson5*, M.C.T.F.M de Krom7, H. van Lambalgen2, J. van Manen* (Chair 1980–1989), H. Meinardi1*, Th. Rentmeester3*, F.B.J. Scholtes4*, R.T.M. Starrenburg3*

a Many persons have occasionally attended the meetings as guest or as short term participants. In this list only those that have been actively involved for the whole period or major lengths of time are listed. The members of the still existing subgroup for psychosurgery are not mentioned. For a list of members of the original group 1971–1979 see reference 61. * Past member.

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Paediatric Neurology O. van Nieuwenhuizen,5 W.O. Renier* Neurosurgery H. Baaijen,6 J. Dings,7 P. Gosselaar5, G. van Overbeke5*, P. van Rijen5, C.W.M. van Veelen5*, V. Visser-Vandewalle7 Neuropsychology W.C. Alpherts,1 M.L. Franken3*, M.P. Hendriks3, A. Jennekens-Schinkel5*, M. Klein6, J. Vermeulen1 Neuroradiology L.C. Meiners,5* G.A.de Kort5, L.M. Ramos5*, T.D. Witkamp5* Psychiatry W.P. Haaijman*

Research associates A.P. Aldenkamp,2 J.Arends,2 E. Arronica9, P.A.J.M. Boon2, A.van Dieren5, B.W. van Dijk6, W.H. Gispen8, J.A. Gorter9, P.N. de Graan8, M. v.d. Heide1, G. Hoogland8, G.J. Huiskamp8, F. Jansen5, S. Kalitzin1, F. H. Lopes da Silva9, H. Meeren6, J. C. de Munck6, P. Ossenblok2, E.A. Proper8, J.P. Pijn1 †, N. Ramsey5, G.J. Rutten5, P. Suffczinski1, D. Troost9, M. Vreugdenhil9, W. J. Wadman9 Participating Hospitals 1 Epilepsy Centre Meer and Bosch; SEIN, Heemstede, 2Epilepsy Centre Heemstaete; SEIN, Zwolle, 3Epilepsy Centre Kempenhaeghe, Heeze, 4Epilepsy Centre Dr. H. Berger kliniek, Breda, 5University Medical Centre Utrecht, 6Free University Medical Centre Amsterdam, 7Academic Hospital Maastricht Main Associated research groups 8 Rudolf Magnus Institute of Neuroscience, Utrecht, 9 Swammerdam Inst. of Life Science, Amsterdam

REFERENCES 1. References in the text almost exclusively refer to original publications. For all Dutch historical and biographical data without specific references the source is: Frederiks JAM, Bruyn GW, Eling P, eds: History of Neurology in the Netherlands. Boom: Amsterdam, 2002. From this book notably the following chapters were consulted: Chapter 3. Koehler PJ, The Extra-Academic Centres, 37–51; Chapter 7. Alphen HAM van, Neurosurgery, 93–121; Chapter 11. Jonkman EJ, Clinical Neurophysiology, 193–215; Chapter 13. Meinardi H, Epileptology, 221–40; Chapter 19. Bruyn GW, Koehler PJ, B. Brouwer 1881–1949, 299–308; Chapter 27. Bruyn RPM, Bruyn, GW, C. T. van Valkenburg 1872–1962, 367–76; Chapter 29. Bruyn RPM, J. K. A. Wertheim Salomonson 1864–1922, 387–92; Chapter 30. Koehler, PJ: C. Winkler, 1855–1941, 393–401. For the sections concerning the post World War II developments and the period of the Dutch Collaborative Epilepsy Surgery Program, moreover, use was made of personal communications of O. Magnus, C. W. M. van Veelen, A. C. van Huffelen, E. van WijkLeenaars, H. Meinardi, F. Lopes da Silva, and A. W. de Weerd and of the private archive of DCESP and other documents of WvEB. 2. Tilanus JWR. Overzicht over de ontwikkeling der chirurgie in de laatste 30 jaren. Ned Tijdschr v Geneesk 1882-II; 26:214–19. 3. Winkler C, Rotgans J. [L’etat actuel de la chirurgie nerveuse] Pays Bas. In: Chipault A ed: L’Etat Actuel de la Chirurgie Nerveuse Vol I, 658–755. Rueff: Paris, 1902 (Preprint: No place, 1901 pp 1–98; Reprint: Winkler C: Opera Omnia Vol. 3 549–640. Bohn: Haarlem, 1918). 4. Mesdag MJ. Bibliographie van de werken van Nederlandse schrijvers op het gebied van de neurologie en psychiatrie en aanverwante vakken. Vol.II, systematisch gedeelte. No Publisher [Amsterdam University Clinic of Psychiatry and Neurology]: Amsterdam, 1923. 5. Winkler C. Herinneringen. Van Loghum Slaterus: Arnhem, 1947 (Reprint: Bohn: Scheltema & Holkema, Utrecht, 1982). 6. Winkler, C. Bijdrage tot de Hersen-Chirurgie uit de Diaconesseninrichting te Utrecht. II: Tumoren. Ned Tijdschr v Geneesk 1891I;35:371–418 (Reprint: Winkler C. Opera Omnia Vol 2, 33–77. Bohn: Haarlem, 1918. 7. Guldenarm JA, Huysman J, Winkler C: Bijdrage tot de HersenChirurgie uit de Diaconessen-Inrichting te Utrecht. Ned. Tijdschr v Geneesk 1890-I;34:657–64 (Reprint: Winkler C. Opera Omnia Vol 2, 3–11. Bohn: Haarlem, 1918). 8. Guldenarm JA, Winkler C. Bijdrage tot de Hersen-Chirurgie uit de Diaconessen-inrichting te Utrecht. III: Cerebrale verschijnselen na een trauma van den schedel. Ned Tijdschr v Geneesk 1891II;35:217–30 (Reprint: Winkler C: Opera Omnia Vol 2, 78–89. Bohn: Haarlem, 1918).

9. Winkler C. Bijdrage tot de Hersen-Chirurgie uit de Diaconesseninrichting te Utrecht IV: Siphylitische tumoren, diffuse gliomata en gliosarcomata, tumoren ontstaan na schedeltraumata, cysten en verkalkingen. Ned Tijdschr v Geneesk 1893-I;37:209–254 (Reprint: Winkler C. Opera Omnia Vol 2, 203–241. Bohn: Haarlem, 1918). 10. Buringh Boekhoudt H. Bijdrage tot de Hersen-Chirurgie uit de Diaconessen-inrichting te Utrecht V: Haematoma Durae Matris. Ned Tijdschr v Geneesk 1893-I;37:309–14. 11. Winkler C. L’intervention chirurgicale dans les epilepsies. Bohn: Haarlem et O. Doin: Paris, 1897 (Reprint: Winkler C: Opera Omnia Vol 3, 95–155. Bohn: Haarlem, 1918). 12. Lens PCTh. Trepanation in einem Falle Jacksonischer Epilepsie [thesis] Giessen, 1891. 13. Hermanides RS. Operatieve behandeling van Hersengezwellen [thesis] J.v. Boekhoven: Utrecht, 1894. 14. Hermanides RS: Operatief behandelde hersengezwellen. Ned Tijdschr v Geneesk 1895-I;39:302–18. 15. Winkler C. Een proeve om met behulp van driehoeksmeting de betrekkelijke ligging der windingen en sleuven van de groote hersenen tegenover de door huid bedekte schedeloppervlakte te bepalen. Ned Tijdschr v Geneesk 1892-II;36:158–73 (Reprint: Winkler C. Opera Omnia Vol 2, 97–115. Bohn: Haarlem, 1918). 16. Winkler C. Over hersenchirurgie. De Gids 1895;59:58ff (Reprint: Winkler C. Opera Omnia Vol 2, 309–33. Bohn: Haarlem, 1918). 17. Brekelmans GJF. Clinical Neurophysiology in the Presurgical Evaluation of Patients with Intractable Epilepsy [thesis]. Utrecht, 1999. 18. Eyk HH van. Partieele epilepsie en hare heelkundige behandeling [thesis], Van Heteren: Amsterdam, 1897. 19. Chipault A. France. In: Chipault A, ed: L’Etat Actuel de la Chirurgie Nerveuse Vol I, 84–92. Rueff: Paris, 1902. 20. Wertheim Salomonson J. Particuliere correspondentie. Ned Tijdschr v Geneesk 1898-I;42:190–9. 21. Rutgers M. XXVIII Congres van het Duitsche Gezelschap voor Chirurgie te Berlijn. Ned Tijdschr v Geneesk 1899-I;43:647–50. 22. Boks DB. 29ste Congres van de Deutsche Gesellschaft f¸r Chirurgie. Ned Tijdschr v Geneesk 1900-I;44:1090–6. 23. Boks DB. Operatieve behandeling van Epilepsie. Ned Tijdschr v Geneesk 1900-I;44:768–79. 24. Indemans JWM. Twee gevallen van partieele epilepsie van Jackson. Ned Tijdschr v Geneesk 1903-II;47:659–69. 25. Iterson JE van: De ontwikkeling der heelkunde. Ned Tijdschr v Geneesk 1899-II;43:87–94. 26. Eling P, Keyser A: Louis Muskens: a leading figure in the history of Dutch and World epileptology. J Hist Neurosci 2003; 12:276–85.

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The development of epilepsy surgery in the Netherlands and Belgium 27. Muskens LJJ. Neurologie en Neurochirurgie. Psychiat Neurol Bladen 1915;19:492–9. 28. Muskens LJJ. Psychiatrie, Neurologie und Neuro-Chirurgie. Monatschr Psychiat Neurol 1915;37:374–80. 29. Muskens LJJ. International League Against Epilepsy in war and postwar time. Epilepsia 1937;1(2nd series); 14–22. 30. Muskens LJJ. Epilepsie: vergelijkende pathogenese, verschijnselen, behandeling. Van Rossen: Amsterdam, 1924 (German edition: Epilepsie: vergleichende Pathogenese, Erscheinungen, Behandlung. Springer: Berlin, 1926; English edition: Epilepsy: Comparative Pathogenesis, Symptoms, Treatment. London; Ballière, Tyndall and Cox, 1928. 31. Muskens LJJ. Das supra-vestibuläre System bei den Tieren und beim Menschen. Noord Holland: Amsterdam, 1935. 32. Muskens LJJ. De ontwikkeling van het specialisme in de geneeskunde. [Public lecture, University of Amsterdam] Bohn: Haarlem, 1906. 33. Muskens LJJ. Mededeelingen omtrent de heelkunde van het centrale zenuwstelsel. I. Een betrekkelijk gevaarlooze techniek van heelkundig onderzoek der hersenen. Ned Tijdschr v Geneesk 1911-II;55:983–1002. 34. Muskens LJJ. Mededeelingen omtrent de heelkunde van het centrale zenuwstelsel. II. Ruggemergoperaties. Ned Tijdschr v Geneesk 1911-II;55:1053–63. 35. Muskens, LJJ. Mededeelingen omtrent hersenchirurgie. III. Het segmentaal beginsel in de gevoelsprojectie op de hersenschors. Ned Tijdschr v Geneesk 1912-I;56:70–85. 36. Muskens, LJJ. Mededeelingen omtrent de heelkunde van het centrale zenuwstelsel. IV. Uitkomsten van inwendige en heelkundige behandeling van traumatische epilepsie. Ned Tijdschr v Geneesk 1912-I;56:366–76. 37. Korteweg JA. Eenige opmerkingen over: Mededelingen, enz. door Dr. L.J.J. Muskens. Ned Tijdschr v Geneesk 1911-II;55:1134–8. 38. Muskens, LJJ. Antwoord op prof. Korteweg’s artikel. Ned Tijdschr v Geneesk 1912-I;56:85–6. 39. Korteweg, JA. Wederwoord op Muskens’ antwoord. Ned Tijdschr v Geneesk 1912-I;56:184–5. 40. Londen DM. Het segmentaal beginsel in de gevoelsprojectie op de hersenschors. Ned Tijdschr v Geneesk 1912-I;56:185–6. 41. Muskens, LJJ. Antwoord aan de Heeren Korteweg en Van Londen. Ned Tijdschr v Geneesk 1912-I;56:259–60. 42. Korteweg JA. Wederwoord op Dr. Muskens’antwoord. Ned Tijdschr v Geneesk 1912-I;56:317. 43. Burger H. Wederwoord op Dr. Muskens’antwoord. Ned Tijdschr v Geneesk 1912-I;56:317. 44. Scheer WM van der (minutes). Voordrachten-Vergadering der Nederlandsche Vereeniging voor Psychiatrie en Neurologie, 25 Juni 1916. Psych Neurol Bladen 1916;20:543–66. 45. Muskens LJJ. Brief uit Antwerpen. Ned Tijdschr v Geneesk 1914II;58:1006–8. 46. Valkenburg, CT van. ‘Sensibele punten’ op de schors der groote hersenen van den mensch. Ned Tijdschr v Geneesk 1914I;58:2142–54. 47. Valkenburg, CT van. Plaatselijke hersenvliesaandoening, haar diagnose en heelkundige behandeling. Ned Tijdschr v Geneesk 1915I;59:2055–67. 48. Valkenburg, CT van. Een dubbele vertegenwoordiging van het gevoel op de schors der menschelijke groote hersenen. Ned Tijdschr v Geneesk 1916-I;60:2181–92. 49. Vet, AC de. Over de diagnostiek van het meningeoma cerebri. [thesis], Scheltema & Holkema: Amsterdam, 1936. 50. Vet, AC de. Een glasmodel van het cerebrale ventrikelsysteem. Ned Tijdschr v Geneesk 1940-I;84:2034–36. 51. Vet AC de. Translucent model of the cerebral ventricular system. J Neurosurg 1951;7:454–5. 52. Operatieregister Koningin Emma Kliniek 1938–1956 [register of surgeries] manuscript. Historical Collection Stichting Epilepsie Instellingen Nederland, Heemstede, the Netherlands. 53. Vet AC de. Neurosurgical diagnosis and therapy of epilepsy. Fol Psychiat Neurol Neurochir Neerl 1949;52:59–71. 54. Gelderen C van. Hersengezwel en electrencephalogram, Ned Tijdschr v Geneesk 1941-II;85:3605–8. 55. Vet, AC de. Neurochirurgie en epilepsie. Annalen 1939;31:134–43. 56. Magnus O, de Vet AC, van der Marel A, Meyer E. Electrocorticography during operations for partial epilepsy. Develop Med Child Neurol 1962;4:35–48. 57. Vet AC de: Temporal Epilepsy, c.q. Psychomotor Epilepsy. Experiences and present-day conceptions. Arch Suisses Neurol Neurochir Psychiat 1972;111:453–61. 58. Vet AC de, Leyten AMJ: De betekenis van de leucotomie. Ned. Tijdschr. v. Geneesk 1963-I;107:447–456.

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59. Huffelen AC van, Lopes da Silva FH, Donker DNJ: In memoriam prof. dr. W. Storm van Leeuwen. Ned Tijdschr v Geneesk 2006;150:110. 60. A.E.H. Sonnen, Jan van Manen and B. van Dijk: Results of Amygdalotomy and Fornicotomy in Temporal Lobe Epilepsy and Behaviour Disorders. Acta Neurochirurgica (1976), suppl. 23: 215–19. 61. Storm van Leeuwen W: Neuro-Physio-Surgery in the Netherlands Since 1971. Acta Neurochir 1982;61:249–56. 62. Crow HJ, Cooper R, Phillips DG. Controlled multifocal frontal leucotomy for psychiatric illness. J Neurol Neurosurg Psychiat 1961;24:353–60. 63. Veelen CWM van, Debets RMC, van Huffelen AC et al. Combined use of subdural and intracerebral electrodes in preoperative evaluation of epilepsy. Neurosurgery 1990;26:93–101. 64. Bancaud J, Talairach J, Bonis A. La stéréo- électroencéphalographie dans l’épilepsie. Informations neurophysiopathologiques apportées par l’investigation fonctionelle stéreotactique. Paris: Masson, 1965. 65. Brekelmans GJF, van Emde Boas W, Velis, DN et al. Additional value of the use of combined versus subdural or intracerebral electrodes alone in presurgical focus localisation. Epilepsia 1998;39:1290–301. 66. Binnie CD, Rowan AJ, Overweg J et al. Telemetric EEG and video monitoring in epilepsy Neurology 1981;31:298–303. 67. Alpherts WCJ. Neuropsychological Aspects of Epilepsy Surgery. [thesis], Utrecht, 2003. 68. Meiners LC. The Role of MR in Drug Resistant Epilepsy with Special Emphasis on Mesial Temporal Sclerosis [thesis], Utrecht; 1997. 69. Huffelen AC, van Isselt JW, van Veelen CWM et al. Identification of the side of epileptic focus with 123 I-iomazenil SPECT. A comparison with 18 FDG-PET and ictal EEG findings in patients with medically intractable complex partial seizures. Acta Neurochir (Wien) 1990;50(suppl): 95–9. 70. Veelen CWM van, van Rijen PC, Debets, RMC et al. Het Nederlandse epilepsiechirurgieprogramma: aanvalsreductie, operatieve complicaties en vermindering van medicatie bij 338 patiënten. Ned Tijdschr v. Geneesk 2001;145: 2223–8. 71. Haas LF. Jean Baptiste van Helmont. J. Neurol Neurosurg Psychiatry 1998;65:916. 72. Crocq J. Belgique. I. Etude Générale. In: Chipault A ed.: L’Etat Actuel de la Chirurgie Nerveuse, Vol I, 543–649. Paris: Rueff, 1902. 73. Zwaardemaker H, Muntendam, P. Zesde Vlaamsche natuur- en geneeskundig congres. Ned Tijdschr vvGeneesk 1902-II;46:807–21. 74. Calliauw L. Neurosurgery in Belgium. Acta Neurochir 2001; 143:273–5. 75. Sorel L. Review of social and medical services for epileptic patients in Belgium. Epilepsia 1963;4:167–78. 76. Bancaud J, Talairach J, Waltregny P et al. Stimulation of focal cortical epilepsies by megimide in topographic diagnosis.Clinical EEG and SEEG study. Rev Neurol (Paris) 1968;119:320–5. 77. Vanbogaert P, Massager N, Tugendhaft P et al. Statistical parametric mapping of regional glucose metabolism in mesial temporal lobe epilepsy. Neuroimage 2000;12:129–38. 78. Boon P, Calliauw L, Vandekerckhove T et al. Epilepsy surgery in Belgium: the Flemish experience. Acta Neurol Belg 1996;96:6–18. 79. Boon P, Vandekerckhove T, Achten E et al. Epilepsy surgery in Belgium, the experience in Gent. Acta Neurol Belg 1999;99:256–65. 80. Vonck K, Boon P, D’Have M et al. Long-term results of vagus nerve stimulation in refractory epilepsy. Seizure 1999;8:328–334. 81. Vonck K, Boon P, Achten E et al. Long-term amygdalohippocampal stimulation for refractory temporal lobe epilepsy. Ann Neurol 2002;52:556–65. 82. Sadzot B, Debets RM, Maquet P et al. Regional brain glucose metabolism in patients with complex partial seizures investigated by intracranial EEG. Epilepsy Res 1992;12:121–9. 83. Van Paesschen W, Dupont P, Van Driel G et al. SPECT perfusion changes during complex partial seizures in patients with hippocampal sclerosis. Brain 2003;128:1103–11. 84. Boon P, D’Have M, Adam C et al. Dipole modelling in epilepsy surgery candidates. Epilepsia 1997;38:208–18. 85. Achten E, Boon P, De Poorter J et al. An MR protocol for presurgical evaluation of patients with complex partial seizures of temporal lobe origin. AJNR 1995;16:1201–13. 86. Deblaere K, Backes W, Hofman P et al. Developing a comprehensive presurgical functional MRI protocol for patients with intractable temporal lobe epilepsy. Neuroradiology 2002;44:667–73. 87. LeVan Quen M, Martinerie J, Navarro V et al. Anticipation of epileptic seizures from standard EEG recordings. Lancet 2001;357: 183–8.

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88. Ossenblok P, Leijten F, de Munck, J et al. Magnetic source imaging contributes to the presurgical identification of sensorimotor cortex in patients with frontal lobe epilepsy. Clin Neurophysiol 2003;114:221–32. 89. Van Rijckevorsel K, Abu Serieh B, de Tourtchaninoff M, Raftopoulos C. Deep EEG recordings of the mammillary body in epilepsy patients. Epilepsia 2005;46:781–5. 90. DeSmedt T, Vonck K, Raedt R et al. Rapid kindling in preclinical anti-epileptic drug development: the effect of levetiracetam. Epilepsy Res 2005;67:109–16.

91. Van Hese P, Martens JP, Boon P et al. Detection of spike and wave discharges in the cortical EEG of Genetic Absence Epilepsy Rats from Strasbourg. Phys Med Biol 2003;48:1685–700. 92. De Deurwaerdere S, Vonck K, Van Hese, P et al. The acute and chronic effect of vagus nerve stimulation in Genetic Absence Epilepsy Rats from Strasbourg (GAERS). Epilepsia 2005;46 (suppl 5): 94–7. 93. Lakaye B, De Borman B, Minet A et al. Increased expression of mRNA encoding ferritin heavy chain in brain structures of a rat model of absence epilepsy. Exp Neurol 2000;162:112–20.

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History of epilepsy surgery in the Middle- and East-European countries and Russia P Halász

Epilepsy surgery in the Middle- and East-European region and in Russia developed under the influence of the USA and of the French schools. In the majority of countries a strong neurosurgical school developed at the beginning of the 20th century, and epilepsy surgery was built up with a more or less delay on a double basis: on classical neurosurgery and on independently developing clinical neurophysiology. The two disciplines have been amalgamated by the emerging clinical epileptological knowledge throughout the world in the multidisciplinatory assessment of epilepsy surgery. In these countries the development of epilepsy surgery was severely hindered by the information blockade due to the realm of the antidemocratic political power and to the delayed application of the contemporary neuroimaging techniques due to economical reasons. Presently the development of epilepsy surgery practice reached the international standards of leading centers in the world in Poland, Czech Republic and Hungary.

Poland In the second half of the 19th century surgical treatment was directed to vascular surgery, mainly on the sympathetic system, according to the theory that the disturbance in blood supply, especially vasospasm, was the direct cause of the epileptic seizure. R. Baracz in 1888 and 1893 published papers ‘On the ligation and resection of the vertebral arteries and the resection of sympathetic nerve for treatment of spontaneous epilepsy’. In the same year (1893) J. Bogdanik published a similar paper ‘On the resection of sympathetic nerve in treatment of spontaneous epilepsy’ and found improvement after such operations. Later on this procedure was applied by Raum and others as well. Later it was held that epilepsy is the consequence of the collection of cerebrospinal fluid on the surface of the brain in various kinds of cysts and can be treated by trephination and decompression. Decompressive trephinations were used by Baracz in 1890, Krajewski in 1894 and 1899, Schramm in 1899, and Raum in 1900. A. Domaszewicz and J. Zaczek published the paper (1922): ‘On the surgical treatment of epilepsy with personal experience’ describing the operative findings and the results of the decompressive craniotomy. Founder of the modern Polish neurosurgery was Jerzy Choróbski (1903–1986), head of the Department of

Neurosurgery in Warsawa. He was Penfield’s pupil spending several years working with him and started neurosurgery in Poland in 1935. At the beginning, during World War II and directly after, he performed several procedures for removing brain scars in cases of posttraumatic epilepsy, so important at that time. As soon as conditions after the war allowed and necessary equipment was obtained, among others EEG apparatus, he carried out the first surgery of focal, cryptogenic epilepsy on 27 November 1957 by temporal lobectomy. Diagnosis was derived from the clinical picture, PEG, EEG, and was proved intraoperatively by electrocorticography and brain electrostimulation. Later Choróbski was doing mostly temporal resections or, in special cases, hemispherectomy. The epilepsy surgery team included L. Ste˛ pie n´ and J. Bidzinski ´ (neurosurgery), T. Bacia (electrophysiology), all trained at the Montreal Neurological Institute and J. Wislawski (neuropathology). After Choróbski’s retirement, the next head of the Department, Lucjan Ste˛ pien, ´ continued this work with the above mentioned co-workers. Anatomical hemispherectomy was replaced by functional hemispherectomy. Extensive electrophysiological non-invasive investigations included various pharmacological activations and whole night physiological sleep. New diagnostic methods were consequently introduced: the Wada test (1960), psychological examination, invasive diagnosis as stereotactically implanted chronic electrodes, chronic epi- and subdural electrodes (Bidzinski ´ and Bacia in 1974). PEG was replaced by CT and NMR, and isotope studies were introduced. The results of their work were published in several publications with very long followup of several hundred patients and presented at international meetings. Beyond resective surgery, other methods, such as stereotactic lesions (amygdala, Forel’s field, Bidzinski ´ in 1981) and cerebellar electrostimulation (Bidzinski and Bacia in 1981) were tried with questionable results. The Next head of the Department, J. Bidzinski, continued epilepsy surgery and introduced anterior callosotomy and vagal nerve stimulation in Poland (1990). The present head of the Department, Prof. A Marchel with co-worker A. Rysz, are continuing the tradition of epilepsy surgery in this department with electrophysiology. As the surgical treatment of epilepsy became more popular, new neurosurgical centers started to offer surgical treatment. E. Mempel in Warsawa for many years did stereotactic 97

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amygdalotomy in patients with emotional disturbances in epilepsy and introduced acute stereoEEG in 1968. Since 1961, Z. Huber in Pozna n´ has performed several temporal lobectomies in adults and recently in children. Specially important was the establishment of an epilepsy surgery center for children at the Children’s Hospital, Mother Health Center in Warsawa, in 1995 (head, M. Roszkowski.), and at the Children’s Hospital in Lodz, in 2001 (head, L. Polis). In these centers children are treated up to 16 years of age. Recently two more neurosurgical departments joined the centers doing epilepsy surgery: in 2002 the Department of Neurosurgery in the Ministry of Administration Hospital in Warsawa (head W. Maksymowicz) and in 2004 the Department of Children’s Neurosurgery Medical University in Katowice (head M. Mandela).

Russia Epilepsy surgery in Russia and the former Soviet Union dates back to the end of the 19th and the beginning of the 20th centuries. In his ‘clinical lectures’ published in St Petersburg in 1898, A. Tauberg described cases of surgical treatment of ‘cortical epilepsy’ after brain trauma. F. Rein (1897) published a paper ‘Results and indications for the surgical tratment of Jacksonian epilepsy’. V. A. Muratov considered Jacksonian type seizures to be the indication to surgery. S. Timopheev (1913) and L. Pusepp (1919) reported long-term follow up of patients operated because of ‘Jacksonian epilepsy’. There were also several attempts to treat non-focal epilepsies surgically at that time. Various types of operations has been suggested, including operations on the autonomic nervous system. Later the idea of surgical treatment of focal epilepsies was supported by the famous Russian neurosurgeon N. Burdenko. Since the middle of 20th century epilepsy surgery has been developed in several regions of the Soviet Union: in St Petersburg Bechterewa, in Tbilis, Georgia (P. Saragishvily and P Chencheli), in Kiev, Ukraine (A. RomodanovÍ), in Sverdlovsk (now Ekaterinburg) (D. Shefer), and in Omsk (Yu. Savchenko). Stereotactic methodology of the Paris school was the basis of surgical interventions in these centers. Several papers and books dedicated to epilepsy surgery have been published in the Russian language by the above-mentioned authors. Presently in Russia, epilepsy surgery is being performed in St Petersburg (V. Bernsev), Ekaterinburg (A. Shershever), Viatka (B. Bein), and Omsk (A. Savchenko) on a considerable number of patients. The basic diagnostic disciplines, the diagnostic system used, the participation of neuroimaging methods in the presurgical procedure are deviating in several aspects from the contemporary European and USA epileptological standards. Evidence based evaluation of the results have so far not been published. Five years ago a joint surgery program was established in Moscow between the Department of Neurology and Neurosurgery of the Russian State Medical University and the Institute of Neurosurgery, based on a multidisciplinary team. This team decided to join to the contemporary epilepsy surgery programs in Europe using the same standards, evaluation and surgical methods. More than 400 patients have been

evaluated and from them 58 patients selected for presurgical evaluation, 30 patients were operated, mainly on the temporal lobe, with good results.

Romania The founder of Romanian neurosurgery was Prof. Dimitrie Bagdasar, trained in Prof. Cushing’s Department in Boston, and the first dedicated neurosurgical department in Bucharest was founded by him in 1935. His follower Prof C. Arseni was the next determining leader in neurosurgery until 1989. The modern era of Romanian neurosurgery was introduced by Prof. Al. Constantinovici and later by Prof. A.V. Ciurea. In 1993, a large neurosurgical hospital was established in Bucharest, named ‘Bagdasar-Arseni’, having departments for general neurosurgery, pediatric nerosurgery, spine neurosurgery, and adult neurosurgery. In March 2005 a neuroimaging department was added. Epilepsy surgery is still restricted to resective procedures of standard temporal lobectomies (3–4 yearly), a few tailored temporal surgical procedures (5–7 yearly) and 3–4 extratemporal resections yearly, in the last three years. Within this hospital a multidisciplinary team is starting to perform epilepsy surgery together with the Romanian National Reference Center of ILAE ruled by Dr. R. Rogozea. They are equipped with video-EEG, SPECT, and 1.5 Tesla MRI, using special ‘epilepsy protocols’, they recently introduced cortical mapping by subdural electrodes, and transcranial magnetic stimulation. They do not have as yet PET, fMRI, or MEG.

Czech Republic Epilepsy surgery in the Czech Republic (at that time part of Czechoslovakia) started in departments of neurosurgery of Medical Faculties of Charles University in Prague and Hradec Králové. Since 1956 patients with epilepsy were operated in the Department of Neurosurgery of Faculty of General Medicine of Charles University and the Military Hospital in Prague. There were two young associate profesˇ sors (Sourek and Vladyka) deeply interested in epilepsy. At first they performed excisions of cortical foci and temporal lobe resections. Stereotaxic operations were introduced later. At the beginning surgery was performed only in patients with intractable epilepsy lasting for tens of years. Therefore the number of successful outcomes was relatively low but it increased with the shift to patients with a shorter history of ˇ therapy resistant epilepsy. Sourek and Vladyka introduced a method of local cooling of the temporal lobe with the aim to open the blood–brain barrier and then apply intravenously a bolus of an antiepileptic drug. Until 1974 they used this method on 71 patients and approximately 25% of them remained seizure free, unsuccessful operations also represented 27% of patients and the remaining patients exhibited different degrees of improvement. The number of neurosurgery departments interested in epilepsy progressively increased so that there are at present at least seven departments performing more or less frequent

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History of epilepsy surgery in the Middle- and East-European countries and Russia epileptosurgical operations (Prague, Brno, Hradec Králové, Plzen, ˇ and Olomouc). Modern techniques, including video-EEG studies and intracranial explorations, were introduced during the 1990s. The Homolka Center in Prague had been educated primarily in English-speaking countries, and subdural recordings were the dominant method of invasive explorations (62%). The Epilepsy Center Brno was based on the model of a French school using the stereo-EEG method when invasive intracranial detection was necessary (92%). A recent analysis of the surgical results of the two centers in 248 adult patients with post-surgical follow-up of at least two years displayed Engel I in 58.9%, Engel II in 15.5%, Engel III in 13.3%, and Engel IV and V in 11.3%.

Turkey2–6 Epilepsy surgery has a relatively long history in Turkey although a modern teamwork approach was started during 1990s. Prof. Kenan Tukel (Figure 11.1) who was a pupil of Penfield and Jasper in the Montreal Neurological Institute established the first EEG lab in the early 1950s in Istanbul University. However, the first case report related to epilepsy surgery was published from Hacettepe University Medical Faculty, Ankara in 1960 by V. Turkmen and A. Erbengi. It was about a patient with infantile hemiplegia operated by hemispherectomy. The first electrocorticography (ECoG) during surgery was applied again in the same hospital in 1965 where epilepsy surgery gained speed with the efforts of O. Kalabay and V. Bertan from the departments of neurology and neurosurgery. In 1986, A. Erdem performed extratemporal cortical

Figure 11.1

99

resections guided by ECoG in Ankara University. After being trained by G. Yasargil in Zurich, A. Erdem in Ankara and later E. Ozyurt in Istanbul introduced selective amygdalohippocampectomy in the early 1990s. Epilepsy surgery teams working in a multidiciplinary fashion were established in 1993 in Hacettepe and 1995 in Cerrahpasa Medical faculties and have continued since then with addition of different centers including Gazi University, Istanbul Medical Faculty, Marmara University and others.

Estonia7–11 The founder of the national school of neurosurgery in Estonia was Professor Ludvig Puusepp (1875–1942) who operated 318 epileptic patients during 1901–1920. Thereafter, the summary of operations in 1921–1930 (1–5 cases per year) were published. During the following years the number of operations have fallen dramatically, primarily due to effective medical treatment. In Tartu, EEG has been available since 1961, intraoperative electrocorticography (ECoG) since 1967, computerized tomography scanning since 1983, and magnetic resonance imaging since 1992. In 1996, the measurement of AED concentration just became available for routine use. Long-term video-EEG has been available in Tartu since 2003. In recent years all patients for epilepsy surgery were investigated in long-term video-EEG (only scalp-electrodes). An average of two patients per year has been operated, all typical MRI-positive hippocampal temporal lobe epilepsies. ECoG was performed in 50% of the cases.

Dr. Kenan Tükel as a member of the Montreal team in 1952.

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Latvia12–17 Episodical epilepsy surgery in the case of symptomatic disease (mainly tumors) in the territory of Latvia was performed at the beginning of the 20th century (A. von Bergmann, P. Klemm, L. Bornhoupt, E. von Schwartz in Riga’s 1st Hospital). During the 1920s and 1930s neurosurgical operations in 3 hospitals in Riga were performed by general surgeons (V. Minz, J. Jankovsky, P. Mucenieks, A. Udre, P. Stradins, K. Dolietis et al.), and in rare cases neurosurgical operations were made for cerebral disease with epilepsy. In the year 1939, K. Dolietis became the first certified neurosurgeon in Latvia and operated several patients with symptomatic epilepsy. At the end of the World War II, K. Dolietis emigrated to Sweden. Development of neurosurgery continued in Riga’s 1st Hospital; in 1946, the Clinic of Neurology and Neurosurgery was opened (A. Liepukalns and K. Arajs). In 1969 I. Purins organized the Neurosurgical Center on the basis of P. Stradin’s Clinical Hospital in Riga. Soon after that T. Apinis and Z. Grinbergs, doctors of this hospital, made the first steps to specialized epilepsy surgery after practices in the clinics of Moscow and Leningrad. The main method for epilepsy surgery was temporal lobectomy. Sometimes intraoperative cerebral surface electrodes were used for more precise diagnosis of the lesion locus. Other types of operations were frontal lobotomies, gyrotomies, callosotomies; some hemispherectomies were also performed. Fifteen operations of intracranial superficial hypothermia in patients with epilepsy did not give any influence to the disease course. A total of 145 operations for epilepsy were registered in this hospital during the period from 1974 to 1988. Epilepsy surgery in other hospitals of Latvia at this time was not very significant. Recently epileptic patients were selected for surgery in two neurosurgical departments of Riga: in the Clinical Hospital ‘Gailezers’ and in the P. Stradin’s University Hospital. The surgery for symptomatic epilepsy due to cerebral tumors, dysplasias, heterotopias, mesial sclerosis etc. is accentuated; the number of operations of such type is approximately 20–30 per year. The new technologies (neuronavigation and invasive electrode techniques) are also used in the epilepsy surgery.

one who developed epilepsy surgery in Lithuania. Also, he was the founder and the president of the Society for Epileptology of Lithuania, which joined ILAE as a chapter in 1995. In 2001 the Neurosurgery Clinic was reorganized, and a specialized unit for cerebral surgery was established, with the Sector for – Zobakas. ˇ Epilepsy Surgery included and headed by Dr. Arunas The diagnostic method implanted depth electrodes was introduced in 1982, and the use of subdural electrodes for the localization of the epileptogenic focus in 1989. Sleep EEG and video-EEG for presurgical diagnostics have been introduced at Kaunas University Hospital since 2000. The development of comprehensive presurgical multidisciplinary evaluation is one of the strategic plans at Kaunas University Hospital for the near future.

Hungary18–21 Kálmán Sántha and István Környey, friends and legendary personalities in the Hungarian history of neurology contributed equally to establish neurosurgery in the 1930s in Szeged and later in the 1940s in Pécs and Debrecen. István Környei was educated in Boston and Ann Arbor, Kálmán Sántha (Figure 11.2) in Montreal by W. Penfield, supported by the Rockefeller fellowship. Sántha, together with Cipriani, was the first to provided evidence that during an epileptic seizure it was not vasoconstriction (as was stated in the theory of Mayer) but just the opposite procedure, an important elevation in blood flow, that occured (Sántha, Cipriani, and Penfield 1938) (Figure 11.3). This work should be held as a first move toward the contemporary development of the ictal SPECT method. The first decisive steps of Hungarian epilepsy surgery were taken by J. Hullay in Debrecen, a pupil of Sántha, who reported on 50 temporal lobectomies as early as 1958.18,19 Later in the 1970s in the same institution (Department of Neurology, Medical University of

Lithuania The first specialized neurosurgery unit in Lithuania was established in 1951 at Kaunas Clinical Hospital (Kaunas University Hospital at present). The start of epilepsy surgery took place in 1974 when the first temporal lobe resection was performed by doctors Henrikas Juozakas and Vytautas Paˇskauskas. Since 1976 subpial cortical suction, and since 1978 stereotactic hippocampo-amygdalotomy have been introduced, the latter also being performed nowadays. The stereotactic method for epilepsy surgery has been introduced and is still being develˇ skis. In 1980 the Neurosurgery oped by docent Juozas Sidiˇ Clinic was established in Kaunas, with six specialized neurosurgery units. The Unit of Functional Surgery was a specialized unit for epilepsy surgery and microneurosurgery, with Professor Egidijus Jarûemskas as the Head until 1998, and Dr. Jonas Gel–unas until 2001. Professor E. Jarˇzemskas was the

Figure 11.2

Prof. Dr. Kálmán Sántha.

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History of epilepsy surgery in the Middle- and East-European countries and Russia

(a) Figure 11.3

(b)

Registration of blood flow changes during experimental and human epileptic seizures. Sántha and Cipriani MNI, 1938.

3%

6%

22%

15%

20%

35%

9%

6%

1. Year (N=75)

5. Year (N=33)

2. Year (N=64) 41%

68%

75% seizure freeñ with medication

seizure freeñ without medication 12%

16%

8%

Not improved

NEG

TUMOR

Etiology 33% 24%

improved

HS

7%

DYSGENESIS CAVERNOMA others

Figure 11.4

101

Surgical results, TS, TLE (1989-2001) National Institute of Psychiatry and Neurology.

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Debrecen) within the framework of the epilepsy surgery program, invasive presurgical monitoring with the Bancaud–Tailerach stereotactic methods was carried out on several patients.20 The new wave of modern epilepsy surgery was started in the 1990s with the foundation of a ‘Co-operative epilepsy surgery program’ in which under the leadership of the National Institute of Psychiatry and Neurology, Epilepsy Center, several neurological institutions, and the National Institution of Neurosurgery participated including the Bethesda Children Hospital where a video-EEG monitoring unit has been working since 1997.21 The number of patients involved and operated using the presurgical protocol is 20–30 yearly. The overwhelming majority of surgical interventions are partial temporal lobectomies in therapy resistant MTLE syndrome, but a few extratemporal surgeries are done yearly

with invasive presurgical evaluation by subdural strips and grids. Results of temporal lobe surgery are illustrated in the Figure 11.4. In 2005 a new epilepsy surgery program was started in Pécs in the Neurological Clinic of the Medical University.

Acknowledgments I am really grateful to Prof. Alla Guekht (Russia), Prof Jerzy Bidzinski (Poland), Prof. Pavel Mares and Prof. Ivan Rektor (Czech Republic), Dr. V. Ciobotaru (Romania), Prof. Cigdem Özkara (Turkey), Prof. Milda Endziniene and Dr. Arunas Zobakas (Lithuania), and Dr. André Öun (Estonia), for providing essential information not easily obtainable / elsewhere.

REFERENCES 1. 2. 3. 4. 5. 6.

7. 8. 9.

10.

Bidzinski J. Historia operacyjnego leczenia padaczki w Polsce (History of surgical treatment of epilepsy in Poland) Neurol. Neurochir. Pol. 1998: Suppl. 2:19–23. Türkmen V, Erbengi A. An infantile hemiplegia case presentation and hemispherectomy. Turkish Journal of Pediatrics 1960;3(3):135–139. Avman N, Erbengi A, Kalabay O. Role of electrocorticography in surgery of focal epilepsies. Çocuk Saˇgliˇgi ve Hastaliklari Dergisi (Journal of Paediatrics) Turkish 1965;8(1):26–35. Erdem A, Yasargil G, Roth P. Microsurgical anatomy of the hippocampal arteries. J Neurosurg 1993;79(2):256–65. Bertan V, Tahta K, Saygi S. Results of surgical intervention in patients with drug-resistant epilepsy. E.A.N.S Winter Meeting, Feb 17–19, 1994. Özkara Ç, Ozyurt E, Hanoglu L, Eskazan E, Dervent A, Kocer N, Ozmen M, Onat F, Oz B, Kuday C. Surgical outcome of epilepsy patients evaluated with a noninvasive protocol. Epilepsia 2000;41: S4:41–4. Puusepp L. Treatment of epilepsy. (in Estonian). Eesti Arst 1922;8/9: 403–10. Puusepp L. Treatment of epilepsy. (in Estonian). Eesti Arst 1922;10: 464–9. Perk J. Surgical treatment of neurological diseases during 1921–1930 in the department of neurology, Tartu University (in Estonian). Folia Neuropathologica Estoniana 1931;9:108–13. In the after-war period, 1945–1966, the number of operation increased to 12–38 per year. Raudam E, Paimre R. Development of neurology and neurosurgery in Tartu (in Estonian). Tartu Vabariikliku Kliinilise Haigla

11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.

konverentside materjale Proceedings of the conference, Tartu 1969;1:195–211. Õun A, Eelmäe J Epilepsy surgery in Tartu 1991–2000. Proceedings of the III Baltic Congress of Neurosurgeons, Tartu. Tartu, 2000. The text of the poster is attached to the mail. Derums VJ, New Dates about Trepanations in Latvia at Middle Ages. From the History of Medicine, Riga, 1984:52–53 (in Russian). Landa BF, Dubinsky MB. About History of Surgery in Riga’s City Hospital. Works of Riga’s 1st Hospital, Riga, 1957:63–76 (in Russian) Viksna A. Adolf von Bergmann and surgery in Riga. Latvijas Arsts, Riga, 1994;8:678–680 (in Latvian). Apinis T, Neurosurgery in Stradin’s Hospital through Ages. Stradin’s Hospital Works, Riga, 2000:70–75 (in Latvian). Sverzickis R, Aksiks I, Valeinis E, Pukitis E, Dzelzite S, Migals A, Otisone I, Bluma I, Plotniece R. Stereotactic neurosurgery: practice and possibilities. Arstu Zurnals, 2003:5/6:32–38 (in Latvian). Apinis T. Personal communication, 2006. Hullay J. Results of 50 surgically treated temporal epileptic patients. Acta Neurochir (Wien).1958;6(3):169–74. Kajtor F, Hullay J, Farago L, Haberland K. Electrical activity of the hippocampus of patients with temporal lobe epilepsy. AMA Arch Neurol Psychiatry. 1958 Jul;80(1):25–38. Hullay J, Gombi R, Velok G. Effects of stereotactic lesions in intractable epilepsy. Acta Neurochir (Wien).1976;(23 Suppl):205–9. Balogh A, Borbély K, Czirják S, Halász P, Juhos V, Kenéz J, Vajda J. Tapasztalataink a temporális epilepsziás betegek mütéti kezeléséveltöbbközpont–u vizsgálat. Clinical Neurosci/Ideggyógyászati Szemle 1997;50(7–8):221–32.

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Epilepsy surgery in Canada W Feindel

The Montreal School From 1934, Wilder Penfield with his surgical partner William Cone, their associates and many successors, developed at the Montreal Neurological Institute a center that became known world-wide for its systematic surgical treatment, research and teaching related to epilepsy (Figure 12.1).1–6 Following Victor Horsley’s pioneer efforts,7 many surgeons in North America ventured to operate on patients suffering from seizures related mostly to cerebral trauma or tumors.8,9 But their reports were often a litany of failures. Harvey Cushing had treated patients with seizures by surgery under local anesthesia and was the first to report mapping by electrical stimulation of the sensory cortex.10 But Cushing centered his main interest on brain tumors, noting in 1932 to Wilder Penfield his former student, at all events, you can see that I, too, just thirty years ago was extirpating a cortex for epilepsy. If I had the industry and ability that you and Foerster combine, I might have gone ahead with it and made something of it. But I soon dropped it for things I thought I could do better.11 While at Columbia-Presbyterian Hospital in New York, in the 1920s, Penfield had taken a special interest in the problem of how a wounded brain heals, hoping that a better understanding would lead to improvement in excision of brain lesions, such as the post-traumatic scars associated with epilepsy.5,11 He pursued this interest by going to Madrid in 1924, where he studied with Ramon y Cajàl’s brilliant student Pio del Rìo-Hortega the role of neuroglia and microglia in brain healing, tumors and inflammation.12 As the first English speaking pupil of the Cajal school of neurohistology, Penfield returned to New York and applied his unique expertise to neurosurgical problems, and especially to epilepsy. Then in 1928 during his transition between New York and taking up neurosurgical practice in Montreal, he spent six months with Otfrid Foerster in Breslau. Here he learned the technique of electrical stimulation of the cortex with the patient awake under local anesthesia. He also took advantage of his familiarity with the Spanish methods to study the histology of the meningo-cerebral cicatrix in a dozen patients, mostly with head injuries, upon whom Foerster had operated for seizures.13 In September 1928, Penfield arrived in Montreal on the invitation of Edward Archibald to take over his neurosurgical practice at the Royal Victoria Hospital associated with

McGill University. Archibald had been a student in 1906 of Sir Victor Horsley and Sir William Gowers at the National Hospital, Queen Square, and thus became the first surgeon in Canada to focus on neurosurgery. In 1908, he published the 375-page monograph on ‘Surgical Affections and Wounds of the Head’ in Bryant and Buck’s American Practice of Surgery.90 It was the same year that Harvey Cushing’s extensive review of 259 pages on neurosurgery appeared in Keen’s Surgery: Its Principles and Practice.91 But Archibald began to take greater interest in thoracic surgery, in which he would become one of the American leaders. He also turned to the problem of post-graduate surgical education and directed his influence to establishing the American Board of Surgery. Earlier at McGill University, William Osler was a keen protagonist for the emerging specialty of neurosurgery. From 1869 to 1884 he performed a thousand autopsies at the Montreal General Hospital. Among these, he reported many examples of neurological disorders, including epilepsy.14,15 In commenting on the first operation for a brain tumor performed by Rickman Godlee in 1884 at London, Osler compared his own case where a post-mortem examination in 1883 disclosed a small glioma in the leg center of the cortex. This had caused Jacksonian seizures for twelve years, eventually ending in a fatal bout of status epilepticus: ‘an instance’, Osler wrote, ‘in which operation would have been justifiable and possibly have been the means of saving life’.16 Osler’s spirited humanism and his positive attitude toward brain surgery influenced the field of neurosurgery through his friendships with both Harvey Cushing and Wilder Penfield.17,18

The Royal Victoria Hospital, Montreal (1928–1934) In November 1928, two months after Penfield moved with his surgical partner William Cone from New York to Montreal, he performed his first operation at the Royal Victoria Hospital for focal epilepsy. (Figure 12.1) The young patient (RM) had fallen from a horse ten years earlier when he required surgery for a right-sided subdural hematoma and brain contusion. He developed seizures with increasing frequency, from 5 to 20 a day. Eventually, this complex post-traumatic epileptogenic lesion required three operations to control these intractable seizures. At the first procedure, a small area of cortex was

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The Montreal Neurological Institute

Figure 12.1 Wilder Penfield (left) and William Cone, the neurosurgical partners, at the Royal Victoria Hospital, 1932.

excised near the motor strip that was defined by stimulation. The attacks continued. A second exploratory craniotomy followed a few months later to expose the frontal lobe on the opposite side; no abnormalities were found so no removal of any sort was made. For the third and final operation, three years later, Stanley Cobb and William Lennox came from Boston as consultants. Cobb’s sketch and Penfield’s comments (in bold letters) show the sites of the stimulation responses and delineates the thin scarred cortex of the temporal area that was widely resected (Figure 12.2). Penfield referred to this as his first temporal lobectomy for seizures. He had applied stimulation and excision techniques learned in Foerster’s clinic at Breslau (Foerster and Penfield, 1930b) In the first few years after operation, the patient had a greatly reduced number of seizures. After starting dilantin in 1939, his attacks numbered four in the next 13 years.20 In 1930, Penfield listed the neurosurgical cases for the preceding two years at the Royal Victoria Hospital. Among the 325 operations carried out by him and William Cone, there were fourteen examples of surgery for focal epilepsy. The successful transfer to Montreal of the laboratory of neurocytology, which they had started in New York, was already attracting students from the United States and abroad. During this period Penfield edited for publication a three volume multi-authored work destined to become a neurological classic, Cytology and Cellular Pathology of the Nervous System.21

After a refusal and several delays, the Rockefeller Foundation responded in 1932 to the proposal of Wilder Penfield and McGill University for a Neurological Institute ‘to provide,’ Penfield hoped, ‘a center for neurological thought that would serve the whole continent.’ He envisaged clinical neurology and neurosurgery carried on in the same building that contained laboratories for research in neuropathology, neurophysiology and the anatomy and psychology relating to the nervous system.22 The Montreal Neurological Institute (MNI) opened its doors in 1934. An interesting hybrid, it was unique in its time, a 50-bed hospital for patients with neurological disorders, combined with a research center for the scientific study of the nervous system and a teaching Department of Neurology and Neurosurgery for McGill University. With the provision of endowment by the Rockefeller Foundation of $1,000,000, further support garnered from generous citizens in Montreal as well as ongoing pledges by the City and Provincial governments for hospital support, the stage was set and the actors were in place to carry out Penfield’s master plan.5,20,23 Penfield and his surgical partner, William Cone, expanded their studies on the histopathology of brain scars and brain tumors with an enthusiastic and ever growing team of young assistants. They made persistent efforts to treat intractable epilepsy caused by trauma or tumors, applying the Foerster technique to score some brilliant successes. At multidisciplinarian weekly conferences, seizure patterns of patients were scrutinized in great detail, catalogued, and matched with the type and location of the lesions predicted by X-ray and EEG and as revealed and photographed at operation. Meticulous analysis of hundreds of stimulation points were plotted out to constitute brain maps of the sensory and motor areas that gave more detail than the earlier maps published by Horsley, Foerster, Krause, and Cushing.24,25 These findings extended eventually to the definition of speech areas26 and to the complex problem of how the brain remembers.27,28,29 Maximal removals of frontal tumors and scars causing epilepsy resulted in surprising retention of intellectual functioning in the patients as determined by.29,30 Hebb’s studies on Penfield’s patients also activated the field of clinical neuropsychology which at the MNI over many years has been of critical importance for the pre- and post-operative evaluation of patients.31 Cortical stimulation: the homunculus In 1937, Penfield with Edwin Boldrey reviewed 163 patients, who were operated upon under local anesthesia and in whom the motor-sensory responses to cortical stimulation were carefully plotted. These composite stimulation maps became familiar in the numerous publications from Penfield and his team over the years. Their report marked also the first appearance of the ‘homunculus’ (Figure 12.3) who would later appear in several guises (Figure 12.4) to highlight the cortical localization subserving anatomical regions of the body (Penfield and Rasmussen, 1950; Penfield and Jasper, 1954).

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Figure 12.2 Penfield’s sketch and notes during the operation on patient R.M. The brain is upside down as viewed by the surgeon, with the frontal lobe to the left. Two excisions, outlined by dashed lines, include a small area in front of the motor cortex (1A) and a much larger resection of the temporal lobe shown in the upper part of the sketch. Penfield’s notes are in bold script; the notes in finer lettering and possibly some of the details of the sketch are in Stanley Cobb’s hand.

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ttl

g in R dle x id de M In mb u Th eck N ow Br all b eye d n e a d Fac li Eye Lips

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Figure 12.4 A later version of the homunculus, with reference to the representation in the motor cortex, from the studies of Penfield and Rasmussen in 1948.

Figure 12.3 Homunculus appearing first in the article by Penfield and Boldrey in 1937, to illustrate the relative size of body parts represented on the motor cortex as defined by electrical stimulation at operation.

Herbert Jasper and the advent of electroencephalography A chance encounter at Brown University in 1937 led Penfield to bring Herbert Jasper to Montreal to apply the new techniques of electroencephalography (EEG) and electrocorticography (ECG). Jasper with Carmichael in 193593 had reported on the application of Berger’s new technique of EEG, in the same year that the Boston group led by Gibbs had noted its value in epilepsy.32 EEG refined the task of localizing the site of origin of seizure discharge by recording spikes and sharp waves that were pathognomonic for epilepsy.33 This greatly improved the selection of patients with focal seizures for surgical treatment. ECG mapped the localization of seizure activity during surgery by recording directly from the cortex and by monitoring stimulation responses. The application of the new technology to epilepsy resulted in a long series of clinical studies by Penfield, Jasper and their associates. Jasper’s background in psychology and

electrophysiology also generated at the MNI an expansion in neurophysiological research which over the years elucidated the complex mechanism of epilepsy and sharpened the criteria for surgical treatment.34 Jasper’s chapter in the monograph by Penfield and Erickson of 1941 on Epilepsy and Cerebral Localization provided the first comprehensive review of the use of EEG and corticography in the diagnosis and surgical treatment of epilepsy.94 Numerous monographs and publications by Penfield with his associates, Jasper, Kristiansen, Rasmussen and a long list of neurosurgical Fellows, continued to document from 1934 to 1950 much detailed evidence for the successful surgical treatment of focal epilepsy at the MNI.20

Surgery for temporal lobe seizures The anterior and lateral temporal cortex The emergence at the MNI in the early 1950s of surgery for seizures related to the temporal lobe opened a new era for what has now become the most frequent surgical approach for the surgical treatment of epilepsy. There were several phases in the development of such surgery, each distinguished by a substantial increase in knowledge about the pathophysiology of seizures arising from the temporal lobe. Penfield and Flanigin35 reviewed 68 temporal lobe operations carried out over the decade from 1939 to 1949, which had arrested or controlled seizures in over one-half of the patients. The resections in this series were limited mainly to the anterolateral temporal cortex; in only 10 cases was the uncus removed and in only two was a part of the hippocampus also removed. Bailey and Gibbs36 in the meantime performed antero-lateral cortical removal in a series of patients, with no encroachment on

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Epilepsy surgery in Canada mesial temporal structures because Bailey was aware of the severe behavioral deficits in monkeys after bilateral mesial temporal ablations as reported by Klüver and Bucy92 beginning in 1939.37 This limited anterolateral approach was also supported by the pre-operative localization offered by EEG, either antero-lateral temporal, anterior Sylvian, or fronto-temporal.38 Related experimental studies at the MNI were thus directed to clarify the connections of the temporal pole.39,40 This is also well illustrated by similar anterolateral temporal localization of ECG foci registered by Jasper and two young neurosurgeons41 in 39 of the same series of patients reported by Penfield and Flanigin in 1950. In only a few patients was ECG abnormality detected in the inferior and mesial part of the temporal lobe. (Figure 12.5). The mesial temporal region The success rate of just over 50% in the two major surgical series, reported from Montreal by Penfield and Flanigin35 and from Chicago by Bailey and Gibbs36 indicated that resection limited to the antero-lateral temporal cortex did not eliminate all the epileptogenic tissue in many patients. Indeed in some cases persistent seizures led Penfield to persevere and carry out a second operation. In these, he extended the resection, under electrocorticographic control, sometimes posteriorly along the lateral temporal cortex (if on the nondominant side for speech) and also included more of the uncus and hippocampus.20

ECG foci in group I 18 cases

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A second phase in the surgical approach to temporal lobe seizures unfolded rapidly in the early 1950s. Clues from experimental animal studies by Gastaut et al.42 and Kaada43 and from stimulation at operation44,45 pointed to the mesial and inferior surfaces of the temporal lobe for the origin of the epileptic attack. Penfield noted instances where stimulation in the uncinate region produced auras of the patients’ attacks. In one such instance, a seizure with automatism was recorded consisting of low voltage fast activity followed by 3 per second waves to spread from the stimulation point to involve a wide region of the temporal cortex. (Figure 12.6). These findings led Penfield in this case to extend his resection to include the mesial temporal region. Stimulation responses from the claustro-amygdaloid complex The most convincing evidence that the mesial temporal region was a crucial zone for the generation of temporal lobe seizures came in a third phase of surgical studies. This was the reproduction of the patient’s habitual auras and other typical features of these attacks by anatomically directed depth stimulation or stimulation under direct vision at operation within and around the amygdala involving also the ventral claustrum and the anterior insula.46 The resulting seizure discharges on corticography were seen to spread rapidly to encompass not only the temporal cortex but the exposed frontal parietal cortex. In 1951, the surgical findings in the first patient in this series, initiated convincing evidence for the role of the amygdaloid region in temporal lobe seizures.27

Lesions in group I 14 cases

A

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8 7

Figure 12.5 Localization of ECG foci and lesions reported by Jasper, Pertuiset, and Flanigan in 39 patients operated upon for temporal lobe seizures by Penfield. The maximum changes, areas indicated in black, involve mainly the antero-lateral cortex of the temporal lobe.

Case report Patient P.S., Age 26 He had a difficult birth and, from the age of 12, attacks which began with a vision of colored lights, a ‘shock in the head’, after which he became unresponsive, fumbled with his clothes and would later have no memory of his actions during this period. Pre-operative EEG study showed abnormal spike activity over the lateral and inferior temporal regions on the right side. At operation, a depth electrode was directed through the second temporal convolution 3.5 cm from the tip of the temporal lobe toward the region of the amygdala. One of his typical small attacks was produced with the electrode tip deep in temporalinsular sulcus, with electrodes recording from the lateral and inferior surface of the temporal lobe (Figure 12.7). Epileptic spikes were suddenly replaced by low voltage rapid activity, the patient was seen to stare and become unresponsive to questioning, while he plucked at the anaesthesist’s coat and made chewing movements. His appearance was much like that seen in his habitual attacks. The electrographic changes lasted a minute and a half, at which time the patient appeared to have recovered, but seemed unaware of the attack (Figure 14.7). There was smallness and toughness of the first temporal convolution and mesial temporal region, as well as a zone of gelatinoid tissue about the size of a small walnut deep in the temporal lobe, lateral and inferior to the ventricle and encroaching on the amygdala. Microscopically, this showed dense astrocytic gliosis. On later review, the neuropathologist interpreted this as a grade I astrocytoma. Resection included

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Figure 12.6 ECG recording at operation by Penfield. After stimulation of the uncinate region, a seizure discharge was recorded from a wide area of the inferior temporal cortex.4,41

6 cm. of antero-lateral cortex, as well as the mesial temporal region (amygdala; hippocampus) harboring the lesion. The patient continued free of attacks for 37 years later, with no reappearance of the tumor. The role of the claustro-amygdaloid complex In 15 other patients from that same study, similar features of automatism and amnesia were reproduced by stimulation in the peri-amygdaloid region (Figure 12.8). This first examination of stimulation and electrographic responses from the human amygdala demonstrated its role in visceral responses such as fear and its critical relation to recent memory.46 It was noted that these findings corresponded to the localization for ‘a particular variety of epilepsy’ that had been proposed by Hughlings Jackson and others, just before the turn of the century: the discharge-lesions in these cases are made up of some cells, not of the uncinate gyrus alone, but of some cells of different parts of a region of which this gyrus is part – a very vague circumscription, I admit – the uncinate region.47 The rich network of connectivity subtended by the amygdala offered a valid explanation for many of the characteristic clinical features of ‘uncinate’ attacks described by Jackson.27 Thus, the patient’s epigastric aura, sometimes associated with a sense of fear, was reproduced from stimulation either of the amygdala itself or of the adjacent anterior insular cortex, which would later be shown to be physiologically associated with gastric movement.48 The various emotional, autonomic, and visceral responses likewise seemed explicable because of

the robust anatomical pathways then known from the amygdala to the septal and hypothalamic regions. The initial feature of brief tonic movement with some temporal lobe attacks could be effected by the amygdaline efferent pathways to the striatum; chewing and swallowing movements could be explained by connections with the brain stem. The interference of the epileptic discharge with memory recording, characterized by the profound postictal amnesia, could reasonably be related, it was proposed, to the amygdala–hippocampal connection as well as the projection of the amygdala to the reticular system of the brain stem.49 Curiously, stimulation of the hippocampus directly at operation in the Montreal experience rarely produced such responses, even though epileptic abnormality might sometimes be recorded from the anterior part of the structure.50 Thus, this evidence indicated that the amygdala and the juxtaposed gray matter, including the ventral claustrum and the anterior insular cortex, could generate temporal lobe seizures; this provided a physiological hypothesis that explained for the first time many of the clinical aspects of these attacks (Figure 12.9a, b). It also indicated that the periamygdaloid zone should be removed in the surgical resection in order to produce the most beneficial outcome. This critical role of the peri-amygdaloid region in mesial temporal seizures became confirmed in many later studies, as summarized for example in the monograph by Gloor in 1997.51 Incisural sclerosis The pathological counterpart of this physiological hypothesis was offered in a concurrent study by Earle, Baldwin, and Penfield in 1953.52 They introduced the concept of incisural

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Figure 12.7 (a) Brain drawing to show electrode positions (in numbered circles) and depth stimulation in the amygdaloid region (black circles) from patient P.S.27 (b) ECG showing rapid low-voltage activity from the temporal lobe and then return of the prestimulation spike activity. The patient had automatism and amnesia for the episode. Compare with Figure 14.6.27

sclerosis, which they postulated was due to herniation of the mesial part of the temporal lobe over the tentorial edge associated with increased intracranial pressure during a difficult birth (Figure 12.10). They considered this to cause injury to the hippocampal region, both by direct compression of the tissue and by arterial and venous vascular compression with resulting ischemia. Although they did not emphasize this, the uncus with the contiguous amygdala and entorhinal cortex are even more likely to herniate into the prepeduncular space and to be subject to compressive damage.

Application of the Montreal procedure Based on these new findings from stimulation results and pathological studies, a radically different surgical approach was developed, with excision not only of the

anterolateral cortex, but also removal under direct vision of the mesial part of the temporal lobe to include the amygdala, hippocampus and entorhinal cortex. Details of this operative technique were first described by Penfield and Baldwin in 195253 (Figure 12.11) and revised in 1961 by Penfield et al.54 With the application of this approach, successful surgical outcome improved from 50% to 65%. From 1953 onward, many neurosurgical centers, often involving surgeons and scientists who had studied at The Montreal Neurological Institute, took up the procedure of temporal lobe resection for the treatment of seizures. A colloquium on advances in the surgical treatment of temporal lobe epilepsy, organized by Gastaut and his associates in Marseilles in 1954, gave an opportunity for Penfield to provide an overview of the early experimental and surgical results of his team, which firmly established the important role of the mesial temporal region in the pathogenesis and surgical treatment.55 The extensive monograph of 1954 by Penfield

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Insula and brain stem removed

INSULA REFLECTED POSTERIORLY

AMYGDALOID NUCLEUS

Figure 12.8 Sites of stimulation from 16 operations that produced features of temporal lobe seizures such as epigastric area, fear, memory disturbance, automatism and amnesia.

and Jasper reviewed this Montreal experience.(Figure 12.12) A second colloquium sponsored by Maitland Baldwin and Pearce Bailey56 in 1958 at the National Institutes of Health, USA, extended and confirmed the significance of subtotal temporal lobectomy, including particularly the mesial temporal structures, for treating temporal lobe seizures.57 Memory deficit with bilateral temporal lesions Scoville and his group at Hartford44 had also produced stimulation responses from the uncus which resembled some features

(a)

of temporal lobe seizures. This induced him to carry out bilateral resection of the mesial temporal region by a subfrontal approach in a few patients with epilepsy. One of these patients, H.M., who has since become noteworthy in the annals of neuropsychology, developed a severe deficit in recent memory.58 This was similar to the syndrome that had been reported earlier by Milner and Penfield28 from the MNI series, in three patients after unilateral temporal excision in the presence of what later became recognized as bitemporal mesial temporal pathology, especially involving the hippocampus.59,60 These findings, together with the initial observation by Feindel and Penfield27 that stimulation of the amygdala evoked ictal amnesia, directed attention to the important role of the mesial temporal structures in memory mechanisms.28 Toward a surgical cure The surgery of focal temporal seizures, augmented by many contributions, has become one of the most successful therapeutic measures in modern neurosurgery.61,62 Many thousands of patients have had the benefit of such surgery. The patterning of the surgical resection in order to obtain the most satisfactory surgical outcome and at the same time to minimize neurological deficit continues to be examined currently in over 100 neurosurgical centers.23,62 A vast literature has now become available on the anatomy, physiology, pathology, and cognitive aspects of the temporal lobe.63–68 Gloor summarized this field in 1997 in his masterly monograph on the temporal lobe and limbic system.51 The developments in EEG such as sphenoidal recordings and computerized-video monitoring greatly enhanced the pre-operative localization of the epileptogenic region.69 The increasing use of detailed neuropsychological evaluation by Milner and her associates and the application of the intracarotid amytal test developed by Wada and Rasmussen for defining lateralization of speech and memory function proved to be invaluable adjuncts.28,69,70

(b)

Figure 12.9 (a) Enlarged view of the claustro-amygdaloid complex which shows the Sylvian fissure (SF), claustrum (CL), anterior commissure (AC), globus pallidum (GP), centro-medial and baso-lateral nuclei of the amygdala (C-M, B-L) hippocampus (H), ventricle (V), and collateral fissure (C-F).27 (b) A more anterior coronal section shows the Sylvian fissure (SF) and grey matter of the ventral claustrum (VCL). This section relates to the site of the depth stimulation.27

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Ant. choroidal a Post. cerebral a.

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Figure 12.12 Wilder Penfield (seated), and Herbert Jasper photographed in 1954 on the publication of their monograph, Epilepsy and the Functional Anatomy of the Human Brain.

Figure 12.10 Drawing to show the region of sclerosis and the mesial blood vessels involved in tentorial herniation of the uncinate region, for example, during abnormal birth.52

Further surgical evidence from the MNI76 indicates that temporal corticectomy with radical resection of the amygdala and uncus but with minimal removal of the hippocampus can achieve an excellent surgical outcome in 65% of patients (Figure 12.13a) At the same time the relative sparing of the hippocampus reduces the possibility of deficit in memory function which had been assigned by Milner and others31,69 to varying degrees of damage to the hippocampal regions.

Surgical techniques have become refined and selection of patients for the surgical procedure has grown far more enlightened.71–73 Amygdalo-hippocampectomy introduced by Niemeyer in 195874 and adopted enthusiastically by Wieser and Yasargil in 1982,75 has yielded an excellent surgical outcome and may well prove on evidence to become the resection of choice in selected patients.72

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TEMPORAL LOBE SUPERIOR and MESIAL SURFACES

Figure 12.11 Drawing to show subtotal temporal lobectomy that includes the amygdala and up to 4 cm of the hippocampus as well as the antero-lateral temporal cortex, as described by Penfield and Baldwin in 1952.53 This operation became widely adopted.

Figure 12.13 (a) Anatomical dissection of the temporal lobe to show cortico-amygdalectomy (hatched line on the left) compared to cortico-amygdalo-hippocampectomy (hatched line on the right).76 (b) Post-operative MRI to show radical excision of the amygdala and minimal removal of the hippocampus.9

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The acquisition at the MNI of magnetic resonance imaging (MRI) in 1985 gave a significant new dimension to the selection of patients for operation by identifying small structural lesions in the temporal lobe in more than 25% of patient and also the presence in another 30% of patients of mesial temporal sclerosis involving the hippocampus and later demonstrated also to include the amygdala and entorhinal cortex.73,77,78 MRI also provided the sine qua non for monitoring the exact anatomical extent of the surgical resection to compare with the type of surgical outcome reported from different centers.20 In the span of fifty years covered by this review, the effective control of temporal lobe seizures by surgical treatment has thus improved from 50% to almost 90%, with minimal morbidity and mortality.71,79 The role of mesial temporal sclerosis in the pathogenesis of temporal lobe seizures is now widely recognized.68 The significance of the amygdalo-hippocampal region in the physiopathology has been well substantiated from many stimulation studies,80,81 and by greater detail available on the anatomy and pathology of these structures.82–84 Marked improvement based on limited excision of the hippocampus but radical resection of the amygdala and minimal cortical ablation has been achieved in the surgical cure of temporal lobe seizures.76

Contributions from the Toronto school Kenneth McKenzie trained with Harvey Cushing at Boston in 1923 and returned to establish the first neurosurgical unit in Toronto in 1924.15,85 He performed the first hemispherectomy for seizures in 1936. He reported the case in 1938 at a meeting of the American Medical Association. The patient, a 16-year-old woman, had seizures from infancy and progressive hemiplegia. After operation she was seizure-free and lived with her family for another 23 years. McKenzie’s experience antedated by 14 years the series of 12 patients with seizures treated by hemispherectomy by R.A. Krynau and published in 1950. McKenzie never published his case but the patient was studied and reported by Williams and Scott86 in 1939 in relation to autonomic responses following hemidecortication. At the Sick Children’s Hospital in Toronto, Stobo Pritchard established a comprehensive neurological clinic for childhood epilepsy. On his foundation the pediatric neurosurgeons of the Toronto school, especially Harold Hoffman, developed an active center for surgical treatment of epilepsy in the 1970s.

Epilepsy program at London, Ontario In 1977 Warren Blume, a neurologist and epileptologist, and John Girvin, a neurosurgeon and neurophysiologist, both trained at the MNI and McGill, established an Epilepsy Unit, coordinating a multidisciplinary team of health care professionals. Although somewhat in the shadow of the illustrious team led by Drake, Barnett, Ferguson, and Peerless, who were world-leaders in the cerebrovascular field, the Epilepsy Unit developed successfully over the next two decades. A convincing milestone in the long record of evidence for the effectiveness of surgery for temporal lobe epilepsy was reported by the London group from an ingen-ious randomized trial comparing medical treatment with surgical treatment at this unit from July 1996 to August 2000.87 From a study of 80 patients

divided into two groups, they found that 64% of the 36 patients operated upon by temporal lobe resection were free of seizures compared to 8% in the group assigned to medical treatment, an eight-fold benefit. The pre-operative investigation and selection for surgery in this London project evidently followed the same lines as those practiced for many years at the Montreal Neurological Institute. The pattern of surgical excision, based on the procedure introduced by the Montreal group in the 1950s,53 included the antero-lateral temporal cortex and the mesial structures, especially the amygdala and hippocampus.88 Thus the London study was another vindication of the successful results of surgery reported from the MNI over a period of 50 years and documented in extensive long-term follow-up studies by Rasmussen and many colleagues. These demonstrated a post-operative outcome of 65% of patients seizure-free and over 85% showing significant improvement in regard to seizure control.89

Other Canadian centers Neurological and neurosurgical trainees from the Montreal Neurological Institute and McGill introduced neurosurgical treament for epilepsy in many other Canadian cities, including Edmonton, Saskatoon, Vancouver, Calgary, Winnipeg, and Halifax. Returning to Montreal, the major neurosurgical unit at Notre-Dame Hospital affiliated with the University of Montreal and first established in 1947 by Claude Bertrand, who had trained with Penfield and Cone at the MNI, became a world center for functional neurosurgery. This included the operative treatment of epilepsy. Although many children with focal epilepsy had been treated over the years at the MNI by Penfield and his team, in the 1970s an active group dealing with childhood epilepsy was established through the efforts of Preston Robb, head of neurology, and Kathleen Metrakos in charge of EEG. José Montes after completing his training at the MNI developed one of the most active centers at the Montreal Children’s Hospital (MCH) for the surgical treatment of epilepsy in children.

Conclusion This historical outline highlights the contributions in Canada that enhanced our basic understanding of the surgical treatment of epilepsy. From 1934 to 1984 the MNI was headed by three successive Directors who were neurosurgeons with a persisting interest in epilepsy surgery (Figure 12.14). Trainees in neurosurgery, neurology, EEG, neurophysiology, neuropsychology and neuroimaging from the MNI have translated the benefits of surgical treatment throughout Canada and to many other countries around the world. In particular, many of the major centers for epilepsy surgery in the United States were established by MNI graduates. Since the early 1970s, the revolutionary advances in brain imaging have elucidated the pathological and neurochemical changes in epilepsy and also provided elegant three-dimensional visualization to the surgeon for pre-operative diagnosis, precise anatomical navigation during operation and exact monitoring of the surgical resection to correlate with clinical outcome.

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Figure 12.14 Successive neurosurgical directors of the MNI, from the left, Theodore Rasmussen, William Feindel, and Wilder Penfield who promoted research, teaching, and surgical treatment of epilepsy. Photograph taken in 1974 at the celebration of the 40th Anniversary of the MNI.

Acknowledgments This review reflects contributions over the past 60 years of my teachers and colleagues at the MNI as credited in the selected list of references. I appreciate the help of Helmut Bernhard, Department of Neurophotography for formatting the illustrations and thank Ann Watson and Linda Zegarelli for editorial assistance. The illustrations are reproduced from the Wilder

Penfield Archive and the Neuro Archives of the Montreal Neurological Institute. Research for this review was supported by the Class of Medicine McGill 1945 Wilder Penfield Archive Fund, the Thomas Willis Fund of the Montreal Neurological Institute, and by grants from the Donner Medical Foundation and Associated Medical Services, Inc. (through the Jason Hannah Institute for the History of Medicine), for the NeuroHistory Project, Montreal Neurological Institute.

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Cendes F, Andermann F, Gloor P, Feindel W. Relationship between a trophy of the amygdala and ictal fear in temporal lobe epilepsy. Brain 1994;117:739–46. Bernasconi A, Bernasconi N, Andermann F et al. Entothinal cortex in temporal lobe epilepsy: a quantative MRI study. Neurology 1999;52:1870–6. Yasargil MG, Teddy PJ, Roth R. Selective amygdalo-hippocampectomy. Operative anatomy and surgical technique. Adv Tech Stand Neurosurg 1985;12:93–123. Talairach J, David M, Tournoux P. l’Exploration Chirurgicale Stéréotaxique du Lobe Temporale dans l’Épilepsie Temporale. Repérage Anatomique Stéréotaxique et Technique Chirurgicale. Paris: Masson, 1958. Crandall PH. Historical trends: a conical spiral, in Apuzzo MLJ (ed): Neurosurgical Aspects of Epilepsy. Park Ridge, Ill: American Association of Neurological Surgeons, 1991;3–13. Mathieson G. Pathology of temporal lobe foci. Adv Neurol 1975;II:163–85. Pringle CE, Blume WT, Munoz DG, et al. Pathogenesis of mesial temporal sclerosis. Can J Neurol Sci 1993;20:184–93. Bruton CJ. The Neuropathology of Temporal Lobe Epilepsy. New York, NY: Oxford University Press, 1988. Morely TB. Kenneth George McKenzie and the Founding of Neurosurgery in Canada. Markham, ON: Fitzhenry and Whiteside, 2004.

86. 87. 88. 89. 90. 91. 92. 93. 94.

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Williams DJ, Scott JW, The functional responses of the sympathetic nervous system of man following hemidecortication. J Neurol Neurosurg Psychiat 1939;2(ns):313–21. Wiebe S, Blume WT, Girvin JP et al. A randomized, controlled trial of surgery for temporal-lobe epilepsy. New Engl J Med 2001;345:311–18. Girvin JP, Resection of intracranial lesions under local anesthesia. Int Anesthesiol Clin 1986;24:47–73. Rasmussen TB. Surgical treatment of complex partial seizures: results, lessons, and problems. Epilepsia 1983;24(suppl 1): S65–S76. Archibald E, Surgical affections and wounds of the head. In: Bryant JD, Buck AHT eds) American Practice of Surgery. New York: W. Wood & Co., 1908;4:3–378. Cushing H. Surgery of the head. In: Keen WW (ed): Surgery, its Principles and Practice. Philadelphia: WB Saunders Co., 1908;17–276. Klüver H, Bucy PC. Preliminary analysis of functions of the temporal lobes in monkeys. Arch Neurol Psychiat 1939;42:979–97. Jasper HH, Carmichael L. Electrical potentials from the intact human brain. Science 1935;81:51–3. Jasper HH, Electroencephalography. In: Penfield W, Erickson TC, eds. Epilepsy and Cerebral Localization. Springfield, IL: Charles C Thomas, 1941:380–454.

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A brief history of epilepsy surgery in the United States PJ Connolly, DD Spencer, and AA Cohen-Gadol

If I wished to show a student the difficulties of getting at the truth from clinical experience, I would give him The History of Epilepsy to read. Oliver Wendell Holmes1 The history of epilepsy treatment revolves around individuals who through their ingenuity and innovation have elucidated the understanding of epilepsy pathophysiology. In the following chapter, we will review some of the contributions of these key individuals from the United States of America.

responsible for epilepsy in the absence of a structural lesion. In 1948, the Gibbs studied 300 patients’ EEG findings associated with psychomotor seizures localized to the anterior temporal lobe.3 They convinced Percival Bailey (who was trained by Cushing) to perform anterior temporal resections for psychomotor epilepsy. By 1954, Bailey had operated on 72 patients with a five year follow-up and concluded that ‘major convulsions are abolished or greatly reduced in half of the cases.’ The hippocampus and hippocampal gyrus were spared in these operations.4 The Gibbs’ and Bailey’s efforts were one of the earlier attempts at surgical treatment of non-lesional epilepsy.

Benjamin Winslow Dudley Dudley who had earned his MD from University of Pennsylvania, traveled to England and France to learn the art of surgery and trephining. When he returned to Kentucky in 1818, he became the first American to perform surgery for epilepsy and the first surgeon to ever publish a series (five) of epilepsy surgery patients. He conducted surgery for post-traumatic epilepsy. All five patients in his series survived, three were seizure free and the other two had decreased seizure frequency.2 Dudley attributed his success to the ‘good clean air’ of the Kentucky frontier.

Harvey W Cushing The history of modern epilepsy surgery in many ways reflects the history of neurosurgery in the late 19th and early 20th centuries. During his training, Cushing (considered to be the father of modern neurosurgery) went abroad in 1901, where he visited Horsley but he was not impressed by Horsley’s speedy surgical techniques. Upon his return to the United States and expansion of his practice at Peter Bent Brigham Hospital in Boston, Cushing established the safety of intracranial surgery and neurosurgery training programs. He had a particular interest in surgical treatment of brain tumors. He demonstrated the localizing value of epileptic syndromes although he had no special interest in electrophysiology. He trained many future leaders in epilepsy surgery including Percival Bailey and Wilder Penfield.

Bailey and Gibbs As early as 1938, Frederic and Erna Gibbs along with Lennox had suggested the idea of operating on an electrical focus 116

More recent generation of epilepsy surgeons in the United States Earl Walker’s5 physiological studies on the brain and more specifically thalamus provided further data regarding electrophysiological mechanisms underlying epilepsy. Arthur Ward6,7 was the first to perform intracellular recordings from human epileptic neurons. His demonstration of temporal lobe electrophysiology responsible for epilepsy further complemented Crandall’s8 pioneering work in chronic depth electrode recordings. An amalgam of Falconer’s demonstration of anatomic abnormalities and Crandall’s analysis of corresponding electrophysiological characteristics has founded our current comprehension of temporal lobe epilepsy. The more complex electrophysiology responsible for extra-temporal epilepsy has partly delayed our more detailed understanding of mechanisms involved in extra-temporal epilepsy syndromes.

Other surgical procedures for epilepsy Hemispherectomy was initially described by Dandy in 1928 for gliomas, and used by Krynauw9 in 1950 for children with epilepsy and infantile hemiplegia. As was mentioned previously, Rasmussen described ‘functional hemispherectomy’ which further minimized the complications associated with an anatomic hemispherectomy. Based on Horsley’s and Erickson’s observations regarding the importance of corpus callosum in transferring epileptic discharges between hemispheres, Van Wagenen and Herron performed the first corpus callosotomy in 1940.

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A brief history of epilepsy surgery in the United States As the first part of the 20th century demonstrated the efficacy of epilepsy surgery; the second part of century defined who would be likely to benefit most from surgery and also expanded the repertoire of surgical technique: callosotomy,10 focal cortical resection,11 multiple subpial transactions.12 Multiple subpial transaction was first described in 1989.12 The technique has been applied successfully to epilepsy foci in eloquent cortex by severing the ‘horizontal’ or traversing fibers while preserving the descending fibers, therefore; isolating the route of seizure spread. In addition, application of intracranial monitoring strategies has made epilepsy surgery available for patients with focal epilepsy and non-structural abnormalities. Other procedures such as vagus nerve stimulation (VNS) (approved in 1997) has been used for patients with generalized seizures who have typically bilateral or non focal epileptiform activity on EEG and are not candidates for resective surgery. The mechanism of action of VNS is not known, but it may reduce seizure frequency with a similar efficacy as those of new generation of anticonvulsant drugs. Another new procedure for intractable generalized seizures is deep brain stimulation in the anterior nucleus of thalamus.13 The anterior thalamus is known to play a role in seizure propagation. This is a novel treatment for patients with generalized seizures, who are not typically candidates for resective surgery. The future treatments in epilepsy will depend on a better understanding of the cellular phenomenon and networks involved in seizure generation.

Neuroimaging and epilepsy The evolution of imaging modalities has significantly expanded the application of surgery through improved localization of seizure foci. In 1930s, Penfield used ventriculography, pneumoencephalography and angiography to evaluate epileptogenic mass lesions. MRI scanning was a significant

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advance due to its high resolution of soft tissues revealing anatomic details and pathologic signal changes with striking clarity. Multiplanar imaging allowed visualization of medial temporal and neocortical structures in anatomically useful cross sections.14 With the advent of MRI, there was a preoperative correlate to EEG. Hippocampal sclerosis and atrophy on the side of seizure origin was found to effectively predict seizure remission.15 Furthermore, the degree of hippocampal resection was found to affect seizure outcomes.16 Further evolution of imaging modalities including functional MRI, positron emission tomography and single photon emission computed tomography have further facilitated delineation of more subtle areas of structural and metabolic abnormality. Regions of electrographic abnormality have become correlated with areas of radiographic abnormality as disclosed by magnetic resonance imaging. Localization of a ‘seizure generator’ by two independent methods has improved the likelihood of obtaining a surgical cure. Functional imaging coregistered with structural and electrographic data has become an important tool in epilepsy surgery.17

Conclusions In the present chapter, we reviewed an abbreviated history of epilepsy surgery in the United States. We highlighted the milestones in the development of epilepsy surgery which began with an understanding of cortical electrical activity and its role in epilepsy. Advances in electrical localization, beginning with scalp EEG recordings and shortly followed by cortical and depth recordings, have enhances our preoperative localizing power, significantly increasing the effectiveness of epilepsy surgery. Further improvement in our treatment paradigms is possible with multicenter trials and understanding the networks and molecular basis of epilepsy.

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9.

Holmes G. Evolution of clinical medicine as illustrated by the history of medicine. BMJ 1946;2:1–4. Dudley D. Observations on injuries of the head. Transylvania J Med 1828;1:9–40. Gibbs E, Gibbs F, Fuster B. Psychomotor epilepsy. Arch Neurol Psychiatry 1948;60:331–9. Bailey P. Surgical treatment of psychomotor epilepsy: five year follow-up. South Med J 1961;54:299–301. Walker A. Stereotaxic methods for the study of subcortical activity in epilepsy. Confin Neurol 1962;22:217–22. Ward A, McCullough W, Kopeloff N. Temporal and spatial distribution of changes during spontaneous seizures in monkey brain. J Neurophysiol 1948;11:377. Ward A, Thomas L. The electrical activity of single units in the cerebral cortex of man. Electroencephalogr Clin Neurophysiol 1955; 7:135–6. Babb T, Mariani E, Crandall P. An electronic circuit for detection of EEG seizures recorded with implantd electrodes. Electroencephalogr Clin Neurophysiol 1974;37:305–8. Krynauw R. Infantile hemiplegia treated by removing one cerebral hemishphere. Neurol Neurosurg Psychiatr 1950;13:243–7.

10. 11. 12. 13. 14. 15. 16. 17.

Wilson D, Reeves A, Gazzaniga M. Division of the corpus callosum for uncontrollable epilepsy. Neurology 1978;28:649–53. Palmini A, Anderman F, Olivier A, Tampieri D, Robitaille Y. Focal neuronal migration disorders and intractable partial epilepsy: results of surgical treatment. Ann Neurol 1991;30:750–7. Morrell F, Whisler W, Bleck T. Multiple subpial transaction: a new approach to the surgical treatment of focal epilepsy. J Neurosurg 1989;70:231–9. Hodaie M, Wennberg R, Dostrovsky J, Lozano A. Chronic Anterior Thalamus Stimulation for Intractable Epilepsy. Epilepsia 2002; 43:603–8. Diaz-Arrastio R, Agostini M, VanNess P. Evolving treatment strategies for epilepsy. JAMA 2002;287:2917–20. Jack C, Sharbrough F, Twome C, et al. Temporal lobe seizures: lateralization with MR volume measurement of the hippocampal formation. Radiology 1990;175:423–9. Wyler A, Hermann B, Richey E. Extent of medial temporal resection on outcome from anterior temporal lobectomy: a randomized prospective study. Neurosurgery 1995;37:982–91. Kuzniecky R. Neuroimaging of epilepsy: advances and practical applications. Rev Neurol Dis 2004;1:179–89.

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Epilepsy surgery in Latin America J Godoy, AC Sakamoto, and ALF Palmini

Although waxing and waning, interest in epilepsy surgery appeared in Latin America shortly after this therapy was introduced by Penfield’s pioneering work at the Montreal Neurological Institute. The first systematic resective surgeries for epilepsy were performed in the region in the 1940s.1 For decades, this treatment was used mainly in isolated, anecdotal cases or performed in very small series, having included almost all its modalities: temporal and extratemporal resections, hemispherectomies, callosotomies, lesionectomies, stereotaxia, and amigdalo-hippocampectomies.2–4 During the last 15 years several systematic epilepsy surgery programs have been established in the region, including some centers that use advanced techniques. However many Latin-American countries still have not performed any epilepsy surgery and some even lack the facilities for a complete patient presurgical evaluation. As in the rest of the world, the actual number of epilepsy surgeries represents a very small fraction of the total number of patients that need this type of therapy. Certainly one of the main challenges on this regard is to make this treatment available to the whole region. Three are two major difficulties for the development of epilepsy surgery in Latin America. The first is economical limitations and the second the unawareness of the usefulness of surgical treatment and its proper timing within the neurological and neurosurgical community. Although unified by a common language and socio-cultural roots, Latin America is a continent where healthcare systems coexist with major differences not only between countries but also within a same country. According to World Bank data,5 per capita income in Latin America ranges from US$400 in Haiti to US$6,230 in Mexico, while health expenditure per capita ranges from as low as US$29 per year in Haiti up to US$361 per year in Uruguay, compared to US$5,274 in the USA. This latter figure is higher than the total per capita income of almost all countries in the region. The impact of the economical development on epilepsy care is shown by the fact that the five countries with the highest income in the region have established epilepsy surgery programs while none of the five poorest countries have them. In this context of economical constraints it is easy to understand that there are quite a number of priorities that compete for health resources and explains why epilepsy surgeries are virtually nonexistent in public health systems in the region, with very few exceptions. On this regard, a major political step in favor of the development of epilepsy surgery in Latin America was made on September 9, 2005, in Santiago, Chile, where the ‘LatinAmerican Declaration on Epilepsy’ was read on behalf of several international organizations, including ILAE, IBE, WHO, and UNICEF, as part of the ‘Epilepsy out of the Shadows’ global campaign. This declaration included a statement calling 118

to warrant availability and access to ‘surgery and all forms of effective treatments’.6 Even more critical than the economical restrictions is the need for well-trained medical professionals who not only make epilepsy surgery programs technically feasible but also inform and teach local and regional neurological communities about this modality of therapy, and promote changes in healthcare systems for setting up the epilepsy surgery programs. Indeed all current epilepsy surgery centers in the region are led by epileptologists and neurosurgeons trained at top world-class epilepsy centers, mainly the Montreal Neurological Institute and the Cleveland Clinic. Probably the best contribution first-world epileptologists can do for the further development of epilepsy surgery in Latin America is to train physicians and other professionals in the different disciplines needed in this field.

Precursors Before the development of modern neurophysiological techniques, surgery was performed in Latin America mainly for post-traumatic epilepsy.2,7 Usually, the site of an obvious structural lesion or simply the site of a head injury was selected for resection. Preoperative investigations were very limited because no EEGs were performed. Some patients were operated on based only on clinical history and plain skull X-ray findings (fractures, depressions, etc.). It is surprising to know that this approach was occasionally used in Latin America as early as the end of the 19th century. Razetti et al., in Venezuela, and Maldonado et al., in Colombia, operated on patients with jacksonian post-traumatic epilepsy, in 1893 and 1897, respectively;8 in 1894 Navarro,9 in Montevideo, Uruguay, operated on a patient who developed frequent seizures after a head injury with a skull depression. He used a silver plate as a craneoplasty; the patient developed a right hemiplegia and remained with seizures for a few days, improving afterwards and being able to return to work 6 weeks later.

Argentina The first systematic epilepsy surgery attempts were made almost 50 years ago in this country. In 1957, Ghersi et al.10 reported a series of 25 patients with no demonstrable structural lesion who underwent temporal lobectomies or gyrectomies based on clinical history, surface EEG, and intraoperative corticograms (performed before and after the

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Epilepsy surgery in Latin America initial resections in all cases). Although all patients improved significantly (40–80% seizure reduction), none was completely cured; their series also included some hemispherectomies which had good outcomes. Pardal et al.11 performed stereotaxic surgery on six epileptic patients in 1960 and reported good outcome in all of them. A few years later the group of Basso and Betti,3 from the University of Buenos Aires, using Bancaud and Talairach’s technique, implanted electrodes for acute or chronic recordings in 61 patients, 36 of whom had temporal lobe epilepsy. They explored the amygdala, hippocampus, temporal cortex, thalamus, and other structures; in some patients they produced thalamic injuries and in others they destroyed epileptogenic areas with yttrium (Y-90) or performed amygdalo-hippocampotomy. Unfortunately, detailed preoperative and follow-up protocols were not provided. These authors also used combined surgical approaches, which included stereotaxic treatment for temporal lobe epilepsies and, in case of failure, topectomy of the affected cortex or temporal lobectomy.3 In 1977 Chescotta et al.12 reported a group of 62 epileptic patients on whom amygdalotomies and fornicotomies were performed; a significant improvement was obtained in 66% of the patients. Costales and Ferrarese13 from Bahía Blanca, Argentina, presented a case report on a patient with a refractory status epilepticus successfully treated with temporal lobectomy. Nowadays, there are four groups performing epilepsy surgery in Argentina. The group of Pomata, working in Buenos Aires at Juan P. Garrahan National Pediatric Hospital and at the FLENI Institute, started epilepsy surgery in 1995 (Pomata H, personal communication). Up to 2005 their series included 158 temporal and 139 extratemporal lobe surgeries, 34 hemispherectomies (2 of them anatomical), 35 callosotomies, and 13 vagal nerve stimulators. These authors reported part of their experience in 2001,14 describing 60 children with extratemporal epilepsies, treated with resections, disconnections, and in one case, hemispherectomy; 10 of these patients underwent invasive evaluations; the one year follow-up showed that 38 patients were on Engel’s class I. They also presented a small group of patients with Rasmussen encephalitis who underwent hemispherectomy,15 and additionally described a 6 year-old child with refractory status epilepticus successfully treated with multiple subpial transection.16 Another epilepsy surgery program in Buenos Aires is located at the Hospital Italiano where Rabadan et al. have performed epilepsy surgery since 1999. They reported part of their series in 2000.17 As of 2005 they have operated on 35 adult patients, including temporal and extratemporal resections as well as callosotomies (Rabadan A, personal communication). Also in Buenos Aires, at the Ramos Mejia Hospital, Kochen, Silva, Seoane, and Consalvo continued the work of Basso and Betti.18 They introduced Video-EEG monitoring in 1996, invasive studies in 2001, and started extratemporal resections in 2003. They have also performed some callosotomies and vagal nerve stimulation since 2001 (Kochen S, personal communication). Outside the capital city, epilepsy surgery has been performed in two provinces. One in the northern city of Cordoba, where Bulacio, Sfaello, and Mu~ noz started an epilepsy surgery program at The Santisima Trinidad Children’s hospital and at the Center for the Study and Treatment of Epilepsy and Sleep Disorders (Bulacio J, personal

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communication); they have practiced temporal and extratemporal resections in a small group of patients since 2004. In Mendoza city, the above-mentioned neurosurgeon Pomata has also performed temporal and extratemporal resections in children (Pomata H, personal communication).

Bolivia In this country, cortical resections were reported in post-traumatic epilepsies by Enriquez in 1959.7 In his series, no EEG recordings were practiced and therefore patients were operated on based only on clinical history and plain skull X-ray findings, mainly guided by fractures and depressions. This same author also described the use of suboccipital pneumoencephalography for treating epilepsies after central nervous system infections, but no controlled results were reported.7 There are currently no established epilepsy surgery programs in Bolivia not are these known surgical treatment attempts in the past.

Brazil In the largest Latin-American country interest in epilepsy surgery goes back to the 1950s, and the most important and original contribution from the Brazilians to this field was made by the neurosurgeon Paulo Niemeyer Soares, one of the founders of the Brazilian League against Epilepsy, who also made contributions in several other neurosurgical pathologies, including Parkinson’s disease surgery (Figure 14.1).19 Niemeyer, who started to work at the Santa Casa de Misericordia Hospital, in Rio de Janeiro, initially as a general surgeon, was the first to propose and to perform amygdalohippocampectomies for the treatment of temporal lobe epilepsy. He used a transventricular approach, a technique that he presented for the first time in Washington in 1957, and later described in more detail in a book chapter.20 In 1973 his group presented a

Figure 14.1 Dr Paulo Niemeyer Soares, brazilian neurosurgeon who first described amygdalohippocampectomy in 1957 (courtesy of Americo Sakamoto, MD).

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series of 42 patients who underwent amygdalohippocampectomies,4 reporting satisfactory results in 74% of the patients, after a follow-up period ranging from 6 months to 10 years; this figure was similar to the one the same group had obtained in 35 temporal lobectomies with resections tailored according to post-ablation electrocorticographic recordings. In order to better understand the meaning of post resection epileptiform discharges he eventually left in place tiny copper electrodes over the operated cortex and performed post-surgical recordings.19 These electrodes were externalized through small trepanation holes and after finishing the recordings were simply pulled out. With this technique, he soon realized that there was an immediate post-operative worsening of the frequency of epileptiform discharges, an effect that vanished in hours or a few days. Many years later this finding was replicated in a prospective study by Cendes et al.,21 in a group of amygdalohippocampectomy patients; these authors coined the term ‘Niemeyer effect’ to describe this phenomenon. Niemeyer and his group also performed the first electrocortical recordings in Brazil in the early 1950s, using a single channel Garcier electroencephalograph.19 While Niemeyer’s pioneering work in the field of epilepsy surgery was developed as part of his extensive practice as a general neurosurgeon, more recent initiatives in Brazil already embraced the idea of a comprehensive epilepsy surgery program, involving a multidisciplinary team including neurologists, neurosurgeons, psychologists, technologists, and more recently, neuroradiologists, psychiatrists, social workers, and physicists. According to this principle the first Brazilian epilepsy surgery center was established in the 1970s, at the Hospital das Clinicas da Universidade de S~ ao Paulo, in the city of S~ ao Paulo, led by neurosurgeon Raul Marino Jr., who started a program mainly focused on treating diffuse epileptic encephalopathies through corpus callosotomy.22 In the 1980s the second epilepsy surgery center was implemented at the Instituto Neurologico de Goiânia, led by neurologist Paulo C. Ragazzo, who was trained at the MNI and had previously participated in the team from the Hospital das Clinicas da Universidade de S~ ao Paulo. It was really in the 1990s that the field of epilepsy surgery experienced major developments in Brazil. Two major reasons were of paramount importance in this move to provide the country with epilepsy surgery centers at the level of firstclass centers of the developed world, not only in terms of infrastructure and methodologies, but also in terms of results for both adult and pediatric patients.23,24 The first reason was the return to Brazil of well-trained physicians who established new epilepsy surgery centers and introduced state-ofthe-art methodologies for the presurgical evaluation and selection of surgical candidates, as well as for the surgical treatment itself. Two new centers were implemented in that decade, one at the Pontificia Universidade Católica, in Porto Alegre, in the early 1990s, under the leadership of the neurologists André L.F. Palmini (trained at the MNI) and Jaderson C. da Costa (trained in pediatric neurology at Boston Children’s Hospital), and the second at Hospital das Clinicas de Ribeir~ ao Preto, Universidade de S~ ao Paulo, in Ribeir~ ao ~ Preto, State of S ao Paulo, in the mid 1990s, under the leaderships of the neurologist Américo C. Sakamoto (trained at The Cleveland Clinic Foundation, Cleveland, USA, and Epilepsy Center Bethel, Bielefeld, Germany) and neurosurgeon Jo~ ao A. Assirati Jr. (extensive neurosurgical training in various

centers in the USA). The second and more important reason was the establishment of a national epilepsy surgery program in 1994, within the public health system, sponsored and coordinated by the Health Department. This program was created after joint effort from the Brazilian League of Epilepsy, the Brazilian Society of Clinical Neurophysiology, and the Brazilian Society of Neurosurgery, all of them active participants of a committee named directly by the Minister of Health. The main objectives of this committee were three-fold: (a) to establish a nationwide epilepsy surgery program, (b) to implement internationally accepted medical standards, and (c) to compromise maximal resources and minimal costs. In order to achieve these goals a two-steps strategy was implemented, which included strict criteria for accreditation of epilepsy surgery centers based on minimal requirements and clearly defined guidelines for indication of epilepsy surgery (temporal and extratemporal resective surgery, hemispherectomy and callosotomy). After completion of the first 10 years of experience (1994–2004), the program was shown to be highly successful in many different aspects. It started out in 1994 with three initially accredited centers (Hospital das Clinicas da Universidade de S~ ao Paulo – S~ ao Paulo, Instituto Neurologico de Goiânia – Goiânia, and Hospital S~ ao Lucas da Pontifícia Universidade Católica – Porto Alegre), and progressively expanded to the current eight centers distributed in different geographical regions, seven of them connected to academic institutions dedicated not only to medical assistance but also to education and research. In recent years many other epilepsy surgery centers were established and reached accreditation status: at the Hospital das Clinicas da Universidade Estadual de Campinas, in Campinas, under the leadership of the neurologist Fernando Cendes who was trained at the MNI, at the Hospital da Universidade Federal de S~ ao Paulo, in S~ ao Paulo, under the leadership of neurologists Américo C. Sakamoto and Elza M. T. Yacubian (trained at the National Institutes of Health, Bethesda, USA), at the Hospital das Clinicas da Universidade Federal do Paraná, in Curitiba, under the leadership of the neurologists Luciano de Paola (trained at the University of Minneapolis) and Carlos S. Silvado; and at Hospital Regional, in S~ ao José do Rio Preto, under the leadership of neurologist Lucia H. Marques (trained at Universidade Estadual de Campinas). Other emerging centers are currently applying for accreditation as epilepsy surgery centers, in an organized process led by the Health Department. The nationwide implementation of this program was able to assure universal access to epilepsy surgery in Brazil, to increase 13 times the total number of epilepsy surgery per year, to increase 2.7 times the number of epilepsy surgery accredited (or in final stages to be accredited) centers, to increase 5 times the number of surgeries per center per year, to boost the scientific development in the field of epileptology, and equally important, to create a network of centers with full capacity of training young Brazilian professionals in the area of epilepsy surgery, warranting the expansion and continuity of the program in the country, and consequently, the future of epilepsy surgery in Brazil.

Chile In this country there is also a lengthy history on epilepsy surgery. Alfonso Asenjo, who is recognized as one of the founders

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Epilepsy surgery in Latin America of Latin American neurosurgery, was actively involved in promoting this therapy more than 50 years ago. He established in 1950 the Instituto de Neurocirugía e Investigaciones Cerebrales de Chile (currently The Asenjo Institute), one of the first teaching and investigation centers in neurosurgery in Latina America, where hundreds of neurosurgeons have been trained, from Chile and other South and Central American countries. Asenjo worked with Carlos Villavicencio, a neurophysiologist trained in Montreal between 1939 and 1941 under Wielder Penfield25 and who started electroencephalography in Chile in 1944, in a room called ‘Hans Berger’, at the Instituto de Neurocirugía, in Santiago. In 1951 they published,2 a series of 221 epilepsy surgery patients, although only 96 of their patients had lesions without surgical indication per se, most of them frontal and mainly post-traumatic. Preoperative investigations included repeated surface electroencephalograms (EEGs), plain skull X-rays, cerebral angiograms, pneumoencephalograms, and ventriculograms; intraoperative corticograms and electrical stimulation were performed for tailoring the resections. The authors reported significant improvement or complete control in up to 69% of the patients. Other surgical procedures were also practiced at that time, such as hemispherectomies, performed in 1954 at the same institution;25 The group continued to perform epilepsy surgery for some years but with a progressive decay in interest. A new impulse came at this center in 1990 when a pediatric epilepsy surgery program started, under the leadership of Lilian Cuadra. Up to 2004, they have operated on more than 100 children, mainly using temporal lobectomies and callosotomies (Cuadra, personal communication), entirely supported by public funds. Another center with a long history in epilepsy surgery in Chile is the Hospital de la Universidad Catolica, where epilepsy surgery was initiated in 1962 led by Cristian Vera, a neurosurgeon trained at the Montreal Neurological Institute from 1956 to 1961; anecdotically, he had the opportunity to assist in the last epilepsy surgery that Penfield performed at the MNI. In Chile, Vera himself not only performed the surgery but also the electrocorticograms, using a portable eightchannel Hofner equipment, going back and forth from the operation table to the EEG machine. His group, that included Luis F. Quesney as a novel student, who later became a distinguished epileptologist, performed both temporal and frontal resections as well as hemispherectomies. Patients were also evaluated with surface EEG, skull X-rays, pneumoencephalography and an amytal test (Vera, personal communication). They also operated at the Hospital Psiquiatrico in Santiago, to where they eventually moved the only EEG machine they had. In some patients, before the resections, they made recordings from the amygdala, using implanted gold electrodes while at the same time tested memory. Again, interest decayed and no epilepsy surgeries were performed for almost 20 years, until 1990, when a new program was started by the neurophysiologist Godoy, trained at the Cleveland Clinic, and the neurosurgeon Torrealba;26 this program had an additional impulse in 1996, when Campos, neurosurgeon trained in Bonn, joined the group. At this center temporal and extratemporal resections are performed and patients undergo prolonged Video EEG monitoring, and when needed, evaluation with subdural grids or foramen ovale electrodes.27,28 In addition to high resolution MRI,

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SPECT (ictal and interictal) are performed and more recently PET scanning. Several stereotaxic techniques were used in the past both at the Asenjo Institute and at the Santiago’s Psychiatric Hospital.29 In this latter center this epilepsy surgery was performed in the 1960s and 1970s, led by Mario Poblete (L. Aranda, personal communication).

Colombia In Colombia, Sierra et al.30 reported in 1960 a Sturge– Weber–Dimitri patient with intractable epilepsy, successfully treated with hemispherectomy; he had no seizure recurrence, even after complete anti-convulsant withdrawal. GutierrezLara et al.31 performed stereotaxic surgery in 15 children between 1973 and 1976. Patients underwent Forel campotomy, amygdalotomy and, in those with associated hyperkinetic syndrome (probably meant attention deficit disorder), hypothalamotomy; they described good results in 8 patients, with a 6–18 month follow up. One of the largest, oldest and most significant epilepsy surgery program in Latin America has been developed in Cartagena de Indias, Colombia by Jaime Fandi~ no-Franky.32,33 It is worth mentioning that a huge personnel effort has been put by Fandi~ no-Franky, who has been able to overcome all kind of difficulties and established a comprehensive epilepsy program supported by non-governmental entities for more than 20 years. In 1996, an international workshop on specific aspects of epilepsy in the developing world was organized by ILAE Commission of Epilepsy in Developing Countries, during which it was stated that ‘Fandino-Franky inspired the entire Workshop when he described his experiences’.34 He was trained in Sweden and shortly after his return to Colombia got actively involved in epilepsy. Fandi~ no-Franky performed the first anatomical hemispherectomy in Colombia in 1981 and in 1989 founded an epilepsy hospital (Hospital Neurologico) that belongs to the Colombian League Against Epilepsy; the same year his group performed the first callosotomy and the first anterior temporal lobectomy. As of 2005 they have performed 680 epilepsy surgery procedures, including temporal and extratemporal resective surgeries, callosotomies, hemispherectomies (anatomical and functional), multiple subpial transections etc. This comprehensive program also includes a nicely developed rehabilitation program (Fandi~ no-Franky, personal communication). Other efforts have also been made in Colombia. In Bogotá, Nari~ no et al. developed an epilepsy surgery at the Hospital Central de la Policía and at the Palermo Clinic. They have already operated on 45 patients, including some with invasive studies (Nari~ no, personal communication).

Costa Rica Epilepsy surgery has been performed only recently in Costa Rica. Sittenfeld and his group at the Hospital Doctor Carlos Saenz, have operated on 45 children since 200l. the group includes callosotomies, temporal lobectomies and extratemporal resections; some patients required invasive studies. At 2-year follow-up the authors report Engel’s class I outcome

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in 2/3 of their patients, both temporal and extratemporal groups as well as significant seizure reduction in 8/17 callosotomies practiced on children (Sittenfeld, unpublished work).

Cuba An epilepsy surgery program was created in 2000, at the International Center for Restorative Neurology (CIREN) in Havana,35 where they have started to perform video-EEG monitorings in 2000; the first surgical procedures, temporal resections, began in 2002 and later a few callosotomies have been performed. The medical team, which includes neurophysiologists, epileptologists, neuropsychologist, and neurosurgeon, was trained at the MNI. Patients are evaluated with surface video-EEG monitoring, neuroimaging, and SPECT; Wada tests are not performed (Bender, personal communication).

Dominican Republic In this country there were no known epilepsy surgery treatments in the past. Since 2003 Video-EEG monitoring has been practiced at the Corazones Unidos Clinic, in Santo Domingo City where anecdotical extratemporal resections have been performed recently (Santos-Viloria, personal communication).

Ecuador There has been no known epilepsy surgeries performed in Ecuador. Just recently Video-EEG monitoring was started at the ‘Hospital Metropolitano’, in Quito, the capital city, by the epileptologists Abad and Pesantes and the neurosurgeon Varsallo, trained in epilepsy surgery in Freiburg, Germany (Pesantes J, personal communication).

Mexico The first communications about epilepsy surgery in Mexico date back to the early 1950s and were performed by Manuel Velasco Suarez, one of the most distinguished Mexican neurosurgeons. In 1951 he founded the Mexican League Against Epilepsy and later, in 1964, the National Institute of Neurology and Neurosurgery (Mexico City).36 Later, a pioneering work on deep brain stimulation has been developed since the mid-1980s by two other neurosurgeons, Francisco and Marcos Velasco, from the Instituto Mejicano de Seguridad Social Medical Center. They proposed centromedian median thalamic nuclei stimulation for the treatment of patients with intractable generalized tonic-clonic seizures,37–39 using this therapy for up to 2 years, through a special device they had developed; they described good outcomes in generalized seizures but not in generalized tonic nor complex partial seizures. These same authors also reported the use of subacute electrical hippocampal stimulation, with either depth or subdural electrodes, in 10 patients who had withdrawn anticonvulsants for 48–72 hours; after a stimulation period of 2–3 weeks the patients underwent anterior temporal resections. With this method seizures were abolished in

seven of these patients and even the interictal spiking was reduced significantly.40 The Velascos have also reported on the use of bilateral cerebellar stimulation in a group of five refractory epilepsy patients, in a double-blind controlled study which used the same patients as controls, and obtained a statistically significant seizure reduction.41 An epilepsy surgery program that uses a more conventional approach was established in Mexico City, at the National Institute of Neurology and Neurosurgery, where temporal and extratemporal resections are performed, using intraoperative electrocorticography and cortical stimulation whenever appropriate. A 2-year follow-up report of 100 resective surgeries in temporal lobe epilepsy was presented in 2004, showing seizure free outcome in 84% of the patients.42 At this center, vagal nerve stimulation was also implemented for refractory epilepsy in 2001.43 Pella et al., also in Mexico City, established an epilepsy surgery program at the Angeles del Pedregal Hospital in 1995. They have performed more than 100 surgeries, in both children and adults, including temporal and extratemporal lobectomies, callosotomies, and radiosurgical procedures (Pella et al., personal communication). Recently epilepsy surgery has been developed at the Instituto Potosino de Neurociencias, in San Luis de Potosí. Villalobos et al.44 reported their experience in a group of 40 patients, children and adults, who underwent resective surgery.

Peru Esteban Rocca, a neurosurgeon trained under the Chilean Alfonso Asenjo in the 1940s, founded the Neurosurgery Unit at the Hospital Obrero in Lima in 1947.45 Working with Juan Franco, a neurosurgeon trained in Chile and the USA, he performed resective surgeries in 1955, using corticograms as guidance.46 However, details of the surgical procedures and results were not presented. In Arequipa, a southern Peruvian city, Ortega and Gamero47 in 1973 reported on 30 intractable patients with generalized seizure disorders that were treated with surgical section of the genu of the corpus callosum and anterior white commissure; significant improvement or complete control was achieved in 90% of these patients. No epilepsy surgery programs are currently established in Peru.

Uruguay Alejandro Schroeder, the founder of Uruguayan neurosurgery, introduced the EEG and initiated epilepsy surgery at the Instituto Neurologico in Montevideo. He was initially trained in central nervous system histology in Hamburg, Germany and later he had the chance to work with Ostrid Fester in Breslau; after this latter experience he became interested in neurosurgery, starting his practice in 1930.9 In 1949 he reported the first Latin-American series on lesionectomies at the Third South American Neurosurgery Congress held in Buenos Aires, Argentina.1 It included ten patients studied preoperatively with surface EEG and cerebral angiograms; intraoperative electrocorticography was also performed and used as the main criterion for guiding surgery, since resections were done only when corticograms showed spikes, which was the case in the seven patients. The authors stated

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Epilepsy surgery in Latin America that, after clinical and EEG studies, ‘we mark on the skin the epileptic focus as exactly as possible’. Also in Montevideo, Arana I~ niguez, a neurosurgeon trained in Santiago, Chile, and Boston, USA performed one of the earliest hemispherectomies in Latin-America.9 In 1961, Bogacz et al.48 studied 62 patients with unilateral temporal lobe foci, using nasopharyngeal and sphenoidal electrodes. Seven of these patients underwent invasive studies with deep electrode threads for 24 hours, followed by temporal lobectomy. As has happened in many other countries, no further epilepsy surgeries were performed for decades and only recently has an epilepsy surgery program been started in Montevideo at the Instituto de Neurologia del Hospital de Clínicas, led by Alejandro Scaramelli. Up to date they have performed 17 temporal lobectomies using non-invasive techniques (Scaramelli, personal communication).

Venezuela Arminio Martinez et al.49 working at the José María Vargas Hospital, in Caracas, the capital city, started temporal lobectomies in 1955, following the Montreal Neurological Institute approach, including the use of intraoperative electrocorticography and electrical stimulation; up to 1972 they had operated on 13 patients, reporting complete control in 9 and improvement in 2 patients. The same group performed the first hemispherectomy in Venezuela in 1959. After several decades Scholtz and Ponce, at the same Vargas Hospital, performed some other epilepsy surgery procedures. In 2000, Soto, et al. established a new epilepsy surgery program, working at the Domingo Luciani University Hospital and the Floresta

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Medical Institute where they have performed temporal and extratemporal resections, callosotomies, and vagal nerve stimulations (Soto, personal communication).

Concluding remarks The history of epilepsy surgery in Latin America parallels the rest of the world. Very early attempts to develop this therapy following the Montreal Neurological Institute’s approach can be found in several countries of the region. The pioneering work of the Brazilian neurosurgeon Paulo Niemeyer Soares, who proposed almost 50 years ago the selective amygdalohippocampectomy, a technique still used nowadays, is a good example of the interest Latin America has historically shown in epilepsy surgery. More recently in the region, epilepsy surgery has followed the extraordinary development in first-world countries, including the area of neuroimaging. Unfortunately, Latin America has also great diversity in the organization of the health system and the breach between the number of patients needing epilepsy surgery and the actual amount of surgeries performed is certainly much larger than in developed countries. Only Brazil has a nationwide epilepsy surgery program and this experience, in this respect, probably has unique features, due to its universality (available to every citizen independent of socioeconomic status), high medical standards at minimal costs (strict definitions of human and technical requirements, and surgical protocols), and a controlled and organized accreditation system (supervised by Health Department and medical societies) which could be seen as an example not only for developing but also to developed countries.

REFERENCES 1. 2. 3. 4. 5. 6.

7. 8. 9. 10. 11. 12.

Schroeder A, Arana R, Fuster B, San Julian J. Contribución al tratamiento quirúrgico de la epilepsia. Actas III Congreso Sudamericano de Neurocirugía 1949;272–3. Asenjo A. Villavicencio C, Contreras M, Fierro J. Estado actual del tratamiento quirúrgico de la epilepsia. Neurocirugía 1951;8:86–130. Basso AA, Betti OO, Clucellas JL, et al. Stereo electroencephalography in temporal epilepsy. Acta Neurol Latinoamer 1969;15:72–86. Amygdalohippocampectomy for temporal lobe epilepsy. Excerpta Medica 1973;293:20. 2005 World Development Indicators. The World Bank. Available from http://devdata.worldbank.org/wdi2005. Devilat M. Conduciendo a la epilepsia fuera de las sombras. Declaración para la epilepsia en Latinoamérica. In: Campos M, Kanner A, Eds. Epilepsias. Diagnóstico y tratamiento 847–52. Mediterráneo: Santiago, 2004. Enríquez N. Nuestra experiencia en el tratamiento quirúrgico de la epilepsia post traumática. In: Homenaje a Alfonso Asenjo Gómez. Lima: Médica Peruana. 1959:38–56. Christiansen JC. History of neurosurgery in South America. Acta Neurol Latinoamer 1962;8:63–76. Wilson E. Historia de la neurocirugía en Uruguay. In: Mendez J. ed. Historia de la Federación de Sociedades Latinoamericanas de Neurocirugía 332–62. Barlovento: Santiago, 2002. Ghersi JA, Piaquadio N, Costales A. Nuestra experiencia electroencefalográfica en las epilepsias temporales. Actas VII Congreso Latinoamericano de Neurocirugía 1957;345–6. Pardal E, Morete de Pardal ML, Betti O. Cirugía estereotáxica de la epilepsia en los ganglios de la base. Anales de Neurocirugía 1960;5:9–23. Chescotta AR, Gotusso C, Stella O, Chinela A. Stereotaxic surgery for epilepsy. Excerpta Medica 1977;418:224–5.

13. 14. 15. 16. 17. 18. 19. 20.

21. 22.

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Costales A, Ferrarese L. La indicación quirúrgica en el estado de mal epiléptico focal irreversible. Neurocirugía 1960;18:387–94. Pomata HB, Gonzalez R, Bartuluchi M et al. Extratemporal epilepsy in children: candidate selection and surgical treatment. Child Nerv Syst 2000;16:842–50. Caraballo R, Tenembaum S, Cersosimo R et al. Rasmussen syndrome. Rev Neurol. 1998;26:978–83. D’Giano CH, Del C Garcia M, Pomata H, Rabinowicz AL. Treatment of refractory partial status epilepticus with multiple subpial transection: case report. Seizure 2001;10:382–5. Rabadan A, Baccaneli M, Consalvo D et al. Cirugía de la epilepsia refractaria. In: Devilat M, ed. La Epilepsia en Latinoamérica 276. Editorial Iku: Santiago, 2000. Silva W, Consalvo D, Solis P et al. Results of the temporal lobe epilepsy surgery in a developing country. Epilepsia 2002;43 (suppl 7):334. De Paiva Bello, H. Homenagem ao Dr. Paulo Niemeyer. J Epilepsy Clin Neurophysiol 2004;10:241–4. Niemeyer P. The transventricular amygdalohippocampectomy in temporal lobe epilepsy In: Baldwin M, Bailey P, and Eds. Temporal Lobe Epilepsy 461–82. Charles C Thomas: Springfield, Ill, 1958. Cendes F, Dubeau F, Olivier A et al. Neocortical spiking and surgical outcome after selective amygdalo-hippocampectomy. Epilepsy Res 1993;16:195–206. Huck F, Radvany J, Camargo CHP et al. Anterior callosotomy in epileptics with multiform seizures and bilateral synchronous spike and wave EEG pattern. Acta Neurochirurgica 1980;30 (suppl): 127–35. Paglioli E, Palmini A, Paglioli E et al. Analysis of the surgical outcome of temporal lobe epilepsy due to hippocampal sclerosis. Epilepsia 2004;45:1383–91.

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Textbook of epilepsy surgery Terra-Bustamante VC, Inuzuka LM, Fernandes RMF, et al. Surgically amenable epilepsies in children and adolescents: clinical, imaging, electrophysiological, and post-surgical outcome data. Childs Nerv Syst 2005;21:546–71. Nevens V. Inicios de la electroencefalografía en Chile. Rev Chil Epilep 2000;1:29–31. Torrealba G, Godoy J. Cirugía de la epilepsia. Cuándo, cómo y porqué. Rev Chil Neuropsiq 1989;43:239–45. Godoy J, Torrealba G, Aranda L, et al. Foramen ovale electrodes in the study of temporal lobe epilepsy. Rev Med Chil. 1992;120:134–9. Campos MG, Godoy J, Mesa MT, et al. Temporal lobe epilepsy surgery with limited resources: results and economic considerations. Epilepsia 2000;41 (suppl 4):S18–S21. Chiorino R, Donoso P, Díaz G, Aranda L, et al. Consideraciones sobre cirugía estereotáxica en el tratamiento de la epilepsia a propósito de una nueva técnica: la campotomía. Neurocirugía 1966;26:143–7. Sierra R, Bustamante E. Hemisferectomía en un caso de enfermedad de Sturge-Weber-Dimitri. Neurocirugía 1960;18:242–5. Gutierrez-Lara F, Alandete J, Vargas L, Díaz L. Stereotaxic surgery in the treatment of epilepsy. Excerpta Medica 1977; 418:225. Fandi~ no Franky J. Low cost Epilepsy Surgery in Colombia. In: Pachlatko Ch, Beran RG, Eds. Economic Evaluation of Epilepsy Management 91–104. Libbey Publishers: London, 1996. Fandi~ no-Franky J. Corpus Callosotomy in Colombia and Some Reflections on Care and Research Among the Poor in Developing Countries. Epilepsia 2000;4l (Suppl. 4):S22–S27. Jallon P. Epilepsy in developing countries. ILAE workshop report. Epilepsia 1997;38:1143–51. Bender JE, García I, Morales L et al. Epilepsy surgery. Preliminary Study. Rev Mex Neuroci 2004;5:239. Carrasco-Rojas JA. Distinción Dr. Clemente Robles Castillo al Dr. Manuel M. Velasco Suárez Humanista Universal. Cir Ciruj 2001;6:316–20. Velasco F, Velasco M, Ogarrio C, Fanghanel G. Electrical stimulation of the centromedian thalamic nucleus in the treatment of

38.

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43. 44. 45. 46. 47. 48. 49.

convulsive seizures: a preliminary report. Epilepsia 1987;28: 421–30. Velasco F, Velasco M, Velasco AL, Jimenez F. Effect of chronic electrical stimulation of the centromedian thalamic nuclei on various intractable seizure patterns: I. Clinical seizures and paroxysmal EEG activity. Epilepsia 1993;34:1052–64. Velasco F, Velasco M, Velasco AL, et al. Electrical stimulation of the centromedian thalamic nucleus in control of seizures: long-term studies. Epilepsia 1995;36:63–71. Velasco F, Velasco M, Velasco AL, et al. Electrical stimulation for epilepsy: stimulation of hippocampal foci. Stereotact Funct Neurosurg 2001;77:223–7. Velasco F, Carrillo-Ruiz JD, Brito F, et al. Double-blind, randomized controlled pilot study of bilateral cerebellar Stimulation for treatment of intractable motor seizures. Epilepsia 2005;46: 1071–81. Castillo MCR, Alonso-Vanegas MA, Brust-Maschere E et al. Institutional experience in one hundred surgically treated temporal lobe epilepsy patients with a follow-up over 2 years. Rev Mex Neuroci 2004;5:236. Alonso-Vanegas MA, Austria VJ, Santiago E. Vagus Nerve stimulation in patients with medically refractory epilepsy. Rev Mex Neuroci 2004;5:240. Villalobos R, Guzmán F, Torres JG, Rodriguez R. Epilepsy surgery assessment, pathology and prospective outcome variability in Mexico. Rev Mex Neuroci 2004;5:239. Uruiaga FJ. Historia de la Neurocirugía Peruana. In: Mendez J. ed. Historia de la Federación de Sociedades Latinoamericanas de Neurocirugía 286–297. Barlovento: Santiago, 2002. Rocca ED, Franco P. La electrocorticografía en Neurocirugía. Neurocirugía (Lima) 1955;4:3–5. Ortega VM, Gamero V. Anterior comissurotomy in the treatment for epilepsy. Excerpta Medica 1973;293:20. niguez R, García-Austt E. Complex Bogacz J, Vanzulli A, Arana-I~ structure of temporal epileptiform foci. Acta Neurol Latinoamer 1961;7:310–17. Martínez A, Poblete R, Galera R. Síndromes epilépticos, sus aspectos quirúrgicos. Arch. Venez Psiq Neurol 1972;39:93–112.

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Epilepsy surgery in Africa MF Moodley and EL Khamlichi

Introduction Epilepsy is the most common chronic neurological disorder estimated to affect at least 50 million people worldwide; 80% of whom reside in developing countries.1 In Africa where 50% of the population is under 16 years of age, the prevalence is even higher making epilepsy a significant health and socioeconomic burden. Africa is the second largest continent with 35 million square kilometers and more than 800 million people distributed in 52 different countries.2 Seventy-five percent of people with epilepsy in Africa receive inadequate or no treatment at all. Paralleling the enormous geographic, cultural and economic differences in this continent the neurological and neurosurgical services are equally diverse. Limited financial resources, illiteracy, social instability, war, lack of prioritization, poor health system infrastructure, and inadequate supplies of antiepileptic drugs in concert hinder the delivery of appropriate treatment. Furthermore, the vast majority of Africans still live in villages and there is a significant rural/urban divide in epilepsy services, with the vast majority of neurologists and neurosurgeons being concentrated in the major cities. Belief in supernatural causes and traditional treatment of epilepsy in Africa further contribute to the under-utilization of available medical services, to discrimination and social isolation.

Epidemiology and etiology of epilepsy In Africa preventable causes of epilepsy (central nervous system infections, head trauma, poor antenatal and perinatal care) are more frequent resulting in greater disability and mortality in Africa than elsewhere.3 The high incidence figures for epilepsy in developing countries is significantly attributable to symptomatic epilepsies caused by a host of parasitic and infectious diseases that are largely absent in industrialized countries.4–6 Neurocysticercosis, for example is frequently found in people with epilepsy in developing countries and in South Africa it is a major cause of seizures in both children and adults.4,7 Furthermore, in South Africa, 50% of children with recurrent seizures had had their first seizure before the age of 2 years, and 32% and 11% of the patients studied had a history of perinatal complications and meningitis respectively.6 Epidemiologic studies from North Africa are scarce, but in general, prevalence and incidence of epilepsy are much lower, perhaps because of a lower rate of infection than in SubSaharan Africa, better medical infrastructures, and more

trained medical personnel in the North than in Sub-Saharan Africa.8 Despite the advent of modern anti-epileptic drugs in the last three decades, 30–40% of patients with epilepsy have intractable seizures. Almost half of these patients are potential surgical candidates and of these carefully selected patients, chance of freedom from seizures after surgery is in the range of 60–75%. If we consider the high number of African patients with refractory epilepsy, the cost of the anti-epileptic drugs, hospitalization, and the economic conditions of the majority of patients, it becomes clear that surgical treatment is more cost effective than sustained pharmacotherapy. Epilepsy surgery has thus become readily adapted in many developing countries with limited resources like Brazil, China, India, and Turkey.9,10 These all argue in favor of the development of epilepsy surgery programs in Africa, and African neurologists and neurosurgeons should develop epilepsy surgery programs with the knowledge that the success of epilepsy surgery depends more on well-trained clinical teams, than on high-level technology.

Contribution of Africa to the history of epilepsy and epilepsy surgery Epilepsy is an ancient disorder, well described in many early civilizations with remarkable descriptions of epileptic attacks in early Babylonian texts of medicine (1000 BC)11 Despite this very ancient description, the concept of epilepsy etiology has remained for centuries dominated by supernatural views, considering seizure attacks as a divine visitation (religious concept), or with an invasion of the body by evil spirits (superstitious concept). Consequently the treatment was not medical but spiritual with religious and/or various social approaches. The contributions of Africa, particularly the Northern part, to the history of epilepsy had been significant in the Middle Ages, between the 9th and 13th centuries, the golden age of the Arab–Islamic civilization, which extended at the time around the Mediterranean Sea. Among some outstanding individuals with medical knowledge, two individuals stand out: Abu-Bakr Al Razi, ‘Rhazes’ (830–923) and Hussein Ibn Sina, ‘Avicenna’ (980–1037), who left us the best descriptions of epilepsy.12 In his huge monograph (‘Alkanun FiTib’, Rules of Medicine), Avicenna described different types of epilepsy syndromes: tonic-clonic seizures, absence and focal seizures including focal-motor seizures, with its typical extension from the toes to the proximal lower limbs and from the fingers to the proximal upper limbs, and known today under the name 125

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of Jackson, who described it 800 years later.13 In Avicenna’s monograph he also described many symptoms which can occur before or after a seizure which we now recognize as auras and postictal phenomena. The interesting point in this historical manuscript is that Avicenna, referring to Hippocrates, mentions the concept that epilepsy is a brain disease and that seizures result from an invasion of the frontal lobes by a noxious substance which then propagates towards the posterior part of the brain and later to the spinal cord and the peripheral nerves. This propagation engenders generalized seizures. He considered these seizures of the body as resulting from a contraction of the brain which is necessary for the expulsion of noxious substances, and comparing also these contractions of the brain to the contractions of the stomach during hiccup or vomiting in order to ‘chase noxious food’.13 This medical knowledge about epilepsy and many other brain diseases that excelled between the 9th and the 13th centuries in Fez and Marrakech (Morocco), in Kairouan (Tunisia), and in Cairo (Egypt), was later transmitted to Europe in the 14th and 15th centuries, where it would be improved to prepare the Renaissance movement of neurology in the 18th and 19th centuries and the modern era of epilepsy. As far as African neurosurgery is concerned it is well known that during the pharaonic era, neurosurgical procedures like trephinations were widely used in the whole continent, practiced and taught by healers in African tribes.14 The technical concepts of this trephination are based, to a great extent, on the descriptions of Arab physicians of the Middle Ages.14 Of the many outstanding Arab physicians it was mainly Abulkassim Al Zahraoui (Abulkassis) who was the pioneer of neurosurgery. He is credited with devoting a volume of his treatise (made up of 30 volumes) to neurosurgery, a precise description of many aspects of neurosurgical pathology, its treatment, instruments and neurosurgical techniques.14 In Kenya, the traditional art of skull trephination, passed down from generation to generation, and is still practiced by the Kisii tribesmen in the highlands of the South Nyanza District of Kenya.15 As recently as 1982 a local daily newspaper featured an article entitled ‘Skull Surgeon Who Never Went to Medical School’. This story focused on one of the well-known practitioners of trephination since 1955 having learned it from his grandfather. He claimed that he had performed hundreds of these procedures and that most of his patients had already been treated at hospitals without success.15 He added, ‘Doctors in Kenya are not able to open the skull the way I do, and when a patient goes to them full of broken bones in the head, the treatment is often incomplete.’ Neurosurgeons in Kenya encounter patients who have undergone this procedure. The openings in the skull vary from a few centimeters to removal of the entire vault. Trephinations were made for ritual or therapeutic purposes. It is speculated that they were intended to free the body from devils and spirits. It is thus easy to imagine that epileptics, in many African cultures viewed as possessed, underwent these trephinations.15 It is interesting to note that despite these significant contributions and the fact that this land was the birth place of our early human ancestors the vast majority of its population has not yet been part of the great technological/industrial revolutions that has occurred in many other parts of the world.

Thus, the challenges facing Africa in the domain of medicine remain immense.16 Neurosurgical practice developed in many African countries only during colonization, together with the development of the health system as soon as the European colonizers came to these countries. Initially, neurosurgery was practiced in the departments of general surgery either by general surgeons or rarely by neurosurgeons themselves.14 Modern neurosurgery was introduced and started to develop in most African countries in the early 1960s, and the teaching of this subspecialty in many African universities began between 1960 and 1970, soon after their independence. However, in South Africa neurosurgery as an independent discipline commenced much earlier at the Groote Schuur Hospital in Cape Town with the return of Hermann de Villiers Hammann from Munich, Germany in 1946.17 Neurosurgery for intractable epilepsy, on the other hand, was practiced even earlier as the late 1940s. Roland A. Krynauw, a neurosurgeon from the Department of Neurosurgery, Johannesburg Hospital in South Africa pioneered hemispherectomy for children, adolescents and young adults with intractable seizures accompanying infantile hemiplegia.18 Over a 5-year period he performed hemispherectomies on 12 patients with intractable seizures accompanying infantile hemiplegia with remarkable success. Epilepsy, either focal or generalized, was present in 10 of the 12 patients and in all these patients epileptic manifestations ceased in the post-operative period without any sedative medication. Furthermore, marked improvement in personality, behavior, and mental function was noted in all cases. His success with hemispherectomy soon attracted world wide attention to this neurosurgical procedure for intractable seizures.18

Management of epilepsy in Africa While remarkable progress has been made worldwide in the second half of the 20th century in the diagnostic evaluation of neurological diseases, including epilepsy, in Africa this development was mainly-in the more affluent North and South Africa and remains restrained in the rest of the continent by the poor socio-economic conditions. In many countries in Sub Saharan Africa neurological and neurosurgical services are nonexistent creating a broad divide – ‘From excellence to total absence’. Fortunately, EEG is available in the majority of countries in Africa (82.4%), however, the availability of other investigations are limited in the majority of African countries.19 Video EEG monitoring is available in 25.7% of African countries, 18 African countries have no CT scanners, 13 countries have only 1 CT scanner for each country and only 13 other countries have more than 2 CT scanners. Only North African countries and South Africa have an adequate number of CT and MRI scanners.19–21 In addition, even in those countries with neuroimaging equipment, the majority of the population who live in rural areas do not have access to this equipment, because of limited economic resources and a lack of medical insurance. In the absence of these advanced technologies, most of the common causes of symptomatic epilepsy cannot be diagnosed in many countries in Africa. The management of epilepsy in Africa is highly influenced by the socio-cultural misrepresentation of epilepsy. Consequently,

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Epilepsy surgery in Africa less than 20% of patients will seek medical attention after their first seizure, the other 20–30% will seek a healer or marabout (holy temple) for traditional treatment.22 The remaining 50–60% will not seek any treatment. This delays diagnosis and treatment, with more than 50% of patients seeking medical help one year after their first seizure, and 30% 5 years after their first seizure.23,24 The mainstay of pharmacological treatment throughout Africa is phenobarbital, which has two main advantages: reliability of supplies and affordability with 50–80% of treated patients being on phenobarbital.25 Most of the other older anticonvulsants like phenytoin, carbamazepine, valproic acid, and benzodiazepine are available in secondary and tertiary hospitals. The ‘new’ anticonvulsants discovered in the last 15 years are generally not available in the vast majority of countries in Africa. In South Africa on the other hand, it is available in most tertiary and quartenary hospitals and also in private clinics but cost is again a prohibitive factor for its widespread use.

Epilepsy surgery in Africa Epilepsy surgery is a well accepted, safe and effective alternative treatment for patients with medically intractable epilepsy in developed countries.26,27 However, in addition to appropriate technologies for pre-surgical evaluation, the success of epilepsy surgery depends on availability of well-trained clinical teams made up of neurologists, neurosurgeons, clinical neurophysiologists, neuropsychologists, and neuroradiologists, components not easily available in developing countries. In the 1990s, 10 of 142 developing countries conducted epilepsy surgery and by 2000, 26 such countries have reported results of epilepsy surgery in carefully selected patients and this number is gradually increasing.10 In Africa most of these reports emanate from the two extremes of the continent, the more affluent North and South Africa with almost the entire rest of the continent still experiencing a significant delay in the development of neurosurgery. The challenge is resource allocation in competition with other demands, in particular primary healthcare. A survey conducted in 1998 under the hospices of WHO, found only 565 neurosurgeons for a population of over 800 million (ratio of 1 neurosurgeon to 1,352,000 people).20 The world wide ratio is 1 neurosurgeon to 230,000 people with 1 neurosurgeon to 121,000 people in Europe and 1 Neurosurgeon to 81,000 people in North America.2 The distribution of neurosurgeons in the African continent shows that the majority are located in North Africa (Egypt 165, Algeria 130, Morocco 80, Tunisia 25) and South Africa (86). Consequently the total number of neurosurgeons in these countries is 486 for a total population of 174 million, with a ratio of 1 neurosurgeon to 358,000 people. Between North and South there are three countries that have between 8 and 15 neurosurgeons (Nigeria, Senegal, and Kenya), and the majority of other countries have between 1 and 5 neurosurgeons, with no neurosurgeons at all in 11 countries. Therefore, the ratio in Sub-Saharan Africa is 1 neurosurgeon to 7 million people. The biomedical equipment available has almost the same distribution.2 A local training program in neurosurgery is currently available only in North African countries and in South Africa.

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Most young neurosurgeons in the rest of Africa are trained outside the continent, mainly in Europe. Currently in South Africa there are a few centers in Cape Town, Johannesburg and Durban that have impressive pre-surgical technology and clinical teams who perform epilepsy surgery in carefully selected patients. (personal communication Roger Melville and James Butler). Subdural electrode placements, temporal lobectomies, and cortical resections account for the bulk of the surgery performed. Multiple subpial resections and functional hemisperectomies are also performed occasionally (personal communication Roger Melville). In Morocco it took many years to find motivated people to create a multidisciplinary team and to commence epilepsy surgery which only began in February 2005. Surgical procedures so far have included temporal lobectomies and simple structural lesion surgery. Faced with the reality of a scarcity of human and technological resources, is there room for epilepsy surgery in developing countries like those in Africa? Because of the high prevalence of epilepsy in Africa, the high cost of sustained pharmacotherapy, its medical intractability, and the high frequency of symptomatic epilepsy, epilepsy surgery offers a potential treatment to rescue a large number of patients with epilepsy in Africa. Moreover, these are the reasons behind the development of many epilepsy surgery programs in countries with limited resources, like Brazil, China, and Turkey and these programs have demonstrated that surgery is more cost effective than sustained pharmacotherapy.9 In addition, surgery will have a positive impact on the mental capacity of epileptic patients and of society in Africa, allowing patients to conceive of epilepsy as an organic disease originating from the brain, which can be cured with surgery. Even with limited technological and human resources carefully selected patients from an abundance of surgical candidates, the teams achieve outcomes comparable to those in the developed world with direct epilepsy surgery costs at a fraction of those in the developed world.

Future of neurosurgery and epilepsy in Africa More than 80% of the 50 million people suffering from epilepsy around the world live in developing countries like those of Sub-Saharan Africa where the vast majority do not receive any modern treatment or are not even identified.28 The main reasons behind this treatment gap are poor health care systems, illiteracy and cultural beliefs especially in SubSaharan Africa. Some other potential causes of this treatment gap are a lack of prioritization of epilepsy as a public health issue, inadequate preventative programs and a high prevalence of epilepsy in Africa. Regarding the ‘surgical treatment gap’ in epilepsy there is a great divide – well catered for in North African countries (Egypt and Morocco) and South Africa and almost non-existent in the rest of the continent.10,29 If we consider the proposed ratio by H. G. Wieser of 1 epilepsy center for 7 million people as estimated in developed countries, Africa with more than 800 million people, needs more than 100 epilepsy surgery centers making the bridging of the surgical treatment gap in

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epilepsy in Africa an impossible dream.10 The main problem to overcome is the scarcity of neurosurgeons and neurologists in the majority of African countries. Without their expertise it becomes difficult to organize any multidisciplinary team to solve the huge challenge of reducing the treatment gap in epilepsy between Africa and the developed world. Pioneering African neurosurgeons should develop neurosurgery in their countries by encouraging local training programs which remain the major pillar in the development and quicker promotion of neurosurgery in their countries as exemplified by North African countries and South Africa. African trainees in developed countries generally are not keen to return, and when they return do not have the resources which they have trained with rendering them ineffective or demoralized and thus paving the way for the growing ‘brain drain’ from Africa to Europe and North America. The second main problem is to convince the political authorities and health planners that epilepsy is a public health issue, despite other high priority health demands, as in most African countries epilepsy and neurosurgery in general seem to have a very small place on public health priority programs. Neurologists and neurosurgeons as advocates for patients with epilepsy should sensitize other individuals including non-medical professionals, patients and community NonGovernmental Organization (NGOs) to apply pressure on governments, health planners, and decision makers so that proposals for building sustainable training programs are put in place. Epilepsy care development in Africa can also benefit from international cooperation and the help of international institutions like the WHO, the ILAE, and the International Bureau for Epilepsy (IBE). These three institutions make a major collaborative effort through the global campaign against epilepsy ‘Out of the Shadows’, which was launched in 1997 ‘to improve acceptability, treatment, services and prevention of epilepsy worldwide in order to address discrimination against people with epilepsy and to diminish the treatment gap in the developing regions of the world.’1 Three other institutions can efficiently help epilepsy programs in Africa: The World Federation of Neurosurgical Societies (WFNS), the World Federation of Neurology (WFN),

and the Pan-African Association of Neurological Sciences (PAANS).30 These institutions can help at different levels: at the information level by sending reports on the epilepsy care situation in Africa to governments and universities in African countries; at the training and research levels by organizing courses, seminars, and granting fellowships to young African doctors to be trained in neurology and neurosurgery. In 1998 the WFNS initiated the creation of the ‘WHO Africa Sub-Committee in Neurosurgery,’ which prepared a report on the state of neurosurgery in Africa, which was presented to the WFNS and the WHO working group in Neurosurgery in 1999,20 resulting in the creation of the ‘WFNS Foundation For Training Young Neurosurgeons from developing countries’ in 2002. It also created the first reference center in the Department of Neurosurgery at the University Hospital in Rabat to train young African doctors, and the Mohamed V University of Rabat arranges and insures their training.

Conclusion Epilepsy remains an important public health problem in Africa. With its high prevalence and the lack of appropriate diagnostic and therapeutic facilities it represents an important economic and social burden in the majority of African countries. The main constraints widening the treatment gap in epilepsy include lack of knowledge about epilepsy, cultural attitudes especially in rural people, poor advocacy for neurosurgery at governmental level, and the limited human and material resources in the majority of African countries. The optimistic element, however, is the existence of neurosurgical centers of excellence at the two extreme parts of the continent, namely North and South Africa. Neurosurgeons in these areas can integrate epilepsy surgery in a fairly rapid way in their centers, using non-invasive pre-surgical investigations to successfully select the patients with intractable epilepsy. With the combined effort of North Africa and South Africa and substantial support for African neurosurgery from the international community, the development of neurology and neurosurgery in Sub-Saharan Africa can be improved and the treatment gap in epilepsy can be filled.

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8.

Scott RA, Lhatoo SD, Sander JWAS. The treatment of epilepsy in developing countries: where do we go from here? Bulletin of the World Health Organization 2001;79:344–51. Kalangu KKN. Pediatric neurosurgery in Africa–present and future. Child’s Nervous System 2000;16:770–5. Commission on Tropical Diseases of the International League Against Epilepsy. relationship between epilepsy and tropical diseases. Epilepsia 1994;35:344–51. Moodley M, Moosa A. Treatment of neurocysticercosis. “Is Praziquantel the New Hope.” Lancet 1989;(8632):262–3. Moodley M, Bullock MRR. Severe neurological sequelae of childhood bacterial meningitis: S Afr. Med. J 1985;68(8):566–70. Leary PM, Morris S. Recurrent seizures in childhood: western cape profile. South Afr. Med J 1998;74:579–81. Dawood AA, Moosa A. Cerebral cysticercosis in children. J Trop Pediatr 1984; June 30(3):136–9. Marie-Preux P, Druet-Cabanac M. Epidemiology and etiology of epilepsy in Sub-Saharan Africa. Lancet – Neurology 2005;4:21–31.

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10. 11. 12. 13. 14. 15. 16.

Engel J Jr. et al. Alternative treatments in epilepsy: global issues for the practicing neurologist. World Federation of Neurology Seminars in Clinical Neurology. New York, NY. Demos 2005:95–105. Wieser HG, Silfvenius H. Overview: epilepsy surgery in developing countries. Epilepsia 2000;41(Suppl 4):S3–S9. Kinnier Wilson JV, Reynolds EH. Translation and analysis of a cuneiform text forming part of a Babylonian treatise on epilepsy. Medical History 1990;34:185–98. Ammar S. En souvinir de la medecine arabe. Quelques-uns de ses grand noms. Ed Soc. Tunisienne de diffusion. Tunis 1965. Ibn Sina AH. Al Kunun FiTib, Tome 2, 76–89 (in Arabic). El Khamlichi A. African neurosurgery. Part 1: Historical outline. Surgical Neurology 1998;49:222–7. Dar J. Perspectives of international neurosurgery: neurosurgery in Kenya: Neurosurgery 1985;16:267–9. Peter JC. Pediatric neurosurgery–a South African perspective. Child’s Nervous System 2003;19:133–6.

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Epilepsy surgery in Africa 17. 18. 19. 20. 21. 22. 23.

Peter JC. The Department of Neurosurgery of the University of Cape Town: a brief historical overview. Neurosurgery 1999; 45(S):1228–36. Krynauw RA. Infantile hemiplegia treated by removing one cerebral hemisphere. J Neurol Neurosurg Psychiat 1950;13:243–67. WHO: Atlas Epilepsy Care in the World 2005. El Khamlichi A. African neurosurgery: current situation, priorities and needs. Report presented to the WHO Working Group on Neurosurgery, Geneva, February 20, 1999. El Khamlichi A. African neurosurgery: current situation, priorities, and needs [Special Reports]. Neurosurgery 2001;48(6);1344–7. El Khamlichi A. Contribution à l’étude de l’épilepsie en milieu marocan. 1974; Thése de doctorat, Université Mohamed V, Rabat. Danesi MA, Adetunji JB. Use of alternative medicine by patients with epilepsy: a survey of 265 epilepsy patients in a developing country. Epilepsia 1994;35:344–51.

24. 25. 26. 27. 28. 29. 30.

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Reis R. Evil in the body, disorder of the brain; interpretations of epilepsy and the treatment gap in swaziland. Trop Geogr Med 1994;46:S40–3. Kissani N, Belaidi H, Bennani Othmani M. et al. Comparison du profil des patients épileptiques au Maroc à plusieurs années d’intervalle. Epilepsies 2001;13:251–7. Engle J Jr. Surgery for seizures. N Engl J Med 1996;334:647–52. Williamson PD, Jobst BC. Epilepsy surgery in developing countries. Epilepsia 2000;41 (Suppl 4):S45–50. Jallon P. Epilepsy in developing countries. Epilepsia 1997;38: 1143–51. Meinardi H. et al. on Behalf of the ILAE Commission on the Developing World. The treatment gap in epilepsy: the current situation and ways forward. Epilepsia 2001;42:136–49. Bower JH, Zenebe G. Neurologic services in the nations of Africa. Neurology 2005;64:412–15.

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History of epilepsy surgery in Southeast Asia S-H Lim

Overview of epilepsy surgery in Southeast Asia Southeast Asia (SEA) covers an area of about 4 100 000 square kilometers containing the following countries: Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand, and Vietnam. As of 2007, there are more than 580 million people living in this region. If the epilepsy prevalence rate is 5 per 1000 population, SEA would have around 2.9 million people with epilepsy (PWE). If a quarter of these PWE are medically refractory, more than 700 000 of them could be evaluated for epilepsy surgery. However the epilepsy surgery treatment gap is huge in SEA. An informal survey conducted by the author in 2003 (unpublished data) showed that selective amygdalo-hippocampectomy) while the rest were lesionectomy, neocortical resection, corpus callosotomy, hemispherectomy, and implantation of vagus nerve stimulator (VNS). Similar to the results in countries belonging with developing economies, 60–70% of temporal lobectomy patients achieved Engel Class I seizure outcome, while another 10–15% had rare seizures or worthwhile improvement. These surgeries were performed at tertiary referral centers, established in the late 1980s in Thailand, early 1990s in Singapore, and in the second half of the 1990s in Malaysia, Philippines, and Indonesia. There are currently 1–4 centers per country, located in capital cities. Each centre has 1–5 epileptologists and 1–2 neurosurgeons with special interest and/or trained in epilepsy surgery. Many centers perform long-term video-EEG monitoring and structural MRI routinely. The usage of SPECT, Wada Test, MRS, neuropsychological testing, and psychiatric assessment is variable. Intracranial EEG recordings are rarely performed and PET study is only available in two countries. To date, there is no epilepsy surgery program in Brunei, Cambodia, Laos, Myanmar, or Vietnam. There are common issues in SEA that continue to retard the development of epilepsy surgery in this region. Costs of evaluations and surgery are relatively high in most countries. Socially and culturally, many patients were reluctant to undergo cranial surgery for a condition not considered immediately life-threatening by these patients and their 130

family. This tied in with the perception by the lay that cranial surgery is oftentimes morbid and considered an extreme intervention. Family support in SEA was relatively strong, thereby obviating the need for independence and selfsupport. Many patients in the rural areas are still probably undiagnosed and not informed of the epilepsy services available in the country. Public transport services in big cities are fairly prevalent and convenient. The need to be seizure free to drive was not as pressing as in other countries like the United States. The following sections describe the development of epilepsy surgery in Indonesia, Malaysia, Philippines, and Singapore. The epilepsy surgery programe in Thailand is briefly mentioned here as the details are described in Chapter 19.

History of epilepsy surgery in Indonesia Indonesia is the largest country in Southeast Asia with a population of 224 millions and has the largest pool of epilepsy patients who require epilepsy surgery. However, there was no epilepsy surgery program till the end of the 1990s. Unlike other SEA countries where epilepsy surgeries are driven by trained epileptologists, surgery for epilepsy in Indonesia was initiated by a neurosurgeon, Dr Zainal Muttaqin from Semarang, Indonesia. Dr Muttaqin, influenced by the blooming of epilepsy surgeries in other parts of the world, developed an increasing interest in epilepsy surgery in the middle of the 1990s. To increase the awareness of clinicians and lay-public in epilepsy surgeries, he organized an epilepsy surgery symposia at national and regional neurology scientific meetings, at which Prof T Hori from Japan was a keynote speaker. He also started writing review articles on surgery for epilepsy in Indonesian language medical journals. He then decided to acquire the skills of epilepsy surgery and traveled to Hiroshima, Japan many times between 1996 and 2001 to learn epilepsy surgery from Dr Kazunori Arita and Prof Kaoru Kurisu, at the Hiroshima University. With their help, the first case of left temporal lobectomy was performed in 1999. Surgery was performed based on clinical information suggestive of temporal lobe seizures and MRI evidence of left temporal sclerosis. Another 10 cases were operated in 2000–2001, all based on clinical history suggestive of TLE semiology and unilateral hippocampal structural abnormality on MRI.

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History of epilepsy surgery in Southeast Asia Due to the limitation of financial resourses, most of the MRI machines were of 0.5 Tesla in strength, including the only centre (Diponegoro University Hospital) that performed epilepsy surgery. Only a few hospitals affiliated to universities had acquired 1.5 Tesla machines which are not used for presurgical evaluation. Prolonged EEG recording with video monitoring facility is still lacking, thus it is not part of presurgical evaluation protocol. Even for routine EEG recording, most of the machines were 10 channels, though a few of the nonepilepsy surgery centers have acquired 20–32-channel EEG machines with video recording capability. There is also a lack of trained electroencephalographers (EEGers) in Indonesia. Between 2000 and 2006, there were three adult neurologists who received 6–12 months of training, mainly in routine and noninvasive long-term EEG monitoring and clinical epileptology. Other issues included inconsistent presurgical evaluation protocols, postoperative follow-up mainly by neurosurgeon, no other trained neurosurgeon, as well as late identification and referral of intractable cases. As such, decision for surgery was made mainly by Dr Muttaqin, very often based mainly on the findings obtained from low-resolution MRI imaging. Despite the above-mentioned limitations, more than 100 patients had epilepsy surgery between 1999 and 2006. Over 90% had temporal lobectomy with removal of mesial structures, mainly for patients with mesial temporal sclerosis. A few patients had a Wada test and subdural grid recording (in those with normal MRI). One patient had intraoperative ECoG. For those with temporal lobectomy that had 12–82 months of follow-up, about 75% had Engel’s class I seizure outcome and two-thirds of these patients could have their AEDs withdrawn. A few patients had lesionectomy, multiple subpial transaction, functional hemispherectomy and corpus callosotomy.

History of epilepsy surgery in Malaysia Malaysia has a population of 28 million people but only had one ‘one-stop’ epilepsy surgery center in the 1990s and early 2000s. The adult epileptologist who pioneered the epilepsy surgery programme in Malaysia was Professor Raymond Azman Ali. He was trained by Prof David Fish in video-EEG monitoring, presurgical evaluation, and neuroimaging at the Institute of Neurology, Queen Square, London, from 1992 to 1994. At the same time, a neurosurgeon, Prof Benedict Selladurai, was also trained at the institute by Prof David Thomas and Mr. William Harkness in epilepsy surgery. Upon returning to Malaysia in 1994, they together started the epilepsy surgery programme in 1995 at the Universiti Kebangsann Malaysia Hospital. The first operation was performed on an 11-year-old boy with a dysembryoplastic neuroepithelial tumor in the mesial temporal region, who became seizure free. When they announced the successful operation in one of the national newspapers, interest in epilepsy surgery amongst PWE increased tremendously. Not all surgical patients were from the same hospital, as many were referred from other major hospitals, including Kuala Lumpur Hospital and University Malaya Medical Centre. The hospital was supportive in upgrading the neurophysiology laboratory and neuroimaging service. However, they did not have a stand-alone

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epilepsy surgery centre, in-patient ward or epilepsy nursing staff. They also employed neuropsychologists interested in epilepsy. One of the psychiatrists went on to subspecialize in neuropsychiatry. In 2000, Prof Lai-Choo Ong, a pediatric neurologist, received training in Royal Melbourne Children’s Hospital under the supervision of Dr Simon Harvey. Another adult neurologist, Dr Hui-Jin Tan, is currently being trained in clinical epilepsy. EEG facilities included a video-EEG monitoring unit using scalp and sphenoidal electrodes. A few patients had intraoperative ECoG. They have not developed intracranial EEG capability. As for neuro-imaging capability, they have 1.5 T MRI machine and are able to add MRS to their evaluation protocol. Ictal SPECT was rarely performed. Neuropsychological evaluation was routine, but there was no expertise in performing WADA tests. Standard anterior temporal lobectomy was started in 1996, followed by selective amygdalohippocampectomy and lesionectomy in 1999. Hemispherectomy, corpus callosotomy, and implantation of vagus nerve stimulator were started in 2001. Between 1996 and 2006 around 75 cases of anterior temporal lobectomy and 15 cases of selective amygdalohippocampectomy were performed with 70% of these patients achieving Engel’s Class I seizure outcome. Two patients had hemispherectomy and both became seizure free. Twelve patients had lesionectomy and 55% achieved Class I seizure outcome. There were three cases of corpus callosotomy and one VNS and all had Class IV seizure outcome. The main challenges encountered in developing the epilepsy surgery programme were lack of full-time staff (epileptologists, epilepsy neurosurgeons, neuroradiologists, neuropsychologists, nurses, and neuroanaesthesiologists). Currently only one centre performs a consistent number of epilepsy surgeries. Even then, the infrastructure for this ‘one-stop’ centre is underdeveloped.

History of epilepsy surgery in the Philippines The Philippines have a population of 87 millions. There are 3–4 hospitals offering epilepsy surgery since the late 1990s. With the continued return of clinicians trained in epileptology and subsequently in epilepsy surgery, the comprehensive epilepsy program was established in 1997 at the St. Luke’s Medical center. This center is one of the premier private hospitals in the country with the necessary resources to support the epilepsy surgery program. The center had a ‘multidisciplinary team’ composed of the following members: epileptologists, an epilepsy surgeon (Dr Annabelle Chua), neurophysiologists, psychiatrist, nurses, EEG technicians, and dieticians. The objective of the program was not only to evaluate patients and their suitability for epilepsy surgery, but also to offer overall better management and control of patients with difficult to control seizures. The Epilepsy Monitoring Unit at the St. Luke’s Medical Center is a three-bed unit capable of offering 2-hour and prolonged video-EEG monitoring. In addition, there are three other one-bed units in other hospitals with in-house epileptologists trained in video-EEG monitoring, namely the University of the Philippines-Philippine General Hospital, the Philippine Children’s Medical Center, and the Makati Medical

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Center. Epilepsy clinics were established in two training hospitals: the University of the Philippines-Philippine General Hospital and the University of the East-Ramon Magsaysay Medical Center. Presurgical evaluation included CT scan, MRI, PET scan, video-EEG, neuropsychological evaluation and WADA test. For the latter, this is being done only at St. Luke’s Medical Center, with its performance being limited by the difficulty in procuring amobarbital from the United States. There was also intracranial electrode placement, extraoperative monitoring, intraoperative ECoG, and mapping of eloquent cortex. Most patients who had resective surgery had either hippocampal sclerosis or lesion such as tumors and vascular malformations. Detailed information on the number and types of surgery, as well as seizure outcome were not available.

History of epilepsy surgery in Singapore Singapore is the smallest country that provides epilepsy surgery in SEA. It has a population of 3.6 million, and thus the number of potential surgical candidates is considered relatively low. An epilepsy surgery programme was established in Singapore in 1992 after the return of an adult neurologist, Dr Shih-Hui Lim, from the Cleveland Clinic Foundation (CCF). With the sponsorship of the Ministry of Health, Singapore, Dr Lim completed a formal clinical fellowship in epilepsy and clinical neurophysiology under the supervision of Prof Hans O Lüders from 1989 to 1991. He also obtained board certification by the American Board of Clinical Neurophysiology. A year later, another adult neurologist, Dr Michael WL Chee, also sponsored by the Ministry, completed similar training at CCF from 1990 to 1992. In addition, Dr Prem Kumar Pillay, a Singaporean doctor receiving his neurosurgery residency training at CCF in the late 1980s and early 1990s, was trained in epilepsy surgery by Dr Isam Awad. In the early 1990s, a pediatric neurologist, Dr Wei-Ling Lee received pediatric epilepsy training at Toronto Children’s Hospital in Canada as well as at the CCF. In the mid-1990s, Dr Ngai-Kun Loh, an adult neurologist spent a year and Dr Kheng-Kooi Tan, a neurosurgeon, spent a few months at CCF. Dr Andrew Pan, an adult neurologist, was sent by Ministry of Health to CCF from 1999 to 2001 to be trained in Epileptology and Sleep Disorders. Thus the epilepsy surgery programe in Singapore in the first 10 years was considerably influenced by the philosophy of Dr Lüders. In 2003, Dr Nigel Tan received his epilepsy training with Prof Sam Berkovic at the Comprehensive Epilepsy Program at Austin Health. His return added value to the existing epilepsy surgery programme. One-Bed video-EEG monitoring unit was first set up at Tan Tock Seng Hospital in 1992 and at Singapore General Hospital in 1993. Scalp and sphenoidal electrodes were used routinely. Most patients were monitored for 4–5 days after stopping medication, with an aim of recording at least three seizures. Due to administrative and logistic reasons, early postictal SPECT was carried out during office hours at the Singapore General Hospital. For those who had postictal SPECT had interictal SPECT during the monitoring period. All patients had structural MRI (1.5 T) which included oblique coronal

images with flash/gradient echo, T2-weighted, and FLAIR sequences. Volumetric study was performed as part of the research. MRS was introduced towards the end of the 1990s. FMRI for language lateralization was started in the early 2000s, mainly for research purposes. From 2005, structural MRI using a 3.0 T MRI machine became more common. WADA tests were performed routinely in the 1990s and infrequently in the 2000s. Neuropsychological and psychiatric assessments were routine. Decision for surgery was made mainly based on structural MRI findings, scalp EEG data, and analysis of semiology of recorded seizures. As long as there was no discordant information, good candidates would proceed with resective surgery. Depth electrodes implantation was performed only once in 1994 to lateralize seizure onset. Chronically implanted subdural grid electrodes and extraoperative cortical mapping were carried out in four patients with nonlesional extratemporal lobe epilepsy in 1994 and 1995. Due to the poor seizure outcome from these cases, better MRI imaging facilities, avoidance of performing resective surgery in patients with no lesion on MRI, as well as constraint of doctors’ time, invasive intracranial EEG recordings were rarely performed in the 2000s. As expected from a center conducting mainly noninvasive presurgical evaluation, temporal lobe surgeries (standard anterior temporal lobectomy cases were more than selective amygdalohippocampectomy) and to a lesser extent, lesionectomy, were the most commonly performed surgeries. Corpus callosotomy, extratemporal resective surgery, hemispherectomy and implantation of vagus nerve stimulator were much less frequently performed. Between 1992 and 2002, more than 110 patients had temporal lobectomy, 12 had lesionectomy, four had corpus callosotomy, three had extratemporal resection, two had hemispherectomy and seven had VNS implanted. They have been followed-up for an average of 8.5 years (range 5–15 years). There was no death or irreversible complications from surgery or intracranial EEG recording. Of those who had temporal lobe surgeries, about 66% had Class I seizure outcome (including 2 patients who had re-operation), 20% had worthwhile improvement (>90% seizure reduction) and the rest had no significant change (300) in the last 10 years. As described in Chapter __, the were two eras of epilepsy surgery in Thailand: the era of general neurosurgery before the 1990s and the era of epilepsy surgery as a specialty after the 1990s. For the latter, detailed neuroimaging and clinical neurophysiology information became an integral part of the presurgical evaluation process. Professor Sira Bunyaratavej and Professor Pongsakdi Visudhipan from Ramathibodi Hospital played an important role in the development of the new epilepsy surgery era in the 1990s.

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History of epilepsy surgery in Southeast Asia The major epilepsy surgery center in Thailand is the Chulalongkorn Comprehensive Epilepsy Program (CCEP) at Chulalongkorn University Hospital, Bangkok, Thailand, led by Dr Chaichon Locharernkul, an adult epileptologist and Dr Teeradej Srikijvilaikul, an adult and pediatric neurosurgeon. Dr Chaichon was trained in presurgical evaluation by Prof GA Ojemann and Prof GE Chatrain at University of Washington at Seattle, USA and by Dr A Ebner at the Bethel Epilepsy Center in Germany. Dr Srikijvilaikul was trained by Dr WE Bingaman at CCF. Other team members included Drs Tayard Desudchit, Krishnapundha Bunyaratavej, Chusak Limotai, and Jakrin Loplumlert, all had formal training in USA (three at CCF). Together, they offered the most comprehensive presurgical evaluation, including the routine use of SISCOM and 3.0 T MRI. Other centers providing epilepsy surgery programme were located at Pramongkutklao Hospital and Bangkok General

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Hospital. Both centers were established by Dr Yotin Chinvarun in 2001 and 2002, respectively. Dr Chinvarun was an adult epileptologist trained by Prof Sam Berkovic in Australia. Members in his team included Dr Siraruj Sakoolnamarka and Dr Dittapong Boonnampol (both were adult and pediatric neurosurgeons), as well as Dr Chachrine Nabangchang (a pediatric epileptologist). This is the only center in SEA that provided gamma knife surgery for epilepsy. Acknowledgments The author greatly appreciates the following persons who have given the above information: Dr Zainal Muttaqin from Indonesia, Dr Raymond Azman Ali from Malaysia, Dr Annabelle Chua from the Philippines, Drs Pongsakdi Visudhipan, Chaichon Locharernkul, and Yotin Chinvarun from Thailand.

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Epilepsy surgery in India DK Lachhwani and K Radhakrishnan

Although trephination as a treatment for epilepsy might have been practiced in ancient India more than 4000 years ago,1 the first modern epilepsy surgery in India was undertaken in the year 1952.2 As has happened elsewhere in the world,3 surgical treatment of epilepsy in India went through three phases: an initial enthusiasm (1951–1970), followed by a period of decline and a recent resurgence (from 1995). In this chapter, we intend to trace the evolution of epilepsy surgery in India along with a brief biographical sketch of the pioneers who contributed to its early development, and discuss in detail its present state and future perspectives.

The beginning The modern era of neurosurgery in India commenced with the establishment of the first department of neurosurgery by Dr. Jacob Chandy (Figure 16b.1a) in 1949 at the Christian Medical College, Vellore, in the erstwhile state of Madras (present Tamil Nadu) in southern India.4 After completing his medical education at Madras Medical College, Madras and Masters in Surgery at the University of Pennsylvania, Philadelphia, Chandy underwent neurosurgical training at the Montreal Neurological Institute during 1945–1948 under Dr. Wilder Penfield. After a brief assignment with Dr. Theodore Rasmussen, who was then setting up a neurosurgery department at Chicago, Chandy returned to India and joined the Christian Medical College, Vellore in 1949. One year later, Dr. Baldev Singh (Figure 16b.1b) joined Chandy as a neurologist. After completing his medical graduation, Singh joined King Edward Medical College, Lahore in 1922, where his initial interest in neuroanatomy developed. During his training in neurology at the National Hospital, Queen Square, London, Singh was fortunate to work with Kinnear Wilson, Lord Brain and McDonald Critchley. Reading about Berger’s rhythm, stimulated Singh to undergo a training course in electronics and construct an indigenous apparatus in the 1940s to record the electrical activity of the brain of experimental animals. Singh went over to Gibbs’s laboratory at Chicago in 1950 and spent the year, where he met Dr. Percival Bailey and participated in EEG recording on epilepsy patients on whom Bailey operated. This training proved useful to Singh to develop an epilepsy surgery program at Christian Medical College, Vellore. Coinciding with Penfield’s visit to Christian Medical College, Vellore, the first epilepsy surgery in India was performed on Aug 25, 1952 by Chandy on a 19-year old male patient with infantile right hemiplegia. Singh was in the operation theater supervising the EEG recording. 134

At that time, 150 km north of Vellore, in the city of Madras, the second department of neurosurgery in India was being developed by Dr. B. Ramamurthi (Figure. 16b.1c). After a brilliant undergraduate education, he secured Master of Surgery and Fellowship of the Royal College of Surgeons of Edinburgh in 1947. Ramamurthi received his initial training in neurosurgery at Newcastle, UK. He subsequently visited various neurosurgical centers in Europe and spent four months with Penfield at the Montreal Neurological Institute. In October 1950, Ramamurthi joined the Madras General Hospital and Madras Medical College and started the department of neurosurgery, which he later developed into the Institute of Neurology, Madras.5 Ramamurthi was helped with the EEG recording by Dr. T. S. Narasimhan (Figure 16b.1d), a neurosurgeon and electroencephalographer practicing in the city of Madras, who also held an honorary attachment in the Madras General Hospital. The first epilepsy surgery at the Madras General Hospital was done by Ramamurthi in 1954. Incidentally, the four pioneers who were involved with the early development of epilepsy surgery in India – Chandy, Singh, Ramamurthi, and Narasimhan – started the Neurological Society of India in 1951 at Madras.5 While three of them passed away, (Narasimhan in 1959, Singh in 1998, and Ramamurthi in 2003), Chandy expired on June 23, 2007.

Initial enthusiasm During the 1950s, 1960s, and the first half of the 1970s, several patients with uncontrolled epilepsies were operated at Christian Medical College, Vellore,2,6,7 and Institute of Neurology, Madras.8–10 The localization of the epileptogenic focus was based on seizure semiology as obtained by history, and data from scalp interictal EEG and radiological investigations available then such as skull radiograph, pneumoencehalogram, and carotid angiogram. At the Christian Medical College, Vellore, while local anesthesia was favored during the first decade and half, most of the subsequent surgeries were performed under general anesthesia.6,7 Pre- and post-resection electrocorticogram (ECoG) was routinely done using surface and depth electrodes. Cortical stimulation to map motor and language areas and induction of seizures intraoperatively were practiced when indicated. In a recent retrospective analysis of the clinical profile and outcome of 141 patients operated for intractable epilepsy at Christian Medical College, Vellore (a majority of them during 1950s, 1960s, and first half of the 1970s), 102 (73%) had temporal

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Epilepsy surgery in India

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Figure 16b.1 The pioneers who contributed to early development of epilepsy surgery in India. (a) Professor Jacob Chandy (1910–2007). (b) Professor Baldev Singh (1904–1998). (c) Professor B. Ramamurthi (1922–2003). (d) Dr. T. S. Narasimhan (1913–1959).

lobe, 23 (16%) had extratemporal, and 16 (11%) had multifocal seizures.11 The surgical procedures undertaken for TLE were lesionectomy (28 patients), temporal lobectomy with amygdalotomy (25 patients), temporal lobectomy with amygdalotomy and hippocampectomy (10 patients), amygdalotomy alone (15 patients), and lesionectomy with amygdalotomy in one case. For extratemporal epilepsies, lesionectomy was done in 24 patients and lobectomy for 2 patients. For multififocal epilepsy, 12 hemispherectomies and 4 stereotactic anosotomies were performed. The overall outcome was assessed as total or near total seizure control in 53% of patients and a worthwhile improvement in 20% of patients.11 In the mid-sixties, functional neurosurgery was established in the Institute of Neurology, Madras and stereotactic procedures for focal and generalized seizures were practiced.5 Stereotactic lesions were made in the amygdalohippocampal region for TLE and in the central medial nucleus of the thalamus, the field of Forel, and in the internal capsule for generalized seizures and infantile spasms.8–10

The decline In the mid-seventies, epilepsy surgery took a dramatic downward trend in the country. Thus, 100 out of the 102 patients with intractable TLE operated on at Christian Medical College, Vellore, until 1990,11 were performed before 1980.7 The retirement from active service of Chandy and Ramamurthi from the centers they almost single-handedly developed, less than expected post-operative seizure outcome, availability of more effective antiepileptic drugs, and stigma associated with epilepsy surgery due to its mistaken identity with psychosurgery collectively contributed to this decline.

The resurgence The recognition in the 1990s that a majority of patients with medically refractory partial seizures have surgically remediable lesions that can be identified by relatively simple non-invasive studies such as magnetic resonance imaging (MRI) and scalp recorded interictal and ictal EEG has resulted in the evolution

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of epilepsy surgery programs in developing countries with results comparable to that of developed countries.12,13 A recent survey revealed that, in 26 of 142 (18.3%) developing nations, at least one center regularly conducted epilepsy surgery.14 One of the authors (KR) returned to India in 1994 after having had training at the Epilepsy Program, Mayo Clinic, Rochester, MN and developed the R. Madhavan Nayar Center for Comprehensive Epilepsy Care at the Sree Chitra Tirunal Institute for Medical Sciences and Technology, a tertiary referral center, situated at Trivandrum, the capital city of the South Indian state of Kerala.15 Since mid-1995, this center has undertaken, on average, 66 epilepsy surgeries per year. Almost simultaneously, epilepsy surgery programs were started at the All India Institute of Medical Sciences, New Delhi, and National Institute of Mental Health and Neurosciences, Bangalore. During the last decade, these three centers together have undertaken nearly 1000 epilepsy surgeries, which is five times more than the epilepsy surgeries performed in India during the previous four and half decades.

Present state The success of epilepsy surgery is dependent upon the early identification of potential surgical candidates, and selecting from them, ideal candidates destined to have a postoperative seizure-free outcome.16 Two basic requirements must be fulfilled before an epilepsy surgery program can be introduced in any geographical region: existence of a level of medical infrastructure to identify epilepsy patients with medical refractoriness, and a comprehensive epilepsy care organization where such patients can be subjected to a multidisciplinary evaluation to decide about surgical candidacy. There are only about 800 neurologists for the 5–10 million persons with epilepsy in India. While 70% of the people with epilepsy in India reside in rural areas, almost all the neurologists practice in urban areas.17 A majority of patients with epilepsy in India and other developing countries are therefore treated and followed-up by primary- and secondary-care physicians, who have little knowledge about the recent trends in the management of epilepsies. To many of them, epilepsy is still an incurable chronic disorder. Epilepsy clinics in a developing country set-up have to cater to a large number of patients with very limited skilled personnel. Overcrowding with patients and the consequent overburdening of the service providers, make time available for clinical assessment of individual patients very limited.18 A frequent difficulty encountered in identifying medical refractoriness among patients with chronic epilepsy in developing countries is that, although many drugs have been used, none were given for sufficiently long periods and in adequate dosages, either alone or in proper combinations.19 These factors contribute to considerable delay in the identification of prospective surgical candidates. Epilepsy surgery centers in developing countries will lack the full range of state-of-the-art technologies such as single photon emission tomography (SPECT), positron emission tomography (PET), and magnetoencephalography usually available in centers in the developed world to perform noninvasive presurgical evaluation.20 In India, patients or their families will have to bear the cost of epilepsy care. Although the

total direct cost of presurgical evaluation and surgery in developing countries amounts to a small fraction of the cost incurred in the Industrialized World, this expenditure is beyond the reach of the majority.21 Very few patients in India can afford the cost of intracranial electrodes used for invasive evaluation. In order to become cost-effective, epilepsy surgery centers in developing countries will have to achieve excellent results by selecting candidates destined to have a seizure-free outcome using locally available limited technology and expertise, without compromising on patient safety.21 Because of these reasons, the process of selection of patients for epilepsy surgery in India to some extent differs from that of developed countries. Patients with medical refractory epilepsy belong to different categories depending upon the degree of complexity involved in presurgical evaluation and the post-operative seizure outcome.22 The prototype of a surgically remediable syndrome is mesial TLE with hippocampal sclerosis (MTLEHS), which constitutes more than half of those patients with medically refractory epilepsy worldwide.23 Non-invasive evaluation utilizing history, high resolution MRI, scalp videoEEG, and neuropsychological findings can identify patients with mesial temporal lobe epilepsy and those with other circumscribed, potentially epileptogenic lesions, 70–90% of whom become seizure-free following resective surgery.16,24 Selected mesial temporal lobe epilepsy patients with consistent unilateral temporal interictal epileptiform abnormalities may not even require ictal video-EEG recordings.25 Patients with large epileptogenic lesions involving primarily one hemisphere, and those with diffuse epileptic encephalopathies and multifocal disease can be selected for functional hemispherectomy or hemispherotomy and corpus callosotomy, respectively, based on non-invasive data.22 Patients with extratemporal partial seizures, disorders of cortical development, and those with normal MRI will require extensive, sometimes repetitive studies with PET, SPECT, and intracranial electrode placement, which escalate enormously the cost of presurgical evaluation.20 Even with these expensive evaluations, in this group of patients, the postoperative outcome is often not favorable.26,27 A stepwise approach by initially operating on best outcome patients and reserving more difficult to treat patients to a later date as experience develops will help each center to understand its capabilities and limitations and to move forward.21 As detailed below, in evolving the most productive epilepsy surgery program in India today, the R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Trivandum, has given due emphasis to address the above special issues relevant to epilepsy care in developing countries. R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Trivandum The center is named after the late R. Madhavan Nayar, a pioneering industrialist of Kerala, who donated a generous sum of money to start a comprehensive epilepsy care program.15 Three neurologists, two neurosurgeons, two neuroradiologists, a psychologist, a psychiatrist, and a medical social worker spend 25–50% of their working time with the epilepsy program. A three-patient video-EEG monitoring facility performs on an average 300 long-term monitoring studies

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Epilepsy surgery in India annually. A facility to do functional studies, spectroscopy, and T2 relaxometry was added recently to the 1.5 Tesla MRI already available. Patients are classified according to their income into four categories; while the poorest group (~15% of patients) receives totally free treatment, the richest group (~30%) will have to bear the total hospital charges, and the intermediate groups pays 50–75% of the incurred actual cost. The center is sustained by the income generated through patient charges and by the financial support received from the Government of India for caring for the underprivileged. In addition, a local patient organization, Epilepsy Self Help Group, chips in with financial assistance for the needy through the donations it receives.15 The first epilepsy surgery (anterior temporal lobectomy with amygdalohippocampectomy) at the R. Madhavan Nayar Center for Comprehensive Epilepsy Care was undertaken on March 20, 1995. The patient was a 25-year-old gentleman with left mesial temporal sclerosis and medically refractory complex partial seizures. The important milestones of the surgical program and the break up of 706 epilepsy surgeries performed upto December 31, 2005 are provided in Tables 16b.1 and 16b.2, respectively. prior to September 2001, all the candidates were selected by noninvasive protocol utilizing history, clinical examination, interictal and ictal scalp EEG, high resolution MRI, and neuropsychological evaluation data, and all surgeries were done under general anesthesia. Nearly 90% of the patients operated during this period had MTLE-HS or MRI identified other focal lesions not adjacent to eloquent areas. Sphenoidal electrodes were inserted during long-term video-EEG monitoring of patients with suspected TLE only

Table 16b.1 Major milestones of the R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Trivandrum 1st epilepsy surgery 100th epilepsy surgery 200th epilepsy surgery 300th epilepsy surgery 400th epilepsy surgery 500th epilepsy surgery 600th epilepsy surgery 700th epilepsy surgery

March 20, 1995 October 28, 1997 April 22, 1999 October 5, 2000 March 25, 2002 August 1, 2003 September 24, 2004 November 24, 2005

Table 16b.2 Epilepsy surgeries undertaken at the R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Trivandrum from March 1995 through December 2005 Procedure Temporal lobe resections Extratemporal resections Corpus callosotomy Hemispherectomy/hemispherotomy Total

No. 588 70 18 30 706

137

when initial scalp recorded ictal EEG pattern is poorly visualized or contaminated by movement artifacts.28 Wada test was undertaken only in those patients in whom dominant extended temporal lobe resection is planned and in whom neuropsychological testing has revealed bilateral or discordant memory dysfunction. Even in patients with apparent TLE and normal MRI, careful analysis of the non-invasive data could identify favorable surgical candidates.29 Such strategies prevented unnecessary escalation of the cost of temporal lobe epilepsy surgery. The non-invasive presurgical evaluation data of every patient is thoroughly discussed in the weekly patient management conference to collectively decide about surgical candidacy and to decide about further evaluation strategy in those with discordant features (Figure 16b.2). With the experience gained through the initial five years, intraoperative ECoG, subdural and depth electrode placements, and intraoperative and extraoperative cortical stimulation and mapping was started in 2001. These procedures have helped us to select patients whose epileptogenic zone could not be localized by non-invasive means and those with lesions such as malformations of cortical development close to eloquent areas. The R. Madhavan Nayar Center for Comprehensive Epilepsy Care is presently the only center in the country performing invasive presurgical evaluation. Upto December 31, 2005, 18 patients underwent long-term monitoring with bilateral temporal depth electrodes and 25 patients with subdural grid and strip electrodes placements. The Wada test is being replaced by functional MRI. During the last year, more restricted resective procedures such as selective amygdalohippocampectomy through subtemporal approach were being increasingly undertaken. Functional hemispherotomy is preferred to hemispherectomy for extensive unihemispherical lesions. The step-wise evolution of the epilepsy surgery program at the R. Madhavan Nayar Center for Comprehensive Epilepsy Care as outlined above is illustrated through some case scenarios in Figure 16b.3. Out of 351 patients with MTLE-HS operated on between March 1995 and March 2002 and have completed 2 years or more of post-operative follow-up, 286 (81.5%) are seizurefree, and 132 (37.7%) of them have been completely weaned off the antiepileptic drugs. During the median follow-up period of 4 years following surgery, out of 34 patients with tumoral TLE, 27 (79%) achieved a completely seizure-free state. Out of 46 patients with lesional extratemporal lobe epilepsies, 25 (55.6%) were seizure free during a median postsurgery follow-up of 4 years. Of the 6 patients operated for hypothalamic hamartoma through a transcallosal interforniceal approach, two were completely seizure free and three had more than 75% reduction of the seizures. Out of the 21 patients who completed ≥1 year of follow up following hemispherectomy/hemispherotomy, 18 patients (90%) became seizure free and 2 patients had more than 75% seizure freedom. One patient died a few hours following an uneventful anterior temporal lobectomy, the cause of which remained obscure. Three patients, following anterior temporal lobectomy, developed disabling hemiplegia due to vascular injury. An abscess at the site of an intracranial grid electrode occurred in one patient, who made a recovery without sequel following

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(a)

(b) Figure 16b.2

Discussion on (a) clinical, (b) radiological and

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139

(c) Figure 16b.2 cont’d (c) video-EEG data in progress during the weekly patient management conference at the R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Trivandrum.

surgical drainage and antibiotic therapy. The rest of the complications were either minor or transient. Other epilepsy surgery centers The All India Institute of Medical Sciences, New Delhi has undertaken 273 epilepsy surgeries from April 1995 through December 2005, the break-up of which is given in Table 16b.3. Among the 121 patients operated for refractory epilepsy at the National Institute of Mental Health and Neurosciences, Bangalore, between 1998 and December 2005, 90 had anterior temporal lobectomy, 30 had lesionectomy, and 1 had corpus callosotomy. Detailed post-operative outcome data from these centers are not yet available, although preliminary results are comparable to those from the R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Trivandrum.30,31 The following centers in India have performed less than 50 epilepsy surgeries, during the last five years, Nizam’s Institute of Medical Sciences, Hyderabad, CARE Hospital, Hyderabad, KEM Hospital, Mumbai, Jaslok Hospital, Mumbai, Poona Neurological Institute, Poona, Jahanghir Hospital, Poona, Postgraduate Institute of Medical Education and Research, Chandigarh, and Lourdes Hospital, Kochi. The National Hospital, Colombo, Sri Lanka has a very successful epilepsy surgery program and has offered surgery to nearly 60 patients in the last 3 years. The R Madhavan Nayar Center for Comprehensive Epilepsy Care, Trivandrum has actively participated in the development of the Sri Lankan program.

Future perspectives In India, with over one billion inhabitants, there are approximately one million persons with medically refractory epilepsy; among them as many as one-quarter to one-half are potential surgical candidates. However, no more than 150 epilepsy surgeries are currently being performed per year in India. Thus, only a minuscule of potential surgical candidates in India and other developing countries ever get a chance to undergo presurgical evaluation. The lack of availability and affordability has resulted in an enormous gap in developing countries between number of patients who could be benefited from epilepsy surgery and those who actually receive this treatment, which can only be minimized by developing more centers in the country, where epilepsy surgery can be undertaken. The out-of-pocket payment for epilepsy surgery (including non-invasive presurgical evaluation) at the R. Madhavan Nayar Center for Comprehensive Epilepsy Care is Rs. 50,000 (US$1200).21 With invasive evaluation the cost would escalate to two to threefold of this amount. The computed direct total cost for caring a patient with refractory temporal lobe epilepsy from age 26 to 60 years works out to be Rs. 200,000 (US$5000).21 The results from R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Trivandrum and other epilepsy surgery centers in India show that over 70% of patients will be seizure-free following surgery for temporal lobe epilepsy, and there is a 30% chance that they will be

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(a)

(b)

(c)

(d)

(a)

(b)

Figure 16b.3 Case scenarios from R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Trivandrum, to illustrate step-wise progress with time from straightforward to more complicated and advanced presurgical evaluation and surgical strategy. (i) Selection for epilepsy surgery by noninvasive evaluation: (a) right temporal spike discharges on scalp EEG, (b) right hippocampal atrophy on T1 weighted coronal MRI, (c) left upper extremity dystonic posturing during a complex partial seizure, and (d) rhythmic EEG activity during the seizure. Patient is seizure-free since right anterior temporal lobectomy with amygdalohippocampectomy on May 1997. (ii) A 14-year-old boy with refractory partial seizures with inconclusive scalp EEG data: (a) left occipital gliotic lesion in T1 weighted MRI, (b) left occipital-parietal grid electrode, and

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Epilepsy surgery in India LOG1-FPZ

141

11:29:37

LOG2-FPZ LOG3-FPZ LOG4-FPZ LOG5-FPZ LOG6-FPZ LOG9-FPZ LO10-FPZ LO11-FPZ LO12-FPZ LO13-FPZ LO14-FPZ LO17-FPZ LO18-FPZ LO19-FPZ LO20-FPZ LO21-FPZ LO25-FPZ LO26-FPZ LO27-FPZ LO28-FPZ LO29-FPZ LO30-FPZ ROS1-FPZ ROS2-FPZ ROS3-FPZ ROS4-FPZ ROS1-FPZ ROS2-FPZ ROS3-FPZ ROS4-FPZ FPZ

(c)

Figure 16b.3, cont’d (c) seizure origin from left occipital region. Seizure free since left occipital lobectomy on January 2002. (iii) A 42-year old male with inconclusive scalp EEG data. Inset shows stereotactically placed bilateral temporal depth electrodes. Seizure origin from anterior contacts of right hippocampal depth electrode. Seizure-free since right anterior temporal lobectomy with amygdalohippocampectomy on April 2003. Continued

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(a)

(b)

Figure 16b.3, cont’d (iv) A 20-year-old female with (a) left frontal cortical dysplasia close to motor and speech areas in T2 weighted MRI, (b) awake craniotomy and cortical stimulation mapped motor cortex (m), sensory cortex (s), Broca’s area (l), and central sulcus (c). Area R was resected without any neurological deficit on June 2004. After a complete seizure freedom during first post-operative year, she had had recurrence with few non-disabling seizures.

(a) Figure 16b.3, cont’d (v) A 13-year-old left handed boy with refractory focal seizures and mild right hemiparesis due to hemorrahagic disease of new born. (a) axial MRI FLAIR sequences shows marked gliosis and atrophy of the left hemisphere with relative preservation of the primary sensory-motor cortex (arrow).

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(b)

Figure 16b.3, cont’d (b) inline BOLD MRI right finger tapping versus rest shows left motor cortex activation, and (c) inline BOLD MRI verbal fluency versus silence shows strongly right hemisphrere lateralized language distribution. Based on the information, left motor strip was spared during hemispherotomy performed on July 2005 with little post-operative weakness of right-sided extremities. No seizure recurrence during six months’ follow-up.

Table 16.3 Epilepsy surgeries undertaken at the All India Institute of Medical Sciences, New Delhi, from April 1995 through December 2005 Procedure Temporal lobe resctions Extratemporal resections Corpus callosotomy Hemispherectomy/hemispherotomy Total

No. 204 51 12 6 273

employed, achieve an improved quality of life, and often becomes a productive member of society. Therefore, surgical treatment of refractory temporal lobe epilepsy is definitely a better cost-effective option than continued medical treatment even in developing countries. Epilepsy centers in developing countries could effectively use these statistics to obtain governmental subsidies and non-governmental financial supports for implementing and sustaining epilepsy surgery programs.

Conclusions completely off antiepileptic drugs within 2 years following surgery.12,30 Even with new antiepileptic drugs, complete seizure freedom occurs in only less than 10% of temporal lobe epilepsy patients.32 A seizure-free person could be better

In order to become cost-effective, epilepsy surgery centers in India will have to achieve excellent results by selecting candidates destined to have a seizure-free outcome using locally available limited technology and expertise, without compromising on patient safety. The recent experience from epilepsy

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surgery centers in India illustrates that this goal can be accomplished by selecting patients whose epileptogenic zone can be unquestionably established, based on history, high resolution MRI, and interictal and ictal scalp EEG findings such as those with MTLE-HS, and those with circumscribed potentially epileptogenic lesions. A stepwise approach by reserving more difficult to treat patients at a later date as experience develops,

or by referring them to a better-equipped center, will help each center to understand its capabilities and limitations and to move forward. It is encouraging to note that, despite major challenges, in the last decade, several epilepsy centers in India have not only successfully implemented epilepsy surgery programs, but have also produced results comparable to that from developed countries at a fractional cost.

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

16. 17. 18.

Sankhyan AR, Weber GHJ. Evidence of surgery in ancient India: Trepanation at Burzahom (Kashmir) over 4000 years ago. Int J Osteoarchaeol 2001;11:375–80. Chandy J. Surgical treatment of epilepsy. Neurol India 1954;2:37–41. Wolf P. History of epilepsy surgery: introduction. In: Lüders HO, Comair YG, eds. Epilepsy Surgery, Second Edition. Philadelphia: Lippincott Williams & Wilkins, 2001:19–21. Karpurkar AP, Pandya SK. Neurosurgery in India. Neurosurg Rev 1983;6:85–92. Ramamurthi B. Uphill All the Way. An Autobiography. Chennai: Guardian Press, 2000. Mathai KV, Chandy J. Surgical treatment of temporal lobe seizures. Neurol India 1970;18:158–64. Abraham J. Surgery for temporal lobe epilepsy. Neurol India 1980;28:175–9. Ramamurthi B. Focal fits. Arch Neurol 1965;13:545–6. Ramamurthi B, Balasubramaniam V, Kalyanaraman S, Arjundas G, Jagannathan K. Stereotaxic ablation of the irritable focus in temporal lobe epilepsy. Confin Neurol 1970;32:316–21. Ramamurthi B. Myoclonic epilepsy treated by combined stereotactic lesions (a case report). Neurol India 1972;20:158–60. Daniel RT, Chandy MJ. Epilepsy surgery. Overview of forty years experience. Neurol India 1999;47:98–103. Rao MB, Radhakrishnan K. Is epilepsy surgery possible in countries with limited resources? Epilepsia 2000;41(Suppl. 4):S31–4. Özkara Ç, Özurt E, Hanoglu L, et al. Surgical outcome of epilepsy patients evaluated with a noninvasive protocol. Epilepsia 2000;41(Suppl. 4):S41–4. Wieser H-G, Silfvenius H. Overview: epilepsy surgery in developing countries. Epilepsia 2000;41 (Suppl. 4):S3–9. Radhakrishnan K. The R. Madhavan Nayar Center for Comprehensive Epilepsy Care. In: Radhakrishnan K, ed. Silver Lines. Trivandrum: Sree Chitra Tirunal Institute for Medical Sciences and Technology 2004:163–89. Engel J Jr. Surgery for seizures. N Engl J Med 1996;334:647–52. Mani KS. Global campaign against epilepsy. Agenda for IEA/IES. Neurol India 1998;46:1–4. Gopinath B, Radhakrishnan K, Sarma PS, Jayachandran D, Alexander A. A questionnaire survey about doctor-patient communication, compliance and locus of control among South Indian people with epilepsy. Epilepsy Res 2000;39:73–82.

19.

20. 21. 22. 23. 24. 25. 26. 27. 28. 29.

30. 31. 32.

Radhakrishnan K, Nayak SD, Kumar SP, Sarma PS. Profile of antiepileptic pharmacotherapy in a tertiary referral center in South India: a pharmacoepidemiologic and pharmacoeconomic study. Epilepsia 1999;40:179–85. Engel J Jr. Multimodal approaches in the evaluation of patients for epilepsy surgery. Clin Neurophysiol 1999;50(Suppl):40–52. Sylaja PN, Radhakrishnan K. Surgical management of epilepsy. Problems and pitfalls in developing countries. Epilepsia 2003;44 (Suppl. 1):48–50. Radhakrishnan K. Medically refractory epilepsy. In: Radhakrishnan K, ed. Medically Refractory Epilepsy. Trivandrum, India: Sree Chitra Tirunal Institute for Medical Sciences and Technology, 1999:1–39. ILAE Commission Report. Mesial temporal lobe epilepsy with hippocampal sclerosis. Epilepsia 2004;45:695–714. Radhakrishnan K, So EL, Silbert PL et al. Predictors of outcome of anterior temporal lobectomy for intractable epilepsy. A multivariate study. Neurology 1998;51:465–71. Holmes MD, Dodrill CB, Ojemann LM, Ojemann LM. Five-year outcome after epilepsy surgery in nonmonitored and monitored surgical candidates. Epilepsia 1996;37:748–52. Zentner J, Hufnagel A, Ostertun B, et al. Surgical treatment of extratemporal epilepsy:clinical, radiologic, and histopathologic findings in 60 patients. Epilepsia 1996;37:1972–80. Edwards JC, Wyllie E, Ruggeri PM, et al. Seizure outcome after surgery for epilepsy due to malformations of cortical development. Neurology 2000;55:1110–4. Sylaja PN, Radhakrishnan K. The role of scalp EEG in the presurgical evaluation of patients with medically refractory temporal lobe epilepsy. Am J END Technol 2001;41:116–35. Sylaja PN, Radhakrishnan K, Kesavadas C, Sarma PS. Seizure outcome after anterior temporal lobectomy and its predictors in patients with apparent temporal lobe epilepsy and normal MRI. Epilepsia 2004;45:803–8. Bhatia M, Singh VP, Jain S, et al. Epilepsy surgery in India: All India Institute of Medical Sciences experience. J Assoc Physicians India 1999;47:492–5. Shukla G, Bhatia M, Singh VP, et al. Successful selection of patients with intractable extratemporal epilepsy using non-invasive investigations. Seizure 2003;12:573–6. Walker MC, Sander JWAS. The impact of new antiepileptic drugs on the prognosis of epilepsy: seizure freedom should be the ultimate goal. Neurology 1996:46:912–14.

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Treatment of epilepsy in Australia A Mohamed

Introduction Despite a relatively small population, Australia is the sixth largest nation in area following Russia, Canada, China, the United States of America, and Brazil. It is a very dry continent with most of the population living in its coastal margins. It is a federation of six states and two territories. The largest state, Western Australia, is about the same size as Western Europe. Over 60,000 years before the arrival of European settlers in 1788, Aboriginal and Torres Strait Islander peoples inhabited most areas of the Australian continent. There were an estimated 300,000 Indigenous Australians living on the continent. Today, the population of Australia is slightly over 20 million and concentrated in large cities around the coast (Table 17.1).

Epilepsy and illness in the indigenous population Aboriginal groups prior to European settlement were traditional hunter and gatherer communities and had enviable health in terms of nutrition and leisure. They lived in small closed groups of kin. The population numbers depended on availability of water and other essential resources. These groups followed up a more or less nomadic lifestyle. Most aboriginal groups were spread sparsely over the continent that mitigated against the spread of disease. These small groups followed a seasonal pattern of movement within a defined territory to which they had spiritual ties. Periodically, they would congregate in large numbers for ceremonial purposes or seasonal abundance of some food store at a particular site.1 In aboriginal culture prior to European settlement, sorcery or black magic provided an explanation of illness, pain, or death where the cause was not known or obvious. The explanations were always personal or spiritual. Someone or some spiritual powers performed black magic on the victim because of animosity or because the victim had broken a taboo. Aboriginal healers were able either to restore health or at least the group, via sorcery, could retain equilibrium. Not to know the cause of the illness or death was a disturbing factor in the psychological and social life of the group – therefore an acceptable explanation was necessary to enable the community to readjust itself to the events and go about its business.2 The sick were kept tranquil in a familiar environment with their own people about them hearing familiar voices and passed away in peace with their own kind when death was upon them.1 The aboriginal healer symbolically extracted a bone, quartz, or other stone from the patient’s body or would bring back the

wandering soul through rituals, and all was well. If the patient could not be healed, both the patient and group would prepare for death. The patient was also in a condition of high suggestibility and was ready to realize the idea suggested by the aboriginal healer. If told that he was healed, he would be reassured and prepare for improvement. Likewise, if a doctor suggested that death was inevitable, the patient would think of the spirits of the departed, turn his face to the wall, and prepare for death.2 There is no evidence that aboriginal culture placed a premium on abnormality or the epileptic. There was no reverence for epileptic patients as found in other cultures.2 Aboriginal medicine men, far from being charlatans, were men of high degree and had degrees in the secret of life beyond that taken by most adults. This required discipline, mental training, courage and confidence. Their positions commanded respect, and they were men of outstanding personality. In addition, the psychological health of the group largely depended on their powers, and they specialized in the working of the human mind.2 Despite some notable improvements in the past 20 years, the health status of aboriginal people remains of great concern. They carry a double burden of disease – not only disease of poverty but increasingly disease characteristic of a Western lifestyle. Leading causes of death includes cardiorespiratory diseases, accidents and to moving trauma, suicide, violence, and cancer.1 Incidence of epilepsy existing in the Aboriginal community is at least of the same proportion as the rest of Australia (1–2%). However this is probably an underestimate due to lifestyle factors such as alcoholism, substance abuse, and injury.

History of epilepsy in Australia after European settlement The early history of the treatment of epilepsy in Australia closely followed the path paved in the UK because of the close relationship between the two countries. Australia’s geographical isolation and low population density were compensated for by a tradition of overseas travel by doctors to undertake postgraduate studies in Europe. As with many European countries, during the 19th century, it was customary for epileptics to be institutionalized as they were thought as unfit to be at large. Epilepsy was thought to be a precursor of insanity. Many with brain disorders were institutionalized in prisons side-by-side with felons. In early Australian European settlements, the incidence of epilepsy in the prison population varied from 7 to 13%.3 The conditions in the prisons were grim and poor and it was not until later in 145

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Textbook of epilepsy surgery Table 17.1

Population and area of Australian state and territories

State or territory Queensland New South Wales Australian Capital Territory Victoria Tasmania South Australia Western Australia Northern Territory Australia

Area (square km) 1,723,936 800,628 2,358 227,010 64,519 978,810 2,526,786 1,335,742 7,659,861

Population

Capital city

3.64 m 6.61 m 0.32 m 4.82 m 0.47 m 1.51 m 1.9 m 0.2 m 19.47 m

Brisbane (1.65 m) Sydney (4.15 m) Canverra (0.32 m) Melbourne (3.49 m) Hobart (0.20 m) Adelaide (1.11 m) Perth (1.38 m) Darwin (0.11 m) 12.41 m

Source: Australian Bureau of Statistics Census 2001. Estimated June 30 2001.

the 19th century where most people with epilepsy were managed in asylums for the mentally ill.3 Towards the end of the 19th century, in the two large colonies of the time, New South Wales and Victoria, the decision was made to manage epileptics in institutions for the mentally ill.3,4 The very first asylum was created in 1811 in Castle Hill in the outskirts of Sydney. The second asylum outside New South Wales opened in 1848 at Yarra Bend in Victoria, although many sufferers were still managed at home by family and local doctors.5 Poverty, strained family relationships, and unemployment often played in large part in incarceration of these patients. Conditions in these asylums were very poor. Many of these patients suffered from a large number of physical illnesses including tuberculosis.6 In Sydney, patients in one institution (Galdesville Hospital) were dying from typhoid and infectious diseases due to inadequate sewerage.4 Early in the 20th century, there was a shift of attitudes that allowed the liberation of epileptics to asylums. This change in attitude together with campaigns by medical practitioners and activists led to a number of government inquiries4 that in turn led to the development of epileptic colonies in Sydney and Melbourne. In Sydney, moral therapists spearheaded these reforms. Work was created for epileptics and seen as a therapeutic instrument.3 Attendance of church was encouraged and libraries and newspapers were furnished for the patients. Prior to Hughlings Jackson’s postulate that epilepsy was disease of the cortex, a variety of causes were hypothesized for seizures. These included alcohol, worms, anxiety, and masturbation.3 In the late 18th century, medical treatments of epilepsy in Australia included:3 ● ● ● ●

● ● ● ● ● ● ●

Quiet rest, the feet placed in hot water and mustard bath Shaving of the scalp Mustard plaster to the back of the head Cooling of the head by a mixture of spirit of vinegar and water Bleeding in letting five fluid ounces of blood at a time Leeches to the temples Blister to the nape of the neck Use of prolonged chloroform anaesthesia Morphia Bromides introduced by Dr. Smith in 1873 Blistering where local limb auras occurred.

At this time the treatment for epilepsy in the USA included bromides, arsenic, quinine, cod liver oil, iron, and hysterectomies.7 The concept of epilepsy as a disease of the cortex was introduced to Australia in a paper in 1886 by John Springthorpe.8 He also recommended a systematic approach to treatment. This included removal of any irritants: bromides, zinc oxide, belladonna, atropine, cannabis, digitalis, and a Seton tie at the back of the neck. The Seton tie was a silk or cotton twine that was inserted through a large flap of skin and left there until a chronic running sore was created with drainage of pus from around the seton.9 The surgical treatment of epilepsy was first detailed by Dr. John Maund10 in 1856 and later by Dr. Poulton in 1890.11 In 1856 a patient with post-traumatic epilepsy who had an old depressed skull fracture and had failed medical therapy was treated successfully with trephining and removal of the bone at the side of the fracture – this occurred prior to the introduction of antiseptic techniques in cranial surgery by Horsely in 1880s.3

The beginnings of epilepsy surgery in Australia Peter Bladin created the first epilepsy center in 1969 at the Austin Hospital in Melbourne. This was a nationwide service that provided the first comprehensive epilepsy program in Australia. Between 1969 and 1991 this program performed over 200 temporal lobectomies for refractory epilepsy.12 In the late 1970s and early 1980s epilepsy centers were also established in three other Melbourne hospitals. In the early 1970s in Sydney, a lavishly equipped and staffed Brain Research Institute at Rozelle Hospital was established, where psychiatrists, neurologists, and neurosurgeons worked together to select patients for psychosurgery. Part of the workup involved the insertion, under stereotactic guidance, of recording electrodes into the hippocampus and amygdala. They were particularly interested in rage attacks, and whether these were due to epileptic activity in the amygdala. In the late 1970s there was public disquiet over such surgery (Figure 17.1). A royal commission was called that led to the shut down of this unit. The first comprehensive epilepsy center in Sydney was established in 1977 in Royal Prince Alfred Hospital13 (Figure 17.2) with centers at Prince Henry

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(a)

Figure 17.1 A Sydney tabloid reports on psychosurgery in 1977 (copyright permission).

and Westmead Hospitals being established soon after. Between the years 1990 and 1997, 226 temporal lobectomies and 40 extra temporal lobe surgeries were performed at the three adult epilepsy centers in Sydney (personal communication). Epilepsy surgery for refractory epilepsy in children were first performed at The Royal Children’s Hospital in Melbourne in 1979 and in Sydney in 1988. An epilepsy surgery center was established in Western Australia in 1989 and by 2002, 122 patients were assessed for surgery.

Conclusion There is little known of the treatment of epilepsy by the aboriginal population prior to European settlement.

(b) Figure 17.2 Epilepsy monitoring unit at Royal Prince Alfred Hospital in 1990.

However, various sources suggest that the aboriginal had good health and a spiritualistic approach to illness. The treatment of epilepsy in Australia after 1788 paralleled that seen in Europe and in particular in the UK due to the close ties between the two countries. Epilepsy surgery, first pioneered in Melbourne, has become available at a number of epilepsy centers in a country with a large geographical area, and its population concentrated in large coastal cities.

REFERENCES 1. 2. 3.

4. 5. 6. 7.

Bates D. The Passing of the Aborigines. London: Granada Publishing Ltd., 1972. Pelkin AP. Aboriginal Men of High degree. St. Lucia: University of Queensland Press, 1945. Bladin PF. A Century of Prejudice and Progress: A Paradigm of Epilepsy in a Developing Society, Medical and Social Aspects, Victoria, Australia, 1835–1950. Camberwell [Australia]: Epilepsy Australia, 2001. Garton S. Palaces for the unfortunate: lunatic asylums in New South Wales 1880–1940. Journal of the Royal Australian Historical Society 1991;76(4):297–312. Springthorpe JW. Notes on 21 cases of epilepsy. AMJ 1886: 101–105. Chesters J. ‘Not under proper care and control’: researching mental illness in East Gippsland. In: Gippsland Heritage Journal 1996:15–20. Mills CK. The treatment of epilepsy. JAMA 1886;154.

8. 9. 10. 11. 12. 13.

Bladin PF. John William Springthorpe, 1855–1933: Early Australian epileptologist and keeper of the flame for neurosciences. Journal of Clinical Neuroscience 2004;11(1):8–15. Bladin PF. A seton tried in the back of the neck: chronic suppuration in the treatment of epilepsy. Journal of Clinical Neuroscience 1998;5(1):17–19. Maund J. Epilepsy produced by pressure on the brain. AMJ 1856; 1:97–9. Poulton B. The case of trephining for epilepsy. Australasia Medical Gazette 1890:88–9. Popovic EA, Fabinyi GCA, Brazenor GA, Berkovic SF, Bladin PF. Temporal Iobectomy for epilepsy – complications in 200 patients. Journal of Clinical Neuroscience 1995;2(3):238–44. Radmanovich A, McMahon C, Noakes P, Healy L. The programme for the surgical treatment of epilepsy at the Royal Prince Alfred Hospital, Sydney, NSW. Australasian Journal of Neuroscience 1991;4(2):13–18.

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Epilepsy surgery in Korea BI Lee

Traditional oriental medicine Historically, Korean traditional medicine largely adopted the Chinese medicine since its beginning about 5,000 years ago. ‘Fifty-two Diseases’, the earliest Chinese medical record written 3,000 years ago, described symptoms of epilepsy and its treatment consisting of ‘repeat bathing with fluid containing a brain pill’ called ‘ ( : brain, : tablet, : drug)’. This indicated that ancient Chinese doctors had already known that epilepsy was originating from the brain. Despite their clear insight on the origin of epilepsy there has been no record describing any surgical treatment of epilepsy throughout the prolonged history of Chinese medicine. The major treatment modality of epilepsy in Chinese medicine consisted of various prescriptions using herbs, minerals, and materials from animals, and various procedures such as acupunctures, massages, and moxacautery. In the early 16th century, Dr. Joon Huh, the father of Korean traditional medicine, wrote a book called ‘ ( : east, : medicine, : gems, : book)’, which had summarized his clinical experiences as well as previous medical knowledge available in Korean and Chinese medical literature. He classified epilepsy into eight types based on charateristic symptoms, age of onset, and the traditional concept of etiopathogenesis. The book, which is still regarded as the textbook of Korean traditional doctors, has described more than 300 prescriptions and various procedures applicable to different types of seizures but none for the surgical treatment of epilepsies.1

Severance Medical School was united with Yonhee University to form Yonsei University.2 Korea was colonized by Japan from 1910 to 1945 and the Korean War occurred from 1950 to 1953. During the period, Korean society was seriously abandoned and most post-war medical activities were heavily dependent upon US aid. The modern medical management of epilepsy was initiated by Dr. L. Robinson (Figure 18.4) who was also an American medical missionary. She treated a girl suffering from epilepsy with phenytoin in 1963 and organized a mobile epilepsy clinic in association with Korean neurosurgeons and psychiatrists in 1964. These activities generated great hope among many patients and their families to organize the ‘Rose Club’, which did take initiatives of social movement as well as medical care for epilepsy. The rising phase of the Rose Club reached its peak during the 1970s and the first International Bureau Workshop for Epilepsy was held in the Severance Hospital on December, 1974. The Rose Club had grown to a huge social organization holding approximately 100,000 patients and their families and became a local chapter of IBE in 1979. Starting from 1980, the Korean economy had risen rapidly and most antiepileptic drugs became widely available in community hospitals. During this transitional period, the epilepsy care in Korea has gradually shifted from the Rose Club to community hospitals and the activities of the Rose club had gradually transformed into that of a lay

Era of Western medicine Western medicine was first introduced by Dr. H.N. Allen (Figure 18.1) in 1884, who was the medical missionary from the North Presbyterian Denomination. He built a Royal Hospital called ‘ ’ (House of Universal Helpfulness, Figure 18.2) in 1885 by the sponsorship of King Kojong of Lee Dynasty. which was the first hospital practicing western medicine in Korea. In 1886, Dr. Allen started his medical education which was succeeded by Dr. Avison. He was the first principal of (Chejungwon Medical School) and trained several assistant students. Among these, seven students had graduated in 1908 who were the first Korean medical doctors. In 1900, Mr. Severance in Cleveland, Ohio, donated $15,000 for the construction of a modern medical school and hospital which was opened in 1904 (Figure 18.3). The new medical complex was named the Severance Hospital and Medical School in memory of his generous contribution. In 1959, 148

Figure 18.1 Dr. Horace Newton Allen (1858–1932). He founded the first hospital practicing western medicine (Chejungwon) in 1885 with the support of King Kojong of Lee dynasty.

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Figure 18.2 (House of Universal Helpfulness). The first hospital practicing western medicine, which was established by Dr. H.N. Allen in 1885. The hospital was located in Che-dong, Seoul.

people’s organization. In 1982, the Korean Neurology Association was established to start a nationwide training program of neurology residents. In 1988, an epilepsy clinic was opened at Yonsei University Medical Center (Severance Hospital), which was the beginning of a specialized program for the care of epilepsy in Korea. In 1996, the Korean Epilepsy Society was organized and the major part of the Rose Club became the Korean Epilepsy Association, which has greately promoted the quality of epilepsy care in Korea.

Era of epilepsy surgery Dr. C.K. Lee (Figure 18.5), a neurosurgeon who had a postdoctoral training at the Montreal Neurological Institute in Canada, started epilepsy surgery from 1966 and published his surgical experiences of 51 cases suffering from intractable epilepsies in 1972.3 His surgical technique was the electrocoagulation of the

Figure 18.3 Severance Hospital and Medical School in 1904, which was built with the generous donation of Mr. Severance in Cleveland, Ohio. This building was located in Do-dong, Seoul. In 1995, this building was replaced by a 20-storey office building (Yonsei Severance Building) for the purpose of finacially supporting Yonsei University.

149

Figure 18.4 Dr. Lennabelle Robinson (1904–) in the center, who is discussing with Korean doctors (Dr. M.H. Kim in the left and Dr. W.S. Kang on the right) about the activities of the Rose Club.

preoccipital cortex. He considered that the preoccipital cortex was the main pathway of spreading ictal discharges and its interruption by electrocoagulation should be beneficial for the amelioration of seizures. He recorded electrocorticography (ECoG) before the electrocoagulation and observed its change after intracortical injection of procainamide to predict surgical outcome (Figure 18.6). Among 51 patients, 3 patients became seizure free and 26 patients achieved a significant improvement after the procedure. In 1980, Dr. D.S. Chung and his colleagues at Catholic University started epilepsy surgery and published their surgical experience consisting of seven cases of corpus callosotomy and eight cases of selective amygdalohippocampectomy in 1989.4 Nine patients showed significant improvement and none got worse. In this series, they did not perform any dedicated presurgical evaluations but their surgery was undertaken on the basis of clinical judgment, routine scalp EEG, and CT scan. The modern epilepsy surgery program employing the protocol of advanced presurgical evaluation was initiated at the Severance Hospital of Yonsei University Medical

Figure 18.5 Dr. Chu Kul Lee (1914–) is the first neurosurgeon to perform epilepsy surgery in Korea.

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Textbook of epilepsy surgery 1 2 3

4 5 6

(a) 1 2 3

4 5 6

(b)

(c)

1 2 3

4 5 6

(d)

(e)

Figure 18.6 The first publication of epilepsy surgery in Korea (1972). Baseline electocorticogram of a patient showing multiple spikes at both preoccipital (leads 1, 2 and 3) and motor (leads 4, 5 and 6) areas (a) electrocorticograms showed no suppression of epileptiform discharges from the preoccipital region during (b) and after (c) procainization of the motor cortex. Electrocorticograms from the motor cortex showed the clear response during (d) and after (e) the procainization of the preoccipital cortex.

Center in 1988 by Dr. B.I. Lee and K. Huh who had returned to Korea after their completion of training in neurology (University of Minnesota) and epileptology (Cleveland Clinic and University of Georgia) in the USA. In the early 1990s many young neurologists and neurosurgeons with an interest in epilepsy surgery started to have fellowship trainings abroad and established surgery programs in major university hospitals upon their return to Korea.

Current status of epilepsy surgery With the opening of a specialized epilepsy care program at Yonsei University Medical Center in 1988, epilepsy sugery has

become rapidly recognized as an effective therapeutic measure for patients suffering from medically intractable epilepsies. In addition, the wide availability of MRI and EEG telemetry systems encouraged the organization of surgery programs in major university hospitals in Korea. During the late 1990s, 12 centers performed about 500 cases of epilepsy surgery annually and their surgical experiences started to appear in international epilepsy journals. However, the flourishing activities of many surgical centers had gradually declined from the year 2000, largely relating to the emergence of failure cases, shortage of patients requiring only basic presurgical evaluations, tough competitions among centers, and financial restrictions of presurgical evaluations imposed by National Health Insurance. As PET, SYSCOM, and advanced MR

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Table 18.1 Surgical cases performed by epilepsy surgery centers during 2005 in Korea Epilepsy surgery centers Procedures ATL/SAH CS: lesional Non-lesional HS/MLR Corpus callosotomy MST only VNS DBS r-Knife surgery Total

AMC

CBUH

DSMC

24 6 1 1 3 4 1 2 4 46

16 3 2 – 6 – – – – 27

12 5 3 – – – 5 – – 25

PHIU 1 2 3 4 4 – 5 – – 19

SNUH 29 56 14 1 2 – 6 – 2 111

SMC

YUMC

26 18 6 4 2 – 6 2 3 67

35 15 2 3 16 – 24 1 – 96

ATL/SAH, anterior temporal lobectomy/selective amygdalohippocampectomy; CS, cortisectomy; HS/MLR, hemisperectomy/multilobar resection, MST, multiple subpial transection; VNS, vagus nerve stimulation; DBS, deep brain stimulation; AMC, Asan Medical Center of Ulsan University (Seoul); CBUH, Chonbuk University Hospital (Cheonju); DSMC, Dongsan Medical Center of Kyemyung University (Daegu); PHIU, Paik’s Hospital of Inje University (Seoul); SNUH, Seoul National University Hospital (Seoul); SMC, Samsung Medical Center of Sungyunkwan University (Seoul); YUMC, Yonsei University Medical Center (Seoul).

technologies became available in the late 1990s, advanced imaging technologies became the forerunner of interhospital competitions and centers not equipped with these facilities faced great restrictions in their activities to close their surgical programs. At present, seven centers are mantaining their surgical activities and the number of surgical cases has diminished to around 350 cases per year (Table 18.1). Compared to the

gradual decrease in the number of resective surgeries, there has been a trend to increase implant of vagus nerve stimulation (VNS) for its simplicity, safety, and broad indications as well as its coverage by National Health Insurance. Deep brain stimulations (DBS) is also applied in a few centers despite its experimental stage of develop-ment. Magnetoencephalography (MEG) has become available recently.

REFERENCES 1. 2. 3.

Duk Gon Kim. Epileptology of Oriental Medicine, Seowondang Publisher, 1998. History of 100 years of Yonsei University (1885–1985) Yonsei University Press. 1985: Volume 1. Lee CK. Surgical treatment of epilepsy: preoccipital coagulation. J Kor Neurosurg Ass 1972;1:1–14.

4.

Chung DS, Sung KW, Lee JS, Choi CR, Song JU. The clinical analysis of surgical treatment in the medically intractable seizure. J Kor Neurosurg Ass. 1989;18(6):910–5.

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Epilepsy surgery in Thailand T Srikijvilaikul, C Locharernkul, and A Boongird

The history of epilepsy surgery in Thailand can be divided into the era before and after 1990. Before 1990 was the time of modern neurosurgery establishment by Thai pioneer neurosurgeons. After 1990, advanced epilepsy surgery has been established in Thailand in parallel with the development of a comprehensive epilepsy program with standard and state-of-the-art clinical practice.

History of epilepsy surgery in Thailand before 1990s Modern neurosurgery in Thailand began after a number of neurosurgeons returned from formal training in the USA in the late 1960s and established neurosurgical services at Siriraj and Chulalongkorn hospitals, the first two medical schools in Thailand. Pioneers on epilepsy surgery in the country were distinguished neurosurgeons, namely Professor Sira Bunyaratavej and Professor Charas Suwanwela. Due to the lack of computer technology and advanced imaging at that time, localization mainly relied upon clinical information, namely detailed history taking, highly precise neurological examination (Figure 19.1) and surface electroencephalogram (EEG) (Figure 19.2). Early imaging included skull series, scintigraphy or isotope brain scan, cerebral angiography, pneumoencephalograhy, and after the mid1970s, computerized tomography (CT). The surgical outcomes varied among patients. Surgical treatment of epilepsy was mainly resection of structural lesions causing seizures such as tumors, abscesses, vascular malformations, and depressed skull fracture scars. However, a few operations for intractable epilepsy were also performed. Hemispherectomy for a Sturge–Weber patient was first done by Professor Sira Bunyaratavej in 1966 (Bunyaratavej S, personal communication). Stereotactic amygdalotomy was performed in a case of temporal lobe epilepsy by Professor Charas Suwanwela in 1977 (Suwanwela C, operative record). At King Chulalongkorn Memorial Hospital, modern surgery of the brain was first established in 1963 by Professor Charas Suwanwela. Granted by the prestigious Anandamahidol Foundation under His Majesty King Bhumibol Adulyadej of Thailand, he finished his neurosurgical residency training from North Carolina and certified American Board of Neurological Surgery in 1961. He began modern neurosurgical therapy for Thai people at the Bangkok Bank Building (Figure 19.3). Early brain surgeries regarding epilepsy were mainly surgical removal of intracranial space occupying lesions producing seizures as 152

well as other neurological symptoms. However, the number of brain operations directed toward the correction of epileptic seizures was modestly reported. There were at least three patients who received cicatrectomy for their long-standing epilepsy. Two cases had refractory seizures from undiagnosed depressed skull fractures long after their head injuries. One of the two was a hospital worker who had become seizure free after the cortical scar was completely removed and with antiepileptic drugs maintained. Another patient suffered from a brain abscess close to the motor area. Intractable epilepsy developed one year after the abscess was drained.1 After the fibrous wall of the healed abscess was removed, his seizures were abolished without any post-operative neurological deficit. One hemispherectomy was performed on 13 November, 1989 by Professor Charas Suwanwela on a patient with cerebral hemiatrophy (Davidoff–Dyke syndrome) (Suwanwela C, personal communication). A 9-year-old boy suffered from very frequent desperate seizures and mental deterioration. Left hemiatrophic limbs with good motor powers were noted on examination. His CT scan revealed small right hemicranium with dilated ventricles. After one year of unsuccessful antiepileptic drug therapy, modified anatomical hemispherectomy was performed on the right cerebral hemisphere. Post-operatively, his seizures decreased significantly to 1–2 attacks per month resulting in much relief of his caregivers. Although left-sided hemiparesis was acquired from surgery and a wheelchair was

Figure 19.1 Professor Charas Suwanwela, a distinguished physician of early modern neurosurgery in Thailand, performing a highly precise neurological examination on a Thai patient in the 1970s.

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Development of epilepsy surgery after the 1990s

Figure 19.2 Professor Tongchan Hongsaladarom, a pioneer neurologist and electroencephalographer of Thailand, with the first ‘Grass’ paper EEG machine at EEG laboratory, Chulalongkorn University Hospital in the early 1960s.

needed, his postoperative reduction in seizures was greatly appreciated by his family. His condition has remained the same during the regular follow-up period of over 10 years. There was a study on focal convulsions from small cortical lesions by Suwanwela C et al. (unpublished data). Twenty-two patients who had epileptic attacks from lesions within the cerebral cortex were analyzed. Lesions larger than 2 cm in diameter were surgically removed. Among these cases, brain abscess were found in two patients and cysticercosis in one patient. However, conservative treatment was found to be the option in most patients since periodic brain CT disclosed spontaneous resolution in many cases and cysticercosis was postulated to be the cause of these vanishing granulomas. The authors recommended observation and follow-up instead of doing resective surgery in these epileptogenic infectious lesions.

The era of comprehensive epilepsy surgery program starts from early 1990, after a few young Thai neurologists and neurosurgeons returned from their full epilepsy trainings in distinguished western epilepsy centers. Brought back were the technical knowhow in modern epilepsy presurgical evaluation, state-of-the-art in surgical techniques and their enthusiasm in relieving epilepsy burden in Thai epileptics. A group of clinicians established the first comprehensive epilepsy program under a university hospital environment in 1994 known as Chulalongkorn Comprehensive Epilepsy Program, or CCEP (Table 19.1) with the second author being the founder and the director of the program. During this period, surgical treatment for epilepsy relied upon neurophysiologic data and advanced imagings. The first temporal lobectomy series for intractable epilepsy was introduced by Professor Sira Bunyaratavej and Professor Pongsakdi Visudhipan in July 1993.2 The epilepsy society of Thailand has been established by Professor Pongsakdi Visudhiphan and committee since 1996. The aim of the organization has focused on identification of surgical candidates for intractable epilepsy and educated both clinician and non-clinician workers to understand the options of epilepsy surgery and other medical aspects of epileptic patients care. This organization has consistently maintained policy and enrolled as a member of the International League Against Epilepsy (ILAE) in 1997 and the International Bureau for Epilepsy in 2004. The organization was honored to host the 5th Asian and Oceanean Epilepsy Congress in 2004. Other than CCEP and Ramathibodi hospital, there have been other epilepsy surgery services established in Bangkok, namely the Phramongkutklao Hospital and the Prasat Neurological Institute. However, CCEP has been considered the only advanced comprehensive epilepsy surgery center in Thailand since 1994.3,4 The details of CCEP development will be described in this chapter.

The strategies

Figure 19.3 The Bangkok Bank Building, ideally designed for neurology, neurosurgery, and psychiatry services on each floor in its three-storied structure was opened in 1960. Early neurosurgery, of the 1960s to modern epilepsy surgery of the 21st century took place here in its long evolutionary history. Now the location of the Chulalongkorn Comprehensive Epilepsy Program.

Thailand, as a developing country, has adapted its own pattern of epilepsy surgery development. Due to its 64 millions population in 2004, with accordingly high numbers of epilepsy cases, low average income per capita, and limited resources (Human Development Index rank 74 by United Nations Development Programme’s Human Development Report 2006), the surgical program development has aimed to serve most patients under cost-effective, sustainable, and selfsufficient economic strategies. In order to utilize resources as effective as possible, CCEP has been developed in four progressing phases, starting from the optimizing medical treatment phase (phase I, 1994–1996), the presurgical evaluation development phase (phase II, 1997–2000), the basic epilepsy surgery phase (phase III, 2001–2003) to the phase of surgery using advanced techniques (phase IV, 2004–present). The presurgical work-up using minimal standard procedures was developed step-by-step as necessary, to reach the target of rationale and economic practices.

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Table 19.1 Milestones of epilepsy surgery development at CCEP, Bangkok, Thailand The medical-technology arm 1994 1996

1997

1998 1999

2000

2001

2002

2003

2004

2005

Epilepsy Clinic* New AED trial

The public arm and the Royal patronage

Phase I (1994–1996) – Optimizing medical treatment 1996 Home visit program to improve patients’ compliance by CCEP and Thai Red Cross Society volunteers

Phase II (1997–2000) – Developing epilepsy presurgical evaluations 24-hour video EEG telemetry* 1997 Media and magazine campaigns on Epilepsy presurgical conference* epilepsy and epilepsy surgery First lesionectomy (temporal ganglioglioma) MRI using epilepsy protocol* 1998 Epilepsy patients working as volunteers Ictal SPECT* and employees in the epilepsy program Sphenoidal electrodes* 1999 ‘Light for Life Foundation for Epilepsy’ Wada test –Thai language version* established under HRH’s patronage for First anterior temporal resection for HS financial support of low-income patients for epilepsy treatment MRS 2000 CCEP website, www.thaiepilepsy.org fMRI for motor area for patient and public information as Intraoperative ECoG* well as medical consultation Phase III (2001–2003) – Surgery for high-yield remediable syndromes Short course in epileptology for Thai 2001 The ‘New Life’ social events performed physicians by seizure-free patients under Royal Textbook of Comprehensive attendance Epileptology (Thai) Mobile epilepsy training for rural doctors Neuropathology of epilepsy in the 4 main parts of Thailand in cooperation with Thailand Ministry of Public Health (MOPH) Seizure free patients worked as volunteers and CCEP staffs Clinical practice guideline (CPG) for 2002 Financial support for referred epilepsy epilepsy & epilepsy surgery (Thai) surgery to the program by Thailand First Surgery of hypothalamic MOPH hamartoma First Corpus callosotomy 2003 The ‘Nom Klao’ vocational rehabilitation CCEP-Bethel epilepsy management program under HRH’s patronage conference A Thai novel based on a story of a seizure Subtraction-coregistration SPECT to free surgical case by a renounced MRI (SISCOM) * author NPT, WPSI-Thai language version* Personnel training and development in invasive EEG and advanced epilepsy surgery in Germany and U.S.A. Phase IV (2004–) – Epilepsy Surgery using Advanced Techniques Stereotactic frameless guidance 2004 Government financial support for VNS Awake operation and intraoperative devices cortical stimulation First Functional hemispherectomy* First VNS implantation* First invasive EEG (SDE) monitoring and cortical stimulation mapping* First propofol Wada test* Multilobar resection Re-evaluation and re-operation for 2005 ‘Princess Epilepsy Congress 2005’ – relapse after surgery Scientific and Public Congress on Expanding video/EEG monitoring advanced epilepsy surgery on the facilities; using of digital video/EEG auspicious occasion of HRH’s 48th Epilepsy fellowship training,* approved Birthday Anniversary by The Royal College of Medicine, Issues on epilepsy and the law, literatures, Thailand and arts liberated to public and media First frameless DBS (for PD and The ‘New Life Project ‘under Thai movement disorders)† government’s support – providing 300 First multiple subpial transection epilepsy surgeries free of charges from (MST)* 2005 to 2008, to cerebrate HRH’s 48–50th Birthday Anniversary

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Table 19.1 cont’d The medical-technology arm 2006

First FDG-PET for epilepsy presurgical evaluation* First depth electrode implantation* Textbook of Comprehensive Epileptology vol. II (Thai) Genetic studies in Thai epileptic patients with AED allergy

The public arm and the Royal patronage 2006

CCEP, King Chulalongkorn Memorial Hospital, MOPH and National Health Security Office signed MOU on development of epilepsy clinics in main hospitals throughout Thailand using CCEP as a training model, establishing online epilepsy registration and referral system for epilepsy surgery Implementation of the issue ‘Epilepsy and the Law’ in Thailand

* First time developed in Thailand. † First time performed in Asia.

Only international standard presurgical and surgical techniques have been used at the CCEP. Experimental therapeutic procedures and those unproven efficacy by evidence-based reviews were not used during the program development. The optimization of medical treatment at the initial phase has reflected pictures of inappropriate medical treatment of epilepsy long being practiced among Thai general practitioners. Among the most common examples were inadequate adjustment of antiepileptic drug (AED) types and doses to reach the maximal effectiveness (40.9%), inappropriate choice of AEDs due to unclassified seizure types (17.4%), and early AED polytherapy (10.8%). Continuing use of failed drugs was found in a small proportion (2.4%) since sub-therapeutic dosing has been acquainted in most clinical practices.5 After phase I, the burden of truly medically intractable epilepsy was able to be determined. At phase II when needs have been clearly realized, standard presurgical diagnostic facilities have been successively developed. The introduction of surgery for high-yield remediable syndromes at phase III has eliminated fear and doubt of this new approach among Thai epileptics. The good surgical outcomes have gained dramatic acceptance and subsequent yearning for surgery from patients all over the country. The success of surgery has also brought public attention and continuing donation to the program. When discordant cases from basic evaluations have accumulated, advanced techniques have been developed at phase IV. Epilepsy surgery dealing with incongruent cases then began using relevant high cost, invasive diagnostic or intraoperative techniques. Many epilepsy presurgical and surgical techniques developed at CCEP have been considered for the first time ever in the medical history of Thailand.

The medical technology arm development A specialized epilepsy clinic was first established in September 1994. The clinic provided evidence-based medical treatment for epilepsy out-patients to achieve the best seizure control and to define medically intractable cases. Subsequently, standard presurgical evaluation facilities have been developed. A well-equipped two-bed epilepsy monitoring unit (EMU) comprised of 24-hour video EEG telemetry was first established in 1997 (Figure 19.4). Special electrode placement over true anterior temporal regions according to the international 10–10 system (T9T10, FT9FT10, F9F10)6 has been routinely used in adults since late 1997. Sphenoidal electrode placement was first performed in January 1999. The first epilepsy case management conference for surgical selection was conducted in June 1997 followed shortly by the first CCEP epilepsy surgery. Lesionectomy for right temporal ganglioglioma was performed on 16 June, 1997 by Professor Charas Suwanwela, rendering the patient seizure free for more than 9 years and AED totally discontinued for more than 7 years.

The structure CCEP, located at Bangkok Bank Building, King Chulalongkorn Memorial Hospital, Thai Red Cross Society is run as a charitable organization under the university hospital environment. CCEP comprises multidisciplinary medical staff of the Faculty of Medicine, Chulalongkorn University. CCEP has a structure of two arms developed in parallel, namely the medical technology arm and the community arm, with one heart, i.e. the program has been privileged to be under Royal patronage.

Figure 19.4 Epilepsy monitoring unit (EMU) equipped with long-term video/EEG telemetry was established in 1997. A 128channel digital video/EEG analogue for cortical stimulation mapping and the four-bed facility were completed in 2004.

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Figure 19.5 The first anterior temporal resection with amygdalo-hippocampectomy in a Thai MTLE patient (drawing by Professor Charas Suwanwela, the CCEP senior neurosurgeon, October 1999).

A 1.5 tesla high resolution MRI was first used for epilepsy in 1998.7 Epilepsy protocol (thin cut on temporal lobes with planes parallel and perpendicular to hippocampal long axis) has been used. Fluid attenuation inversion recovery (FLAIR) technique has been added to routine epilepsy protocol since January 1999. Three-dimensional and reformatted software was developed in 2000 for detection of subtle cortical dysplasia. Magnetic resonance spectroscopy (MRS) and functional MRI (fMRI) for hand motor function were also developed in 2000. Single photon emission tomography (SPECT) began in May 1998.8 99mTc-Ethyl Cysteinate Dimer (ECD) has been used for ictal and interictal injections. Ictal SPECT was limited only to official hours when ECD and scanner were available. A 3-head gamma camera scanner was first used in January 1999 which produced satisfactory high resolution images. Thai language Wada test was invented by Tayard Desudchit et al.9 Intracarotid amytal injection was, for the first time, performed to lateralize memory and speech functions in a Thai TLE patient in September 1999. All epilepsy presurgical evaluations were completed and the first temporal lobectomy on intractable epilepsy from hippocampal sclerosis (HS) was performed at CCEP on 14 October 1999 by Professor Charas Suwanwela (Figure 19.5) which rendered the patient seizure free for over 7 years. Surgical series that followed were the most prevalent and the most beneficial surgically remediable syndromes. These mainly included concordant temporal lobe epilepsy (TLE) with unilateral HS and localization related (focal) epilepsies from circumscribed tumors. Almost every candidate underwent the multidisciplinary presurgical evaluation and epilepsy conference. Mesial temporal lobe epilepsy (MTLE) is the most common adult epileptic syndrome operated, comprised of up to two-thirds of medically intractable cases, from which good surgical candidates can be found in 68% of cases.10 The yield of excellent surgical outcome (>90% seizure freedom) in early surgical series had gained wide public acceptance. Subsequently, patients came to CCEP for surgical evaluation by information from others rather than by public information or referral system. The success in surgery obviously improved post-operative quality of life and relieved psychosocial stigmas of seizure-free patients. Many have become helpful volunteers of the program or even CCEP staffs in the expanding epilepsy service. Unfortunately, in early 2000, such success was acknowledged among the patient themselves rather than among medical personnel. In 2001, a short course on epileptology was held by CCEP in Bangkok for education and training of general practitioners and physicians in related fields. The first book on

epileptology was published in Thai to distribute recent advances and CCEP experiences in intractable epilepsy management to medical professions. A mobile epilepsy training module on epilepsy for rural doctors was conducted in 2001 in four main regions of Thailand, with partial funding from the Thai Ministry of Public Health (MOPH). In 2002, the first Clinical Practice Guideline (CPG) in Epilepsy and Manual on Epilepsy Surgery were published for Thai medical personnel for awareness and early referral to an epilepsy surgical center. Surgeries were later performed in highly concordant TLE by using fewer resources as well as in less concordant cases. MRI and 24-hour video/EEG monitoring remains the minimal standard for presurgical evaluation of concordant right mesial TLE. The duration of hospital stay for monitoring was shortened significantly as skills in video/EEG recording and interpretation increased. Unnecessary SPECT and Wada tests were limited. The average scalp video/EEG monitoring period of 9 days in 1999 was reduced to 7.7 days in 2003 and 5.5 days in 2005. Personnel training as well as technology development for advanced surgery have been conducted according to the CCEP plan. The Cleveland Clinic Foundation (CCF) Cleveland, Ohio, the University of Washington Regional Epilepsy Center, Seattle, USA, and the Bethel Epilepsy Center (BEZ), Bielefeld, Germany have contributed greatly to CCEP in such objectives and have created strong collaboration between the centers until now. The Chulabhorn Foundation under Professor Doctor Her Royal Highness Princess Chulabhorn’s patronage has, for the first time, granted a qualified neurosurgeon (the first author) for 2-year epilepsy surgery fellowship training at CCF in 2001 to 2003. Invasive monitoring, cortical functional mapping as well as some aspects on neuropsychological tests, are among the transferred technology from BEZ to an adult epileptologist and two technicians from CCEP in late 2003. Since then, expansion of advanced techniques has taken place at CCEP, most of which is the first time in Thailand. The first transcallosal resection of hypothalamic hamartoma was successfully done in September 2002.11 Vagal nerve stimulation (VNS) was first implanted on 12 May, 2004 in a patient with Lennox–Gastaut syndrome. The first invasive EEG monitoring (IEM) and cortical stimulation mapping using subdural grid and strip electrodes was performed on 15 November, 2004, in a refractory TLE patient who had failed gamma knife radiosurgery at a private hospital, resulting in seizure freedom for more than 2 years.12 The worldwide shortage of sodium amytal in 2003 urged CCEP to study the use of propofol for the Wada test. The first intracarotid propofol procedure was performed on 22 October, 2004 with good results.13 Digital video/EEG

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Epilepsy surgery in Thailand no.

157

Numbers and Types of Epilepsy Surgery at CCEP

120 100 2

9 8

1

9

12 7

23

80 60

10 4 2 24

40 1 20 0

4

1

3

2

2

3

3

9

57

55

2 23

43 Year

1999

2000

ATL for HS

2001

2002

Lesionectomy for tumors

2003

2004

Other surgeries

2005

2006

Invasive EEG

VNS

Figure 19.6 Numbers and types of epilepsy surgery at CCEP from 1999 to 15 December, 2006. The total numbers have reached 325 cases. The surgeries have been greatly increased since 2004, including cases receiving invasive EEG implantation.

telemetry, subtraction of ictal and interictal SPECT co-registered to MRI (SISCOM) and neuropsychological testing in Thai language are among other diagnostic facilities developed in parallel to the above advanced surgical techniques. First multiple subpial transection (MST) was performed on 26 December, 2005 in a case of left insular cortical dysplasia with diffuse ictal onsets over eloquent frontotemporal regions. 18 FDG-PET was first used as a part of presurgical evaluations in July 2006. First depth electrode implantation was done on 21 August 2006 in a discordant unilateral MTLE patient. Neurosurgical pathology also revealed many interesting epilepsy substrates from CCEP series. Many cases such as Rasmussen’s encephalitis and desmoplastic infantile ganglioglioma (DIG tumor) were first reported in Thailand.14 A case of low-grade hypothalamic neuronal tumor with gelastic/dacrystic seizure found at CCEP has never been reported in the world medical literature. The number of surgical cases has tripled in 2004 (Figure 19.6). Anterior temporal lobectomy for HS is the most performed operation until now. Surgery on difficult cases with poorly defined epileptogenic zones such as cortical dysplasia (CD), bitemporal disease, and non-lesional epilepsy have increased in 2005. Moreover, the time after video/EEG monitoring to surgery, as well as the duration of hospital stay after surgery, has been reduced significantly in the last 3 years.

The community arm Public activities have developed in parallel to medical technology. Serial public campaigns via media and magazines along with initial excellent surgical outcomes have dramatically converted initial fear and doubt in epilepsy surgery among the Thai population into the voluntary seeking of surgical therapy at the CCEP. The number of patients registered to the center has been increasing continuously to reach 3000 patients in 2006.

The ‘Light for Life Foundation for Epilepsy’ was founded in August 1999 as a charitable organization giving continuous financial support to low-income epilepsy patients. The foundation provides expenses for new AEDs, transportation, presurgical and surgical interventions including VNS supplies. Additional support was provided by the Thai MOPH with CCEP negotiation, i.e. funding for some anterior temporal lobectomy individuals from 2002 to 2004 and for VNS from 2004 to the present time. A study from CCEP has shown that epilepsy surgery has magnificent impacts on the patients’ QOL after surgery, when evaluated by occupational achievement and income acquisition.15 Of the 111 adult epileptic patients operated between January 2002 and December 2004, an overall seizure free rate of 83% was obtained. There were 62% reduction of the unemployment rate, 43% increase of the postoperative professional achievement, and 48% increase of the average annual income per capita, when compared to the preoperative period (p80 years) have

200 180 Annual incidence per 100,000

9781841845760-Ch26

160 140 120 100 80 60 40

Iceland Rochester

20 0 0

10

20

30

40 50 Age(years)

60

70

80

90

Figure 26.1 Incidence of epilepsy by age in Rochester, MN, US and Iceland. Data adapted from the original articles.26, 27

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Epidemiology of the intractable generalized epilepsies

209

incident rates considerably higher than those seen in infants.25–28

Relative frequency of catastrophic epilepsies

Age and type of epilepsy Part of the age-related pattern for the incidence of epilepsy is due to the occurrence of generalized seizures and epilepsies, many specific forms of which occur almost exclusively in infants, children, and young adolescents. This can be clearly seen in the Icelandic study where, for generalized seizures other than generalized tonic-clonic, the incidence is very high in infancy and drops precipitously in childhood, practically to disappear in adults.27 The CAROLE study from France provides some of the most stable estimates of the relative occurrence of syndromes throughout the age span.29 New onset generalized epilepsies of any kind account for little of epilepsy beginning in adults but are quite common in children and intermediate in adolescents and young adults.

The incidence figures provide a rough idea of how often some of the more common catastrophic epilepsies occur in the population. For understanding how common they are in the epilepsy clinic, other sources of information are more revealing. The CAROLE study as well as other community- and population-based studies provide the distribution of types of epilepsy at initial diagnosis (incident cases) as well as in crosssection (prevalent samples). While these are not always strictly speaking ‘population-based studies’ and therefore precise incidence estimates cannot be obtained from them, the studies are representative of patients seen in the populations from which they come and can be reasonably used to estimate relative frequencies of different forms of epilepsy. In children, the encephalopathic disorders as a whole represent between 10 and 21% of epilepsies 29,41–43 although the highest estimate was based on the most clinic-based (referral center) of the reports.43 Syndromes such as West, Lennox-Gastaut, and MAE account for the majority of the children who have catastrophic epilepsies. Individually, each may account for 1–5% of pediatric epilepsy cases. Estimates from the rare syndromes are harder to come by. In a US study, Dravet was found in 0.5% of children recruited at the initial diagnosis of epilepsy. 38 Another study from Israel reported that syndromes such as Ohtahara and Landau-Kleffner accounted for 0.2% each of pediatric epilepsy.44 Generally, such estimates are based on one or a few cases out of several hundred. In all, what is apparent is that those forms of generalized epilepsies most likely to be intractable occur relatively rarely in absolute terms and represent a relatively small proportion of all individuals with epilepsy in the population although they represent an important minority of children.

Incidence of the catastrophic epilepsies The Icelandic data provide incident rates by age and overall category of epilepsy.27 The category for cryptogenic and symptomatic generalized epilepsy (dominated by West and Lennox-Gastaut syndromes) has an overall incidence of 0.7/100,000 per year in the general population; however, all cases observed in that population occurred in infants, and among infants ( Rt, max Lt Anterior/ Lateral FrontalECoG: Sporadic Spikes near the cicatrix on orbital surface & rhythmic sharp and slow complexes on adjacent gyrus Automatisms - Scalp EEG: -B/L Frontal SD (throat discharge in grids: clutching, the Frontal discharge tearing lobe (uncertain across Lt clothing) w/ if Rt/Lt)-B/L OFC w/out occasional Frontal SDG clinical

Perceptual N/A (only illusion ‘slow aura motion reported) sensation’: slowing down of moving objects or of person’s speech; impression that walking person is suspended in air ‘indescribable weak feeling terrible feeling’; in Lt arm/ ‘things going leg → LOC away’

Aura

4:10 PM

14

N/A

Onset (yrs)

3/19/08

Case #2 (D.Tr.) 18M/-

Age/ Sex/Han dedness

A compendium of published cases of presumed orbitofrontal epilepsy (from 1951–2005)

Authors/ Year/ Center

Table 37.1

9781841845760-Ch37 Page 291

291

30F/Rt

22M/-

11M/-

Schneider 1961 Ann Arbor, MI Neurology Case #1

Niedermeyer* 1971 Baltimore, MD

Tharp* 1972 Stanford, CA Epilepsia

6

20

No

No

(total of 4) i Rt/Lt Mesial Frontal ii. Rt/Lt OFC

IED

Imaging

Resection

surgeries: i) resection of area w/ max ECoG abnormality ii) Rt Frontal

Rt Frontal lobectomy

Nl skull X-rays, 2 Pneumoencephalo gram & B/L carotid arteriograms

N/A

change, then 2:40min later spread to Rt Hemisphere w/ Rt head/ eye turning & Rt arm jerk - eCS of Lt - Skull X-rays Complete Temporal lobe: Nl; - Carotid excision of no auras were arteriogram: firm 2.5cm elicited Rt shift of mass at the (Lt Frontal Lt ACA tip of Lt lobe not - Ventriculogram: Frontal pole stimulated; Rt shift of w/ firm pt became ventricular stalk uncooperative) system w/ projecting posterior from track displacement originating of Lt frontal in roof Lt horn c/w Lt orbit w/ frontal spaceosteomyelitis occupying of Lt orbital lesion inferior bone (*) to the lateral ventricles

IOZ

- Scalp: B/L highvoltage delta in prefrontal regions, also Lt Anterior & mid Temporal - Subcortical electrodes in i) Superior Temporal: few slow waves ii) Superior Frontal ‘Nl alpha’ iii) Anterior Midfrontal gyrus: slow waves at 2cm level; no waves at 4cm (mass on palpation) Oroalimentary - Scalp: Depth: lowest automatisms; Generalized, ADT in Rt occasionally irregular slow OFC tonic body SWC 1-2.5Hz, posturing or max Lt Frontal, ‘grand mal’ Lt Frontopolar & Anterior Temporal - Depth: Spikes Rt Orbito-Frontal, Rt Caudate Nucleus & B/L Amygdala; also Lt OFC during sleep Facial flushing, Scalp: Periodic, 2 surgeries: piloerection, asymmetrical i) I/Op ECoG: frightened B/L Sharp/Slow Multifocal look → wave complexes Spikes & Complex Rt>Lt (Fp2> Polyspikes motor w/ Fp1& F4>F3) over

Rt head/eye deviation & Rt arm jerks → amnesia, confusion

Ictal Semiology

Rt lateral OFC Clusters ≥ 50/day, for several months w/ long sz-free intervals

Nl cortex & Class 1 >2 yrs dural vein (varix) → reop: Firm ‘gliotic’ tissue in the Rt lateral

(*) Postop course complicated by extradural abscess requiring bone flap removal, abscess evacuation, debridement & delayed cranioplasty

Ηx of MVA 5 yrs prior a/w Lt eye injury requiring enucleation & Lt orbital prosthesis

for ‘peculiar behavior’

Location/ Comments

Hx of Rt FrontoParietal skull fracture at 20yrs s/p removal of extradural hematoma & debridement of Rt Frontal lobe

Class 1(f-up = 10 months)

Outcome

Encephalomal ‘much acia & improved’ sz multiple cystic frequency but cavities and developed calcifications marked within area of hyperdisorganized sexuality & gliotic post-op cortex

Encapsulated brain abscess w/ purulent exudate of coagulase (+) hemolytic Staph aureus

Histopathology

4:10 PM

Hallucinations: Auras only -Visual formed in Rt field: headless persons, circles, bars, colored butterflie Auditory: whistling like sound of wind Olfactory: odor of foul cigar smoke

Aura

3/19/08

30

Age/ Sex/Han Onset dedness (yrs)

cont’d

292


Table 37.1

9781841845760-Ch37 Page 292


32M/Lt 9

#2. I/Op ECoG: Lateral Inferior TG w/ eCSinduced Automatism → Rt Temporal lobectomy

#1. Rt posterior OFC

N/A

#2. Class 4

#1. Class 4

Continued

Initial invasvive evaluation w/ bitemporal superficial & depth electrodes: no epileptiform activity even during clinical sz

At onset given diagnosis of ‘psychoneurotic hysteria’ and treated w/ ECT

Duration: few sec to min

4:10 PM

No ECoG discharges postresection

N/A ‘recently operated’

at surgery (no histological examination)

Resection of N/A posterior OFC & Gyrus rectus, Amygdala & Hipocampus, 3cm of Superior TG & 5cm of Middle, TG + Inferior TG

lobe resection anterior to precentral gyrus including mesial frontal & anterior cingukate

3/19/08

Case #2

Ludwig* 1975 38M/Lt 18 NINDS, MD Epilepsia Case #1

every 0.5– 6 sec resembling SSPE, enhanced by sleep

Anterolateral Rt Frontal lobe ii) I/Op Depth in orbital: Active spiking lateral OFC; also sharp-slow waves, but no seizures recorded Cephalic Sudden loss of -Scalp: 1. SWC or - Scalp: Pneumoencepha aura = responsiveness Sharp/Slow over 1. Obscured logram: mild ‘unusual’ w/ staring → Lt Anterior + or Nonlocalizable symmetric feeling Automatisms Middle 2. Rhythmical dilatation of (fumbling, Temporal 10Hz Sharp ventricular blinking, 2. Spikes Lt >> Rt Waves Lt system sitting up from Basal leads Frontal) recumbent) 3. Bisynchronous -Extradural flaps sometimes a/w Sharp/Slow (Temporal & Frontal pallor, lasting Frontopolar, & Depth for 30 sec → max Lt (Hippocampus + oriented & - Extradural flaps posterior OFC): fluent Depths: Spikes build- up of but amnestic independent & Spikes in posterior equal Posterior OFC → rhymical OFC & 15MH → 25–30Hz Hippocampus for 15sec exquisitely I/Op ECoG: localized to OFC Spikes in - eCS-induced posterior OFC Automatisms in Hippocampus; No AD or clinical changes in OFC Feeling ‘off Unresponsiveness - Scalp: - Scalp: 1. No EEG Pneumoencepha balance’, → kicking & 1. Intermittent Rt changes logram: slight ‘choking’ cursing (rarely Temporal theta concomitant w/ dilatation of or feeling hears voices or 2. Rare sharp spontaneous szs. lateral the room sees faces) transients Rt - PTZ-induced sz: ventricles ‘closing in’ lasting Rt; N1 B/L oriented & bisynchronous SWC carotid fluent but - Epidural electrodes arteriograms amnestic Rt Frontal, Temporal: Low-voltage fast 25Hz Rt Frontal - Flap, Needle & Cortical electrodes: rhythmic 20Hz trains exclusively Spike to posterior OFC flap

screaming. Able to follow simple commands, but amnestic of events

9781841845760-Ch37 Page 293

Basal frontal lobe epilepsy 293

13M/Lt

Case #4

N/A

7

6

Unresponsi veness w/ facial pallor → Complex motor (foot stamping, kicking, running) ± Lt oculocephalic deviation, lasting induced w/ brief for speech Lt Anterior flattening → Temporal 2–3Hz SWC over Lt OFC w/ spread to Rt OFC - I/Op ECoG: Anterior parts of Lt Middle + Inferior TG & middle FG Visual Upward mouth - Scalp: B/L - Scalp: PTZPneumoencehallucination movement synchronous induced ‘diffuse Rtphalogram: or Perceptual (either side) w/ Sharp/Slow & sided activation’ moderate illusion ‘silly laugh’ SWC over - Rt-sided SD: dilatation of (feels as if → unresponsiFrontal + OFC, Superior + entire smiling/ veness w/ Lt Frontopolar, Inferior Frontal & ventricular unable to head turning & max Rt (F4/ Midparasagittal: system speak) Lt arm waving Fp2) - SD: No spontaneous purposelessly Mesial Rt OFC szs * eCS-induced → Complex rhythmical typical sz only w/ motor (moves 2Hz waves & Rt OFC stimuation* about, independent * PTZ-induced: undresses Sharp waves flattening → self ) Rare from Rt rhythmical 2.5–3Hz generalized superior SWC Rt OFC w/ motor szs Frontal spread to Lt OFC convexity → rhythmic SWC well localized over Rt Superior frontal (F4) ‘buzzing noise Staring → Complex ** Depth: Rt OFC ** & visceral motor (kicking, localization sensation’ thrashing, pelvic thrusting) w/ genital manipulation & alleged retention of awareness, lasting ~15sec

No

Aura

Histopathology

Rt Frontal lobectomy

Felt to have ‘at least two independent epileptogenic foci’

‘dense orbitofrontal gliosis’

No resection N/A (aborted because of Suspicion of skull infection)

extensive Lt N/A Temporal lobectomy: 7 cm along Middle + Inferior TG & 5.5cm along Superior TG & Hippocampus 2.5cm

Resection

Location/ Comments

Class 4 ** Sz-free × 1yr, then recurred w/ frequency of 8/yr

No resection History of purulent Rt ear infection at 6yrs

Class 3 ‘very few’ seizures ‘short follow-up’

Outcome

4:10 PM

-/-

26M/Lt

Case #3

Onset (yrs)

3/19/08

Williamson 1985 Yale, CT Ann Neurol


cont’d

294


Table 37.1

9781841845760-Ch37 Page 294


Munari 25M/Rt 6 1995 Grenoble, FL France Adv. Neurol.

Rare: Sensation of cold & Piloerection on Back & Thorax or feeling as if ‘my brain is being crushed’

Sudden loss of contact → Ambulation & Automatisms: Oral / Gestural (‘as if trying to catch things in the air’) / Verbal (incomprehensible utterances) → rotation of trunk Lt > Rt & eyes rolling to the Lt → rare GTC

Scalp EEG: Rt Large signal anterior onset; change on Rt evolution c/w Frontopolar & initial Frontobasal Frontobasal onset → very regions, w/out rapid spread to evidence of anterior & midprogression temporal regions - sEEG: Lowvoltage fast on Rt mesial & lateral OFC w/out clinical signs for first 35sec except for some bradycardia (from 77 to 63 beats /min); szs

CT: Nl

Gliosis & areas w/ Intracytoplasmic neuronal inclusions of PAS(+) granules c/w focal lipofuscinosis

- Inferior Frontal N/A region including Forntal pole - Temporal pole & uncus - Anterior & mid-Temporal neocortex (including first, second & third temporal gyri)

-Postresection ECoG: some Frontal discharges Superior & Posterior to the excision considered insignificant

Tailored resection of Rt OFC & adjacent portion of Rt Lateral Frontal

Rt OFC / clusters 5–10/d w/ sz-free intervals up to 1–2 weeks Initial sEEG w/ depths in Rt mesial Frontal, mesial Temporal & Anterior Cingulate (failed to identify area of ictal onset)

Basal frontal lobe epilepsy Continued

Class 1 * Hx of Rt Frontal (26 months) Frontal tumor s/p resection at age 7 (details N/A) followed by chemo- & radiotherapy;

Class 1>Positive FH of 6 yrs seizures -off AEDs Psychiatric for > 5 yrs comorbidity: -apparent - Depression resolution - Violent outbursts of premorbid psychiatric problems

Rt Orbital gyri, No abnormal- Class 1 gyrus rectus ities 18 months & subcallosal area

4:10 PM

&

Scalp EEG: Obscured by artifact (only one Aura w/ Rt Temporal rhythmic theta) SD strips (B/L Temporal; & Medial + Lateral Frontal): Rt Infraorbital rhythmic fast activity w/ attenuation in all contacts

- Scalp EEG: Sudden CT: Nl attenuation of (also N1 background Ventrifollowed by culography movement & Carotid artifact angiogram) - sEEG: Repetitive Spikes localized to Rt OFC only

- Scalp EEG: 1.Bisynchronous asymmetric IEDs anteriorly w/ shifting Rt or Lt preponderance; 2. IEDs widely distributed over Rt Frontotemporal - Sphenoidal: Bisynchronous Basal IEDs maximal Rt - Infraorbital: IEDs maximal infraorbitally strips: Spikes Rt Infraorbital - I/Op ECoG: Spikes in entire Rt OFC & Anterior portion of Inferomedial Temporal Scalp-EEG: Thetadelta activity & occasional Spikes over Rt Fronto-temporal region

- Scalp EEG: Sharp waves Rt Frontotemporal (F8-T4) - sEEG: Spikes localized to Rt OFC (w/ occasional propagation to contralateral Lt OFC)

3/19/08

or

8

Chang 1991 36M/Seattle, WA Epilepsia

- Staring w/ semipurposeful & thrashing movements; shouting incoherent words (occasional laughter) & amnesia for events - Occasional GTC out of sleep Sensation of - Cessation of whole body activity areas w/ numbness → Right body/ starting in the head turning → feet → flash Complex motor backs from behavior past/butterflies (struggling, in stomach kicking) & or feelings vocalizations of fear indicating fear, lasting ~30 sec w/ abrupt return of consciousness - GTC out of sleep

10 No

Rougier and 29M/Loiseau 1988 Bordeaux, France JNNP

9781841845760-Ch37 Page 295

295

28F/Rt

Shihabuddin 2001 Vanderbilt, TN Seizure

19

34M/Rt 13

Case #3

unrelated

13

42F/Rt

Case #2

IED

IOZ

Imaging

Resection

Histopathology

Outcome

Spikes in Lt OFC + Lt posterior mesial Temporal

Rt mesial OFC Lesionectomy

-

Rt OFC

posterior OFC

-Uncus & lateral

Class 1 19 months

surgery 11 months post-op (gliosis w/ out cell loss), age 16 → sz-free × 6yrs age w/ recurrence of habitual szs

Single seizure type w/ respect to ictal semiology Mild word-finding difficulties postop Only 2 szs on day of

No significant post-op neuropsychologyical deficits

Location/ Comments

Pilocytic Class 3 Positive FH of szs astrocytoma - Cluster of in 1st degree habitual cousin Sz szs post-op frequency: day#1 - sz -CPS: 20/month free × 1yr- - 2∞ GTC:10/mo then 3 ‘atypical’ szs in

‘unremarkable’

- OFC: NI amygdala 2×3

become symptomatic after spread to inferior frontal, temporal pole, anterior & mid-temporal neocortex Staring w/ occasi- - Scalp/sphenoidal - Scalp/sphenoidal MRI: Nl Both the central Maloriented Class 1 onal manual EEG: Spikes Rt EEG: 2Hz δ at F4 hippocampal OFC (SD cells 17 months automatisms mesial (Sp2) & & T8 → bifrontal volumetry strip) + of glial & midtemporal (T8) & Rtmidtemporal δ lateral OFC neuronal - I/op ECoG: w/ Sharp waves at Sp2 (ECoG origin c/w Spikes localized - B/L SD: Central abnormality) focal MCD to lateral OFC & Lateral contacts w/ firm mass of portion of Rt OFC strip slightly w/spread discolored to Rt subtemporal tissue Staring w/ - Scalp/sphe- Scalp/sphenoidal MRI: Nl including - 4cm lateral - Hippocam- Class 3 unresponsivenoidal EEG: EEG: (i) Bi- frontohippocampal temporal pus: no 15 months ness & oral autoIndependent temporal 3/6 volumetry; neocortex evidence matisms mostly bitemporal (ii) Lt mesial PET:↓10% FDG -3cm of of sclerosis out of sleep Spikes Lt >> temporal -B/L SD & in Lt Temporal hippocampus & but missing Rt (20:1) Depth: parahippocampal portions - I/op including ECoG: (i) Focal Lt gyrus of CA3

Ictal Semiology

hippocampal 4/8 & (ii) Central contacts of Lt OFC strip w/ spread to Rt OFC ‘feeling of N/A (only aura None reported - Scalp/sphenoidal MRI: ATL defect déjà vu’ → reported) EEG: Rt Fronto4.5cm from sensation of Temporal tip w/ disorientation - Unilateral SD (Rt complete Fronto- temporal): resection of Medial contacts Mesial of OFC SD strip structures w/ spread to Dorsolateral Frontal feeling of Restless, - Scalp/sphenoidal - Scalp/sphenoidal - MRI: Lesion ‘butterflies hyperkinetic w/ EEG: Rt EEG: Regional, Rt 20 × 8mm2 in in the UE automatism Inferomesial Inferomesial Rt mesial OFC stomach’ a/w (Rt >Lt), drinking, Temporal Spikes Temporal (Nl hippocampi) fear dressing, & later (Sp2) & ‘atypical (rhythmic theta) - PET: ↓FDG in oroalimentary trains of Spikes & Rt Temporal automatisms polyspikes’ Polyspike- SDG: (both mesial + a/w LOA + ictal (Sp2) postictally(i) Clinical szs: lateral) speech → SDG: frequent Rt mesial Frontal - SPECT: ≠uptake

None reported

Bad taste or smell & awareness of accelerated heart rate

Aura

4:10 PM

15

Onset (yrs)

3/19/08

Roper and 17F/Rt Gilmore 1995 Gainesville, FL J Epilepsy Case #1


cont’d

296


Table 37.1

9781841845760-Ch37 Page 296


21F/Rt 9

Rheims 2005 Lyon, France Epil Disord

Image- guided Rt Substantial Inferior Frontal diffuse resection gliosis w/ astrocytosis (predominantly in the white matter w/ mild intracortical gliosis w/out dysgenesis) Metallic taste, Unresponsiveness - Scalp: Lt Frontal -Scalp: Nonlocalized MRI: Nl Complete Gliosis in the head tingle, or arrest of convexity tF3) - Depth: ‘nonlesional’ resection molecular ‘déjàvu’ activity → ‘Electrodecremental’ ictal + layer + vocalization Lt posterior OFC interictal focus white matter (shouting, w/out clinical as defined w/ mild & laughing) change for ~16sec by Depths = patchy gliosis until spread to B/L posterior in other Mesial Temporal 3.5cm OFC layers No Unresponsiveness - Scalp: ‘Diffuse -Scalp: Nonlocalized MRI- identifiable Complete Old posttraumor arrest discharges’ (No invasive lesion resection old atic hematoma activity → studies) (posttraumatic) posttraumatic cavity w/ oromanual cavity & surrounding automatisms surrounding sclerotic sclerotic tissue tissue Lt TemporoBehavioral - Scalp EEG: Lt -scalp EEG: lowMRI: circumscribed Lt Frontopolar Cortical parietal arrest → Lt & Frontal Spikes & voltage fast MCD Lt Fronto& OFC Dysplasia cephalgia downward slow waves Lt Frontal → polar suggesting (resection ‘typical of oculocephalic - sEEG: active B/L Frontal ‘minor form’ of sEEGthose seen deviation w/ Spike focus Lt SWC of TSC defined area) in TSC’ grimacing & Frontopolar - sEEG: (i) Localized Lt vocalization→ Frontopolar hypermotor onset w/ spread to Lt OFC (ii) Onset & predominant evolution in Lt OFC

No

Class 1 > 2 yrs

Class 1

Class 1

Class 4 Recurrence after 6 mos sz-free → ‘shorter & less disabling’ ‘Engel IIA’

Mother w/ TSC & epilepsy Patient w/out TSC stigmata

No identifiable risk factors

Abbreviations: AD = Afterdischarge; AEDs = Antiepileptic Drugs; Angio = Angiography; ATL = Anterior Temporal Lobectomy; a/w = associated with; B/L = Bilateral; c/w = consistent with; eCS = Electrical Cortical Stimulation; ECoG = Electrocorticography; ECT = Electroconvulsive therapy; EEG = Electroencephalography; F = Female; FG = Frontal Gyrus; FH = Family History; f-up = follow-up; GTC = Generalized Tonic-Clonic; Hx = History; IEDs = Interictal Epileptiform Discharges; I/Op = Intraoperative; IOZ = Ictal Onset Zone; Lt = Left; LOA = Loss of awareness; LOC = Loss of consciousness; M = Male; max = maximum; max = maximum; MCD = Malformation of Cortical Development; min = minutes: mo = month; MRI = Magnetic Resonance Imaging; MVA = Motor Vehicle Accident; N/A = Not available; Nl = Normal; post-op = postoperatively; Rt = Right; s/p = status post; sec = seconds; sEEG = stereo-encephalography; OFC = Orbitofrontal cortex; PAS(+) = Periodic Acid-Schiff positive; post-op = postoperatively; PTZ = Pentylenetetrazol; SD = Subdural; SDG = Subdural Grid; s/p = status post; SSPE = Subacute Sclerosing PanEncephalitis; SWC = Spike & Wave Complex; sz = seizure; TSC = Tuberous Sclerosis Complex; TG = Temporal Gyrus; UE = Upper Extremity; w/ = with; w/out = without; yrs = years; 2∞ = Secondarily; -/= not provided; δ = delta

N/A

-/-

Case #2

23

4:10 PM

N/A

36F/-

1mo & sz-free for another 6 months

3/19/08

Smith 2004 -/Augusta, GA & Munich, Germany SFN Case #1

Rugg-Gunn FJ 2002 London, U.K. Lancet

Spikes Rt (inferior/anteri Rt Temporal mesial OFC; or aspect) (injection also Spikes Rt (ii) Subclinical 15sec after sz Lateral & Basal szs: Rt OFC onset) Temporal (mesial aspect) Sudden LOA a/w - Scalp: Rt F-T -Scalp: Regional Rt -Conventional truncal rocking slow waves Frontalhigh-resolution mvts, reperated -Intracranial: 4 MRI: Normal grabbing hand typical & 10 -DTI: Area of ≠ mvts & aimless subclinical szs w/ Diffusivity in wandering Rt OFC onset Rt OFC

GTC sz

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respect to seizures following epilepsy surgery.54 Careful review of these cases, with the above criteria in mind, reveals that in most instances localization of the epileptogenic zone within the OFR is either presumed or unconfirmed. Our inability to determine the extent of the epileptogenic zone and its relationship to the OFR, when surgical resection involves extra-orbital areas adjacent to the basal frontal lobe or when an extensive frontal lobectomy has been performed reflects a well-recognized inherent limitation of most human surgical studies.35 Seizure (clinical) semiology The most widely used system for classification of epilepsies was revised in 1989 by the Commission on Classification and Terminology of the International League Against Epilepsy (ILAE).55,56 The 1989 Proposal for the Classification of the Epilepsies and Epileptic syndromes describes a separate anatomically defined seizure pattern in regards to the orbitofrontal area: ‘The orbitofrontal seizure pattern is one of complex partial seizures with initial motor and gestural automatisms, olfactory hallucinations and illusions, and autonomic signs’.55 The commission prefaces the 1989 report with a cautionary note: ‘... inferences regarding anatomical localization must be drawn carefully’. Attempts to classify seizures according to location (anatomic lobes or sublobar regions) are confounded by the fact that seizures usually give rise to ictal manifestations by virtue of propagation to eloquent areas of cortex. Large cortical areas in the anterior neocortex such as the prefrontal cortex may be clinically silent, when activated by seizure discharges or electrical stimulation. Consequently, the first clinical evidence of a seizure may reflect propagation to areas remote from the region of seizure origin.57 Seizures arising from a distinct focus within the frontal lobe may rapidly involve multiple frontal lobe regions concealing specific seizure patterns.58 On the other hand, extensive, nondiscrete, or multifocal epileptogenic zones and rapid spread patterns within the ipsilateral or contralateral frontal lobe will lead to overlapping, coincidental clinical phenomena. As a result of these limitations, attempts to classify frontal lobe seizures on the basis of distinct anatomic subdivisions may be restrictive and potentially misleading.35,59 Moreover, only a handful of patients with unequivocal focal epilepsy arising from the orbitofrontal area have been reported in the literature, as is evident from the earlier discussion and the cases listed in Table 37.1. In their comprehensive review of ‘complex partial seizures of extratemporal lobe origin’ Swartz and Delgado-Escueta remarked that only eleven cases of ‘orbitofrontal complex partial seizures’ existed in the literature in a period spanning almost 20 years (from 1957–1975; all 11 cases are included in Table 37.1). And only nine of these were thought to carry ‘strong proof ’.60 Electrical stimulation studies Direct electrical stimulation of the cortex has been used to study the results of epileptic activation of various cortical sites.61 Stimulation studies with an effective stimulus intensity reveal that the majority of human cortex is symptomatically silent, and provide further evidence to suggest that cortical activation by epileptiform discharges will not produce symptoms, unless the electrical activity spreads to adjacent eloquent cortical sites.34

Stimulation of the OFR has been reported to produce a variety of responses. Smith and co-workers report that stimulation of the lateral and mesial posterior OFR (including the apparent ictal onset zone in a patient with pharmacoresistant focal epilepsy) did not produce any observable clinical phenomena. Such findings lend support to the hypothesis that clinical manifestations of basal frontal epilepsies may in fact begin outside the basal frontal area.51 The same group stimulated 13 posterior orbitofrontal sites using laterally placed depth electrodes in nine patients, who did not have evidence of focal epilepsy arising from the OFR. An assortment of sensations were elicited in this group including ‘body tingling’ on six occasions, and ‘a spacedout, confused feeling’ on four; ‘an unpleasant feeling’, an illdefined smell, an olfactory hallucination, a cephalic sensation, lightheadedness, and ‘fuzzy vision’ were reported on one occasion each.51 In their series of orbitofrontal stereo-EEG depth electrode investigations Munari and Bancaud report that an olfactory hallucination can be elicited in the presence or absence of ‘a localized afterdischarge’ following posterior orbitofrontal stimulation.36 Smith and co-workers postulate that such provoked olfactory symptoms may actually reflect activation of the adjacent lateral olfactory striae,51 which is possible, given that afterdischarges related to electrical stimulation often activate a more extensive cortical region beyond the cerebral tissue surrounding the directly stimulated electrode.61 Lastly, autonomic responses resulting from OFR stimulation in humans were reported in older studies;62,63 these include blood pressure elevation or bradycardia,64 respiratory arrest or increased amplitude of respiration, and increased esophageal contractions or decreased gastrointestinal motility. Ictal manifestations As discussed earlier, the large prefrontal cortical region can be viewed as a collection of heteromodal association areas, which share elaborate connections with other frontal and extrafrontal cortical and subcortical structures.65 Hence, seizures arising from several regions within the anterior part of the frontal lobe – including the orbitofrontal, frontopolar, anterior cingulate, and medial intermediate frontal regions – may display overlapping clinical characteristics as a result of the rapid and simultaneous activation of cortical sites within the PFC and its connections.58,66 In general, seizures arising from the frontal lobe may start and end abruptly with little if any postictal confusion, and tend to have a shorter duration (lasting less than 30 seconds) and higher frequency (oftentimes occurring in clusters) compared to seizures of temporal lobe origin.35 Ictal behavior is commonly characterized by prominent and often complex motor manifestations. Because of their bizarre appearance at times, frontal lobe seizures are not infrequently mistaken for nonepileptic, psychogenic events.67 The somewhat circuitous and dichotomous term ‘frontal lobe complex partial seizures’ has been proposed by some authors to describe these events.53,68,69 Stereotypic recurrence of the various clinical components in individual patients is key in establishing the correct diagnosis of seizures arising from the frontal lobe.53,67 Again, it is important to recognize that the observed seizure semiology reflects epileptic activation of the symptomatogenic zone.34 When seizures originate from silent areas of the brain there will be no outward manifestations without propagation of seizure activity to the symptomatogenic zone. Studies with

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Basal frontal lobe epilepsy depth electrodes have shown that ictal onset within the OFR may precede the onset of clinical manifestations by as much as 60 seconds suggesting asymptomatic activation of this area.37,51,70 Two separate groups of investigators have observed that patients may in fact remain completely asymptomatic, when the epileptic discharge stays localized within the OFR.37,47 Summarizing their experience of more than 150 patients, in whom the orbitofrontal region was investigated using stereoEEG, Munari and co-workers concluded that ‘the only clinical from characteristic of well-limited discharges in the orbital cortex was the absence of any objective clinical symptomatology’.71 Based on these observations, the limited number of welldocumented published cases, and the functional heterogeneity of the OFR, it is difficult to assume a unique seizure semiology that is characteristic for this part of the frontal lobe. A review of reported cases reveals some common themes: lack of aura or nonspecific auras, autonomic changes, behavioral arrest and/or impaired awareness, complex motor and ‘hypermotor’ activity, vocalization, oculocephalic deviation, olfactory or gustatory hallucinations, occasional secondary generalization.55,66,72 Occurrence in clusters, nocturnal preponderance, relatively brief duration and brief if any postictal confusion are also observed. Based on the cases reported by Ludwig41 (see Table 37.1) Bancaud and Talairach identified two ‘recognizable seizure patterns’ associated with seizures of orbitofrontal origin,73 as follows: (1) Olfactory auras, defined as seizures beginning with an olfactory hallucination or illusion. The olfactory symptoms may be accompanied by gustatory auras, autonomic changes, oroalimentary and/or gestural automatisms and ‘thymic alterations’. These associated symptoms have been attributed to propagation of ictal discharges to the adjacent opercular-insular-amygdalar region (autonomic manifestations, gustatory hallucinations or illusions, and oroalimentary activity) and/or to anterior cingulate region (complex gestural activity ‘automatic gesticulations’, and mood changes).36 Other studies have shown that olfactory auras usually point to seizures originating from the limbic mesial temporal structures, which are also involved in olfactory function.74,75 In fact, published reports suggest that olfactory auras constitute an uncommon manifestation of seizures arising from the basal frontal region.76 (2) Autonomic seizures, defined as seizures of prevalent ‘vegetative components’. They present with a variety of paroxysmal autonomic disorders including cardiovascular (heart rate changes, facial flushing, pallor), respiratory (apnea), digestive (sensation of hunger and/or thirst), urogenital (urge to urinate and periictal urination) and thermoregulatory disturbances (sensation of cold with piloerection and/or sensation of heat). Ictal ‘vegetative’ manifestations are thought to result from activation of the orbitofrontal and opercular insular regions.35,73 The so-called ‘hypermotor seizures’ constitute another ictal pattern commonly associated with this region. According to the Semiologic Seizure Classification hypermotor, seizures are defined as seizures manifesting with complex motor automatisms – organized motor activity, which primarily affects the proximal body segments and results in relatively large amplitude movements.77 The term ‘organized’ refers to movements

299

that imitate natural movements as opposed to dystonic, tonic or clonic movements, but does not specify whether they are voluntary, involuntary or semipurposeful (e.g., evoked in response to environmental stimuli).78 When rapidly executed these movements may appear violent, for example thrashing, bicycling, vigorous kicking, frenetic striking or flailing of limbs and other rather peculiar motor behaviors.76 The repetitive character of these motions has been attributed to the central role of the prefrontal and premotor areas of the frontal lobe in the sequential design of movements.79 In a large series of suspected frontal or temporal lobe epilepsies Manford and co-workers identified 13 patients with a CT and/or MRI-demonstrable lesion (‘lesional focal epilepsy’) and hypermotor seizures, characterized by early ‘motor agitation’. The authors noted that the structural lesions involved the OFR in the majority of cases (7 out of 13). Lesions extended to the frontopolar cortex in Six of these Seven patients.80 The remaining Six cases with early motor agitation showed no consistent lesion localization (their lesions resided in various other frontal or temporal areas). Such observations may support the 1989 ILAE classification of anatomically defined seizure types of possible orbitofrontal origin. It should be noted however, that this was not a series of patients undergoing resective epilepsy surgery, and that the definition of the presumed epileptogenic focus was based on somewhat loose and often discordant clinical, EEG and MRI/CT localization criteria. In his review of structural lesions in the frontal lobe Goldensohn found ‘… too few cases with discrete lesions with sufficiently detailed seizure descriptions of possible orbitofrontal and cingulate origin to allow separate categorizations’.66 The author concluded that symptoms and signs commonly linked to orbitofrontal and/or cingulate epilepsy (such as autonomic or mood and affect changes, gestural automatisms, and versive movements preceding automatisms) do not appear to differentiate between lesion cases involving the orbitofrontal, anterior cingulate or other areas of the anterior third of the frontal lobe.66 Finally, it should be emphasized that epileptogenic foci within the OFR can give rise to seizures, which are electroclinically indistinguishable from temporal lobe seizures given the widespread connections between the limbic system and the OFR.39,47,50 In other words, basal frontal epilepsy may manifest itself with seizure spread outside the lobe of origin, as illustrated by Shihabuddin and colleagues in their case of a small right orbitofrontal pilocytic astrocytoma. Invasive recordings demonstrated seizure generation in the right OFR with spread to the ipsilateral mesial-basal temporal region – seizures were eliminated almost completely following right mesial orbitofrontal lesionectomy.50 Electroencephalography Surface EEG The ability of the scalp EEG to detect interictal activity depends on the extent of the irritative zone, the location and proximity of the generator in relation to the scalp and the orientation of the dipole.81 In general, interictal or ictal surface EEG studies are not very helpful in identifying epileptogenic foci residing in the basal frontal lobe because of the hidden, distant location of this part of the cortex with relation to scalp electrodes. Even long-term sleep-deprived interictal EEG

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recordings may be completely normal despite activation procedures. This apparent lack of interictal and/or ictal EEG abnormalities is a well-known weakness of electroencephalography.74 When detected on scalp EEG, interictal epileptiform discharges are helpful in establishing the diagnosis of epilepsy. Prolonged daytime EEG studies with recordings of 1–2 hours of sleep, as well as nocturnal sleep recordings increase the yield of interictal epileptiform abnormalities in individuals with epilepsy.82–84 Increased sampling using special electrodes (such as sphenoidal, anterior temporal or ear electrodes)85,86 and closely spaced additional scalp electrodes87–89 may be helpful in distinguishing temporal from frontal lobe foci. Home videotape recordings, when available, can provide valuable diagnostic information by capturing ictal manifestations. Prolonged inpatient video-EEG monitoring is indicated in patients with pharmacoresistant epilepsy as well as patients with paroxysmal events of unclear etiology. Careful video analysis of ictal semiology may lend support to the diagnosis of frontal lobe epilepsy, even in some cases where EEG is inconclusive. Polysomnographic recordings with additional EEG montages should be considered, in cases of predominantly nocturnal paroxysmal phenomena.90,91 Typically, abnormalities that are detectable on scalp EEG do not allow for topographic localization of foci residing in the basal frontal lobe. When present, spikes or sharp waves may have a regional distribution or appear generalized as a result of secondary bilateral synchrony.87 False localization to the anterior temporal region is not uncommon in patients with basal frontal epilepsies, who present with anterior temporal interictal epileptiform discharges (Figure 37.6) on their scalp EEG.57 Occasionally, propagated epileptiform activity can be present over central or frontolateral regions.76 Moreover, epileptiform

abnormalities may have a misleadingly widespread appearance, because of the large distance and intervening cortical area that separates the epileptogenic zone from the scalp EEG electrodes.81,92 Interictal sharp waves may be reflected over a wide bifrontal region as a result of volume conduction (Figure 37.7) such bilateral discharges may sometimes exhibit a shifting right or left preponderance or a misleading contralateral maximum.35 The inaccessibility of the basal frontal surface and other areas of the frontal lobe to scalp electrodes, the widespread connectivity of the OFR, the variable size and location of epileptogenic foci within this region and the potential for bilateral epileptogenicity as a result of bifrontal injuries are among the factors accounting for the lack of adequate topographic scalp EEG localization in basal frontal lobe epilepsies.33 Large and somewhat blunted sharp waves were demonstrated by Tharp in his patients with presumed orbitofrontal epilepsy.52 Case reports by Ludwig and co-workers highlighted the occurrence of bilaterally synchronous, paroxysmal epileptiform discharges, with a bifrontal or frontopolar maximum, as well as discharges involving one anterior quadrant, with or without evidence of additional temporal lobe involvement.41 In the single patient described by Chang and colleagues sphenoidal recordings exhibited a consistent preponderance on the side of the epileptogenic OFR. In this well-documented case report the addition of sphenoidal and infraorbital scalp electrodes revealed that the observed bisynchronous discharges had a more basal distribution with a maximum in the infraorbital regions.39 The close anatomical connections between the mesial temporal and orbitofrontal regions have already been discussed. In their classic (1958) paper, Kendrick and Gibbs used the technique of strychnine neuronography in the course of temporal

Spike, Maximum Sp1 Fp1–F7 50 uv

F7–SP1 SP1–T7 T7–P7 P7–O1 Fp2–F8 F8–SP2 SP2–T8 T8–P8 P8–O2 SP1–SP2 TP9–TP10 Fp1–F3 F3–C3 C3–P3 P3–O1 FP2–F4 F4–C4 C4–P4 P4–O2 EKG1–EKG2 2000 uV

Figure 37.6 Interictal scalp EEG tracing. Predominant spike focus in the left anterior temporal region, maximum in the left sphenoidal electrode (Sp1), as seen on this longitudinal bipolar montage (the temporal chains have been extended to include the left and right sphenoidal electrodes).

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Spike, Generalized Fp1–F7 50 uV

F7–T7 T7–P7 P7–O1 Fp2–F8 F8–T8 T8–P8 P8–O2 Fp1–F3 F3–C3 C3–P3 P3–O1 Fp2–F4 F4–C4 C4–P4 P4–O2 F7–Cz Cz–Pz EKG1–EKG2 2000 uV

Figure 37.7 Interictal scalp EEG tracing. Less frequently, generalized epileptiform discharges (with a shifting bifrontal maximum; higher on the right side in this instance) were seen during prolonged video-EEG recordings, as illustrated on this routine longitudinal bipolar montage.

lobectomies to demonstrate the bidirectional interrelationship between these two regions in humans.93 Local application of strychnine through needle electrodes produced ‘artificial’ spike foci in the frontal and temporal lobes of 34 patients. The authors observed that strychnine-induced spikes in the mesial temporal region commonly spread to the mesial orbital surface of the ipsilateral frontal lobe as well as to the tip of the ipsilateral temporal lobe. On the other hand, strychnine injected into the mesial OFR resulted in spike discharges that propagated first to the ipsilateral mesial temporal cortex, and later to the contralateral mesial OFR and to a lesser extent to the frontal poles. The authors concluded that discharges may spread in either direction – depending upon whether strychnine is first applied in the mesial temporal or orbitofrontal area – and implicated the ‘pathway afforded by the uncinate fasciculus’ to explain the observed spread patterns. Ictal scalp EEG recordings (Figure 37.8) during seizures of frontal lobe origin, as a whole, may provide poorly localizing94,95 or misleading information.96 Seizure duration is usually short and muscle artifact often obscures ictal EEG activity. Furthermore, observed patterns and frequency of activity at the time of electroencephalographic seizure onset do not correlate with the cortical area generating seizures.97 When ictal EEG is inconclusive or normal, diagnosis will rely on the history and ictal semiology. In cases where the clinical pattern does not provide additional clues with respect to lateralization to one hemisphere, detailed analysis of clinical seizure onset may be helpful in disclosing a clearly defined focal symptomatology.98 The localizing value of ictal scalp EEG is generally inferior in extra-temporal epilepsies.33,99 Using lateralized rhythmic discharges, postictal slowing and EEG activity at seizure onset

only 47–65% of extratemporal seizures are correctly lateralized, as opposed to 76–83% of temporal lobe seizures.99 Surface ictal EEG recordings were retrospectively analyzed in a recent series of 46 patients with neocortical focal epilepsy, who became seizure free after surgical resection of a single lobe (lateral frontal=15, mesial frontal=8, neocortical temporal=10, parietal=7 and occipital = 6). In this series, virtually all seizures that were either obscured by artifact or had no identifiable EEG change had a frontal lobe origin.33 Localized EEG patterns were more common with seizures arising from the dorsolateral frontal region. Intracranial EEG Patients with suspected pharmacoresistant focal epilepsy should be referred to a comprehensive epilepsy center for a thorough presurgical evaluation, which includes prolonged video-EEG recordings, high-resolution structural and functional imaging and neuropsychological assessment. When results of presurgical studies are inconclusive or incongruent and epilepsy surgery is being considered, invasive EEG recordings with subdural grid and/or depth electrodes may be necessary to delineate the epileptic focus. Invasive approaches to verify the location of the epileptogenic focus include: intraoperative electrocorticography, extraoperative invasive electrode recordings (using extradural, subdural and/or intracerebral electrodes), and stereo-electroencephalography.60 It is important to emphasize that invasive electrodes record from limited parts of the cortex only, and do not provide the global picture of brain activity afforded by scalp electrodes.100,101 Hence, intracranial electrode monitoring should only be utilized, once a reasonable hypothesis

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Textbook of epilepsy surgery EEG_ONSET Rhythmic change in Lt hemisphere

Fp1–F7 20 uV

F7–SP1 SP1–T7 T7–P7 P7–O1 Fp2–F8 F8–SP2 SP2–T8 T8–P8 P8–O2 SP1–SP2 TP9–TP10 FP1–F3 F3–C3 C3–P3 P3–O1 Fp2–F4 F4–C4 C4–P4 P4–O2 EKG1–EKG2 1000 uV

Fp1–F7

> HR increases to 84bpm

>

> > 20s + EEG onset

50 uV

F7–SP1 SP1–T7 T7–P7 P7–O1 Fp2–F8 F8–SP2 SP2–T8 T8–P8 P8–O2 SP1–SP2 TP9–TP10 Fp1–F3 F3–C3 C3–P3 P3–O1 Fp2–F4 F4–C4 C4–P4 P4–O2 EKG–EKG2 1000 uV

Figure 37.8 Ictal scalp EEG tracings on a routine longitudinal bipolar montage during a typical nocturnal seizure: (a) The electrographic onset (EEG onset) is punctuated by the appearance during sleep of an initial low voltage semi-rhythmic activity, which gradually evolves into more rhythmic and sharply contoured delta slowing over the left hemisphere; (b) 20 seconds later repetitive spikes within the ill-defined slowing.

about the possible location(s) of the epileptogenic zone has been made based on the results of a detailed presurgical evaluation.102 When epileptogenicity involving the basal frontal lobe is suspected, electrode coverage of both the frontal and the temporal lobe may be necessary, to better localize the epileptogenic zone and differentiate between frontal and temporal involvement (Figures 37.9 and 37.10). Furthermore, use of bilateral frontal electrodes may be contemplated as a means

of improving the investigators’ ability to study lateralization and mode of propagation of ictal discharges.103 Stereotactically placed depth electrodes are useful in accurately targeting/evaluating deep structures, but sample only a restricted area. On the other hand, subdural electrodes provide better spatial resolution and can sample a larger expanse of cortex as they record directly from the cortical surface that underlies the pia matter. However, only about one-third of the

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Basal frontal lobe epilepsy CLIN_ONSET Elevate Rt arm

Fp1–F7

> > Rhythmic theta max sp1 40s + onset

303

SEIZURE seizure button

100 uV

F7–SP1 SP1–T7 T7–P7 P7–O1 Fp2–F8 F8–SP2 SP2–T8 T8–P8 P8–O2 SP1–SP2 TP9–TP10 Fp1–F3 F3–C3 C3–P3 P3–O1 Fp2–F4 F4–C4 C4–P4 P4–O2 EKG–EKG2 1000 uV

Fp1–F7

> Head turn to Rt

> > Vocalize, extend Rt arm forward Eyes to Lt",

Sign of four,

quickly

followed by

200 uV

F7–SP1 SP1–T7 T7–P7 P7–O1 Fp2–F8 F8–SP2 SP2–T8 T8–P8 P8–O2 SP1–SP2 TP9–TP10 FP1–F3 F3–C3 C3–P3 P3–O1 Fp2–F4 F4–C4 C4–P4 P4–O2 EKG1–EKG2 1000 uV

Figure 37.8, (c) low-amplitude repetitive spiking (~5–7Hz) seen over the left temporal region at the time of clinical onset, which occurs approximately 40 seconds following EEG onset. (d) muscle artifact obscuring EEG activity at the beginning of secondary generalization, which occurs approximately 50 seconds following EEG onset.

cortex is exposed, and generators located within the depth of a sulcus cannot be sampled adequately unless they extend to the cortical surface or crown.104 Subdural grid or strip electrode arrays are inserted under general anesthesia following craniotomy and incision of the dura. Such arrays are usually slid under the edges of the exposed dura, in contact with the brain surface, without direct visualization for the purposes of recording from the orbitofrontal and adjacent inferior temporal areas.105 The current approach at both the Cleveland Clinic Epilepsy Center and at the Texas Comprehensive Epilepsy Program is to sample the basal frontal region using a 4 × 4 subdural electrode array (Figure 37.9); made of four rows and four columns of platinum-iridium disk electrodes, each of

which has a 4mm diameter and is separated from neighboring electrodes by a center-to-center distance of 1cm.106 As described above, the OFR has widespread connections with the anterior and mesial temporal regions, the insula, opercular areas and cingulate gyrus. Adequate sampling of these areas is recommended during invasive recordings in patients with suspected basal frontal epilepsies.107,108 Good communication between the neurosurgeon and the epileptologist/neurophysiologist involved in the clinical management and interpretation of presurgical studies is essential during the planning stage. In addition, functional mapping by means of electrical cortical stimulation may be necessary to identify eloquent cortex such as language areas and motor cortex.

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Brain Map-Left

A

DSF

B

DIF D

E

E

F

C

Figure 37.9 Invasive EEG evaluation using a combination of multiple subdural electrodes covering the left frontal and temporal lobes along with two intracerebral depth electrodes targeting the area of encephalomalacia. Subdural electrode arrays: A = 8×8 plate, covering the left perirolandic region; B = 4×6 plate, covering the left dorsolateral frontal region, anterior to the A plate; C = 4 ×4 plate, covering the orbitofrontal area; D = 2×6 plate, covering the lateral aspect of the temporal lobe; E and F = 1×6 strips, covering the anterior and mid subtemporal regions. Intracerebral depth electrodes targeting the encephalomalacic area: DSF with entry point in the superior frontal gyrus, and DIF with entry point in the inferior frontal gyrus, as seen in this schematic representation.

Roper and Gilmore used a single subdural strip electrode to sample the orbitofrontal cortex in all cases of limbic epilepsy referred for invasive monitoring during a period of 1 year.46 A total of 15 patients underwent invasive evaluations during this period (unilateral investigations with temporal, frontal, and orbitofrontal subdural electrodes were performed in eight and bilateral studies using bitemporal depth electrodes along with bilateral inferolateral temporal and orbitofrontal subdural electrodes were performed in seven patients). Three patients out of the 15 patients with intractable limbic seizures were found to have seizures originating from within the OFR (see Table 37.1). Subdural strip electrodes identified the OFR as the site of seizure origin (ictal onset zone), but were insufficient to define the actual boundaries of the epileptogenic zone. To better delineate the boundaries of the epileptogenic area the authors supplemented their investigations with the use of intraoperative electrocorticography (ECoG). These investigations and subsequent surgical excisions led the authors to conclude that unilateral OFR resections can be beneficial in a subset of patients with orbitofrontal epilepsy and can be performed without significant neuropsychologic impairment. Stereo-electro-encephalography (stereo-EEG, sEEG) refers to the methodology of stereotactically-guided depth electrode recordings, which was originally developed by Bancaud and Talairach in France. Ictal anatomo-electro-clinical correlations based on sEEG recordings are utilized in identifying the cortical area(s) primarily involved in the generation of spontaneous ictal discharges, and provide a guide to tailored cortical resection.109 For the school of stereo-EEG investigations individualized planning of electrode implantation

is critical. The surgical team is assigned with the task of finding the best compromise between the ‘ideal’ position of the electrode and the constraints introduced by the various vascular segments, which the electrode may encounter along the length of its trajectory from the surface to the deeper brain targets.103,110 In their review of the electroclinical features of orbitofrontal seizures Munari and Bancaud summarized their experience in a series of 60 patients, who underwent stereo-EEG investigations with at least one orbitofrontal depth electrode. The majority of these stereotactically implanted multilead electrodes (total of 10 contacts, each 2mm in size and 1.5mm apart) were inserted via an orthogonal, lateral approach and aimed to explore both the medial and lateral aspects of the OFR.36 An oblique approach was used in a few cases and a vertical approach was utilized in a single patient. Spread between OFR and temporal lobe may occur extremely rapidly via the uncinate fasciculus as documented by stereo-EEG investigations of spontaneous seizures arising from the basal frontal lobe.36 Other investigators have observed that ‘orbitofrontal seizures’ propagate more slowly compared to seizures arising from other extratemporal locations.101 This observation comes out of a fairly small study of 10 patients with extratemporal neocortical epilepsy. A total of 25 seizures were studied with intracranial recordings using a combination of subdural strips, subdural grids, and depth electrodes implanted ‘as clinically indicated’. Two patients in this group were thought to have seizures arising from the OFR and both underwent bilateral intracranial EEG investigations. A total of eight ‘orbitofrontal seizures’ were studied, although details on individual seizures were not provided. The authors defined the ipsilateral and contralateral propagation time as the time elapsed from electrographic seizure onset to first spread either to an adjacent ipsilateral lobe or to the contralateral hemisphere. For ‘orbitofrontal seizures’ spread to the ipsilateral temporal lobe occurred within a period ranging from 12.5 to 85 seconds, and to the contralateral frontal lobe within a period ranging from 9.8 to 92 seconds (compared to a more rapid ipsilateral or contralateral spread, as early as within 0 to 0.4 seconds, in some seizures arising from other frontal or parieto-occipital locations).101 The small patient number and the potential spatial sampling limitations of invasive recordings need to be taken into account, when interpreting these results. Structural and functional imaging Structural imaging High resolution anatomical MRI should be performed to search for focal intracerebral lesions, and ideally interpreted by expert radiologists, experienced in imaging of the epilepsies.111 Identification of a structural abnormality by MRI adds substantially to the process of localizing the site of seizure onset and selecting favorable candidates for resective epilepsy surgery.112 Structural abnormalities may be found in up to 80% of patients with refractory focal epilepsy using optimal anatomical MRI imaging.113 Structural MRI can provide reliable information about the pathology of the suspected epileptogenic lesion. Common MRI-identifiable pathologies include disorders of cortical development and foreign-tissue lesions (such as

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EEG_ONSET SC1–Ref

500 uV

SC2–Ref SC3–Ref SC4–Ref SC5–Ref SC6–Ref SC7–Ref SC8–Ref SC9–Ref SC10–Ref SC11–Ref SC12–Ref SC13–Ref SC14–Ref SC15–Ref SC16–Ref SD1–Ref SD2–Ref SD3–Ref SD4–Ref SD5–Ref SD6–Ref SD7–Ref SD8–Ref SD10–Ref SD11–Ref SD12–Ref

EEG onset + 10 sec. SC1–Ref 500 uV

SC2–Ref SC3–Ref SC4–Ref SC5–Ref SC6–Ref SC7–Ref SC8–Ref SC9–Ref SC10–Ref SC11–Ref SC12–Ref SC13–Ref SC14–Ref SC15–Ref SC16–Ref SD1–Ref SD2–Ref SD3–Ref SD4–Ref SD5–Ref SD6–Ref SD7–Ref SD8–Ref SD10–Ref SD11–Ref SD12–Ref

Figure 37.10 Ictal invasive EEG recordings on a referential montage displaying the electrode contacts on the C (orbitofrontal) and D (lateral temporal) plates: The electrographic onset is punctuated by the appearance of focal repetitive spiking involving the mesial, posterior corner of the orbitofrontal plate (electrodes C1 followed by electrodes C2 and C5). This activity remains confined to the orbitofrontal area without evidence of concurrent involvement of other electrodes for several (~25) seconds.

tumors and vascular malformations). Furthermore, findings on MRI help tailor the surgical procedure and assess the extent of resection postoperatively.112 A particular challenge for T2 weighted MRI sequences investigating the human OFR using is the potential for susceptibility artifacts resulting in signal dropout or geometric distortion as a result of the close proximity of the OFR to the air-filled sinuses.7 When MRI is negative but EEG or other testing points to a potential area of focal epileptogenicity, dedicated MRI

sequences114 with thin cuts through the region(s) of interest should be obtained. Imaging with higher magnetic fields or three-dimensional MRI techniques may further increase the yield and allow for presurgical identification of epileptogenic lesions.115 As illustrated in the case reported by Rugg-Gunn and colleagues48 the use of diffusion tensor imaging and advanced postacquisition processing analyses can enhance the detection rate of subtle abnormalities in patients with so-called ‘nonlesional’ focal epilepsies.116,117

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Functional imaging Functional imaging with interictal PET and/or ictal SPECT studies may be employed as a means of identifying seizure foci in the basal frontal lobe and guiding surgical resection. Interictal studies of brain metabolism using 18FDG-PET (fluoro-deoxyglucose positron emission tomography) may disclose areas of hypometabolism in up to 60% of patients with frontal lobe epilepsy. However, almost 90% of these patients will have an underlying MRI-identifiable structural abnormality.118 In neocortical epilepsy it is often difficult to interpret small or subtle focal areas of hypometabolism of questionable clinical relevance in the absence of a structural lesion.119 Consequently, 18FDG-PET studies may be of limited value in nonlesional frontal lobe epilepsies. Single photon emission computed tomography (SPECT) has been used in patients with focal epilepsy to assess alterations of cerebral perfusion that may reflect the approximate location of the epileptic focus. Ictal SPECT is the only available, noninvasive modality practically suited for functional brain imaging during an actual seizure.119 Digital subtraction techniques allow for comparison of an individual patient’s interictal (baseline) and ictal SPECT images. The relatively low-resolution subtraction images afforded by SPECT can then be coregistered to the patient’s anatomical MRI for more precise localization.119 This computer-aided process was found to be diagnostically superior, when compared to routine side-by-side visual inspection of ictal and interictal SPECT scans.120 Recent studies suggest that subtraction SPECT images are useful in guiding the location and extent of surgical resection in patients with extratemporal epilepsy.121 There have been no specific reports related to subtraction/ictal SPECT imaging in patients with seizures arising from the basal frontal lobe. Because of their sometimes brief duration and propensity of frontal lobe seizures for rapid secondary generalization it may particularly difficult to obtain and interpret ictal SPECT studies. In contrast to the aforementioned nuclear imaging techniques, magnetoencephalography (MEG) is a neurophysiological method with high temporal and spatial resolution. Results of MEG source localization can be co-registered to structural MRI data and produce the so-called magnetic source imaging (MSI), which is currently explored as a means of improving noninvasive localization of epileptogenic foci. The conjugation of noninvasive neurophysiology and anatomical neuroimaging using MEG/EEG along with MRI can provide important insights into the generation and spatiotemporal evolution of neocortical discharges. However, the results obtained require careful clinical analysis, integration and comparison with available preoperative testing and further validation.122 MSI123 along with ictal SPECT studies124 may play an increasingly important role in directing placement of electrodes in patients with suspected frontal lobe epilepsy, being considered for resective surgery.125 At this time, however, the role of MSI in the presurgical evaluation of patients with suspected basal frontal lobe epilepsies remains unclear. Etiologies of basal frontal lobe epilepsy Out of the 23 cases assembled in Table 37.1, a brain abscess was identified in two patients, and a tumor in another two (one had a pilocytic astrocytoma; the tumor type was unknown in the second case). Two more patients were found

to have cortical dysplasia, while four patients were suspected to have a posttraumatic etiology. Histo-pathological examination showed nonspecific ‘gliosis’ in five patients and no abnormalities in three. Details on histopathology of resected tissue were not provided/not known in the remaining five cases. The OFR is a common site for closed-head injury. Nonpenetrating head traumas may produce forces that move the basal frontal brain parenchyma across the underlying uneven surface of the orbital roof.126 Falls or blows on the front of the head produce direct frontal lobe damage, while trauma to the occipital region produce basal frontal and fronto-polar injury by a contre-coup mechanism. Hence, posttraumatic epilepsy following closed head injury often involves the frontal and/or temporal lobes. The diffuse nature of nonpenetrating head injuries often limits localization of the epileptogenic focus, especially in patients without distinct, MRI-identifiable focal lesions.127 It should also be noted that extensive cortical abrasions and/or lacerations in the orbitofrontal region may not be easily detected by CT and/or MRI because of the relatively limited three-dimensional volume of these lesions and the artifacts introduced by the surrounding bony irregularities of the cribriform plate.128 The prognosis and risk of later epilepsy depends on the severity of the trauma and concomitant cerebral complications.129,130 Post-traumatic epilepsy refers to the recurrent, unprovoked seizures developing more than one week after penetrating or closed head injury.131 Nearly 40% of seizures appear within the first 6 months, and 70–80% by the first 2 years after the injury.132 The risk of posttraumatic epilepsy falls rapidly as the post-injury seizure-free interval increases, but does persist for more than 15 years after the injury, especially in cases of moderate to severe trauma.130 The olfactory nerves are located immediately below the OFR and are similarly susceptible to injury following closed head trauma. Post-traumatic anosmia usually results from shearing of the olfactory nerve fascicles as they traverse the cribriform plate to enter the olfactory bulb.133 Because of this shared mechanism of injury posttraumatic anosmia may serve as an important clinical sign of concomitant orbitofrontal damage. Significant hypoperfusion in the OFR has been demonstrated with the use of HMPAO-SPECT in a series of 18 patients, who had been rendered completely anosmic as a result of a remote head injury.134 In a similar study of 11 anosmic patients with a history of prior head injury quantitative PET studies showed evidence of hypometabolism in the OFR as well as in the medial temporal region compared with controls.135 In a similar series of 20 head-injury patients the finding of marked post-traumatic anosmia was taken as a strong indication of damage to the OFR.128 Most of these patients appeared intact on psychometric neuropsychological testing and were generally preserved in areas such as intelligence, memory and language. Nevertheless, they faced major psychosocial difficulties; most of them were unemployed and showed evidence of poor empathy, poor judgment and absent-mindedness. It is not uncommon for patients with OFR injuries to perform normally on a variety of standard neuropsychological tests.128,136 More specialized testing is required to expose deficits related to decision making and executive planning. The authors concluded that posttraumatic anosmia has a close and specific relationship with a particular locus of injury (OFR) and a

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Basal frontal lobe epilepsy specific set of neurobehavioral symptoms that constitute the so-called ‘orbitofrontal syndrome’. Another common insult with predominant temporal and/or orbitofrontal localization that deserves mentioning in this section is herpes simplex encephalitis. Herpes simplex virus (HSV) is the cause of the most common sporadic viral encephalitis in adults and children older than 6 months.137 Encephalitis due to HSV infection (both primary and recurrent infection) is a serious disease with an untreated mortality approaching 70% and substantial morbidity despite antiviral therapy.138 Pathological studies of HSV encephalitis have shown predominant viral-related damage in limbic structures as well as neighboring areas including the mesial temporal lobe (hippocampal formation, amygdala, parahippocampal gyrus, and perirhinal cortex), orbitofrontal region, insula and cingulate gyrus.139 The selective and often remarkably segregated involvement of temporal and orbitofrontal locations may in part reflect the route of entry of the virus into the host. In primary infection HSV may gain access to the brain via an olfactory route reaching the olfactory bulbs through the cribriform and subsequently spreading along the base of the frontal lobe. In reactivation of latent HSV infection the virus may spread from the trigeminal ganglion along meningeal branches of the trigeminal nerve.137,140 The long-term sequelae of rigorously confirmed HSV encephalitis in the era of antiviral therapy (with acyclovir) were investigated in a retrospective study from New Zealand, in which a total of 42 acyclovir-treated patients were followed for a period of up to 11 years.141 The mortality rate was 12% at 1 month and 14% at 6 months. All but one of the surviving patients had persistent neurological impairment. The most common and most disabling complication was that of memory dysfunction (especially short-term memory). Personality and behavioral disorders occurred in almost half of the long-term survivors, albeit less severe compared to reported disability before the introduction of acyclovir. Epilepsy was present in 24% of surviving patients. Of note, two-thirds of survivors were found to have unilateral or bilateral anosmia, although may of these patients were unaware of the deficit.141 Other common substrates of extratemporal focal epilepsy include tumors, vascular anomalies and developmental disorders. The importance of MRI-identifiable lesions involving the deeply situated orbitofrontal region should not be underestimated. Studies of anatomically defined lesions in various locations of the brain cortex indicate that these lesions will more often than not harbor the site of the epileptogenic focus.142 In this case complete excision of the lesion along with the surrounding ‘epileptogenic tissue’ provides an excellent chance for a seizure-free outcome.38,66 Studies have shown that one of the best prognostic factors in epilepsy surgery is in fact the completeness of such lesionectomies.143 Poor surgical results are more common in cases, where postoperative MRI provides evidence of incomplete resection of the lesional pathology.144 With improvements in neuroimaging, cortical dysplasias and other developmental disorders are increasingly recognized as causes of pharmacoresistant focal epilepsy. It is estimated that nearly 30% of surgical specimens from patients with neocortical epilepsy contain some type of malformation of cortical development.145 In fact, dysplastic lesions (ranging

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from heterotopias to subtle cytoarchitectural abnormalities) are the most common histopathological finding in some surgical series of frontal lobe epilepsies.38 Among the various vascular anomalies, cavernous angiomas (cavernous malformations, CM) and arteriovenous malformations (AVM), are more likely to cause seizures. The epileptogenicity of these lesions is believed to result from pathological changes imparted on tissue surrounding the vascular malformation due to ongoing microhemorrhage and hemosiderin deposition.146 Therefore, surgical excision should not only target the lesion but extend to the adjacent hemosiderin-stained tissue.147 Frequently encountered tumoral pathologies associated with pharmacoresistant epilepsy include gangliogliomas, dysembryoplastic neuroepithelial tumors (DNETs) and lowgrade gliomas. In cases involving the basal frontal lobe, a gross total resection to clear margins provides the best chance for control from both the oncology and epilepsy standpoint.148 Gliosis as a result of previous anoxia, head trauma, or other unknown causes may be the only identifiable in pathology in surgical specimens obtained from patients with focal epilepsy. Lastly, a curious clinicopathologic entity of intracranial choristomas involving the gyrus rectus has been reported recently in two adult patients with seizures. In both cases the epileptogenic lesions were composed of heterotopic epithelial, glial and mesenchymal components. The histogenesis of these lesions is unclear, but the preferential involvement of the gyrus rectus, which is in close proximity to the frontal bone, led the authors to speculate a common origin from neural crest progenitors.149 Medical therapy Seizures arising from the basal frontal region may respond to standard anticonvulsant agents (AEDs). As the seizures are focal in origin carbamazepine (or phenytoin) has been recommended as first line of treatment.150 Alternatively monotherapy with a newer AED such as lamotrigine, oxcarbazepine, topiramate or gabapentin could be considered based on drugdrug interactions and side-effect profile.151 If patients do not respond to monotherapy trials at maximum tolerated doses a second agent may be added. Valproic acid may have a role in preventing secondarily generalized seizures. Other adjunctive agents include levetiracetam, zonisamide and tiagabine.152 Approximately 65% of patients with focal epilepsy respond to appropriate anticonvulsant therapy.153,154 When medical therapy provides inadequate control of seizures or unacceptable side effects, the possibility of resective surgery should be explored. Patients with evidence of pharmacoresistant focal epilepsy should be referred to a specialized epilepsy center for presurgical evaluation and management. Patients who are not favorable surgical candidates or have failed surgical resection may be considered for implantation of a vagus nerve stimulator (VNS). Unfortunately, it has not been possible to predict which patients will benefit from chronic VNS before implanting the device.155 Surgical approaches to the OFR The surgical anatomy of and surgical approaches to the orbitofrontal region have not been well characterized in the published literature. One possible reason for this may be

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the fact that prior to the widespread application of invasive electrophysiology in surgical epilepsy programs the OFR has generally not been viewed as a target for resection. While portions of the basal frontal lobe are routinely retracted during neurosurgical procedures for vascular or neoplastic abnormalities, resections of the OFR itself are uncommon. A notable exception is the resection of the gyrus rectus that is carried out to facilitate exposure during pterional/subfrontal approaches to aneurysms involving the anterior communicating artery and proximal A2 segment of the anterior cerebral artery. The epilepsy surgeon accessing the OFR should, therefore, familiarize him/herself with the anatomy of the region and discuss the goals of the planned procedure with the treating epileptologist. Invasive monitoring of the OFR The investigation of nonlesional basal frontal lobe epilepsy is challenging, yet necessary, given the ‘buried’ nature of the cortex in this region. We prefer the use of subdural electrodes to depth electrodes to investigate the OFR. If a fronto-temporal craniotomy is planned, it is extended anteriorly to expose most of the frontal operculum; if burr holes and strip electrodes are planned, one burr hole is placed over the pterion (‘the keyhole’). In the case of a craniotomy, a 4×4 electrode array, with its lead situated laterally, is placed over the orbital roof, to cover a significant portion of the OFR. If burr holes are used, a 4-contact strip electrode is placed over the posterior portion of the OFR. Resections of the OFR The surgical approach to the OFR is dictated by the surgeon’s familiarity with a particular approach, the pathologic process being treated (lesion resection versus regional OFR excision for intractable epilepsy), the location of the lesion, and whether or not the resection involves the (presumed or apparent) dominant hemisphere. Another important consideration during surgical planning should be the connections of this region with the anterior and medial temporal lobe and the cingulate gyrus. Incomplete resection of epileptogenic cortex left attached to these structures, may compromise surgical outcome. Given that these connections extend from the posterior edge of the OFR, and that the posterior boundary is intimately linked to multiple structures (anterior perforated substance, optic nerve and anterior cerebral artery) – damage of which can result in significant deficits – an intimate knowledge of the anatomy of the OFR is crucial to successful surgical outcomes. Prior descriptions of surgery in the OFR have variously delineated the posterior extent of orbito-frontal excisions as being about 1–2cm in front of Broca’s area in the languagedominant hemisphere or extending posteriorly to the ipsilateral internal carotid artery156 and the intersection of the optic and olfactory nerves.107 We find a subpial approach combined with intraoperative frameless stereotactic navigation to be safer, and prefer to use the proximal anterior and middle cerebral arteries (viewed through intact pia) to delimit the resection margins (Figure 37.2). The OFR may be approached using three possible trajectories, depending on the nature and location of the lesion (Figure 37.3): ● ● ●

Lateral frontal; Anterior frontal; and Intermediate or anterolateral approach, which may be combined with orbito-zygomatic osteotomy.

The lateral frontal is by far the commonest approach for an OFR resection in the context of epilepsy surgery. This is because many such resections occur in the context of a large fronto-temporo-parietal craniotomy performed for placement of subdural electrodes for invasive electrophysiology. The resection is usually carried out at the time of electrode removal, and the orbital cortex is therefore approached from its lateral aspect. An en bloc resection of all, except the most posterior aspect, of the lateral, posterior and medial orbital gyri, and a portion of the anterior inferior frontal gyrus is carried out. This is followed by subpial aspiration of gyrus rectus. The ipsilateral anterior cerebral artery (ACA) is identified and traced posteriorly to the rostrum of the corpus callosum. Finally, the posterior limits of the orbital gyri and the subcallosal (rostral) cingulate gyrus are aspirated using a subpial technique (Figures 37.4 and 37.5). Identification of the ACA helps determine the posterior extent of the medial resection. The M1 segment of the middle cerebral artery (MCA) may be used to define the posterior edge of the resection. Use of a subpial technique during the medial and posterior aspect of the resection is crucial in minimizing risks to the anterior perforated substance, olfactory tract, and optic nerves. The anterior approach is principally used for excisions of overt OFR lesions and resections in the context of depth electrode recordings. Preoperative placement of a lumbar drain minimizes the need for retraction. A bicoronal scalp incision is made, following which a frontal craniotomy bone flap is elevated – from just above the frontal sinus, just lateral to the midline (and anterior sagittal sinus) and extending laterally to the anterior attachment of the temporalis muscle. A frameless stereotactic system may be used to demarcate the edges of the craniotomy and facilitate approach to the lesion. The dura is opened, with its base on the sagittal sinus, following which the lesion is resected. Subpial techniques should be used when there is a need to remove abnormal (gliotic, hemosiderin stained etc.) cortex surrounding the lesion. A principal advantage of the anterior and antero-lateral approaches is that the inferior frontal gyrus is more easily spared (Figure 37.7). The antero-lateral approach, combined with an orbitozygomatic osteotomy may be useful in cases where a large lesion is situated in the postero-medial OFR, and the intention is to minimize dissection and retraction of uninvolved cortex. A frontal craniotomy incision extending to the contralateral midpupillary line is used, following which a frontal craniotomy and orbito-zygomatic osteotomy are carried out. The dura is then opened with its base on the orbital contents, and resection of the lesion is performed. A lumbar drain placed prior to the craniotomy further helps in minimizing retraction. Occasionally invasive recordings may suggest independent ictal onsets originating from both the medial temporal and orbitofrontal regions. These cases can be managed with concurrent resections, possibly guided by the judicious use of intra-operative electro-corticography (ECoG) to measure the impact on electric activity in one region after the other is resected. Routine resection of the OFR concurrent with a temporal lobectomy is not recommended – although some authors have adopted a combined approach guided solely by the apparent location of interictal abnormalities.157

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Basal frontal lobe epilepsy Possible complications related to surgery in the OFR include: infection of the surgical site, osteomyelitis and/or CSF fistulae from opening the frontal sinus mucosa during craniotomy; hemorrhage from injuring the anterior sagittal sinus; venous infarcts when sacrificing veins leading into the sinus; visual deficits following injury to the optic nerve; ischemic events following injury to perforating vessels in the anterior perforating substance; CSF rhinorrhea through the cribriform plate and anosmia if the olfactory nerve and tracts are destroyed; and inadvertent injury to the contralateral frontal lobe if the medial frontal pial layer is not recognized and respected. In addition, there may be impacts upon personality and social behavior following OFR resections – such deficits are not adequately assessed with the current, standard neuropsychological measures employed in patients undergoing epilepsy surgery. Outcome There is no systematic study of outcomes related to resections for the treatment of basal frontal lobe epilepsy, and studies examining neuropsychological function in patients with epilepsy arising from this region are lacking. In general, just as for other extratemporal epilepsies, outcomes following resective epilepsy surgery anywhere in the frontal lobe are considered to be ‘not as good’ as those after temporal lobectomy.121,144 The presence of a lesion on neuroimaging increases the chances for seizure-freedom or significant improvement.35 Cumulative results of surgical treatment for various frontal lobe epilepsies in the pre-MRI era have been characterized as ‘unsatisfactory’ or ‘mediocre’.103 As a rule, results following removal of discrete frontal lesions are superior to those with more diffuse lesions or without demonstrable lesions.66 In a study of 68 consecutive patients, who underwent epilepsy surgery involving the frontal lobe good outcome at last follow-up was reported in 72% of patients with evidence of a lesion on neuroimaging, as compared to only 41% of the ‘nonlesional’ cases.158 We recently performed a retrospective review of all frontal lobe resections performed by a single neurosurgeon for the treatment of pharmacoresistant focal epilepsy at the Cleveland Clinic Foundation during a 6-year period (from 1998 to 2004). All cases had undergone a comprehensive presurgical evaluation including high-resolution preoperative MR imaging and presentation at a multidisciplinary patient management conference. Out of a total of 130 patients, who had frontal resections during the study period, basal frontal lobe epilepsy was suspected in eight patients.159 In these patients, MRI demonstrated a lesion restricted to the OFR, and/or invasive recordings provided clear evidence for ictal onset within the OFR. Patients with more extensive MRI lesions were excluded. Only two cases were nonlesional (i.e., there was no identifiable structural abnormality on high-resolution anatomical MRI); in three of the six ‘lesional’ cases the MRI detected blurring of the gray-white junction in the medial OFR. Histopathology revealed malformations of cortical development in the majority of patients (5 of 8); cavernomas were found in two, and gliosis in one patient. Resections were restricted to the OFR only in four of the eight patients; the other four underwent larger resections that extended into the lateral frontal region. In this study median follow-up was only 14 months. Seven patients were seizure free, while one had rare seizures postoperatively (Wieser class 3).54

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Illustrative case presentation The patient is a 33-year-old, right-handed young man with frequent pharmaco-resistant seizures dating back to the age of 26 years. The patient has a history of a motor vehicle accident at the age of 21 years, when he drove into a telephone pole. He lost consciousness upon impact, and had peritraumatic amnesia and a left-sided skull fracture. He did not require neurosurgical intervention and did not experience seizures at the time of the accident. Seizures started approximately 5 years later. Initial seizures were primarily nocturnal occurring out of sleep. Family members described ‘whole body convulsions’ followed by stertorous respirations and loss of urine control lasting for less than 1–2 minutes. Postictally the patient reported tiredness, muscle soreness and occasional tongue biting. These seizures have been disabling and have persisted despite several trials of antiepileptic agents with an average frequency of at least one to four per month. A second ‘mild seizure type’ was reported. During wakefulness he would have a warning described as ‘feeling unwell’ or having ‘a funny feeling in the head’ lasting for a few seconds, and followed by loss of awareness. Family members described staring and unresponsiveness for 2–3 minutes. During this period the patient had been observed to have complex movements involving the legs and hands. Patient was not sure as to the frequency of this second seizure type. He reported having auras at least once a month. He had no history of prolonged, unremitting seizures or physical injury as a result of seizures. He has been unable to work for the last 7 years, because of seizures. Examination and investigations Physical and neurological examinations were normal. Routine outpatient EEG was normal. Magnetic resonance imaging revealed an area of focal encephalomalacia in the ventral and basal aspects of the left anterior frontal lobe abutting the roof of the left orbit. The patient was admitted for video-EEG monitoring. Background EEG was normal. Interictal epileptiform activity was recorded predominantly arising from the left temporal region (maximum at the left sphenoidal electrode (Figure 37.6). Less frequent generalized epileptiform discharges with a shifting bifrontal maximum were also present (Figure 37.7). In addition, rare right temporal sharp waves were described. Three typical nocturnal seizures were recorded during sleep. They were characterized by an early change in facial expression and unresponsiveness, followed by tonic stiffening and elevation of the right arm (sign of four, right arm extended with the left arm flexed at the elbow), and right head turning preceding the onset of the secondarily generalized tonic-clonic seizure. Interictal FDG-PET showed mild decrease of FDG uptake in the left orbitofrontal region, corresponding to the area of MRI abnormality. Wada testing (with intracarotid administration of methohexital) demonstrated left hemispheric dominance for language and bilateral memory representation. Baseline neuropsychological evaluation suggested bilateral frontotemporal dysfunction. The patient appeared to have greater difficulties with verbal than visuospatial intellectual measures. He exhibited evidence of compromised executive function in the course

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of problem solving, impaired verbal memory performance and some deficiencies in vocabulary, naming and reading. The case and results of presurgical studies were discussed in a weekly, interdisciplinary patient management conference attended by experts in clinical epileptology, electroencephalography, structural and functional neuroimaging and neuropsychology. The impression was that the patient’s epilepsy may be arising from the left orbitofrontal region ‘perhaps deep in the area of encephalomalacia’. A temporal onset could not be excluded. An invasive evaluation with a combination of chronically implanted subdural and depth electrodes was recommended to further delineate the seizure onset zone, and its relationship to the encephalomalacic lesion (Figure 37.9). In addition, this approach would allow functional mapping of adjacent eloquent cortex (anterior language area) by means of extraoperative electrical cortical stimulation. Six typical nocturnal seizures were recorded in the span of 8 days of invasive recordings. All seizures were characterized by focal EEG changes restricted to the mesial, posterior edge of the orbitofrontal plate (Figure 37.10). Based on three-dimensional MRI reconstructions of the electrode location and underlying epileptogenic lesion the area of seizure onset was found to correspond to the posterior edge of the encephalomalacia. Treatment and outcome A resection of the left orbitofrontal and anterior ventral frontal regions was performed. Postoperatively the patient experienced a single breakthrough seizure at 3 months and a cluster of three seizures within one day (in the context of a flulike illness) at approximately 6 months. At his last follow-up

the patient has been seizure-free since for more than a year on a stable combination of lamotrigine and levetiracetam.

Summary The basal frontal lobe is perhaps one of the least explored and least understood regions of the human cerebral cortex. This highly multimodal area is characterized by its functional heterogeneity and widespread connections within the frontal lobes and limbic system. The anterior part of the OFR has the appearance of granular isocortex and is connected to the heteromodal prefrontal cortex. The posterior OFR has a more primitive, dysgranular architectonic appearance and is intimately connected with the limbic system. Localization of epileptogenicity arising from the basal frontal lobe is particularly difficult because of the absent or potentially misleading information derived from scalp EEG recordings, and the lack of distinct ictal manifestations. The advent of sophisticated neuroimaging techniques (especially high-resolution anatomical MRI) and the increasing capability to perform invasive recordings from the OFR has made it possible to delineate epileptogenic foci within this region. A limited number of patients with identifiable lesions in the orbitofrontal area and very few patients without evidence of MRI abnormalities have been reported to be seizure free after localized surgical resections. The intimate spatial and functional relationship of the OFR with limbic structures and the reported successes following targeted resections underscore the utility of evaluating this region closely in cases of focal epilepsy presumed to originate in the frontal or temporal lobes.

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Parieto-occipital lobe epilepsy V Salanova

Introduction Occipital lobe epilepsy was first recognized by Gowers in 18791 when he described a 30-year-old man with ‘epileptoid attacks with visual aura’. The patient described a very brilliant image before him ‘like a gold serpent’. This patient at other times had episodes of transient blindness. The patient was found to have an occipito-parietal tumor at autopsy. Gowers interpreted the aura as follows: ‘at first there was apparently an over action of the center – a bright light; afterwards paroxysmal defective action, due to temporary exhaustion or inhibition, shown in the narrowing of the field of vision’. When Gowers examined his records,2 he found that 84 of his 1000 patients with epilepsy exhibited a ‘special sensory aura’ which was referred as ‘the organ or sense of sight’, he subdivided these ‘ocular and visual warnings’ into five categories: a sensation in the eyeball itself, diplopia, an apparent increase or diminution in the size of the objects, loss of sight, and distinct visual sensations such as elementary visual hallucinations. The symptomatology of occipital epilepsy was further defined in 1927 by Gordon Holmes3 when he studied patients who had sustained gunshot wounds to the occipital region who exhibited occipital auras, characterized by elementary visual hallucinations or transient blindness, and in 1941 by Penfield and Erickson,4 who described the clinical manifestations of several patients with ‘visual seizures’, including blindness, and coloured moving lights, and were able to elicit the auras by cortical stimulation. In 1951 Penfield and Kristiansen5 reported that 11 of 222 patients with focal epilepsy treated surgically had ‘visual sensations’ as the first manifestation of their seizures, characterized as sensations of lights, darkness of colour, and five patients reported that the visual image was ‘revolving’ or ‘rotating’. Penfield and Jasper,6 described several patients with ‘visual seizures’, including the patient C.Fr. with a traumatic scar of the pole of the right occipital lobe who had an incomplete left homonymous hemianopia. The patient felt that the seizures were induced by a bright light, to the point that he refused to have the examiner shine a light in his eye. Wilder Penfield stated that ‘This is an example of sensory precipitation of a visual seizure’. The patient described lights followed by blurring of the vision progressing to complete blindness and then a sensation of stiffness in the left hand, and right hand, followed by a generalized seizure. Penfield stated ‘The somatic sensation in both hands suggests that the spread of discharge was from the calcarine cortex to the supplementary area 314

within the sagittal fissure. At the onset of the generalized seizure the head and body turned to the left’. Penfield and Jasper7 also reported two patients whose spontaneous seizures began with elementary visual hallucinations, followed by complex visual images. In both patients the habitual complex visual hallucinations were elicited at surgery by stimulation of the right posterior temporal region, suggesting that during the spontaneous attacks the hallucinations probable represented spread of the ictal discharge to the temporal lobe. Ludwig and Ajmone Marsan7 reported the clinical manifestations in 55 patients with electrographic evidence of occipital lobe involvement, and noted that as many as two-thirds had lateralized visual manifestations, Blume et al.8 found that in 13 of 19 (68%) of their patients the most common initial ictal symptoms were visual phenomena, and Williamson et al.9 reported that in 22 of 25 patients (88%) with occipital lobe epilepsy, early signs or symptoms ‘would had provided clues for the correct diagnosis’. In the series from the Montreal Neurological Institute10 in more than two-thirds of the patients the clinical manifestations indicated the occipital onset of the seizures. Functional anatomy Von Economo11 divided the occipital cortex into striate, peristriate, and parastriate regions. The striate cortex contained within the walls of the calcarine fissure, constitutes Brodmann’s area 17, and it is recognized by the thick strip of granular cells in layer IV that is split by the geniculocalcarine band of Gennari. All layers of this cortex reveal marked granularization. All six layers of cortex are delineated in the peristriate and parastriate cortices (areas 18 and 19). Numerous pyramidal cells are found in layers II, III, and V and giant pyramidal cells populate area 18, immediately bordering on the striate cortex. Jones and Powell12 studied the distribution of projection pathways emanating from areas 17, 18, and 19 by selectively ablating these areas in adult rhesus monkeys. The striate cortex projected to areas 18 and 19, whereas areas 18 and 19 projected fibers to area 8 in the frontal lobe and the adjacent temporal and parietal association cortices. The pathways include the superior longitudinal, the inferior longitudinal and the fronto-occipital fasciculus. Areas 18 and 19 also project deep fibers to the midbrain tegmentum. Further elucidation of the occipital lobe functional anatomy arose from electrical cortical stimulation studies in

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Parieto-occipital lobe epilepsy humans undergoing epilepsy surgery. Wilder Penfield and Theodore Rasmussen in the Cerebral Cortex of Man,13 found that 22 patients reported gross visual sensations as the result of stimulation. These visual responses were elementary sensations of light, darkness, and color. They also reported that ‘complicated visual hallucinations do occasionally result from epileptic or electrical stimulation, but these are phenomena of another order and are associated with activation of the temporal lobes’. They observed that ‘the visual responses appear in the secondary visual areas of Brodman (18 and 19) as well as in the primary calcarine area 17. They noted that ‘in general, it would appear that the calcarine image was more often colored while images produced from the secondary visual zone more often consisted of colorless light’. Symptomatology and pathophysiology of occipital lobe seizures An analysis of 42 patients with refractory occipital lobe epilepsy treated surgically at the Montreal Neurological Institute (MNI) between 1930 and 199110 showed that the clinical features of occipital lobe epilepsy can be divided into those representing seizure phenomena of occipital lobe origin, which include elementary visual hallucinations, ictal blindness, blinking and ocular movements and those resulting from ictal spread to adjacent cortical areas. Fifty-nine percent had visual field deficits. Seventy-three percent of the patients had visual auras. In those patients where the data were available, the elementary visual hallucinations were contralateral to the epileptogenic area. One patient with left occipital microgyria and a right homonymous hemianopsia described ‘dancing lights, whirling lights to the right’ followed by right head and eye deviation, and right head and eye clonic activity. Another patient with left occipital microgyria and a right homonymous hemianopsia described a slowly rotating disk of light in the right visual field. Others described flashing colors, and change in perception of shapes and colors. Another patient with left occipital cortical dysplasia and right upper quadrantanopsia described ‘circles, triangles squares, all colors’, and a visual sensation of movement, followed by conscious right head and eye deviation and right arm posturing. A patient with left occipital gliosis described ‘colored squares of light’ followed by blindness, right head and eye deviation and postictal dysphasia. Four patients had elementary visual hallucinations followed by complex visual hallucinations: a 12-year-old with a history of birth trauma and right occipital gliosis had elementary visual aura characterized by colored triangles followed by a complex hallucination in which he saw a robber, or a man with a gun; sinister characters from comic books, followed by conscious adversion to the left, nystagmoid eye movements, left arm clonic activity and postictal left hemiparesis. Another patient with a left hemianopia described ‘a square with a circle in it’, faces, pictures like Rembrandt’s self portrait. The reason for these complex visual hallucinations is most likely ictal spread to the posterior temporal region, as Penfield and Perot14 found that complex visual hallucinations could be elicited by posterior temporal stimulation near the occipital cortex, and Gloor et al.15 reported that experiential phenomena (visual and auditory) ‘did not occur unless a seizure discharge or electrical stimulation involved limbic structures’.

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Ictal blindness has been a consistent symptom of patients with occipital lobe epilepsy. Twenty-eight percent of patients from the MNI had ictal blindness as an initial manifestations of their seizures which lasted as long as a few minutes. A 24year-old patient with left occipital gliosis described a shadow moving to the right, ‘ombrage’ followed by blindness, and conscious adversion to the right. Russel and Whitty16 reported blurring or extinction of vision in 40% of their patients with traumatic occipital lobe epilepsy, and Williamson et al.9 reported that 10 of 25 (40%) of their patients with occipital lobe epilepsy exhibited ictal amaurosis. Barry et al.17 reported five patients with ictal blindness and electrographic (EEG) monitoring revealed that complete blindness occurred with ictal spread to the contralateral occipital lobe, demonstrating that ictal blindness is caused by seizure induced bilateral occipital lobe dysfunction. Other authors have also reported lateralized visual auras in patients with occipital lobe epilepsy, Sveinbjornsdottir and Duncan,18 Aarli and Engelsen,19 Geller et al.,20 Boesebeck et al.,21 Taylor et al.,22 and Blume et al.23 Other occipital manifestations in the MNI series included eye pulling or moving sensations, blinking, nystagmoid eye movement and contralateral eye movements. Nineteen percent of the MNI patients exhibited blinking and 7% had contralateral nystagmoid eye movements. In one patient, studied with depth electrodes, the nystagmoid eye movements were contralateral to the seizure discharge. Munari et al.24 described 16 patients with stereo EEG who had seizures with ocular deviation within the first 10 seconds of the seizure onset. In 14 patients the ocular deviation was tonic and in all was contralateral to the ictal discharge, which generally originated in the medial occipital structures. Cortical stimulation studies in animals and humans demonstrate that eye movements can be initiated by occipital mechanisms.25,26 Contralateral head and eye deviation was present in half of the MNI patients. Two of these patients were studied with depth electrodes and had contralateral head and eye deviation while the seizure remained localized to the occipital lobe. Ludwig and Ajmone-Marsan7 reported contraversive movements of head and eyes in 29% of their 55 patients. Automatisms similar to those from patients with temporal lobe epilepsy occurred in 50%, and focal motor activity in 38% of the MNI patients, and one-third of the patients had more than one seizure type. Ajmone-Marsan and Ralston27 suggested that seizures originating in the occipital lobe could have multiple spread patterns. Subsequently this was confirmed by intracranial recordings in humans28,29 and animal experimental data.30 The inferior longitudinal, superior longitudinal and the fronto-occipital fasciculus are involved in this spread. Etiologies of occipital lobe epilepsy Rasmussen,31 identified the etiology of refractory occipital lobe epilepsy, established by history and pathological findings in 23 patients; one-third had a history of head trauma or anoxia; 9% had gliomas and 13% postinflamatory brain scarring. In 26% of patients no cause could be determined. The remaining patients had other lesions including pial angiomatosis. In the updated series of 42 patients from the

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MNI, 21% had a history of significant head trauma with loss of consciousness, 24% had a history suuggestive of birth trauma or hypoxia, 7% had a history suggestive of encephalitis, and 10% had slow growing glial tumors. Others had focal cortical dysplasia. Ludwig and Ajmone-Marsan7 reported that 24% of their patients had a history of birth injury, hypoxia, and severe head trauma; 13% had a history of encephalitis or meningitis; 14% vascular lesions, and 7% expanding lesions. In 25% the etiology was unknown. A recent series from the Yale Epilepsy Center, of 35 patients with intractable occipital lobe epilepsy treated between 1986 and 1995, reported that most of their patients had developmental abnormalities or tumors,32 and Lee et al.33 reported that 20 of 26 of their patients with occipital lobe epilepsy had a pathological diagnosis of cortical dysplasia. EEG findings in occipital epilepsy In the MNI series, the most common location of interictal epileptiform discharges was the posterior temporal-occipital region (46%). Interictal epileptiform discharges were localized to the occipital lobe in only 18% of patients. One-third of the patients had synchronous lower amplitude epileptiform discharges from the contralateral homologous head regions, suggesting secondary bilateral synchrony. Bitemporal interictal epileptiform discharges were recorded, in 24% of the patients. This is probably a manifestation of secondary bilateral synchrony and/or secondary epileptogenesis.34,35 The most common type of surface ictal onset was regional involving the posterior temporal occipital region. Ictal onsets on surface recordings restricted to the occipital lobe were seen in only four out of 24 patients (17%). Six patients had intracranial recordings with depth electrodes. Ictal onsets were predominantly regional rather than focal and involved widespread areas of the mesial and lateral occipital cortex, often involving the supra and infracalcarine structures and, in some seizures, the posterior temporal region. The most common pattern of spread involved the ipsilateral temporol-mesial structures. Aykut-Bingol et al.32 found that of 35 patients who had occipital lobe epilepsy surgery between 1986 and 1995, interictal scalp EEG was localized to the occipital, temporal, and occipitotemporal regions in 17%, 27%, and 24% of patients, respectively. Ictal events were recorded in 30 patients. Ictal onset was localized to the occipital lobe in 30%, and temporal and occipitotemporal in 27%; in the rest it was more diffuse. Nineteen patients underwent intracranial EEG studies. Foldvary et al.36 analyzed the localizing value of ictal EEG in focal epilepsy, and found that ‘false localization/ lateralization occurred in 28% of occipital seizures.’

Parietal lobe epilepsy Historical background, and functional anatomy Wilder Penfield, Theodore Rasmussen, and their colleagues divided their patients with refractory epilepsy into those whose epileptogenic areas involved the frontal, central (sensorimotor area), parietal and occipital regions.4,6,13 Patients with epileptogenic lesions involving the pre- and post-central gyrus were grouped together, because lesions in

this cortex produced sensorimotor deficits, and as Penfield and Erickson4 stated ‘the precentral and postcentral gyri in man constitute a functional unit. Close interrelationship of motor and sensory cortical areas is established by the numerous connecting U-shaped fibers which pass under the bottom of the central fissure’. Penfield and Rasmussen,13 noted that ‘by Parietal area is meant that portion of the classical parietal lobe which lies behind the post central gyrus’, ‘if the lower parietal area which constitutes the parietal speech area on the dominant side be excluded, the superior parietal cortex could be removed with a comparatively small functional penalty’. Penfield and Erickson4 had described that ablation of the parietal association cortex left little obvious functional deficits though ‘disturbances of speech and disturbances in perception of form in the opposite homonymous visual field has been noted’. Rasmussen37 continued to use the functional division of the brain developed by Foerster and Penfield,38 since their definition of the parietal lobe differs from the generally employed in reviewing the MNI series of parietal lobe epilepsy, we refer to ‘parietal association area’ to define the region behind the postcentral gyrus and in front of the occipital lobe. Foerster and Penfield,38 described patients with epileptogenic lesions and ‘parietal field attacks’, characterized by painful sensations, vertigo, paresthesias, head and eye deviation, a sense of movement of one extremity, visual illusions, and complex movements of arms and legs, and reproduced these symptoms by faradic stimulation. Cushing39 expanded on these observations when he described 12 patients with parietal meningiomas; nine of them had a contralateral sensory aura, described as numbness, tingling, painful sensation or a feeling of warmth or heat. Since then few series of patients with parietal lobe epilepsy have been reported. Clinical manifestations and pathophysiology Patients with parietal lobe epilepsy with epileptogenic areas in the parietal cortex behind the postcentral gyrus, comprised 6% of patients operated at the Montreal Neurological Institute (MNI) between 1929 and 1980.40,41 Eighty-two patients had nontumoral parietal lobe epilepsy (Figure 38.1), with a mean age of seizure onset of 14.1 years and mean duration of epilepsy 8.1 years. Twelve patients had contralateral sensory deficits which were found during detailed examination and consisted of contralateral impaired two pointpoint discrimination, isolated diminished stereognosis, without two point discrimination, was reported in only two patients. Sixteen percent of patients had smallness of the contralateral extremities, 8% contralateral visual field deficits, most commonly inferior quadrantic defects. Impairment of spatial orientation and right–left disorientation were described in three patients, disturbance in the field of written language, and mild aphasia in two others. Ninety-four percent of patients exhibited auras. The most common were somatosensory, described by 52 patients as tingling or numbness; they were contralateral to the epileptogenic zone in 51 patients and bilateral in one; 13 of these patients described a painful, and five a thermal sensation. The second most common auras were disturbances of body

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parietal lobe to the temporo-limbic areas. This pattern of spread is supported by Reesnick et al.,44 who used subdural electrodes in the evaluation of patients with refractory epilepsy, and is a reflection of the connection of the parietal lobe with the supplementary motor area, and with the temporo-limbic region,.45,46 Other authors and recent reviews have also reported asymmetrical tonic seizures and automatisms in patients with parietal lobe epilepsy, and have emphasized that many of these patients have more than one seizure type.18,47–50

Figure 38.1 Original operative map of patient A. H. operated on by Dr Penfield in 1946. 25 year old with history of head trauma. The seizures were described as ‘does not know where he is, cannot concentrate, cannot see well’, followed by turning to the left.

image exhibited by nine patients; three patients mentioned a sensation of movement in one extremity, and another a sensation that the leg was absent. Twisting or turning sensations of the extremities were also described. Visual illusions were reported by nine patients as ‘figures look larger’ or ‘things on the wall turning’. A few patients exhibited complex visual or auditory hallucinations, suggesting ictal spread to temporo-limbic areas.15 Eighty patients underwent intraoperative cortical stimulation studies and the habitual auras were reproduced in 55% of patients. These included auras with a disturbance of body image or visual illusions, indicating an epileptogenic zone in the parietal association cortex. However, somatosensory auras also occurred in patients with lesions limited to the parietal association cortex, suggesting ictal spread to the somatosensory cortex. Thus, the symptomatogenic zones were distant from the epileptogenic zones in the parietal association cortex, Luders and Awad.43 Other seizure characteristics The other clinical manifestations were due to ictal spread. The ictal semiology indicated several dominant spread patterns, including spread to the sensorimotor cortex, the premotor eyefield, supplementary motor area, and the temporolimbic region. Twenty-eight percent had tonic posturing of the extremities, 57% had focal motor activity, 17% had oral-gestural automatisms, and 4% had complex automatisms. Fortyone percent had head deviation, 22% had Todd’s paralysis and 7% had postictal dysphasia. Many patients had more than one seizure type reflecting the different spread patterns. Sixty-one percent of patients with tonic posturing had epileptogenic zones which included the superior parietal lobule, and 79% of those with automatisms had epileptogenic zones extending into the inferior parietal lobule. This suggest preferential spread with ictal activity from the superior parietal lobule more commonly spreading to the supplementary motor area, and the one from the inferior

Etiologies of nontumoral parietal lobe epilepsy Thirty-five patients from the MNI series had a history of head trauma, and 16% had a history of birth trauma. The remaining patients had a history of encephalitis, febrile convulsions, gunshot wounds to the head, forme fruste of tuberous sclerosis, hamartomas, vascular malformations, tuberculoma, arachnoid or porencephalic cysts, microgyria and post-traumatic thrombosis of the middle cerebral artery. Tumoral parietal lobe epilepsy Thirty-four of 116 patients (29%) from the MNI series with parietal lobe epilepsy had slow growing tumors (Figure 38.2), most commonly astrocytomas (62%) and meningiomas (14%). The remaining patients had hemangiomas, oligodendrogliomas, and mixed astrocytoma and oligodendroglioma. Forty-seven percent had impaired two point discrimination in the contralateral fingers, 38% had mild contralateral weakness, 6% aphasia, 3% smaller extremities contralateral to the epileptogenic zone, one right to left disorientation and acalculia and two spatial disability. Only one patient exhibited definite astereognosis without coexisting primary sensory cortical deficit. Seventy-nine percent exhibited auras, most commonly somatosensory, contralateral to the the epileptogenic zone in

Figure 38.2 Original operative map of patient E. O’k. operated on by Dr Penfield in 1947. 25 year old with weakness of left foot and absent two-point discrimination in left leg. The seizures began by a sensation in the left great toe, tingling in the left vulva, spreading to left breast (not sexual), followed by left leg and left arm jerking.

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all except for one patient. Four described a painful sensation. Twelve percent had visual illusions, 9% aphasic aurae, 6% disturbance of body image, 3% complex auditory hallucinations, and 3% a feeling of movement in one arm. Some patients had two or more auras. The clinical manifestations indicated different spread patterns; 21% had tonic posturing of the extremities, 28% had focal clonic activity always contralateral to the epileptogenic lesion, 15% had head deviation, 9% automatisms, and 6% difficulty speaking. Thirty-two percent had Todd’s paralysis and 18% had post-ictal dysphasia.

EEG findings in parietal epilepsy Surface EEG was available in 66 patients of the nontumoral parietal lobe epilepsy MNI series and seizures were recorded in 36 patients. The interictal epileptiform discharges were recorded from the fronto-centro-parietal region in 33% of patients, parieto-posterior temporal in 14%, parietal in 14%, parieto-occipital in 9%, fronto-centro-temporal in 4.5%, fronto-temporal-parietal in 4.5%, hemispheric, maximum posterior head region in 9%, and bilateral in 4.5%. No interictal epileptiform discharges were recorded in 7.5% of patients. Secondary bilateral synchrony was described in 32% of patients. Ictal discharges were predominantly lateralized, in some patients the maximum ictal activity was recorded over the centro-parietal region and in others over the posterior head region. Localized parietal seizure onset was recorded in four patients. Williamson et al.47 and Cascino et al.48 emphasized that surface EEG monitoring is often non-localizing in parietal lobe epilepsy, and Foldvary et al.36 reported false localization/lateralization in 16% of parietal lobe seizures.

Conclusions In more than two-thirds of the patients with occipital lobe epilepsy, clinical manifestations indicated the occipital onset of the seizures. Visual auras were reported in 47–73% of patients. Most patients exhibited contralateral elementary visual auras, and a few exhibited ictal blindness. Seven to nine percent of patients exhibited nystagmoid eye movements. Many of the disabling clinical manifestations resulted from ictal spread to adjacent cortical structures, 29–88% of patients exhibited automatisms typical of temporal lobe epilepsy, and 38–47% had focal motor activity. Some patients had more than one seizure type reflecting these different spread patterns. Contralateral visual field deficits were reported in 20–59%, and abnormal imaging studies in 37–72% of patients. EEG recordings often showed posterior temporaloccipital interictal epileptiform discharges, and ictal onsets were regional often involving the posterior temporal region. A quarter of patients had bitemporal independent interictal epileptiform discharges, and one-third had bilateral synchronous epileptiform discharges over the posterior head regions. Ninety-four percent of patients with parietal lobe epilepsy exhibited auras. The most common auras were somatosensory, including painful sensations. However the auras experienced by some patients, like disturbance of body image may have indicated an epileptogenic zone in the association parietal cortex. The ictal semiology indicated several dominant spread patterns; 28% had tonic posturing of extremities, 57% focal motor clonic activity, and 17% had oral-gestural automatisms. The surface EEG was often lateralizing rather than localizing. Brain tumors are often the cause of parietal lobe epilepsy and were found in one-third of 116 MNI patients.

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Cushing H. The parietal tumors. Inaugural sensory fits. In: Cushing H, ed. Meningiomas: Their Classification, Regional Behaviours, Life History, and Surgical End Results. Springfield IL; Charles C.Thomas, 1938:632–56. Salanova V, Andermann F, Rasmussen T. et al. Parietal lobe epilepsy: clinical manifestations and outcome in 82 patients treated surgically between 1929–1988. Brain 1995;118:607–27. Salanova V, Andermann F, Rasmussen T. et al. Tumoural parietal lobe epilepsy: clinical manifestations and outcome in 34 patients treated between 1934 and 1988. Brain 1995;118:1289–304. Gloor P. Experiential phenomena of temporal lobe epilepsy. Facts and hypotheses. Brain 1990;113:1673–94 Luders HO, Awad I. Conceptual considerations. In: Lüders HO, editor. Epilepsy Surgery. New York: Raven Press, 1991:51–62. Resnick TJ, Duchowny M, Jayakar P et al. Clinical semiology of parietal lobe epilepsy (abstract). Epilepsia 1993;34 Suppl 6:29. Jones EG, Powell TPS. An anatomical study of converging sensory pathways within the cerebral cortex of the monkey. Brain 1970; 93:793–820. Pandia DN, Yeterian EH. Architecture and connections of cortical association areas. In: Peters A, Jones EG, eds. Cerebral Cortex, Vol. 4. New York: Plenum Press, 1985:3–61 Williamson PD, Boon PA, Thadani VM. et al. Parietal lobe epilepsy: diagnostic considerations and results of surgery. Ann Neurol 1992;31:193–201. Cascino GD, Hulihan JF, Sharbrough FW et al Parietal lobe lesional epilepsy: electroclinical correlation and operative outcome. Epilepsia 1993;34:522–7. Loiseau P. Parietal lobe epilepsies. In: H Meinardi ed. Handbook of Clinical Neurology: Vol. 73(29); The Epilepsies, part II, Amsterdam: Elsevier Science B.V., 2000:97–106. Siegel AM. Parietal lobe epilepsy. In: Siegel AM, Andersen RA, Freund HJ, Spencer DD, ed. Advances in Neurology: Vol. 93. The Parietal Lobes. Philadelphia: Lippincott Williams & Wilkins, 2003:335–45.

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Insular epilepsy J Isnard, P Ryvlin, and F Mauguière

Introduction The concept of insular epilepsy was debated in the early fifties when it was observed that insular stimulation could evoke symptoms very similar to those of temporal lobe seizures. This similarity could be such that confusion between insular and temporal lobe seizures might explain some of the failures of temporal lobectomy. In ‘Historical background and basic concepts’ we review the historical background and concepts on which are grounded recent depth Stereotactic EEG (SEEG) studies aiming at identifying the actual symptoms reflecting discharges located in the insular lobe. ‘The insula as an ictal symptomatogenic area’ is devoted to the description of an ictal symptomatic sequence, which occurs in full consciousness, and is highly suggestive of an epileptic discharge in the insular lobe. Based on SEEG recordings of spontaneous seizures and stimulation data, this sequence includes an initial pharyngeal and/or laryngeal discomfort with thoracic oppression or dyspnea, unpleasant paresthesiae, warmth or pain sensation in the perioral region or spreading to a large somatic territory, followed by dysarthric or dysphonic speech and ending by focal somato-motor manifestations. Several cortical areas, with which the insula is connected, are involved in most of the focal seizures originating in, or spreading to, the insula. Based on clinical observation of ictal symptomatology, invasive EEG investigations must be targeted to explore the whole extent of the suspected epileptogenic network in order to assess the role of the insula in seizure development. ‘The insula as a mode in distributed epileptogenic networks’ provides the arguments supporting identification of three major epileptogenic networks (temporo-perisylvian, temporo-limbic and mesialorbital frontal) where the insula participates as a node in the building of ictal symptomatology, including that of nocturnal frontal hypermotor seizures where the antero-superior part of the insula can be a clinically silent seizure onset zone. The final three sections are devoted to the review of etiologies, presurgical evaluation and treatment of insular epilepsies. Most cases reported in the literature as insular epilepsies are symptomatic of a focal epileptogenic lesion located in the insula, some of which were successfully operated upon, while the few cases of cryptogenic epilepsies hitherto available are those reported in this chapter. EEG plays a minor role for investigating insular epilepsies because interictal paroxysms and seizures originating in the insula are unlikely to be detected by scalp recordings. The roles of MEG and functional interictal neuroimaging remain incertain as well as the results of insular surgical resection based on SEEG data or of SEEG-guided thermo-coagulation in cryptogenic cases. Conversely seizure 320

freedom can be obtained after surgical resection of the lesion in symptomatic cases, provided that ictal symptoms are compatible with an epileptogenic zone located close to the lesion in the insular lobe.

Historical background and basic concepts The insula as the fifth lobe of the brain In an article published in 1896 that was devoted to the comparative anatomy of the insula, Clark1 quoted 39 synonyms used in anatomical literature to name the fifth lobe of the brain buried in the lateral sulcus and covered by the opercular parts of the frontal, parietal, and temporal lobes, among which the term insula, first proposed by Reil in 1804, has prevailed. The anatomical situation of the insula and its cytoarchitectonic organization lent some substance to the view that it might be an isolated lobe of the brain mostly devoted to the processing of body and visceral sensation including gustation, pain and other emotions, and to viscero-motor and autonomic control. In monkeys the insula includes Brodmann’s areas 13 to 16 and shows a caudo-rostral sequence of distinct cytoarchitectonic areas namely; a granular cortex, at its upper and posterior part, very similar to that of the second somatosensory (SII) area and involved mostly in somatosensory, pain and auditory functions; a transitional dysgranular field localized in its antero-superior part involved in gustation and and viscero-sensitive functions; an antero-ventral agranular field, which is in continuity with the temporal pole and olfactory proisocortex, and related to olfactory and autonomic functions (see ref 2 for a review). For the past 10 years the question of insular physiology has been addressed by numerous studies using neuroimaging, evoked potentials and direct stimulation in humans as well as microelectrode studies in monkeys. These studies have confirmed the role of the insula in: ●

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Somatosensory and pain sensation as assessed by numerous anatomical,3,4 functional imaging studies5–8, as well as by our recent studies of somato-sensory and pain evoked responses9 and direct electric stimulation of the Insular cortex10, 11 Visceral sensation and viscero-motor control12–14 including processing of visceral pain15 Cardiovascular function as demonstrated by insular stimulation in epileptic patients before temporal lobectomy that produced changes in heart rate or in blood pressure

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in 50% of cases,16 thus leading to suspect a role of insular discharges in cardiac arrhythmias causing sudden death during epileptic seizures. Gustation as assessed first by the stimulation studies of Penfield and Faulk17 and further confirmed by neuroimaging studies18, 31 as well as by microelectrode recordings of a large number of insular neurons in monkeys,20 these physiological findings being consistent with the altered taste perception observed in patients with insular lesion.21 Audition and language, in particular allocation of auditory attention, tuning in to novel auditory stimuli, temporal and phonological processing of auditory stimuli.22 Furthermore several studies suggest that both right and left insulae are involved in the control of speech production.23–28

More recently, some studies suggested that the insular lobe could belong to the mirror-neuron system that characterizes regions of the brain that are able to respond when the subject performs an action and when the subject observes another individual doing a similar action (see ref 29 for a review), but also regions able to encode for a sensation (or emotion) perceived by the subject and to respond to the observation of others experiencing that sensation (or emotion). In the human insula regions involved in visceral sensation or viscero-motor responses also respond to faces expressing disgust.30,31 Similarly the human insula responds to both pain perception and empathy for others’ pain.32 From what precedes one can conclude that the insula represents a highly organized lobe with specific functions comparable to the other lobes of the brain and, therefore, consider that an epileptogenic zone located in this area will cause seizures characterized by a specific ictal symptomatology. This point is addressed in details in the second section of this chapter where we discuss the localizing value of a sequence of ictal symptoms that are highly suggestive of an epileptic discharge affecting the insula. The insula as a node in distributed cortical networks As the other lobes of the brain, the insula is characterized by anatomical borders that are defined by a limiting sulcus (the circuminsular fissure) but also by fuzzy cytoarchitectonic borders with neighboring cortical areas and by a dense network of cortico-cortical connections with adjacent or more distant cortical areas. Therefore its function, as well as its implication in epileptic seizure development, cannot be sketched as an isolated functional center, as suggested by the term ‘insula’. A complete description of insular connections is given in the review by Augustine2 showing that the insula is connected with the limbic areas, the amygdalar nucleus, the basal ganglia, and all of the cortical lobes, except the occipital lobe. Several attempts have been made to identify functional networks in which the insula could play the role of a functional node.33–35 Among these networks the perisylvian-insular, the temporolimbic-insular, and the mesial-orbito-frontal-insular networks deserve the attention of epileptologists because epileptic discharges propagating in each of them will produce seizures where the symptoms attributable to the insula will reflect only part of the ictal symptomatology. In part III of this chapter we discuss the difficulties in identifying insular epilepsy among epilepsies where the epileptogenic zone spreads outside the

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limits of the insular lobe, and the utility of the concept of epileptogenic networks for planning the depth electrodes implantation in the presurgical evaluation of these patients. The concept of insular epilepsy In the late forties and early fifties Guillaume et al.36 followed by Penfield and Jasper37 were the first authors to call attention upon the concept of insular epilepsy. Penfield and Faulk38 concluded the review of their personal experience of insular stimulation by noting that the majority of the positive responses to stimulation of the insula consisted either in sensations resembling that produced by stimulation of the superior bank of the sylvian fissure (SII area), or in abdominal feeling secondary to motor change in the gastrointestinal tract. This latter finding suggested that seizures originating in the insular cortex were able to mimic temporal lobe seizures to such a degree that confusion between the two types of seizures might explain part of temporal lobectomy failures.36 This concept was mostly based on data from electrocorticography (EcoG) carried out during the surgical treatment of patients suffering from temporal lobe epilepsy (TLE) under local anaesthesia. Moreover EcoG recordings revealed a rich interictal spiking paroxysmal activity in about half of these patients.34 However, in spite of an EcoG strategy exploring systematically the insula, Penfield and his collaborators never succeeded to record spontaneous epileptic discharges with a focal onset in the insular cortex. Furthermore they were unable to provide the argument that insular cortectomy, as a complement to conventional temporal lobectomy in TLE patients, could improve the surgical outcome.39 Thus the concept that specific symptoms could reflect insular discharges into the insular lobe fell into dereliction. More recently, several case reports showed that seizures could be stopped by the surgical removal of insular lesions40–42 and reactivated the research for identifying the insula as a symptomatogenic area in focal epilepsy.

The insula as an ictal symptomatogenic area Identification of a given cortical area as a symptomatogenic zone is mostly based on correlations between the ictal symptomatology and data from ictal discharge recordings using invasive EEG procedures.43 In the case of the insular lobe such correlations are often uneasy because, even though the insula is frequently involved during temporal lobe seizures, most insular discharges develop concomitanty in the temporal, perisylvian, or frontal cortex, so that symptoms reflecting discharges in the insular cortex are difficult to disentangle from those related to the involvement of these neighboring areas in the building of ictal symptomatology. The patients’ file of our department reflects the rarity of focal seizures involving exclusively, or preferentially, the insular lobe. Of the 180 patients with temporal lobe epilepsy (TLE) referred to our department for presurgical evaluation since 1996, 83 were explored using depth electrodes implanted in the lateral and mesial regions of the temporal lobe, of whom 50 also had depth electrodes implanted in the insular. We have been able to identify an ictal symptomatic sequence associated with a focal discharge restricted to the insula in only eight of them (16%).

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Ictal symptoms reflecting seizure activity in the insula What we know about the electroclinical manifestations of insular seizures mostly stems from SEEG data from a few patients referred mostly for TLE surgery. Electrode implantation in the insula is usually decided on the basis of ictal symptoms or scalp video-EEG data suggesting an early spread of seizures either to the suprasylvian opercular cortex, such as tonic or clonic mouvements of the face, dysarthria or motor aphasia, gustatory hallucinations, hypersalivation, post ictal facial paresis,44 or to the infrasylvian opercular cortex such as auditory hallucinations or early sensory aphasia.45 For the description of insular ictal symptoms we selected seizures that were characterized by a SEEG discharge involving selectively the insula at any moment of the seizure development. In six patients discharges originated from the insula itself (cases 3 to 8 in Figure 39.1) and in two (cases 1 and 2 in Figure 39.1) discharges originated in the hippocampus but propagated exclusively to the insular cortex without spreading to any other cortical structure. Video recordings of patients’ behavior during insular seizures are illustrated in Figure 39.1. The five ictal features that were invariant in repeated seizures in a given individual and observed when the ictal discharge selectively involved the insular cortex are the following: (a) Consciousness and contact with the environment are fully preserved (b) Paresthesiae (lines B and C in Figure 39.1) represent the second feature that is reported by all patients during insular discharges. They are described as an unpleasant sensation of electricity or warmth that can be painful (2/8). They are either restricted to peri-or intra-oral areas (line B in Figure 39.1), or distributed to a large cutaneous territory (face-shoulder-arm and trunk, upper limb-trunklower limb) most often opposite to the insular discharge (line C in Figure 39.1), or bilateral (2/8) affecting either territories close to midline, such as mouth and oral cavity

1

2

3

4

(1B and 2B in Figure 39.1), or more distal somatotopic areas such as both lower limbs (3C in Figure 39.1). Although the onset site and spreading of paresthesiae can vary from one seizure to the other, there is usually no somatotopic Jacksonian march as often reported in SI somatosensory seizures.46 (c) Motor and sensory pharyngo-laryngeal symptoms are other frequent manifestations (6/8) that are accompanied by the spontaneous gesture of seizing the neck with the hand ipsi- or contralateral to the discharge, or with boths hands, as illustrated in patients 1–6 in Figure 39.1 (line A). This sensation can be isolated or preceded, or followed, by other sensations such as a retro-sternal or abdominal heaviness that can be accompanied by rumbling noises and vomiting (image 1B in Figure 39.1), or a short breath with dyspnea as reported in the early descriptions of anterior insular stimulations by Penfield and Faulk.38 Its intensity is variable according to patients and is described either as an unpleasant sensation of throat constriction, or as the sensation that the salivary glands are under pressure preceding hypersalivaltion (image 2A–5A in Figure 39.1), or even as a terrifying sensation of strangulation with suffocation (images 1A and 6A in Figure 39.1). (d) A dysphonic and dysarthric speech evolving progressively toward a complete muteness is as frequent as the laryngeal sensation described above (6/8). It may persist several tens of seconds after the end of the discharge. (e) Finally, the clinical manifestations of insular seizures often (5/8) end with motor symptoms (cases 4–8, line D in Figure 39.1) that are either lateralized and opposite to the discharge (tonic spasm of face and upper limb), or more diffuse (head and eyes rotation, generalized dystonia). In a given patient the occurrence of motor symptoms is usually inconstant from one seizure to the other.

5

6

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8

A

B

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D Figure 39.1 Video sequence of ictal symptoms in the eight patients with insular seizures. Empty areas correspond to missing symptoms in the sequence. All illustrated seizures are simple partial seizures with complete preservation of contact during phases A, B, and C of the sequence. A brief loss of contact occurred in phase D for patients 6 and 7 in association with intense somatomotor convulsive symptoms. A: Laryngeal constriction (6 patients). B: Paresthesiae in the perioral region (6 patients). C: Lateralized somatosensory symptoms in upper limb (7 patients). D: Focal somatomotor symptoms (5 patients). *For patient 3 somatomotor symptoms(D) did not occur during the three Video-SEEG recorded seizures, while most of spontaneous seizures in patient’s history ended by this type of symptoms. Colored frames distinguish rostral (green) from caudal (red) insular seizures. Green frame: symptoms associated with anterior insular ictal discharge Red frame symptoms associated with posterior insular ictal discharge.

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Insular epilepsy When observed at any given moment in the seizure such symptoms suggest that the insular lobe is included in the symptomatogenic zone; when observed at the onset of seizures they indicate that the insula should be involved in the surgically resected area to achieve postsurgical control of seizures; when an insular lesion is present their occurrence at seizure onset suggests that the epileptogenic zone is close to the lesion. This latter statement is illustrated by the patient whose brain MRI is shown in Figure 39.2. This female patient, aged 22, had suffered since the age of 16 from seizures begining by unpleasant and intense paresthesiae that involved a large proportion of the left side of her body including face, whole upper limb and trunk followed by a ‘strange taste’ in her mouth. Her seizures ended with hypersalivation and clonic jerks in her left face. MRI showed a cavernous angioma located in the posterior insular cortex, the removal of which was followed by the disappearance of seizures. Since surgery this patient has remained free of seizures and antiepileptic drugs, with a postsurgery follow-up of two years. Localization specificity of insular ictal symptoms: data from direct electric cortical stimulations Electric stimulation of the insula in patients presenting with one or more of the above listed ictal symptoms is useful for mapping

(a)

L

R

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Figure 39.2 Sagittal (a), coronal (b) and axial (c) MRI slice showing a right posterior insular cavernous angioma in a patient with painful seizures on the left side of the body, who became seizure free after lesionnectomy (see text for details).

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the symptomatogenic area when it reproduces symptoms that are immediately identified by the patient as identical to their spontaneous ictal symptoms. Thus lateralized and widely distributed paresthesiae could be triggered by stimulation in five of the eight patients whose ictal behavior is shown in Figure 39.1 (cases 1, 3, 5, 6 and 8), focal perioral paresthesiae in four (cases 1, 2, 3, and 6), laryngeal sensation in three (cases 2, 4, and 5), dysarthric speech in one (case 5) and abdominal pain in one (case 1). More generally direct stimulation of the insula, even in patients whose seizures are of extrainsular origin, is able to elicit all of the ictal symptoms of insular seizures. In our experience, the insula is one of the most eloquent cortical areas when electrically stimulated by shocks47 or trains11 at low intensities (1–3 mA). Insular stimulation sites explored in our group of 50 consecutive patients are plotted in Figure 39.3. Of these 144 sites, 125 were clinically responsive to stimulation in the absence of any after discharge, and a total amount of 139 evoked clinical responses could be collected (Figure 39.3b). Thirty-one of them were identified by the patients as identical to one of the ictal symptoms of their spontaneous seizures, 108 were reported as unknown and not belonging to the usual ictal symptomatology. As for ictal symptoms, these responses can be subdivided into five main categories: somatosensory (Figure 39.3Ca), viscerosensitive (Figure 39.3Cb and c), auditory (Figure 39.3Cd), dysarthria and missing words (Figure 39.3Ce), others including sensation of unreality, whole body sensations, olfacto-gustatory hallucinations, and vegetative responses (Figure 39.3Cf). Somato- or viscero-sensory responses represent nearly twothirds of evoked responses, of which more than half concern the cervical-laryngeal region. There is thus converging evidence from seizure analysis and stimulation data that these somatosensory symptoms, particularly in case of warmth or pain sensation, suggest an ictal involvement of the posterior insula. Similarly the laryngeal and visceral sensations reported by our patients during their seizures, and reproduced by electric stimulation suggest an anterior insular propagation of the epileptic discharge. This conclusion contrasts with the commonly accepted view that visceral and laryngeal ictal sensations indicate a hippocampal or amygdalar origin when observed in the context of TLE seizures.48, 49 Auditory symptoms and dysarthric speech immediately follow somatic and visceral sensations, in terms of frequency, in the list of responses evoked by insular stimulation. Auditory symptoms are currently attributed to ictal discharges in the temporal operculum and first temporal gyrus. Our data suggest that they may also reflect an insular propagation of the discharge. However, there are no types of auditory illusions or hallucinations that can be considered as specific to insular ictal semiology, because stimulation of the Heschl’s gyrus can evoke auditory symptoms very similar to those produced by insular stimulation. Conversely, though dysarthria is considered to reflect frontal opercular discharges,50 we never observed this symptom in isolation when stimulating this region outside Broca’s area. Moreover, ictal dysarthria was associated with discharges in the nondominant hemisphere for language in the three patients whose insular seizures included this symptom, and it was reproduced as often in the right or left hemisphere by direct cortical stimulation. Somato-motor ictal manifestations differ from others in that they usually cannot be reproduced by insular stimulation and reflect seizure propagation outside the insular lobe. They have been considered as predictors of a bad outcome in

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VAC

VPC

i1

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AC-PC

i3

R

L

A

B C

(a)

(b)

(c)

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Figure 39.3 SEEG exploration of the insular lobe. A: Fusion of skull radiography and coronal MRI slice in the anterior commissure vertical plane at scale 1. This picture illustrates the positions and trajectories of the electrodes exploring the insular cortex (i1, i2, and i3) in an individual patient. The two deepest contacts of each electrode are located in the insular cortex. The more superficial contacts are located in the suprasylvian (i1) and infrasylvian opercular cortex (i2 and i3). (R: right, L: left). B: Plotting of the 144 insular contacts (yellow dots) in the 50 patients on a sagittal MRI slice of the insula. The borders of the insular lobe are drawn in red. Most of the insular surface has been explored except its most anterior part. The white lines represent the axis of the bicommissural stereotactic space of Talairach and Tournoux.97 AC-PC: anterior commissure-posterior commissure horizontal plane; VAC: vertical anterior commissure plane orthogonal to the AC-PC plane; VPC: vertical posterior commissure plane orthogonal to the AC-PC plane C: Functional mapping of the insula. This figure illustrates data from direct electrical stimulations of the insular cortex in the 50 patients of this study. In each of the six Ca to Cf insets all of the 144 stimulated points are plotted as black circles (see ref. 11 for details on stimulation procedure, safety and accuracy). The 138 responses evoked by electrical stimulations are represented according to the functional categories detailed in the results section. Ca: Somatosensory responses. Simple paresthesiae are represented in yellow, paresthesiae with warmth sensation in orange and painful paresthesiae in red. Cb: Viscero-sensitive responses are in blue, of which one was painful (in red). Cc: Sensations of laryngeal constriction are in green, of which two were painful (in red). Cd: Auditory responses (lilac). Ce: Dysarthric speech and missing words (cream white). Cf: Miscellaneous responses: Sensation of unreality (light blue); Olfacto-gustatory responses (orange); Vestibular responses (pink), Vegetative responses (purple). From Isnard et al. 2004 with permission.69 (See Color plates.)

temporal lobectomy and their occurrence makes questionable the diagnosis of TLE.51 Indeed such symptoms are exceptional in seizures originating in the mesial temporal lobe, while they occur at the end of nearly two-thirds of insular seizures. Thus, in patients whose ictal symptomatology is compatible with TL seizures, their occurrence during the development of the seizure strongly suggests a seizure onset in the insular lobe. Finally, 10% of the responses evoked by insular stimulation (Figure 39.3Cf) reproduce ictal manifestations that are only

occasionally observed in spontaneous insular seizures such as vegetative responses, feeling of unreality, olfacto-gustatory and visceral sensations. The insular origin of these rare symptoms is in agreement with the functional role of the insular lobe in the control of taste52–56 and visceral functions.31, 57 None of our patients with SEEG documented insular seizures reported vertigo or sensation of body tilting as part of their ictal symptomatology and insular stimulation exceptionally produced a vestibular sensation (3/139: 2.1%, purple points

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Insular epilepsy in Figure 39.3Cf). This finding contrasts with some observations where parieto-insular strokes manifested by such sensations.58–60 It is in line with cortical stimulation data by Penfield and Jasper37 and more recently by Kahane et al.61 showing that vestibular sensations are mostly observed after stimulation of the superior temporal neocortex and lateral aspect of the inferior parietal cortex.

cavernous angioma or a low grade tumor, is observed within the insula, invasive EEG investigations, based on clinical observation of ictal symptomatology, must be targeted to explore the whole extent of the suspected epileptogenic network in order to assess the exact role of the insula in seizure development. Three major types of epileptogenic networks involving the insula can be distinguished: ●

What, if anything, is an insular seizure? Based on the above detailed observations is it possible to add an ‘insular’ category to the list of epileptogenic zones that can be used as one of the dimensions of a patient-oriented epilepsy classification?62 In other words, is there any sequence of symptoms that are specific enough to locate the epileptogenic area in the insula and to predict that the removal of the insular cortex is necessary to make the patient seizure free? Even though SEEG-documented seizures are scarce an affirmative answer can be given to this question when, during spontaneous seizures, the patient experiences in full consciousness a symptomatic sequence made of a pharyngeal and/or laryngeal discomfort with thoracic oppression or dyspnea, unpleasant paresthesiae, warmth or pain sensation in the perioral region or spreading to a large somatic territory, followed by dysarthric or dysphonic speech and ending in focal somato-motor manifestations. Knowing that in patients illustrated in Figure 39.1, most of the antero superior quadrant of the insula has not been explored (see Figure 39.3), two variants can be distinguished according to whether the insular discharge originates from the anterior or posterior part of the insula. In rostral insular seizures viscero-motor and laryngeal symptoms are predominant (green frame in Figure 39.1), while in caudal insular seizures the ictal symptomatology is dominated by somato-sensory symptoms, which are all the more so specific that they affect a large, eventually bilateral, territory and manifest as a warm or painful sensation (red frame in Figure 39.1)! Thus most of the insular seizures can be described as a combination of vegetative and somatosensory auras according to the semiological seizure classification proposed by Lüders et al.63

The insula as a node in distributed epileptogenic networks As for any other types of partial seizures, the concept of a distributed epileptogenic network can be applied to describe insular seizures where the insular cortex is involved as a node, or as a relay in seizure propagation, and not as a single focus. This situation is likely to be more frequent than that where seizures remain confined to the insular cortex. The occurrence of a sequence of ictal symptoms reflecting the insular involvement at seizures clinical onset, as described above, proves effective to delineate the various clinical situations where epileptic discharges might originate in the insula. It must be reminded, however, that identification of these symptoms does not allow to firmly conclude on the insular origin of seizures, since they might as well follow the primary involvement of noninsular portions of a larger epileptogenic network where the seizure onset zone can keep clinically silent.64 Thus, apart from the situation where a clear-cut epileptogenic MRI lesion, such as a

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Temporo-perisylvian-insular networks that include the various brain regions bordering the sylvian fissure, i.e., the frontal, parietal and temporal operculum, together with the insula; Temporo-limbic-insular networks, which primarily involve the mesial temporal structures and/or the temporal pole; Mesial and orbito frontal-insular networks, in the context of the so-called nocturnal frontal lobe epilepsy.

This subdivision remains partly artificial, however, since some patients combine electro-clinical features that belong to at least two of these networks, as detailed below. Temporo-perisylvian-insular networks The concept of ‘perisylvian epilepsy’ was originally introduced by Munari et al.,50 in an attempt to distinguish this form of epilepsy from temporal lobe epilepsy proper. It should be noted, however, that in perisylvian the epileptogenic zone often encompasses the first temporal gyrus, accounting for the frequent presence of simple auditory hallucinations in this form of epilepsy, and explaining why the term ‘temporo-perisylvian’ is preferable to that of ‘perisylvian’. Apart from simple auditory hallucinations, temporo-perisylvian seizures are characterized by the presence of symptoms reflecting the involvement of the frontal and parietal operculum (hemifacial motor or somato-sensory symptoms, gustatory hallucinations, hypersalivation), the secondary somato-sensory area (various types of ipsilateral, contralateral or bilateral somatosensory symptoms), and the temporo-perisylvian vestibular cortex (vertigo).61 Part of the semiology initially ascribed to frontal or parietal opercular ictal discharges in the early study of Munari et al.,50 which did not benefit from the placement of depth electrodes within the insula, does in fact reflect the involvement of the insular cortex. One such example is that of gustatory hallucinations, previously thought to reflect a fronto-parietal opercular discharge,52 but that can be elicited by stimulating the insula rather than the opercular region.17 Furthermore, both the insular cortex and parietal opercular somato-sensory (SII) cortex can be responsible for similar ictal somato-sensory symptoms affecting large cutaneous territories, even though the somatotopic fields are much larger in the insula than in SII65 Finally, the tight anatomical connections and cytoarchitectonic continuum observed between the fronto-parietal and temporal perisylvian cortex on one hand, and the insula on the other, also militates for including all these brain regions within the temporo-perisylvian network that must be explored by SEEG recordings before surgery. For instance, in two of the patients presented in section II (#4 and #5), one of whom presented with a parietal cortical dysplasia (#4), the SEEG involvement of part of the

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opercular regions was judged important enough to lead to a surgical resection or a thermolesion of that structure together with the posterior insula, resulting in seizure control in both patients (class Ib of Engel). In another recent series,66 the role of the insula in a temporo-perisylvian epileptogenic network can be suspected in six patients in whom temporal lobe surgery was unsuccessful in controlling seizures despite intracranial EEG evidence that the temporal lobe participated in seizures genesis. In these patients a somato-sensory aura was interpreted as reflecting a discharge in the parietal lobe and the inferior parietal region was indeed also involved at ictal onset on intracranial EEG recordings, but its secondary removal did not result in better seizure control. The authors acknowledged that the insula might have participated to the complex epileptogenic network observed in their patients, inasmuch as one presented with an insular hyperperfusion on ictal SPECT. They could not confirm this hypothesis, however, due to the lack of intracerebral electrodes directly placed within the insula. Temporo-limbic-insular networks One major challenge in epilepsy surgery remains to understand the origin of postoperative seizure recurrence in a still significant proportion of operated patients, despite the presence of typical clinical and MRI features of mesial temporal lobe epilepsy. Part of these surgical failures might reflect the involvement of the insular cortex within a larger epileptogenic network encompassing the sclerotic mesial temporal structures.67 This issue is well illustrated by patient #6 in Figure 39.1, whose history has been further detailed in a recent review.68 Indeed, this patient fulfilled the major criteria used to define mTLE, including a rising and distressing epigastric sensation at seizure onset rapidly followed by oroalimentary automatisms, MRI signs of unilateral hippocampal sclerosis; ipsilateral temporo-limbic interictal FDG-PET hypometabolism, and an anterior temporal scalp-EEG ictal discharge. However, other ictal signs and symptoms suggested a rapid involvement of the perisylvian region, including early simple auditory hallucination and rapid occurrence of mastication and left face tonic contraction, leading to the decision of performing an invasive SEEG monitoring. The latter revealed that the patient suffered two seizure types, one arising from the sclerotic mesial temporal structures that secondarily propagated to the ipsilateral insula and opercular regions, and another arising from the posterior insula before invading the ipsilateral mesial temporal and opercular regions. Interestingly, the insular seizure type, but not that arising from the temporal lobe, selectively occurred during sleep. Resection of the epileptogenic temporal lobe controlled daytime seizures type for a few months only, whereas nocturnal seizures have continued unchanged. Overall, this case report illustrates the possibility of observing insular seizures in a patient with the major clinical and MRI features of mesial temporal lobe epilepsy, suggesting an epileptogenic zone encompassing the temporo-limbic regions and the insula. This patient also demonstrated an intense and rapid involvement of other temporo-perisylvian regions, suggesting that these different networks might be intermingled and overlapping in the same patient.

Other patients might present with comparable ictal semiology, EEG and neuroimaging data, and will eventually prove to have an epileptogenic zone limited to the temporo-limbic cortex. This alternative situation is illustrated by another patient from our series (#2 in Figure 39.1) whose intracerebral EEG recordings demonstrated a mesial temporal ictal discharge that invaded the insula very rapidly and intensively, suggesting that the insular cortex might be part of the epileptogenic zone.69 However, long-term seizure freedom was achieved after an anterior temporal lobectomy. More generally, seizures originating in the mesial temporal lobe are likely to propagate to the ipsilateral insula, though less rapidly and intensively than in the above patient, and this propagation70 does not preclude seizure freedom after temporal lobectomy. Several issues remained unsolved regarding the connections involved in the propagation of ictal discharges between the temporo-limbic system and the insula. Due to the frequent participation of the temporal pole at ictal onset,71 we prefer using the terminology ‘temporo-limbic’ rather than ‘mesial temporal’, knowing that part of this brain region is located outside the mesial aspect of the temporal lobe and is closely connected to the insula. In fact, according to Mesulam’s description of the paralimbic regions, two major belts should be considered, one including the orbito-frontal cortex, the temporal pole, and the insula, while the parahippocampal and cingulate gyrus form the other.33 Indeed, as already discussed, the insula has strong reciprocal connections with the temporal pole, but also with the entorhinal cortex and the amygdala. In addition, it projects to the anterior hippocampus but does not receive major direct afferents from this structure. It is yet unclear which of the above regions is predominantly involved in the insular propagation of temporo-limbic ictal discharge. Conversely, the posterior and anterior-inferior aspects of the insular cortex are predominantly involved in seizures propagating to the mesial temporal structures.68, 69 Mesial and orbital frontal-insular networks A recent issue concerns the role of the insula as a part of the epileptogenic network in fontal lobe epilepsies and, more precisely, in NFLE, which is is primarily characterized by seizures occurring exclusively or predominantly during sleep, the semiology of which suggests a frontal lobe origin, as for example nocturnal paroxysmal dystonia (NPD) or hypermotor seizures.72 An autosomal dominant inheritance (ADNFLE) is found in 8–43% of patients, and several mutated genes have been identified.72–76 However, many uncertainties persist regarding the neural networks underlying the cryptogenic and idiopathic forms of NFLE, inasmuch as very few patients have been investigated with intracranial EEG recordings.77, 78 We have recently reported three patients with a typical form of nocturnal hypermotor seizures suggesting cryptogenic NFLE in two, and autosomal dominant NFLE (ADNFLE) in another, whose ictal onset zone proved located in the anterosuperior portion of the insula.79 In the two patients presenting with a seemingly cryptogenic NFLE, intracerebral EEG recordings demonstrated a very focal interictal focus in that same region, consisting of frequent bursts of high frequency discharges and high amplitude spikes (Figure 39.4). In the ADNFLE patient, the epileptogenic zone appeared larger, extending to the frontal operculum.

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LEFT INSULA

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1 sec.

Figure 39.4 Intra-cerebral EEG investigation of a patient with a clinically-defined cryptogenic nocturnal frontal lobe epilepsy showing almost permanent high amplitude spikes (left EEG traces), and a high frequency discharge at ictal onset (right EEG traces) in the antero-superior portion of the left insula (i1,i2), slightly diffusing to the nearby deepest aspect of the frontal operculum (i3–4), but not to more lateral probes. Note that all leads are displayed with a similar amplification.

High frequency electrical stimulation of the antero-superior portion of the insula, but of no other region, could elicit a typical aura or full-blown seizure in two patients. However, because none of the three patients underwent epilepsy surgery, we cannot firmly conclude on the precise extent of their epileptogenic zone. Interestingly, these three patients represent 30% of all those with nocturnal hypermotor seizures and no MRI brain lesion who underwent an intracerebral EEG investigation in our study. Among the seven other patients, a mesial or anterior frontal seizure onset was demonstrated and resected, but three continued to suffer postoperative seizures. One might speculate on the role of the insula in these patients seizures, provided that it was not investigated during their intracerebral EEG recordings. Overall, an insular seizure onset zone might be responsible for a significant proportion of so-called cryptogenic NFLE, at least among those resistant to antiepileptic drugs. At the present time, no clear indicator other than intracerebral EEG recordings allows to distinguish these patients from those presenting NFLE proper. In fact, our patients with an anterosuperior insular ictal onset started their hyperkinetic behavior only when the mesial frontal cortex was invaded. The propensity for insular seizure to occur during sleep has not been previously reported. However, it is interesting to note

that this propensity was also observed in one of our patient with temporo-insular epilepsy (see previous section). The role of the insula in sleep physiology is not known, but recent functional neuroimaging studies have shown a marked deactivation of the anterior insula during sleep.80, 81 Overall, insular seizures might be associated with various types of ictal semiology, reflecting the subregion of the insular cortex primarily affected, as well as the related multilobar network: the posterior and antero-inferior aspect of the insula appears to be mostly involved in temporo-perisylvian and/or insulo-temporo-limbic epileptogenic networks mimicking the different forms of TLE; the antero-superior portion of the insula seems to play a more important role in the insulo-frontal networks mimicking NFLE. At the present time, there is no available data suggesting a primary role of the insular cortex in seizures originating from other brain areas than those listed above.

Etiology of insular epilepsy Lesional insular epilepsy The majority of cases reported in the literature as insular seizures or epilepsies derives from patients with an obvious

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epileptogenic brain lesion located in the insula, some of which were subsequently and successfully operated upon. 41,42,54, 69, 82,–85 These lesions primarily included low grade brain tumors, including gliomas and dysembryoplastic neuroepithelial tumors, cavernomas, and cortical dysplasia. However, all potentially epileptogenic brain lesions might be observed in the insula, such as stroke or encephalitis.86, 87 Cryptogenic and idiopathic epilepsy primarily involving the insula To our knowledge, the only published cases of cryptogenic epilepsy primarily involving the insula are those published by our group.68,69 They represent a very limited number of patients, none of whom underwent a surgical resection of their epileptogenic but MRI negative insula. No pathological data is thus available, but SEEG findings suggested the possibility of a MRI occult cortical dysplasia in a minority of patients. For instance, one of our patients with NFLE of insular origin presented an intracerebral SEEG pattern typical of an underlying cortical dysplasia, with very focal and permanent high amplitude spikes intermingled with bursts of high frequency discharges (Figure 39.4).79 In the same series, one who presented with a typical form of ADNFLE, but none of the known mutation of the α 4 and β 2 subunits of the nicotinic acetyl-choline receptor, should be considered to suffer an idiopathic form of partial insulo-opercular epilepsy, according to the familial inheritance of his epileptic disorder and the result of his SEEG investigation.79,88 To our knowledge, no other patient with ADNFLE has undergone an intracerebral EEG investigation, and we therefore ignore the proportion of such patients who might also demonstrate an insular epileptogenic zone.

Presurgical evaluation Noninvasive investigations EEG and MEG According to the deep location and specific gyral organisation of the insula, interictal or ictal epileptiform discharges originating in this lobe are unlikely to be detected by scalp-EEG recording, unless these discharges propagate to lateral neocortical regions. This has been shown in our first description of insular discharges70 and is also illustrated by Figure 39.4. Accordingly, neither interictal nor ictal scalp-EEG abnormality could be recorded in this patient, accounting for the fact that the epileptic origin of his seizure disorder has been strongly debated. However, scalp-EEG recordings might provide some clue regarding a temporo-perisylvian epileptogenic zone, indirectly reflecting the potential involvement of the insular cortex. In particular, both interictal and ictal EEG abnormalities will display a more widespread distribution over the infra- and suprasylvian elecrodes. To our knowledge, a single case report has assessed the diagnostic value of MEG in a patient with an insular epileptogenic DNET, and concluded that MEG could detect epileptiform abnormalities within the concealed insular cortex.82

Functional interictal neuroimaging In patients with typical TLE, [18F]FDG-PET and [11C] Flumazenil-PET studies have reported that interictal hypometabolism and decreased benzodiazepine receptor density observed in the temporal lobe could extend to the insula in some patients.89–92 At the present time, the presence of such insular abnormalities have not been clearly associated with a higher risk of postoperative seizure relapse, but this issue still needs to be addressed in larger populations. In the few well-documented cases of insular epilepsy, [18F]FDG-PET, [11C]Flumazenil-PET, and ictal SPECT did not demonstrate distinctive features from those encountered in TLE or NFLE, and in particular no clear cut insular abnormality.67,68 Finally, [18F]FDG-PET and ictal SPECT have shown abnormal findings in the insula of a few patients with uncertain epileptogenic zone, where one might speculate on the involvement of the insula.66,93,94 These include patients with nocturnal hypermotor seizures,93,94 as well as one patient with somato-sensory aura and a seemingly temporo-parietal ictal onset zone not controlled by surgery sparing the insula.66 Overall, whether functional imaging will eventually prove useful in the clinical assessment of insular epilepsy remains an open issue. Invasive investigations In the stereotactic implantation technique first described by Talairach and Bancaud,95 intracerebral electrodes are implanted perpendicular to the midsagittal plane using Talairach’s stereotactic grid and can be left in place chronically up to 15 days.96 The position of each contact can be plotted on the corresponding slice of the atlas of Talairach and Tournoux97 and by fusing the frontal skull radiography with the coronal MRI slice, both at scale 1/1, corresponding to the electrode trajectory (Figure 39.3a). Oblique electrode trajectories can be also useful to explore the insula.79 Interictal insular recordings The few available data from literature on interictal insular paroxysmal activities in surface or depth recordings were reported in the fifties.36, 98, 99 These early studies showed that spikes or spike-waves are recorded in the insula of nearly 50% of TLE patients. In SEEG recordings they are present in all patients with insular seizures. They are sporadic or intermittent in TLE and most often frequent in patients with insular seizures, particularly in those with focal dysplasia.91 Since the early study of Silfvenius et al.39 it has been acknowledged that their presence is not predictive of a poor outcome of temporal lobectomy in TLE, so that they do not indicate an insular epileptogenic zone. Spikes in the amygdala, hippocampus or temporal pole usually co-exist, and are most often asynchronous, with insular paroxysms. Contacts located in supra- or infrasylvian opercular cortex or adjacent amygdalo-hippocampal structures are often blind to insular paroxysms, which are thus unlikely to be recordable by subdural electrodes grids placed over the sylvian fissure or on the mesial surface of the temporal lobe (Figure 39.5).

Figure 39.5 SEEG recordings in patient 8 using three transopercular electrodes exploring the right insular lobe (cf Figure 39.3a). An abundant paroxysmal interictal activity made of subontinuous spikes and spike-waves is picked up by the insular contacts (A’, C’), to which which more superficial opercular contacts are blind. (i) MRI sagittal slice in the insular plane. (op) MRI sagittal slice in the opercular plane. A, B and C: postions of the insular contacts; A’, B’ and C’: positions of the opercular contacts.

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Figure 39.6 SEEG recording of an ictal discharge in patient 8 beginning in the insular cortex (Arrow 1) by a large spike-wave complex followed by a low voltage fast activity and a recruiting discharge of high frequency spikes and spike-wave affecting preferentially the posterior insula. This ictal spiking activity reaches the opercular cortex 8 seconds after the insular onset time (Arrow 2). This discharge spreads later on to the frontal (G, G’) and parietal (E, E’) ‘lobe, sparing the temporal lobe (D, D’).

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Insular epilepsy Ictal insular SEEG recordings In terms of onset site, propagation and morphology, the insular discharge patterns are very similar from one seizure to the other in a given patient, suggesting an individual organization of the insular epileptogenic neuronal network. They are made of a low voltage fast activity (LvFA) that may begin abruptly, or be preceded by changes in interictal activity. These preictal changes manifest by an increase in the frequency of spikes that become more regular or rhythmic and/or by the appearance of spikes and poly-spike-waves. Ictal LvFA can remain confined in the insula during several tens of seconds, or spread outside the insula in a few hundreds of milliseconds. During their intrainsular development LvFAs are not detectable by SEEG contacts located in neighbouring structures, in particular in the temporo-parieto-frontal opercular cortex, the activity of which is either unchanged or shows only rhythmic slow waves without sharp paroxysms during insular LvFA discharges (Figure 39.6). We have never observed an insular LvFA not spreading, either step by step to perisylvian cortical areas, or more abruptly at distance to ipsilateral amygdala, hippocampus or posterior mesial frontal cortex. Lastly, in two patients with a bilateral SEEG exploration we could observe that an insular LvFA can propagate to the contralateral insula. This anecdotal observation does not allow any conclusion as to the frequency of insular seizures bilateralization, but suggests that the insula is not only a possible relay for intrahemispheric propagation of focal seizures (see section III), but also a route for their interhemispheric transfer.

Treatment Based on electrocorticography, insular resections were attempted as early as the late forties to improve the surgical outcome of temporal lobectomy.36,39,98,99 This procedure has been abandoned because it proved to have a much greater morbidity than the usual temporal lobectomy alone without improving significantly the seizure control. Progress in surgical techniques now allows, with an acceptable risk level, the removal of focal epileptogenic lesions located in the insula, such as tumors42 and cavernous angiomas.100,101 The outcome in terms of seizures control is usually good,102 so that a lesionnectomy can be proposed, without presurgical invasive EEG recordings, whenever an insular lesion manifests clinically by seizures with insular ictal symptomatology, as in the case illustrated in Figure 39.2.

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Figure 39.7 Sagittal (1), coronal (2) and axial (3) control brain MR images after insular radio frequency thermo lesions using the SEEG electrodes contacts implanted in the epileptogenic areas of patient 5. This procedure was performed immediately before SEEG electrodes removal and thus did not entail the risk of additional electrodes implantation. These RM images acquired 15 days after this procedure show the thermo-lesions located at the insular onset site of seizures (A), and in the parietal opercular cortex (B), which was the first propagation relay of insular discharges.

Partial or subtotal resection of the insular cortex is also feasible in a patient without a space-occupying lesion (case 4 in Figure 39.1). However, this remains an aggressive procedure that necessitates the removal of part of the opercular parietofrontal or temporal cortex, and entails a lesional risk in the deep territory of the middle cerebral artery. In the absence of a lesion no tailored insular cortectomy can be undertaken without presurgical SEEG exploration of the entire cortical network suspected as epileptogenic (see the third main section), with recordings of several spontaneous seizures and insular stimulations. An alternative to cortectomy is represented by SEEG guided radio-frequency (RF) thermocoagulation.71 RF thermocoagulation is performed using adjacent contacts of SEEG electrodes in sites where discharges have been recorded. It produces focal lesions of 5–7 mm diameter with minimal risk (Figure 39.7). Two of the eight patients reported in this chapter (see the second main section) have benefited from RF thermocoagulation (# 5 and 8), with a follow up of 36 and 17 months, respectively. Both are free of disabling seizures (class Ib of Engel).

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Cingulate epilepsy E Garzon and HO Lüders

Introduction Between the 1940s and 1950s, studies on experimental animals and observations on human beings with destructive lesions led to the discovery of a possible relationship between the anterior portion of the cingulate gyrus (CG) and behavioral disorders. Those studies also led to the use of surgical ablation of the anterior portion of the CG or of cingulum disconnection for the treatment of severe behavioral illnesses. Many advances have been made in the last 20 years and, even if a clear understanding of all its connections and functions is still far in the future, the CG has been shown to be, indeed, a heterogeneous structure. Because of peculiarities of its vascular irrigation (the pericallosal artery and its branches irrigate the medial portion of the frontal lobe and part of the medial portion of the parietal lobe), ischemic or hemorrhagic lesions circumscribed to the CG are rare. Small tumors or malformative lesions relatively restricted to the CG are also uncommon. These facts limit our ability to study CG function based on lesional observations. Noninvasive neurophysiological studies provide only partial or inconclusive data because of the anatomical location of the CG (medial and distant from the cerebral surface, with significant portion of the CG buried in the depths of the pericallosal and cingulate sulci). This makes it difficult to define the ictal clinical manifestations of the CG as a symptomatogenic zone. The objective of the present chapter is to describe the clinical characteristics of epileptic seizures most probably originating in the CG. As an introduction a brief review of the cytoarchitecture, connections and functions of the CG of humans and experimental animals will be presented.

Cytoarchiteture Brodmann’s cytoarchitectural map of the cerebral cortex has been used as the standard for human brain research. The CG is divided into anterior and posterior parts (Figure 40.1). The anterior part consists of the perigenual portion, areas 25 and 33, and of the midcingulate portion, areas 24 and 32. The posterior cingulate consists of the posterior cingulate cortex, areas 23 and 31, of the retrosplenial portion, areas 29 and 30, and the ectosplenial portion, area 26. Areas 29, 30, and 26 are narrow and located in the isthmus of the CG.1 More recent cytoarchitecture studies have confirmed that an important part of the CG cortex is buried in the depth of the sulci (Figure 40.1). The anterior cingulate cortex (ACC) 334

is agranular, with a prominent Va layer. Not all the cortex of area 24 is exposed on the surface2 and histological differences exist between the caudal and rostral parts of area 24, which is, therefore, subdivided into 24a, 24b, 24c, and 24d.3 The main difference resides in the composition and thickness of layers Va and Vb.3 Area 24c lies primarily within the ventral bank of the cingulate sulcus.2 This area is called the cingulate motor cortex, since pyramidal Betz cells have been demonstrated in layer Va.4 Compared with the Betz cells of the primary motor field, those of the cingulate area display numerous primitive traits.5 In non-human primates, in addition to cytoarchitectural differences there are differences in inputs. While the rostral portion of area 24 receives substantial input from the amygdala, the caudal portion receives a large component of parietal lobe afferents.6 The posterior CG consists of the posterior cingulate cortex (PCC), areas 23 and 31, and the retrosplenial and ectosplenial areas 29, 30, and 26. Areas 29, 30, and 26 are buried in the depths of the pericallosal sulcus. Area 23 is located in the caudal portion of the CG and extends into the caudal part of the cingulate sulcus before it arches to form the marginal sulcus. The PCC is characterized by granular layers II and IV,2 except for area 30 whose layer IV is dysgranular.7 Area 23 is subdivided into 23a, 23b, 23c, and 23d as a function of the degree of differentiation of layer III and of the size and distribution of neurons of layers IV and Va.3

Connections The cingulate cortex is considered to be part of the limbic system and is also a component of the Papez circuit. Outputs from the amygdala, septal area, entorhinal cortex, and hippocampus travel via the fornix to the mammillary bodies of the hypothalamus; from there via the mammillothalamic tract, to the anterior thalamic nucleus (anteroventral subdivision); and via the thalamocortical fiber system to the CG, and then back to the hippocampus via the cingulum and entorhinal areas. This closed circuit of connections was described by Papez8 and became known as the Papez circuit. Studies in rhesus monkeys using retrograde tracer horseradish peroxidase have shown that both the ACC and the PCC receive thalamic inputs. Although each area of the CG receives inputs from distinct thalamic nuclei, the anterior thalamic nucleus (anteromedial subdivision) sends afferent fibers to areas 25, 24, and 23, thus forming a certain connectional link between all cingulate areas.9

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Cingulate epilepsy VCA

VCP

335

CS

6

7

9 8 12

CA-CP STG

Figure 40.1 Cingulate gyrus cytoarchitectural areas. Areas 24, 25, 23, and 31 are located on the mesial surface. Small portions of areas 24 and 23 are buried in the depth of the cingulate sulci. Areas 32, 33, 26, 29, and 30 are buried in the depth of the cingulate and pericallosal sulcus (ACG = anterior cingulate gyrus; PCG = posterior cingulate gyrus; CC = corpus callosum; CS = cingulate sulcus, MR = marginal ramus)

The ACC and PCC also receive a large contingent of afferents from the frontal lobe, especially the dorsolateral and orbital areas, and also from the parietal lobe. Most of the frontal cortical afferents reach area 24, whereas area 23 preferentially receives inputs from the parietal lobe.6 The ACC also receives afferents from the insula cortex and the PCC receives a small proportion of afferents from the occipital lobe, area 19.6 The CG also has extensive efferents connections. Studies on rhesus monkeys have shown that areas 23 and 24 have extensive and widespread projections to several regions of the cerebral cortex (Figure 40.2). Area 24 projects to the premotor region (areas 6 and 8), the orbito-frontal cortex (area 12), the rostral part of the inferior parietal lobe, the anterior insular cortex, the perirhinal cortex, and the laterobasal nucleus of the amygdala. Area 23, likewise, sends its connections to the dorsal prefrontal cortex (areas 9 and 10), the rostral orbital cortex (area 11), the parietotemporal cortex (posterior part of the inferior parietal lobule and the superior temporal sulcus), the parahippocampal gyrus, the retrosplenial region, and the presubiculum.10 The anterior cingulate cortex also sends projections to brainstem motor systems including the caudate, pontine, and red nuclei.11,12

Functions Structural lesions, surgical ablations, or functional alterations due to electrical stimulation of the CG in animals and humans shed some light on the function of the CG. These studies have been complemented by microelectrode recordings, and positron emission tomography in experimental animals and human beings. Changes in behavior can occur due to lesions in area 24, although in many of these reports on humans and experimental animals additional damage was also evident in the adjacent areas 6, 8, 9, 10, and 25 and in the corpus callosum. In monkeys, ablation of area 24 was marked by increased restlessness, hyperactivity, loss of their previous apprehension to certain aspects of their environment, apparent loss of fear, increased

24 CG

CC

23 RS PS

PHG

Figure 40.2 Cingulate gyrus simplified sketch showing efferent connections from areas 23 and 24 in the monkey’s brain (CC = corpus callosum; CG = cingulate gyrus; PHG = parahippocampal gyrus; PS = presubiculum; RS = retrosplenial area; STG = superior temporal gyrus).

tameness, and reduction of aggression.13 In animals with a longer survival time these changes tend to be reduced or to disappear. Behavioral changes such as indifference, docility, inappropriate urination, severe lack of attention, lack of social restraint, heightened sexuality, bulimia, and aggressiveness have also been reported to occur in humans as a consequence of unilateral14 or bilateral15 lesions in the anterior portion of the CG. Bilateral lesions of area 24 also cause the so-called anterior cingulate gyri syndrome which clinically manifests as apathy, akinesia, mutism, urinary incontinence, and indifference to pain.16 Structural lesions and studies of cortical stimulation have also correlated the anterior cingulate with autonomic phenomena such as piloerection,13 changes in blood pressure, tachycardia, mydriasis, and increased respiration frequency.17,18,19 The structural basis for involvement of area 25 in visceromotor activity is well known. Area 25 projects directly to the parasympathetic nucleus of the solitary tract,20 dorsal motor nucleus of the vagus, and to the sympathetic thoracic intermediolateral cell column.21 The anterior cingulate is also involved in the emotional aspects of pain perception.22,23 The ability of the anterior cingulate to participate in or execute motor functions has been studied extensively. The presence of Betz cells in area 24 supports the hypothesis of the possible existence of a motor area in the CG. In experimental animals the lower bank of the anterior cingulate sulcus is involved in self-initiated movements.24 There is also evidence

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that areas 24c and 23c send inputs to the motor and supplementary motor cortices in a somatotopic distribution.25 Additionally, there are reports that cortical stimulation of the ACC evokes motor responses in man.26–29 The nature of the responses obtained differ among the various studies, but include repetitive movements of the hands, fingers, and lips that can be classified as automatisms, tonic contractions involving the hands and arms, or an irresistible urge to grasp something. The posterior CG probably integrates visual information recognized in the visual cortex and an emotion-related substrate is processed in the anterior cingulate.30 Electrical activity of PCC is detected during eye movements in several species while assessing large visual field patterns. The activity is linked to the position of the eye in the orbit and the direction and amplitude of saccadic eye movements.31–33 Several observations have suggested that the PCC contributes to orientation of the animal in the environment and to spatial memory. Lesions of the posterior cingulate disrupt a rat’s ability to swim to a hidden platform.34 The observation of the deficits due to lesion of the retrosplenial region of rats has led to the assumption that the damage may disrupt the integration and transmission of both movement-related information and visuospatial information from cortex to hippocampal formation. The hypothesis is that the retrosplenial region is important not for memory of landmarks or other visuospatial cues, but rather the functional role of this region may be to purposefully organize the movements with respect to surrounding visual landmarks.35

Cingulate seizures Overview The semiologic characterization of epileptic seizures originating in the CG cortex is a challenge in epileptology. As mentioned before, the anatomical location of the CG makes neurophysiological studies with scalp electrodes difficult. Similar problems are encountered with invasive neurophysiological recordings. The presence of large caliber blood vessels on the medial surface of the brain and the fact that a considerable proportion of the cortex is located inside sulci make invasive evaluation of this area difficult. Ideal cases for the study of ictal clinical manifestations would be small medial epileptogenic lesions practically limited to the CG. These cases are relatively rare and literature data are limited to case reports or relatively small series. Thus, the semiologic aspects of the epileptic seizures of this region are still poorly defined. Most cases in the literature do not provide direct evidence that the epileptogenic zone was in the CG or actually limited to the CG. The gold standard would be cases in which a resection of an epileptogenic zone limited to the CG renders the patient free. Such cases do not exist in the current literature. Therefore, the following review of the literature refers to cases in which the lesion was mainly in the CG, even if there was no direct proof that the seizures originated from the CG, i.e., patients were not necessarily seizure free after surgery and/or the surgery was not limited to the cingulated gyrus. Although auras are considered rare,36 autonomic symptoms such as tachycardia, mydriasis, and changes in respiratory frequency are considerate common.37 Other descriptions are sensation of fear, dizziness,37 and painful sensations.38

In general, reports in the literature tend to stress that seizures originating from the cingualte gyrus are frequent, brief, nocturnal and do not include significant preictal or postictal alterations.36 The ictal semiology that has been related to the anterior cingulate is relatively varied. Some ictal manifestations like complex automatisms, laughter, and altered level of attention or consciousness have been described more frequently. Table 40.1 summarizes literature cases with seizures originating in the anterior portion of the cingulate, as confirmed by scalp video-EEG evaluation and/or invasive recording in lesional and non-lesional cases. Complex gestural movements,36–40 laughter,36,38,39,41 tonic contraction,36 lapses of attention, blinking, and oroalimentary automatism40 were the most common clinical manifestations. For comparative purposes, on the basis of described data, we reclassified the seizures according to the semiological seizure classification (Table 40.1).42 The most frequent types of epileptic seizures reported as originating from the anterior portion of the CG were bilateral asymmetric tonic seizures, gelastic seizures, hypermotor seizures, and complex motor seizures. In two cases the seizures were preceded by a somatosensory and autonomic aura respectively. In one case an autonomic seizure was documented (mydriasis). Dialeptic seizures were reported in only one report. This patient by history had atonic and complex motor seizures, but dialeptic seizures were documented during evaluation by video-EEG.40 Stimulation with depth electrodes have shown that continuous movements may be elicited by electrical stimulation of the anterior region of the CG. These movements were classified as automatisms and primarily involved the fingers, hands, lips, and tongue. The movements were ‘primitive’ and simple such as touching, leaning, rubbing, stretching, or sucking. The movements were frequently integrated with more complex movements that were adapted to the situation and thus represent, as a whole, what the authors called ‘types of behavior’.19,26 Cleveland clinic series In an attempt to better define the semiology of seizures originating from the CG, we reviewed the Cleveland Clinic Epilepsy database. To analyze the semiology and the electroencephalographic findings of seizures originating from the CG, patients of any age range evaluated by video-EEG and with symptomatic focal epilepsy secondary to a single structural lesion identifiable by magnetic resonance and localized in the CG, anterior, or posterior region were selected. No attempt was made here to define if the observed ictal semiology was due to direct activation of the CG (symptomatogenic zone in the CG) or due to spread an activation of extra-CG symptomatogenic areas such as, for example, the adjacent supplementary sensory-motor area. Only cases in which at least 90% of the lesion was located in the CG were included. Patients with extensive lesions with a small proportion in the CG or with extensive lesions widely involving the CG and adjacent regions as also non-lesional cases were excluded. Of patients evaluated between 1990 and 2005 who had received a diagnosis or a diagnosis of probable cingulate epilepsy, 76 were selected. The clinical data and the

Type

Case report

Case report

Review and 2 cases description

Chassagnon et al., 200338

McConachie & King, 199739

Devinsky et al., 199536

Laughter, repetition of the phrase ‘Oh my God’, small repetitive neck and trunk flexion, and bilateral arm extension, repeated touching of the forehead and mouth. Amnestic for the seizures

Grotesque facial contortions (tongue thrusting, a strangulated yell), neck and trunk flexion, bilateral arm and leg extension with side-to-side thrashing and occasional progression to a generalized tonic-clonic seizure Consciousness preserved

Male 28yrs

Male 29yrs

1. Sudden inappropriate laughter and kicking movements of the lower limbs. 2. Screaming, falling to the ground, holding his right arm in the air, thrashing his other limbs and wetting himself.

90% and one had 75% in 6/19 patients (31%) with complete disappearance in one. The authors assumed they had, at times, spectacular results in the cryptogenic LGS, with no clinical or EEG evidence of focalization, which contrasts with the results obtained by other authors. They also mentioned improvement in awareness and alertness, not attributable to changes in antiepileptic medication. In one patient, a new seizure type occurred after surgery, consisting of nocturnal focal adversive and clonic seizures. These data are consistent with the data reported by Spencer et al.27,28 on the occurrence of more intense focal seizures after callosal section. In the same way Spencer et al.29 have analyzed the EEG ictal patterns before and after CC, showing that the bilateral synchronous pattern was replaced by a unilateral or a focal onset, and that seizures newly localized to a lobe could occur, mainly in the frontal, sometimes in the parietooccipital lobe. Quattrini et al.30 observed the same changes in the postoperative ictal discharges. They also observed that after certain time, generally some months, lateralized discharges tend to generalize again, confirming that CC is replaced in discharge diffusion by other structures (brainstem, diencephalon). Ritter et al.31 reported 27 patients with LGS who underwent CC (19 complete, eight partial anterior). The selection criterion was the presence of drop attacks or frequent secondary generalized tonic-clonic seizures. Duration of follow up was 2–18 months (median 6 months). Overall, 70% of the patients had marked improvement in seizure control: tonic seizures decreased in frequency >80% in 14 of 23 patients (60%); GTC in nine of 15 (60%); atonic in seven of eight (87%), and seizures associated with dropping in 13 of 21 (61%). Repeated episodes of status epilepticus ceased in three of four patients. Provinciali et al.32 reported on the neuropsychological changes after partial CC in 15 patients with SGE, of which five were LGS. They tested memory, attention, visuo-motor ability, posture, motor dexterity, language, praxis and gnosis, as well as social behavior, one month before surgery, then 15–20 and 90–100 days postoperatively, without modifying the medical treatment. The short-term neuropsychological cost of this procedure appears to be low and seems to depend mostly on surgical parameters and brain conditions before the operation.

Nakatani et al.33 and Sakaki et al.34 reported respectively four and two patients operated upon in Japan with a satisfactory result with respect to the seizures for all, in spite of a disconnection syndrome in three patients, transient in one and lasting in two. Gates 35 reviewed three series of CC, including 17, one and five patients with LGS in the respective series. Among them 15 achieved a satisfactory outcome. Gates reported that the presence of bilateral independent foci with capacity for secondary generalization was an indicator of good outcome. Pinard et al.36 had operated on 34 patients with more than three seizures a day, among whom eight patients were diagnosed as having LGS. Patients were followed prospectively for at least 2 years after anterior CC (19 patients) and for 1 year after complete CC (15 patients). The eight patients with cryptogenic LGS improved after anterior CC. Septien et al.37 emphasized the good results obtained in children with psychiatric problems. They had performed partial anterior CC in two children with LGS and major psychiatric troubles: frontal syndrome with hyperkinesia, distractibility, aggressiveness, alexithymia, loss of planning abilities. They observed a progressive improvement of this frontal syndrome during the 2 postoperative months, with the possibility of learning new skills, without a change in IQ. Associative functions depending on the posterior third of the corpus callosum were preserved. They thought this improvement was related to the reduction of seizures. Claverie and Rougier38 studied the outcome in terms of quality of life in 20 patients submitted to CC for intractable epilepsy, including three cases of LGS. In two of these three they observed a substantial change; they became capable of independent living, and one attended a specialized school. In the whole series it appeared that the psychosocial benefits obtained in 40% of the patients were linked not only to the seizure reduction but also to the precocity of the intervention. Matsuzaka et al.39 studied 22 consecutive patients who underwent an anterior CC for intractable epilepsy. Seventeen of these patients had SGE, of whom eight had LGS. A crosscorrelation analysis and measurements of amplitude differences were performed between bilateral homologous regions pre-and postoperatively. The surgical outcome was excellent in 14 (63.6%), including a complete elimination of seizures in four; good in three (13.6%); and poor in five (22.7%) patients. After surgery, interictal generalized synchronous SW bursts in the SGE patients were disrupted and changed to unilateral SWs in 11 patients and to bilaterally independent SWs in six. The unilateral group had better surgical outcome than the bilateral independent group. Preoperatively the first group had significantly lower interhemispheric synchrony and fewer regional changes in the side leading in time and the side dominant for amplitude, suggesting unilaterally predominant epileptogenesis that triggered the secondary bilateral synchrony. These findings lead to the hypothesis that a considerable range of variation exists in the underlying condition of epileptogenesis in each hemisphere, even in SGE, affecting the postoperative EEG changes and surgical outcome. Preoperative quantitative EEG analyses enabled the authors to predict the underlying conditions of epileptogenesis and the surgical outcome. Unfortunately the authors were not precise in indicating to which group the patients with LGS belonged.

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The Lennox–Gastaut syndrome: a surgically remediable epilepsy? Kwan et al.40 analyzed findings and acute changes in electrocorticograms (EcoG) obtained during CC, in order to identify any relationships with the postoperative outcome of seizure activity, in 48 patients with LGS, all followed postoperatively for more than 4 years. Of these patients, 31 (64.6%) had significant improvement in seizure control. EcoG displayed bisynchronous discharges in 79.2% of the 48 patients, and they were blocked during CC in 69.7%, who achieved the best postoperative outcomes. But the difference did not reach statistical significance. Therefore, the changes in preoperative EcoG are not predictive. The largest series was reported by Cukiert et al.41 who performed one-stage callosal section, leaving only the splenium intact, in 76 patients with Lennox–Gastaut (n = 28) and Lennox-like (n = 48) syndromes. However, the latter is not defined by the authors. All patients were severely mentally impaired. Mean follow-up time was 4.7 years. Worthwhile improvement (>50%) was noted in 69 patients, with 90% or more seizure reduction in 52, 100% in seven. As in other series, the drop attacks were the most responsive seizure type (92%), followed by atypical absences (82%), tonic-clonic (57%), and tonic (51%) seizures. Postoperative EEGs were obtained in 56 patients. In 42 they showed complete disruption of secondary bilateral synchrony, in six only partial disruption, in eight no change. But a postoperative acute callosal disconnection syndrome appears in 72 patients (apathy, urinary incontinence, right hemineglect, low verbal input, one mutism) which lasted for 8–50 days. After this period, the attention abilities were substantially improved. Interestingly, in two patients who had LGS with reflex seizures these seizures were reduced by 60% in one (startle epilepsy) and disappeared in the second (tap epilepsy), unfortunately with a relapse after one year in the latter.42 In all series, postoperative complications and side-effects were rare. When it appears, the disconnection syndrome is transient. All the authors underline that in children CC is usually followed by an evident improvement in psychomotor development and behavior, though it is not measurable by usual assessment methods.35,37,38 At the end of this brief and incomplete survey, it appears that a number of patients with LGS can really improve with a partial anterior CC. In any case it is not a curative but a palliative treatment which can control the most ominous seizures represented by the drop attacks, mainly tonic in nature in this syndrome. Few papers give data on long-term results (more than 5 years’ follow-up) but it is never mentioned that good results were transitory. Spencer et al.26 followed patients postoperatively from 2–7 years. They indicate that ‘the stability of generalized seizure control after CC continues over many years of follow up’. The problem is not knowing the factors which could allow predicting the result of this intervention. Most authors reported better outcome in patients with a lateralized lesion or lateralized EEG anomalies, but in one series43 some cryptogenic LGS without asymmetry have been improved. Nevertheless, it is important to conduct a good preoperative EEG analysis in order to detect the type of electrogenesis in each hemisphere. The presence of a mental deficit is not a contraindication. Neuropsychological consequences are usually rare after partial section. It is recommended to perform surgery before the age of 10, in order to preserve a good intellectual outcome and to restore a good quality of life.

391

Vagus nerve stimulation In the numerous publications studying the effects of VNS on epilepsy, the patients with LGS were often included in series of patients with ‘refractory’ or ‘intractable’ seizures, or with a low IQ. Few details were provided by the authors. The effect of VNS was evaluated at different times after surgery and was variable, from 50% and more seizure reduction in few patients44, 45 up to more than 90% seizure reduction.46,47 Most of the authors also indicate some degree of improvement in behavior, such as alertness and social communication. The side-effects were never disabling, consisting of change in the voice, hoarseness, sometimes coughing, at the time of the stimulation, and usually persisted only for some weeks. From the year 2000, LGS patients have been reported as a group and the conclusions are also variable. Moreover, the criteria for diagnosing LGS often lack and these groups include also cases designated as Lennox-like syndromes. The best study of VNS in patients with LGS was published by Majoie et al.,48 who gave the results of this procedure in 16 patients, aged from 7–18 years, accurately analyzed in terms of seizure and epilepsy type, frequency of the different seizure types, cognitive functions, quality of life and cost-effectiveness. This prospective, longitudinal cohort study included 16 ‘Lennox-like’ patients, among whom 12 with LGS, three with myoclonic astatic epilepsy, and one with myoclonic absences, followed from 6–12 months. The overall results showed that 25% of the patients had a reduction of seizures of 50% or more, with a mean for the individual patient of approximately 20–30%. No patient was completely seizure free. There were no significant differences between the various seizure types and for patients with drop attacks (n = 10) only one was seizure free and one had more than 50% reduction. The effects were moderate on neuropsychological functioning, a slight improvement appearing in the group with the highest mental age and not correlated with the seizure frequency reduction. The effects on EEG were not studied, but the best results were obtained in the patients with the best EEG background activity. The side-effects were low and transitory. The costeffectiveness analysis showed a decrease of 2876.06 € in the postoperative period of 6 months (1 € was approximately equivalent to 1 $). The same authors reported the results after a 2-year follow-up,49 which were substantially the same with persistence of the seizure reduction rate at the same level and no more improvement in the neuropsychological functioning. Frost et al.50 reported a multicentric retrospective study of 50 LGS patients, aged from 5 to 27 years (median = 13 years), 42% younger than 12. Data were gathered at 1, 3, and 6 months after implantation. They had multiple seizure types, 66% presenting with drop attacks. At 3 months, data were available for 43 patients. Seizures had decreased by >75% in 15 (35%), and by =50% in 24 (56%), and they have increased by >50% in 3. After 6 months, data were available for 24 patients (due to the data collection cutoff point). Seizures had decreased by >75% in 9 (38%) and by =50% in 14 (58%), and no increase was reported. No patient was seizure free. According to the authors, drop attacks and atypical absences seemed to equally respond, but it was difficult to affirm that, since there was no prolonged video recording. They also mentioned an improvement in quality of life, which requires further studies because the scales they applied were very simple. The side-effects were similar to those in previous studies, but

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hypersalivation and worsened behavior and hyperactivity were also noted in respectively 4 and 3 patients. Buoni et al 51 reported a series of 13 patients, 7 with LGS of whom 6 with atonic seizures. Three had a 50% or more seizure frequency reduction, mainly for atonic seizures, which the authors considered one good responsive seizure type, in contrast with the results by Majoie et al.48 However, their sample is small and atonic seizures are not always responsible for falls (drop attacks). Data about the effectiveness of VNS in LGS as regards other epilepsy types are unclear. Some authors 46 found a high rate of seizure reduction (from more than 50% up to more than 90%) and others seem to indicate that it is equivalent48 or lower. Labar, 52 in a survey of 269 patients with 1-year follow-up, concluded that VNS responsiveness was associated with older age, longer duration epilepsy and syndromes other than LGS. As for CC, up to now there are no outcome predictive factors allowing the selection of patients with a good chance of improvment by VNS. Janszky et al.53 conducted a study in 47 patients, with long-term ictal and interictal EEG recordings, with a 1-year follow-up. Only four patients had a symptomatic generalized epilepsy. They concluded that only two factors were predictive for a complete control of the seizures, the presence of a cortical dysplasia and the absence of bilateral interictal epileptiform discharges, the latter independently. These preliminary results would be rather discouraging for LGS patients. Another group54 also attempted to find prognostic electroclinical features and studied seizure patterns in 17 patients, mainly with focal epilepsies (16 with falls) and including four LGS patients. Only four patients had a significant seizure reduction, a better outcome occurring in those seizures with a temporal lobe onset, and the poorest outcome occurring in frontal and fronto-central seizures. In the LGS patients there were no significant improvement, except a diminution of retropulsive falls.

Conclusion In conclusion, one must underline that none of the published patients treated by VNS for a LGS has been completely seizure free, even if one seizure type could have disappeared in few of them (atonic seizures).51 For this reason, the choice between the two types of palliative surgery, CC and VNS, should be discussed case by case. It is known that a real improvement in quality of life is obtained only in patients who become seizure free and not in patients with a seizure frequency reduction 90% reduction in seizures is used.8 Difficulties arise when a Class III ‘worthwhile’ outcome is not specified either in number of seizures or percentage reduction from baseline. The substantial reduction group would also include the Duke ‘Significantly Improved’ outcome of 99% >99% 80% >99% 80% 75% >99%

89% 100% 90% >90%

Specifity

Contralateral Contralateral Contralateral Contralateral

Hemisphere of the epileptogenic zone

Localized somatosensory aura Hemifield visual aura Focal tonic/clonic activity Forced head version lateral parieto-occipital More likely occipital or temporal, but all lobes possible Basal temporal, TPO junction Basal temporal, occipito-temporal

Occipital, temporal Occipital, parietal, posterior temporal All lobes

If lateralized, contralateral

Temporal, parietal, occipital

No

More likely Heschl’s gyrus More likely auditory association cortex All lobes, more frequently temporoparietal Amygdala, insula Insula, mesial temporal

Temporal Frontal, temporal Temporal Parietal, temporal, frontal

If lateralized, contralateral

Frontal, insular, mesial temporal Temporal, insular

No If lateralized contralateral

Insula Insula, anterior cingulate, SSMA, amygdala, hippocampus, hypothalamus Insula Insula, mesial temporal, mesial frontal

Insular Temporal, (orbito-) frontal, insular

No No

Temporal, insular All lobes, most often temporal

More often ND Right, if associated with vomiting

Amygdala, hippocampus, mesial frontal Temporal Mesial > lateral temporal Lateral temporal, TPO junction TPO junction

(Mesial) temporal or frontal

No

Temporal Temporal Temporal, parietal Temporal, parietal

More often ND More often ND No No

All lobes

No

More often mesial frontal or post. temp.

No

More often frontal or temporal, but all lobes possible SS II, SSMA

More often ND

More often ND

Abbreviations: SS I: primary somatosensory area, SS II: second somatosensory area, SSMA: supplementary sensorimotor area, TPO: temporoparieto-occipital, ND: nondominant hemisphere

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Auras: localizing and lateralizing value

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Lüders H, Lesser RP, Dinner DS et al. The second sensory area in humans: evoked potential and electrical stimulation studies. Ann Neurol 1985;(2):177–84. Lim SH, Dinner DS, Pillay PK et al. Functional anatomy of the human supplementary sensorimotor area: results of extraoperative electrical stimulation. Electroencephalogr Clin Neurophysiol 1994;91(3):179–93. Manford M, Fish DR, Shorvon SD. An analysis of clinical seizure patterns and their localizing value in frontal and temporal lobe epilepsies. Brain 1996;119:17–40. Salanova V, Andermann F, Rasmussen T, Olivier A, Quesney LF. Parietal lobe epilepsy. Clinical manifestations and outcome in 82 patients treated surgically between 1929 and 1988. Brain 1995;118:607–27. Blume WT, Jones DC, Young GB, Girvin JP, McLachlan RS. Seizures involving secondary sensory and related areas. Brain 1992;115:1509–20. Isnard J, Guenot M, Sindou M, Mauguiere F. Clinical manifestations of insular lobe seizures: a stereo-electroencephalographic study. Epilepsia 2004;45(9):1079–90. Tuxhorn IE. Somatosensory auras in focal epilepsy: a clinical, video-EEG and MRI study. Seizure 2005;14(4):262–8. Erickson JC, Clapp LE, Ford G, Jabbari B. Somatosensory auras in refractory temporal lobe epilepsy. Epilepsia 2006;47(1):202–6. Nair D, Najm I, Bulacio J, Lüders H. Painful auras in focal epilepsy. Neurology 2001;57:700–2. Young GB, Blume WT. Painful epileptic seizures. Brain 1983;106:537–54. Siegel AM, Williamson PD, Roberts DW, Thadani VM, Darcey TM. Localized pain associated with seizures originating in the parietal lobe. Epilepsia 1999;845–55. Sveinbjornsdottir S, Duncan JS. Parietal and occipital lobe epilepsy: a review. Epilepsia 1993;34(3):493–521. Erratum in: Epilepsia 1994;35(2):467. Kahane P, Hoffmann D, Minotti L, Berthoz A. Reappraisal of the human vestibular cortex by cortical electrical stimulation study. Ann Neurol 2003;54(5):615–24. Holtzmann RN. Sensations of ocular movement in seizures originating in occipital lobe. Neurology 1977;27:554–6. Kofman O, Tasker R. Ipsilateral and focal inhibitory seizures. Neurology 1967;17:1082–6. Horrax G, Putnam DJ. Distortions of the visual fields in cases of brain tumors: the field defects and hallucinations produced by tumors of the occipital lobe. Brain 1932;55:499–523. Richer F, Martinez M, Cohen H, Saint-Hilaire JM. Visual motion perception from stimulation of the human medial parieto-occipital cortex. Exp Brain Res 1991;87(3):649–52. Laff R, Mesad S, Devinski O. Epileptic kinetopsia: ictal illusory motion perception. Neurology 2003;61(9):1262–4. Ludwig BI, Ajmone-Marsan C. Clinical ictal patterns in epileptic patients with occipital electroencephalographic foci. Neurology 1975;25(5):463–71. Blanke O, Landis T, Seeck M. Electrical cortical stimulation of the human prefrontal cortex evokes complex visual hallucinations. Epilepsy Behav 2000;1(5):356–61. Beauvais K, Biraben A, Seigneuret E, Saikali S, Scarabin JM. Subjective signs in premotor epilepsy: confirmation by stereo-electroencephalography. Epileptic Disord 2005;7(4):347–54. Blume WT, Wiebe S, Tapsell LM. Occipital epilepsy: lateral vs mesial. Brain 2005;128:1209–25. Bien CG, Benninger FO, Urbach H et al. Localizing value of epileptic visual auras. Brain 2000;123:244–53. Salanova V, Andermann F, Olivier A, Rasmussen T, Quesney LF. Occipital lobe epilepsy: electroclinical manifestations, electrocorticography, cortical stimulation and outcome in 42 patients treated between 1930 and 1991. Brain 1992;115:1655–80. Russell WR. Whitty CW. Studies in traumatic epilepsy. 3. Visual fits. J Neurol Neurosurg Psychiatry 1955;18(2):79–96. Cohen L, Gray F, Meyrignac C, Dehaene S, Degos JD. Selective deficit of visual size perception: two cases of hemimicropsia. J Neurol Neurosurg Psychiatry 1994;57(1):73–8. Muller T, Buttner T, Kuhn W, Heinz A, Przuntek H. Palinopsia as sensory epileptic phenomenon. Acta Neurol Scand 1995;91(6): 433–6. Meadows JC, Munro SS. Palinopsia. J Neurol Neurosurg Psychiatry 1977;40(1):5–8. Mullan S, Penfield W. Illusions of comparative interpretation and emotion. Arch Neurol Psychiatry 1959;81:269–84.

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Textbook of epilepsy surgery Celesia GG. Organization of auditory cortical areas in man. Brain 1976;99(3):403–14. De Graaf JB, Liégeois-Chauvel C, Vignal J-P, Chauvel P. Electrical stimulation of the auditory cortex. In: Lüders HO, Noachtar S, eds. Epileptic Seizures: Pathophysiology and Clinical Semiology. Philadelphia: Churchill Livingstone, 2000:228–36. Foldvary N, Acharya V, Lüders HO. Auditory auras. In: Lüders HO, Noachtar S, eds. Epileptic Seizures: Pathophysiology and Clinical Semiology. Philadelphia: Churchill Livingstone, 2000: 304–12. Smith BH. Vestibular disturbances in epilepsy. Neurology 1960;10: 465–9. Lobel E, Kleine JF, Bihan DL, Leroy-Willig A, Berthoz A. Functional MRI of galvanic vestibular stimulation. J Neurophysiol 1998;80: 2699–709. Kahane P, Hoffmann D, Minotti L, Berthoz A. Reappraisal of the human vestibular cortex by cortical electrical stimulation study. Ann Neurol 2003;54(5):615–24. Brandt T, Dieterich M. The vestibular cortex. Its locations, functions, and disorders. Ann NY Acad Sci 1999;871:293–312. Kluge M, Beyenburg S, Fernandez G, Elger CE. Epileptic vertigo: evidence for vestibular representation in human frontal cortex. Neurology 2000;55:1906–8. Acharya V, Acharya J, Lüders H. Olfactory epileptic auras. Neurology 1998;51:56–60. Fried I, Spencer DD, Spencer SS. The anatomy of epileptic auras: focal pathology and surgical outcome. J Neurosurg 1995;83(1): 60–6. Jasper HH, Rasmussen T. Studies of clinical and electrical reponses to deep temporal stimulation in man with some considerations of functional anatomy. Res Publ Assoc Res Nerv Ment Dis 1958;36:316–34. Bancaud J, Talairach J. Clinical semiology of frontal lobe seizures. Adv Neurol 1992;57:3–58. Munari C, Tassi L, Di Leo M et al. Video-stereo-electroencephalographic investigation of orbitofrontal cortex. Ictal electroclinical patterns. Adv Neurol 1995;66:273–95. Greenberg MS. Olfactory hallucinations. In: Serby MJ, Chobor KL, eds. Science of Olfaction. Berlin: Springer-Verlag, 1992:467. Hausser-Hauw C, Bancaud J. Gustatory hallucinations in epileptic seizures. Electrophysiological, clinical and anatomical correlates. Brain 1987;110:339–59. Pool JL, Ransohoff H. Autonomic effects on stimulating the rostral portion of the cingulate gyrus in man. J Neurophysiol 1949;12: 385–92. Van Buren J, Ajmone-Marsan C. A correlation of autonomic and EEG components in temporal lobe epilepsy. Arch Neurol 1960;91:683–703. Halgren E, Walter RD, Cherlow DG, Crandall PH. Mental phenomena evoked by electrical stimulation of the human hippocampal formation and amygdala. Brain 1978;101:83–117.

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Ojemann GA, Van Buren JM. Respiratory, heart rate and GSR responses from human diencephalon. Arch Neurol 1967;16: 74–88. Baumgartner C, Groppel G, Leutmezer F et al. Ictal urinary urge indicates seizure onset in the nondominant temporal lobe. Neurology 2000;55(3):432–4. Loddenkemper T, Foldvary N, Raja S, Neme S, Lüders HO. Ictal urinary urge: further evidence for lateralization to the nondominant hemisphere. Epilepsia 2003;44(1):124–6. Van Buren JM. The abdominal aura. A study of abdominal sensations occurring in epilepsy and produced by depth stimulation. Electroencephalogr Clin Neurophysiol 1963;15:1–19. Bartolomei F, Barbeau E, Gavaret M et al. Cortical stimulation study of the role of rhinal cortex in déjà vu and reminiscence of memories. Neurology 2004;63:858–64. Henkel A, Noachtar S, Pfänder M, Lüders HO. The localizing value of the abdominal aura and its evolution: a study in focal epilepsies. Neurology 2002;58(2):271–6. Kotagal P, Lüders HO, Williams G, Nichols TR, McPherson J. Psychomotor seizures of temporal lobe onset: analysis of symptom clusters and sequences. Epilepsy Res 1995;20(1):49–67. Mendez MF, Cherrier MM, Perryman KM. Epileptic forced thinking from left frontal lesions. Neurology 1996;47:79–83. Stefan H, Schulze-Bonhage A, Pauli E et al. Ictal pleasant sensations: cerebral localization and lateralization. Epilepsia 2004;45(1):35–40. Janszky J, Ebner A, Szupera Z et al. Orgasmic aura – a report of seven cases. Seizure 2004;13(6):441–4. Weinand ME, Hermann B, Wyler AR et al. Long-term subdural strip electrocorticographic monitoring of ictal déjà vu. Epilepsia 1994;35(5):1054–9. Comment in: Epilepsia 1995;36(5):522. Bancaud J, Brunet-Bourgin F, Chauvel P, Halgren E. Anatomical origin of déjà vu and vivid ‘memories’ in human temporal lobe epilepsy. Brain 1994;117:71–90. Blanke O, Landis T, Spinelli L, Seeck M. Out-of-body experience and autoscopy of neurological origin. Brain 2004;127:243–58. Nair DR, Lüders HO. Cephalic and whole-body auras. In: Lüders HO, Noachtar S, eds. Epileptic Seizures: Pathophysiology and Clinical Semiology. Philadelphia: Churchill Livingstone, 2000: 355–60. Jobst BC, Siegel AM, Thadani VM et al. Intractable seizures of frontal lobe origin: clinical characteristics, localizing signs, and results of surgery. Epilepsia 2000;41(9):1139–52. Laplante P, Saint-Hilaire JM, Bouvier G. Headache as an epileptic manifestation. Neurology 1983;33(11):1493–5. Bernasconi A, Andermann F, Bernasconi N, Reutens DC, Dubeau F. Lateralizing value of peri ictal headache: a study of 100 patients with partial epilepsy. Neurology 2001;56:130–2. Wieser HG, Williamson PD. Ictal semiology. In: Engel J Jr, ed. Surgical Treatment of the Epilepsies, 2nd ed. New York: Raven Press, 1993:161–71.

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Autonomic seizures: localizing and lateralizing value V Nagaraddi and HO Lüders

Summary Autonomic symptoms are common during epileptic seizures, mainly in conjunction with other more prominent symptoms. However, in selected cases autonomic symptoms may also constitute the predominant ictal manifestation. Autonomic seizures are actually mediated by activation of the central autonomic network and are not an adjunct to motor and other manifestations of seizures. Autonomic seizures have been divided into cardiovascular, respiratory, gastrointestinal, cutaneous, papillary, and urogenital, depending upon the symptoms.1 Certain autonomic symptoms provide lateralizing and/or localizing information about the ictal onset zone, due to specific representation of the central autonomic network in the cortex. Autonomic symptoms range from subtle changes, which are apparent only with video-EEG monitoring, to severe, sometimes life-threatening events. When autonomic symptoms are the sole seizure manifestation, they can be difficult to differentiate from psychogenic non-epileptic seizures. Finally, autonomic symptoms during seizures provide a unique opportunity to study the functional organization of the central autonomic network.1

Introduction Autonomic symptoms occurring during seizures have been recognized for more than 100 years. Changes in heart rate and respiration during a generalized tonic–clonic seizure are predictable and are obvious to an observer. Autonomic symptoms during focal seizures have long been observed as well, including goose bumps, flushing, pallor, sweating, sexual sensations, and pupillary changes.2 In 1981, the commission on classification and terminology of the International League against Epilepsy included autonomic seizures as a subdivision of simple partial seizures in the revised seizure classification. This subdivision included among others, epigastric sensations, pallor, sweating, flushing, piloerection and pupillary dilation.3 Autonomic symptoms can occur either during the ictus or postictally. They may also play a role in some interictal epileptic behaviors. Autonomic symptoms are being recognized with increasing frequency. Nevertheless, autonomic seizures are still frequently under- or misdiagnosed, resulting in expensive investigations and inappropriate therapies, leaving incapacitating and potentially fatal symptoms untreated.4

Both focal and generalized seizures alter the central autonomic functioning during ictal, postictal, and interictal states. All aspects of autonomic function can be affected, including the parasympathetic, sympathetic, and adrenal medullary systems. Focal and generalized seizures typically activate the sympathetic nervous system, increasing the heart rate and blood pressure, although parasympathetic activation or sympathetic inhibition may predominate during some focal seizures.5

Neuroanatomy of the autonomic system The preganglionic sympathetic and parasympathetic efferent pathways are regulated by reciprocally interconnected cortical, subcortical, and brainstem regions. The components of the central autonomic network have been established by experimental methods, and include the insular cortex, the medial prefrontal cortex, the central nucleus of the amygdala, the nucleus of the stria terminalis, the hypothalamus, the midbrain periaqueductal gray matter, the pontine parabrachial region, the nucleus of the solitary tract and the intermediate reticular zone of the medulla.6 Anatomic and physiologic studies have defined a topographically organized visceral map in the insula, supporting the concept of the insula as a ‘visceral sensory cortex’, with localization of gustatory responsive neurons to the rostral agranular region and gastric mechanical responsive neurons to the caudal granular region. Electrical stimulation studies of the insular cortex have demonstrated heart rate, blood pressure, respiratory, piloerector, pupillary, gastrointestinal, salivatory, and adrenal responses. Intraoperative stimulation studies of the human insular cortex have suggested that tachycardia and pressor responses occur more commonly with right anterior insula stimulation, whereas bradycardia and depressor responses are more common with left anterior insular stimulation.7,8 Stimulation of the medial prefrontal cortex produces profound changes in blood pressure, heart rate, and gastrointestinal motility. A viscerotopic map of this region, which includes the anterior cingulate gyrus and the inferior and prelimbic cortices, supports the concept of the medial prefrontal cortex as a ‘visceral motor cortex.’ Intraoperative human stimulation studies of the cingulate gyrus have demonstrated changes in heart rate and blood pressure.4,9 443

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Definition of autonomic seizures Autonomic seizures have a measurable or visible autonomic symptom or manifestation, for example change in the heart rate or piloerection, which is also a prominent or predominant feature of the seizure. The symptom is usually verifiable by an observer, reproducible over several seizures and can be documented quantitatively or qualitatively. This is important in distinguishing autonomic seizures from autonomic auras, which are symptoms perceived by the patient, such as feeling hot, or cold and clammy etc., but there is no change that can be verified by observation or measurement, such as the temperature being assessed by touch or measured by a thermometer and sweating documented by either touch or observation. The limitation is that many of the autonomic symptoms in question, are not quantifiable in most routine settings, because there is no simple, practical means of measuring it, for example peristalsis, pupillary changes etc. It should also be noted that almost all epileptic seizures have some autonomic symptoms, especially cardiac and respiratory changes. Most focal and generalized tonic-clonic seizures have changes in heart rate, as measured by the EKG. In most of these cases, there is sinus tachycardia at the onset of seizure and to a lesser extent sinus bradycardia. Similarly, there are changes in the respiratory pattern and rate, which could be either due to modulation of the respiratory centers in the cortex and brainstem due to the spread of the seizure or as a result of the tonic contraction and spasms of the diaphragm and intercostal muscles. In these seizures, the predominant feature is either the alteration in consciousness and or the motor manifestations accompanying it and therefore they are not classified as true ‘autonomic seizures’.4,5

Cardiac manifestations Cardiac manifestations are the most studied autonomic alterations, partly because of trying to elucidate the pathophysiology of SUDEP and also because most EEG recordings have an EKG channel that can be easily analyzed. Ictal tachycardia An increase in the heart rate is seen in the vast majority of all epileptic seizures, including subclinical electrographic seizures.10–13 Depending upon the definition of tachycardia, usually >100 beats per minute, the incidence of ictal tachycardia varied from 33–87%.14–18 Furthermore, there is a significant preponderance of ictal tachycardia in temporal lobe epilepsy versus extratemporal lobe epilepsy (62% versus 11%, p < 0.0018)19 and in one study ictal tachycardia was seen in 98% of temporal lobe seizures.16,20,21 Within the temporal lobe, ictal tachycardia was found to be more prevalent in seizures arising from the mesial temporal lobe.15,21 The onset of tachycardia tended to precede the EEG seizure onset, more so in temporal lobe versus extratemporal lobe seizures and mesial temporal lobe versus lateral temporal lobe seizures.13,17,21 Finally, ictal tachycardia has been lateralized to the right hemisphere in several studies.17,22 This suggests that early and significant tachycardia was primarily associated with right mesial temporal lobe seizures.20

Ictal bradycardia A decrease in the heart rate is a lot less common and varied from 0-5% of seizures reported in several studies.14,16,17,20 There are mixed results to the localization and lateralization of ictal bradycardia. Most of the prior reports had shown a predilection of ictal bradycardia in left temporal lobe seizures.23–25 However, a recent study and other reports dispute this finding and suggest that there is usually bilateral involvement in seizures causing ictal bradycardia.24,26 The reason may be due to the fact that ictal bradycardia is relatively uncommon and the number of seizures with ictal bradycardia in all of the studies were small, which included several case reports. Ictal asystole The incidence of ictal asystole is extremely rare,27,28 though it may be higher than previously estimated especially in focal intractable epilepsy.29–31 It has been implicated as one of the causes of SUDEP. There are several anecdotal case reports of ictal asystole following ictal bradycardia in left hemispheric seizures, mainly left temporal and frontal lobe seizures.28,32–35 Single cases of ictal asystole in seizures arising from the left cingulate gyrus36 and right frontal lobe37have also been reported. Ictal arrhythmia High-risk or fatal cardiac arrhythmias during epileptic seizures are thought to be uncommon,38,39 however the incidence of ictal arrhythmias appears to be more common in intractable and generalized seizures.40 Various cardiac arrhythmias that have been reported during epileptic seizures include atrial fibrillation (AF), supraventricular tachycardia (SVT), premature ventricular contraction (PVC), premature atrial contraction (PAC), bundle branch block (BBB), ST depression and T-wave inversion.39,40 None of these ictal cardiac arrhythmias seem to have any localizing or lateralizing value.

Respiratory manifestations Respiratory manifestations are not as common as cardiac manifestations but is probably the second most common manifestation of autonomic seizures. Most of the studies have been done in pediatric patients as they appear to be more common in children Ictal hyperventilation Ictal hyperventilation, defined as a 10% increase in the respiratory rate from the pre-ictal baseline, was seen in 56% of focal seizures recorded from 37 children.41 In another study, hyperventilation was seen in 18% of children with autonomic seizures and was more common in temporal lobe epilepsy compared to extra temporal lobe epilepsy, but this was not statistically significant.42 A study in adults found hyperventilation in both temporal and frontal lobe epilepsies, but occurred more in mesial compared to lateral temporal lobe epilepsy.43

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Autonomic seizures: localizing and lateralizing value Ictal apnea Ictal apnea is most commonly reported in neonates and infants, typically lasting 1–2 minutes.44–51 It was seen in 20% of children,42 58% of adults52 and 30% of focal epilepsies.41 When localized, it was mostly seen in temporal lobe epilepsies,44–48,51,53 with cases lateralizing to both the left53 and right47,51 temporal regions. Ictal dyspnea and stridor This is not a well defined entity in the available literature. It was seen in 15% of children and two-third were associated with the tonic phase of epileptic seizures.42 A case report describes stereotypical episodes of dyspnea over 4 months which turned out to be due to a right mesial temporal lobe epilepsy.54 Postictal nose wiping/postictal coughing These two manifestations are thought to be due to same mechanism, which is increased parasympathetic activity, resulting in increased nasal and/or pharyngeal secretions, which then cause the patient either to wipe the nose or induce coughing. These reflexive maneuvers are usually seen postictally because during the ictus, both reflexive maneuvers are inhibited. Postictal coughing is most commonly seen in temporal lobe epilepsies, but has not been consistently lateralized to either the right or left hemisphere.42,55,56 However, the hand used in postictal nose wiping seems to lateralize and or localize to the ipsilateral temporal lobe.57–60

Gastrointestinal manifestations Gastrointestinal manifestations are the earliest autonomic symptoms to be described and studied. These symptoms generally have good lateralizing and localizing value except for ictal defecation because it is relatively rare and probably under reported. Abdominal epilepsy has been included here, even though it actually constitutes several different autonomic symptoms, but they are primarily gastrointestinal manifestations. Epigastric aura Epigastric aura is the earliest autonomic manifestation to be described61and the most commonly reported aura,62 it has significant localizing value, arising from the mesial temporal lobe structures and the insula primarily.63,64 In terms of lateralizing value, some authors claim that it is more common in nondominant hemispheric epilepsy,65,66 but it has not been confirmed by others.67–69 Abdominal epilepsy Abdominal epilepsy is the earliest autonomic seizure to be described, and was previously called visceral seizures.9,70 It is more common in children71,72 than adults.73,74 It is characterized by recurrent paroxysmal abdominal pain, usually associated with nausea, vomiting, lethargy and confusion.75–78 Abdominal epilepsy has not been consistently lateralized73 but has been localized to the temporal lobe in several reports.42,79–82 Most patients reported as abdominal epilepsy had paroxysmal

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autonomic symptoms but no objective proof that these symptoms actually were an expression of epileptic seizures. Ictal vomiting (Ictus emeticus) In contrast to abdominal epilepsy, in which vomiting usually accompanies the abdominal pain and the patient is aware of it, vomiting in ictus emeticus occurs as the sole manifestation83,84 or may be associated with other symptomatology of temporal lobe seizures, but the patient is usually amnesic of the vomiting.85–87 Ictal vomiting is a relatively rare manifestation of temporal lobe seizures in adults.84,88 It has been postulated to arise mostly from the non-dominant temporal lobe70,86–90 however there have been several reports of ictal vomiting with dominant temporal lobe epilepsy.42,91–95 On the other hand, ictal vomiting is the predominant manifestation of the early onset benign childhood occipital lobe epilepsy, which affects 13% of children aged 3-6 years.96–101 Ictal vomiting is also seen in extraoccipital benign childhood epilepsies and carries the same prognosis.102,103 Ictal vomiting is thought to occur when the epileptic discharges involve the medial and lateral aspects of the temporal lobe and the adjacent insular cortex.85–87,104,105 Even in extra-temporal lobe epilepsies, it has been shown that ictal vomiting occurs when the ictal discharge spreads to the temporal lobe from the extratemporal focus, which in most cases is the occipital lobe.104,106 Ictal spitting (Ictus exporatus) Ictal spitting is a rare manifestation of epileptic seizures, with an incidence of 0.2 to 2.2% of patients in epilepsy monitoring units.107–109 It has been lateralized and localized to the nondominant temporal lobe in most of the studies,42,108–112 but has been reported in dominant temporal lobe in a couple of studies.107,113 Ictal spitting is also thought to arise from the insular cortex.109 Ictal defecation Ictal defecation is the urge to defecate, associated with the onset of a focal seizure, which has been reported anecdotally by several authors.64,70,114,115 A.L. Reeves mentioned several cases in a review article, of patients with the urge to defecate at the onset of a seizure. A recent case report describes a 47 year old right handed woman with the urge to defecate at the onset of a seizure and the EEG was lateralized to the right hemisphere during the seizure.116

Cutaneous manifestations Cutaneous manifestations are rare autonomic expressions of focal epilepsy, that were first described by Penfield,114 Mulder70, Daly115 and Van Buren.64,64,64 They usually occur in conjunction with one another, in addition to other common manifestations of focal epilepsy. Other cutaneous manifestations, which have been cited in the literature include sweating, cyanosis and purpura, but will not be covered here because there have been no reported localizing or lateralizing value to any of these manifestations and most of these studies were case-reports.

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Ictal piloerection (goose bumps) Ictal piloerection was identified in only 0.4% of 3500 patients undergoing video-EEG monitoring in a single epilepsy center over a 7 year period.117 It has been localized to the temporal lobe in the majority of the patients reported in the literature,117–119 including confirmation with cortical stimulation.117,120 The piloerection mostly tended to occur unilaterally and often had a ‘Jacksonian march’ and in most of the cases, it was ipsilateral to the onset of the focal epilepsy.117–119,121 The etiology was diverse, and included tumors,121,122 hippocampal sclerosis,120,121,123,124 limbic encephalitis,125 hyperosmolor non-ketotic hyperglycemia,126 post-traumatic127 and cryptogenic.118,124 However, it has not been consistently lateralized to either hemisphere and with several case reports of left118–120,124,128 and right122,123,127,129 hemispheric onsets. Ictal pallor The only comprehensive study of ictal pallor was a recent study in 100 children, in whom 11 were found to have ictal pallor. In this study 11 children had left temporal lobe epilepsy.130 This has not been replicated in adults with only a handful of reports and in most of these reports, ictal pallor was usually concomitantly associated with other cutaneous manifestation. Ictal flushing In contrast to ictal pallor, ictal flushing was observed in 19 out of 100 children undergoing video-EEG monitoring. Ictal flushing showed neither lateralizing nor localizing value. Flushing was mostly facial and happened not only during simple partial (motor) seizures but also during complex partial (temporal lobe) seizures, which suggests that flushing is due to both skin hyperperfusion during motor activities but also due to central autonomic involvement.42

Pupillary manifestations Pupillary manifestations are rare autonomic manifestations, with only a handful of case reports in the literature and hence have limited localizing and lateralizing value. Ictal mydriasis Bilateral mydriasis is a common concomitant of generalized convulsive seizures, both primary and secondarily generalized, most probably due to the diffuse spread of the epileptic discharges, thus activating widespread subcortical midline structures and the central sympathetic nervous system.1,4 Unilateral mydriasis is far less common and has been reported to be ipsilateral in focal occipito-temporal seizures131 and contralateral in a young boy with a ‘ benign left frontal epileptic focus’.132 Ictal miosis Bilateral miosis has been described in a case of generalized photosensitive epilepsy along with bilateral adduction as part

of a near reflex accommodation spasm.133 Bilateral miosis has also been described with bilateral internal ophthalmoplegia in a patient with left temporo-occipital epilepsy134 and without internal ophthalmoplegia in a 3-year-old girl with rightsided mesiotemporal ganglioglioma.42 Unilateral miosis associated with ptosis has been reported in two patients with temporal lobe epilepsy, with one case presumed to be ipsilateral and the other contralateral to the unilateral miosis.135 Left miosis associated with left homonymous hemianopia and visual hallucinations has also been reported in a patient with right occipital lobe epilepsy due to a small cavernous hemangioma.136

Urogenital manifestations Urine incontinence is the most common urogenital manifestation and is a common feature of generalized tonic-clonic seizures and usually occurs after the clonic jerking stops. It is not due to increased intravesicular pressure during the seizure, but rather depends on relaxation of the vesical sphincter during the phase of muscular recovery and occurs only if the bladder is full at the time of the attack. However, urine incontinence does not have any localizing or lateralizing value. Ictal urinary urge The aura of urinary urgency during seizures has been shown to be a lateralizing sign for non-dominant temporal lobe in two studies with a total of 12 adults undergoing video-EEG monitoring.137,138 A single case of ictal urinary urge associated with confusion, oral and genital automatism has been reported in a 6-year-old boy with a left temporal lobe seizure.139 Sexual/orgasmic aura Sexual auras refer to seizures that include erotic thoughts and feelings, sexual arousal, and orgasm. They may be accompanied by genital viscerosensory phenomena, vulvovaginal secretory activity, and olfactory hallucinations. Sexual auras are reported more frequently by women and may be associated more commonly with right temporal lobe epilepsy.140–142 Orgasmic auras, a subset of sexual auras, have been lateralized to the right hemisphere in the majority of the cases reported in the literature.143 In a case series of seven patients experiencing an orgasmic aura, six had right temporal lobe epilepsy confirmed by EEG, MRI, and ictal SPECT and the remaining patient who was left hemisphere dominant as confirmed by WADA, had left temporal lobe epilepsy.144 There are, however, also isolated reports of orgasmic auras with seizures from the left hemisphere, as determined by EEG.145 Genital aura Genital auras are characterized by unpleasant, sometimes painful, frightening, or emotionally neutral somatosensory sensations in the genitals and can be accompanied by ictal orgasm. Genital auras are localized to the parasagittal postcentral gyrus, where genital sensations are represented.

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Autonomic seizures: localizing and lateralizing value When these sensations are bilateral, then the secondary somatosensory area is also thought to be involved.145–147 Sexual automatisms Sexual automatisms, characterized by hypermotor movements consisting of writhing, thrusting, and rhythmic movements of the pelvis, arms, and legs, sometimes associated with picking and rhythmic manipulation of the groin or genitalia, exhibitionism, and masturbation, are localized to seizures from the frontal lobe. In addition, sexual automatisms were seen from different subcompartments of the frontal lobe, including the frontal convexity, the orbitofrontal region, and the supplementary sensorimotor area.148–151

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Genital automatisms Genital automatisms, characterized by discrete genital automatisms such as grabbing or fondling the genitals, which can be accompanied by masturbatory activity and exhibitionistic behavior, were generally associated with temporal lobe seizures, but could not be lateralized.141,142,152–154 Several recent studies in both adults and children have not shown any localizing or lateralizing value to genital automatisms. However, genital automatisms did localize to the temporal lobe when associated with ictal urinary urge or unilateral hand automatisms in adults. In children, the hand used for genital automatisms was more frequently ipsilateral to the seizure onset zone.155,156

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Masnou P, Gagnepain JP, Fouad A, Ducreux D, Adams D. Pilomotor seizures associated with sequential changes in magnetic resonance imaging. Epileptic Disord 2006;8(3):232–237. Seo DW, Lee HS, Hong SB, Hong SC, Lee EK. Pilomotor seizures in frontal lobe epilepsy: case report. Seizure. 2003;12(4):241–4. Fogarasi A, Janszky J, Tuxhorn I. Ictal pallor is associated with left temporal seizure onset zone in children. Epilepsy Res 2005;67(3):117–21. Masjuan J, Garcia-Segovia J, Baron M, Alvarez-Cermeno JC. Ipsilateral mydriasis in focal occipitotemporal seizures. J Neurol Neurosurg Psychiatry 1997;63(6):810–11. Gadoth N, Margalith D, Bechar M. Unilateral pupillary dilatation during focal seizures. J Neurol 1981;225(3):227–30. Shahar E, Andraus J. Near reflex accommodation spasm: unusual presentation of generalized photosensitive epilepsy. J Clin Neurosci 2002;9(5):605–7. Rosenberg ML, Jabbari B. Miosis and internal ophthalmoplegia as a manifestation of partial seizures. Neurology 1991;41(5):737–9. Afifi AK, Corbett JJ, Thompson HS, Wells KK. Seizure-induced miosis and ptosis: association with temporal lobe magnetic resonance imaging abnormalities. J Child Neurol 1990;5(2):142–6. Lance JW, Smee RI. Partial seizures with visual disturbance treated by radiotherapy of cavernous hemangioma. Ann Neurol 1989;26(6):782–5. Loddenkemper T, Foldvary N, Raja S, Neme S, Luders HO. Ictal urinary urge: further evidence for lateralization to the nondominant hemisphere. Epilepsia 2003;44(1):124–6. Baumgartner C, Groppel G, Leutmezer F et al. Ictal urinary urge indicates seizure onset in the nondominant temporal lobe. Neurology 2000;55(3):432–4. Inthaler S, Donati F, Pavlincova E, Vassella F, Staldemann C. Partial complex epileptic seizures with ictal urogenital manifestation in a child. Eur Neurol 1991;31(4):212–15. Remillard GM, Andermann F, Testa GF et al. Sexual ictal manifestations predominate in women with temporal lobe epilepsy: a finding suggesting sexual dimorphism in the human brain. Neurology 1983;33(3):323–30. Currier RD, Little SC, Suess JF, Andy OJ. Sexual seizures. Arch Neurol 1971;25(3):260–4. Freemon FR, Nevis AH. Temporal lobe sexual seizures. Neurology. 1969;19(1):87–90. Janszky J, Szucs A, Halasz P et al. Orgasmic aura originates from the right hemisphere. Neurology 2002;58(2):302–4. Janszky J, Ebner A, Szupera Z et al. Orgasmic aura – a report of seven cases. Seizure 2004;13(6):441–4. Calleja J, Carpizo R, Berciano J. Orgasmic epilepsy. Epilepsia 1988; 29(5):635–9. Ruff RL. Orgasmic epilepsy. Neurology 1980;30(11):1252. York GK, Gabor AJ, Dreyfus PM. Paroxysmal genital pain: an unusual manifestation of epilepsy. Neurology 1979; 29(4):516–19. Spencer SS, Spencer DD, Williamson PD, Mattson RH. Sexual automatisms in complex partial seizures. Neurology 1983;33(5):527–33. Williamson PD, Spencer DD, Spencer SS, Novelly RA, Mattson RH. Complex partial seizures of frontal lobe origin. Ann Neurol 1985;18(4):497–504. Bancaud J, Talairach J. Clinical semiology of frontal lobe seizures. Adv Neurol 1992;57:3–58. Jobst BC, Siegel AM, Thadani VM et al. Intractable seizures of frontal lobe origin: Clinical characteristics, localizing signs, and results of surgery. Epilepsia 2000;41(9):1139–52. Hooshmand H, Brawley BW. Temporal lobe seizures and exhibitionism. Neurology 1969;19(11):1119–24. Mascia A, Di Gennaro G, Esposito V et al. Genital and sexual manifestations in drug-resistant partial epilepsy. Seizure 2005;14(2):133–8. Leutmezer F, Serles W, Bacher J et al. Genital automatisms in complex partial seizures. Neurology 1999;52(6):1188–91. Dobesberger J, Walser G, Unterberger I et al. Genital automatisms: a video-EEG study in patients with medically refractory seizures. Epilepsia 2004;45(7):777–80. Fogarasi A, Tuxhorn I, Tegzes A, Janszky J. Genital automatisms in childhood partial seizures. Epilepsy Res 2005;65(3):179–84.

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Simple motor seizures: localizing and lateralizing value S Noachtar and S Arnold

Definition of simple motor seizures

Myoclonic seizures

Simple motor seizures are characterized by unnatural, relatively simple movements that can be reproduced by electrical stimulation of the primary and supplementary sensorimotor areas.1 Simple motor seizures can be divided into the following subtypes depending on the duration of the muscle contraction, the rhythmicity of movement repetition, and the muscles involved: myoclonic seizures (negative myoclonic seizure), clonic seizures, tonic seizures, epileptic spasms, versive seizures, and tonic-clonic seizures.1–3 In contrast to simple motor seizures, during complex motor seizures the patients perform movements that imitate natural movements, are relatively complex, and tend to involve different body segments moving in different planes. These movements have also been labeled automatisms. If a given seizure cannot be classified into the following categories based on the available information the term simple motor seizure is recommended.1–3

Myoclonic seizures consist of sudden muscle jerks of short duration (less than 400 ms), which do not recur in a rhythmical fashion. They can be either bilateral (generalized) or unilateral (Figure 51.1–51.2). Generalized myoclonic seizures, which predominantly affect the shoulders and proximal arms, are typical for patients with juvenile myoclonic epilepsy4 and have already been recognized in the mid-19th century.5 Generalized myoclonic seizures are also frequently seen in patients with Lennox-Gastaut syndrome6 and the rare MERRF syndrome (myopathy, encephalopathy, ragged red fibers) (Figure 51.1) or Unverricht-Lundborg-syndrome. Electroencephalographically, generalized myoclonic seizures are frequently associated with generalized polyspikes that have a fronto-central maximum. Bilateral myoclonic seizures are rarely observed in patients with focal epilepsies (Figure 51.2). The primary motor cortex or premotor areas are most likely involved in the generation of this seizure type.

Bilateral Myoclonic Seizure Fp2–A2 F8–A2 T4–A2 T6–A2 Fp1–A1 F7–A1 T3–A1 T5–A1 F4–A2 C4–A2 P4–A2 O2–A2 F3–A1 C3–A1 P3–A1 O1–A1 Fz–A2 Cz–A1 EMG1 EMG2 EKG

Figure 51.1. The generalized polyspikes in this 28-year old patient with MERFF syndrome are consistently associated with generalized myoclonic jerks of the trunk and proximal limbs, whereas single spikes, spike-wave complexes and less dense polyspikes were not. Longitudinal bipolar montage including EMG of both legs (EMG1=left anterior tibial muscle; EMG2= right anterior tibial muscle).

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Bilateral Myoclonic Seizure fc2–P8 c2–P8 cp2–P8 Fz–P8 fcz–P8 Cz–P8 cpz–P8 Pz–P8 f1–P8 fc1–P8 c1–P8 cp1–P8 F3–P8 fc3–P8 C3–P8 cp3–P8 F7–P8 T7–P8 fc5–P8 c5–P8 cp5–P8 P3–P8 F4–P8 C4–P8 ali bli are bre

R

L

100 µV 1 sec

Figure 51.2. This 53-year-old patient has myoclonic seizures of both legs with a right zentral perinatal lesion. EEG is referenced to the electrode P8. ali= left brachioradial muscle EMG; bli=left anterior tibial muscle EMG; are=right brachioradial muscle EMG; bre=right anterior tibial muscle EMG.

Unilateral myoclonic seizures are very rare and occur contralateral or predominantly contralateral to the epileptogenic zone. Figure 51.2 shows the rare occasion that left central polyspikes in the EEG were consistently associated with myoclonic jerks of the both legs in a patient with a left central perinatal lesion. Some patients with juvenile myoclonic epilepsy report unilateral myoclonic jerks although video recording usually establishes the bilateral character of the myoclonic jerks. These patients typically favor the dominant arm.7

Negative myoclonic seizures Negative myoclonus is a rare epileptic seizure type which is characterized by brief periods (20–400 ms) muscle atonia (Figure 51.3).8 Negative myoclonus occurs only if muscle activity is exerted and the sujdden muscle atonia leads to the drop of the limb. Polygraphic recordings are helpful to document muscle atonia in the EMG associated with negative myoclonic seizures and epileptiform discharges in the EEG

Right Arm Epileptic Negative Myoclonus M. abd. dig. I M. deltoideus F7–F3 F3–Fz Fz–F4 F4–F8 A1–T3 T3–C3 C3–Cz Cz–C4 C4–T4 T4–A2

1 sec

Figure 51.3. The transverse bipolar EEG montage shows that the left central sharp wave elicited a atonia of muscle activity in the right abductor digiti minimi and the right delta muscle, which documents an epileptic negative myoclonus. The MRI of this patient showed diffuse left hemisphere perinatal lesion and atrophy.

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and distinguish negative myoclonus from myoclonic seizures, which may be difficult visually (Figure 51.3). Negative epileptic myoclonus has been described in patients with frontal and paracentral epilepsies.9,10 Bilateral negative myoclonus also occurs in different encephalopathies.8 In unilateral negative myoclonus, the epileptogenic region is contralateral to the affected limb. The central primary somatosensory cortex is considered responsible for the generation of negative myoclonus but there is very little data available.11 The cortex in the postcentral gyrus has been shown to generate contralateral negative myoclonus.10

Clonic seizures Clonic seizures consist of repeated, short contractions of various muscle groups (agonists and antagonists) usually characterized by jerking or twitching movements recurring at a regular interval between 0.2 and 5 per second (Figure 51.4). The jerks seen with myoclonic and clonic seizures are the same except that myoclonic seizures consist of single jerks which repeat in an irregular fashion whereas with clonic seizures the jerks have a regular rate. In other words, clonic seizures consist of ‘myoclonic jerks’ recurring at a regular repetition rate. The movements may affect any part of the body. Generally they are an expression of epileptic activation of the primary motor or the premotor areas.12 Focal clonic seizures mostly affect the distal segments of the extremities, e.g., the hand or the face. Clonic activity may show a ‘march’ from the distal to the proximal parts of the extremities, reflecting the spreading activation of the primary motor cortex. Electrical stimulation of the supplementary sensorimotor area can elicit distal clonic movements, but only very rarely.13 Typically clonic seizures start with a tonic phase, which frequently is not clinically

detected unless polygraphic recordings reveal that the frequency of muscle contraction is higher in the beginning of the seizure and gets gradually slower, thus leading to recognizable clonic jerks.14 Unilateral clonic seizures typically involve the face or hand area and less frequently the leg or trunk15–17. Clonic seizures were first systematically described in 1827 by Bravais18 who distinguished facial, brachial, and crural onset clonic seizures and described the typical unilateral march of the convulsion which was later associated with Hughlings Jackson’s name. In a large series of 8938 epileptic patients clonic seizures have been found to be rare occurring in only 2.2% of the patients.19 However, clonic seizures were relatively frequent in those 127 patients who had somatosensory auras. One third (34.3%) of these patients had clonic seizures.19 Of 52 patients reported by Hallen in 1952, clonic seizures started in the hand in 16, in the face in 14, in the foot in ten, in the shoulder in four, in the leg in four, in the head in two, in the thorax in one and in the neck in another patient. The seizures types preceding and following clonic seizures are very variable. We analyzed all patients in whom clonic seizures were recorded at the Epilepsy Monitoring Units of the Bethel Epilepsy Center from 1991–1994 and the University of Munich Epilepsy Program from 1994–1995. We identified 127 patients with clonic seizures occurring in 162 different seizure evolutions from the data bases (Figure 51.5). Thus, some patients had more than one seizure evolution. Clonic seizures were the initial seizures in 33 patients. In the remaining 129 seizure sequences usually automotor (n=45) and tonic (n=45) seizures preceded the clonic seizures. The different seizure types preceding clonic seizures are listed in Figure 51.5. The clonic seizures evolved typically into generalized tonic-clonic seizures (n=58) and less frequently into other seizure types such as tonic or versive seizures (Figure 51.5). No following seizure types were observed in 42 patients.

Right shoulder clonic seizure fcz–poz cz–poz cpz–poz Pz–poz fcI–poz CI–poz cpI–poz fc2–poz c2–poz cp2–poz R

EMG–RSH

L

70 µV 1 sec

Figure 51.4. This 14-year-old boy had clonic seizures of the right shoulder secondary to a low-grade glioma, which were consistently associated with left central spikes in the surface EEG. Selection of ten EEG channels in a referential montage to the electrode POZ. EMG-RSH=EMG of the left delta muscle.

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Simple motor seizures: localizing and lateralizing value Seizure Evolutions 127 Patients with Focal Clonic Seizures Preceding seizure types

Following seizure types

automotor sz. (45) tonic sz. (45)

gen.tonic-clonic sz. (58

no preceding sz. (33) versive sz. (11) som.sens. aura(9)

no following sz. (42)

other aura(8) hypermotor sz. (4) hypomotor sz. (3) myoclonic sz. (3)

tonic sz. (9) Clonic seizure 162

versive sz. (9) automotor sz. (5) gen.clonicsz. (4) hypermotor sz. (2)

atonic sz. (1)

Figure 51.5. Seizure types preceding and following clonic seizures in 162 seizure evolutions of 127 patients who underwent EEG-video monitoring. Clonic seizures were the initial seizure manifestation in 33 seizure evolutions. The frequency of preceding and following seizure types are given in parenthesis. Clonic seizures were preceded by other seizure types in 129 seizure evolutions.

Clonic seizures may represent the initial seizure symptomatology but may be preceded by other seizure types such as auras, automotor or tonic seizures (Figure 51.5). Clonic seizures can evolve into other seizure types most commonly into generalized tonic clonic seizures (Figure 51.5–6). Unilateral clonic seizures are present in several focal epilepsies. In patients with frontal lobe epilepsy, clonic seizures tend to occur early in the seizure evolution and the patient is usually conscious at the time the clonic activity begins (Figure 51.6).12,20 When clonic seizures are the result of spread of epileptiform activity into the frontal lobe from the occipital or temporal lobe, consciousness is usually altered at the onset of unilateral clonic seizures. Generalized clonic seizures only very rarely occur with preserved consciousness.21

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Fincher and Dowman22 reported on a series of 130 patients with ‘Jacksonian’ seizures. Eighty-four patients had ‘purely motor’ seizures. In 20 patients somatosensory auras were followed by motor seizures and in nine patients motor features immediately preceded sensory ‘attacks’. In 17 instances there were sensory and motor ‘attacks’ occurring simultaneously. The authors mention two patients, in whom generalized jerkings were not associated with loss of consciousness. Consciousness is usually preserved if unilateral clonic activity is the initial seizure manifestation. If an automotor seizure precedes a clonic seizure, which we observed only in temporal lobe epilepsy and not in frontal lobe epilepsy consciousness will typically be disturbed during the clonic seizure.23 A series of ‘pure’ frontal lobe epilepsies of the Montreal Neurological Institute showed focal ‘sensorimotor seizures’ in 27% of the patients.24 Automotor seizures were as common in this series (30%). Geier et al.25 found ‘clonic and/or tonic seizures’ which were not further specified in 77.3% of 22 patients with frontal lobe epilepsies. Disturbance of consciousness (100%), deviation of head and eyes (86.4%), vocalisation (86.4%), and falling (81.8%) were more common in this study than clonic seizures. In a recent study of 252 patients with focal epilepsies 14 patients had clonic seizures.20 In the 14 patients with clonic seizures a structural lesion could be demonstrated in the primary motor cortex in seven patients, in the premotor region in one patient and in the parietal cortex in another patient. Clonic seizures occurred both in temporal and frontal lobe epilepsies but the seizure evolution was different: if the clonic seizures occurred early in the seizure evolution there was a significant association with frontal lobe epilepsy.20 In a series of 40 patients with frontal lobe epilepsies who underwent selective epilepsy surgery of the parasagittal convexity of the frontal lobes (PSC) or anterolaterodorsal convexity (ALDC) and remained seizure free, seizure onset in the PSC (eight of ten patients) was more frequently associated

Clonic Seizures in Frontal Lobe Epilepsies Preceding seizure types

Following seizure types

no preceding sz. type (6) 6 aura (3) 1 2 no aura (10)10 abdominal aura (1) 1

focal tonic sz. (14)

somato– sensory 1 aura (2) dialeptic 1 sz. (4)

1

hypermotor seizure (1)

4 7 2 1 1 1

no following sz. type (8) focal clonic sz. head (6)

3

arm (9)

4

arm & leg (3)

1

1

gen. ton.–clon. sz. (9)

leg (2) non– spec. (2)

versive seizure (1)

8

1 1 gen. clon. sz. (2)

Figure 51.6. Seizure types preceding and following clonic seizures as documented by EEG-video monitoring in 19 patients with frontal lobe epilepsies. Clonic seizures were the initial seizure manifestation in seven seizure evolutions. Focal clonic seizures evolved further either into generalized tonic-clonic or generalized clonic seizures.

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with focal motor seizures than seizure onset in the ALDC (15 of 30 patients).26 In a later report of the same group 29% to 60% of the patients with ‘dorsolateral frontal lobe epilepsies’ had clonic seizures.27 The authors concluded that clonic seizures occur in patients with epilepsy of different frontal compartments and are not a reliable indicator of seizure onset location.27 A neuroimaging study using FDG-PET in patients with probable frontal lobe epilepsy reported clonic seizures in nine of 22 patients. In six patients clonic activity was the initial seizure symptom. Precentral seizure onset was assumed in three, premotor onset also in three, and mesial onset in another three patients.28 A study of ten patients with medial frontal or orbitofrontal seizure onset did not describe clonic seizures.29 These patients had seizures characterized by complex motor automatisms with kicking and trashing movements and a bizarre appearance frequently leading to erroneous diagnosis of non-epileptic psychogenic seizures. Data about seizure evolution of focal clonic seizures is sparse. Thirty percent of 24 patients with frontal lobe epilepsy have been described to have clonic seizures.30 In three of these patients the clonic seizures were preceded by conscious contralateral version. The clonic seizures were followed by tonic seizures consisting of tonic posturing of all extremities in three patients. Harvey et al.31 reported clinical seizures characteristics in 22 children with frontal lobe epilepsies who underwent ictal SPECT studies. Ten children had clonic seizures. Seizure evolution commenced most frequently with behavioral arrest (n=13) or auras (n=6) which evolved into tonic seizures (n=11), hypermotor (n=6), or automotor seizures (n=2). The clonic seizures were preceded by tonic seizures in seven patients, by an aura in one patient, by behavioral arrest in one patient, and by an automotor seizure in another patient. Only one patient had clonic seizures as the inital seizure manifestation. In one child the clonic seizures further evolved into generalized tonic-clonic seizures. We identified 19 patients of the above mentioned series of 129 patients with clonic seizures who had a frontal lobe epilepsy. The seizure evolutions in these cases are shown in Figure 51.6. Only in six patients the seizures started with clonic activity. More commonly, the clonic seizures were preceded by one or two other seizure types such as auras and tonic seizures. In conclusion, the occurrence and frequency of clonic seizures in frontal lobe epilepsy varies considerably between studies. It seems that the occurrence of clonic seizures depends on different locations of seizure onset in the frontal lobe and individually different seizure spread patterns. In our series, tonic seizures typically preceded clonic seizures and only a minority of the patients had clonic seizures as the initial seizure type. In temporal lobe epilepsy, complex motor activity like oral automatisms was seen most frequently (10%) whereas simple motor activity like facial and brachial twitching without Jacksonian march occurred ‘less commonly’ (4%).32 Another study only mentions automatisms as the ictal symptomatology of seizures in patients with temporal lobe epilepsies.33 In a cluster analysis of 59 patients of ‘primary psychomotor epilepsy’ unilateral and bilateral tonic, clonic, and versive activity was described.34 Most commonly the face area was involved unilaterally (about 30–50% of the seizures), followed by the hand (20%) and the leg (7%). In this report tonic, clonic, and versive seizures were all lumped together.34

A recent study of seizures in 31 patients with temporal lobe epilepsy who underwent epilepsy surgery and were seizure free reported unilateral clonic activity in the face in eight and in the arm in three patients.35 Bilateral clonic activity of the arms was observed in 14 patients and of the legs in one patient.35 These findings are in agreement with the study of Abou-Khalil et al.36 who observed focal clonic activity in eight of their 32 patients with unilateral temporal lobe epilepsies documented by EEG-video recordings. In three of these patients the clonic activity was concomitant with head turning to one side. However, the study did not distinguish between head turning that looks like a normal movement and the forceful ‘version’ frequently associated with unilateral clonic movements which is almost pathognomonic of regional contralateral epilepsy.37 The study of Manford et al.20 reported on clonic movements in 17 of 58 ‘temporal seizures’ in 42 patients with temporal lobe lesions. Clonic movements were observed more frequently in patients with frontal lobe lesions (35 of 61 seizures of 49 patients). However, clonic movements are only suggestive of frontal lobe epilepsy when they occur early in the evolution of a seizure.20 We evaluated the seizure sequences in our series of 24 patients with temporal lobe epilepsies who demonstrated clonic seizures during EEG-video recordings (Figure 51.7). All 24 patients had automotor seizure preceding the clonic seizures and in no case did the clonic seizures involve primarily the leg. In three patients, automotor seizures first evolved into versive seizures and then eventually into clonic seizures. All patients had generalized tonic-clonic seizures following the clonic seizures. We recently found statistically significant differences in the seizure evolutions of mesial and neocortical temporal lobe epilepsy.38 Abdominal auras and contralateral dystonic posturing were more frequent in patients with mesial temporal lobe epilepsy whereas early clonic seizures occurred more frequently in patients with neocortical temporal lobe epilepsy. This might reflect different cortical spread of seizure activity.38 In conclusion, clonic seizures are usually preceded by automotor and followed by generalized tonic-clonic seizures in temporal lobe epilepsy. Thus, the seizure sequences of clonic seizures in temporal lobe epilepsy is clearly different from the seizure sequences in frontal lobe epilepsy (Figure 51.6–7). It is well known that tumors in the paracentral (perirolandic) region are frequently associated with epilepsy.39 Most studies about focal epilepsy syndromes distinguish frontal and parietal lobe epilepsies. However, in a considerable number of patients the seizure anatomically involves both, the frontal and the parietal lobe. The observation that seizures arising from the frontal and parietal lobes outside the perirolandic region behave differently both, clinically and pathophysiologically to seizures arising from the perirolandic (paracentral) region has been recognized for decades and is reflected in the studies of the Montreal school.30, 40 About one third (34.3%) of 127 patients who had somatosensory auras had also had clonic seizures.19 Fifty percent of the lesions of these patients were located in the contralateral central region.19 In a series of 28 patients in whom extratemporal seizure onset had been documented by means of invasive EEG recordings, nine patients had clonic seizures and two of them had epilepsia partialis continua.41 The seizure onset

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Clonic Seizures in Temporal Lobe Epilepsy preceding seizure types

abdominal aura (15)

following seizure types

no preceding sz. type (0)

psychic aura (3) no aura (1) abdominal & psychic aura (2)

clonic sz. automotor 11 4 seizure sz. 5 1 3

other aura (2) visual autonomic psychic aura (1)

no following sz. type (0)

face 11

11

face & arm 5

5

arm 7 lateralized 1

versive 1 sz. 2

gen. ton.–clon. sz. (24)

7 1

Figure 51.7. Seizure types preceding and following clonic seizures as documented by EEG-video monitoring in 24 patients with temporal lobe epilepsies. All clonic seizures of this series were preceded by other seizure types. Most commonly clonic seizures involved the face and were preceded by automotor seizures. All patients showed an evolution to generalized tonic-clonic seizures.

was perirolandic in six of these nine cases and six patients had auras preceding the clonic seizures. Of 34 patients with parietal lobe tumors who underwent surgical resection at the Montreal Neurological Institute between 1934 and 1988, 82% had focal clonic activity in the course of their seizures.42 In a greater series of 82 patients with parietal lobe epilepsy of the same institution 57% had clonic seizures.40 However, as mentioned above, in the MNI series parietal lobe epilepsy usually refers to the parietal lobe posterior to the postcentral sulcus and does not include the postcentral gyrus.40 In another series, clonic seizures occurred in three of ten patients with lesions in the parietal lobe (including the postcentral gyrus).43 One patient had ‘focal motor seizures’ which were preceded by a somatosensory aura of the right hand. In two patients somatosensory auras preceded the clonic seizures, in one patient clonic seizures were the initial seizure manifestation. In another study of 11 patients with parietal lesions most probably also involving the postcentral gyrus, clonic seizures were reported in 4 patients.44 Somatosensory auras were present in 7 patients of this series. In a recent report of 11 patients with seizures involving the supplementary sensorimotor area, all patients showed clonic movements present in one or more extremities following tonic posturing which usually lasted 10–30 seconds.45 The clonic movements and the tonic posturing are usually bilateral, but unilateral clonic activity is an excellent lateralizing sign.26,46 Seizures involving the supplementary sensorimotor area are typically either tonic or less frequently hypermotor seizures,23 e.g., consisting of bizarre and violent movements predominantly of the trunk and the proximal extremities.45,47–49 Tonic and clonic seizures have been described in patients with occipital lobe epilepsy.50,51 The initial seizure symptomatology most frequently includes visual auras and other signs such as eye blinking or eye deviation. Spread to the frontal lobes is usually associated with tonic and/or clonic activity. This has been reported in three of 25 patients as the only spread pattern. In another 11 patients of this series, a combination of

‘frontal’ and ‘temporal lobe type’ seizure was observed.51 However, no data were available in this study regarding the exact seizure semiology and frequency of tonic or clonic seizures.51 In another study of eight patients in whom occipitotemporal seizure onset was documented by invasive EEG studies, no patient had clonic seizures of the extremities.52 One patient had jerking eye movements to the right. In the series of 42 patients with occipital lobe epilepsies of the MNI treated between 1930 and 1991, 13 patients had unilateral clonic seizures of the arm or face.50 In ten patients versive head and/or eye deviation preceded the clonic seizures.50 The detailed evolution of the clonic seizures is not mentioned. Since the early reports it has been recognized that children with benign focal epilepsy of childhood frequently have clonic seizures.53 Characteristic seizures consist of tonic, tonic-clonic, or clonic seizures involving the face area. Usually this is preceded by an unilateral somatosensory aura of the face.54 Spreading of the clonic activity to the ipsilateral hand or arm (‘Jacksonian march’) occurs only infrequently. Usually the seizures occur during sleep and evolve into generalized tonic-clonic seizures. In these cases a focal seizure onset may be overlooked. Rasmussen’s encephalitis almost invariably is associated with clonic status which usually is restricted to the arm and less frequently to the face and leg of one side.55 Clonic status usually occurs with the progression of this syndrome which typically includes hemiparesis of the affected limbs (Figure 51.8). Generalized clonic seizures are frequently seen following generalized tonic seizures in grand mal epilepsy. This type of seizures (generalized tonic-clonic seizures) will be discussed in detail in another chapter. Isolated generalized clonic seizures are rare in adults but may, for instance, occur in patients with progressive myoclonic epilepsies.7 These patients typically have generalized myoclonic seizures which are not as repetitive and rhythmic as clonic seizures. In newborns, generalized clonic seizures are more frequently observed but may still have a focal seizure onset in the EEG.56 We identified two patients who had generalized clonic seizures in our series of frontal

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Textbook of epilepsy surgery Left leg clonic status

A1–T7 T7–C3 C3–CZ CZ–C4 C4–T8 T8–A2 P7–P3 P3–PZ PZ–P4 P4–P8 EMG L M.TIB. ANT.

50 µV 1 sec

Figure 51.8. Sixty-nine-year old man with continual jerking of the left foot and leg for several weeks, without loss of consciousness. Electromyography from the left anterior tibial muscle showed that jerks occurred synchronously with each burst of polyspikes on EEG. Polyspikes were maximum at left vertex electrodes, presumably as a result of paradoxical lateralization of the discharge from the right interhemispheric region.

lobe epilepsies. Both patients had focal tonic seizures preceding the generalized clonic seizures. Jackson’s clinico-pathological observations showed that motor seizures are associated with lesions of the motor cortex.57 Electrical stimulation of the primary motor area (Brodmann’s area 4) or the premotor areas (area 6) can elicit clonic movements.58–60 It is therefore reasonable to conclude that clonic seizures are an expression of epileptic activation of the motor cortex. Electrical stimulation of the supplementary sensorimotor area can elicit clonic movements, but this occurs only very rarely and typically not at seizure onset but later in the seizure evolution.13,62 The fact that the hand and face area are most commonly involved in clonic seizures is usually attributed to the large cortical representation of these parts of the body. In contrast, the rare occurrence of clonic seizures limited to the trunk reflects its small cortical representation.17 Spread of clonic seizures may reflect the cortical representation of the body in the motor cortex. It has been speculated that the variability of the observed spread patterns may reflect interindividual variability of the cortical representation.15 It is important to remember also that clonic seizures can only be elicited when the epileptic discharge is strong enough to produce suprathreshold activation of a given region of motor cortex. Experimental studies have shown that different regions of the motor cortex have also different thresholds to electrical stimulation.63 It is important to point out that high-frequency electrical stimulation (50–60 Hz) of the primary motor area in wake humans ictally causes tonic contractions, which evolve into clonic twitching of the affected muscles at a frequency of ca. 1–2 Hz.14 The epileptic clonus consists of simultaneous contractions of agonistic and antagonistic muscles at regular intervals and is separated by periods of complete muscle relaxation. Epileptic clonic muscle contractions are generated by localized polyspike-wave activity in cortical primary motor areas. The periods of muscle relaxation occur during the EEG slow waves. The study of Hamer et al.14 suggests that focal

clonic seizures are focal tonic-clonic seizures. It is known that single or short series of electrical stimuli only elicit muscle responses if relatively high intensities are used.60,64 Temporal and spatial summation of the stimuli were needed for clonus generation.65 This principle is illustrated in the patient with the left calf clonic status shown in Figure 51.8. This explains why single spikes or slow, repetitive spikes frequently do not elicit muscle twitching, whereas polyspikes or runs of paroxysmal fast activity are usually associated with muscle responses. Most probably temporal facilitation elicited by repetitive stimulation is necessary to exceed the threshold of the motor cortex. Jerking of the left calf was always accompanied by polyspikes in the EEG (Figure 51.8), whose potential field extended from the vertex to the left central region. Conversely, individual spikes that did not correlate with jerking of the foot had a slightly different potential field extending to the right centroparietal area. The polyspikes in this case have a maximum ipsilateral to the affected leg. This is an example of paradoxical lateralization.66–68 The EEG of generalized clonic seizures shows generalized epileptiform discharges. There is typically a 1:1 relationship between muscle twitch and epileptic discharge, and the background activity between the discharges is generally suppressed. Generalized fast activity usually leads to tonic ‘posturing seizures’ and only exceptionally to clonic movements. Generalized clonic seizures are assumed to be the result of intermittent generalized epileptic activation of the motor region of the cortex (Brodman areas 4 and 6). We have also observed cases in which epileptic seizures originating in the supplementary sensorimotor area led to bilateral clonic movements of the upper extremities without any clouding of consciousness. In these cases no generalized spike-and-wave discharges occurred. It is quite probable that the generalized clonic seizures in these cases are caused by restricted activation of one or both of the supplementary sensorimotor areas.

Tonic seizures Tonic seizures consist of a sustained contraction of one or more muscle groups usually lasting at least 3 sec leading to posturing of the limbs or whole body.3,23,69 Tonic seizures in patients with focal epilepsy preferentially affect proximal muscle groups on both sides of the body. However, they predominate most often in the contralateral body, leading to an asymmetric posture.70 In most patients with focal epilepsy, consciousness is unclouded, at least at the onset of such unilateral or asymmetric seizures.25,71,72 If clearly unilateral, tonic seizures have a high lateralizing significance, pointing to a contralateral seizure onset. Ictal EEG in frontal epilepsies shows a low-amplitude high-frequency pattern (‘recruitment pattern’) (Figure 51.9). Consciousness is disturbed from the beginning of generalized tonic seizures, which are common in patients with Lennox-Gastaut syndrome.6 Generalized tonic seizures usually last from 3–10 sec. The ictal EEG of generalized tonic seizures in patients with Lennox-Gastaut syndrome is similar to the ictal EEG in frontal lobe epilepsies showing a diffuse low-amplitude high-frequency recruiment pattern (Figure 51.9). Tonic seizures in focal epilepsies are more commonly bilateral (76%) than unilateral (24%).73 The majority of bilateral tonic seizures involve the whole body (both arms

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457

Bilateral asymmetric tonic seizure F7–F3 F3–Fz Fz–F4 F4–F8 A1–T7 T7–C3 C3–Cz Cz–C4 C4–T8 R

L

T8–A2 100 µV 1 sec

Figure 51.9. This transverse bipolar EEG montage of a 17-year old female with a low grade glioma in the medium frontal gyrus shows a typical EEG seizure pattern during a bilateral asymmetrical tonic seizure. After a high amplitude midline sharp wave the EEG shows low amplitude high frequency activity with a midline frontocentral maximum (recruitment pattern). The arrow marks the clinical seizure onset.

and legs and trunk).73 Unilateral tonic seizures affected most commonly one arm (56%) or one side of the body (20%).73 Tonic seizures occur most commonly in frontal lobe epilepsy (62.2%) and very rarely in temporal lobe epilepsy (1.7%). In the latter only unilateral tonic seizures occurred, whereas 32% of the tonic seizures in frontal lobe epilepsies were bilateral.73 Focal tonic seizures most probably originate in the cortical motor areas, i.e., the primary motor and the supplementary sensorimotor areas. However, the reticular formation of the brain stem and the thalamus were reported to be involved in the generation of tonic seizures in patients with LennoxGastaut syndrome.74 Phonatory seizures could be considered tonic seizures of the phonatory muscle system. They result from activation by the ictal discharge of the primary motor cortex or the SMA.75 Phonatory movements have been elicited on stimulation of the SMA or the primary motor cortex below the tongue or lip area. Vocalization in SMA seizures is more often sustained than interrupted, whereas seizures involving the primary motor area tend to produce interrupted sounds. Paroxysmal dystonia resulting from subcortical pathology such as brainstem dysfunction or multiple sclerosis has to be considered in the differentialdiagnosis of focal tonic seizures.

to flexion of the neck (and legs) and abduction of both arms. Less frequently myoclonic or tonic extension may lead to an opisthotonic posture. Epileptic spasms usually last 2–10 seconds and frequently occur in clusters. Short myoclonic contractions may mix with tonic contractions in one cluster. The ictal EEG of patients with West syndrome during epileptic spasms typically shows an attenuation of the background activity and depending on the resolution of the EEG system a low-amplitude high-frequency pattern (Figure 51.10). This seizure type is age specific and also occurs in focal epilepsies with different epileptogenic zones. Well established examples have been published like for instance an 11-month-old with epileptic spasms secondary to a right temporal hamartoma which was seizure free postoperatively.23 Consequently, Epileptic Spasm West–Syndrome Fp1–F3 F3–C3 C3–P3 P3–O1 FP2–F4 F4–C4 C4–P4

Epileptic spasms

P4–O2 FZ–CZ

Epileptic spasms typically occur between 3–12 months of age. They are a frequent seizure type in children with West syndrome and in this context have also been called ‘infantile spasms’.76 Epileptic spasms consist of relatively symmetric tonic and myoclonic features, which may vary in the same patient from one seizure to another. The muscle contractions predominantly affect the proximal and axial muscles and typically lead

CZ–PZ EKG

1 sec

100 µV

Figure 51.10. The epileptic spasm of this 8-month-old child with West syndrome is electroencephalographically associated with a diffuse attenuation of the hypsarrhythmia during the seizure.

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epileptic spasms do not allow localization. Children with epileptic spasms typically develop other seizure types after the age of 3–5 years77 as in the above-mentioned case, in whom at the age of 2 1/2 years mild automatisms occurred.23

Versive seizures Versive seizures consist of a sustained, unnatural turning of the eyes and head to one side.37 The version usually consists of a smooth, tonic lateral deviation of the eyes with, not infrequently, a clonic superimposed component. Often the angle of the mouth is also deviated to the same side and the neck is extended. These seizures are the expression of epileptic activation of the frontal eye field (inferior/medial frontal gyrus) that is contralateral to the side to which the eyes turn.60,78 Epileptic activation from the temporal lobe or other structures distant from the frontal eye fields may spread into the frontal eye field, giving rise to versive seizures.37 In temporal lobe epilepsy, version occurs when the patient has already lost consciousness and the version is frequently preceded by oral and maunal automatisms (automotor seizure). A study of patients with extratemporal and temporal epilepsies showed that version occurred earlier than 18 seconds in seizures with an extratemporal onset and later than 18 seconds in the vast majority of temporal lobe epilepsies,79 which reflects faster spread to the frontal eye fields from extratemporal particularly

frontal lobe regions than from the temporal lobes. Patients may be unconscious (n=16) or conscious (n=7) depending from which region of the cortex the seizures originated in 222 patients considered for epilepsy surgery at the Montreal Neurological Institute.80 The early 1980s witnessed a controversy surrounding the lateralizing value of versive seizures in temporal epilepsy.81,82 Then Wyllie et al. defined version as a forced, sustained, and unnatural movement. On the basis of this definition, versive seizures have a high lateralizing significance to seizure onset in the contralateral hemisphere, particularly when they occur immediately before a generalized tonic-clonic seizure.46 The mechanisms involved in the contralateral head version is not well understood considering that for a version of the head to the contralateral side the ipsilateral sternocleidomastoid muscle needs to be activated.83 Quantitative movement analysis was able to demonstrate that in temporal lobe epilepsy there is a initial ipsilateral head turning followed by a contralateral head version which last longer and occurs prior to secondary generalization.78

Tonic-clonic seizures Tonic-clonic seizures are characterized by a typical sequence of a generalized tonic contraction followed by clonic contractions. Grand mal (= ‘the great evil’) is a synonym for generalized

EMG Artifactduring a Generalized Tonic-Clonic Seizure FP2–F8 50 uV F8–T8 T8–P8 P8–O2 FP1–F7 F7–T7 T7–P7 P7–O1 FP2–F4 F4-C4 C4–P4 P4–O2 FP1–F3 F3–C3 C3–P3 P3–O1 FZ–CZ CZ–PZ EKG1–EKG2

(a) FP2–F8 50 uV F8–T8 T8–P8 P8–O2 FP1–F7 F7–T7 T7–P7 P7–O1 FP2–F4 F4-C4 C4–P4 P4–O2 FP1–F3 F3–C3 C3–P3 P3–O1 FZ–CZ CZ–PZ EKG1–EKG2

(c)

FP2–F8 50 uV F8–T8 T8–P8 P8–O2 FP1–F7 F7–T7 T7–P7 P7–O1 FP2–F4 F4-C4 C4–P4 P4–O2 FP1–F3 F3–C3 C3–P3 P3–O1 FZ–CZ CZ–PZ EKG1–EKG2

(b) FP2–F8 50 uV F8–T8 T8–P8 P8–O2 FP1–F7 F7–T7 T7–P7 P7–O1 FP2–F4 F4-C4 C4–P4 P4–O2 FP1–F3 F3–C3 C3–P3 P3–O1 FZ–CZ CZ–PZ EKG1–EKG2

(d)

1sec

Figure 51.11. Typical EMG artifact illustrating the course of a generalized tonic-clonic seizure. Initially the tonic activity increases in amplitude (a–b) followed by gradually increasing clonic activity with periods of reduced EMG artifact (c–d). The duration of the pauses inbetween the clonic activity increases towards the end of the clonic activity. This EMG artifact is very typical for generalized tonic-clonic seizures and may even help to distinguish them from non-epileptic pseudoseizures.

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Figure 51.12. The increased intrathoracal pressure during the tonic phase may lead to subcutan petechial bleeding, which can be seen in the periorbital region of this 16-year-old male. He had his first generalized tonic-clonic seizure the day before. This phenomenon is typical for generalized tonic-clonic seizures.

tonic-clonic seizure, which is the only seizure type in grand mal epilepsies (Epilepsy with grand mal [generalized tonicclonic] seizures on awakening) (Commission on Classification and Terminology of the International League Against Epilepsy.84 The seizures have a typical evolution, initially occurring with tonic posturing, adduction with extension of all four extremities, and flexion of the wrist and fingers. This phase lasts for approximately 5 (to 12) seconds and then evolves into a ‘tremor-like’ twitching.85 The ictal EEG shows a typical EMG artifact (Figure 51.11). The repetition rate of the twitches gradually becomes slower and the amplitude increases, giving rise to the clonic phase (Figure 51.12). The clonic phase consists predominantly of flexion myoclonic

459

jerks of the elbow, hip, and knee. The duration of the tonicclonic seizures varies between 1–2 minutes.85 Consciousness is always disturbed with the beginning of the tonic phase. Generalized tonic-clonic seizures are followed by a prolonged postictal coma and confusion. During the tonic phase increased intrathoracal pressure may lead to petechial subcutan bleeding in the periorbital region (Figure 51.12). Generalized tonic-clonic seizures may occur in generalized and focal epilepsy syndromes. Occasionally other generalized seizure types may evolve into generalized tonic-clonic seizures (i.e., generalized myoclonic seizure → generalized tonic-clonic seizure or dialeptic seizure → generalized tonic-clonic seizure). The evolution of generalized myoclonic seizures into generalized tonic-clonic seizures is typical for juvenile myoclonic epilepsy. In focal epilepsies, generalized tonic-clonic seizures usually constitute the end of a seizure evolution. The focal seizure types preceding a generalized tonic-clonic seizure depend on the cortical region, which gives rise to the seizure. Secondarily generalized tonic-clonic seizures may infrequently evolve into a short (2–10 sec) focal motor seizure that may be generated by persisting epileptiform discharges in the hemisphere of origin or may involve the contralateral hemsiphere (paradoxical version).86,87 The clonic phase of generalized tonicclonic seizures may end asymmetrically, showing clonic jerks persisting in the limbs ipislateral to the hemisphere of seizure onset.85 It is speculated that this seizure evolution reflects earlier seizure cessation in the hemisphere of seizure onset, whereas the contralateral hemisphere still continues to seize. Patients with juvenile myoclonic epilepsy may have generalized myoclonic seizure preceding the generalized tonic-clonic seizures, particularly after sleep deprivation. Clinical experience shows that there are some patients with clonic-tonic-clonic seizures but there are only anecdotal reports on this observation.7 The pathophysiological considerations on the origin of generalized tonic-clonic seizures are the same as discussed above for generalized tonic and generalized clonic seizures.

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Complex motor seizures: localizing and lateralizing value MM Bianchin and AC Sakamoto

Introduction Clinical signs and symptoms expressed during epileptic seizures are thought to be generated by widespread neuronal matrices, linked together by anatomic connections, and further strengthened through repeated use.1–4 Although presenting great interindividual variability such neural networks share similarities among different patients, permitting the expression of stereotyped ictal behaviors that might indicate the underlying neural substrates. When motor networks are activated during seizures, patients may exhibit motor behaviors that can be classified as simple motor seizures (reproducible by direct stimulation of the primary motor cortex) or complex motor seizures.5,6 Classifying seizures according to semiological ictal findings, and particularly according to motor behavior is especially useful during presurgical videoEEG evaluations. This semiological-oriented classification was first proposed by Lüders and colleagues as an alternative classification to that of ILAE.5,6 Semiologic Seizure Classification (SSC) might provide a more comprehensive picture of epileptic seizures, notably in patients with focal epilepsy, being very useful for both, everyday clinical practice and more specialized evaluations in epilepsy centers.7–9 The relevance of this semiological-based approach is well demonstrated by Chee and colleagues10 who reported that the epileptogenic region can be correctly lateralized by semiological analysis in 78% of patients, with positive predictive value of 94%, and very good interobserver reliability. When combined with video-EEG analysis, semiological findings might allow lateralization and/or localization of epileptogenic and symptomatogenic zone in most patients.11–13 According to the SSC complex motor seizures encompass three main seizure types: (1) automotor seizures; (2) hipermotor seizures; and (3) gelastic seizures. Automotor and hypermotor seizures are more frequently associated to temporal or frontal lobe epilepsies, respectively,5 while gelastic seizures are usually related to hypothalamic hamartoma.5,14 Complex motor behaviors may also be observed in the late course of posterior cortex seizures, once these might propagate to more anterior regions.15–18 The reader must observe four important points regarding this classification. First, the complex motor behaviors observed during seizures are usually similar to complex movements executed during common life diary activities (e.g., coughing, swallowing, lip smacking, clapping hands, among many others), or alternatively, can resemble motor behaviors 462

observed in movement disorders (e.g., limb dystonic posturing), suggesting they share common functional anatomic substrates.5 Second, the ictal motor behavior can be qualified as ipsi- or contralateral, according to the lateralization of the epileptogenic zone. Third, distinct from ILAE’s classification,19 in the SSC the term ‘complex’ refers to the complexity of the movement, and not to the patients’ state of consciousness.5 Forth, classifying seizures according to ictal motor behavior is a purely semiological concept, and therefore, based exclusively on clinical manifestations observed during seizures.5 When these ictal signs and symptoms are sequentially considered, they may additionally indicate specific propagation patterns and reflect the anatomical sites involved during seizure propagation, the sequences of these involvements, and some mechanisms of ictal spreading. The assessment of symptomatogenic motor regions and networks through ictal semiology is of paramount importance for the process of epileptogenic and symptomatogenic zone localization. In addition, ictal semiology might also hold postsurgical prognostic significance. In this chapter we will address the complex motor seizures, mainly emphasizing motor components and localizing and/or lateralizing features. Periictal complex motor phenomena, when common, stereotyped, and consistently associated with complex motor seizures will also be described, since they might also carry valuable localizing and lateralizing information. In addition, we will briefly review the existing evidences on the mechanisms and anatomic areas possibly involved in the production of complex motor seizures and associated common behaviors. Table 52.1 summarizes existing data on complex motor seizures. Preliminarily, however, a brief consideration about auras will be presented, once auras antecede complex motor behaviors in most patients.

Auras Auras are reported by most patients with automotor or hypermotor seizures. Automotor seizures are more frequently associated to temporal lobe epilepsy, and by far epigastric aura with raising sensation is the most common type of aura anteceding these seizures. Epigastric aura might also occur in association with frontal lobe epilepsy, although much less frequently.20–26 Also common in automotor seizures are auras of fear, anxiety, or other related symptoms.20,24–26 Other types of auras common to automotor seizures but less frequently

Most patients.

Very common.

10% of patients with FLE or TLE.

15–70% of patients with TLE or FLE.

50% of FLE patients. 15–20% of TLE patients. 5–28% of patients with TLE. Less than 1% of patients.

Limb automatisms

Oral automatism

Genital and sexual automatisms

Unilateral dystonic limb posturing

Unilateral tonic posturing

24% of FLE patients. 6% of TLE patients.

75% of TLE patients. 50% of FLE patients.

35% of TLE patients. 20–60% of FLE patients.

15–20% of secondary generalized seizures.

0.8–1.5% of patients.

Pelvic thrusting

Non-versive head turning

Head version

Head and eye ipsiversion at the end of generalized seizure

Unilateral eye blinking

Postictal palsy

Ipsialateral in 80% of patients.

Ipsilateral if initial head version vanish during generalization.

Contralateral in more than 90% of patients.

Usually ipsilateral (see text for details).

None.

Contralateral in most patients with automotor seizures. Contralateral in all patients.

Contralateral in 40–90% of patients.

Contralateral in more than 90% of patients.

Mostly temporal in automotor seizures.

Frontal or temporal.

Not determined. Basal ganglia (striatum) might be involved. Frontal or temporal.

Usually frontal, may be temporal.

Frontal or temporal.

Temporal.

Temporal or frontal.

Temporal or frontal.

Highly suggestive of MTLE when associated with contralateral dystonic posturing. Suggests temporal lobe. May be observed in seizures originating in frontal lobe. Frontal or temporal.

Epileptogenic zone

Not determined.

Cotralateral Boardman’s area 6 and 8.

Broadmann’s area 6 and 8.

Unknown.

Possible exhaustion or inhibition of Brodmann area 4 and 6. Unknown.

Temporal, frontal, parietal and basal ganglia (Putamen). Supplementary motor area, basal ganglia, other frontal areas cannot be excluded. Contralateral frontal lobe.

Unknown.

Limbic system.

Variable. Frontal or temporal activation. May correspond to releasing phenomena.

Simptomatogenic zone

Complex motor seizures: localizing and lateralizing value Continued

Associated with conjugate eye versions to the same side and preceding (10 seconds or less) secondary generalizations. If initial head version is maintained during seizure, late head version still contralateral to epileptogenic zone. Involvement of inferior postcentral area has been suggested.

May be observed in pseudoseizures (17% of patients). Lateralizatory value is controversial.

In hypermotor seizures, suggest frontal lobe. In automotor seizures, suggest temporal lobe. When associated with unilateral automatisms suggests mesial temporal epilepsy. May be differentiated from dystonic posturing by absence of rotational components. Probably a negative motor phenomenon. Should be differentiated from ictal unilateral immobile limb.

When automotor and associated with preserved responsiveness suggest nondominant temporal lobe (6% of TLE). Positive ictal activation or releasing phenomena.

Observation

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Poor. Lateralizatory value on depending other signs.

Usually ipsilateral in MTLE, contralateral in NTLE, and nonlateralizing in frontal lobe seizures. Nonlateralizing.

Lateralizing value

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Unilateral immobile limb

Frequency

Selected motor behaviors observed in association with complex motor seizures

Motor characteristics findings

Table 52.1

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cont’d

2% of TLE patients.

Less then 1% of patients.

2.5% of TLE patients. are in other Epilepsies.

15% of TLE patients.

9–40% of patients.

Rare.

More then 50% of FLE patients. 2–3% of TLE patients.

Rare

Ictal vomiting

Ictal spitting

Ictal urinary urge

Periictal water drinking

Periictal cough

Unilateral ear-plugging

Complex hypermotor ictal behaviors

Gelastic seizures

Nonlateralizing.

Nonlateralizing.

Suggests contralateral epileptogeni c zone.

Nonlateralizing.

Suggest nondominant epileptogenic zone.

Suggests nondominat epileptogenic zone.

Simptomatogenic zone

Highly suggestive of frontal lobe. Might be observed in seizures from other regions due to ictal propagation. Highly suggesive of hypothalamic hamartomas. Other lesions also possible, mostly frontal or temporal.

Anterior cingulated regions inolved in motor aspects of laughter. Temporal lobes involved in mirth.

Frontal lobe.

Suggest mesial temporal Unknow. Might reflect epileptogenic zone. olfactory hallucinations, Might be extratemporal. nasal secretion or abnormal amygdalar network functioning. Suggests nondominant Activation of limbic structures, temporal lobe. insula, and mesial frontal regions. Suggests nondominant Cortical activation or releasing temporal lobe or phenomena of unknown hemisphere. networks. Suggests nondominant Insular cortex, mesial frontal temporal lobe. region, medial temporal gyrus, and operculum. Suggests nondominant Amigdala, hippocampus, temporal lobe. and parahippocampal gyrus. Hypothalamus? Suggests temporal lobe. Unknown. Might be due to activation of central autonomic pathway. Suggests neocortical Auditory cortex, on superior temporal cortex. temporal gyrus.

Epileptogenic zone

Mirth is only possible with conscience preservation during at least part of the seizure.

Multiple mechanisms. Increased respiratory secretion might have a role. Probably a stereotyped response to annoying auditory phenomena. There is no consensus on the specific localization of epileptogenic or symptomatogenic zones in frontal lobes.

It is not due to bad mouth sensation, excessive salivation, or drooling. Suggests activation of specific nondominant hemispheric bladder control centers. Unknow. Propagation of ictal activity to hypothalamus has been suggested.

Unknown mechanisms.

May reflect contralateral postictal movement abnormalities or neglect.

Observation

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Suggests nondominant epileptogenic zone.

Suggests nondominant epileptogenic zone.

Ipsilateral to temporal lobe epileptogenic zone in 70–90%. Nonlateralizing in frontal lobe seizures.

Lateralizing value

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Observations: Data regarding adult patients. Motor symptoms might be observed in posterior cortex epilepsy due to seizure propagation. The general predominance of central autonomic networks in nondominant or right hemisphere might account for nondominant (right) periictal-related behaviors. Frequencies are taken from reports on different series of video-EEG monitoring. For references, consult text. Ipsilateral or contralateral refers to the epileptogenic zone. Legends: FLE = frontal lobe epilepsy; TLE = temporal lobe epilepsy, MTLE = mesial temporal lobe epilepsy; NTLE = neocortical temporal lobe epilepsy. ETLE = extra-temporal lobe epilepsy.

50–85% of MTLE patients. 10–33% of extratempor al patients.

Nosewiping

Frequency

464

Motor characteristics findings

Table 52.1

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Complex motor seizures: localizing and lateralizing value observed are déjà vu, jamais vu, olfactory auras, feelings of depersonalization.20,24 Some auras preceding automotor seizures are difficult to be characterized by patients and neurologists because they consist of complex subjective symptoms exclusively felt during seizures, and not usually experienced in other contexts. It is not uncommon that patients with automotor seizures and mesial temporal lobe epilepsy have history of auras in the past that no longer exist. This should be specifically asked to patients, once past or present history of auras is an important aspect of automotor seizures. Depending on the series, 15–69% of patients have auras preceding complex motor seizures of frontal lobe origin, a region more often associated with hypermotor seizures. 21,23,27–29 These auras consist of feelings of tightness or tingling of certain body parts, auras of whole body sensation, cephalic sensation, and other nonspecific feelings.21,23,27–31 Palpitations, fear, anxiety, and even panic have also been reported, although much less frequently.21,23,27–29,32,33 When comparing seizures of temporal lobe origin with those emanating from frontal lobes, psychic, gustatory, olfactory, fear, auditory, visual, or experiential auras suggest temporal lobe seizure onset and therefore are more frequently associated with automotor seizures.24 A nonspecific general body sensation is much more suggestive of frontal lobe epilepsy, frequently preceding hypermotor seizures.23,33 Cephalic sensations or other vague complaints are nonspecific and might occur in both, automotor and hypermotor seizures. Because auras are among the first clinical seizure symptoms, they might reflect initial and more circumscribe regional alterations, having diagnostic and prognostic significances.31,34 For these reasons, detailed evaluation of auras should not be forgotten during complex motor seizures evaluations. The reader should review the chapter about auras for a more detailed discussion.

Automotor seizures Automotor seizures (SSC) or complex partial seizures (ILAE’s classification) are by far the commonest type of complex motor seizures observed in video-EEG units. Automotor seizures are more commonly observed in association with temporal lobe epilepsy. These seizures are usually preceded by auras and their most remarkable characteristics are the impairment of consciousness and the presence of automatisms (e.g., oral automatisms, and limb automatism) and/or stereotyped motor behaviors (e.g., dystonic posturing), involving mainly hands, mouth, or tongue.5 The lateralizing and localizing semiological findings in automotor seizures are rich, especially when observed in association with temporal lobe epilepsy, where the number of clinical symptoms per seizures and duration of the seizures are usually higher than in other complex motor seizures.23 Consciousness is affected, but can be preserved in variable degrees, especially when seizures originate and remain restricted to the nondominant hemisphere.10,12,35–37 In the following sections we will review in detail these automatisms and most common associated periictal motor behaviors. A short discussion about mechanisms of all these ictal or periictal motor behaviors is also presented.

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Automatisms Oral or alimentary automatisms and automatisms of limbs usually more exuberant in the upper limbs are commonly observed in automotor seizures. These automatisms are significantly more observed in temporal lobe epilepsy but can be also seen in extratemporal seizures.16,23,33,38,39 Typical automatisms observed in automotor seizures can be discrete, consisting of repetitive and stereotyped involuntary actions as is the case of oral automatisms,10,40,41 or more complex, characterized by involuntary, learned and semipurposeful complex motor acts, like fumbling, picking, or gesticulating movements.24,40,42–45 By comparing automatisms between patients with ‘pure culture’ of temporal and frontal lobe epilepsies, Kotagal and colleagues23 observed that alimentary automatisms, repetitive upper limb automatisms, perseverative automatisms, looking around and complex gestures were much more commonly seen in temporal lobe epilepsy, while hypermotor seizures were much more frequent in frontal lobe epilepsy. Indeed, although in surgical series of frontal lobe epilepsies up to 77% of patients might present some type of automatism during seizures, they are usually hyperkinetic and qualitatively distinct from automotor automatisms. These aspects will be discussed further in hypermotor seizures.21,23 Automatisms in automotor seizures may be interpreted as release phenomenon and/or the result of activation or disruptions caused by seizure propagation to limbic system, subcortical structures, and/or other cortical regions.40,45–47 In the following sections we will better characterize the most common types of automatisms associated with automotor seizures, namely, oral and gestural automatisms, and discuss their underlying mechanisms. Oral automatisms Automatisms involving the oral region including masticator movements, swallowing, lip smacking, kissing or other tongue movements are classically observed in automotor seizures from temporal lobe origin.33,40,48 However, they can also occur in extratemporal seizures, especially when ictal discharges spread and secondarily involve the temporal lobes.16,18,21,38,39,49,50 When occurring in frontal lobe epilepsy, these automatisms are more common in association with orbito-frontal seizures.21 Precise mechanisms of oral automatisms are still poorly elucidated. They may represent release phenomenon or positive activation of the limbic system.40 Electrical stimulation of limbic structures, and particularly of amygdala, can induce oral automatisms, but only when associated to clinical seizures or widespread afterdischarges.2 In line with this observation, Maillard and colleagues45 observed that oral automatisms occur relatively early during seizures initiated in medial-lateral temporal structures, but only late in medial temporal seizures, suggesting that oral automatisms require widespread dysfunction of medial and neocortical temporal lobe structures for their expression.45,51 Gestural automatisms Gestural automatisms observed in automotor seizures are far more prominent in upper limbs and face. Lower limb automatisms although less frequent and more discrete share similar mechanisms and significances.52 In unilateral temporal lobe automotor seizures, while the contralateral limb is usually tonic, dystonic, or immobile, the ipsilateral limb may present

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several different patterns of gestural automatisms.10,40,41,53–57 Depending on the series, limb automatisms are reported in more than 80% of temporal lobe epilepsy patients,10,57,58 being exclusively unilateral in more than 50% of the patients.58 Gestural automatisms are usually observed after the initial instants of the seizure, which seems to be the time necessary for the ictal spread to limbic-neocortical structures.45 During video-EEG it is useful to observe that limb automatisms are predominantly ipsilateral to the epileptogenic zone in patients with mesial temporal lobe epilepsy, but contralateral in patients with neocortical temporal lobe epilepsy.57,59 In mesial temporal lobe epilepsy, automatisms occur just before or simultaneously to dystonic posturing. This pattern suggests that ictal activity spreads from mesial temporal lobe structures sequentially to medial frontal cortex and then to striatopallidal complex, or that it spreads to medial frontal cortex and basal ganglia simultaneously.57 Unilateral ictal automatisms associated with contralateral dystonic posturing are highly suggestive of mesial temporal lobe epilepsy.58,60 However, the lateralizing value of unilateral automatisms not associated with dystonic posture has limited lateralizing value.58 When occurring isolated and left-sided, they might indicate ipsilateral epileptogenic zone. When observed right-sided, without contralateral dystonia, they have no lateralizing value.58 It is interesting to note that unilateral automatisms in automotor seizures of mesial temporal lobe origin might correspond in fact to bilateral automatisms, being the automatisms contralateral to the epileptogenic zone overridden by dystonic or tonic posture, or by ictal paresis.58,60 With very rare exceptions, automatisms observed in automotor seizures with preserved responsiveness are characteristic of epileptogenic zone in the nondominant temporal lobe.35–37,61 Gestural automatisms have complex mechanisms, most of them not elucidated yet. By stimulating the anterior gyrus cinguli and mesiotemporal structures, oral and hand automatisms can be evoked,62–64 thus suggesting that these automatisms can be caused by ictal spreading activity. However, other authors have suggested also that at least some automatisms may correspond to releasing phenomenon, not being caused by direct ictal activation.35,58,65 Genital and sexual automatisms Genital automatisms are defined as repeated ictal fondling, grabbing, scratching or other genital manipulations. They must be differentiated from other genital or seizure manifestations, like sexual or orgasmic auras, genital sensory phenomena, or hypermotor sexual automatisms.66–70 Genital and sexual automatisms are observed in about 10% of the patients referred for epilepsy surgery.71 While orgasmic auras originate from the nondominant temporal lobe,70,72,73 genital and sexual automatisms are essentially nonlateralizing, and may be seen in seizures originating from frontal as well as temporal lobes.69,71,72,74–76 According to Leutmezer and colleagues,76 the term ‘sexual’ refers to symptoms or signs with erotic components while the term ‘genital’ refers to symptoms or signs involving the genitalia but without erotic components. The quality of genital or sexual automatisms might indicate the lobe of seizure origin. Aggressive sexual pelvic or truncal movements are usually automatisms appearing in the context of hypermotor seizures associated with frontal lobe epilepsy,71,75,76 while subtle genital automatisms like fondling or grabbing the genitals are more commonly observed in

temporal lobe seizures.69,71,76 The latter occur more frequently in men and may localize the seizure onset to the ipsilateral temporal lobe only when associated to unilateral hand automatisms (70% of patients), or to the nondominant temporal lobe when associated with periictal urinary urge (in 22% of patients).69 Pelvic thrusting is a complex motor behavior that needs some consideration because it might be observed in a moderate number of patients, with different meanings. Geyer and colleagues reported that pelvic thrusting is more commonly observed in frontal lobe seizures (24% of the patients) or in pseudoseizures (17% of the patients),77 but it can be also observed in temporal lobe seizures, in a smaller percentage of cases (6% of the patients). It does not have any lateralizing value.77 The mechanisms underlying sexual and genital automatisms are also not well understood. A transitory Klüver and Bucy syndrome-like phenomenon caused by bi-temporal lobe dysfunction, a nonspecific behavioral pattern, or even a specific behavior related to limbic activation, or a reaction to other internal stimuli were all hypothesized mechanisms, but so far not corroborated by electro-clinical supportive data.69,78 Stereotyped ictal or periictal motor behaviors Prominent stereotyped motor behaviors are integrant components of complex motor seizures, mainly automotor seizures. The assessment of their semiological characteristics is of diagnostic importance since they frequently carry useful and reliable information for the localization of the epileptogenic zone. The main clinical features of the most common types of ictal stereotyped motor behaviors are described in the following sections. Dystonic limb posturing Dystonic limb posturing consists of a sustained limb posturing similar to that observed in movement disorders, very often occurring in the course of automotor seizures. Unilateral or predominantly unilateral dystonic posturing of the upper limb is perhaps the most reliable lateralizing sign in temporal lobe automotor seizures.10,54,55,57,79–84 Although less frequently it can also occur in frontal lobe epilepsy, where it might be observed latter in the course of the seizures. Depending on the series and on the clinical criteria of inclusion, dystonic posturing can be observed in 15–70% of the patients.10,40,55,57,81,82,84–86 When present, unilateral dystonic posturing is usually observed several seconds after seizure onset, suggesting that seizure propagation is necessary for producing it.87 Dystonic posturing occurs contralateral to the epileptogenic zone in more than 90% of the patients with temporal or extratemporal seizures.54,82,84,88 Contralateral dystonic posturing associated with head turning and automatisms ipsilateral to the epileptogenic zone are findings highly suggestive of mesial temporal lobe epilepsy.55,57,79,81,89 Rusu and colleagues also associated dystonic posturing with hypersalivation, somatomotor manifestations, secondary generalization, profound clouding of conscience, and prolongued postictal confusion to mesial temporal lobe epilepsy.84 Dystonic posturing may occur in different degrees of complexity and duration, and has been correlated with different seizure patterns of propagation to temporal, frontal, and parietal lobes.84,87,90,91 However, most

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Complex motor seizures: localizing and lateralizing value authors agree that direct or indirect basal ganglia activation,87,90,91 and more specifically, the putamen seems to be necessary for ictal dystonic posturing.87,92,93 PET and SPECT findings are in line with these evidences,94 and additionally revealed alterations in insula, inferior and superior frontal gyri, cingulated gyri, as well as in parietal areas.84,94 Taken together, these findings suggest that dystonic posturing results from widespread subcortical and cortical involvement of different neural networks. This observation agrees with those suggesting that dystonic posturing might be a negative predictor for good surgical outcome in mesial temporal lobe epilepsy,84,95 once broad spread of ictal activity has been previously reported to be accompanied by worse post-surgical outcome.96 Unilateral tonic posturing Contralateral tonic limb posturing, although less frequent and less specific, is also considered an important lateralizing sign in temporal lobe automotor seizures. It is observed in about 17% of temporal lobe epilepsy patients, being contralateral to the epileptogenic zone in 40 to 86% of them.54,82 Unilateral tonic limb posturing may be also observed in up to 15% of extratemporal seizures,54 being contralateral to the seizure focus in 67–89% of these patients.54,85 Tonic posturing has been differentiated from dystonic posturing by the absence of rotational or torsion components. However, it can be observed co-occurring with dystonic posturing and it has been considered as a muted expression of more classical dystonic posturing by some authors.54,84 Unilateral tonic posturing are most likely due to the activation of the supplementary motor area (SMA), although basal ganglia, cingulate gyrus, and primary motor area cannot be ruled out in the generation of tonic posturing.65,97 Unilateral immobile limb Unilateral immobile limb or unilateral ictal akinesia was initially described as ‘ictal paresis’ or ‘ictal paralysis’ and can be defined as a sudden loss of tone in one upper limb while the opposite side expresses automatisms. It is often observed during temporal lobe seizures, being considered as highly specific for lateralizing the epileptogenic zone.54 Ictal immobile limb is reported in about 5–28% of the patients, being contralateral to the epileptic focus in virtually all patients.54,98,99 It is frequently associated to ipsilateral limb automatisms, usually occurring immediately after the initial symptoms.99 In some seizures it occurs after patients had already initiated bilateral automatisms, while in others it may appear concomitantly with the onset of the ipsilateral automatisms. In about 70% of the seizures, unilateral immobile limb may precede typical ictal dystonia. In the other 30%, it may be followed by more complex automatisms, other signs of frontal lobe involvement, or secondary generalization. Authors have excluded tonic posturing as cause of upper limb immobility, despite the fact that muscle tonus had been tested in only few patients.98 Ictal paresis should be differentiated from postictal paresis or Todd’s palsy, a transient focal motor deficit that might occur after a seizure in 0.5–13.4% of the patients, depending on the series.100,101 It lasts about 3 minutes, ranging from 11 seconds to 22 minutes, usually being unilateral and contralateral to the seizure focus.101 Bilateral postictal paresis has also been described.101,102 Postictal limb paresis might be

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associated with ictal unilateral clonic activity (55.6% of seizures), dystonic posturing (47.9% of seizures), and ictal limb paresis (24.6% of seizures).100 The mechanisms underlying ictal unilateral immobile limb are not completely elucidated, corresponding probably to a negative motor sign. Ictal invasive recordings performed in few patients suggested epileptic activation of the contralateral premotor cortex, prefrontal cortex, anterior cingulate gyrus and orbitofrontal cortex as the neural substrates involved in this motor behavior.99 Congruent with these findings, negative motor responses can be elicited by stimulation of mesial and lateral frontal lobe regions.103–105 Eyes motor behaviors Conjugated and sustained tonic versive eye movement occurring shortly before generalization is the most reliable ocular sign for seizure lateralization. It usually occurs associated to head version. Both, head and eyes version, frequently appear contralaterally to the epileptogenic zone,106,106,107 due to seizure propagation to Broadman’s area 8. Although they are simple motor phenomena, they were included here because head and eyes version may be observed in the context of complex motor seizures. Unilateral eye blinking is rare and may be observed in about 0.8 to 1.5% of seizures from patients referred to video-EEG, being ipsilateral to the epileptogenic area in about 80% of the patients.65,108,109 The mechanisms underlying ipsilateral ictal eye blinking are still unclear. Nistagmus is another eye motor sign, observed in less then 1% of patients during video-EEG and reviewed here because it is a motor sign with lateralizing properties. Nistagmus is usually observed in association with posterior cortex epilepsy, the fast phase being contralateral to the epileptogenic zone in all well-documented cases.110–117 Mechanisms of ictal nistagmus are complex and still not elucidated. Intermitent, but periodic activation of cortical saccade areas by ictal activity, activation of slow ipsiversive smooth pursuit region, or even activation of cortical optokinetic regions and subsequently subcortical structures were all mechanism hypothesized.117 Head turning and head version Versive and nonversive head turnings are common signs of automotor seizures. Version classically defines a tonic, unnatural, and forced lateral gyratory movement while head deviation or head turning refers to other head gyratory movements with more natural and unforced components. While some controversy exists about the significance and reliability of ictal nonversive head turning as a lateralizing sign, authors agree that forced versive head movements are contralateral to the epileptogenic zone in more then 90% of cases, especially when associated to conjugated eyes version and occurring shortly (usually 10 seconds or less) before secondary generalization.10,21,43,81,85,106,107,118–121 When contralateral to epileptogenic zone, head versions are sometimes referred as adversion or contraversion. Depending on the series, head version is observed in approximately 35% of patients with temporal lobe epilepsy and in 20–60% of patients with extratemporal epilepsies, mainly frontal lobe epilepsies.10,21,43,81,85,106,107,118–121 Nonversive head turning occurs in up to 73% of the temporal lobe seizures, but its value as a lateralizing sign has been controversial.120 In focal seizures without generalization, when a single head turning occur, it is ipsilateral to the epileptogenic

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focus in up to 94% of the seizures.120 When two head turnings occur to the same direction (19% of the seizures), they are usually ipsilateral to the seizure focus. However, in focal seizures with secondary generalization, when two head turnings occur, the first is usually ipsilateral to the seizure onset and the second is contralateral to the epileptogenic zone, usually appearing shortly before generalization.81,120 Head turning or deviation can be observed in about 50% of patients with frontal lobe seizures, being also ipsilateral to the epileptogenic zone in most cases. When patients show both sides head gyratory movements, ipsilateral head turning usually occurs earlier and precedes contralateral head turning. Late ipsiversion of head and eye at the end of a generalized tonic-clonic seizure might be observed in 15–20% of patients. When initial contraversion persists during the generalization phase, late head deviation is usually contralateral. When initial contraversion vanish during the generalized phase, late version is usually ipsilateral.10,106 Head version can be elicted by direct electric stimulation of the premotor areas (Broadman’s areas 6 and 8). Thus, propagation of seizures to these areas might underlie this behavior shortly before generalization. This seems to be also the mechanism of late ipsiversion, when activation of contralateral nonepileptogenic hemisphere predominates, after the initial ictal activity in the epileptogenic hemisphere is already exhausted or inhibited.10,106,117 The mechanisms of other nonversive head turning are less well understood. The association of ipsilateral head turning with contralateral dystonic limb posturing has led some authors to associate ipsilateral head turning with seizure spreading to the basal ganglia, and more specifically to the striatum.81,120,121 However, other authors have suggested neglect of the contralateral space as the possible mechanism involved in ipsilateral head turning.107,121 Facial alterations Facial expression changes occur in virtually all types of complex motor seizures. In automotor seizures, most patients exhibit neutral facial expression and staring, but emotional facial changes (e.g., disgust, happiness, and sadness) may also be observed.122–124 Expressions of anger, surprise, or fear are not commonly seen in automotor seizures, but frequently occur in hypermotor seizures.122,124–126 Although emotional facial asymmetry is not a specific ictal motor abnormality, it deserves a brief mention here because it might help in lateralizing the epileptogenic zone. Observed in about 70% of temporal lobe epilepsy patients, inferior facial weakness is usually, but not always, contralateral to the epileptogenic zone.127–130 Ictal smile was reported in children, occurring in 11% of frontal lobe seizures, in 3% of temporal lobe seizures, and in 26% of posterior cortex seizures, where it is significantly more common. This finding might lateralize the epileptogenic zone to the nondominant hemisphere.131 Rarely, ictal cry may be observed in patients with temporal or medial frontal lobe epilepsy.132,133 Mechanisms involved in ictal facial expression changes are multiple and complex. Facial alterations might be caused by direct seizure activation or disconnections of cortical or subcortical motor areas involved in facial muscle control,122,134–139 or be provoked by ictal alterations in emotion-regulation networks. Seizures originating from or involving limbic and related structures may also activate or disrupt regions involved

in the modulation of emotional responses, provoking emotional facial alterations that can appear associated to complex motor behaviors, like fear or anger, sometimes being quite dramatic and resembling panic attacks.124,126,140 Associated emotional behavior may be observed in temporal lobe epilepsy, but extreme emotional ictal behaviors (usually intense agitation, screaming, facial expression of rage, fear, or anger) are more commonly observed in frontal lobe seizures.125,126 The analysis of the neural substrates underlying emotional responses is particularly complex, once emotions and related behaviors are difficult to be reproduced and studied under controlled situations. Nevertheless, an increasing body of evidence has pointed amygdala, prefrontal cortex, hypothalamus, cingulate cortex, orbitofrontal cortex, insular cortex, and the ventral striatum as components of a complex neural emotional network.141–144 More complex emotional motor behaviors might be related to seizure propagation to rostral cingulate (M3) or caudal cingulate areas (M4), regions that might be responsible for ‘emotional facial movements’.46,136,139 Nosewiping or nose-rubbing Many epileptic patients wipe or rub their nose during or shortly after ictal period (less then 60 secounds) and this motor behavior appears to have localizatory and lateralizing value.117,145,146 Nosewiping is significantly more frequent in mesial temporal lobe seizures than in other temporal lobe or extratemporal lobe seizures.147,148 In temporal lobe epilepsy, ictal or postictal nosewiping might be observed in 50–85% of the patients and in 43% of the seizures, while it might be observed in only 10–33% of all patients with extratemporal epilepsy.145,148,149 In automotor temporal lobe seizures, nosewiping has lateralizing properties, being performed with the hand ipsilateral to the epileptogenic zone in about 75–90% of patients.145,146,148,149 In extratemporal epilepsies nosewiping might be observed in about 50% of the patients.149 Nosewiping is uncommon in patients with generalized epilepsy, after secoundarily generalized seizures or during nonepileptic events.146 Nose wiping is hardly lateralizatory in frontal lobe epilepsy.150 The pathophysiology of ictal and postictal nose wiping remains uncertain but it might reflect ictal olfactory hallucinations or increased nasal secretions.148 Earlier ictal amygdala involvement is more common in nosewiping. This finding together with observations that amygdala has a particular role in the olfactory system2,148 might suggest that direct amygdala ictal activation or disorganization of amygdale-related neural network might play an important role in the genesis of ictal or postictal nosewiping.2,148 The use of the ipsilateral hand may be related to contralateral postictal movement abnormalities or neglect.151–153 Other stereotyped motor behaviors Some ictal or periictal complex motor behaviors may be determined by special and well-characterized physiological states that can cause stereotyped and well-defined clinical situations such as cough, urinary urgency, thirst, vomiting, spitting, orgasmic related behaviors, among others. These periictal complex motor behaviors possibly have some common points that might allow them to be grouped together. In this venue, it is interesting to note that many of these behaviors are more

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Complex motor seizures: localizing and lateralizing value commonly observed in patients with nondominant temporal lobe epilepsy. Although several mechanisms could be involved, it is tempting to hypothesize that some of these abnormal behaviors can only be observed because patients keep some degree of awareness about their own feelings, about themselves, and about the surrounding ambient during seizures. Moreover, some of these behaviors correspond to autonomic responses, and the predominance of autonomic functions in the nondominant temporal lobe has also been advocated.154 Ictal vomiting Ictal vomiting is an unusual manifestation, observed in about 2% of patients submitted to video-EEG.89,155,156 Frequently associated with nondominant temporal lobe epilepsy, it might be also observed in language-dominant temporal lobe epilepsy.155,157–163 The mechanisms of ictal vomiting are not yet completely elucidated. However, seizure activity in mesial temporal structures, other limbic structures, insula, and mesial frontal regions seems to be necessary. This association is supported by several clinical-electrografic correlations,155,158–163 direct electrical stimulation157 and evidences obtained from SPECT studies.159 Ictal spitting Ictal spitting is another uncommon ictal behavior, occurring in less than 1% of the patients referred for video-EEG monitoring.164,165 It is usually observed in seizures involving nondominant temporal lobe epilepsy,164,165 but seizures of language-dominant temporal lobe and extratemporal lobes were also reported.166 The mechanisms underlying ictal spitting remain largely unknown. Increased salivation, a rare finding also associated with nondominant temporal lobe epilepsy has not been associated with spitting in most patients.167 It appears that spitting corresponds to complex automatisms similar to other oroalimentary automatisms. The association of ictal spitting with nondominant hemisphere further suggests involvement of autonomic mechanisms. However, ictal spiting is hardly explained by bad mouth sensations, excessive salivation or drooling, as one could intuitively suppose.166,167 Ictal urinary urge Ictal urinary urge provokes characteristic motor behavior in association with seizures,168,169 usually with epileptic focus located in the nondominant hemisphere.168,169 It might be observed in 0.2–2.5% of patients during video-EEG, being more common in temporal lobe epilepsy.65,168,169 The lateralizing significance of this sign can be explained by a hemispheric specific representation of central bladder control. PET studies on brain activation during micturition in normal subjects suggested a predominance of the right hemisphere in central bladder control.170,171 The symptomatogenic zone probably involves the insular cortex, mesial frontal region or the medial temporal gyrus and operculum.168–172 Periictal water drinking Water drinking is also a characteristic behavior occasionally observed during or up to 2 minutes after an automotor seizure.154,173,174 It occurs in about 15% of patients and it is usually associated with nondominant temporal lobe epileptogenic zone. Depth electrodes recordings have evidenced

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seizures starting in the amygdala, hippocampus, and parahippocampal gyrus.153,154,174 Propagation of seizures from these structures to hypothalamus was suggested as the cause for water drinking.154 As in other nondominant temporal lobe seizures, the general predominance of central autonomic networks functioning in the nondominant hemisphere has been also advocated,154 but more specific mechanisms remain uncertain. Ictal or periictal cough Cough is a relatively common ictal or periictal finding in epilepsy, being observed in 9–40% of patients during videoEEG.175–177 Coughing may be observed in temporal lobe seizures as well as in extratemporal seizures, but it is rare in pseudoseizures. Some authors have suggested that periictal coughing is more often observed in temporal lobe epilepsy, although without lateralising properties.175–177 Mechanisms of periictal cough are complex and might differ between temporal and extratemporal lobe seizures.176,177 Nevertheless, perictal coughing is thought to be consequence of increased respiratory secretion or provoked by direct activation of the central autonomic pathways.177 Unilateral ear plugging Ear plugging may be observed in some epileptic patients, probably representing a stereotyped response to an annoying auditory phenomenon. It is usually observed in children with epilepsy and learning disabilities or poor communication skills.178 Similar to nose rubbing, ear plugging is not a primary motor seizure, but a motor behavior probably performed in response to an auditory hallucination provoked by seizures involving the contralateral superior temporal gyrus.178 Thus, this behavior may occasionally be helpful in indicating the localization of the epileptogenic zone in the contralateral auditory cortex, on the superior temporal gyrus.178

Hypermotor seizures Hypermotor (Semiological Classification) or hyperkinetic seizures (ILAE Classification) were first defined as hypermotoric turning movements and postures,42 and further detailed by Lüders and colleagues as seizures in which the main clinical manifestations consist of complex movements involving the proximal segments of limbs and trunk. These characteristics result in large movements that might appear violent when occurring in high speed.5 These seizures are commonly refereed as complex gestural automatisms, gestural motor symptoms, hyperkinetic or hypermotoric behavior.166 Motor activity includes axial motor components like trashing, jumping, or body rocking. It might involve lower or upper extremities like thrashing of the extremities, bicycling leg movements, stepping, pedaling, hand flapping, clapping, slamming, pounding, fist clenching, grasping, shaking or playing with objects. Sexual automatisms are common and characterized mainly by pelvic thrusting and aggressive genital manipulations. Vocalization, laughing, shouting, or crying are frequently associated, but considered not specific findings of hypermotor seizures.21,23,32,75,179–181 Not only the pattern of motor behavior, but also its quality, i.e., agitated, frenetic, and hyperkinetic, characterizes seizures as hypermotor seizures.

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Although movements might seems violent, emotional or affective signs are reported as minimal and rare.126,182 Nevertheless some patients might exhibit emotional components associated with hypermotor seizures,126 but these aspects cannot be easily characterized and as a consequence, they are far less studied. The combination of all these components results in the large clinical variability of hypermotor seizures and unique and very bizarre-appearing seizures, sometimes suggesting pseudoseizures for those not habituated with video-EEG. For those habituated, hypermotor seizures are perhaps too bizarre for pseudoseizures.181,183 Hypermotor seizures usually originate in the frontal lobes,42,184 but it may also begin in the temporal lobes, posterior cortex, and insula.18,39,185,186 In the next sessions we discuss hypermotor seizures and other complex motor ictal behaviors related with frontal, temporal, and insular regions, pointing some important clinical differences of these seizures. Hypermotor seizures and frontal lobe Frontal lobe seizures express one of its main function: triggering, organizing, and performing most diverse motor activity. Except for ‘frontal lobe absences’ where little or no motor activity is observed, some form of motor activity is observed in virtually all patients with frontal lobe epilepsy and more complex motor ictal behaviors are very common.21–23,32,33,38,97,166,179,181,187–192 However, it is important to remember that these seizures are not exclusively characterized by motor activity. In fact, many patients may have auras preceding complex motor ictal behaviors of frontal lobe origin.21,23,28,166,183,193 Moreover, in spite of being much less evident, motor behavior is preceded or followed by tonic muscle activity of limbs. Mainly due to the exuberance of the hypermotoric behaviors and short duration of episodes, auras and other periictal subtle muscle activities are usually underestimated, and specific efforts in their identification may be necessary. During hypermotor seizures, conscience may be preserved to some degree in many patients and this aspect, associated with the brevity of seizures might account for minimal postictal confusion.179 Considering all types of automatisms observed in surgical series of frontal lobe epilepsy, hyperkinetic automatisms seems to be the most common type of automatisms, occurring in more than 50% of these patients.21 They are usually observed early (first half) in the seizure.184 When paroxysmal dystonic movements are observed in association with nocturnal hypermotor seizures, autosomal dominant nocturnal frontal lobe epilepsy should be suspected.194–196 When associated with hyperkinetic automatisms, some other clinical characteristics classically suggest seizures originating in frontal lobe. These findings are brief seizures, seizures of sudden onset and termination, early motor signs, minimal post ictal confusion, seizures that occur in cluster, seizures occurring during sleep, and seizure with tendency to rapid generalization, although not as frequent as previously suggested.21,23,32,179–181 More recently, authors have been observing that some of these associations might be clinically nonelevant or even controversial.21,181,184,197 Nevertheless, some of these characteristics seem to be a direct consequence of seizure spreading properties in the frontal lobe. Indeed, it is interesting to note that in spite of the intense interconnections of frontal lobes with other brain regions, ictal activity of

complex motor seizures remains restricted to the frontal lobe where it originates. When propagating outside the frontal lobe of origin, it usually spreads to the contralateral frontal lobe. Because of the limited ictal spreading for an appreciable period of time, some authors were able to lateralize clinical seizure findings in up to 75% of patients with frontal lobe epilepsy.198,199 However, it is also interesting to note that the variable and often bilateral limb motor phenomena observed in hypermotor seizures of frontal lobe origin may reflect prominent multiple target corticofugal projections from the epileptogenic zone and significant projections to proximal limbs.199,200 Thus, bilaterality of clinical expression of motor components observed in hypermotor seizures from frontal lobe origin does not necessarily reflect bilateral cortical spread. When seizures spread to other brain regions outside frontal lobes, ictal activity frequently invades the temporal lobes, leading to false impression of temporal lobe seizures.181,192,201–203 Differences between complex ictal motor behaviors in frontal lobe epilepsy and temporal lobe epilepsy have been observed since Penfield and Jasper.23 Even when limited to the frontal lobe of origin, hypermotor seizures are characterized by involvement of all limbs, being bilateral, like thrashing or hitting, and include the lower limbs in movements resembling running, kicking, crossing and uncrossing the legs, or pedaling movements. They might be frenetic and bizarre, and patient may vigorously rock to and from, pound the bed or other objects with their hands, and jump or scramble about. It might be associated with pelvic trust and aggressive genital manipulation.23,75,180,204 It is not uncommon that patients yell, growl, shout expletives, bark, laugh, whistle, or hum. Head and eyes deviation are frequently observed during hypermotor seizures but are of lesser lateralizing or localizatory value, except when versive, sustained and occurring late in seizures, shortly before generalization, being in this case contralateral to the epileptogenic zone. These patients might have poor surgical prognostic.21,85,205 Conscience might be preserved during episodes, in spite of patients not being able to cooperate with test performed during the ictal period. Depending on the authors, some complex motoric behaviors observed in frontal lobe epilepsy may be seen as adapted behaviors to the environment or active interactions with surrounding objects, an observation in line with findings of some conscience maintenance during hypermotor seizures.179 When frontal lobe and temporal lobe ictal automatisms are compared, differences are indeed quite evident and should be stressed here. Perseverative automatisms and complex gestures occurring in more homogeneous and stereotyped clinical patterns are usually observed in association with temporal lobe seizures. Upper extremities automatism observed in MTLE involve the distal segments of the fingers and hands and are discrete, repetitive and stereotyped, characterizing automotor seizures.184 By contrast, upper extremity automatisms observed in most frontal lobe seizures present great clinical variability, being coarse, irregular, complex, semi-purposive, and involving more proximal muscles of shoulder, elbows, as well the hands, characterizing hypermotor seizures.184,206 Alimentary automatisms might occur in both type of epilepsy, but are more frequent and occur early in temporal lobe epilepsy.33,184 When observed in frontal lobe seizures, ‘automotor-type’ automatisms have been associated with seizure origin in orbito-frontal regions and as stated before, it might

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Complex motor seizures: localizing and lateralizing value reflect seizure propagation from frontal to temporal lobe, leading to false localization of the epileptogenic zone localizing in the temporal lobe.202,203,206 This situation might be particularly tricky in presurgical evaluation of patients with normal neuroimaging findings, where extra-caution is necessary. When multiple motor symptoms are considered together, complex motor seizures might be better characterized and understood. Differences between complex motor seizures of frontal and temporal lobe origin might be also better appreciated. In this venue, Kotagal and colleagues23 demonstrated that complex motor seizures of frontal lobe origin are characterized by a cluster of repetitive proximal upper extremity movements, complex motor activity, and hypermotor activity. In contrast, complex motor seizures of temporal lobe origin are better characterized by a cluster of oroalimentar automatisms and repetitive distal upper extremity movements. Usually but not always, alteration of conscience is associated with both seizure patterns.23 Although infrequent, mixed semiology might suggest propagation from one lobe to another. In these situations, a very careful analysis of initial symptoms and the sequence of appearance of ictal motor findings are particularly important. Such approach might indicate more precisely the initial symptomatogenic zone and the patterns of seizure propagation. When clustered together, some clinical seizure patterns may indicate the ictal activation of functionally and/or anatomically related areas, an observation that might help during clinical evaluation of patients, especially in those with normal neuroimaging findings.23 Origin of hypermotor seizures in frontal lobe Although the association between hypermotor seizures and frontal lobes overall is well accepted, there is no consensus on the specific localization of the symptomatogenic zone responsible for complex motor behavior observed in frontal lobe seizures. This fact reflects mainly the relative few studies on ‘pure culture’ frontal lobe epilepsy and series with limited number of patients included. Also account for these difficulties, the intrinsic proprieties of frontal lobe, such as its large volume as well as the complexity of connections of its neural networks, leading to rapid seizure propagation in variable spreading patterns within the frontal lobes. According to Bancaud and Tailarach, there are five different frontal regions from which complex motor seizures might originate: anterior cingulated gyrus, frontopolar cortex, orbito-frontal cortex, opercular-insular cortex, and medialintermediate region.207 More recently, hypermotor seizures have been associated with seizures originating from medial or orbitofrontal regions,206 an association further confirmed by SPECT findings in few patients.208,209 Also in hypermotor seizures, PET revealed interictal hypometabolism involving frontomesial, anterior cingulate, perirolandic, and anterior insular/frontal opercular areas.210 However, none of ictal complex motor behavioral patterns were observed to be exclusive from these regions, once there are well-documented examples of such seizures initiating in other frontal lobe regions as well.21,181,188,208 Other authors have further differentiating prefrontal seizures in ventro-medial prefrontal seizures or dorsolateral prefrontal seizures. Seizures arising from ventral or ventro-medial regions appear to correspond to those initially described as ‘complex partial seizures of frontal origin’. 179,180 Some of these patients exhibit hypermotor seizures resembling

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intense and dramatic behavioral reaction to fear, with semipurposeful gesticulation, like kicking or punching, bipedal cycling movements or attempts to escape. On its turns, seizure originating in dorso-lateral prefrontal regions might be characterized by tonic eye deviation preceding head version and complex semi-purposeful gestural automatisms that might be directed toward the same location as the gaze.179 However, as stated before, the origin of hypermotor complex behaviors within the frontal lobe is a matter of ongoing research. In spite of some seizure patterns being associated with specific frontal lobe regions by some authors, others could not observe such associations. On the contrary, they simply concluded that hyperactive seizures with frenetic automatisms, characteristic of hypermotor frontal lobe epilepsy, do not seem to be associated with any specific sublobar region within the frontal lobes.181,206 In line with this last hypothesis, a mechanism proposed for complex ictal motor behaviors observed in frontal lobe epilepsy is that epileptic activity may simply disrupt the control normally exerted by higher brain centers over other regions, allowing release phenomena or disinhibition of more primitive and stereotyped behaviors.179 It is possible that frontal lobe seizures might leads to an imbalance between internally generated control of movement and response to environmental cues.179 This phenomenon would be the basis of the complex motor behaviors observed in frontal lobe epilepsy. Nevertheless, frontal lobe epilepsy remains the next frontier.191 Whether hypermotor seizure or complex ictal motor phenomena have origin in specific subregions within the frontal lobe or not is still unknown. Studies with larger groups of patients with pure frontal lobe epilepsy, evaluated with modern neuroimaging appropriately combined with electrophysilogical techniques and proven seizure free after surgery, are necessary to solve this problem. Hypermotor seizures in temporal lobe epilepsy Much less frequently, hypermotor seizures are observed in seizures originating in the temporal lobes, even if sleeprelated.185,197 This should not be a surprise if one considers that temporal and frontal structures are highly interconnected and under certain aspects, some of these regions might be considered as a physiological continuum, as is the case of limbic and para-limbic structures. In this venue, Carreno and colleagues,185 analyzing a series of 502 patients with temporal lobe epilepsy identified only 12 individuals (2.4%) with seizures originating from mesial or neocortical temporal lobes, who exhibited complex motor behaviors similar to those observed during frontal lobe seizures. Large amplitude movements mainly involving the proximal segments of the limbs were observed in six of these patients, four other patients presented unilateral hemiballismus-like movements and the remaining two had movements affecting all four members, resembling rowing or bicycling (one patient) and violent and disorganized thrashing (the other patient). As observed by those authors, these patients might present ‘temporal lobe’ auras preceding the hypermotor phase, a finding that although far from being specific, might help differentiate hypermotor temporal lobe seizures from frontal lobe seizures. It is also possible that careful evaluation of the very early symptoms in these patients might provide additional clues for temporal lobe seizure onset, with rapid, but latter propagation

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to frontal lobes. Indeed, although the epileptogenic zone in those cases is located in the temporal lobe, there are growing evidences suggesting that the symptomatogenic zones are in fact located in the anterior cingulated cortex and/or the orbitofrontal cortex.125,126,211 This pattern of propagation with ictal discharges spreading to frontal lobe structures would explain the frontal-like symptomatology presented by this particular group of temporal lobe epilepsy patients. Surgical results in these patients are mainly dependent on the etiology of the epilepsy (mesial temporal sclerosis, malformations of cortical development, tumors, among others), being similar to those observed in patients with typical temporal lobe seizure semiology.185 Hypermotor seizures in insular lobe Ryvlin and colleges186 recently reported on three patients with medically intractable nocturnal hypermotor seizures whose depth electrodes investigation had demonstrated non-equivocal insular origin, more specifically in its anterosuperior portion. This observation was further corroborated by additional findings, with patient’s habitual seizures being triggered by electrical stimulation in one patient, and interictal spikes over the insular region in the other two patients (suggesting its involvement in the origin of the hypermotor seizures). Thus, as in the case of seizures emanating from temporal lobes, seizures originating in insular regions might be associated with hypermotor behaviors as well. Epileptogenic zone in bimanual-bipedal automatisms Bimanual-bipedal automatisms are one of many automatisms observed during hypermotor seizures. However, because it is frequent, better characterized in literature, stereotyped, and easily recognizable during video-EEG, it deserves additional comments. Although usually seen as a frontal lobe clinical finding, it might be observed in few patients with seizures originating in temporal lobes as well.212,213 Swartz212 reported that bimanual-bipedal automatisms occur in 27% of patients with frontal lobe seizure onset and in 7% of patients with temporal lobe epilepsy. Disputing this, other authors report these behaviors as being exclusive of frontal lobe epilepsy semiology.23 According to Swartz mesio and/or latero-temporal plus orbital areas seem to be activated in seizures originating from temporal lobes, while dorsolateral and mesiofrontal areas were more commonly activated in seizures originating from the frontal lobes.212 Thus, although symptomatic areas of bipedalbimanual automatisms are frontal lobes, epileptogenic areas might be frontal or temporal. Gyratory ictal behavior Gyratory ictal behavior, commonly refereed as gyratory seizures, is characterized by ictal rotation usually around the body axis for at least 180 degrees.214 It was included here because gyratory ictal behaviors might be observed as integrant components of complex motor seizures. It is a non usual ictal clinical finding, observed in about 4% of patients referred to epilepsy surgery and hardly observed in pseudoseizures.183 Gyratory ictal behaviors are more commonly observed in

seizures originating from frontal lobes, but it might be also observed in seizures originating from the temporal lobes.214 Gyratory ictal behaviors might have localizatory and lateralizing value. When following a forced head version, the rotation side is usually contralateral to the epileptogenic zone. Conversely, when not preceded by a forced head version, the direction of rotation is usually toward the side of seizure onset.214 The mechanisms involved in the genesis of these behaviors are unknown.

Gelastic seizures Gelastic seizures are seizures whose main characteristics are brief periods of laughter or grimaces, accompanied or not by subjective feelings of mirth. The term ‘gelastic’ is originated from the Greek word gelos which means joy, an expression referring to the observation of laughter during seizures.14,215–219 Gelastic seizures are uncommon type of seizures, better classified apart from other complex motor seizures due to their peculiar characteristics. Although this semiological finding strongly suggests hypothalamic hamartoma as the cause of the seizures, rare patients might experience gelastic seizures due to other types of brain lesions, located in diverse brain areas.14,14,215–224 Hypothalamic hamartomas are rare but well-recognized developmental malformations of the tuber cinereum, associated with precocious puberty and gelastic seizures. Although there is a spectrum of epilepsy severity associated with hypothalamic hamartomas, patients with hypothalamic hamartomas who present the classical form of the disease develop gelastic seizures during infancy or early childhood, followed by appearance of generalized seizures associated with broad cognitive and behavioral deterioration. Endocrine disorders are also observed, leading to precocious puberty.14,14,215–219 Rare patients might experience milder forms of the disease, with seizures only characterized by pressure to laugh.225 Typically, gelastic seizures might be difficult to recognize as epileptic events until an average of 4 years. These patients are poorly responsive to pharmachological treatments. Alternatives therapies, such as vagal nerve stimulation and the ketogenic diet have not shown clear benefits. However, because gelastic seizures originate and propagate from hypothalamic hamartomas, surgical seizure control is possible. Advances in surgical techniques have allowed safe resections of hypothalamic hamartomas, leading to drastic improvements in seizure control.14,220–223,226–231 Surgical treatment is also possible in refractory cases associated with lesions other than hypothalamic hamartoma.215,217,224,232–235 In these cases the prognosis is mainly dependent on the local and extension of the lesion. As is the rule in epilepsy surgery, small epileptogenic lesions located outside the eloquent cortical areas, and whose epileptogenic zone can be completely excised, carry good surgical prognosis. The pathophysiology of gelastic seizures remains undefined but it is mainly dependent on the lesion from where seizures emanate. In the case of hypothalamic hamartomas, investigations involving ictal recordings from implanted electrodes, including electrode contacts placed directly into the hypothalamic hamartoma, suggested that gelastic seizures arise directly form these lesions.14,236 Recently, Wu and collegues237

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Complex motor seizures: localizing and lateralizing value have demonstrated that hypothalamic hamartoma cells exhibit intrinsic pacemaker-like activity, a finding suggesting these cells might underlay the genesis of epileptic activity. Although this finding might provide evidences for seizure generation, less is known about the microcellular network associated with these cells or the hypothalamic hamartoma neural network involved in seizure spreading.237–244 Although seizures seem to originate in the hypothalamic hamartoma itself, the neural networks and pathways which are activated during seizure propagation seem to be directly responsible for promoting the laughter or joy and different patterns of propagation might account for some clinical variability of gelastic seizures. These circuits are still not completely defined. Circuits involved in physiological laughter and/or mirth seem to be activated during seizure propagation in these patients, resulting in the gelastic seizures. The same brain networks might be activated during gelastic seizures originated from other brain lesions that not hypothalamic hamartomas. Although various anatomical regions may elicit laughter, it seems that the anterior cingulate regions are involved in the motor aspects of laughter, while temporal lobes, and particularly its basal regions, seem to be mainly involved in the processing of mirth.217,233,238,245 Although laughter is quite evident in these patients, mirth is a subjective sensation and patients need to keep some degree of awareness of the seizures in order to be able to report it.

Complex motor seizures in children Clinical features of complex motor seizures are distinct in children. Not only the etiological profile and associated pathologies are diverse246–249 but differences in brain maturation also seem to influence seizure semiology.41,42,246–248,250–256 Adapting Gloor’s concepts,1 it is probably appropriate to consider that clinical phenomenology of seizures in children is generated by widespread immature neuronal matrices, not fully specialized, linked together by still in-development anatomical connections that are just beginning to become strengthened through repeated use.1,2 Indeed, it is during brain maturation that neuronal matrices are formed and wired together, creating the organized and specific neuronal networks characteristic of adult life. In immature neural matrices, the epileptic electrical activity seems to evolve according to patterns of propagation distinct from those observed during adulthood.251,257 Differences in propagation patterns seem to be influential to the clinical course of complex motor seizures in children. These theoretical considerations are important once they might help to explain the occurrence of a certain gradient of motor findings between childhood and adulthood, evolving from more simple, prominent and broader, to more elaborate, discrete, and focal complex motor patterns. In children under 3–4 years old with temporal lobe epilepsy, seizures tend to manifest with prominent tonic, clonic, or myoclonic patterns that are sometimes bilateral and symmetrical, with ictal characteristics closer to seizures from generalized epilepsy syndromes. Although lateralising signs might be observed with very good interobserver agreement in up to 75% of children under 13 years old, the lack of specific clinical lateralizing signs, especially unilateral automatisms,

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dystonic posturing, version, postictal dysphasia, and postictal facial wiping is not unusual in young children.256 Postictal nose wiping, unilateral tonic seizures, Todd’s paralysis, unilateral clonic seizures, and ictal nistagmus are among lateralising signs observed earlier.42,246,248,251,258–262 When automatisms are observed, they tend to be less elaborated and are usually restricted to oroalimentar automatisms.251 These features may be also seen in focal epilepsies originating in other brain areas.249,258–261 As the child grows, the motor manifestations become more elaborated. These modifications seem to become clinically evident after 3.5–4 years of life, probably coinciding with more advanced stages of brain maturation.251 At these later stages, motor signs become progressively less prominent, giving room to more complex automatisms that increases in complexity as the child grows. At this age, many children might also show dystonic posture or versive movements.42,246 After six years of age, motor phenomenology of temporal lobe seizures become similar to that observed in adults.42,246,248,256 As can be concluded from above, complex motor seizure analysis is particularly challenging in young children, once they present less frequently lateralizing and localizing signs, and they are usually unable to give reliable information about auras or other subjective symptoms. Oller-Daurella and Oller,263 studying focal seizures in 154 children during the first 3 years of life observed that only 23% of them had focal ictal signs suggestive of focal pathologies. All the others had nonfocal seizures. In a postsurgical retrospective analysis, Loddenkemper and colleges262 studied ictal lateralizing findings in infants from 1 to 32 months of age with focal epilepsy. They observed reliable lateralizing motor signs in only 58% of the seizures, in 63% of the children, mostly consisting of lateralized simple motor seizures. Complex motor behaviors were not observed or were not reliable for focus localization.262 Head and eye version were common, but shifted laterality, consequently being nonreliable as lateralizing signs.262 In young children, temporal, temporo-parietal, or occipital lobe seizures are more commonly characterized by impaired responsiveness and awareness (difficult to evaluate in very young children) and decreased motor activity. This pattern is usually referred as hypomotor seizures. Hypermotor seizures might occur, but it is sporadic.56,252,264 These seizures are clearly distinct from seizures initiating in frontal, central, fronto-central or fronto-parietal regions, that are characterized by motor alterations consisting of tonic, atonic, or clonic movements.56,264 Pediatric frontal lobe epilepsy might be especially challenging for epilepsy surgery. When compared with those children with temporal lobe epilepsy, children with frontal lobe epilepsy had more frequent seizures, seizures of brief duration, and seizures occurring more often during sleep. Other characteristics of pediatric frontal lobe epilepsy are seizures of explosive onset with scream or cry, marked agitation during seizures, stiffening, kicking, or bicycling of legs, incontinence, and rapid recovery, with only brief postictal phase.265,266 In older children, seizures assume patters of adulthood epilepsy. In mesial temporal lobe epilepsy seizures are usually of automotor type while in patients with frontal lobe epilepsy seizures might be complex hypermotor seizures or simple motor seizures, like asymmetric tonic seizures or focal clonic signs.265 Epileptic spasms are nonspecific findings

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regarding lateralization, once it can be observed in association with focal lesions in all regions cited above.264

Final comments The reader must keep in mind that, although several aspects of complex motor seizures might help in localize and lateralize the seizure onset zone, semiological findings cannot be 100% accurate. Some discrepancy should always be expected between the epileptogenic and symptomatogenic zone once these zones are conceptually distinct, and although overlapping is common, there exist considerable intra- and interpatient variability. Also because of this variability, exceptions in the lateralizing and localizatory value of many signs may be expected. Nevertheless, careful descriptions of the complex motor findings observed during ictal periods are accurate enough for correct semiological seizure classification, frequently providing useful evidences supporting surgical decisions.7–9 In this venue, besides studying isolated clinical signs

and describing them in detail, epileptologists should also concentrate research efforts in specifying common patterns of composed motor behaviors, as well as in the establishment of common patterns of temporal and sequential evolution of these behaviors. Although not practical during actual routine presurgical evaluation, it is however possible that such analysis might be particularly relevant in near future. For example, combining two motor signs might improve the diagnostic power of the epileptogenic zone, as is the case of ipsilateral automatism associated with contralateral dystonic posturing in automotor seizures. Also, some patterns might have prognostic significances, as is the case of patients that evolve to generalization during ictal spreading of mesial temporal lobe seizures.95 For these matters, cluster analysis,184,267 neuroetholgy,268 or other techniques developed in order to group common events together and establish timerelated sequences of behaviors might add further insights to clinical analysis of isolated signs. We believe such approaches might help planning more tailored surgical resections in future.

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Textbook of epilepsy surgery Swartz BE. Electrophysiology of bimanual-bipedal automatisms. Epilepsia 1994;35:264–74. Picard F, Chauvel P. Autosomal dominant nocturnal frontal lobe epilepsy: the syndrome. Rev Neurol 1999;155:445–9. Dobesberger J, Walser G, Embacher N et al. Gyratory seizures revisited: a video-EEG study. Neurology 2005;64:1884–7. Garcia A, Gutierrez MA, Barrasa J et al. Cryptogenic gelastic epilepsy of frontal lobe origin: a paediatric case report. Seizure 2000;9:297–300. Daly DD, Mulder DW. Gelastic epilepsy. Neurology 1957;7: 189–92. Arroyo S, Lesser RP, Gordon B et al. Mirth, laughter and gelastic seizures. Brain 1993;116 (4):757–80. Black DW. Pathological laughter. A review of the literature. J Nerv Ment Dis 1982;170:67–71. Likavec AM, Dickerman RD, Heiss JD et al. Retrospective analysis of surgical treatment outcomes for gelastic seizures: a review of the literature. Seizure 2000;9:204–7. Striano S, Striano P, Sarappa C et al. The clinical spectrum and natural history of gelastic epilepsy-hypothalamic hamartoma syndrome. Seizure 2005;14:232–9. Mullatti N, Selway R, Nashef L et al. The clinical spectrum of epilepsy in children and adults with hypothalamic hamartoma. Epilepsia 2003;44:1310–19. Cascino GD, Andermann F, Berkovic SF et al. Gelastic seizures and hypothalamic hamartomas: evaluation of patients undergoing chronic intracranial EEG monitoring and outcome of surgical treatment. Neurology 1993;43:747–50. Nguyen D, Singh S, Zaatreh M et al. Hypothalamic hamartomas: seven cases and review of the literature. Epilepsy Behav 2003;4:246–58. Dericioglu N, Cataltepe O, Tezel GG et al. Gelastic seizures due to right temporal cortical dysplasia. Epileptic Disord 2005;7:137–41. Sturm JW, Andermann F, Berkovic SF. ‘Pressure to laugh’: an unusual epileptic symptom associated with small hypothalamic hamartomas. Neurology 2000;54:971–3. Akai T, Okamoto K, Iizuka H et al. Treatments of hamartoma with neuroendoscopic surgery and stereotactic radiosurgery: a case report. Minim Invasive Neurosurg 2002;45:235–9. Palmini A, Chandler C, Andermann F et al. Resection of the lesion in patients with hypothalamic hamartomas and catastrophic epilepsy. Neurology 2002;58:1338–47. Choi JU, Yang KH, Kim TG et al. Endoscopic disconnection for hypothalamic hamartoma with intractable seizure. Report of four cases. J Neurosurg 2004;100:506–11. Delalande O, Fohlen M. Disconnecting surgical treatment of hypothalamic hamartoma in children and adults with refractory epilepsy and proposal of a new classification. Neurol Med Chir 2003;43:61–8. Freeman JL, Harvey AS, Rosenfeld JV et al. Generalized epilepsy in hypothalamic hamartoma: evolution and postoperative resolution. Neurology 2003;60:762–7. Rekate HL, Feiz-Erfan I, Ng YT et al. Endoscopic surgery for hypothalamic hamartomas causing medically refractory gelastic epilepsy. Childs Nerv Syst 2006;22(8):874–80. McConachie NS, King MD. Gelastic seizures in a child with focal cortical dysplasia of the cingulate gyrus. Neuroradiology 1997;39:44–5. Coria F, Bahillo ME, Moral BM et al. Late-onset isolated gelastic epilepsy secondary to entrapment of the right temporal horn. Neurologia 2000;15:204–7. Kurle PJ, Sheth RD. Gelastic seizures of neocortical origin confirmed by resective surgery. J Child Neurol 2000;15:835–8. Chassagnon S, Minotti L, Kremer S et al. Restricted frontomesial epileptogenic focus generating dyskinetic behavior and laughter. Epilepsia 2003;44:859–63. Kuzniecky R, Guthrie B, Mountz J et al. Intrinsic epileptogenesis of hypothalamic hamartomas in gelastic epilepsy. Ann Neurol 1997;42:60–67. Wu J, Xu L, Kim DY et al. Electrophysiological properties of human hypothalamic hamartomas. Ann Neurol 2005;58:371–82. Cascino GD, Andermann F, Berkovic SF et al. Gelastic seizures and hypothalamic hamartomas: evaluation of patients undergoing chronic intracranial EEG monitoring and outcome of surgical treatment. Neurology 1993;43:747–50. Freeman JL. The anatomy and embryology of the hypothalamus in relation to hypothalamic hamartomas. Epileptic Disord 2003;5:177–86. Kahane P, Ryvlin P, Hoffmann D et al. From hypothalamic hamartoma to cortex: what can be learnt from depth recordings and stimulation? Epileptic Disord 2003;5:205–17.

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Kerrigan JF, Ng YT, Chung S et al. The hypothalamic hamartoma: a model of subcortical epileptogenesis and encephalopathy. Semin Pediatr Neurol 2005;12:119–31. Leal AJ, Passao V, Calado E et al. Interictal spike EEG source analysis in hypothalamic hamartoma epilepsy. Clin Neurophysiol 2002;113:1961–9. Leal AJ, Moreira A, Robalo C et al. Different electroclinical manifestations of the epilepsy associated with hamartomas connecting to the middle or posterior hypothalamus. Epilepsia 2003;44:1191–5. Leal AJ, Dias AI, Vieira JP. Analysis of the EEG dynamics of epileptic activity in gelastic seizures using decomposition in independent components. Clin Neurophysiol 2006;117:1595–601. Iwasa H, Shibata T, Mine S et al. Different patterns of dipole source localization in gelastic seizure with or without a sense of mirth. Neurosci Res 2002;43:23–9. Wyllie E, Chee M, Granstrom ML et al. Temporal lobe epilepsy in early childhood. Epilepsia 1993;34:859–68. Ray A, Kotagal P. Temporal lobe epilepsy in children: overview of clinical semiology. Epileptic Disord 2005;7:299–307. Terra-Bustamante VC, Inuzuca LM, Fernandes RM et al. Temporal lobe epilepsy surgery in children and adolescents: clinical characteristics and post-surgical outcome. Seizure 2005;14:274–81. Terra-Bustamante VC, Fernandes RM, Inuzuka LM et al. Surgically amenable epilepsies in children and adolescents: clinical, imaging, electrophysiological, and post-surgical outcome data. Childs Nerv Syst 2005;21:546–51. Fogarasi A, Janszky J, Faveret E et al. A detailed analysis of frontal lobe seizure semiology in children younger than 7 years. Epilepsia 2001;42:80–5. Fogarasi A, Jokeit H, Faveret E et al. The effect of age on seizure semiology in childhood temporal lobe epilepsy. Epilepsia 2002;43:638–43. Fogarasi A, Boesebeck F, Tuxhorn I. A detailed analysis of symptomatic posterior cortex seizure semiology in children younger than seven years. Epilepsia 2003;44:89–96. Loddenkemper T, Wyllie E, Neme S et al. Lateralizing signs during seizures in infants. J Neurol 2004;251:1075–9. Fogarasi A, Janszky J, Tuxhorn I. Ratio of motor seizure components in childhood temporal lobe epilepsy. J Child Neurol 2005;20(11):932–932. Fogarasi A, Tuxhorn I, Hegyi M et al. Predictive clinical factors for the differential diagnosis of childhood extratemporal seizures. Epilepsia 2005;46:1280–5. Fogarasi A, Janszky J, Tuxhorn I. Peri-ictal lateralizing signs in children: blinded multiobserver study of 100 children < or =12 years. Neurology 2006;66:271–4. Holmes GL. Epilepsy in the developing brain: lessons from the laboratory and clinic. Epilepsia 1997;38:12–30. Fogarasi A, Janszky J, Faveret E et al. A detailed analysis of frontal lobe seizure semiology in children younger than 7 years. Epilepsia 2001;42:80–85. Fogarasi A, Boesebeck F, Tuxhorn I. A detailed analysis of symptomatic posterior cortex seizure semiology in children younger than seven years. Epilepsia 2003;44:89–96. Fogarasi A, Tuxhorn I, Hegyi M et al. Predictive clinical factors for the differential diagnosis of childhood extratemporal seizures. Epilepsia 2005;46:1280–5. Fogarasi A, Janszky J, Tuxhorn I. Peri-ictal lateralizing signs in children: blinded multiobserver study of 100 children < or =12 years. Neurology 2006;66:271–74. Loddenkemper T, Wyllie E, Neme S et al. Lateralizing signs during seizures in infants. J Neurol 2004;251:1075–9. Oller-Daurella L, Oller LF. Partial epilepsy with seizures appearing in the first three years of life. Epilepsia 1989;30:820–6. Acharya JN, Wyllie E, Lüders HO et al. Seizure symptomatology in infants with localization-related epilepsy. Neurology 1997;48:189–96. Lawson JA, Cook MJ, Vogrin S et al. Clinical, EEG, and quantitative MRI differences in pediatric frontal and temporal lobe epilepsy. Neurology 2002;58:723–9. Sinclair DB, Wheatley M, Snyder T. Frontal lobe epilepsy in childhood. Pediatr Neurol 2004;30:169–76. Wieser HG, Meles HP, Bernoulli C et al. Clinical and chronotopographic psychomotor seizure patterns (SEEG study with reference to postoperative results). Acta Neurochir Suppl 1980;30:103–12. Dal Col ML, Terra-Bustamante VC, Velasco TR et al. Neuroethology application for the study of human temporal lobe epilepsy: from basic to applied sciences. Epilepsy Behav 2006;8:149–60.

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Dialeptic seizures: localizing and lateralizing value S Noachtar

Definition Definition of dialeptic seizure The term dialeptic seizure has been introduced by us to allow for a seizure classification which is purely based on ictal seizure semiology.1,2 Dialeptic seizure refers to a seizure whose predominant ictal features are alteration of consciousness, staring and loss, or minimal motor activity. The term absence seizures, on the other hand, describes a subgroup of dialeptic seizures but also includes EEG findings in the seizure classification.3 It was the pioneering work of Gibbs and co-workers who demonstrated that in patients with absence epilepsies dialeptic seizures were associated with generalized 3 Hz spikewave complexes in the EEG.4 Ever since the term absence has been defined as an electroclinical syndrome consisting of loss of consciousness, arrest of activity and an EEG showing generalized spike-wave complexes. It seems therefore appropriate to introduce a new term which describes the ictal loss of consciousness and the arrest of motor activity emphazising a purely clinical seizure classification independent of associated EEG findings. The verb διαλειπειν is old Greek and means to interrupt, stand still, or pass out. Definitions of consciousness are subject to controversy.5,6 A clinically applicable definition of consciousness has to be restricted to awareness and responsiveness which is actually included in the proposal of the International Classification of Epileptic Seizures (ICES).3 However, there are not infrequently limitations and exceptions to this concept. Patients may not infrequently recall the command to push a button during a seizure but may have been unable to do so.7,8 Awareness and responsiveness may be disturbed differently. It has been shown recently, that patients may be fully responsive during focal seizures associated with automatisms and yet not be able to recall the events during the seizure. We could observe this phenomenon prospectively in 10% of the patients with right temporal lobe epilepsies.9 Even with simultaneous Video-EEG recordings it may be impossible to exclude that the patients failure to respond was not caused by an arrest of activity due to epileptic activation of the speech areas. Thus, assessment of consciousness during an epileptic seizure may well not be trivial and remains conceptually difficult.5 For the purpose of the present chapter we will consider that an impairment of consciousness occurred during a dialeptic seizure if either responsiveness or recall were disturbed. Clinically, dialeptic seizures frequently are associated with minimal motor activity such as eyelid myoclonia and upward

eye movements. To classify seizures in children or mentally retarded adults in whom it is sometimes impossible to assess ictal consciousness the term hypomotor seizure has been introduced.10,11 Loss of voluntary tonic motor activity may be present during dialeptic seizures and is clearly distinct from atonia of postural tone leading to drop or fall. If the predominant feature of a seizure is an inability to follow a motor command such as pressing a button with full recall of the event, the seizure should be classified as an akinetic seizure (see Chapter 54a). If motor activity is present during a dialeptic seizure it is usually restricted to some minor motor movements like eye blinking. If motor activity predominates the seizure semiology the seizure will be classified according to the specific motor activity (e.g., automotor seizure, if automatisms occur or clonic seizure left arm, if the left arm is jerking). Subgroups of dialeptic seizures A subclassification of dialeptic seizures seems justified since the above mentioned definition is quite broad. Some patients have very brief dialeptic seizures characterized by an abrupt onset and offset. These seizures when associated with bursts of generalized 3 Hz spike-wave complexes have been classified as typical absences and are usually seen in patients with absence epilepsies.3 On the other hand, the ICES identifies as atypical absences dialeptic seizures in which changes in muscle tone are more pronounced and which usually do not begin and end abruptly and are accompanied by generalized irregular slow spike-wave complexes with a repetition rate of 2.5 Hz or less.3 It has also been proposed to distinguish between ‘simple’ absences and ‘complex’ absences basically depending on the degree of motor activity associated.12,13 Clinically, this subclassification overlaps somewhat with the distinction between ‘typical’ and ‘atypical’ absences which has been proposed by the ICES.3 However, there is evidence to suggest that the distinction between typical and atypical absences depends mainly on the EEG abnormalities associated with the dialeptic seizures.14 Holmes et al.14 analyzed a total of 926 dialeptic seizures in 54 patients with generalized epilepsies and found automatisms more frequently in ‘typical absences’ and more loss of muscle tone in ‘atypical absences’. Both subtypes of dialeptic seizures usually had a sudden onset and end. The authors concluded that typical and atypical ‘absence’ seizures are not discrete entities but rather form a continuum.14 Based on the associated motor or automotor activity dialeptic seizures occurring in patients with generalized epilepsies 479

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(absences) have been subdivided in six subtypes by Penry and co-workers.15 Only about 10% of all absence seizures are characterized by lapse of consciousness usually associated with a change in facial expression (staring) and cessation of motor activity, according to Penry et al.15 Of the patients with absence seizures, 71% showed at least some clonic components.15 Dialeptic seizures with tonic components are rare (3%),15 and show an increase of muscle tone which may cause a backward movement of the head and trunk (‘retropulsiv petit mal’).16 The tonic postural movements usually include both flexor and extensor muscles of the trunk or head, but extensors typically dominate. They can be asymmetric, leading to brief versive movements. Atonic components during dialeptic seizures are usually gradual causing the head to drop slightly or objects fall of the hands. An asymmetry of the decrease of muscle tone may occur. Myoclonic jerks may intermix leading to a rhythmic appearance of a head drop. Rarely the atonia is as severe and lasts long enough to cause the patient fall. Seizures in which the loss of tone is the predominant feature should be classified as atonic seizures or astatic seizures when the patients actually falls. An atonic component occurred in about half of the patients in at least one absence seizure.15 Most patients with dialeptic seizures present some mild automatisms in at least some of their seizures. The automatisms may reflect a continuation of what the patient was doing prior to the seizure onset. The patient may, for instance, continue moving the fork or spoon or chewing if a seizure occurs while eating or continue to walk if a seizure commences while walking. However, the movements will usually be slower and not as elaborate. De novo automatisms typically include simple movements such as lip licking, grimacing, yawning, swallowing, scratching or fumbling. About 88% of the patients of Penry et al. showed some kind of automatisms during their dialeptic seizures,15 and 28% of all dialeptic seizures were subclassified as dialeptic seizures with automatisms. The occurrence of automatisms increases with seizure duration and usually oral automatisms occur first followed by manual automatisms.17 At a seizure duration of 3 seconds in 22% of the seizures automatisms were present, whereas at a seizure duration of 18 seconds in 95% of the seizures automatisms occurred.15 Seizures in which the automatisms constitute a prominent part of the seizure should be classified as automotor seizures. Some dialeptic seizures are accompanied with autonomic components such as pallor of the face, flushing, mydriasis, salivation, tachycardia, piloerection and rarely urinary incontinence. It is important to notice that in 40% of the dialeptic seizures of patients with generalized epilepsies several of the above-mentioned features occurred.15 There was a considerable overlap of the subtypes from one seizure to another in the same individual.15 Fifty percent of the patients evaluated have had only one of the above-mentioned subtypes of absence seizures.15 There are reports which will be discussed later that describe dialeptic seizures in patients with focal epilepsies. However, subtypes of dialeptic seizures are not systematically studied in these patients.18–21 Further studies are currently being undertaken to gain more insight into the semiology of dialeptic seizures in focal epilepsies.22

Relationship of dialeptic seizures with ‘absence seizures’ and ‘complex-partial’ seizures As mentioned above the term dialeptic seizure exclusively refers to an ictal seizure semiology. The ICES, however, is based on both, clinical symptomatology and EEG.3 Therefore, a seizure consisting of lapse of consciousness and minimum of motor activity, i.e., would be classified as ‘complex-partial’ seizure according to the ICES if the EEG reveals focal epileptiform activity.23–24 A seizure with essentially identical seizure semiology would be classified as an absence seizure in ICES, if the EEG showed generalized spike-wave complexes. Thus, absence seizures define an electroclinical syndrome consisting of dialeptic seizures, and less frequently other semiological seizure types like automotor seizures or akinetic seizures, occurring in association with generalized spike-wavecomplexes. Complex partial seizures of the ICES define any seizure occurring in association with an alteration of consciousness and focal epileptiform EEG discharges (or normal EEG) and clinical or imaging features suggesting a focal epilepsy. Dialeptic seizures associated with a focal EEG pattern are actually one type of complex partial seizures of the ICES. The main difference between these terms is that dialeptic seizures refer exclusively to the clinical semiology of the seizures whereas absence seizures and complex partial seizures define electroclinical complexes, i.e., the definition of the terms includes clinical semiology and a specific EEG seizure pattern. In this chapter we will use the above-mentioned clinical definition of dialeptic seizures. This will allow us to use the term dialeptic seizure independently of the EEG. Such an approach may enable us to better assess the mode of appearance and frequency of dialeptic seizures in different epilepsy syndromes and allow us to better investigate the evolution and spread of epileptic seizures.24 Relationship of dialeptic seizures with epilepsy syndromes Dialeptic seizures can occur in different epilepsy syndromes (Figure 53.1). Most patients with dialeptic seizures have generalized epilepsies such as absence epilepsy and Lennox-Gastaut syndrome. Dialeptic seizures also occur even if less frequently in other generalized epilepsies such as generalized myoclonic epilepsy and probably even less frequently in focal epilepsies.18,25–28 We recently reviewed the electronic data files of the Epilepsy Program of the Cleveland Clinic Foundation and identified 34 patients with unequivocal EEG-video documented dialeptic seizures in patients with focal epilepsies (Figure 53. 2).

Clinical characteristics of dialeptic seizures Clinical symptomatology Dialeptic seizures are seen in different epileptic syndromes and tend to vary considerably in their clinical semiology. In the literature there is no good semiological study studying systematically the differences of dialeptic seizures in different epileptic syndromes. Particularly, there is little data on dialeptic seizures in focal epilepsies. Because of this limitation it is necessary to describe the characteristics of dialeptic seizures independently for each epileptic syndrome.

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focal epilepsies

Lennox-Gastaut syndrome

DIALEPTIC SEIZURES

absence epilepsy

juvenile myoclonic epilepsy

Figure 53.1 Dialeptic seizures occur in absence epilepsy, juvenile myoclonic epilepsy, Lennox-Gastaut syndrome and in focal epilepsies.

Dialeptic seizures in patients with absence epilepsy The hallmark of dialeptic seizures in these patients is a sudden lapse of consciousness with amnesia and an arrest of volitional movements. Usually the seizures are brief, lasting about 4–10 seconds.29 Rarely (3%), dialeptic seizures last up to one minute.15–17,30 The seizures may be subtle and go unnoticed by the surrounding. The patient will typically show an arrest of whatever they were doing at the onset of the seizure. A preexisting movement like walking may however sometimes be continued for some time. If a dialeptic seizure occurs while talking, the patient may realize an interruption of the conversation but may otherwise be unaware of having had a seizure. During an dialeptic seizure the patient is unresponsive, but may grunt in reply to a question or verbal commands. Reactivity is frequently disturbed at the beginning of the seizure and is less pronounced after a few seconds.7 Browne et al.7 could demonstrate, that 4 seconds after onset of the spikewave discharges, 52% of their patients with generalized epilepsies had normal reaction time. This can be nicely documented when asking the patient to press a button using the ‘clicker test’. The patients are usually unable to follow the command to press the button but some may recall the command later8.

DIALEPTIC SEIZURES focal epilepsy syndromes __________________________________ frontal

parieto-occipital 6

11

2

15

temporal

unclassified focal

n=34

Figure 53.2 Focal epilepsies in which video-EEG documented dialeptic seizures were seen in 34 patients recorded at the Cleveland Clinic Foundation.

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During a dialeptic seizure motor activity is normally reduced to a minimum, although some minor movements may be present the longer the seizure lasts.17 These typically include clonic or versive upward eye movements, blinking or mild clonic jerks of the face or the extremities. The muscle tone may change during such attacks either presenting an increase of tone such as in a ‘retropulsiv’ movement of the trunk 16 or rarely a decrease of tone leading to dropping of the head or slumping of the trunk. The face usually gives the impression of atonic stare. The eyes become vacant giving a trance like expression. Subtle automatisms like lip smacking, swallowing, or fumbling may also occur but should not predominate otherwise the seizure would be classified as automotor seizure. Polygraphic video-EEG studies have shown that 1.2 seconds after onset ocular movements occur followed by oral automatisms about 4 seconds later and 1 second later manual automatisms develop.17 Dialeptic seizures usually end abruptly, and the patient may commence his previous activities being amnestic for the time of the seizure. Detailed videoEEG analysis supported the clinical experience that most patients demonstrate some mild motor activity during their dialeptic seizures and only rarely lapse of consciousness and arrest of motor activity are the only ictal features.15–17 Dialeptic seizure is the predominant seizure type in absence epilepsies and best described in this epilepsy syndrome. These patients account for 10–15% of epilepsy patients in the pediatric age range.31 The dialeptic seizures in these patients usually last 3 to 10 seconds, occur daily and very frequently (‘pyknolepsy’).32 The age of onset ranges from 3 to 12 years of age and girls account for approximately two-thirds of the affected.16,30 Later in life, patients with absence epilepsies frequently suffer also from generalized tonic-clonic seizures.16,29,33 In long-term follow-up studies, the proportion of patients entering remission varied between 19% to 90%.34–42 Favorable prognostic factors include normal intelligence, lack of additional generalized tonic-clonic seizures, typical 3 Hz Spikewave-complexes and initial response to medical treatment. Generalized tonic-clonic seizures occur in 35–60% of these patients.35,37,38,41 The longer the follow-up period, the poorer seems the remission rate. However, even if the dialeptic seizures have a good prognosis, generalized tonic-clonic seizures may ensue in adulthood.43 In a long-term follow-up study over 20 to 37 years, 92% of the patients, in whom the dialeptic seizures persisted beyond the age of 30 to 61 years, eventually developed generalized tonic-clonic seizures.44 Some authors subdivide absence epilepsies into childhood absence epilepsy and juvenile absence epilepsy according to the age of onset and clinical course.16,45 The patients with juvenile absence epilepsy are reported to have less frequent dialeptic seizures (‘spanioleptic’), generalized tonic-clonic seizures may precede the dialeptic seizures more frequently and the EEG shows more irregular and fast spike-wave-complexes and a higher rate of photoparoxysmal responses 46 as compared to the childhood absence epilepsy group. These differences are considered to reflect genetically different traits.47 Others have questioned the clinical significance of this subdivision of absence epilepsies and propose a continuum of idiopathic generalized epilepsies with a great deal of overlap.48–51 The issue is at present not resolved, but subclassification of the absence epilepsies may be justified in the light of further

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genetic studies47 and possible different prognosis.42,51 Childhood absence epilepsy showed less seizure relapse after discontinuation of antiepileptic medication (19%) than juvenile absence epilepsy (33%),42 but this observation was not supported by others.51 The ictal EEG usually reveals regular spike-wave-complexes which show a repetition rate of 3 Hz. The spikes may be more blunt and the repetition rate will drop the longer the dialeptic seizures last. Patients with absence epilepsies are particularly sensitive to hyperventilation and/or photic stimulation.34,52–54 Of the 374 dialeptic seizures in the 48 patients evaluated by Penry et al., 29% occurred spontaneously. Hyperventilation which is the most potent activator in these patients, provoked 53% and photic stimulation another 18% of the dialeptic seizures.15 Both methods also activate interictal generalized spike-wavecomplexes in the EEG. The evolution of dialeptic seizures depends on the epilepsy syndrome. In generalized epilepsy syndromes the typical evolution of an dialeptic seizure is into a generalized tonic-clonic seizure.16,24 Dialeptic seizures in patients with Lennox-Gastaut syndrome It was already noticed in the early days of EEG that a slow repetition rate of generalized spike-wave-complexes at 2 Hz (‘petit mal variant’) correlates with a milder impairment of consciousness during dialeptic seizures as compared to the 3 Hz spike-wave pattern.54–55 The syndrome has been delineated later referring to patients with frequent tonic-, atonic-, myoclonic- and dialeptic seizures commencing early in childhood and being poorly responsive to medication. The patients usually have or develop mental impairment.56,57 The ICES lists these dialeptic seizures as ‘atypical’ absences (see above).3 In a pediatric age group Lennox-Gastaut syndrome accounted for 1–2%, whereas childhood absence epilepsy for 10–15% and juvenile absence epilepsy for 5%.31 In patients with LennoxGastaut syndrome the onset and end of dialeptic seizures was reported to be more gradual and not as abrupt as in the absence epilepsy patients and the attacks usually last longer. However, the video-EEG study of Holmes et al.,14 on 926 dialeptic seizures in 54 patients did not show any significant difference in the seizure onset and end between typical and atypical absence seizures. Some tonic, atonic and/or clonic movements particularly concerning the eyes and the perioral muscles and automatisms may occur. Dialeptic seizures in these patients are not precipitated by hyperventilation and photic stimulation. Hyperventilation rarely facilitates the occurrence of slow-spikes-wave complexes and photic stimulation does not have any effect.58 The evolution of dialeptic seizures in these patients has not yet been systematically evaluated but they can also evolve into generalized tonic-clonic seizures. Dialeptic seizures in patients with other generalized epilepsies Dialeptic seizures are not infrequently seen in patients with other generalized epilepsies.16,59 Juvenile myoclonic epilepsy occurs in 5% of a pediatric population.31 The frequency of

dialeptic seizures in patients with juvenile myoclonic epilepsy varies between 15–40% of the patients in different studies.16,61–63 Clinically, the dialeptic seizures in this patients group do not differ from those seen in patients with absence epilepsies. However, the ictal EEG in this older age group is not as regular as in the children with absence epilepsies and shows typically irregular spike-wave complexes with a repetition rate faster than 3 Hz. Photic stimulation seems to be particularly useful in patients with juvenile myoclonic epilepsy and elicits epileptiform activity in the EEG of 30% of these patients,46 although dialeptic are rarely provoked. Rarely, other mechanisms such as reading-induced or video-game-induced dialeptic seizures have been reported.64,65 Some authors proposed the classification of an ‘epilepsy with myoclonic absences’ describing an epilepsy syndrome with patients who they felt are inbetween the idiopathic absence epilepsies and the Lennox-Gastaut syndrome.35,66–68 ‘Myoclonic absence seizures’ represent the only or predominant seizure type in these sometimes mentally retarded patients and the myoclonic components are described to be massive as compared to the mild clonic movements recognized in typical dialeptic seizures. These seizures are refractory to medication in about 50% of these patients. This syndrome has been included in the International Classification of Epileptic Syndromes.69 However, a distinction by seizure type alone appears unjustified. Patients with neurological diseases such as Batten disease, Lafora disease, or subacute sclerotic panencephalitis are rarely reported to suffer from dialeptic seizures.70–72 Dialeptic seizures in focal epilepsies Janz73 already pointed out that dialeptic seizures consisting of pure brief lapse of consciousness may occur in epilepsy syndromes other than generalized epilepsies as well and therefore proposed the term ‘pyknoleptic petit mal’ for dialeptic seizures in patients with childhood absence epilepsy. Although several textbooks on epilepsy mention that dialeptic seizures may also occur in focal epilepsies, our knowledge at present is very limited.16,73 Only few data and scattered reports are available which mainly deal, although not exclusively, with patients with frontal lobe epilepsies.25,28 An abrupt ictal onset and end which is a typical feature of dialeptic seizures in childhood absence epilepsies seems also to occur in patients with frontal lobe epilepsies. This observation prompted the French school to coin the term ‘frontal absence’.27,74 Fronto-mesial and fronto-orbital seizure onset has been associated with this kind of seizure.27,74 ‘Complex partial seizures’ including dialeptic seizures (frontal absences) have been reported to occur in 161 seizures of medial intermediate frontal onset of 39 patients.27,74 However, the relative frequency of dialeptic seizures (frontal absences) was not specified. The symptoms observed during these ‘frontal absences’ include disturbance of consciousness (loss of contact), speech arrest, arrest of movements, simple gestures (automatisms), conjugate deviation of the eyes and head, and immediate recovery of consciousness.27,74 Patients with temporal lobe epilepsies not infrequently also have seizures consisting of an arrest of movement and lapse of consciousness without automatisms or other

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Dialeptic seizures: localizing and lateralizing value motor movements.21,78 Because these seizures resemble the dialeptic seizures (‘absences’) seen in patients with generalized epilepsies the term ‘pseudoabsence’ has been proposed.26,78,79 Karbowski et al. described this phenomenon in 5 of 12 children evaluated.80 Wieser et al. reported that ‘pseudoabsence’ seizures have been the predominant seizure type in 2 out of 25 patients evaluated.79 Shimizu et al. reported that the interictal PET regional hypometabolism was identical in 18 temporal lobe patients regardless whether they had seizures characterized by automatisms (‘automotor seizure’) or motionless staring (‘dialeptic seizures’).81 Wieser subclassified focal seizures arising from frontal and temporal lobe according to seizure onset as documented by depth recordings.82 However, no clear clinical distinction was made with regard to dialeptic seizures. Recently, a study using cluster analysis in seizures of patients with frontal and temporal lobe epilepsies concluded that dialeptic seizures may occur in both syndromes and cannot be distinguished on clinical grounds only. The distinction of dialeptic seizures consisting of an arrest of movement and lapse of consciousness arising from the temporal lobes and dialeptic seizures particularly in patients with Lennox-Gastaut syndrome (‘atypical’ absences) is sometimes impossible based on clinical semiology.83 We reviewed the database at the Epilepsy Monitoring Unit of the Cleveland Clinic Foundation from 1991 to 1995 looking for patients who underwent prolonged video-EEG Monitoring and in whom at least one unequivocal dialeptic seizure was recorded. Dialeptic seizures were defined purely on clinical grounds as seizures in which arrest of activity and lapse of consciousness were the predominant ictal features, and other features such as automatisms are not as prominent. We identified 34 patients with focal epilepsies in whom dialeptic seizures were documented by EEG and video. Fifteen of these 34 patients had focal epilepsies of one hemisphere but the epileptogenic zone could not be localized further. Eleven patients had temporal, six patients frontal and another two had parieto-occipital lobe epilepsies (Figure 53.2). The proportion of patients with temporal lobe epilepsy may be biased because these patients tend to be over-represented in epilepsy surgery centers. In focal epilepsies hyperventilation may provoke focal epileptiform discharges in up to 10% of the patients, but it is not known whether this activates dialeptic seizures. Photic stimulation is not an activator of focal seizures except rarely in parieto-occipital epilepsies. It is not known if dialeptic seizures can be triggered by photic stimulation. The semiology of the dialeptic seizures was similar independent of the lobe of seizure origin. Thus, analysis of the dialeptic seizure itself did not allow differentiation of the epileptogenic zone. However, the evolution of dialeptic seizures may provide lateralizing or localizing information (see below). Dialeptic seizures may be preceded by other seizure types such as auras24,25 (see below). In focal epilepsies the evolutions are more variable: an aura may precede a dialeptic seizure and the dialeptic seizure itself may evolve into other focal seizures such as for instance into a versive seizure. At present no representative data is available as to the evolution of dialeptic seizures. There are two main reasons for this: the term ‘absence’ is by definition of ICES a generalized seizure, and ICES does not allow for classification of seizure evolution in generalized epilepsies. Recently, a study analyzed

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seizure patterns in patients with frontal and temporal lobe epilepsies and used a purely clinically-based definition of the seizure types.84 Most dialeptic seizures (identified as ‘absence’ seizures in this study) commenced without warning, but in 13 of 57 cases auras preceded the dialeptic seizures and further evolved into versive or automotor seizures.84 Pathophysiology Generalized epilepsies The advent of electroencephalography proved the epileptic origin of dialeptic seizures in generalized epilepsies. Gibbs et al. described first that ‘absence’ seizures are associated with a generalized 3 Hz spike-wave pattern in the EEG.4 Since several experimental animal models have been established which served for both the search of the underlying mechanisms of the absence epilepsies and the development of drugs against human dialeptic seizures. Examples include, amongst others, the systemic pentylenetetrazol model,85 the feline generalized penicillin model,86 the rat ICV enkephaline model,87 the systemic gamma-hydroxybutyrate model,88 the tetrahydroxyisoxosolopyridine (THIP) model,89 and genetic models such as the photosensitive Senegalese baboon (papio papio)90 or the tottering mouse.91 The concepts proposed for the generation of dialeptic seizures occurring in generalized epilepsies have been subject to much controversy. Two contrary hypotheses have been debated for decades.92 The centrencephalic theory (Montreal school) proposed that a thalamocortical mechanisms capable of inducing spindles and recruiting responses were involved in the production of generalized spike-wave discharges and typical dialeptic seizures.93,94 It has been postulated that brain stem structures as also the thalamus may play an essential role in the pathogenesis of dialeptic seizures. A recent study using functional MRI supported this view and showed that, during absence seizures of a patient with absence epilepsy, the BOLD effect in the frontal cortex was reduced whereas it was increased in the thalamus.95 In contrast to this concept it has been stated that generalized spike-wave discharges are a cortical phenomenon.96,97 Both concepts were based on the results of experimental studies in animals. In an attempt to reconcile these apparently conflicting views, the corticoreticular hypothesis has been put forward. It postulated that generalized spike-wave discharges result from an abnormal interaction of cortical and diffusely projecting subcortical thalamic and midbrain reticular mechanisms.98,99 Based on this theory, the cortex is the primary generator of spike-wave discharges.100 It could be demonstrated that electrical stimulation of the thalamus which elicited spindles and recruiting responses in control animals elicited spike-wave complexes in cats given penicillin intramuscularly.101 On the other hand, injection of penicillin in the thalamus did not elicit spike-wave discharges, whereas diffuse application on the cortex did. Additional studies could also demonstrate a facilitating effect on spike-wave discharges through a depression of desynchronizing effects of the reticular formation.102 Several further mechanisms, such as altered properties of T-type calcium channels, increased numbers of GABA-B receptors, and changes in the subunit composition of GABA-A receptors have been postulated to be involved in the generation of dialeptic seizures in generalized epilepsies.103 Since the

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predominant clinical feature of dialeptic seizures is an inhibition of motor and cognitive function, it has been suggested that the underlying mechanisms may involve synaptic inhibition.104 It could be demonstrated in the feline generalized penicillin model, that the slow-waves of the spike-wave complexes are associated with GABA-mediated chloride-sensitive IPSPs in cortical neurons.105 Furthermore, GABA agonists like THIP can elicit ‘absence like seizures’ suggesting an effect of synaptic inhibition.89

complexes seen with dialeptic seizures in patients with generalized epilepsies points to the frontal lobes.115 Alternatively, arrest of motor activity could be an expression of the loss of consciousness. However, as mentioned before, preserved perception associated with inhibited motor activity has been documented.116 On the other hand disturbed perception with preservation of some automatic motor activity has also been observed. It therefore seems unlikely that consciousness and motor activity are disturbed by the same mechanisms.

Focal epilepsies The term ‘frontal absence’ has been coined by the French school referring to brief seizures which are clinically not distinguishable from dialeptic seizures of the generalized epilepsies. Invasive EEG recordings in these patients frequently revealed a frontal seizure onset.13,106,107 It has been suggested that epileptic discharges arising from several areas of the frontal lobe, such as intermediate frontal region, orbitofrontal region, and cingulate gyrus may elicit dialeptic seizures.20,74,79,108,109 It is intriguing that a seizure symptomatology which conceptually is so strongly associated with generalized epilepsy can have a focal seizure onset. The concept of ‘frontal absence’ was further supported by studies showing that electrical stimulation of the mesial frontal lobe can give rise to dialeptic seizures as well as to generalized spike-wave discharges at the scalp.18,26 This finding is in correspondence with the EEG observation of secondary bilateral synchrony arising from the mesial frontal lobe.28 Systematic electrical stimulation of the frontal lobe disclosed regions from which an arrest of motor activity could be elicited.110–112 Close connections between the prefrontal cortex and the nonspecific thalamic nucleus and the midline region of the intralaminar thalamic complex are known to exist.113 Seizures may arise from prefrontal cortex rapidly spread to the reticular formation causing an alteration of consciousness and generalization. Epileptic activation of the negative motor regions or the disturbance of consciousness itself may lead to an arrest of motor activity. It is not yet clear whether the frontal cortex or subcortical structures are the pacemaker of these ictal discharges, which usually involves both of them during the course of a seizure.74 Arrest of motor activity and blank staring with loss of consciousness have also been described in patients with temporal lobe epilepsies,19,80 which makes it most unlikely to be specific to a particular cortex region. Epileptic activation of limbic structures has been proposed as the pathogenesis for these dialeptic seizures but this has not yet been proven.73 Invasive recordings have shown that ictal discharges in the mesial temporal lobes may be associated with this symptomatology.82 Ictal SPECT studies in patients with temporal lobe epilepsies have shown that loss of consciousness was associated with hyperperfusion of brainstem structures as a result of spread of epileptic activity.114 Although some invasive recordings can reveal highly localized seizure onset zones, it has to be kept in mind that invasive studies only record from a very limited region of the brain. Theoretically, the degree of arrest of motor activity and loss of consciousness may be a reflection of the volume of cortex involved in the seizure discharge. It is conceivable that motor activity may be inhibited either by epileptic activity excerting an interference on the function of primary motor cortex or epileptic activation of negative motor areas which both lie within the frontal lobe. Source analysis of generalized spike-wave

Illustrative patient This 16-year-old girl has had epilepsy since the age of 14 years. The seizures were characterized by loss of responsiveness and arrest of behavior. Sometimes, her dialeptic seizures were heralded by an aura sensation of vague strangeness or familiarity (psychic aura). Postictally, she had difficulty naming objects but she could describe the use of the objects. The postictal aphasia points to seizure onset in the dominant hemisphere. Ictal EEG showed left temporal seizure pattern. Interictally, the EEG showed spikes and continuous slowing in the left temporal region. MRI showed a low grade astrocytoma in the anterior part of the left inferior temporal gyrus and ipsilateral mesial temporal sclerosis. The patient underwent a left anterior temporal resection including the tumor and remained seizure free for 5 years’ follow-up. Localizing and lateralizing significance The above-mentioned semiological features of dialeptic seizures allow to some extent to identify the epilepsy syndrome and thus the epileptogenic zone. The semiology of dialeptic seizures may provide some clues as to the epilepsy syndrome: shorter duration (< 20 s) is more likely to occur in generalized epilepsy as compared to focal epilepsy.22 Typically additional clinical factors are helpful like for instance the pyknoleptic occurrence of brief dialeptic seizures in a neurological normal child of school age which is highly suggestive of absence epilepsy. Pyknoleptic appearance was extremely rare in focal epilepsy.22 Since, by definition, little additional clinical features are associated with dialeptic seizure it is not surprising that the analysis of these phenomena provides few criteria for differentiation between different epilepsy syndromes. Blinking seems to be significantly more frequent in generalized epilepsy than focal epilepsy.22 The evolution of dialeptic seizures is important for localization and lateralization. If dialeptic seizures are preceded by an aura this fact clearly points to a focal epilepsy and the characteristics of the aura are crucial for further localization. There is scant data on which and how often lateralizing features occur during dialeptic seizures. Somatosensory auras would favor a seizure onset in the paracentral region, or abdominal auras a temporal seizure onset.117 Unilateral clonic seizures which evolved into dialeptic seizure have been reported, but the epileptogenic zone in this patient was most likely rather diffuse as documented by EEG and multiple other seizure types.24 The seizure evolution following a dialeptic seizure is also important: dialeptic seizures which evolve into hypermotor or tonic seizures are highly suggestive of a frontal seizure onset. Automotor seizures of patients with temporal lobe epilepsy frequently show some motionless stare at seizure onset.21 This evolution is typical for automotor seizures and should not be classified as dialeptic seizureÆ automotor.2,118

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Dialeptic seizures: localizing and lateralizing value Postictal phenomena, such as postictal aphasia, point to a seizure onset in the dominant hemisphere as shown in the illustrative patient. We observed a few versive seizures following dialeptic seizures which arose contralateral to the direction of the version.119 Other lateralizing phenomena, such as

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postictal coughing,120 ipsilateral nose wiping,121 sign of four,122 ictal vomiting,123 and unilateral blinking 124,125 occur probably rarely, if at all, during dialeptic seizures but no data is available of the frequency and lateralizing significance in the setting of dialeptic seizures.

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Chauvel P, Kliemann F, Vignal JP et al. The clinical signs and symptoms of frontal lobe seizures: phenomenology and classification. In: Jasper HH, Riggio S, Goldman-Rakic PS, eds. Epilepsy and the Functional Anatomy of the Frontal Lobe. Vol. 66. New York: Raven Press, 1995:115–26. Karbowski K. Proceedings: Absences and absence-like seizures. Electroencephalogr Clin Neurophysiol 1975;39:531. Wieser HG, Swartz BE, Delgado-Escueta AV et al. Differentiating frontal lobe seizures from temporal lobe seizures. In: Chauvel P, Delgado-Escueta AV, Halgren E, Bancaud J, eds. Frontal Lobe Seizures and Epilepsies. Vol. 57. New York: Raven Press, 1992:267–85. Karbowski K, Vassella F, Pavlincova E, Nielsen J. Psychomotor seizures in infants and young children. (German). Z EEG-EMG 1988;19:30–4. Shimizu H, Ishijima B, Iio M. Diagnosis of temporal lobe epilepsy by positron emission tomography. ( Japanese). No to Shinkei – Brain & Nerve 1985;37:507–12. Wieser HG. Electroclinical features of the psychomotor seizure. Stuttgart: Fischer, 1983. So EL, King DW, Murvin AJ. Misdiagnosis of complex absence seizures. Arch Neurol 1984;41:640–1. Manford MR, Fish DR, Shorvon SD. An analysis of clinical seizure patterns and their localizing value in frontal and temporal lobe epilepsies. Brain 1996;119:17–40. Woodbury DM. Applications to drug evaluation. In: Purpura DP, Penry JK, Tower DB, Walter RD, eds. Experimental Models of Epilepsy – A Manual for the Laboratory Worker. New York: Raven Press, 1972:557–83. Quesney LF, Gloor P, Kratzenberg E, Zumstein H. Pathophysiology of generalized penicillin epilepsy in the cat: the role of cortical and subcortical structures. I. Systemic application of penicillin. Electroencephalogr Clin Neurophysiol 1977;42:640–55. Urca G, Frek H, Liebeskind JC, Taylor AN. Morphin and enkephalin: analgesic and epileptic properties. Science 1977;197:83–6. Snead OC. Gamma hydroxybutyrate in the monkey: effects of intravenous anticonvulsant drug. Neurology 1978;28:1173–8. Fariello RG, Golden GT. The THIP-induced model of bilateral synchronous spike and wave in rodents. Neuropharmacology 1987;26:161–5. Kiliam KF, Kiliam EK, Naquet R. An animal model of light sensitivity epilepsy. Electroenceph Clin Neurophysiol 1967;22: 497–513. Noebels JL, Sidman RL. Inherited epilepsy: spike-wave and focal motor seizures in the mutant mouse tottering. Science 1979;204:1334–6. Gloor P. Generalized epilepsy with bilateral synchronous spike and wave discharge. New findings concerning its physiological mechanisms. Electroencephalogr Clin Neurophysiol; (Suppl) 1978:245–9. Jasper H, Droogleever-Fortuyn J. Experimental studies on the functional anatomy of petit mal epilepsy. Res Publ Assoc Res Nerv Ment Dis 1947;26:272–98. Penfield W, Jasper H. Highest level seizures. Res Publ Assoc Res Nerv Ment Dis 1947;26:252–71. Aghakhani Y, Bagshaw AP, Benar CG et al. fMRI activation during spike and wave discharges in idiopathic generalized epilepsy. Brain 2004;127:1127–44. Gibbs FA, Gibbs EL. Atlas of Electroencephalography. Cambridge, MA: Addison-Wesley, 1952. Niedermeyer E, Laws ERJ, Walker AE. Depth EEG findings in epileptics with generalized spike-wave complexes. Arch Neurol 1969;21:51–8. Gloor P. Generalized cortico-reticular epilepsies. Some considerations on the pathophysiology of generalized bilaterally synchronous spike and wave discharge. Epilepsia 1968;9:249–63. Gloor P. Neurophysiological bases of generalized seizures termed centrencephalic. In: Gastaut H, Jasper H, Bancaud J, Waltregny A, eds. The Physiopathogenesis of the Epilepsies. Springfield, IL: Charles C Thomas, 1969:209–36. Fromm GH. The brainstem and seizures: summary and synthesis. In: Fromm GH, Faingold CL, Browning RL, Burnham WM, eds. Epilepsy and the Reticular Formation: The Role of the Reticular Core in Convulsive Seizures. New York: Alan R Liss, 1987:203–18. Gloor P. Generalized epilepsy with spike-and-wave discharge: a reinterpretation of its electrographic and clinical manifestations. The 1977 William G. Lennox Lecture, American Epilepsy Society. Epilepsia 1979;20:571–88.

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Gloor P, Testa G. Generalized penicillin epilepsy in the cat: effects of intracarotid and intravertebral pentylentetrazol and amobarbital injections. Electroenceph Clin Neurophysiol 1974;36:499–515. Snead OC, III. Basic mechanisms of generalized absence seizures. Ann Neurol 1995;37:146–57. Fromm GH. Role of inhibitory mechanisms in staring spells. J Clin Neurophysiol 1986;3:297–311. Giaretta D, Avoli M, Gloor P. Intracellular recordings in pericruciate neurons during spike and wave discharges of feline generalized penicillin epilepsy. Brain Res 1987;405:68–79. Geier S, Bancaud J, Talairach J et al. The seizures of frontal lobe epilepsy. A study of clinical manifestations. Neurology 1977;27:951–8. Gastaut H, Broughton R. Epileptic Seizures. Springfield, IL: Charles C Thomas, 1972. Fegersten L, Roger A. Frontal epileptogenic foci and their clinical correlations. Electroenceph Clin Neurophysiol 1961;13:905–13. Mazars G. Cingulate gyrus epileptogenic foci as an origin for generalized seizures. In: Gastaut H, Jasper H, Bancaud J, Waltregny A, eds. The Physiopathogenesis of the Epilepsies. Springfiled, IL: Charles C Thomas, 1969:186–9. Penfield W, Jasper H. Epilepsy and the functional anatomy of the human brain. Boston: Brown Little & Co, 1954. Lüders HO, Lesser RP, Dinner DS, et al. A negative motor response elicited by electrical stimulation of the human frontal cortex. In: Chauvel P, Delgado-Escueta AV, Halgren E, Bancaud J eds, Frontal lobe seizures and epilepsies. New York: Raven Press, 1992:149–58. Lüders HO, Lesser RP, Morris HH, Dinner DS. Negative motor responses elicited by stimulation of the human cortex. In: Wolf P, Dam M, Janz D, eds. Advances in Epileptology. New York: Raven Press, 1987:229–31.

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Nauta WJH. Some efferent connections of the prefrontal cortex in the monkey. In: Warren JM, Akert K, eds. The Frontal Granular Cortex and Behavior. New York: McGraw Hill, 1964:397–409. Lee KH, Meador KJ, Park YD et al. Pathophysiology of altered consciousness during seizures: Subtraction SPECT study. Neurology 2002;59:841–6. Rodin EA, Rodin MK, Thompson JA. Source analysis of generalized spike-wave complexes. 1994;7:113–19. Lüders HO, Noachtar S. Atlas and Classification of Electroencephalography. Philadelphia: W.B. Saunders, 2000. Henkel A, Noachtar S, Pfander M, Lüders HO. The localizing value of the abdominal aura and its evolution: a study in focal epilepsies. Neurology 2002;58:271–6. Noachtar S, Rosenow F, Arnold S et al. Semiologic classification of epileptic seizures. Nervenarzt 1998;69:117–26. Wyllie E, Lüders HO, Morris HH, Lesser RP, Dinner DS. The lateralizing significance of versive head and eye movements during epileptic seizures. Neurology 1986;36:606–11. Wennberg R. Postictal coughing and noserubbing coexist in temporal lobe epilepsy. Neurology 2001;56:133–4. Hirsch LJ, Lain AH, Walczak TS. Postictal nosewiping lateralizes and localizes to the ipsilateral temporal lobe. Epilepsia 1998;39:991–7. Kotagal P, Bleasel A, Geller E et al. Lateralizing value of asymmetric tonic limb posturing observed in secondarily generalized tonic-clonic seizures. Epilepsia 2000;41:457–62. Kramer RE, Lüders HO, Goldstick LP, et al. Ictus emeticus: an electroclinical analysis. Neurology 1988;38:1048–52. Benbadis SR, Kotagal P, Klem GH. Unilateral blinking: a lateralizing sign in partial seizures. Neurology 1996;46:45–8. Henkel A, Winkler PA, Noachtar S. Ipsilateral blinking: a rare lateralizing seizure phenomenon in temporal lobe epilepsy. Epileptic Disord 1999;1:195–7.

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Special seizures: localizing and lateralizing value SR Benbadis

Introduction ‘Special seizures’ are, in the semiologic seizure classification, those that cannot be classified in any of the other broad categories1 (see Chapter 34 in this volume). Thus, by definition, these seizures do not meet criteria for auras, autonomic seizures, dialeptic seizures, or motor seizures. In general, special seizures represent negative phenomena, which makes them unusual or ‘special’ among epileptic seizures. Special seizures include atonic seizures, astatic seizures, hypomotor seizures, akinetic seizures, negative myoclonic seizures, and aphasic seizures (see Chapter 32 in this book).

Astatic and hypomotor seizures These two categories of special seizures, like others in the semiologic classification, are defined by the predominant phenomenology. What they have in common is that they are also defined by the inability to characterize the mechanism of the symptoms due to lack of information. Thus, they do not represent unique or specific seizure types and do not have a clear localizing value. ●

●

Astatic seizures are seizures whose salient feature is a fall, but in which the mechanism of the fall cannot be further categorized. Thus, this category is most useful when there are incomplete data, e.g., history only or infants. If the predominant historical feature is a fall and there is no further useful information, this category (astatic seizure) is used. When more data are available, especially video-EEG recordings, more a specific seizure type should be identified in most cases. Seizure types that can result in a fall include tonic, atonic, GTC, and (more rarely) myoclonic seizures. Again, these are usually relatively easily identified with video-EEG monitoring. In occasional situations where the seizure cannot be more precisely classified even on video-EEG it is usually because they represent a ‘mixture’ of myoclonic, tonic, and atonic features2. These are usually seen in patients with symptomatic generalized epilepsies of the Lennox-Gastaut type (see tonic seizures in Chapter 53 and atonic seizures below), and in myoclonic astatic epilepsy of early childhood (Doose syndrome).2 Hypomotor seizures are those whose salient feature is immobility or a reduction in movements. As for astatic

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seizures, this category is most useful when there is incomplete data, e.g., history only. If the predominant historical feature is immobility and there is no further useful information, this category (hypomotor seizure) is used. More specific seizure types that can result in a hypomotor behavior include auras (by way of distress or distractibility), dialeptic seizures (where the predominant manifestation is an alteration of consciousness), and negative myoclonic or akinetic seizures (see below), and these can be identified more precisely with video-EEG recordings. Probably the common justified use of this category is in infants and young children where consciousness cannot be assessed. In fact, in this age group hypomotor seizures are likely a bland form of ‘complex partial’ seizures with no or minimal automatisms.3

Atonic seizures Atonic seizures are defined by loss of postural tone. This is usually abrupt and results in a fall, complete or incomplete depending on severity and the patient’s position. They frequently result in injuries. Atonic seizures are seen almost exclusively in patients with symptomatic generalized epilepsies of the Lennox-Gastaut type, so their ‘localizating value’ is that they are usually... generalized. Atonic seizures are, in fact, a type of generalized seizures in the ILAE seizure classification,4 and are typically accompanied, ictally, by generalized seizure patterns such as electrodecrement, paroxysmal fast activity, or spike-wave complexes. There is some evidence for a symptomatogenic zone in deep (nonrespectable) structures such as the brainstem reticular formation5,6 or the thalamus.7 Atonic seizures are considered relatively common in the symptomatic generalized epilepsies of the Lennox-Gastaut type because seizures that cause falls are often assumed to be atonic. However, careful video analysis shows that the majority of epileptic falls are tonic rather than atonic.6, 8 Often it is not completely clear that it is ‘atonia’ that is causing the fall, and it is instead a mixture (or sequence) of myoclonic, tonic and atonic phenomena. Atonic seizures can, rarely, be seen in focal epilepsy but this has not been clearly documented.9 However, even in patients with focal epilepsy (e.g., secondary to a focal cortical dysplasia), ictal SPECT recordings point to a strong inhibition in the bilateral motor cortexes.10 From a practical point of view,

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Special seizures: localizing and lateralizing value atonic seizures do not a have a reliable localizing value for purposes of resective surgery, and their presence should, generally, argue against pursuing resective surgery.

Akinetic seizures and negative myoclonic seizures (epileptic negative myoclonus) That electrical stimulation of the cortex can inhibit movements has been known since the seminal work of Penfield and Jasper.11 More recent studies showed that electrical stimulation of two regions in the frontal lobe elicit inability to initiate or maintain voluntary movements.12–15 The primary negative motor area lies in the inferior frontal gyrus, immediately anterior to the motor face area, close to (and often overlapping with) Broca’s area on the dominant side. The supplementary negative motor area is anterior to the face region of the supplementary sensorimotor area. Electrical activation of these negative motor areas may produce focal as well as bilateral inability to perform voluntary movements.12,13 The fact that responses to electrical stimulation are often bilateral makes these seizures difficult to lateralize on clinical (semiologic) grounds. Studies in primates support observations documenting two similar negative motor areas in the frontal lobe.12 Premotor and primary somatosensory cortex xan also produce (contralateral) negative motor responses.16,17 Epileptic myoclonus is referred to as ‘pure’ when it is not immediately preceded by positive myoclonus, enhancement of EMG, or a motor evoked potential.16 There is good evidence that the presence or absence of an antecedent positive motor phenomenon depends partly on stimulus intensity, except for the SMA where pure silent periods are obtained regardless of stimulus intensity.16 Akinetic seizures Akinetic seizures are defined, in the semiologic classification, by the inability to perform voluntary movements, not due to loss of consciousness (which would make it a dialeptic seizure), or loss of muscle tone (which would make it an atonic seizure). It should be pointed out that the term ‘akinetic seizures’ has different meanings outside of the semiologic classification. A longer duration (several seconds) differentiates it from negative myoclonic seizures, which are much briefer (see below). Akinetic seizures have been reported under other names such as ictal paresis18 and hemiparetic seizures.19 The symptomatogenic zone for akinetic seizures is most likely the primary or supplementary negative motor areas, as can be demonstrated by video-EEG recordings20 and confirmed by electrical cortical stimulation.12–15 Akinetic seizures most often affect distal (hand) muscles. Because of their proximity, the primary motor area are often simultaneously activated, producing clonic jerking of the face or tongue at the same time. Negative myoclonic seizures (epileptic negative myoclonus) Negative myoclonic seizures are brief (often 30–50 msec but by definition < 500 msec) episodes of muscle atonia, and can

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be viewed as the brief (sporadic) version of akinetic seizures. They can in fact be elicited by electrical stimulation using single or low frequency (1 Hz) stimulation.16 This is analogous, on the ‘positive’ side, to myoclonic seizures being the brief (sporadic) version of clonic seizures. They are only clinically apparent if the muscles in question are tonically used at the time (for example, outstretched hands). The muscle atonia can be documented by a silent period on EMG, which is identical whether the negative myoclonus is epileptic or nonepileptic such as asterixis. The epileptic nature of a negative myoclonus, and its symptomatogenic zone, can be documented by its time-locked association to an epileptiform EEG discharge (spike or sharp wave), which typically occurs 15–50 msec prior to the EMG inhibition.21–25 Since negative myoclonic seizures are essentially the brief (sporadic) version of akinetic seizures, their localizing value (or lack thereof) is similar, pointing to the negative motor areas mentioned above: premotor cortex16 post-central primary somatosensory,16 primary2,23 and supplementary negative motor area (dorsolateral frontal).26,27 In keeping with this, when epileptic negative myoclonus is seen in association with clear surface EEG abnormalities, the phenotype resembles benign childhood epilepsy with Rolandic spikes.28

Aphasic seizures Various speech disturbances can occur during seizures.29–31 Ictal aphasia (or dysphasia) is found in about 30% of patients with temporal lobe epilepsy.29,32 However, the term ‘aphasic seizures’ should be reserved for seizures in which aphasia is the predominant ictal symptom, and such seizures are relatively rare (the vast majority of aphasias are caused by head injury, stroke and dementia). In the International Classification of Epileptic Seizures, ‘dysphasic seizures’ are found under ‘simple partial’ seizures (with psychic symptoms), which is appropriate, since by definition aphasia requires intact consciousness. Confusingly, however, it is also stated that these seizures more commonly occur as ‘complex partial’ seizures.4 Studies of electrical cortical stimulation have identified four language areas: Broca’s, Wernicke’s and supplementary motor areas have been known since the work of Penfield and associates,33,11 while the basal temporal language area was described more recently.34–36 Identifying a language disturbance during electrical cortical stimulation requires a meticulous methodology to exclude speech impairment caused by nonspecific motor phenomena (positive, negative or apraxic).34,35 Identifying aphasia during seizures is fraught with the same difficulties, as it requires a selective impairment of language. Consciousness and awareness should be intact. If a patient has a more global impairment or is mute, aphasia may well be present but cannot be identified. As pointed out above, ictal aphasia may be difficult to elicit and diagnose in typical short-lived seizures. Thus, while some reports on ictal aphasia include cases of sporadic seizures,37–42 the majority describe cases of status epilepticus.43–51 Types of aphasia include Wernicke, conduction, anomic, and isolation (transcortical) aphasia.52 However, due to short seizure duration and concomitant symptoms, such complex classification is not possible for ictal aphasia. From a practical

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point of view, ascertaining the presence of a true language disturbances, rather than a nonspecific motor phenomenon (e.g., speech arrest) or a more global alteration in consciousness, is the crucial step. The basic dichotomy (i.e., anterior/ Broca/expressive/nonfluent vs. posterior/Wernicke/receptive/ fluent) is realistically practical for seizures, and consistent with the early reports of ictal dysphasia.32 The easiest type to identify ictally is the anterior type (Broca, nonfluent, expressive,). The posterior type (Wernicke, receptive, fluent) is more difficult to distinguish from less specific alteration of awareness. Further subtypes cannot realistically be identified ictally, which is unimportant since the type of aphasia does not reliably predict the lobe or region of seizure onset.30 The fact that subtypes of aphasia have no specific localizing value is quite consistent with the findings of cortical stimulations, where the type of aphasia may change with the stimulus intensity, and where stimulation of Broca, Wernicke, and basal temporal language areas produces relatively similar deficits.35 Localizing value Most patients with documented aphasic seizures have temporal lobe epilepsy, but this most likely reflects the predominance of such patients in monitoring units. In the only sizeable series of patients with ictal aphasia,32 30 of 34 patients (88%) had left temporal lobe epilepsy (defined preoperatively). Of 17 patients with definite localization (i.e., became seizurefree after temporal lobectomy) and ictal aphasia, 16 (94%) had left temporal

lobe seizures. Ictal aphasia can occur in seizures arising from almost any lobe, including frontal, fronto-temporal, centroparietal, parietal, temporo-parietal, posterior lateral temporal, and temporo-occipital.37,40,45,47,50,51,49,53,55 This is not surprising if one considers the four language areas defined by electrical stimulations. Furthermore, the presence of ictal aphasia in seizures of various origin is also in keeping with the important concept that distinguishes between epileptogenic zone and symptomatogenic zone56; in brief, epileptogenic zones in various locations may be in silent cortex but produce discharges which spread to one or more language areas. In additional to the ‘classical’ language areas, there is also convincing evidence incriminating the basal temporal language area.30,37,38,43 Ictal aphasia as a lateralizing sign By contrast, regardless of the lobe, the lateralizing value of ictal aphasia is excellent, with nondominant seizures being exceptional. Ictal aphasia was seen in two seizures arising from the nondominant hemisphere (in one patient) in the series of Gabr et al.,29 and in that patient aphasia was limited to paraphasia. One similar exception was reported in the series by Serafetinides and Falconer32; although the patient had ictal aphasia and proven right temporal lobe epilepsy (by seizurefreedom after temporal lobectomy), language dominance had not been determined by Wada testing, and the patient may have been right-hemisphere dominant. Thus, when present, the lateralizing value of ictal aphasia is high, and seems to be comparable to that of postictal aphasia, which is 92–100%.29,57

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Rubboli G, Parmeggiani L, Tassinari CA. Frontal inhibitory spike component associated with epileptic negative myoclonus. Electroencephalogr Clin Neurophysiol 1995;95:201–5. Baumgartner C, Poderka I, Olbrich A et al. Epileptic negative myoclonus: an EEG-single photon emission CT study indicating involvement of premotor area. Neurology 1996;46:753–8. Aicardi J, Chevrie JJ. Atypical benign partial epilepsy of childhood. Dev Med Child Neurol 1982;24:281–92. Gabr M, Lüders HO, Dinner D et al. Speech manifestations in lateralization of temporal lobe seizures. Ann Neurol 1989;25:82–7. Benbadis SR. Aphasic seizures. In: Lüders HO, Noachtar S, eds. Epileptic Seizures: Pathophysiology and Clinical Semiology. New York: Churchill Livingstone, 2000:501–5. Yen D, Su M, Yiu C et al. Ictal speech manifestations in temporal lobe epilepsy: a video-EEG study. Epilepsia 1996;37:45–9. Serafetinides EA, Falconer MA. Speech disturbance in temporal lobe seizures. A study in 100 epileptic patients submitted to anterior temporal lobectomy. Brain 1963;86:333–46. Penfield W, Rasmussen T. Vocalization and arrest of speech. Arch of Neurol Psychiatry 1949;61:21–7. Lüders HO, Lesser RP, Hahn J et al. Basal temporal language area demonstrated by electrical stimulation. Neurology 1986;36: 505–10. Lüders HO, Lesser RP, Hahn J et al. Basal temporal language area. Brain 1991;114:743–54. Schaffler L, Lüders HO, Morris HH III, Wyllie E. Anatomic distribution of cortical language sites in the basal temporal language area in patients with left temporal lobe epilepsy. Epilepsia 1994;35:525–8. Abou-Khalil B, Welch L, Blumenkopf B et al. Global aphasia with seizure onset in the dominant basal temporal region. Epilepsia 1994;35:1079–84. Suzuki I, Shimizu H, Ishijima B et al. Aphasic seizure caused by focal epilepsy in the left fusiform gyrus. Neurology 1992;42: 2207–10. Gilmore RL, Heilman KM. Speech arrest in partial seizures: evidence of an associated language disorder. Neurology 1981;31: 1016–19. Rosenbaum DH, Siegel M, Barr WB, Rowan AJ. Epileptic aphasia. Neurology 1986;36:822–5. Spatt J, Goldenberg G, Mamoli B. Simple dysphasic seizures as the sole manifestation of relapse in multiple sclerosis. Epilepsia 1994;35:1342–5.

42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55.

56. 57.

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Smith Doody R, Hrachovy RA, Feher EP. Recurrent fluent aphasia associated with a seizure focus. Brain Lang 1992;42: 419–30. Kirshner HS, Hughes T, Fakhoury T, Abou-Khalil B. Aphasia secondary to partial status epilepticus of the basal temporal language area. Neurology 1995;45:1616–18. Wells CR, Labar DR, Solomon GE. Aphasia as the sole manifestation of simple partial status epilepticus. Epilepsia 1992;33: 84–7. De Pasquet EG, Gaudin ES, Bianchi A, De Mendilaharsu SA. Prolonged and monosymptomatic dysphasic status epilepticus. Neurology 1976;26:244–7. Racy A, Osborn MA, Vern BA, Molinari GF. Epileptic aphasia: first onset of prolonged monosymptomatic status epilepticus in adults. Arch Neurol 1980;37:419–22. Primavera A, Bo GP, Venturi S. Aphasic status epilepticus. Europ Neurol 1988;28:255–7. Boudouresques J, Roger J, Gastaut H. Crises aphasiques subintrantes chez un epileptique temporal: etude electroclinique. Rev Neurol 1962;106:381. Hamilton NG, Matthews T. Aphasia: the sole manifestation of focal status epilepticus. Neurology 1979;29:745–8. Knight RT, Cooper J. Status epilepticus manifesting as reversible Wernicke’s aphasia. Epilepsia 1986;27:301–4. Dinner DS, Lüders HO, Lederman R, Gretter TE. Aphasic status epilepticus: a case report. Neurology 1981;31:888–91. Geschwind N. Aphasia. N Engl J Med 1971;284:654–6. Obana WG, Laxer KD, Cogen PH et al. Resection of dominant opercular gliosis in refractory partial epilepsy. Report of two cases. J Neurosurg 1992;77:632–9. Commission on classification and terminology of the International League Against Epilepsy: Proposal for revised classification of epilepsy and epileptic syndromes. Epilepsia 1989;30:389–99. Salanova V, Andermann F, Rasmussen T et al. Parietal lobe epilepsy: clinical manifestations and outcome in 82 patients treated surgically between 1929 and 1988. Brain 1995;118: 607–27. Lüders HO, Awad I. Conceptual considerations. In Lüders HO, ed: Epilepsy Surgery. New York: Raven Press, 1992:51. Chee MWL, Kotagal P, Van Ness PC et al. Lateralizing signs in intractable partial epilepsy: blind multiple-observer analysis. Neurology 1993;43:2519–25.

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Secondary generalized tonic-clonic seizures SD Lhatoo and HO Lüders

Introduction Secondary generalized tonic-clonic seizures (SGTCS) are a common occurrence in the video-monitoring phase of the presurgical assessment of focal epilepsies, although in contrast to primary generalized tonic clonic seizures (PGTCS), the rather scanty literature available on their semiology and pathophysiology belies this. To date, the most authoritative work on generalized tonic clonic seizures (GTCS) has been the description provided by Gastaut and Broughton in their influential monograph Epileptic Seizures: Clinical and Electrographic Features, Diagnosis and Treatment. Modern epilepsy semiology literature is reliant on their observations and the few contemporary analyses that exist use their description as a benchmark. Gastaut and Broughton acknowledged the difficulty in distinguishing PGTCS from SGTCS when seizures were clinically generalized at onset, a conundrum that has not completely diminished since then, and thus their classical account of the generalized tonicclonic seizure appears to present a composite of mainly ‘grand mal’ primary but also secondary generalized tonic-clonic seizures. However, certain semiological features often differ and may be of critical value in the distinction of one from another. Furthermore, these features may have a lateralizing value that complements the other facets of presurgical assessment.

Semiology of the SGTCS Gastaut and Broughton’s work provides exquisite detail on the semiology and pathophysiology of GTCS with detailed descriptions of electroencephalography, electrocardiography, electrodermography, sphygmomanometry, pupillary measurement, intravesical pressure measurements, and audiometry and spirometry. They divided the various phases of the GTCS into: 1. preictal manifestations 2. the ictal phase a. the tonic phase (including an ‘intermediate vibratory period’) b. the clonic phase c. (concurrent) Autonomic changes 3. immediate postictal features 4. late postictal features It is the first two phases–the preictal phase and the ictal phase, that are of greatest semiological interest, mainly 492

because of the clinical information that they provide as an aid to seizure localization and lateralization. The later phases of the SGTCS are less likely to yield significant information. The preictal ‘myoclonic’ phase (such as occurs in juvenile myoclonic epilepsy (JME)) was thought to occur in the majority and constituted a ‘succession of brief, bilateral and massive muscle contractions which usually last a total of several seconds ... frequently accompanied by a spasmodic cry’. The tonic phase, accompanied by loss of consciousness, was characterized by a brief phase in flexion followed by a longer one in extension, in all lasting ten to twenty seconds. A typical flexion was described as one similar to the response to the command ‘Put up your hands!’ with shoulder elevation, arm elevation and the elbow semiflexion. The lower limbs were described as being less involved but often with flexion, abduction and external rotation of the thighs and legs, completing an emprosthotonic posture (Figure 54b.1). This tonic flexion was followed by tonic extension into an opisthotonic position (Figure 54b.2). Contraction of the thoraco-abdominal musculature produced the ‘tonic epileptic cry’. The arms became semiflexed in front of the chest but also at times became extended, with forearm pronation and either wrist flexion and finger extension or wrist extension and fist clenching. The legs went into forced extension, adduction and external rotation along with extension of the feet and toes into a Babinski-like posture. This ‘tetanic’ phase subsequently became less complete and the rigidity was replaced by a fine tremor that grew in amplitude and slowed in frequency from 8 per second to 4 per second because of recurrent decreases in muscle tone–a so-called ‘intermediate vibratory period’. The clonic phase lasted about 30 seconds and was said to occur when each of the recurrent muscular contractions responsible for the vibratory phase became sufficiently prolonged to completely interrupt the tonic contraction, the resultant flexor spasms of the entire body appearing to resemble an ‘an epileptic form of bilateral myoclonus’. This myoclonus progressively slowed until seizure cessation. Variations to this entire theme were considered occasional and unusual. Asynchrony between two sides during the tonic or clonic phases was one such deviation. This asynchrony could be clinical or only evident on EMG recordings when clinically unnoticed. Lateralization in the initial phase of the SGTCS Two important studies have addressed the issue of the importance of two semiological features at the onset of secondary

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Secondary generalized tonic-clonic seizures

Figure 54b.1

The flexion or ‘emprosthotonic’ posture.

generalization in focal epilepsies that can be an invaluable aid to lateralization. Wyllie et al.2 studied head version in 61 seizures in 27 patients and reported that this occurred contralateral to the hemisphere of seizure onset in all patients. It is important to emphasize here that the definition of head version is crucial to correct lateralization. Only forced and prolonged head turning, usually in a clonic motion with the chin pointing upwards, with eye version to the same side as head version allows precise lateralization (Figure 54b.3). Very frequently, such a version is also accompanied by pulling of the face towards the contralateral, clonic, twitching side. Kotagal et al.3 reported the ‘sign of 4’ or the ‘figure 4 sign’ where the elbow contralateral to the hemisphere of seizure onset extends and the ipsilateral elbow flexes over the chest to produce an upper limbs posture that resembles a figure 4. (Figure 54b.1). In a study that looked at 39 patients with focal epilepsy, correct lateralization with this sign was seen in 90%. Other studies have subsequently confirmed the clinical utility of this sign. However, both head version and the sign of 4 are unreliable signs once the seizure is well established and their main value is derived at the onset of generalization when they are less likely to represent symptomatology remote from the ictal onset zone. Lateralization in the SGTCS and seizure progression A few studies have since examined the progression of the SGTCS (Table 54b.1). A study from Bethesda, Maryland in

Figure 54b.2

493

The extension or (opisthotonic) posture.

19944 presented a videotape analysis of 120 SGTCS in 47 patients with focal epilepsy with an age range between 11 and 56 years. Seizure semiology analysis was carried out jointly by three observers and the generalized phase was divided into five phases that constituted onset of generalization, pretonic clonic, tonic, tremulousness and clonic phases. Eighty-four percent of the seizures had the ‘onset’ phase characterized by vocalization, head version or some form of movement, 48% had a pretonic clonic phase where patients had irregular and asymmetric jerking, 95% a tonic phase and 98% a clonic phase. Only 27% of these seizures exhibited all five phases. The authors noted that generalization was not uniform or symmetric and noted the marked heterogeneity in GTCS phenomenology. Another study that examined SGTCS progression in temporal lobe epilepsy patients in 20015 found the classically described sequence of progression in only half their patients and in a third, a clonic phase preceded the tonic and in a quarter, the progression was one of tonic to clonic to tonic. Asynchrony in the clonic phase was noted in only two patients. An unblinded videotape analysis from Nashville, Tennessee in 19996 compared ten GTCS in nine patients with idiopathic generalized epilepsy and ten GTCS in ten patients with temporal lobe epilepsy. Interestingly, (and this has been noted by subsequent studies), focal features were seen before generalization in seven idiopathic generalized seizures, most commonly comprising head turning, in one patient occurring in different directions in two different seizures. The authors noted that the tonic phase was always symmetric but that in the last generalized

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Figure 54b.3 The sign of 4 with right elbow extension indicating left hemisphere seizure onset. Also notice version of the head to the right.

clonic phase, asymmetry or asynchrony of motor activity was seen transiently in three seizures. In contrast, in the temporal lobe epilepsy patients, focal tonic activity occurred in four seizures, with variable lateralization and there was asymmetric or asynchronous activity in the clonic phase in eight seizures. Seizure progression in these patients was tonic to clonic in eight, clonic to tonic to clonic in one and only clonic in one. A 2003 study from Calgary7 attempted to distinguish primary from SGTCS in children aged 18 months to 17 years by examining 64 GTCS in 13 children with medically refractory epilepsy. The study highlighted mouth movements and motor activity following clinical and EEG seizure end as distinctive features of the SGTCS, although these conclusions and their value in clinical practice is debatable. However, these authors also noted the asymmetry in arm movements in seven out of 12 children and in leg movements in nine out of 12 children during secondary generalization. In five patients, seizure activity continued on one side, with varying lateralization. Thus, no reliable clinical features appear to lateralize the hemisphere of seizure onset once the seizure is well under way. This is not surprising, given that the seizure has propagated to areas distant from the ictal onset zone.

Table 54b.1

Lateralization in the latter phase of the SGTCS Two studies have examined lateralization during seizure termination in temporal lobe epilepsy. They found that in 80–83% of seizures that ended in an asynchronous fashion, the final clonic movements occurred on the side ipsilateral to the hemisphere of seizure onset.8,9 This may reflect on earlier seizure cessation in the hemisphere of seizure onset due to factors such as neuronal fatigue, an exhaustion of excitatory processes, or a predominance of inhibitory processes. The marked slowing usually seen on scalp-EEG during this phase in the hemisphere ipsilateral to the paradoxical movements lends support to this. Paradoxical movements are most likely to be generated in the contralateral cortex and propagated by the pyramidal tract, rather than originating in the brainstem, not least because there is a clear relationship between ipsilateral cortical discharges and strictly contralateral clonic signs. There appears to be some lateralizing value to this sign although it is important to emphasize that the seizure should always be viewed in its entirety and the value of lateralizing signs at seizure onset outweigh the importance of phenomena that occur during or towards the end of seizures. Two common themes emerge from these studies. Firstly, that there is considerable heterogeneity in seizure progression during the phase of secondary generalization as compared to Gastaut’s classical description and secondly, there is asynchrony (disparity of rhythm between the two sides) and/or asymmetry (disparity in amplitude of limb movement between the two sides) during the seizure in a substantial proportion of patients. Contrary to the caution required in interpreting late ictal phenomena, forced head version immediately prior to the onset of secondary generalization and the asymmetric ‘sign of 4’ tonic posturing at the onset of the SGTCS are known to be useful lateralizing features where head version or elbow extension in the sign of 4 occur contralateral to the hemisphere of seizure onset.3 However, there is literature to suggest that focal features also arise in the GTCS of idiopathic generalized epilepsy, although definitions of head version for example, may differ in their interpretation.10

The Cleveland Clinic experience In our own semiological analysis of 24 SGTCS in 14 patients (12 male, two female) aged 9–39 years who underwent

Studies of seizure semiology in secondary generalized tonic-clonic seizures Seizure progression – % of patientsb

Study

No of seizuresa

Theodore 1994 Niaz 1999 Jobst 2001 Trinka 2002 Leutmezer 2002 Kirton 2003

120 10 286 39 74 64

a

TÆC

CÆTÆC

TÆCÆT

80 52

48 10 31

28

Asynchronyc C

yes/no – %

10

Yes Yes Yes Yes Yes

Number of seizures specified rather than number of patients because of seizure heterogeneity in the same patient T = tonic, C = clonic c Asynchrony is used synonymously with asymmetry b

(80) (60) (43) (38.5)

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Secondary generalized tonic-clonic seizures Table 54b.2

495

Clinical characteristics of patients with secondary generalized tonic-clonic seizures

Patient

Sex

Age

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

F M M M M M F M M M M M M M

26 27 18 25 19 14 35 25 18 20 39 23 9 13

Duration of ep. 12 15 13 21 10 9 19 15 15 9 22 20 7 1

Diagnosis

Pathology

Left temporal lobe epilepsy Right temporo-parieto-occipital epilepsy Right mesial frontal lobe epilepsy Left basal temporal lobe epilepsy Left lateral temporal lobe epilepsy Right temporo-parietal epilepsy Right hemispheric epilepsy Left hemispheric epilepsy Right mesial frontal lobe epilepsy Right parieto-occipital epilepsy Right temporo-occipital epilepsy Left lateral frontal lobe epilepsy Right lateral temporal lobe epilepsy Right temporo-occipital epilepsy

Temporal hamartoma Bihemispheric MCD Remote infarct Focal subpial gliosis Focal subpial gliosis Focal cortical dysplasia Bihemispheric MCD Unknown Remote infarct/contusion Focal cortical dysplasia Bihemispheric MCD Focal subpial gliosis Unknown DNET

MCD – malformation of clinical development; DNET – dysembryoplastic neuroepithelial tumor.

video-EEG monitoring as part of their presurgical investigation for medically refractory focal epilepsy, we found confirmation of some of the clinical features described in the literature. All 14 patients had invasive evaluations with subdural grid electrodes and/or depth electrodes. The duration of epilepsy ranged from 1–22 years. Clinical details are provided in Table 54b.2. In each case, the epilepsy diagnosis was made with on the basis of semiology, MR as well as functional imaging, interictal and ictal EEG findings. Seizure semiology was studied from the point of onset of secondary generalization. We employed a practical definition for generalization as that clinical stage where there was

Table 54b.3 Pt. 1. 2. 3. 4. 5a. 5b. 5c. 5d. 6. 7. 8. 9a. 9b. 9c. 9d. 10a. 10b. 10c. 10d. 11. 12a. 12b. 13. 14.

clear evidence of bilateral motor arm and/or leg involvement along with complete loss of consciousness. Thus, we did not include head or eye version in this definition. Mode of onset, progression of generalization, duration of various motor stages, symmetry of seizures, synchrony of the clonic phase, and the presence or absence of paradoxical lateralization were all studied. Asymmetry was defined as a greater than 50% difference in amplitude of movement between the two sides of the body. Asynchrony was defined as a clear difference in the rhythm of movement between the two sides of the body. Table 54b.3 summarizes these findings.

Characteristics of Secondary Generalization in SGTCS Onset ST AST Sign of 4 – rt arm Bilat. arm clonic ST ST Sign of 4 – rt arm ST Bilat. leg clonic AST Sign of 4 – rt arm AST AST Sign of 4 – lt arm Sign of 4 – lt arm ST ST Sign of 4 – lt arm Bilat. arm clonic Sign of 4 – lt arm Sign of 4 – rt arm Bilat. arm clonic AST AST

Tonic phase S A S S S S S A No A S S S A A S S S A A S A A A

Vibratory phase S S S S S No No No No No No S A S A No S S S No No S No No

AST – asymmetric tonic; ST – symmetric tonic; S – symmetric; A – asymmetric.

Clonic phase

Asynchrony

S S S A A S S S A S A S A A A S A S A A S S A A

No Yes No No Yes No Yes Yes Yes No No No Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes

Paradoxical lat. No No No No No No Yes Yes Yes No No No No No No No No No No No No Yes No Yes

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Seizure onset The sign of 4 was seen in eight (seven patients) of 24 (33%) seizures. In seven of these seizures (87.5%), it predicted the side of seizure onset correctly, with arm extension contralateral to the side of seizure onset. In one patient, two further seizures occurred without a sign of 4, suggesting that this does not consistently occur in all seizures in the same patients. In 6/24 (25%) seizures, there was an asymmetric tonic onset to the seizures that did not amount to a sign of 4. In 6/24 (25%), there was a symmetric tonic onset to the generalization. In 4/24 (17%) there was a clonic onset that was asymmetric in all.

2. Type 2 (26%) The body was held in the same position as in Type 1 but with persistent elbow extension rather than flexion (Figure 54b.4b). 3. Type 3 (9%) The body was held in the same position as in Type 1 but with hip and knee flexion rather than extension (Figure 54b.4c). 4. Type 4 (30%) The body was held in a position of bilateral asymmetric tonicity with upper and/or lower limb flexion on one side and upper and/or lower limb extension on the other (Figure 54b.4d).

Seizure progression Progression of generalization through various phases also varied. In 13/24 seizures (54%), there was a tonic phase followed by the vibratory phase, followed by a clonic phase. In 6/24 seizures (25%), there was no intervening vibratory phase. In one patient, there was progression from a tonic to a focal arm clonic phase. The clonic to tonic to clonic progression noted by Gastaut was seen in only 3/24 (13%) of seizures and in one patient, the seizure remained clonic throughout. All seizures had a clonic phase.

1. Type 1 (35%) The upper limbs were held in a position of shoulder adduction, elbow flexion, wrist flexion and finger flexion or extension. The lower limbs were held extended with plantar flexion. The neck was flexed (Figure 54b.4a).

The clonic phase and paradoxical lateralization During the clonic phase, there were asymmetric movements in 13/24 seizures (54%) and asynchrony of limb movements in 15/24 of seizures (62%) (Video.1). During both the tonic phase as well as the clonic phase, asymmetry and/or asynchrony had no lateralizing value. Focal clonic limb movements occurred at the end of the bilateral motor seizure in 8/24 seizures (33%) in seven patients. These comprised strictly unilateral arm clonic movements in seven and clonic movements of the face, arm and leg in one patient. In six (75%), these lateralizing movements occurred paradoxically ipsilateral to the side of seizure onset, a figure that is keeping with similar observations made by previous studies that have examined seizure termination in temporal lobe epilepsy.8,9 Thus, asymmetry and asynchrony at any stage of the secondary GTCS seems a common phenomenon. This is at variance with the primary GTCS, where symmetry and synchrony are more often found.6 However, there are an increasing number of studies that report clinical as well as electroencephalographic focality in patients with primary GTCS. Usui et al11 reported 26 patients with JME, only two of whom had both JME and a focal epilepsy. Of these patients, 46% had focal semiological features that included focal

(a)

(c)

(b)

(d)

The tonic phase During the tonic phase, the dominant posture varied with different patients and with different seizures in the same patients. These postures could be categorized into the following types:

Figure 54b.4

(a–d) Dominant body postures during the tonic phase of the SGTCS.

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Secondary generalized tonic-clonic seizures myoclonus, sign of 4 tonic posturing, forced head version and left arm clonic movements. EEG seizures in these patients were all generalized at the onset, although in two patients with left head version at onset, the EEG lateralized to the right side during the seizure. It is likely, therefore, that primary and secondary GTCS represent a semiological spectrum where symmetry and synchrony are seen most often in primary GTCS, with increasing asymmetry and asynchrony across the continuum towards a typical secondary GTCS. (Figure 54b.5).

Pathophysiology of the secondary GTCS Gastaut, commenting on asynchronous generalized seizures, speculated on the possibility of two independent unilateral seizures occurring, one in each hemisphere. The traditionally held view of ictal cortical activity during a generalized seizure is one of complete synchronization of widespread brain activity. Recently, there has been some debate whether this is true. Investigators have attempted to address these questions with human EEG analyses, both scalp as well as invasive, and with magnetoencephalography (MEG).12 – 15 Synchronization implies the agreement in time of a particular property of two dynamical systems, usually in the time and frequency domains, and biological synchronization (particularly phase synchronization) has been studied in various ways.16 In the context of epilepsy, nearest-neighbor phase synchronization (NNPS) has been used in scalp EEGs as a means to more sensitive seizure detection.15 Whilst synchronization of adjacent brain areas is a not a biologically counterintuitive premise and the results are therefore not surprising, this method does not address the issue of distant brain synchronization during seizures. Furthermore, scalp EEG studies are subject to reference contamination and volume conduction artifacts, issues that may be particularly prominent during generalized seizures. Le Van Quyen13 used the Hilbert transform method and wavelet methods to analyze neural synchrony in a patient with mesial temporal lobe epilepsy undergoing a depth electrode evaluation. A contact each in the ipsilateral amygdala and hippocampus was used against an ear (scalp) electrode that was thought to be quiet. The raw data was digitized at 200 Hz and passed to a 32-channel amplifier system with band-pass filter settings of 0.5–99 Hz. Preseizure recordings showed phase relationship of neuronal activity in the 30–80

Secondary GTCS

Primary GTCS

Synchrony

Increasiing Asynchrony

Symmetry

Increasiing Asymmetry

Figure 54b.5 The semiological spectrum of primary and secondary generalized tonic-clonic seizures.

497

Hz range. At seizure onset, (presumably with a seizure that remained focal) there was a transition to synchrony in the 12–15 Hz and 3 Hz range. As the seizure progressed, there was synchrony in the 3 Hz range that persisted but there was strong desynchronization in the high frequency range. Following the seizure, there was synchrony again in the 30–80 Hz range. Thus, despite the relative proximity of the electrodes studied, there was some evidence of asynchrony. Another patient with orbitofrontal epilepsy was studied with subdural grids. Here, seizure onset was characterized by abrupt synchrony at 8–10 Hz followed by synchronies at 25–90 Hz. As the seizure progressed, there was a progressive decline in synchronization frequency. However, it is not clear if this patient had secondary generalization to the seizure and what precise electrodes, near or distant, showed asynchrony. Gotman in 198717 described interhemispheric interactions in focal seizures after examining the intracranial recordings of eight patients with epilepsy. They compared, where possible, homologous brain regions in each hemisphere and found that interhemispheric coherence or broadly, phase synchrony, was surprisingly low. However, sampling of brain areas was limited to a few depth electrodes and no data on the clinical semiology was presented. Other observers have made observations on pathological synchrony in epileptogenic brain in focal epilepsy through invasive recordings although again, conclusions are restricted by the limited areas covered by the electrode contacts.14 A magneto-encephalographic study with scalp-EEG examined local and distant phase synchronization in generalized seizures.12 Interestingly, distant synchronization was observed to be better in primary generalized absence seizures compared with secondarily generalized motor seizures in focal epilepsy, although in the latter, there was evidence of strong local synchrony in keeping with the scalp EEG data presented by van Putten.15 Thus, although it makes intuitive sense that there should be generalized synchrony in extended brain regions during generalized seizures, the true picture is less clear and there is evidence in the literature that significant asynchrony may occur in SGTCS. Patients undergoing invasive monitoring with subdural grids and/or depth electrodes provide an opportunity to examine these issues.

Brain synchrony in SGTCS and the concept of multiple simultaneous seizures We analyzed the SGTCS of nine seizures in nine of the above patients who underwent an invasive presurgical evaluation for medically refractory epilepsy. Electrodes of seizure onset were screened and referenced to an uninvolved/artifact free intracranial electrode. Pre- and postoperative 3D MRI reconstruction was used with data from somatosensory evoked potentials and cortical electrical stimulation to determine the position of the central sulcus in order to locate electrodes over the motor strip. These were screened and referenced to an uninvolved/artifact free intracranial electrode. The seizure patterns at onset and during each phase of the secondary

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GTCS were analyzed with particular emphasis on synchrony of EEG rhythms. Synchrony was not defined quantitatively but in practical terms as the consistent agreement in time and/or frequency between the electrical activities of one brain region with another. Results of the analysis of synchrony are detailed in Table 54b.4. Synchrony between the motor strip and the brain region of seizure onset was seen only in three patients (33%), one during the tonic phase only and too during the clonic phase only. Thus, in the majority of patients, there was a clear asynchrony with very different seizure rhythms occurring in the two hemispheres or even within one hemisphere. This appeared to confirm Gastaut’s suspicion that there is indeed more than one seizure occurring in the brain during a generalized seizure. In patient 1 for example (Figures 54b.6–8), where there is coverage of both motor strips as well as of the region of seizure onset. A clear difference in seizure rhythms can be visualized between the frontal lobes on either side and between the frontal lobe and temporal lobe in the hemisphere of seizure onset. Thus, synchronization of brain regions does not appear to be necessary during SGTCS. Indeed, different seizures appear to occur simultaneously in different brain regions during the same clinical seizure.

Seizure generation and seizure modulation; the roles of cortex and brainstem As is evident from discussions elsewhere in this book, there is robust animal evidence of brainstem seizure generation. However, it is far from clear that the same is true in humans. It appears likely however, that involvement of the cortex is critical to seizure generation. In all our patients, clinical seizure end always preceded EEG seizure end, suggesting that for the production of clinical seizure symptoms, a cortical discharge is always necessary, unlike the situation with brainstem seizure generation for example, where clinical symptoms could be expected to occur in the absence of cortical discharge. However, it is extremely likely that the brainstem plays an important part in the modulation of the secondary GTCS. Whilst it is easy to visualize the corticospinal tract as the main pathway for the clinical motor expression of the

Table 54b.4 Brain synchrony between different brain regions in secondary generalized tonic clonic seizures

Stage of right head version

1. The ictal onset zone - left temporal lobe

2. The left motor strip

3. The right motor strip

(a) Central sulcus

RIGHT

LEFT

Motor strip electrodes Ictal onset electrodes

(b) Figure 54b.6 Left hemisphere epilepsy – stage of right head version: (a) asynchrony between left temporal lobe and left motor strip. No activity in the right motor strip. (b) 3D MRI brain reconstruction showing the central sulcus and the sampled motor strip electrodes in relation to it.

cortical seizure discharge, there are several other pathways that originate in the frontal cortex that relay in the human brainstem. These include projections to the brainstem reticular nuclei, the vestibular nuclei, the superior colliculus, the red nucleus, and the olivary nuclei, amongst others. There are interneuronal connections between these structures in the

The onset of the generalized tonic phase

1. The ictal onset zone - left temporal lobe

EEG synchrony between regions Patient diagnosis 1. 2. 3. 4. 5. 6. 7. 8. 9.

Lt Hemispheric E Rt TLE Rt TLE Rt Mesial FLE Lt Hemispheric E Lt TLE Rt TOE Rt TPE Rt POE

Tonic phase – + − − − − − − −

Clonic Phase − − − − − − + − +


3. The right motor strip 0

1

2

3

4

5s

Figure 54b.7 Onset of the generalized tonic phase. EEG asynchrony between motor strips and between left temporal lobe and left motor strip in the presence of clinical synchrony.

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Secondary generalized tonic-clonic seizures The generalized clonic phase

1. The ictal zone - left temporal lobe


3. The right motor strip

Figure 54b.8 The generalized clonic phase with persistent EEG asynchrony between motor strips, between the left temporal lobe and the left motor strip during apparent clinical synchrony.

brainstem that probably form networks as part of central pattern generators. From here, the vestibulospinal and reticulospinal tracts project downwards into the spinal cord and are likely candidates for the structures that subserve the variability in tonic posturing that is seen with the secondary GTCS. The vestibulospinal tract for example, produces upper limb flexion and lower limb extension whereas the reticulospinal tract produces the converse. Patients who have undergone anatomical hemispherectomies may provide the best human evidence of brainstem seizure modulation. Video 2 demonstrates a generalized tonic-clonic seizure in a 31⁄2-year-old posthemispherectomy patient who has no residual cortex on the right side. The patient first presented with infantile spasms from birth due

Fp1-F7

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to an extensive right hemispheric malformation of cortical development. A right functional hemispherectomy was carried out with removal of the pericentral and temporal cortices. Following this, the patient continued to have medically refractory seizures although these were now left arm tonic seizures evolving into bilateral asymmetric tonic seizures and generalized clonic seizures, indicating a right frontal lobe onset. An anatomical hemispherectomy was then carried out with complete removal of all cortical structures. Following this surgery, the patient continued to have seizures that now originated from the left frontal region as shown in Figure 54b.9. As evidenced from the video, the tonic and clonic manifestations of the seizure are very symmetric in their expression, rendering it unlikely that the uncrossed ipsilateral corticospinal tract or the ipsilateral supplementary motor cortex have a role in their generation. Both these pathways have a clear predominance of contralateral projections and therefore tend to produce either strictly or predominantly contralateral motor seizures. Therefore, it is more probable that the ipsilateral cortical seizure discharge is being modulated in the brainstem to produce bilateral motor phenomena expressed through the vestibulospinal and/or reticulospinal tracts.

Conclusions In summary, the semiology of the secondary GTCS is phenomenologically heterogeneous, with asynchrony and asymmetry displayed prominently in a substantial proportion of seizures, unlike the GTCS of primary generalized epilepsy where seizures are mostly synchronous and symmetric. Clinical asynchrony and asymmetry are accompanied by electrical asynchrony in the majority of patients as evidenced by the study of seizure rhythms in patients with secondary GTCS

Onset

B5 AF B0 UV

F7-T7 T7-P7 P7-O1 Fp2-F8 F8-T8 T8-P8 P8-O2 Fp1-F3 F3-C3 C3-P3 P3-O1 Fp2-F4 F4-C4 C4-P4 P4-O2 Fz-Cz Cz-Pz

(a) Figure 54b.9 region.

(b) MRI Brain image of patient with right anatomical hemispherectomy. EEG showing seizure onset in the left frontal

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undergoing invasive evaluations. Electrical synchronization of brain activity does not appear necessary in secondary GTCS and indeed, there may be more than one seizure occurring in different brain regions at the same time. In humans, seizure generation is most likely to occur only in the cortex, although

evidence from patients who have undergone anatomical hemispherectomies strongly suggests that significant seizure modulation takes place in the brainstem. Thus, both areas of the brain (cortex and brainstem) are important in the shaping of the semiology of the secondary GTCS.

REFERENCES 1. 2. 3. 4. 5.

6. 7. 8. 9.

Gastaut H, Broughton R Epileptic Seizures: Clinical and Electrographic Features, Diagnosis and Treatment. Springfield IL: Charles C Thomas, 1972:25–90. Wyllie E, Lüders HO, Morris H.H., Lesser R, Dinner DS. The lateralizing significance of versive head and eye movements during epileptic seizures. Neurology 1986;36:606–11. Kotagal P, Bleasel A, Geller E et al. Lateralizing value of asymmetric tonic limb posturing observed in secondarily generalized tonicclonic seizures. Epilepsia 2000;41:457–62. Theodore WH, Porter RJ, Albert P et al. The secondarily generalized tonic-clonic seizure. Neurology 1994;44:1403–7. Jobst BC, Williamson PD, Neuschwander TB et al. Secondarily generalized seizures in mesial temporal epilepsy: clinical characteristics, lateralizing signs, and association with sleep-wake cycle. Epilepsia 2001;42:1279–87. Niaz FE, Abou-Khalil B, Fakhoury T. The generalized tonic-clonic seizure in partial versus generalized epilepsy: semiologic differences. Epilepsia 1999;40:1664–6. Kirton A, Darwish H, Wirrell E. Unique clinical phenomenology can help distinguish primary from secondary generalized seizures in children. J Child Neurol 2004;19:265–70. Leutmezer F, Woginger S, Antoni E, Seidl B, Baumgartner C. Asymmetric ending in secondarily generalized seizures – a lateralizing sign in TLE. Neurology 2002;59:1252–4. Trinka E, Walser G, Unterberger I et al. Asymmetric termination of secondarily generalized tonic-clonic seizures in temporal lobe epilepsy. Neurology 2002;59:1254–6.

10. 11.

12.

13.

14.

15. 16. 17.

Leutmezer F, Lurger S, Baumgartner C. Focal features in patients with idiopathic generalized epilepsy. Epilepsy Res. 2002; 50:293–300. Usui N, Kotagal P, Matsumoto R, Kellinghaus C, Luders HO. Focal semiologic and electroencephalographic features in patients with juvenile myoclonic epilepsy. Epilepsia 2005;46: 1668–76. Dominguez LG, Wennberg RA, Gaetz W et al. Enhanced synchrony in epileptiform activity? Local versus distant phase synchronization in generalized seizures. J Neurosc 2005;25: 8077–84. Le Van Quyen M, Foucher J, Lachaux JP et al. Comparison of Hilbert transform and wavelet methods for the analysis of neuronal synchrony. J Neurosc Meth 2001;111: 83–98. Mormann F, Lehnertz K, David P, Elger CE. Mean phase coherence as a measure for phase synchronization and its application to the EEG of epilepsy patients. Physica D 2000;144: 358–69. van Putten MJ. Nearest neighbour phase synchronization as a measure to detect seizure activity from scalp EEG recordings. J. Clin. Neurophysiol 2003;20:320–5. Brown R, Kocarev L. A unifying definition of synchronization for dynamical systems. Chaos 2000;10:344–9. Gotman J. Interhemispheric interactions in seizures of focal onset: data from human intracranial recordings. Electroencephalogr Clin Neurophys 1987;120–133.

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SECTION 6 The irritative zone

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The irritative zone: general principles M Eccher and D Nair

Introduction There are various cortical zones in epilepsy that have been defined in order to service as tools to aid in the presurgical evaluation for epilepsy surgery. One of these zones is the irritative zone which has been defined as that region of cortex which generates interictal epileptiform discharges. The presence of interictal spikes is a hallmark of epilepsy and often used in corroborating the diagnosis.1,2 In addition, the characteristics of the interictal epileptiform activity can also aid in defining the epilepsy syndrome, such as differentiating focal from generalized epilepsy. in some situations. The irritative zone can be measured by a variety of means: surface and invasive EEG with visual analysis or dipole source modeling of EEG, magnetoencephalography (MEG), and EEG spike triggered functional magnetic resonance imaging (fMRI). The reason to pursue accurate measurement of these cortical zones including the irritative zone is to define the epileptogenic zone in a particular patient. The epileptogenic zone is a theoretical concept but its estimation is a prerequisite in planning of successful resective epilepsy surgery.

Factors affecting the irritative zone The irritative zones can be affected by a number of factors: the type epilepsy syndrome, the conscious state of the patient, changes in temperature, age, presence of anesthesia, and use of anticonvulsants etc. One of the clearest examples of the variance of epileptiform activity based on a change in the state in a pediatric patient is electrical status epilepticus during slow wave sleep3 which demonstrates a dramatic change of spikes frequency from the awake to a sleep state. In many focal epilepsy syndromes NREM sleep may increase the frequency of interictal epileptiform activity in both adult as well as pediatric age groups. In some children with focal epilepsy there may be a presence of nearly continuous production of interictal epileptiform discharges during sleep. The mechanisms for this activation is not yet clear but may involve the activating and synchronizing properties of oscillations generated between cortical and thalamic structures which may lead to the development of paroxysmal synchronization. Focal cerebral cooling has been shown to reduce epileptiform activity in animals as well as reports of cold saline irrigation has been shown to result in transient or complete cessation of spiking.4 There is also reports that dendate spike activity recorded in urethanized infant rats increase severalfold when cooled from 32–27∞ C.5 This raises the

possibility that variation of body temperature may have an effect on frequency of epileptiform spikes. How significant this effect is unclear and is not well studied in the human brain. The effect of anesthetics on interictal spikes has been discussed in some detail in the chapter on intraoperative cortical mapping and electrocorticography. The presence of interictal epileptiform activity can be influenced also by antiepileptic medications. Intravenous benzodiapezines results in both acute seizure control and suppression of interictal epileptiform activity. For epilepsies other than absence, antiepileptic medications given over a medium and long term range has no clear correlation between seizure control and frequency of interictal epileptiform activity.6 In patients whose epilepsy is in remission the persistence of interictal epileptiform discharges has been associated with a higher risk for seizure recurrence upon discontinuation of antiepileptic medications.8,9

Special features influencing the irritative zone There are some interesting features of the irritative zone that are of particular interest. One in particular is that around 10% of patients with epilepsy never show any interictal epileptiform discharges. This is in part due to several limitations inherent to EEG. One main problem is the difficulty with temporal sampling. This is particularly problematic with the short-time sampling that occurs during a routine EEG. Even with long-term monitoring in a video-EEG unit, the time restriction is limited to a few weeks at most. On the other hand, the presence of interictal epileptiform discharges does not always indicate the presence of epilepsy, as a small percentage of normal subjects who never develop epilepsy may still have interictal epileptiform discharges. Another issue affecting EEG interpretation is that the cortical generators of many normal as well as abnormal waveforms recorded on the EEG are not well known, particularly when looking with invasive EEG. This goes hand-in-hand with the notion that all spikes might not be similar. To begin with, the ability to record spikes at the scalp in patients with temporal lobe epilepsy usually involves synchronous or temporally overalapping activation of 10–20 cm2 of gyral cortex.10 So there are many spikes that are seen on intracranial-EEG and not seen at the scalp at all. The significance of these spikes is not known. Additionally, due to the limitations involved with intracranial-EEG, what constitutes an epileptiform spike from a nonepileptiform transient is not clear, as mentioned earlier. 503

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There are a number of normal patterns that are sharply contoured seen on the scalp-EEG which have been shown to be normal variants due the ability to study healthy volunteers with scalp-EEG. Similar investigations of identifying normal patterns are not feasible for intracranial-EEG. Some spikes may have particular characteristics that make them perhaps more significant than other spikes. For example, there may be forms of interictal epileptiform activity seen with such frequency or regularity that they may represent a transitional state from interictal to ictal EEG activity. This was suggested in a study of cortical dysplasia in which continuous epileptiform discharges had a high intrinsic epileptogenic property, so much so that if regions harboring these spikes were left behind during epilepsy surgery those patients uniformly faired poorly from a standpoint of seizure freedom after surgery.11 In contrast to this phenomenon, patients with mesial temporal lobe epilepsy can often have an irritative zone that extends to the opposite hemisphere, as with the case of bitemporal spikes. However, these patients have a very high success rate with unitemporal resection which leaves intact the opposite temporal structures. In generalized epilepsy such as absence, the frequency of 3 Hz-spike and wave has a close correlation with the frequency of detected seizures. In focal epilepsy the correlation is substantially weaker. However, it has been shown in one study of nonlesional intractable temporal lobe epilepsy, patients with few or no interictal epileptiform activity had a later age of seizure onset, less frequent and less severe seizures, and a lower incidence of hippocampal atrophy to suggest that a rarity of spikes could reflect a disease state that is not less severe.12 However, in most cases of focal epilepsy there is very little evidence to suggest that there is a direct correlation between spikes and seizures. Since there is no clear increase in the frequency of spikes before seizures or an increase in spike frequency with a decrease in antiepileptic medications, the mechanisms for interictal and ictal phenomenon may be different.13 The presence of spikes is not usually associated with any clinical manifestation as compared with epileptiform activity consisting of ictal epileptiform activity. However, if epileptiform spikes are of ‘sufficient intensity’ and are being generated in a region within the eloquent cortex, then they may result in symptoms. A clear example is focal myoclonic jerks associated with spikes in the primary motor cortex. This type of myoclonus can be of positive or negative motor activity (Figure 55.1). Some more sensitive measures of clinical observation such as continuous psychological testing can show brief episodes of impaired cognitive function at the time of epileptiform discharges. There also evidence that the localization of the interictal spike activity would predict the impairment seen

Table 55.1

Stim Sigma_ Averaged from 104 ersemble SA5 Ref 100 uV SA6-Ref SA7-Ref

SA9-Ref SA10-Ref SA11-Ref SA13-Ref SA14-Ref SA16-Ref SA17-Ref SA18-Ref SA19-Ref

2C uV 1 second

Figure 55.1 Patient with a history of medically intractable epilepsy who presents with positive and negative myoclonus undergoing an invasive evaluation for epilepsy surgery. Shown on the illustration is a map of the patient’s ‘A plate’ subdural grid, in which spikes are shown maximum at electrodes 7, 8, 11, 13, 16, 17 (marked by the solid circles). Also shown is the EMG activity monitored during the patients spiking activity. The EEG shows 104 averaged spikes. Note the time display is shortened to show the relationship of the spike to the EMG activity. Just prior to the spike there is a marked decrease in EMG activity followed by a myoclonic jerk from the right finger that is timelocked to the interictal spike.

with such testing.14,15 There is some suggestion that suppression of interictal discharges with antiepileptic medications could improve psychosocial function.16

The relationship of the irritative zone to other cortical zones in epilepsy The irritative zone stands in contrast to other defined zones of the epileptic brain (see Table 55.1). The delineation of these individual cortical zones is essential to the process of determining whether a patient with medically refractory focal epilepsy can be offered resection with reasonable chances of seizure freedom or substantial improvement without unacceptable postoperative deficits. It is our contention that the differentiations set forth in this set of definitions is implicit in any evaluation for epilepsy surgery; making them explicit allows for clarity in decision making, and must therefore optimize patient care. Complexities involved in studying these concepts include the current limitations in studying cortical

Zone-wise definitions of the epileptic brain32

Epileptogenic zone Irritative zone Seizure-onset zone Ictal symptomatogenic zone Functional-deficit zone

A plate

SA8-Ref

Region of cortex that can generate epileptic seizures, the total removal or disconnection of which is necessary and sufficient for seizure freedom Region of cortex that generates interictal epileptiform discharges in the EEG or MEG Region of cortex from which clinical seizures originate Region of cortex that generates the initial seizure symptomatology Region of cortex that in the interictal period is functionally abnormal

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The irritative zone: general principles neuronal function in health and pathology. There are various permutations that one can see with the relationship of various cortical zones of epilepsy based on different epilepsy syndromes. Two such examples are illustrated in Figure 55.2. However, the relationships can be even more complex in that even within an epilepsy syndrome such as temporal lobe epilepsy, the relationship of the different cortical zones can be slightly different. For example, in Figure 55.2A, which illustrates a case of temporal lobe epilepsy, bitemporal spikes are depicted. Other cases of temporal lobe epilepsy may have no interictal epileptiform discharges or may have a wider population of spikes. The ability to measure the functional deficit zone might be influenced by the frequency of spikes and/or seizures, so that regions of hypermetabolims may be depicted by a PET scan with an active epileptogenicity. The measurement of these different zones helps in the formulation of a hypothesis of the location of the epileptogenic zone in a particular patient. This concept is the crux of planning resective epilepsy surgery or planning an invasive evaluation for epilepsy surgery.

(a)

505

EEG recordings of the irritative zone The first, and for decades the only, means by which to delineate brain regions giving rise to interictal paroxysmal activity was EEG. EEG enjoys several advantages over other means by which to define the irritative zone. It is of relative technological simplicity in the age of microcomputing, and can be utilized by a single clinician working alone or with the aid of a small number of well trained technologists. It is commonly available, well established in the clinical arena, and well studied in the scientific literature. The irritative zone is localized on scalp-EEG by mapping of the potential differences recorded at the surface.17 Epileptiform potentials are recognized as sharply contoured transients, nearly always of negative polarity, which disturb the background cerebral rhythms. When they are focal in nature, their localization is recognized in a referential montage as the electrode(s) of maximal voltage amplitude, and in a bipolar montage as the electrode(s) across which a phase reversal can be seen. The irritative zone is then concluded to reside in that region of the cerebral cortex underlying the electrodes at which these potentials are recorded. The limitations of scalp EEG in the localization of the irritative zone include the region of cortex required to be recruited in the epileptiform activity before being seen at the scalp. At least 6 cm3 of cortex,18 possibly as much as 20 cm2,10 must be involved if a cortical transient potential is to propagate to the scalp surface. The cortical surface is highly convoluted and spatially complex, and the relationship of the scalp localization to the cortical area of origin is approximate at best

− +

(b) Figure 55.2 The relationship between the different cortical zones is graphically displayed in two examples. The yellow sphere represents the functional deficit zone; the light green sphere represents the irritative zone; the light orange sphere represents the symptomatogenic zone; the red sphere represents the ictal onset zone; and the black star represents the epileptogenic zone; the hashed line represents the division between the two hemispheres. Example a might represent a case of temporal lobe epilepsy in which there might be bitemporal spikes, unitemporal ictal onset, seizure semiology with lateralizing and localizing signs (direction of arrow indicates onset to progression of the semiological signs), and hypometabolism on a PET scan involving the temporal lobe ipsilateral to the ictal onset. In this example, seizure freedom could be achieved with a mesial temporal resection, and one can assume that the epileptogenic zone would have encompassed mesial temporal structures and perhaps the portions of the parahippocampal gyrus (extending just beyond the ictal onset perhaps recorded on depth electrodes as one example). Another situation is shown in Figure 55.2b which might represent a case of supplementary sensorimotor area epilepsy. In this case the irritative zone might be represented by spikes at the midline, ictal onset is lateralized to one hemisphere; there is PET hypometabolism of frontal and temporal lobes ipsilateral to the ictal onset, seizure semiology might imply SSMA onset. The epileptogenic zone is localized to a portion of the SSMA. (See Color plates.)

(a) − +

(b) Figure 55.3 A schematic illustration of electrical potential analysis in clinical EEG. Using either bipolar (a) or referential (b) analysis, the voltage maximum of a transient recorded on clinical EEG can be plotted out; the generator is assumed to underlie the electrode at which the voltage maximum is recorded (used with permission from Fisch.)49

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Figure 55.4 Dipole modeling from EEG. Raw EEG waveform on the left, with cursor at the point of initial deflection, defined as time 0 ms. In the middle, derived surface isopotential lines at 5 ms intervals from 5–30 ms. On the right, four brain models with superimposed dipole model solutions: on the upper left, three single dipole solutions at 0, 15, and 30 msec, and in the other three, current source density solutions, separately for each time point – 0ms upper right, 15 ms lower left, and 30 ms lower right. Single dipole solutions have less visual appeal, but less manipulation and abstraction. Current source density maps could be considered a representation of the irritative zone, but their abstraction from the original dipole must be borne in mind. (Used by permission from Ebersole.)50

and misleading at worst: potentials from the superficial midline cortex can appear to localize opposite the midline from their origin, and potentials from deep midline cortex, orbitofrontal cortex, insular cortex, supratentorial occipitotemporal cortex, and the mesial temporal structures may propagate to the surface poorly or not at all.19 The least invasive means of supplementing scalp-EEG is with the addition of sphenoidal electrodes. These can be performed when a mesial temporal focus is suspected. Placed by needle under the zygomatic arch and over the mandibular ramus, sphenoidal electrodes are intended to reside near the vicinity of the foramen ovale making them more effective in recording potentials of mesial temporal origin as compared with scalp electrodes.20–22 They are generally well tolerated by patients, especially when placed under light sedation, and are of low morbidity in experienced hands. The chief arguments against their use are that they add insufficiently to the overall evaluation of such patients, when other sources of lateralizing information such as imaging and semiology are considered, to justify their modest risk and discomfort (Blume).23 Another, noninvasive, technique developed to augment the localizing potential of surface EEG is electrical dipole source modeling. This technique aims to solve the ‘inverse problem’ of clinical EEG and deduce the cerebral electrical potential giving rise to the electrical potential differences recorded on the surface. The laws of physics dictate that there are infinite possible solutions to any inverse problem, however, and the source can therefore only be modeled as an abstracted single dipole or set of dipoles. Optimizal accuracy requires modeling conductance of electrical signals through four ‘spheres’ of different physical properties–brain, cerebrospinal fluid, skull, and scalp.24 Recent studies indicate that dipole analysis has the potential to provide a reasonable spatial estimate of the source of

surface EEG potentials. Comparison of surface recorded potentials to invasively recorded EEG has suggested that the modeled dipole sources are in fact within several millimeters of the cortex generating subdural EEG discharges. While initially studied in temporal lobe epilepsy, this modality appears to have potential applicability to all forms of localizationrelated epilepsy.25

EEG Fp2-F8 F8-Sp2 Sp2-T8 T8-P8 P8-O2 50uV

MEG

1500fT Common EMEG spike

Figure 55.5 Dipole source modeling, with a current density representation, of the same epileptiform transient in simultaneously recorded EEG and MEG. (Used with permission from Iwasaki et al.)51

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Figure 55.6a Left: 23-channel EEG of frontally maximal discharge with secondary bilateral synchrony. Right: 128-channel MEG of spike corresponding to that on EEG. (Modified with permission from Knowlton and Shih.)52

Dipole source analysis, until fairly recently an investigational tool, is now available as software extensions for many EEG systems, either commercially (e.g., BESA (www.besa.de) or Curry (www.neuroscan.com)) or as somewhat less comprehensive freeware (LORETA (www.unizh.ch/keyinst/ loreta.htm)). This approach can produce graphical representations of the spatial region putatively responsible for the observed surface potantials. These representations can be quite visually appealing, essentially appearing to highlight the area of cortex giving rise to a spike – in short, providing an outline of the irritative zone. Current models, however, have weaknesses inherent in their structure. Optimal dipole modeling requires using not an average head model, but a 3D reconstruction of the patient’s own head.24 Which exact point of the interictal EEG spike is chosen for the model can produce substantial variation in the resulting modeled locus. The best available evidence suggests that the errors introduced by such issues are in the order of a few millimeters, but comparatively few patients have been formally studied versus the gold standard of invasively recorded EEG. In some, the error may approach a magnitude of centimeters.25 Until there is greater confidence regarding in which patients dipole source modeling is essentially 100% accurate, this modality will not achieve replacement of intracranial-EEG. For the near future, it will likely represent merely a complement to such invasive recording,

however, with accruing experience at major centers, such modeling stands poised to spare some patients this step.

Invasive EEG recordings of the irritative zone Until recent years, direct EEG recording from the brain was the only neurophysiological means of characterizing the irritative zone more finely than could surface EEG, and experience with invasive EEG is vast. New utilizations of invasive monitoring have been devised in recent years. Foramen ovale recording, which has fallen out of favor in the U.S. has never been abandoned in many centers, especially in Europe, and studies regarding its use continue.26–28 Placed under fluoroscopy by an anterior approach through the cheek and then the foramen ovale into the subarachnoid space between the mesial temporal lobe and the pons, they are limited to evaluation of patients with mesial temporal lobe epilepsy. These electrodes do not require craniotomy, and can provide semi-invasive lateralization of interictal spikes and ictal onsets when that information is essential and sphenoidal electrode-supplemented surface EEG is insufficient. Foramen ovale electrodes cannot be utilized for functional stimulation mapping, unlike all other intracerebral electrodes, and they can only be utilized in relatively confirmed temporal lobe epilepsy

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Textbook of epilepsy surgery 1

4

2

3

5

(b) Figure 55.6b 1–5: Surface magnetic flux contour plots at 0 ms, 12 ms, 24 ms, 30 ms, and 36 ms of the MEG discharge in Figure 55.6a. Frames 2 and 3 show a lateralized contour pattern potentially attributable to a single dipole, modeled in the lower right; by frame 4, the singularity of the dipole is lost. (Modified with permission from Knowlton and Shih.)52

in which the only question is lateralization. Their proponents tout their high patient tolerability and the fact that they do not require general anesthesia and craniotomy. Whether they are safer than craniotomy and invasive electrode placement unfortunately has not been subjected to rigorous study. Direct invasive EEG is the gold standard for delineation of the irritative zone. It was the first technique introduced for increasing the spatial resolution of surface EEG,29–31 was the basis of the original definition of the irritative zone,32 and remains the gold standard against which all other current techniques are compared (e.g., reference 10). Depth electrodes, subdural electrode strips or grids, or any combination of these can be utilized. Subdural electrodes record from the cortical surface. Depth electrodes have been used in years past to record from various subcortical structures; their most universally accepted use, particularly in the U.S., has been in recording from the amygdala and hippocampus.33 In some centers, particularly in Europe, depth electrodes have been used to the relative exclusion of subdural electrodes in the evaluation of malformations of cortical development and other epileptogenic lesions,34 including even in the sylvian fissure.35 They are placed under fluoroscopic or stereotactic guidance to avoid pial vessels. This approach, termed stereoelectroencephalography, aims to place electrodes on all sides of, and within, the epileptogenic lesion and thereby localize the region of interictal spiking and ictal onset.36 In all approaches, the irritative zone is considered to comprise all tissue from which interictal spikes are recorded. This delineation of the irritative zone is conceptually straightforward, and

does not required computational abstraction or processing. The clinical neurophysiologist evaluating a patient for epilepsy surgery need not have significant additional skills beyond those utilized in surface EEG. It is for these practical reasons, as well as historical ones, that invasive EEG remains the gold standard against which all other techniques are measured. Unfortunately, only tissue upon or into which electrodes have been placed can be evaluated. A firm presurgical hypothesis must have been developed on the basis of imaging, surface EEG, seizure semiology, and the other modalities discussed in this chapter, and invasive electrodes are placed in a specific locale on the basis of this hypothesis.36 Unless electrodes are placed outside the hypothesized irritative zone, invasive EEG cannot provide evidence of a more widespread irritative zone than suspected – this is the chief limitation of invasive EEG in defining the irritative zone.

MEG recordings of the irritative zone Previously an investigational modality, MEG is now making the transition to routine clinical use in some centers. Based on essentially the same physics as EEG, MEG records the magnetic fields generated by neuroglial ion shifts, instead of the electrical fields recorded by EEG. MEG requires superconducting detectors at 4 K (superconducting quantum interference devices, or SQUIDs) – a clinical MEG machine is comprised of several SQUIDs in a large flask of liquid helium. Brain signals are several orders of magnitude weaker than common modern environmental electronic noise, so a MEG machine must be

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Figure 55.7 fMRI of a patient with right central malformation of cortical development and intractable epilepsy. On the left, activation associated with right finger-tapping in blue, left finger-tapping in yellow, and interictal surface EEG spikes in red; on the right, the same motor mapping tasks with activation associated with EEG spikes and slow waves in red. (Modified with permission from Diehl et al.)53 (See Color plates.)

placed in a very carefully magnetically shielded (Faraday cage) room. Obviously, unlike EEG, MEG will remain limited to highly industrialized countries for some years to come. The advantages of MEG over EEG are debated,37–39 but potentially substantial. MEG assesses the strength and orientation of magnetic field, not electrical potential difference – it is therefore reference free, unlike EEG. The orientation of the magnetic field in the tissue is orthogonal to that of the electrical dipole – MEG therefore essentially records dipoles oriented parallel to the scalp, where EEG records those oriented perpendicular to it, so the two are theoretically complementary.40 Without question, MEG can record spikes that are not apparent on EEG, and vice versa.41 MEG therefore offers a complementary means of mapping the irritative zone by exactly the same two means as does EEG – visual analysis and dipole source modeling. Dipole modeling is much more straightforward than with EEG, because the magnetic permitivity of all layers of cerebral tissue, fluid and bone is identical, and the model therefore need not include multiple spheres. As with EEG dipole modeling, a highly visually appealing map of the interictal irritative zone can be produced (see, e.g., Ko et al., Figure 2).42 Unfortunately, to this point, the

published case series comparing MEG to surface and invasive EEG are small. The relative value of the irritative zone map produced by MEG dipole modeling remains to be rigorously validated (the same could be justly said, however, for the irritative zone as mapped by invasive EEG). With further study, MEG stands to become a vitally useful tool in presurgical epilepsy evaluation.

MRI recordings of the irritative zone Also now technically feasible, though less clearly poised to transition from investigation to clinical use, is functional magnetic resonance imaging (fMRI) of the irritative zone. The engineering hurdles associated with recording EEG in the inhospitable environment of the MRI machine have been successfully addressed.43,44 Series are now available that demonstrate that an MRI signal can be acquired in the time window immediately following an interictal spike recorded on concurrent EEG. Contrast of the T2* image in this time window to the average acquired in the comparative resting state permits

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identification of that region of tissue in which a blood–oxygen label-dependent (BOLD) change occurs. The tissue that has a detectable metabolic response concurrent with an EEG spike could be construed to be a better representation of that body of physiologically activated brain tissue than the volume across which the electrical potential is distributed. As with all fMRI assessments, the region of T2* change can be represented graphically, producing a visually appealing representation of, putatively, the irritative zone. There are conceptual problems with this leap, however. It is well known that the BOLD effect on which fMRI is based is spatially skewed towards draining cortical veins.45,46 Also, inherent in the technique is the utilization of a mathematical model of the hemodynamic response; manipulations of the exact time-to-peak-response in the model can profoundly affect the volume of tissue concluded to be ‘involved’.47 Finally, as EEG-spike-triggered fMRI utilizes surface EEG, its resolution is limited to those interictal paroxysms that activate enough tissue that the dipole propagates to the surface. Clarification of the utility of the

fMRI-mapped region of BOLD change concurrent with interictal surface EEG spikes must await future studies.

Conclusions Clearly, multiple physiologically-based techniques are now available for evaluating the volume of brain tissue giving rise to paroxysmal bursts of activity between epileptic seizures. The role that delineation of this zone plays in the presurgical evaluation of each individual patient depends upon the patient’s specific localization-related syndrome. As has long been appreciated,48 the interictal irritative zone may not overlap well, or even at all, with the ictal onset zone, and the relationship of these two cortical areas to the epileptogenic zone as we define it is highly variable between syndromes. Much work remains to be done to clarify which of these techniques, or which combination of these techniques, will best permit us to offer curative surgeries to our patients.

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

18. 19.

Gibbs FA, Lennox WG, Gibbs EL. The electro-encephalogram in diagnosis and in localization of epileptic seizures. Arch Neurol Psychiatry 1939;36:1225–35. Jasper HH. Localized analyses of the function of the human brain by the electro-encephalogram. Arch Neurol Psychiatry 1939; 81:51–3. Tassinari CA, Michelucci R, Forti A et al. The electrical status epilepticus syndrome. Epilepsy Res. Suppl 1992;6:111–15. Karkar KM, Garcia PA, Bateman LM et al. Focal cooling suppresses spontaneous epileptiform activity without changing the cortical motor threshold. Epilepsia 2002;43:932–5. Karlsson KA, Blumberg MS. Temperature-induced reciprocal activation of hippocampal field activity. J. Neurophysiol. 2004;91: 583–88. Duncan JS. Antiepileptic drugs and the electroencephalogram. Epilepsia 1987;28:259–66. Donati F, Hassink RI, Jung H, Vassella F. Factors predicting the risk of relapse after antiepileptic drug discontinuation in children with partial seizures. Eur. J. Pediatr. 1995;154:S44–7. Donati et al.1995. Schmidt and Gram 1996. Tao JX, Ray A, Hawes-Ebersole S, Ebersole JS. Intracranial EEG substrates of scalp EEG interictal spikes. Epilepsia 2005;669–76. Palmini A, Gambardella A, Andermann F et al. Intrinsic epileptogenicity of human dysplastic cortex as suggested by corticography and surgical results. Ann.Neurol. 1995;37:476–87. Rosati A, Aghakhani Y, Bernasconi A et al. Intractable temporal lobe epilepsy with rare spikes is less severe than with frequent spikes. Neurology 2003;60:1290–5. Gotman J. Relationships between interictal spiking and seizures: human and experimental evidence. Can. J. Neurol. Sci. 1991;18: 573–6. Binnie CD. Significance and management of transitory cognitive impairment due to subclinical EEG discharges in children. Brain Dev. 1993;15:23–30. Aldenkamp AP. Effect of seizures and epileptiform discharges on cognitive function. Epilepsia 1997;38 (Suppl 1):S52–5. Binnie CD. Cognitive impairment during epileptiform discharges: is it ever justifiable to treat the EEG? Lancet Neurol. 2003;2:725–30. Hamer HM, Lüders HO. Electrode montages and localization of potentials in clinical electroencephalography. In Levin KH, Lüders HO, eds. Comprehensive Clinical Neurophysiology. Philadelphia: W.B. Saunders Company, 2000:358–86. Cooper R, Winter AL, Crow HJ, Walter WG. Comparison of subcortical, cortical and scalp activity using chronically indwelling electrodes in man. Electroencephalog Clin Neurophys 1965;18: 217–28. Abraham D, Ajmone-Marsan C. Patterns of cortical discharge and their relation to routine scalp EEG. Electroencephalog Clin Neurophys 1958;10:447–61.

20. 21. 22. 23. 24. 25. 26.

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Schomer DL. The sphenoidal electrode: myth and reality. Epilepsy & Behavior 2003;4:192–7. Buchhalter J, Schomer DL, Schachter S. A comparative study on the sensitivity of the mini and standard sphenoidal electrodes. J Epilepsy 1991;4:29–32. King DW, So EL, Marcus R, Gallagher BB. Techniques and applications of sphenoidal recording. J Clin Neurophys 1986;3:51–65. Blume WT. The necessity for sphenoidal electrodes in the presurgical evaluation of temporal lobe epilepsy. J Clin Neurophys 2003;20:305–10. Fuchs M, Kastner J, Wagner M et al. A standardized boundary element method volume conductor model. Clin Neurophysiol 2002;113:702–12. Merlet I, Gotman J. Reliability of dipole models of epileptic spikes. Clin Neurophys 1999;110:1013–28. Zumsteg D, Friedman A, Wennberg RA, Wieser HG. Source localization of mesial temporal interictal epileptiform discharges: correlation with intracranial foramen ovale clectrode recordings. Clin Neurophys 2005;110:2810–18. Fernández Torre JL, Alarcón G, Binnie CD, Polkey CE. Comparison of sphenoidal, foramen ovale and anterior temporal placements for detecting interictal epileptiform discharges in presurgical assessment for temporal lobe epilepsy. Clin Neurophysiol 1999;110: 895–904. Kim OJ, Ahn BI, Lee BI. Analysis of electrical discharges made with the foramen ovale electrode recording technique in mesial temporal lobe epilepsy patients. J Clin Neurophys 2004;21:391–8. Foerster O, Altenberger H. Elektrobiologische vorgänge an der menschlichen hirnrinde. Deutsche Zeutschr Nervenh 1935;135: 277–88. Marshall C, Walker AE. Electrocorticography. Bull Johns Hopkins Hosp 1949;85:344–59. Schwartz HG, Kerr AS. Electrical activity of the exposed human brain. Arch Neurol Psychiat 1940;43:547–59. Lüders HO, Awad I. Conceptual considerations. In: Lüders HO, ed. Epilepsy Surgery. New York: Raven Press. 51–62. Sperling MR. Intracranial electroencephalography. In: Ebersole JS, Pedley TA, eds. Current Practice of Clinical Electroencephalography, 3d. edn. Philadelphia: Lippincott Williams & Wilkins, 2003;639–80. Chassoux R, Devaux B, Landré E, et al. Stereoelectroencephalography in focal cortical dysplasia: a 3D approach to delineating the dysplastic cortex. Brain 2000;123:1733–51. Isnard J, Guénot M, Sindou M, Mauguière F. Clinical manifestations of insular lobe seizures: a stereo-electroencephalographic study. Epilepsia 2004;45:1079–90. Bancaud J. Surgery of epilepsy based on stereotactic investigations: the plan of the SEEG investigation. Acta Neurochir Suppl (Wien) 1980;30:25–34. Lesser RP. MEG: good enough. Clin Neurophys 2004;115:995–7.

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The irritative zone: general principles 38. 39. 40. 41. 42.

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Barkley GL. Controversies in neurophysiology. MEG is superior to EEG in localization of interictal epileptiform activity: Pro. Clin Neurophys 2004;115:1001–9. Baumgartner C. Controversies in neurophysiology. MEG is superior to EEG in localization of interictal epileptiform activity: Con. Clin Neurophys 2004;115:1010–20. Fuchs M, Wagner M, Wischmann H-A. et al. Improving source reconstructions by combining bioelectric and biomagnetic data. Electroencephalog Clin Neurophys 1998;107:93–111. Rodin E, Funke M, Berg P et al. Magnetoencephalographic spikes not detected by conventional electroencephalography. Clin Neurophys 2004;115:2041–7. Ko DY, Kufta C, Scaffidi D, Sato S. Source localization determined by magnetoencephalography in temporal lobe epilepsy: comparison with electrocorticography: technical case report. Neurosurgery 1998;42:414–22. Lemieux L, Salek-Haddadi A, Josephs O et al. Event-related fMRI with simultaneous and continuous EEG: description of the method and initial case report. Neuroimage 2001;14:780–7. Hamandi K, Salek-Haddadi A, Fish DR, Lemeiux L. EEG/functional MRI in epilepsy: the Queen Square experience. J Clin Neurophys 2004;21:241–8. Buxton RB. Introduction to Functional Magnetic Resonance Imaging. New York: Cambridge University Press, 2002.

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Lai S, Hopkins AL, Haacke EM et al. Identification of vascular structures as a major source of signal contrast in high resolution 2D and 3D functional activation imaging of the motor cortex at 1.5T: preliminary results. Magn Reson Med 1993;30:387–92. Bagshaw et al. Meyers R, Knott JR, Hayne R, Sweeney DB. The surgery of epilepsy: limitations of the concept of the cortico-electrographic ‘spike’ as an index of the epileptogenic focus. J Neurosurg 1950;7:337–46. Fisch BJ. Fisch & Spehlmann’s EEG Primer. Amsterdam: Elsevier, 1999. Ebersole JS. EEG dipole analysis. In: Rosenow F, Lüders HO, eds. Presurgical Assessment of the Epilepsies with Clinical Neurophysiology and Functional Imaging—Handbook of Clinical Neurophysiology, Vol. 3. Amsterdam: Elsevier, 2004;471–90. Iwasaki M, Pestana E, Burgess RC, et al. Detection of epileptiform activity by human interpreters: blinded comparison between electroencephalography and magnetoencephalography. Epilepsia 2005;46:59–68. Knowlton RC, Shih J. Magnetoencephalography in epilepsy. Epilepsia 2004;45(suppl 4):61–71. Diehl B, Salek-Haddadi A, Fish DR. fMRI in the evaluation of the irritative zone. In: Rosenow F, Lüders HO, eds. Presurgical Assessment of the Epilepsies with Clinical Neurophysiology and Functional Imaging—Handbook of Clinical Neurophysiology, Vol. 3. Amsterdam: Elsevier, 2004;463–9.

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Noninvasive electroencephalography evaluation of the irritative zone HM Hamer

General concepts The main goal of the presurgical evaluation in patients with medically intractable epilepsy is the identification of the cortical area capable of generating seizures, and whose removal or disconnection will result in seizure freedom. This area is called the epileptogenic zone.1 The irritative zone is the area of cortex capable of generating interictal epileptiform discharges (IED). It does not coincide but frequently overlaps with the usually smaller epileptogenic zone. Extensive experience with routine extracranial EEG shows that in general the location of IED is a good indicator of the area of cortex from which seizures are originating.1,2 The methodology of many studies on this topic, however, is biased towards patients with medically refractory epilepsies.3,4 The term interictal epileptiform discharge (IED) comprises spikes and sharp waves which usually break background activity. Both, spikes with a duration of less than 70 ms and sharp waves with a duration of 70–200 ms, have a pointed peak and are of negative polarity in most cases because they are generated by depolarization of vertically oriented neurons.3,5,6 Positive IED can be seen in electrocorticography and infrequently in patients with a breach rhythm, head trauma or cortical dysplasia.3,7 Spikes and sharp waves convey an increased risk of epilepsy and must be differentiated from benign variants resembling IED.2,3 Some reports suggest that spike suppression and not an increase of IED frequency heralds seizures which proposes that a strong after-inhibition produced by IED protects against the occurrence of ictal discharges by maintaining a low level of excitation in a general condition of hyperexcitability.2,8 This finding, however, remains controversial.9,10 There is evidence that the interictal epileptiform discharges in focal and generalized epilepsies, though not accompanied by obvious clinical events, can induce brief episodes of impaired cognitive function if tested with sensitive methods.11,12 In focal epilepsy, the type of deficit may depend on where in the cortex the IED arises.13 Suppressing interictal discharges could improve behavior in children particularly with focal epilepsy.14 Auditory reaction times was found normal before IED in absence epilepsy but decreased in many patients at the onset and after a delay of 0.5 seconds of IED.12,15 Moreover, chronic and frequent IED on the left may induce a reorganization of speech lateralization.16 512

EEG recorded by scalp and sphenoidal electrodes compared to intracranial electrodes and Magnetoencephalography In general, surface EEG provides a good overview because it samples from a large portion of the brain. However, several square centimeters of synchronously discharging cortex are necessary to be detected by overlying scalp electrodes.17–19 Cerebral activity is attenuated by the impedance of the cerebrospinal fluid, meninges, skull and scalp. Therefore, scalpEEG fails to show a great number of IED recorded by depth or subdural electrodes (Figure 56.1) and interictal activity arising from deep or midline structures is usually not reflected in surface EEG.1 The distribution of IED on the scalp depends on the conductive properties of the surrounding tissue, the spatial characteristics of the generator, propagation pathways and on the spatial resolution of the surface EEG. Consequently, the distribution of interictal epileptic discharges in the scalp EEG can fail to localize or even mislocalize the region or hemisphere of seizure origin.3 Patients with an epileptogenic zone in the frontal, occipital, insular-opercular and orbitofrontal regions may show falsely localizing temporal IED.20–22 Closely spaced scalp electrodes can improve the yield of spike detection and localization over the standard 10–20 system.23,24 It remains controversial whether or not sphenoidal electrodes placed close to the foramen ovale increase the sensitivity of IED detection. While several studies found that in a minority of patients, especially with temporal lobe epilepsies sphenoidal electrodes can record epileptiform activity which does not appear in anterior temporal electrodes (Figure 56.2),25–29 others could not verify this observation.30 Sharp waves with the maximal amplitude at the sphenoidal electrodes can arise from the mesial or lateral temporal lobe or from an orbito-frontal focus.27 Sphenoidal electrodes can register higher amplitudes of IED as compared to scalp electrodes.3,31,32 However, sphenoidal electrodes still fail to detect a large proportion of IED recorded by foramen ovale electrodes (Figure 56.1).30 Multichannel whole-head MEG has a similar sensitivity to detect IED as compared to noninvasive EEG19,33,34 and the combination of both provide complementary and confirmatory information for the localization IED which cannot be obtained with either technique alone. In a study on 70 surgical candidates, MEG identified IED in one-third of EEG negative patients, especially in cases of lateral neocortical epilepsies and epilepsies due to cortical dysplasia.19,35 Conversely, IED were seen only in the EEG in a subset of patients with mesial frontal lobe epilepsy.35

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FOl1–FOl2 FOl2–FOl3 FOl3–FOl4 100 µV FOr1–FOr2 FOr2–FOr3 FOr3–FOr4

Fp1–F7 F7–Sp1 Sp1–T7 T7–P7 P7–O1 Fp2–F8 F8–Sp2 Sp2–T8 T8–P8 P8–O2 20 µV 1 sec

Figure 56.1 Invasive Video-EEG monitoring with bilateral foramen ovale electrodes of a 38-year-old patient with bitemporal epilepsy. In addition, scalp electrodes were attached according to the International 10–20 system and sphenoidal electrodes were bilaterally inserted. Note the interictal epileptiform discharges (IED) recorded maximally at the fourth contact of the right foramen ovale electrode while the scalp and sphenoidal electrodes fail to detect these IED. FOr1, FOr2, FOr3, FOr4: four contacts of the right foramen ovale electrode; FOl1, FOl2, FOl3, FOl4: four contacts of the left foramen ovale electrode; Sp1: left sphenoidal electrode; Sp2: right sphenoidal electrode.

Yield of scalp EEG The first EEG will uncover IED in about 30–50% of the patients with epilepsy and the yield increases to 60–90% by the fourth EEG.2,36–38 This contrasts with the frequency of IED in nonepileptic patients ranging from 0.5% in healthy young men39 to 12% in a study including all age groups and patients with progressive cerebral disorders.40 Specificity is probably lower and sensitivity higher in children as compared to adults, but reliable estimates are not available.2 The frequency of IED in elderly patients with epilepsy is substantially lower than that reported in epileptic populations as a whole.36,41 The majority of reports could not establish a correlation between the levels of anticonvulsants and the frequency of focal interictal spiking, although this issue remains controversial.9,36,42–45 Overall, it can be expected that around 10% of the patients with epilepsy (more with extratemporal than with temporal epilepsy) will show no IED in scalp EEG during wakefulness or sleep in spite of prolonged or repeated recordings.2,46,47 The yield from a single EEG is substantially increased in patients

investigated within one or two days after a seizure, and is greater in patients with monthly seizures than in those who had been seizurefree for a year.36,45,48 The duration of recording may also affect the detection rate of interictal spiking.9 Moreover, the yield can be significantly increased and new abnormalities found, if the EEG includes sleep recordings.2,48,49 IED are seen more commonly during sleep, with the greatest activation during non-REM sleep.1,50–53 Increased neuronal synchronization within thalamocortical projection neurons during non-REM sleep may contribute to the activation process in epileptic cortex.46 The predictive accuracy in lateralization of epileptogenesis is improved during non-REM sleep in patients who showed bilateral or no discharges in wakefulness because unilateral discharges arising de novo in sleep were always correctly lateralizing.46 In patients who had unilateral discharges in the awake state whether ipsilateral or contralateral to the epileptogenic zone, the findings were generally unchanged during sleep although sleep may alter IED morphology and distribution.52 Spikes can be more

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Textbook of epilepsy surgery (a)

(b)

Fp2–F8

F8–T8

T8–P8

P8–O2

Fp2–F8

F8–Sp2

Sp2–T8

T8–P8

P8–O2

ECG 50 µV 1 sec

Figure 56.2 Two examples of interictal epileptiform discharges (IED) of a 39-year-old patient with right mesial temporal epilepsy due to hippocampal sclerosis. Scalp electrodes were attached according to the International 10–20 system and additional sphenoidal electrodes were bilaterally inserted (Sp2: right sphenoidal electrode). The first four channels represent a longitudinal bipolar montage of scalp electrodes over the right temporal area. In the following five channels, the right sphenoidal electrode is included between F8 and T8 in a bipolar fashion. Note the sharp waves recorded by the sphenoidal electrode and missed by the scalp electrodes. ECG: electrocardiogram.

widespread during non-REM sleep than during wakefulness or REM sleep suggesting that the localization of interictal discharges in REM sleep may be a better indicator of the epileptogenic zone than in non-REM sleep.53 Hyperventilation or photic stimulation rarely activate IED in patients with focal epilepsies.54,54–57 Specificity of interictal scalp EEG In general, the frequency, repetition rate, morphologic characteristics and state dependence of interictal epileptiform activity cannot be used to predict the etiology or severity of the disorder.3 However, rhythmic spiking on a slow background activity and not associated with behavioral changes has been found to be characteristic for focal cortical dysplastic lesions.58–60 Tumors tended to cause wider distributed IED as compared to developmental abnormalities or hippocampal sclerosis,21,24,61 which was also true for seizure patterns.62 This may be caused by local neuronal injury, edema, ischemia or

other electrical and/or biochemical effects of the structural lesion on susceptible neighboring brain tissue or homologous contralateral areas.63,64 Prognostic relevance of postoperative IED In both, temporal and extratemporal epilepsy, absence of IED in the 6-month or 1-year postoperative scalp-EEG was associated with good postoperative outcome.65–69 The prognostic value of a 3-month postoperative EEG remains controversial.25,70–72 The presence of IED in the early extracranial postoperative EEG (within 1 or 2 weeks) were not found to be of prognostic value in most of the studies.71,73–76 There are conflicting results on the prognostic value of IED in the postresection electrocorticography (ECoG). Several studies found an association between postresection IED in this test and less favorable outcome 74,77–80 while others did not.25,67,71,73,81–83 The lack of agreement of these studies may be due to differences in the patient populations (e.g. lesional versus nonlesional cases), the recording

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Noninvasive electroencephalography evaluation of the irritative zone techniques and in the anesthetic agents used during surgery. Even in the studies confirming the association of postresection IED and seizure continuation, the percentage of patients with postresection persistence of IED but still favorable outcome varied from 25–47%69,74,78,79 which can make it difficult to estimate the prognosis in individual cases.

Temporal lobe epilepsy (TLE) As mentioned above, several studies indicated that the majority of mesial and neocortical temporal IED fails to be recorded by surface electrodes.4,18,84 The IED which are recorded in the extracranial EEG, however, may show a better correlation with the seizure origin as compared to IED recorded by depth electrodes.85 This suggests that widely synchronous interictal spikes more likely rise from the epileptogenic area than spikes with smaller fields. In addition to IED, temporal intermittent rhythmic delta activity (TIRDA) was also strongly correlated with a clinical diagnosis of TLE85–87 (Figure 56.3). TIRDA was seen in 0.3% of all recordings obtained in a general EEG laboratory 88 but in as many as 28% of patients being evaluated for temporal lobe resection.89 A significant association was found between a mesial temporal epileptogenic zone and TIRDA.90 On the other hand, temporal intermittent polymorphic delta activity

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was recorded in patients with temporal and extratemporal epilepsies.89 Distribution of IED in TLE In TLE, IED tend to produce a stereotyped pattern on the scalp with highest amplitudes at the anterior temporal electrodes. This may be due to the location of the neuronal generators within the temporal lobe and anatomical characteristics of the brain coverings, such as skull discontinuities.17 Children may have a more widespread irritative zone which may be caused by a high frequency of dual pathology.91 Most78,82,92–95 but not all studies47,96 confirmed the finding that IED confined to the anterior temporal region are predictive of good postoperative outcome after TLE surgery. Lateralizing value of IED The incidence of bilateral IED in TLE is estimated to lie between 20 and 44% and may be higher when investigated with invasive EEG.4 The probability of bilateral IED was positively correlated with the duration of the EEG monitoring.96,97 Bitemporal IED increase the likelihood that seizures are arising independendly from both sides98 and can reflect bilateral damage, dysfunction at a distance, or secondary epileptogenesis.21,99,100

Fp1–F7 F7–T7 T7–P7 P7–O1 Fp2–F8 F8–T8 T8–P8 P8–O2 Fp1–F3 F3–C3 C3–P3 P3–O1 Fp2–F4 F4–C4 C4–P4 P4–O2 Fz–Cz Cz–Pz ECG 30 µV 1 sec

Figure 56.3 Interictal EEG of a 21-year-old patient with left temporal lobe epilepsy due to hippocampal sclerosis. Scalp electrodes are attached according to the International 10–20 system. Note the temporal intermittent rhythmic delta activity (TIRDA) in the left temporal region. ECG: electrocardiogram.

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In extracranial EEG recordings, interictal discharges can have a more reliable lateralizing value than ictal changes in temporal lobe epilepsy,100 and they almost always predict seizure origin in TLE and good postoperative outcome if they are exclusive or clearly preponderant on the side of surgery.4,37,71,78,82,85,98,101–108 In a study of 59 candidates for temporal lobectomy, 92% of patents with >90% lateralization of the IEDs had a good surgical outcome, whereas only 50% with 11 years: awake after midnight; 3–11 years; awake after 2 am; 60 electrodes, >10 days of implantation, older age of patient, and left-sided procedures.30 Complication rates also appear to be declining with time, likely as a result of changes in electrode design, better aseptic techniques, and decreased implantation times.31 These factors help explain the broad range of complication rates in the published literature. For subdural grid electrodes, infection rates range between 4–14% and bleeding rates are

between 3–8%.30,32,33 Infarction and significant cerebral edema are much rarer. For subdural strip electrodes placed through burr holes, complication rates are generally much lower, 1–4%,33–35 and primarily involve infection and hematoma. Cerebral edema is rarer, but more likely when large numbers and/or bilateral strips are used. With depth electrodes, the main complication is hemorrhage, with rates in the 1–4% range.36 Another important disadvantage of invasive recordings is their limited coverage. Unlike scalp recordings, which typically provide a sampling of all accessible cortical regions, invasive recordings only cover specific areas.37 Thus, if the actual seizure focus is covered by an electrode, than it will be correctly identified; however, if it is not, then the apparent seizure focus will appear to be the first location that is covered by an electrode. However, this could be a site of seizure spread, not seizure onset. An extreme example would be a situation where the seizure focus is actually in the right hemisphere but subdural electrodes are placed only over the left hemisphere (based on falsely lateralizing imaging and/or scalp EEG recordings). In one series of patients, poor sampling of the epileptogenic zone was felt to be responsible for a failure to localize the seizure focus in 13 out of 110 cases.38 Thus, great care needs to be taken in evaluating all the noninvasive data to plan placement of the invasive electrodes. Sometimes, this concern also forces the use of larger numbers of invasive electrodes than would be necessary otherwise, i.e. if the noninvasive data are unclear or discordant, more electrodes may be necessary to cover the possible areas of seizure onset. Another disadvantage of invasive electrodes is the additional cost incurred, which includes the surgical procedures, the electrodes themselves, and a longer hospital stay, typically about 7–10 days and including 5–7 days of video EEG monitoring.

Case examples Case 1: Scalp EEG is nonlateralizing This patient was a 33-year-old right-handed man with diabetes mellitus type I and hypothyroidism and seizures since age 29. Seizures began with a feeling of déjà vu, and tingling in the arms, and typically progressed to staring, confusion and oral automatisms. Seizures had responded only partially to trials of several medications. Physical exam was significant for some deficits in short-term memory but was otherwise nonfocal. MRI of the brain and PET scan were normal. Previous EEGs had shown some spikes and focal slowing in the left temporal regions. Video-EEG monitoring with scalp-EEG recorded eight typical seizures; two had their onset in left temporal-frontal head regions; the others were nonlocalizing. In the absence of any abnormality on imaging studies, it was felt that the scalp-EEG data was not sufficient to lateralize the patient’s seizure focus. Therefore, bilateral subdural strips were placed through burr holes over the frontal and temporal lobes (Figure 69.2a). On this admission, all clinical seizures showed a left temporal-frontal onset (a more precise localization was not possible with the limited sampling provided by strips). In addition, four electrographic seizures, without obvious clinical accompaniment, were also recorded; three

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(a)

Seizure onset/ Early involvement

(b)

Seizure onset

Figure 69.2 See case 1 for details. a. Reconstructed images based on preoperative MRI of the brain and postoperative 3D head CT showing the locations of subdural strips used to lateralize the patient’s seizures. The electrodes where seizures appeared to start are indicated. Note: due to the limited coverage obtained with subdural strip electrodes, it is usually not possible to distinguish between the true seizure onset and areas which may only be involved early in the seizure. b. Reconstructed images showing the grids and subdural strips used to localize the patient’s seizures. The electrodes where the seizures started are indicated.

originated from the left temporal-frontal region; however, the fourth suggested a possible right-sided focus. Of note, the subdural strips covering the right temporal lobe were not symmetric with those on the left in the anteromesial portion of the temporal lobe (Figure 69.2a, inferior view). Thus, while the majority of the evidence suggested a left temporal-frontal seizure focus, a right temporal focus with rapid spread to the left might have been missed. In the next step, the patient had extensive subdural grids placed over the left temporal and frontal lobes, including the orbito-frontal surface and the mesial and basal portion of the temporal lobes (Figure 69.2b). Two subdural strips were placed over the mesial/basal portion of the right temporal lobe

through a burr hole. On this admission, all seizures originated from the most mesial and anterior contacts over the left temporal lobe. At the completion of this recording, the patient underwent a standard left temporal lobectomy, including the amygdala and hippocampus. As a result, the patient had marked improvement in his seizures. This case provides a good example of the utility and limitations of invasive EEG recording. Without intracranial electrodes, it would not have been possible to localize the patient’s seizure focus and provide the opportunity for surgical resection. However, this case also points out the limited coverage provided by intracranial electrodes. A larger number of electrodes could have been placed during the first

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surgical procedure, but at greater risk to the patient. Often, subdural strips, as in the first procedure, are adequate to localize the seizure focus. However, this case also illustrates the difficulties in accurate placement of subdural strips through burr holes. Case 2: Scalp EEG is lateralizing but nonlocalizing The patient was a 29-year-old right-handed man with a history of meningoencephalitis at age 6 and seizures since age 9. His seizures consisted of loss of awareness, oral automatisms and drooling. His seizures occurred approximately once a month, in spite of trials of multiple medications. Physical examination was significant for loss of vision in the left eye only. MRI of the brain was normal. A PET scan showed subtle left temporal hypometabolism. Video-EEG with scalp electrodes showed diffuse semirhythmical slowing in the left fronto-temporal region followed by build-up of rhythmic activity in the temporal-frontal head regions, maximum in the temporal regions. Thus, scalp-EEG was lateralizing but not localizing. Therefore, the patient underwent placement of

extensive subdural grid electrodes covering the left temporal and frontal lobes, including the orbitofrontal region and the mesial and basal aspects of the temporal lobe (Figure 69.3a). With these electrodes, the seizures appeared to originate from the most medial and anterior contacts on the temporal lobe (Figure 69.3b). The patient underwent a standard left anterior temporal lobectomy and showed marked improvement in the control of his seizures. This case illustrates the situation of a nonlesional patient in whom the scalp EEG was lateralizing but not localizing and intracranial electrodes were necessary for precise localization. Case 3: Scalp EEG localizes the epileptogenic region to be near eloquent cortex The patient was a 34-year-old right-handed woman with a history of intractable complex-partial seizures (staring and decreased responsiveness) that remitted for several years after resection of a left posterior temporal dysembryoplastic neuroepithelial tumor. However, her seizures subsequently returned including some secondarily generalized tonic-clonic

(a)

(b)

Seizure onset Early spread

Figure 69.3 See Case 2 for details. a. Reconstructed images showing location of subdural grids (lateral and inferior view). b. Reconstructed image (inferior oblique view) showing the sites where the patient’s seizures started and those involved very early in the seizure.

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Indications for invasive electroencephalography evaluations seizures and episodes of complex-partial status epilepticus, in spite of continued use of multiple antiepileptic medications. Video-EEG monitoring with scalp electrodes confirmed that the seizures still originated from the left temporal region. MRI of the brain showed no evidence of residual or recurrent tumor. Intracarotid sodium amobarbital test (Wada test) had previously shown that the patient’s left hemisphere was dominant for language. Due to the proximity of eloquent cortical areas to the presumed area of seizure focus, a large subdural electrode array was placed over the posterior portion of the left temporal lobe (extending up to the frontal and parietal lobes as well) with some additional strips wrapping around the inferior aspect of the temporal lobe (Figure 69.4a). Several clinical seizures were recorded and appeared to originate from the lateral contacts on the left temporal lobe. In addition, there were electrographic seizures arising from contacts on the lateral aspect of the basal temporal-occipital cortex. When language function was mapped using electrical stimulation of these same electrodes (Figure 69.4b), some language areas were found to overlap with contacts involved in the electrographic seizures. Thus, the resection margins (Figure 69.4a, dashed lines) were selected to preserve all areas with significant language function, even though this left some presumably epileptogenic areas intact. After this resection, the patient had some limited improvement in her seizures; her language function was entirely preserved. This case illustrates the situation in which both scalp EEG and a known lesion localize the

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epileptogenic region near eloquent cortical areas and intracranial electrodes are used both for precise seizure localization and for functional mapping. It also illustrates the importance of removing the entire ‘epileptogenic zone’ for seizure control. Case 4: Lesion is in a location not well-surveyed by scalp EEG and near eloquent cortex The patient was a 19-year-old right-handed woman with seizures since age 14. Seizures consisted of flashing lights in the left inferior quadrant of the visual field followed by pounding headaches. These occurred 4–5 times per week in spite of trials of multiple antiepileptic agents. MRI of the brain revealed a calcified lesion in the right occipital region; cerebral angiography was unremarkable (Figure 69.5a). Scalp EEG revealed seizures originating in the right occipital region, near electrode O2. Because of the deep midline location of the lesion and the proximity to primary visual cortex, it was felt that scalp-EEG was not sufficient to precisely delineate the epileptogenic zone, and differentiate it from eloquent cortex. Thus, the patient underwent invasive EEG monitoring. A large grid was placed over the right occipital region and a smaller grid was placed in the interhemispheric fissure between the two occipital lobes (Figure 69.5b). Both interictal and ictal recordings showed that the seizure focus was limited to the superior contacts of the interhemispheric grid (Figure 69.5c). This was superior

(a)

Seizure onset Electrographic seizure onset

(b)

No deficits Reading deficits Reading & comprehension deficits

Figure 69.4 See Case 3 for details. a. Reconstructed images showing location of grids along with the site of seizure onset (both clinical seizures, blue, and electrographic seizures without associated clinical activity, red). The dashed lines represent the margins of the planned resection. This based on consideration of the site of seizure onset and the results of cortical mapping shown in b. b. Results of cortical mapping of language function.

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(b)

(c)

Spontaneous seizure onset Stimulated seizure Left lower quadrant flashing during stimulation mapping

Figure 69.5 See Case 4 for details. a. Sagittal and axial T1-weighted MRI showing location of calcified lesion in the midline of the right occipital lobe. b. Reconstructed images showing the grids placed in the interhemispheric fissure between the occipital lobes and on the lateral aspect of the occipital and parietal lobes. c. Reconstructed image showing site of seizure onset along with results of cortical mapping and sites where stimulation provoked seizures.

to the presumed primary visual cortex based on MRI and cortical stimulation mapping. Thus the resection was tailored to remove the known lesion and the region covered by these contacts, with the goal of sparing vision. Note the occurrence of electrical stimulus evoked seizures from regions that were not the focus for the spontaneous seizures. After surgery, the patient continued to have occasional simple partial seizures consisting of flashing lights and headaches. She also had an irregular inferior quadrant visual defect in the left hemifield, but most of her vision on that side was preserved. In this case, although the scalp-EEG suggested a seizure focus near a known imaging abnormality, invasive EEG was necessary for two reasons. First, the abnormality was deep to the surface of the brain in an area not easily assessed by scalp-EEG. Second, the abnormality was near eloquent cortex.

Case 5: Scalp-EEG and imaging are discordant The patient was a 22-year-old right-handed man with seizures since age 21. Seizures consisted of staring, inappropriate answers to questions, automatisms, and excessive drooling with no recollection of the event. Seizures continued every 1–2 months in spite of multiple medications. MRI of the brain showed a 1 cm lesion in the posterior portion of the cingulate gyrus on the right (Figure 69.6a), which had not changed for over 6 months. By MRI plus magnetic resonance spectroscopy, the lesion appeared to be a low-grade tumor. Routine EEGs were normal. With video/EEG with scalp electrodes, interictal spike- and slow-wave complexes were seen over the anterior to middle portion of the right temporal lobe. With his typical seizures, right temporal activity was noted at onset. Even though scalp-ictal and interictal-EEG and clinical semiology suggested seizure

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(a)

(b)

Figure 69.6 See Case 5 for details. a. Sagittal T1-weighted MRI showing location of lesion near right cingulated gyrus (arrow). The remaining of the MRI was normal. b. Sagittal T1-weighted MRI showing track of depth electrodes placed in the right hippocampus (left), and cingulate gyrus (right, arrow).

onset in a surgically favorable site, the anterior right temporal lobe, the presence of a lesion near the right cingulate gyrus raised concerns that scalp-EEG might have mislocalized the site of seizure onset. For this reason, depth electrodes were placed in the right amygdala, right hippocampus and through the right cingulate lesion (Figure 69.6b). Depth electrode recordings revealed that the earliest ictal discharges were in the right cingulate lesion, preceding discharges in the right hippocampus by 6–9 seconds. Thus, the right temporal lobe was a site of seizure spread and may have produced much of the clinical symptomatology (the ‘ictal symptomatogenic zone’4) but was not part of the ‘epileptogenic zone.’ The patient underwent resection of the right cingulate lesion. After surgery, the patient no longer had seizures and had no deficits. In this case, invasive electrodes were essential in resolving differences between scalp-EEG, which localized the seizure focus to the right temporal region, and a known lesion at a site not easily assessed by scalp EEG.

Summary As the above examples illustrate, there are many unique situations that can arise in the course of evaluating a patient for epilepsy surgery. Studies and procedures must be tailored to each individual situation; however, there are basic principles that can be applied as shown in Figure 69.1 and Table 69.1. Invasive EEG recording is neither something to be avoided nor something to use indiscriminately. In situations where there is uncertainty about the location of the seizure focus or about the safety of resecting the seizure focus, i.e., due its to proximity to eloquent cortex, invasive EEG can be invaluable. However, it is also important to acknowledge the risks and limitations of invasive EEG evaluations. First, the question(s) to be addressed by the invasive EEG recordings should be formulated; only then can a surgical plan be made that is likely to be implemented with an acceptable level of risk compared to the likely benefit. If appropriate questions and plans cannot be formulated, invasive recordings may not be needed.

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Jasper HH. Electrocorticography. In: Penfield W, Erickson TC, eds. Epilepsy and Cerebral Localization. Springfield, IL: Charles C. Thomas, 1941:380–454. Penfield W, Rasmussen T. The Cerebral Cortex of Man: A Clinical Study of Localization of Function. New York, NY: Macmillan, 1950. Penfield W, Jasper HH. Epilepsy and the Functional Anatomy of the Human Brain. Boston, MA: Little, Brown and Company, 1954. Rosenow F, Lüders HO. Presurgical evaluation of epilepsy. Brain 2001;124:1683–700. Bancaud J. Apport de l’exploration fonctionelle par voie stereotaxique a la chirurgie de l’epilepsie. Neurochirurgie 1959;5:55–112. Tailarach J, De Ajuriaguerra J, David M. Etudes stereotaxique et structures encephaliques profondes chez l’homme. Presse Med 1952;28:605–9. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342(5):314–9. Gilliam F, Faught E, Martin R, et al. Predictive value of MRI-identified mesial temporal sclerosis for surgical outcome in temporal lobe epilepsy: An intent-to-treat analysis. Epilepsia 2000;41:963–6. Schiller Y, Cascino GD, Sharbrough FW. Chronic intracranial EEG monitoring for localizing the epileptogenic zone: An electroclinical correlation. Epilepsia 1998;39:1302–8. Jayakar P. Invasive EEG monitoring in children: When, where and what? J Clin Neurophysiol 1999;16:408–18. Walczak TS, Radtke RA, Lewis DV. Accuracy and interobserver reliability of scalp ictal EEG. Neurology 1992;42(12):2279–85. Lee SK, Kim JY, Hong KS et al.The clinical usefulness of ictal surface EEG in neocortical epilepsy. Epilepsia 2000;41(11):1450–5. Morris HH III, Lüders HO, Lesser RP, Dinner DS, Klem GH. The value of closely spaced scalp electrodes in the localization of epileptiform foci: a study of 26 patients with complex partial seizures. Electroencephalogr Clin Neurophysiol 1986;63(2):107–11. Wada J, Rasmussen T. Intracarotid injection of sodium amytal for the lateralization of cerebral speech dominance. Experimental and clinical observations. J Neurosurg 1960;17:266–82. Milner B, Branch C, Rasmussen T. Study of short-term memory after intracarotid injection of sodium amytal. Trans Am Neurol Assoc 1962;87:224–6. Lüders HO, Lesser RP, Dinner DS et al. Localization of cortical function: New information from extraoperative monitoring of patients with epilepsy. Epilepsia 1988;29 (Supp. 2):S56–65. Lachhwani DK, Dinner DS. Cortical stimulation in the definition of eloquent cortical areas. In: Rosenow F, Lüders HO, eds. Presurgical Assessment of the Epilepsies with Clinical Neurophysiology and Functional Imaging. Amsterdam, Netherlands: Elsevier, 2004:273–86. Lesser RP, Lüders HO, Klem G et al. Cortical afterdischarge and functional response thresholds: Results of extraoperative testing. Epilepsia 1984;25(5):615–21. Kloss S, Pieper T, Pannek H, Holthausen H, Tuxhorn I. Epilepsy surgery in children with focal cortical dysplasia (FCD): results of longterm seizure outcome. Neuropediatrics 2002;33(1):21–6. Raymond AA, Fish DR, Sisodiya SM et al. Abnormalities of gyration, heterotopias, tuberous sclerosis, focal cortical dysplasia, microdysgenesis, dysembryoplastic neuroepithelial tumour and dysgenesis of the archicortex in epilepsy. Clinical, EEG and neuroimaging features in 100 adult patients. Brain 1995;118(Pt3):629–60.

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Palmini A, Andermann F, Olivier A, Tampieri D, Robitaille Y. Focal neuronal migration disorders and intractable partial epilepsy: results of surgical treatment. Ann Neurol 1991;30(6):750–7. Bernier GP, Richer F, Giard N, et al. E. Electrical stimulation of the human brain in epilepsy. Epilepsia 1990;31:513–20. Tao JX, Ray A, Hawes-Ebersole S, Ebersole JS. Intracranial EEG substrates of scalp EEG interictal spikes. Epilepsia 2005;46(5):669–76. Fernandez Torre JL, Alarcon G, Binnie CD et al. Generation of scalp discharges in temporal lobe epilepsy as suggested by intraoperative electrocorticographic recordings. J Neurol Neurosurg Psychiatry 1999;67(1):51–58. Devinsky O, Sato S, Kufta CV, et al. Electroencephalographic studies of simple partial seizures with subdural electrode recordings. Neurology 1989;39(4):527–33. Cooper R, Winter AL, Crow HJ, Walter WG. Comparison of subcortical, cortical and scalp activity using chronically indwelling electrodes in man. Electroencephalogr Clin Neurophysiol 1965;28:217–28. Worrell GA, Parish L, Cranstoun SD et al. High-frequency oscillations and seizure generation in neocortical epilepsy. Brain 2004;127(7):1496–506. Kothare SV, Van Landingham K, Armon C et al. Seizure onset from periventricular nodular heterotopias: A depth electrode study. Neurology 1998;51(6):1723–7. Behrens E, Schramm J, Zentner J, Konig R. Surgical and neurological complications in a series of 708 epilepsy surgery procedures. Neurosurgery 1997;41(1):1–10. Hamer HM, Morris HH, Mascha EJ et al. Complications of invasive video-EEG monitoring with subdural grid electrodes. Neurology 2002;58(1):97–103. Wiggins GC, Elisevich K, Smith BJ. Morbidity and infection in combined subdural grid and strip electrode investigation for intractable epilepsy. Epilepsy Res 1999;37(1):73–80. Lee WS, Lee JK, Lee SA, Kang JK, Ko TS. Complications and results of subdural grid electrode implantation in epilepsy surgery. Surg Neurol 2000;54(5):346–51. Rydenhag B, Silander HC. Complications of epilepsy surgery after 654 procedures in Sweden, September 1990–1995: a multicenter study based on the Swedish National Epilepsy Surgery Register. Neurosurgery 2001;49(1):51–6; discussion 6–7. Wyler AR, Walker G, Somes G. The morbidity of long-term seizure monitoring using subdural strip electrodes. J Neurosurg 1991;74(5):734–7. Rosenbaum TJ, Laxer KD, Vessely M, Smith WB. Subdural electrodes for seizure focus localization. Neurosurgery 1986;19(1):73–81. Pilcher WH, Rusyniak WG. Complications of epilepsy . Neurosurg Clin N Am 1993;4(2):311–25. Gloor P. Electroencephalography and the role of intracerebral depth electrode recordings in the selection of patients for surgical treatment of epilepsy. In: Porter RJ, Mattson R, Ward AA, Dam M, eds. Advances in Epileptology. New York, NY: Raven Press, 1984:433–7. Siegel AM, Roberts DW, Thadani VM et al. The role of intracranial electrode reevaluation in epilepsy patients after failed initial invasive monitoring. Epilepsia 2000;41(5):571–80.

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Invasive electrodes in long-term monitoring GH Klem and S Nehamkin

The ability to provide long-term monitoring implies that there are adequately trained technologists, skilled in the use of a variety of monitoring equipment. This equipment includes EEG instrumentation, video recording devices, and electrical stimulation equipment to map functional cortex with either direct cortical stimulation of invasive electrodes or evoked potentials from the scalp or invasive electrodes. The variety of electrodes, both scalp and invasive, extracranial as in eye and EKG electrodes, and other devices including pulseoximetry to monitor for oxygen desaturation during events are also routinely used in the long-term monitoring setting. Particular training in the recognition and management of seizures and medical emergencies must be emphasized. Incorporation of these diverse techniques routinely used in both adult and pediatric long-term monitoring units often make the technologist’s role significantly more demanding than in the routine EEG laboratory. In April 1939, Penfield performed trephination over both temporal regions and placed electrodes on the dura, intending to lateralize seizure origin in a patient with bitemporal epilepsy. The patient underwent serial EEGs with this technique. Since this time in medical history it has been shown that localization of epileptic foci and areas of elequent cortical funcation with appropriately placed epidural, subdural, and depth electrodes has helped to make epilepsy surgery a safe and efficacious option for the successful treatment of epilepsy that is refractory to medication. Invasive electrodes can be used both for monitoring and stimulation of the underlying tissue to identify functional cortex.

Epidural pegs Epidural electrodes were first used by Hans Berger.1 Berger’s epidural electrode consisted of a needle inserted epidurally in the area of a skull defect. Many other epidural electrode types have been developed since, including a wire balled fused at the end of the wire as described by Jasper, or an array of multiple contacts imbedded in flexible Silastic stips. There are cases where the usual EEG scalp recordings, even when combined with the use of sphenoid electrodes, do not provide clear evidence of the onset of a focal seizure. When this occurs, it may be difficult to use electrical activity in planning for a more invasive surgical approach in localizing the seizure foci. Epidural electrodes or epidural peg electrodes placed over a variety of locations covering the scalp may be employed.

The epidural peg electrode consists of a 3/16 inch stainless steel disk embedded in a mushroom-shaped body of Silastic. A multistranded stainless steel wire is soldered to the disk and exits through the cap of the electrode. The length of wire exiting the peg is approximately 20–25 cm in length and terminates with a standard electrode jack. These electrodes are placed in the operating room with the patient under general anesthesia. The surgeon places the electrode under the skin, opening the cranium with a twist drill allowing the electrode direct contact with the dura. Localization for the sites is determined through previous recording sessions and special anatomical considerations derived from imaging studies. Technical recording considerations when using epidural pegs include adjustment of the sensitivity setting on the EEG recording equipment to the range of 20–30 microvolts per millimeter (µV/MM), as compared to the usual range for scalp recordings.

Sphenoid electrodes The routine use of sphenoid electrodes for all patients with a history of complex partial seizures aids in the localization of epileptiform discharges. These electrodes in combination with standard scalp electrodes may help in defining whether the foci is in the lateral or mesial structures of the temporal lobe. Although it is generally agreed that the sphenoid electrodes record primarily from the temporal lobe, there is no real evidence that they do not pick up activity from the orbital frontal cortex. The sphenoid electrode consists of a multistranded stainless steel or platinum wire that is insulated except at the tip. Inserted transcutaneously through the mandibular notch the electrode wire that is placed ranges from 50–75 mm and is inserted with a 20 or 22 gauge needle that is removed leaving the electrode wire in place. Sphenoid electrode packages are gas sterilized. These electrodes are inserted using aseptic technique at the patient’s bedside. Topical anesthetics, or in some cases a light sedative, are used prior to electrode placement.

Foramen ovale electrodes Foramen ovale electrodes have been used to record from mesial temporal structures and are less invasive than depth electrodes.2 The electrode consists of platinum pellets embedded 623

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on thin wire in a Teflon tube. The contacts are usually 1–1.5 cm apart and the wires run through the tube exiting at a connector. The electrodes are inserted percutaneously in the operating room through a small incision in the cheek. Passed through a 20 gauge needle, entering Meckel’s cave cistern, the electrode is then advanced so that the most proximal contact rests at the level of the foramen ovale. These electrodes, like sphenoid electrodes, are placed bilaterally. Flouroscopy is used in the operating room to verify placement location. Foramen ovale electrodes are well tolerated by most patients, including adolescents.

Subdural arrays The subdural array is a ‘grid’ or ‘strip’ of electrodes placed directly on the cortex or dura under general anesthesia in an operating room.3–6 Subdural strip electrodes, generally consisting of four to ten contacts spaced at 0.5–1 cm intervals in a single row Figure 70.4. Subdural stips may be placed through a burr hole. Subdural grids are often designed anywhere from two to ten rows in length and four to eight rows in width, with a variety of intraelectrode spacing options, shaped as square, rectangle, or with a curved edge, and are placed through a craniotomy Figures 70.5 and 70.6. The location and size of the subdural array is determined by the results of previous recordings, localization of an intracranial lesion or AVM, vasculature, and scar tissue. Adequate coverage for the most accurate localization must include any lesion or structural abnormality and the surrounding cortex.7–14 The epileptic onset zone may not be located within the borders of the identified structural abnormality, therefore the surrounding tissues must be thoroughly investigated by appropriate coverage with invasive electrodes Figure 70.8. Subdural electrodes consist of stainless steel or platinum disks embedded in a flexible sheet of medical grade silicone. The electrode is soldered to a stainless steel multistranded wire. The wire is insulated with a Teflon coating. Wires are arranged on the array in an order that allows the surgeon to cut out one or more

of the electrode disks in order to adapt the array to the surgical site without compromising the integrity of the electrode. The wires are then gathered into a flexible Silastic tube that terminates into a microminiature connector. The use of this small connector allows the surgeon to tunnel the cable away from the site of the burr hole or craniotomy and exit the scalp through a stab wound. The microminiature connector is then attached to the input cable that will plug into the EEG amplifiers. When a large number of electrodes are required, i.e., an 8 × 8 subdural grid of 64 electrodes, the wires that are connected to the disks are brought through the Silastic tubes terminating in two or four microminiature connectors and number or color coded as 1 through 16, 17 through 32 and so on, corresponding to the pin positions of the amplifier. The total combined number of electrodes, scalp, sphenoidal, subdural, depth, and noncephalic, is limited by the number of amplifier inputs. Our institution, University Hospitals Case Medical Center, utilizes Nihon Khoden equipment which presently allows for 192 electrodes.15–22

Depth electrodes Depth electrodes have been used to record from a variety of locations, primarily from the mesial structures of the temporal frontal, and occipital lobes. The most common use of depth electrodes is for localization of the seizure focus within the temporal lobes, especially when lateralization is difficult (Figures 70.1 and 70.2). These electrodes consist of multiple stainless steel or platinum contacts approximately 2–5 mm wide usually spaced at 2–5 mm intervals encirciling a closed plastic, 0.8 mm tube. The number of contacts is typically between six and twelve. Three dimensional reproductions of the brain recreated with MRI and/or CT imaging allows for minimally invasive implantion of these electrodes through burr holes in a surgical setting. Depth electrodes are often used along with other invasive electrodes to maximize coverage.

Interictal map Brain Map–Basal

RA

LA

Interictal map Spikes: RA2–3–4

RH

RP

Figure 70.1

Interictal map.

LH LP

RH1–2–3–4 Slowing: RA8–10,RH8–10

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Invasive electrodes in long-term monitoring Ictal Map

Brain Map-Basal

RA

LA LH

RH

LP

RP

Ictal Map Sz # 2 Non–localizable (right temporal) Sz # 7 Non–localizable (right temporal) Other Szs onset

Figure 70.2

Ictal map.

Seizure onset with Sharps and ripples

RP2

Figure 70.3

Seizure onset with Sharps and ripples.

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Figure 70.4

Subdural strip electrodes.

Electrical stimulation Electrical stimulation of the subdural stip and grid electrodes and depth electrodes in the long-term epilepsy monitoring unit and the operating room provides detailed information for localizing cortical function relative to the seizure onset zone which is the ultimate surgical target. The patient can be tested at the bedside without the need for any type of local or generalized anesthesia. The rate of testing can be slow allowing time for the patient to rest during relatively long testing periods and in the event of a clinical seizure, either spontaneous or activated by the stimulation.23–28 Electrical stimulation of invasive electrodes may be done with a variety of devices. The free-standing battery-powered Integra Ojeman stimulator, or stimulation delivered through the EEG recording equipment like the Nihon Khoden equipment used at University Hospitals Case Medical Center Epilepsy Monitoring Unit are both reliable options. Electrical stimulation parameters for invasive electrodes consist of 50 Hz, 0.2–0.5 msec alternating polarity square wave pulses of varying duration, usually 5 seconds in

Figure 70.6 Subdural grids designed from two to ten rows in length and four to eight rows in width, with a variety of intraelectrode spacing options, shaped as square, rectangle, or with a curved edge, are placed through a craniotomy.

length. The surrounding EEG activity is watched for afterdischarges. An after discharge is defined for our purposes as a retetitive sharpwave clearly distinguished from the ongoing interictal activity, which occurs immediately following the electrical stimulation and involves one or more electrodes, including always the electrode stimulated Figure 70.7. The duration must exceed 1 second following cessation of the stimulus. Stimulation begins at 0.5–1 mA and increases in increments of 0.5–1 mA until an after discharge occurs, functional alterations occur, or until an intensity of 15 mA is reached. Functional alterations are defined as the occurance of motor contractions, sensory phenomena in the resting patient, or impairment of activity if stimulation occurs during the performance of a task. It is possible that electrical stimulation will not provide the information desired due to the position of the subdural or depth electrodes. In these cases additional electrical stimulation may be carried out in the operating room. Stimulation may be carried out under light sedation with the patient awake, speaking and following commands, or with the patient under

Speech Sensory Face Motor Face/Tongue Bad Electrode Pain Left

Figure 70.5

Subdural grids.

Figure 70.7

Electrical stimulation of invasive electrodes.

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Visual-evoked potentials are routinely recorded from electrodes placed on the occipitals lobes. These techniques combined with direct cortical stimulation assist in identifying cortical function that may not be found in the predicted region of the brain based on normal anatomy.29–33 Evoked potentials may be performed either at the patient’s bedside or in the operating room. Mapping for central sulcus, especially in a patient that may not be able to cooperate during other cortical mapping procedures is a reliable technique for localization.

Conclusion Figure 70.8

Subdural invasive electrodes.

general anesthesia with no muscle relaxant on board to watch motor movements. EEG activity is closely monitored to determine if afterdischarges or seizure activity occurs.

Evoked potentials Somatosensory evoked potentials elicited by stimulation of either the median nerve or posterior tibial nerve may be recorded from the invasive electrodes to identify afferent areas.

The ability of current EEG recording equipment to allow sampling rates as fast as 5000 Hz coupled with the quality of invasive electrodes has created major advances in the field of epilepsy. Recording and identifying high frequency oscillations, called ripples, of 200 Hz and greater, prior to seizure onset may soon be shown to offer more precise localization of epileptic foci Figure 70.3. The priority for all medical professionals should always be maintaining or creating the best quality of life possible for each patient. Advances in computer technology relative to EEG recording equipment, functional mapping techniques, imaging devices, image guided surgical techniques, and invasive electrode options have come together to help insure safe and successful outcomes for epilepsy surgery patients.

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30. 31. 32.

33.

Jasper HH. Report on the committee on methods of clinical examination of electroencephalography. Electroencephalogr Clin Neurophysiol 1958;10:370-375. Lesser RP, Koehl R. Lüders HO. Effect of stimulus intensity on short latency somatosensory evoked potentials. Electroencephalogr Clin Neurophysiol 1979;47:377–82. Morris HH III, Lüders HO, lesser RP, Dinner DS, Klem GH. The value of closely spaced scalp electrodes in the locationion of epileptiform foci: a study of 26 patients with complex partial seizures. Electroencephalogr Clin Neurophysiol 1986. Jasper HH. Electrocorticography. In: Penfield W, Jasper HH, eds. Epilepsy and the Functional Anatomy of the Human Brain. Boston: Little, Brown, 1954:692–738.

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Foramen ovale and epidural electrodes in the definition of the seizure onset zone* HG Wieser and K Schindler

Introduction The objective of presurgical evaluation of patients with focal drug-resistant epilepsy is to delineate the primary epileptogenic zone. The epileptogenic zone is defined as the brain tissue that has to be surgically removed to render the patient seizure free.1 However, the epileptogenic zone is a theoretical concept, a way to think about the structure of the epileptic brain. Therefore it is not surprising that no single diagnostic method is able to detect the epileptogenic zone alone. Instead, a series of methods such as detailed analysis of seizure semiology, noninvasively and invasively recorded ictal and interictal EEG, MRI, PET, neuropsychological assessments and in some patients ictal SPECT and MR-spectroscopy, are clinically applied. The epileptogenic zone is then approximated by the brain region that is shown to be pathologically altered by these different methods. In this process the results of the diverse methods used are differently weighted. One of the most important pieces of information is where the seizures start, i.e., where the seizure onset zone is localized. Actually, other definitions of the epileptogenic zone or epileptogenic focus contain the seizure onset zone as an integral part.2 The initial ictal activity of cortical neuronal networks is typically characterized by fast oscillations, i.e. oscillations in the frequency range of 20 –100 Hz or even higher.3,4 Specifically important in regard to presurgical evaluation is that localized high-frequency activity has been found to be associated with good surgical outcome.5 In addition, recent findings indicate that high frequency epileptiform oscillations do not only spatially delimit the seizure onset zone, but also may occur more often before seizures and therefore be helpful to detect a preseizure time period,6 which is a precondition for developing an EEG based seizure prediction method.7 In vivo and in vitro animal experiments and computer simulations even imply that fast cortical oscillations may have a causal effect in seizure initiation and may be physiologically sustained by interneuronal gap junctions or by synchronizing effects of the electric field.8,9 An important practical problem in presurgical evaluation is that these high frequency cortical oscillations – so important in localizing the seizure onset zone – can not be reliably recorded by scalp electrodes. This is on one hand because of the frequency dependence of transmission from cortex to scalp with a strong attenuation of higher frequency activity due to mutual cancellation by spatial summation.10 On the other hand,

electrical activity from contracting scalp muscles – often occurring at seizure onset – obscures activity of cortical origin most strongly in the frequency range above 20 Hz.11 A way to work around these technical and biological limitations is to use intracranial electrodes, which are mostly unaffected by electromyogenic artefacts and monitor high frequency activity much better. Intracranial electrodes comprise different categories. In this chapter we mainly focus on foramen ovale (FO) electrodes, but also give a brief description of epidural peg electrodes. The latter have been used much less during recent years, mainly due to the very good risk/benefit ratio of other methods such as FO electrodes. A representative case report illustrates how certain limitations of FO electrodes may be compensated for by additional subdural strip electrodes.

Development history of FO and peg electrodes The FO electrode recording technique was developed in Zürich in 1983/412 in order to simplify the neurophysiological investigation of the presurgical evaluation protocol for candidates for selective amygdalohippocampectomy (AHE). Prior to 1983, stereoelectro-encephalography (SEEG) had been used in Zürich in the majority of patients being evaluated for epilepsy surgery.13–15 Accumulated SEEG experience revealed that the mesial temporal lobe structures, and in particular the hippocampus, the parahippocampal gyrus and the amygdala, play the crucial role as seizure generating structures in most patients with temporal lobe epilepsy (TLE). Based on these findings, in 1975 the so-called trans-sylvian amygdalohippocampectomy (AHE)16 was developed and has in the following become the surgical approach of first choice for surgical treatment of mesial TLE (MTLE) in Zürich, but also in many other centers. Data obtained from Engel’s survey carried out prior to the 1992 Palm Desert Conference showed that already then 15 centers (15%) had been using FO electrodes. FO electrodes had been used only in 5% of all *A similar chapter has been published in Engel J Jr and Pedley TA (eds) Epilepsy: A comprehensive Textbook (Lippincott-Raven Publishers, Philadelphia, 1997) 1707–17 and is going to be published in the second edition of this book (Chapter 171; in preparation)

629

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reported patients operated on 1986–1990 (n=7664), but in 21% of 662 reported AHE patients.17 Peg electrodes were developed at the Cleveland Clinic in 1988.18,19 They are usually used as sentinel electrodes in combination with other invasive techniques for obtaining epidural ictal recordings.

Indications FO and peg electrode recording techniques have been referred to as intermediately invasive or semi-invasive approaches. Peg electrodes allow artifact free recording of the electrocorticogram in relatively small but widely separated regions of the cortical convexity to determine surgical suitability in patients in whom the clinical, electrographic and neuroimaging information did not well localize the seizure onset zone. They were also designed to be used when exact placement of a subdural grid array was uncertain from the clinical, neuroimaging and scalp EEG data. Therefore, peg electrodes may serve as sentinel electrodes contralateral to subdural grid placement in order to confirm that ictal discharges are not starting contralaterally. Depending on the particular clinical circumstances, peg electrodes may be used with other electrodes including foramen ovale electrodes, depth electrodes, and subdural strip and grid arrays. FO electrodes record from the mesial aspects of the temporal lobe. Compared to intracerebral depth-, subdural grid-, and most probably also to subdural strip electrodes they are ‘less invasive’, but nevertheless the possibility of complications is inherent to the FO electrode technique, too. Therefore its use should be restricted to presurgical evaluation of possible candidates for epilepsy surgery. Due to their monitoring restricted to the electrical activity of mesial temporal lobes their main indication is for patients with TLE and in particular for patients suffering from the syndrome of MTLE.20 Whereas in Zürich during the period 1970–1983 a total of 94 patients underwent SEEG exploration and this resulted in a total of 69 operations (73%), from 1984 until today FO electrodes have been used in a total of 263 patients resulting in a total of 235 operations (83%). In 18% FO electrodes were combined with other invasive recording techniques. Table 71.1 lists details in this respect.

It is interesting to have a look at the Zürich AHE series, which started in 1975. In this context, it is important to remember that since 1978 there was CT, since 1985 MRI, since 1987 SPECT, since 1988 PET, and since 1987 31P-, and since 1993 proton magnetic resonance spectroscopy (1H-MRS) at the Zürich center. This Zürich AHE series now contains a total of 512 AHE patients. 275 (53.7%) had intracranial EEG monitoring, 32 (6.2%) had SEEG only, 198 (38.7%) had FO electrodes only, 45 (8.8%) had combined intracranial electrodes (SEEG and FO, FO and strips/grids). The remaining 237 (46.3%) had AHE without intracranial recordings (Table 71.2). Table 71.2 shows the obvious trend for less invasive presurgical evaluation in candidates for AHE: In the last years the percentage of AHE without intracranial presurgical evaluation amounted to 69.2%. Despite the overall less invasive presurgical evaluation, the seizure outcome at 1 year after AHE improved steadily over time. In the 1975–1992 period Engel Classes I–IV were 69, 9, 13, 9, and 9% (n=254); in the period 1993–1999 the respective numbers are 75, 10, 13, and 2% (n=115); in the period 2000–2001 the outcome assessment for 50 AHE patients revealed 89, 11, 0, and 0%.21 Table 71.3 lists the types of operations in the most recent consecutive 100 patients with FO electrodes. In these 100 patients who had FO-electrodes alone (n=67) or in combination with other intracranial electrodes (n=33), 87 patients had resective surgery, mainly AHE (n=72). In 13 patients the results of the presurgical evaluation did not indicate ablative surgery. The relatively high number of patients with FO in combination with other intracranial electrodes (33%) reflects two trends. First, MTLE patients with clear-cut concordant findings undergo AHE without intracranial recordings, and secondly, our center is increasingly confronted with more difficult cases in whom more elaborated intracranial seizure monitoring is necessary.

Technical aspects: electrode design, insertion and removal, and recording from the FO electrodes In recent years several types of FO electrodes have become commercially available. However, the original FO electrodes

Table 71.1 Bilateral Patients FO with thermoel.** Patients %

Total 263 14 48 18

Unilateral

no of Electrode Contacts

R+L R L 1 3 4 252 6 5 34† 1 138 6 5 3 FO combined with additional intracranial electrodes +SEEG +Strip +Strip +Grid + Grid 14 31 2 1 5 12 0.8 0.4

R = right hand side L = left hand side † first FO EEG was recorded from a patient with trigeminal neuralgia *43 DIXI Electrodes (DIXI microtechniques, France), the remaining were designed in our own laboratory ** thermoelement for research purpose (Landolt et al.,1995 (23))

8 7

10* 83

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Table 71.2 Number of selective amygdalohippocampectomies total and break-down into four time spans and type of presurgical evaluation (invasive, semi-invasive, non-invasive). 1975-1985, pre-MRI era; 1986-1992, intermediate era; 1993-1999 and 2000-Sept 2005, ECoG era. with modern techniques. The latter is divided according to earlier outcome studies (Wieser et al., 2003 (21)). Prof. G.Yasargil was succeeded by Prof. Y.Yonekawa at the beginning of 1993 1975-1985 n Number of AHE 103 AHE with SEEG 31 alone AHE with combined 7 intracranial electrodes (SEEG+FO; FO+strips/grids) AHE with FO alone 3 AHE with non62 invasive EEG

%

1986-1992 n

%

1993-1999 n

%

n

30.1

151 1

6.8

3

2

32

27.8

3

2.9 60.2

84 63

55.6 41.7

70 13

60.9 11.3

41 99

0.6

used in Zürich were home made.22 In brief, these electrodes consist of ten Teflon-insulated, helically wound silver wires (diameter 0.1143 mm=0.0045 inches) ending in ten poles. They are mounted on a ‘surgical’, i.e., highly corrosion-resistant stainless steel wire 0.1 mm in diameter. This carrier, isolated with a special varnish, has adequate mechanical properties. It is flexible enough and has a special end to avoid penetration of the arachnoidal-pial layer. Each pole consists of 90 parallel windings and is 2 mm long. The distance between two contacts is 2 mm. The external diameter of the FO electrode in use is such that it passes through a special splittable 18-gauge cannula (produced and marketed by Medialimed SA, 1604 Puidoux, Switzerland). This splittable cannula (Figure 71.1B) has an external diameter of 1.23 mm and an internal diameter of 0.93 mm and permits the 4-pin connector to be mounted, soldered, and the stabilizing insulator poured in well before implantation. The electrode impedance ranges from less than 200 ohms to a maximum tolerated 700 ohms, respectively, whereas the DC offset potential is less than 2 mV. Electrodes can be armed with other specific recording devices. Temperature-sensitive devices, have been used in 14 patients,23 and special ictal and interictal DC recording with monopolar FO electrodes were carried out in five patients.24

115 0

2000-Sept 2005 %

143 0

Total n

%

512 32

6.2

2.1

45

8.8

28.7 69.2

198 237

38.7 46.3

Insertion of the FO electrode can be done under local anesthesia. Currently, however, the procedure is done under general anesthesia in Zürich. With the stylet inside the special cannula, the FO electrode is inserted 3 cm lateral to the oral commissure and directed along the intersection of two orthogonal planes: (a) the plane defined by the insertion point, a point on the lower eyelid corresponding to the medial border of the pupil, and the tip of the electrode directed towards the foramen ovale, and (b) a plane defined by the insertion point, a point 5 cm anterior to the external meatus acusticus, and the tip of the electrode directed towards the foramen ovale (Figure 71.1A). To avoid asystoly (atrioventricular block has been reported) we administer atropin before insertion. The patient usually responds to the passage of the needle through the foramen ovale with a wince and a brief contraction of the masseter muscle. After withdrawal of the stylet, cerebrospinal fluid usually drops and the electrode can then be carefully positioned under radioscopic control. In most instances, the tip of the electrode slips without any resistance into the caudal end of the ambient cistern. As can be seen from Figure 71.2F–H, modern 3D image reconstruction and

Table 71.3 Therapeutic actions after presurgical evaluation in the last consecutive 100 patients with FO electrodes Therapeutic actions after presurgical evaluation with FO electrodes alone (n 67) or in combination with other intracranial electrodes (n 33)a

N pts (May 1995–June 2005)

AHE Resection in TL or adjacent areas, other than AHE Re-operation in TL Operation outside Zurich in TL VNS No surgery a

FO and strip (n 28); FO and grid (n 2); FO and grid and strips (n 2); FO and SEEG (n 1)

72 8 2 5 2 11

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(a)

(b)

Figure 71.1 a. Insertion technique of FO electrodes according to the technique of Kirschner30 using the landmarks of Härtel.31 1 = point 5 cm anterior to external auditory meatus. 2 = medial pupillary point. 3 = electrode entry side 3 cm lateral to oral commissure. The index finger is in the pterygoid fossa. The needle is inserted as described in the text, then the special splittable cannula is withdrawn and broken as displayed in b. (Modified from Wieser and Morris, 1997).33

superposition techniques of CT and MRI allow for more precise studies of the anatomical details in relation to the FO electrodes.25 The splittable cannula is then withdrawn and broken (Figure 71.1B) and the freed electrode is fixed by the use of a special clamp to the skin. Gauze and adhesive tape cover the electrode where it penetrates the skin. Oral antibiotic protection is given throughout the recording period and is continued for 3 days after removing the electrode. For the removal of the FO electrode, anesthesia is not necessary. During the withdrawal of the electrode a short-lasting painful sensation in the ipsilateral teeth is relatively common and the patients should be carefully informed about this possibility before the explantation.

Montage, recording and analysis Whereas more sophisticated DC recording was done hard wired with 32 channels in the laboratory (Figure 71.3), longterm digital video-EEG monitoring in AC mode is now possible with up to 128 channels with the patient on the ward. For routine monitoring an uninterrupted bipolar montage connecting the ten contacts of both FO electrodes is recommended, as shown in Figure 71.4. The other channels are used for simultaneous scalp EEG and polygraphy, if indicated. Figures 71.4 and 71.5 give examples of ictal EEG recordings obtained with this system. In Figure 71.6 the case of a 19-year-old patient is illustrated. He suffered from pharmaco-resistant epilepsy. At the beginning of his habitual seizures he would briefly scream and cross his arms. The latter was a ‘semi-automatic’ sign he had learned to use over the years to indicate the beginning seizure to his parents. After becoming confused he would then normally try to get up and walk away (Figure 71.6A–F). MR imaging revealed atrophy and signal hyperintensity of

the mesial temporal lobe structures on the left (Figure 71.6G). In addition, slight atrophy of the lateral left temporal lobe was detected. Because of the pronounced ictal motor signs frontal seizure onset or rapid seizure spread to the frontal lobes were considered. Therefore bilateral FO and additional strip electrode recordings (Figure 71.6H) were used to localize the seizure onset zone. Seizures were demonstrated to always begin in the left mesio-temporal region (Figure 71.6I). However there was intensive interictal epileptiform activity in the left latero-temporal region. Because of the latter finding and the slight atrophy of the left mesial and lateral temporal lobe a resection of the anterior two thirds of the left temporal lobe was performed. Histological examination revealed hippocampal gliosis and loss of neurons and a slightly abnormal focal layering of the neocortex. The patient has been free of seizures and of auras (ILAE outcome 1a) since surgery.

Epidural peg electrodes design Epidural peg electrodes (Figure 71.7) are mushroom shaped composites of silastic plastic with a ‘cap’ diameter of 12.7 mm, a slightly tapered stalk and the tip is a 4.5 mm disc electrode made of either platinum or stainless steel. The electrodes are made with different stalk lengths to adapt to different thicknesses of the skull. A1–1.5 cm scalp incision is made to expose the skull at the predetermined electrode positions. A twist drill with a ‘stop’ is used to create a 4.5 mm burr hole; the electrodes are then inserted by hand into the hole. The 38-gauge Teflon-coated steel wire from the electrode is threaded through a surgical needle and exits the scalp approximately 2 cm distant to the electrode itself. The scalp over the electrode is then sutured. The Bethel Epilepsy Center reported on a slightly smaller version of the original epidural peg electrode.26

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(a)

(b)

(c)

633

(d)

(f) (e)

(g)

(i)

(h)

Figure 71.2 Position of implanted 10-contact FO electrodes as illustrated by ap (a), lateral (b) X-ray and CT imaging (c,d), as well as schematic drawing (e) and three-dimensional anatomical location (f–h) of FO electrodes. In f–h the intracranial course of both FO electrodes is shown in red. The positions of the foramina ovale are marked by the open circles. i. Mean distance of each FO contact to the center of the amygdala. f–i With kind permission of PD Dr.Urs Schwarz; e with kind permission of Dr. Dominik Zumsteg. (See Color plates.)

Patients data of the Zürich FO electrodes series With two exceptions (the first FO electrode patient had no epileptic seizures, but trigeminal neuralgia, and one patient had aggressive outbursts thought to reflect limbic seizures), all patients who underwent FO electrode implantation in Zürich had medically refractory complex partial seizures with or without secondary generalization. In most of the patients, prior to FO electrode implantation, there was rather strong suspicion of mesiobasal limbic seizure foci, as evidenced from the seizure symptomatology, interictal and ictal scalp-EEG, neuropsychological examinations, structural (CT, MRI) and functional (SPECT and PET) imaging. These patients were evaluated with the aim of demonstrating a unilateral mesiobasal limbic seizure focus with the degree of confidence necessary for surgical intervention. Thirty patients had less clear evidence for mesiobasal TL seizure

onset with some contradictory findings pointing to lateral TL or extra-TL seizure onset. These patients were evaluated simultaneously with FO and stereotactic depth electrodes. In 18 patients mesiobasal limbic seizure onset was rather unlikely. These patients underwent long-term monitoring with FO electrodes in order to definitively rule out mesiobasal limbic seizure onset (in which case they would have been no longer candidates for surgical treatment) or to prove a possible secondary pacemaker role of one mesiobasal TL (in which case a so-called ‘palliative’ AHE would be considered as a treatment option). Seventeen percent of this series were considered inoperable and 80% underwent surgery, mostly selective AHE. In the last 10 years 87% of patients with FO electrodes underwent resective surgery (see Table 71.3). Patients evaluated by FO electrodes prior to AHE did not differ significantly in their postoperative seizure outcome when compared to the overall AHE series evaluated mainly by SEEG.27, 28

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Textbook of epilepsy surgery (b)FO.R DC-1 Hz

(a)

FO.R AC 0.1-10 kHz

1s

−179 mV Unilateral Seizure AuraGeneralized Seizure

RFO DC RFO AC

250mV 50µV

(c)

0

R Amygdala RT2ant R Hipp

+179 mV 1 Hz Stimulation Right Hippocampus

Disconnection

1 min

1 min

RT2post

R GCing-par R Par.lat. 1s

50 mV

(d) Stop

R GParahipp

Start Stim

RT2med

Unilat. Generalized Aura Seizure

Figure 71.3 DC-recordings with self-made special FO electrodes. a. Section of combined scalp- FO-electrode- and depthelectrode-EEG recordings with a right hippocampal (R Hipp) seizure discharge with modest spread to the right amygdala, the right parahippocampal gyrus (R GParahipp) and to the ipsilateral parietal cingulate gyrus (R GCing-par) which is reliably depicted by the ipsilateral FO electrode (RFO AC) and accompanied by a negative DC shift (RFO DC). b. Repetitive spikes in the FO electrode recorded in AC mode are accompanied by stepwise negative DC-shifts. c and d (D, detail of C): DC shifts recorded by FO electrode with DC amplifier during an electrically induced partial seizure with an aura and secondary generalisation. During the electrical train stimulation of the hippocampus (Start Stim, Stop) a slight negative shift is seen, which increases during the induced seizure discharge in the hippocampus. With onset of the secondary generalized seizure a further marked DC negativity can be observed, which then inverts to DC positivity. This DC positivity is most probably due to the reference electrode used. The reference electrode for DC recording was a disk-shaped sintered Ag-AgCl electrode 12.5 mm diameter (In Vivo Metric Systems, Healdsburg, CA) subgallealy implanted over the vertex at Cz. The FO electrode used for DC recording consisted of a cylindrical Ag-AgCl pellet (0.4 mm diameter and 4 mm length; for further details see Wieser et al., 1985).12

right Fo

Left Fo

Seizure-Channel FOL6-FOL5

Seizure - Channel FOL5-FOL4

Seizure -

10 11

10

10

9

12

8

13

7

14

6

15

5

16

4

17

3

18

2 1

19 1

1 20

Figure 71.4 On the left the montage for recording from 10-contact FO electrodes is displayed. For routine long-term seizure monitoring we prefer the depicted closed chain with 20 channels (number in boxes). An example of a FO-electrode-recorded seizure onset at contact 5 of the left FO electrode (FOL5) with repetitive 6–7/s sharp waves and evolving rhythmic more wide-spread spike discharges of 19/s. Note that the scalp-EEG channels do not show the seizure onset.

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635

LFO8-LFO6 LFO6-LFO4 19/s LFO4-LFO2 LFO2-LFO2 20 µV

LFO4-LFO3 LFO3-LFO2 LFO2-LFO1 LFO1-RFO1 3/s

34/s

RFO1-RFO2 RFO2-RFO3 RFO3-RFO4

Figure 71.5 Two examples of FO electrode recorded seizure onset patterns in two patients. A. High-frequency low-amplitude spike trains recorded with 10-contact FO electrodes. B. ‘Hypersynchronous onset pattern’ recorded with 4-contact FO electrodes.

Comparison of FO and peg electrodes with other recording techniques Advantages FO electrodes provide a definite advantage over scalp EEG and over sphenoidal electrodes. In a recent study it was for example shown that intracranially recorded epileptiform discharges may often only be detected by scalp electrodes after averaging (Figure 71.8). In several instances, where the Zürich group has used sphenoidal and FO electrodes simultaneously, it was clearly shown that FO electrodes are superior in detecting epileptiform activity from the mesial region of the temporal lobes.27 This is particularly true for epileptiform discharges originating in the posterior hippocampal formation. In comparison with depth electrodes the FO electrodes reliably pick up epileptiform activity generated or involving the hippocampal formation. Pure amygdalar discharges may, however, escape detection in the FO electrodes. A further advantage of FO electrodes is that they offer an excellent possibility to monitor mesial TL EEG changes in selective TL amobarbital tests. As has been shown, appropriate intracranial EEG recorded from depth electrodes or FO electrodes in combination with scalp EEG is indispensable for a reliable interpretation of the amobarbital effects of the selective tests. FO electrodes proved to be very useful, to monitor electrophysiologically the toposelective effects of amobarbital in the so-called selective temporal lobe amobarbital tests.29 The increase of delta activity is considered to be the most typical amobarbital-induced EEG effect. Other amobarbitalinduced EEG patterns are isoelectric lines, the burst suppression pattern, and high and low voltage beta-activity. In the Zürich selective temporal lobe amobarbital series the delta-increase, the ‘activation-phenomenon’ and the spike-reduction were

observed both with scalp- and with intracranial electrodes, but the activation-phenomenon and the spike-reduction were only detected with intracranial-EEG recording techniques. As expected, delta increase at the site of amobarbital action was the most commonly observed EEG pattern and was present in 75%. Interestingly a somewhat unexpected delta-increase was also observed contralateral to the side of injection in 36% of the tests. As a rule contralateral delta-increase was, however, markedly less pronounced and shorter in duration. In a comprehensive study,29 in which the amobarbitalinduced memory performance was correlated with the amobarbital-induced EEG changes, a significant correlation between the dosage and the duration of the EEG changes (p < 0.05), was found, but there was no significant correlation between the dosage and the EEG pattern. Moreover, the appearance of an ‘activation phenomenon’, i.e., the evocation or increase of spikes (or other epileptiform graphoelements) predisposed to a marked decrease of the memory performance not only for material specific for the side of injection, but also for material specific for the contralateral, noninjected hemisphere. Combined FO electrode- and scalp-EEG monitoring during selective TL amobarbital tests is therefore superior in several aspects to functional imaging of the injected area. This is because appropriate EEG monitoring is able to detect the amobarbital induced dysfunction better in time and gives additional information on provoked epileptic phenomena. In summary, the Zürich experience indicates that the FO electrode has substantially facilitated the presurgical evaluation of the majority of candidates for temporal lobe surgery by decreasing the risks of more invasive neurophysiological evaluation without significant loss of information. The main advantages of peg electrodes are that they can be used as sentinel electrodes with better, i.e., muscle artifact-free recordings, of cortical activity. The risks and costs of insertion

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FOR1-FOR2 FOR2-FOR3 FOR3-FOR4 FOR4-FOR5 FOR5-FOR6 FOR6-FOR7 FOR7-FOR8 FOR8-FOR9 FOR9-FOR10 FOL1-FOL2 FOL2-FOL3 FOL3-FOL5 FOL4-FOL5 FOL5-FOL6 FOL6-FOL7 FOL7-FOL8 FOL8-FOL9 FOL9-FOL10 SA1-SA2 SA2-SA3 SA3-SA4 SB1-SB2 SB2-SB3 SB3-SB4 SC1-SC2 SC2-SC3 SC3-SC4 SD1-SD2 SD2-SD3 SD3-SD4 SE1-SE2 SE2-SE3 SE3-SE4 SF1-SF2 SF2-SF3 SF3-SF4

*

200µV

500µV

5s

Figure 71.6 ’Tailored’ presurgical evaluation with FO and additional strip electrodes. A–F. Seizure semiology consists of an initial scream, then crossing of the arms, confusion and deambulation. G. MR imaging (FLAIR sequence) indicates signal hyperintensity and atrophy of the left hippocampus. In addition slight atrophy of the left lateral temporal lobe structure is visible. H. Localisation of electrodes. FOR and FOL are 10-contact FO electrodes. SA-SF denote additional 4-contact strip electrodes. I. EEG during the seizure is displayed in A–F. Seizure onset is first recorded with FOL. There is intense interictal epileptiform activity recorded by SA. * = clinical seizure onset (initial scream).

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Foramen ovale and epidural electrodes in the definition of the seizure onset zone w

(a)

637

(b)

d3

(c) h

d1 d2

Figure 71.7 Epidural peg electrodes. a: The electrode consists of a stainless steel or platinum disc embedded into a mushroomshaped silastic housing. The stalk has a gradual taper from a maximum diameter (d2) of 4.7 mm to a tip diameter (d1) of 4.5 mm. Stalk heights (h) range from 3–19 mm in 2-mm increments to match skull thickness. The cap has a diameter of 12.7 mm (d3) and a height of 2.5 mm (MDX4-4210, Dow Corning Corp., Midland, MI). The peg is implanted via 1.5-cm scalp incision and burr-holes (b). c: lateral skull X-ray with epidural peg electrodes (Modified from Wieser and Morris, 199733; original sources see Barnett et al. 199018 and Awad et al. 1991.19

are considerably less than that for grid electrodes, but peg electrodes may not obviate invasive intracranial evaluations. Limitations FO electrodes have definite limitations: The nature of the FO electrode recording technique implies that only restricted questions can be answered, namely: (a) do the seizures originate at the mesiobasal temporal lobe structures? If yes, (b) are they constantly lateralized? In addition, (c) information is obtained as to whether the seizure origin is more anterior or posterior. However, if the seizures do not originate at one mesiobasal temporal lobe, the patient is by definition no longer a suitable candidate for ‘curative’ selective AHE, and it must then be decided whether further evaluation is indicated with a view toward more extensive temporal lobe or even extratemporal surgery. There is evidently a risk of falsely localizing an apparent seizure origin in the mesiobasal TL and missing the true origin outside these structures when the FO electrode technique is used. The best way to minimize this risk is to carefully study the clinical features accompanying the seizures by recording the occurrence of the subjective auras and/or the objective signal symptoms and to correlate these with the simultaneously recorded EEG. In addition, as already mentioned, FO electrodes can be combined with other recording techniques, such as subdural strips as illustrated by the case described above (Figure 71.6). The most reliable seizure onset patterns recorded with the FO electrodes are the high-frequency low-amplitude discharge pattern and the so-called ‘hypersynchronous’ seizure onset pattern (Figure 71.5)28. In the absence of these patterns,

the localization of the seizure onset zone should be questioned. A very local decrement at the FO electrodes is the most frequently observed initial seizure pattern in the Zürich FO electrode series. If it was followed within 3–5 seconds by a high-frequency discharge at the same localization, it is also a reliable pattern for seizure onset localisation. From analysis of simultaneous recordings from depth electrodes inserted directly into limbic structures, such as the amygdala, anterior and posterior hippocampus, and parahippocampal as well as fronto-orbital and cingulate gyrus, and from FOelectrodes, it became evident that a very local initial flattening of the EEG record from the FO electrode was nearly always associated with a high-frequency low-amplitude discharge observed in the stereotactic depth recordings from the hippocampal formation and/or amygdala. Usually the FO electrodes pick up mesial temporal lobe epileptogenic activity very reliably. Only in the very rare cases of prolonged discharges totally confined to the amygdala and not affecting the hippocampal formation, the FO electrode may miss these amygdala discharges (Figure 71.9). This is because the amygdala behaves like a closed electrical field. In our SEEG series, however, these amygdalar seizures account for only about 3% of all psychomotor seizures. The limited placement of peg electrodes represents their main limitation. The usage of the epidural peg electrodes at the Cleveland Clinic has declined significantly over the past years. In part these changes reflect surgical preferences but to a large extent they are due to improvements in non invasive evaluations including (1) high-resolution MRI scans, (2) volumetric analysis of the hippocampus and (3) digital EEG allowing reformatting and filtering of data. It has also become apparent that

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RFO1-RFO2 RFO2-RFO3 RFO3-RFO4 RFO4-RFO5 RFO5-RFO6 RFO6-RFO7 RFO7-RFO8 RFO8-RFO9 RFO9-RFO10 LFO1-LFO2 LFO2-LFO3 LFO3-LFO4 LFO4-LFO5 LFO5-LFO6 LFO6-LFO7 LFO7-LFO8 LFO8-LFO9 LFO9-LFO10

A

B

C

A

Fp2-F8 F8-T4 T4-T6 T6-O2 Fp1-F7 F7-T3 T3-T5 T5-O1 Fp2-F4 F4-C4 C4-P4 P4-O2 Fp1-F3 F3-C3 C3-P3 P3-O1 M2-T2 T2-Fp2 Fp2-Fp1 Fp1-T1 T1-M1 Fz-Cz Cz-Pz

B

C

−

+

Figure 71.8 Averaged FO electrode and scalp EEG spikes for three representative interictal epileptiform discharges (A,B,C) and statistical LORETA (low-resolution electromagnetic tomography) solutions shown as two-dimensional orthogonal brain slices (right upper part) representing significant cortical activation during the ascending phase of the intracranial spike and topographic voltage maps (right bottom). For A 199, for B 90, and for C 180 events have been used for averaging and statistical nonparametric testing of each spike. Constellation A, i.e., a very restricted activation of ipsilateral mesial temporal lobe, was seen in 11/15 studied patients and represents 19/30 IED patterns (63.3%). The averaged intracranial spike could be reliably detected in the scalp-EEG after averaging. Constellation B, i.e., a widespread neocortical activation involving frontal and temporo-posterior structures, occurred in 5/15 patients and represents 6/30 IED patterns (20.0%). The spikes could be reliably detected in the scalp-EEG without averaging! Constellation C, i.e., a very restricted mesial temporal spike, occurred in 4/15 patient and represents 5/30 IED patterns (16.7%). The spikes could not be detected in the scalpEEG, despite averaging. Courtesy of Dr.Dominik Zumsteg; see also Zumsteg et al., in press).32

1 sec RFO1-RFO2 RFO2-RFO3 RFO3-RFO4 RFO4-LFO4 LFO4-LFO3 LFO3-LFO2 LFO2-LFO1 Depth 1-2 Depth 2-4

A

B

C

Depth 4-7 Depth 7-8 Depth 8-9 Depth 9-10

Figure 71.9 Combined depth- and FO electrode recording with interictal spikes A,B,C (left) and ictal discharge (right). Note the discrepancies between spikes recorded in depth and FO electrodes. Spike A, obviously generated in the right amygdala, is not reliably reflected in the FO electrode contacts, whereas spikes B and C and the discharge at the right are visible in both electrode types, although with obvious form differences. (Modified from Wieser and Morris,1997).33

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Foramen ovale and epidural electrodes in the definition of the seizure onset zone in evaluation of a patient with a focal epilepsy but whose studies include no focal MRI abnormalities and no localizing EEG abnormalities epidural peg electrodes are unlikely to demonstrate a clear epileptogenic focus. In other words they are not very helpful in this kind of ‘fishing expedition’.

Complications In 1987 we had one serious complication in the Zürich FO series consisting of a subarachnoid hemorrhage, which led to a transient upper pontine syndrome. MRI-documented subarachnoid hemorrhages without any neurological deficits occurred in two other patients. Meningitis occurred in two patients and was treated by innaveneas antibiotics without sequels. Placement of FO electrodes may be associated with transient morbidity, especially facial pain. Temporary facial pain has occurred in 19% of our patients. Two patients reported mild transient temporo-mandibular joint dysfunction. Recurrence of labial herpes was seen in 5%. A transient hypo- or dysesthesia, localized in one corner of the mouth, was reported in 9% of the cases. There were no other side effects or complications, and, in particular, no persisting trigeminal impairments. One patient pulled out one FO electrode in a postictal confusional state, one patient damaged one electrode during shaving. Since the information was not sufficient both had to be reimplanted.

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Costs The costs of FO and peg electrodes are considerably less compared to other invasive techniques. Insertion of FO electrodes can be done in local anaesthesia and does not require a sophisticated neurosurgical procedure or a neuroradiological examination under stereotactic conditions. Usually no intensive care is necessary and patients with FO electrodes alone can be evaluated outside highly specialized units. However, the major expenses derive from the long-term monitoring and they are similar whether the electrodes used are semiinvasive or invasive.17

Future directions Whereas FO electrodes may be viewed as a major step in making presurgical evaluation less invasive, the usefulness of peg electrodes remains limited. It is our guess that FO electrodes will continue to be increasingly used in nonlesional TLE patients being candidates for AHE, whereas the use of peg electrodes obviously declines. Arguments for this prediction are that in TLE very effective standardized surgical procedures are offered and the main goal of the preoperative evaluation is to answer the question whether or not a patient is a suitable candidat for one of these surgical procedures. In nonlesional extratemporal epilepsies, however, exact localisation of the epileptogenic area remains still a very demanding and difficult task asking for usually – at least additionally – invasive intracranial recording techniques.

Complications of epidural peg electrodes

Conclusions

By the end of 1993, approximately 77 patients had over 500 epidural peg electrode insertions and studies at the Cleveland Clinic; at the Bethel Epilepsy Center 36 patients underwent evaluation using approximately 420 epidural peg electrodes. In these patients no major complications were seen. In one Cleveland patient a single cortical contusion was discovered on CT scan. Culturing the peg electrodes at time of removal yielded a bacterial colonization rate of approximately 22% in the Cleveland Clinic Series; no patient had a clinical infection due to these electrodes. The lack of clinical infection was in part due to prompt treatment with appropriate antibiotics if the electrode cultures proved positive.

From the Zürich experience based upon strict indications the semi-invasive technique of FO electrode recording is suitable for the evaluation of potential candidates of AHE. Since AHE has virtually abolished larger TL resections in Zürich a considerable proportion of patients considered for surgical treatment of TLE are candidates for bilateral FO electrode evaluation. The aim of the FO electrode implantation is to record and study the patient’s spontaneously occurring habitual seizures. Epidural peg electrodes are a useful and safe addition to the surgical epileptologist’s toolbox. However, they should be seen as being complimentary to other invasive electrodes and not as a replacement.

REFERENCES 1. 2. 3. 4. 5. 7.

Rosenow F, Lüders HO. Presurgical evaluation of epilepsy. Brain 2001;124:1683–1700. Nair DR, Mohamed A, Burgess R, Lüders HO. A critical review of the different conceptual hypotheses framing human focal epilepsy. Epileptic Disord 2004;6:77–83. Allen PJ, Fish DR, Smith SJM. Very high-frequency rhythmic activity during SEEG suppression in frontal lobe epilepsy. Electroencephalograph Clin Neurophysiol 1992;82:155–9. Schiff SJ, Colella D, Jacyna GM et al. Brain chirps: spectrographic signatures of epileptic seizures. Clin Neurophysiol 2000;111:953–8. Alarcon G, Binnie DC, Elwes RDC, Polkey CE. Power spectrum and intracranial EEG patterns at seizure onset in partial epilepsy. Electroencephalograph Clin Neurophysiol 1996;82:326–337. Litt B, Lehnertz K. Seizure prediction and the preseizure period. Curr Opin Neurol 2002;15:173–7.

6. 8.

9. 10. 11.

Worrell GA, Parish L, Cranstoun S et al. High-frequency oscillations and seizure generation in neocortical epilepsy. Brain 2004;127:1496–1506. Traub RD, Whittington MA, Buhl EH et al. A possible role for gap junctions in generation of very fast EEG oscillations preceding the onset of, and perhaps initiating, seizures. Epilepsia 2001;42:153–170. Grenier F, Timofeev I, Steriade M. Neocortical very fast oscillations (ripples, 80–200 Hz) during seizures: intracellular correlates. J Neurophysiol 2003;89:841–52. Pfurtscheller G, Cooper R. Frequency dependence of the transmission of the EEG from cortex to scalp. Electroencephalograph Clin Neurophysiol 1975;38:93–6. Gotman J, Ives JR, Gloor P. Frequency content of EEG and EMG at seizure onset: possibility of removal of EMG artefact by

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15. 16. 17. 18. 19.

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Textbook of epilepsy surgery digital filtering. Electroencephalograph Clin Neurophysiol 1981; 52:626–39. Wieser HG, Elger CE, Stodieck SRG. The’foramen ovale electrode’: a new recording method for the preoperative evaluation of patients suffering from mesio-basal temporal lobe epilepsy. Electroencephalogr Clin Neurophysiol 1985;61:314–22. Crandell PH, Walter RD, Rand RW. Clinical applications of studies on stereotactically implanted electrodes in temporal lobe epilepsy. J Neurosurg 1963;21:827–40. Talairach J, Bancaud J, Szikla G et al. Approche nouvelle de la neurochirurgie de l’épilepsie. Méthodologie stéréotaxique et résultats thérapeutiques. Neurochirurgie 1974;20, Suppl 1 (Masson, Paris):1–240. Wieser HG. Electroclinical Features of the Psychomotor Seizure. (Gustav Fischer/Butterworths:Stuttgart/London,1983). Wieser HG, Yasargil MG. Selective amygdalohippocampectomy as a surgical treatment of mesiobasal limbic epilepsy. Surgical Neurology 1982;17:445–57. Engel J, Jr, Ojemann GA. The next step. In:Engel J, ed, Surgical treatment of the epilepsies 2nd edn. New York:Raven Press 1993;319–29. Barnett GH, Burgess RC, Awad IA et al. Epidural peg electrodes for the presurgical evaluation of intractable epilepsy. Neurosurgery 1990;27:113–15. Awad IA, Assirati JA Jr, Burgess R, Barnett GH, Lüders H. A new class of electrodes of’intermediate invasiveness’: preliminary experience with epidural pegs and foramen ovale electrodes in the mapping of seizure foci. Neurological Research 1991;13:177–83. Wieser HG for the ILAE Commission on Neurosurgery of Epilepsy. ILAE Commission Report. Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis. Epilepsia 2004;45:695–714 Wieser HG, Ortega M, Friedman A, Yonekawa Y. Long-term seizure outcomes following amygdalohippocampectomy. J Neurosurg 2003;98:751–63. Wieser HG, Moser S. Improved multipolar foramen ovale electrode monitoring. J Epilepsy 1988;1:13–22.

23. 24. 25. 26. 27.

28. 29.

30. 31. 32.

33.

Landolt HP, Moser S, Wieser HG, Borbely AA, Dijk DJ. Intracranial temperature across 24-hour sleep-wake cycles in humans. NeuroReport 1995;6:913–17. Stodieck SRG, Wieser HG. Epicortical DC changes in epileptic patients In: Wolf, P, Dam M, Janz D, Dreifuss FE eds. Advances in Epileptology, Vol. 16, New York: Raven Press. 1987:123–7. Wieser HG, Schwarz U. Topography of foramen ovale electrodes by 3D image reconstruction. Clin Neurophysiol 2001; 112:2053–6. Holthausen H, Noachtar S, Pannek H, Ebner A, Tuxhorn I. Foramen ovale and epidural peg electrodes. Acta Neurol Scand 1994;Suppl. 152:39–43. Wieser HG. Stereoelectroencephalography and foramen ovale electrode recording. In: Niedermeyer E, Lopes da Silva F, eds. Electroencephalography: Basic Principles, Clinical Applications, and Related Fields. 3rd edn. Baltimore: Williams & Wilkins, 1993:679–693. Wieser HG, Siegel AM. Analysis of foramen ovale electroderecorded seizures and correlation with outcome following amygdalohippocampectomy. Epilepsia 1991;32:838–50. Wieser HG, Müller S, Schiess R et al. The anterior and posterior selective temporal lobe amobarbital tests: angiographical, clinical, electroencephalographical, PET and SPECT findings, and memory performance. Brain and Cognition 1997;33:71–97. Kirschner M. Electrocoagulation des Ganglion Gasseri. Zbl Chir 1932;47:2841–3. Härtel F. Ueber die intracranielle Injectionsbehandlung der Trigeminusneuralgie. Med Klin 1914;10:582–584. Zumsteg D, Friedman A, Wennberg RA Wieser HG. Source localization of mesial temporal interictal epileptiform discharges: Correlation with intracranial foramen ovale electrode recordings. Clin Neurophysiol (in press Sept 2005) Wieser HG, Morris H III Foramen ovale and peg electrodes. In Engel J Jr, and Pedley TA, Epilepsy: A Comprehensive Textbook. Philadelphia: Lippincott-Raven Publishers, 1997:1707–17.

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Subdural electrodes MZ Koubeissi

Introduction Success of resective surgery for intractable epilepsy is dependent on accurate localization of the epileptogenic focus. Whereas all areas of interictal epileptiform discharges need not be resected in order to achieve seizure control,1 the most reliable criterion for localizing epileptic foci for subsequent surgery is identification of the area of onset of spontaneous seizures.2,3 Localizing epileptogenic focus can be achieved with higher accuracy by recording intracranial ictal discharges, than by other localizing abnormalities, such as imaging, neuropsychological testing, extracranial EEG recordings, and seizure semiology.4-6 The majority of the cases monitored with intracranial electrodes will have successful localization of the epileptogenic region leading to resection.7 Henry et al. found that the ictal onset zones in 47 of 50 patients, who had had inconclusive extracranial ictal EEG, were successfully localized with intracranial recordings, leading to efficacious resections in 38 patients, regardless of the neuroimaging findings.5 Even in situations when there is evidence of more than one epileptogenic focus, monitoring with intracranial electrodes may help identify the focus most responsible for the patient’s stereotypical seizures, the resection of which promises to at least lessen the burden of epilepsy.4 The indications for monitoring with subdural electrodes and the implantation procedures are discussed elsewhere in this book, but will be briefly reviewed here.

Indications Selected patients can undergo resective epilepsy surgery without the need for intracranial monitoring. This commonly occurs when noninvasive presurgical results, including electrophysiologic and neuroimaging data, are concordant.8 However, there are situations when extraoperative monitoring with subdural electrodes is needed to allow identification of the area of ictal onset and its relation to brain regions that need to be preserved by epilepsy surgery. This permits maximal resection of epileptogenic cortex with minimal functional deficits. The following scenarios are examples of situations where subdural electrode implantation is needed. Subdural electrodes are used for localization of ictal onset in patients with medically intractable epilepsy, who have no medical or psychiatric contraindications for invasive monitoring, when: (1) less invasive studies fail to lateralize or localize the epileptogenic focus, e.g., seizure semiology strongly suggests the

area of origin, but extracranial EEG fails to lateralize the ictal discharge, (2) neuroimaging is normal despite clinical evidence of localization-related epilepsy, (3) localization of ictal onset by extracranial EEG is discordant with the results of neuroimaging, raising the question of dual pathology, (4) extracranial EEG and MRI data are concordant, but are discordant with seizure semiology, location of interictal epileptiform discharges, or results of neuropsychological evaluation, and (5) mapping of cortical function is needed, as in patients who appear to have epileptic foci close to, or overlapping with, their eloquent cortex.

Procedure Subdural grid electrodes are implanted under general or local anesthesia. Commonly used electrodes consist of platinumiridium9 or stainless steel discs10,11 with exposed surfaces of 2.3 mm diameter. They are embedded in a transparent soft silastic sheet, and are evenly spaced with an interelectrode distance of 1 cm. Depending on the indication, they can be placed over the cortical convexity, within the interhemispheric fissure, and over the basal surface of the brain. For example, in patients with dominant temporal lobe epilepsy (TLE), a 6 × 8 or an 8 × 8 grid is usually implanted over the perisylvian cortex, and a combination of strips, or a smaller grid, is implanted over the basal temporal cortex. Usually, half of the perisylvian grid is above the sylvian fissure and half is below it. The grid allows electrocortical stimulation mapping of language, as well as the inferior sensorimotor strip that includes the tongue and the inferior portion of the hand areas. In patients with seizure foci in other regions, implantation of subdural electrodes is tailored to maximize the chances of covering the epileptogenic region; they can be implanted over the visual, sensorimotor, or supplementary motor cortices.12 Subdural electrodes are anchored in place by suturing the silastic sheet to the overlying dura mater (Figure 72.1). Subdural strips consist of 4–8 disk electrodes, with an interelectrode distance of 1 cm. They are placed along with grid electrodes through a craniotomy, or through burr holes on either side to help lateralize seizure focus. A common procedure is to implant three to four strips through a frontal burr hole, and three to four through a temporal burr hole on each side. Such an implantation is needed for lateralization of the seizure focus. 641

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Textbook of epilepsy surgery 1–2 weeks for accurate localization of the seizure focus and mapping of eloquent cortical function.13,14

Seizure patterns

(a)

(b)

Figure 72.1 Intraoperative photographs help determine the location of most subdural electrodes with respect to cortical anatomy. a. Left craniotomy in a patient who had been monitored by scalp electrodes with poor localization of seizure onset in the left hemisphere. b. Extensive subdural electrode implantation aims at maximizing the chances of identifying the area of ictal onset as well as mapping eloquent cortical areas. The dura mater has been retracted (white star). The subdural electrodes are embedded in a transparent silastic sheet that allows visualization of the underlying gyral anatomy, and is carefully fitted over the cortical surface and sutured to the overlying dura mater. Note that the 8 × 8 suprasylvian grid is sutured to two 2 × 5 frontal grids (arrows) and to a 4 × 8 infrasylvian grid (arrowheads), and that each cable connects two rows of electrodes to the EEG amplifier.

Intraoperative photographs are important for determining the location of some electrodes with respect to gyral anatomy (Figure 72.1). Some electrodes, however, cannot be directly visualized intraoperatively, as they do not lie within the margins of the craniotomy. The position of such electrodes, and that of strip electrodes implanted through burr holes, are verified by postoperative X-rays, and by superimposition of postoperative volumetric CT scan (with 1.0 mm axial slices to reconstruct the patient’s skull and locations of subdural electrodes) on a cortical surface rendering of a preoperative volumetric magnetic resonance image (MRI) (Figure 72.2). Once implanted, the patient undergoes continuous video/EEG monitoring for

Interpreting ictal patterns recorded by subdural electrodes requires awareness of not only pathologic patterns, but also physiologic and artefactual phenomena. Familiarity with such patterns is needed for identification of the epileptogenic zone, defined as the zone whose resection or complete disconnection is necessary and sufficient to eradicate seizures.15 The ictal onset zone, where the first electrical changes are detected, regardless of their morphology, prior to the clinical manifestations of the seizure (Figure 72.3), is presumably included within the epileptogenic zone.16 Early ictal patterns recorded by subdural electrodes may take one of various morphologies, including rhythmic sinusoidal waves, irregular spike discharge, spike and wave activity, and low voltage fast activity.16 These patterns are not different from those described in extracranial recordings. Blume et al., studied the ictal pattern of partial seizures recorded by scalp EEG in 66 patients,17 and reported electrodecremental pattern in 11% of the seizures recorded, sinusoidal waves in 47%, and repetitive epileptiform discharges (most commonly spikes and sharp waves) in 39%. Originally, guidelines for interpreting intracranial ictal tracings were anecdotal, but the criteria for identifying ictal patterns recorded by subdural electrodes have been evolving. High frequency oscillations, for example, are now recognized as an electrographic ictal signature.18 This has become possible, in part, because digital EEG, unlike analog EEG, is not dependent on the response rate of the pen, and can have sampling frequencies of up to 10 kHz, allowing recognition of faster frequencies. Numerous studies over the past three decades assessed the morphological patterns of ictal EEG, and correlated them with brain region, pathology, and surgical outcome.7,16,18–20 In the context of describing an analog-digital circuit that detects electrographic seizures, Babb et al. defined seizures as high-frequency, high-voltage spikes lasting 5 seconds.2 They argued that, while physiologic brain activity tends to show an inverse relation between voltage and frequency, ictal discharges can have a high frequency (up to 30 Hz), but will still maintain a high amplitude. The same objective of automatic recognition of seizures lead Gotman et al. to define ictal discharges as activity that is paroxysmal, rhythmic, and sustained.21 Other authors defined ictal discharges recorded from intracranial electrodes as significant and specific deviation of EEG patterns from the baseline that consists of electrodecremental patterns or rhythmic activity with or without apiculate waveforms.22 Spencer et al. defined intracranially recorded seizure onset as sustained and rhythmic EEG patterns, with frequencies higher than 2 Hz, that are state-independent and different from the background.7 Such a definition of early ictal patterns precluded assessment of low-voltage fast rhythms in their series, although the authors acknowledged that low-voltage fast activity is a recognized ictal pattern and resection of tissue where such pattern is localized, is associated with a good seizure control prognosis.23

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Figure 72.2 Cortical surface rendering of a presurgical volumetric magnetic resonance image (MRI), with the location of subdural electrodes from a postoperative volumetric head computed tomography (CT) scan superimposed. The coregistration (done with Curry software, Compumedics Neuroscan, El Paso, TX) allows three-dimensional visualization of the implanted electrodes in relation to gyral anatomy. a. Bilateral strip electrodes are placed through burr holes in order to help lateralize the seizure focus. Three (left) and four (right) strips are placed through frontal burr holes, and three through temporal burr holes on each side. b. This is a patient whose extracranial EEG showed an ictal discharge in the left frontotemporal regions several seconds after the clinical seizure onset (see also Figure 72.3). Grid electrodes were implanted over the left frontal and temporal lobes with an 8 × 8 grid covering the perisylvian cortex, and three 1 × 6 strips sampling the basal temporal cortex.

Low voltage fast activity The pioneers of EEG included a gamma band to represent activities higher than 35 Hz, but this band was of very limited clinical use as the analog EEG machines were limited by the response time of the stylus, in addition to using a ‘standard’ low pass filter of 70 Hz.9 The first reports of intracranial recordings that associated high frequency activity with ictal electrodecremental pattern on scalp EEG date back to 1950, when Mazars and collaborators performed corticographic recordings of epileptogenic foci before they attempted surgical resection.24,25 A decade later, Bickford and Klass reported that 19 of 350 seizures started with generalized electrodecrement.26 This pattern was later associated with tonic seizures, infantile spasms and Lennox-Gastaut syndrome, but some authorities

later argued that most partial seizures are initially associated with a low-voltage fast pattern if electrodes are close enough to the seizure focus.9,27 Morris et al. described regional electrodecrement in association with complex partial seizures of temporal lobe origin.11 The invention of digital EEG, and extraoperative monitoring of patients with implanted subdural electrodes, led to further characterization of high frequency activity as an ictal pattern.9,18,19,27 With higher digital sampling frequency and low pass filter, even higher frequency oscillations may be detected that will aid is identifying epileptogenic cortex (see Figure 72.5). Fisher et al. recorded seizures with subdural electrodes sampling the EEG at 2000 points per second, and using a 300-Hz low-pass filter.9 They found that the EEG signal included within the

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Figure 72.3 Ictal EEG recorded intracranially in the patient whose subdural electrodes are shown in Figure 72.2b. Clinical seizure onset, semiologically identical to what has occurred without discernible scalp EEG changes during prior extracranial monitoring, is now seen in association with an electrographic ictal discharge localized to the left mesial temporal region (first page, electrode a). The second page, approximately 1 minute later, shows a fully evolved ictal discharge, which would have become evident by scalp electrodes at that stage. The locations of the most active electrodes are shown on the brain surface.

ictal electrodecremental pattern consisted of a ‘conventionally invisible’ high-frequency band, illustrating the importance of high-frequency recordings in localizing seizure foci. At the start of seizures, the 40–50 Hz portion of the frequency spectrum was doubled and the 80–120 Hz portion increased five times in the region of epileptic focus, but not in remote areas. The same authors reported evidence of high-frequency activity originating in one frontal lobe by subdural electrodes when scalp-EEG recording revealed diffuse electrodecrement as an ictal pattern.27 Semiologically, seizures associated with this pattern were dialeptic, dystonic, tonic, atonic, or a combination of more than one type. Worrell et al. found that 62% of neocortical seizures recorded by subdural electrodes were preceded by an increase in high-frequency activity in the 20 min prior to the clinical onset of the seizure.18 Alarcon et al. used subdural, as well as intracerebral electrodes, to record 78 complex partial seizures.16 They studied five seizure patterns: electrodecremental events, low-voltage fast, short bursts of irregular sharp waves intermixed with slow activity, regular epileptiform discharges, and rhythmic ictal transformation. In 12 out of 15 patients, electrodecremental events constituted the early ictal pattern. The authors also reported that interictal spectral EEG power was generally below 12 Hz,16 but ictal changes appeared more complex and not always localized to one area. A 2006 study concluded that high frequency oscillations occur in epileptogenic areas, both mesial temporal and neocortical, but rarely in areas of seizure propagation.19 The presence of high-frequency oscillations at seizure onset is considered a measure of proximity of the recording electrodes to the epileptogenic focus, whereas absence of such activity indicates poor localization (see Figure 72.4).

Ictal patterns and specific pathology Since extraoperative monitoring with subdural electrodes became common use, several studies attempted to correlate locations of the seizure onset zone and ictal patterns, with their pathologic substrates. However, it is unclear whether specific ictal patterns are strictly related to certain tissue pathology, and it appears that the morphology of the ictal discharge is, at least in part, determined by an interaction between the anatomic location and tissue pathology.28 Correlation between electrocorticographic data and pathology has been studied most in TLE. A study that used lateral and basal temporal subdural electrodes in patients with intractable TLE demonstrated that epileptogenic lesions were likely located in the immediate vicinity of structural lesions.11 The authors also found that macroscopic lesions (i.e., ones that could be seen by head CT scan or by the naked eye intraoperatively) were more likely to be lateral temporal, whereas microscopic lesions were basal or mesial. An earlier study in patients with TLE concluded that ictal and interictal EEG recordings yielded different conclusions about the presence and nature of pathology.29 Other studies related spike-wave discharge or repetitive spikes with cortical dysgenesis,30 periodic spikes preceding seizure onset with reduced cell count in the CA1 region of the hippocampus, and the latency of the ictal discharge propagating to the contralateral hippocampus with reduced cell count in the CA4 region.31 Spencer et al. studied the ictal pattern of 166 seizures in 26 patients recorded intracranially with a combination of depth and subdural electrodes, and correlated the morphological manifestations of the ictal pattern with the pathology of the resected tissue.7 They found that 58% of temporal lobe

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Figure 72.4 Ictal tracing from right occipital lobe subdural grids in a 20-year-old patient with intractable seizures manifesting as elemental visual phenomena in the left hemifield, followed by alteration of awareness, and occasional secondary generalization. This is a bipolar montage with channels 1 through 17 covering the lateral parieto-occipital convexity, and channels 18 through 30 covering basal and medial occipital regions. The digital sampling frequency is 1000 Hz. Notice the regional low voltage, high frequency (approximately 200 Hz) ictal discharge.

seizures with initial ictal discharge frequencies of 13 Hz (p < 0.00001). On the other hand, extratemporal seizures with an initial ictal discharge frequency of 13 Hz with normal tissue. However, all seizure patterns and frequencies were seen in both mesial temporal and extratemporal seizures, and separate seizures were recorded with discharge frequencies of either greater or less than 13 Hz in half of their patients. Conversely, in patients with extratemporal seizures, abnormal pathological findings were not associated with variability of seizure onset frequency. Temporal lobe seizures are more likely than extratemporal seizures to exhibit variable frequency of the initial ictal discharge in the same patient. A study in patients with neocortical epilepsy showed that ictal patterns consisting of gamma range activity were likely to be seen in extratemporal locations and tended to be of regional onset.28 However, beta frequency activity was seen more commonly in temporal lobe seizures and those with more focal onset. Different pathologic substrates were not associated with differences in onset frequency. Of note, seizure freedom was not related to onset frequency or distribution. Another study found no relation between spatial distribution of ictal onset and pathology,32 but at least two studies29,33 associated focal onset with reduced hippocampal cell density.

Localizing value of ictal patterns Localization of the epileptogenic zone can be approximated by the onset of an electrographic seizure, provided it occurs prior to, or at least concomitantly with, the clinical onset. The localizing value of the ictal pattern can be assessed by the surgical outcome, as seizure freedom after epilepsy surgery indicates that the epileptogenic region was included in the resection. Faster frequencies at the onset of the ictal discharge probably signify that the recording electrodes are closer to the ictal onset zone than those with slower onsets.28 Slower onset frequencies may represent propagated activity,34 and regional onset may indicate volume diffusion or spread from a distant generator.35 This view is corroborated by the good outcomes after epilepsy surgery being associated with low-voltage fast activity at seizure onset,36 and with focal onset seizures.29 Some authors, however, found no relation between surgical outcome and the spatial extent of the seizure onset.28 Alarcon et al. used a combination of depth and subdural electrodes to correlate electrographic patterns with surgical outcome in patients with complex partial seizures.16 They reported early electrodecremental patterns with frequencies below 40 Hz in the majority of their patients. Whereas localized high-frequency patterns correlated with favorable outcome after epilepsy surgery, diffuse electrodecremental patterns were not associated with poor outcome. The authors argued that diffuse electrodecremental patterns may not be part of the ictal process itself.

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Figure 72.5 Ictal tracing from a right perirolandic subdural grid in a 33-year-old patient with intractable daily seizures manifesting as left hand sensory symptoms, which then involve more proximal arm regions and face. At times, this is followed by motor symptoms and occasional secondary generalization. Extracranially recorded EEG has shown no ictal discharge is association with seizures manifesting as mere left hand sensations without further progression. With subdural electrodes, however, there is one-to-one correspondence between the onset of her sensory seizures and bursts of fast (85–90 Hz) activity (upper page and insert). Channel 18, where the fast activity is seen, corresponds to a contact over the hand area of the primary somatosensory cortex (confirmed by electrical stimulation mapping). Note that the fast activity is followed 2–3 seconds later by regional electrodecrement (last 2 seconds of the upper page), and, several seconds later, by a higher voltage rhythmic spike discharge. Digital sampling frequency is 1000 Hz, and the low-pass cutoff frequency is 300 Hz. Decreasing the frequency of the low-pass filter increases the likelihood of missing the initial high-frequency activity which is most localizing to the seizure onset zone. Of note, resecting the cortical tissue corresponding to the initial burst of high-frequency oscillation (electrode 18) resulted in total cessation of seizures.

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Subdural electrodes

Limitations The major limitation of recording with subdural electrodes is that they sample only a limited area of the cortex, which increases the likelihood of missing the epileptogenic region. To maximize the chances of covering the area of ictal onset, epileptologists generally plan the implantation after extensive preoperative testing. Nevertheless, in some patients it may be difficult to determine whether the ictal discharge recorded by a certain subset of subdural electrodes is originating from that area or propagating to it. The initial patterns of local onset and propagating electrographic seizures may be identical, although one study found that rhythmic theta-delta activity may be unique to propagating seizures.34 In addition, the spatial extent of the ictal onset zone may be difficult to determine if the initial ictal discharge is detected by electrodes at the border of a grid. Another limitation of recording with subdural electrodes is in patients with deep seizure foci. Although depth electrodes only parsimoniously sample the cortex and cannot be used for mapping of cortical function, they are superior for recording from the mesial temporal structures37 and from some patients

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with neuronal migration disorders.38 Even when subdural electrodes cover the hemispheric convexity, they record activity from only a limited area of the neocortex, and may miss electrical activity in the banks of fissures or sulci. Lüders et al. argued that the inability of subdural electrodes to record from cortical infoldings may explain the difficulty of detecting auditory evoked potentials with perisylvian plates,12 as the auditory cortex is likely probably located deep in the supratemporal plane.39 In TLE, subdural electrodes led inadequate or even false localization of ictal onset in two studies using simultaneous subdural with depth electrodes.40,41 Another study found that lateralization of the seizure onset zone, when detected by subdural electrodes, was always concordant with depth electrode recordings, but subdural electrodes were less sensitive in detecting hippocampal seizures.37 Other authors showed that concordant lateralization by depth and subdural strip electrodes was seen in the majority of recorded seizures in patients with TLE, although some seizures were falsely localized by subdural electrodes.42 The authors concluded that accurate localization is achieved by basal temporal subdural electrodes when the parahippocampal region is covered.


6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

Hufnagel A, Dumpelmann M, Zentner J et al. Clinical relevance of quantified intracranial interictal spike activity in presurgical evaluation of epilepsy. Epilepsia 2000;41:467–78. Babb TL, Mariani E, Crandall PH. An electronic circuit for detection of EEG seizures recorded with implanted electrodes. Electroencephal Clin Neurophysiol 1974;37:305–8. Gloor P. Contributions of electroencephalography and electrocorticography to the neurosurgical treatment of the epilepsies. Adv Neurol 1975;8:59–105. Engel J Jr, Rausch R, Lieb JP et al. Correlation of criteria used for localizing epileptic foci in patients considered for surgical therapy of epilepsy. Ann Neurol 1981;9:215–24. Henry TR, Ross DA, Schuh LA et al. Indications and outcome of ictal recording with intracerebral and subdural electrodes in refractory complex partial seizures. J Clin Neurophysiol 1999;16:426–38. Spencer SS, Spencer DD, Williamson PD et al. The localizing value of depth electroencephalography in 32 patients with refractory epilepsy. Ann Neurol 1982;12:248–53. Spencer SS, Guimaraes P, Katz A et al. Morphological patterns of seizures recorded intracranially. Epilepsia 1992;33:537–45. Thadani VM, Williamson PD, Berger R et al. Successful epilepsy surgery without intracranial EEG recording: criteria for patient selection. Epilepsia 1995;36:7–15. Fisher RS, Webber WR, Lesser RP et al. High-frequency EEG activity at the start of seizures. J Clin Neurophysiol 1992;9:441–8. Ikeda A, Terada K, Mikuni N et al. Subdural recording of ictal DC shifts in neocortical seizures in humans. Epilepsia 1996; 37:662–74. Morris HH III, Estes ML, Lüders HO et al. Electrophysiologic pathologic correlations in patients with complex partial seizures. Arch Neurol 1987;44:703–8. Lüders HO, Awad I, Burgess R et al. Subdural electrodes in the presurgical evaluation for surgery of epilepsy. Epilepsy Res Suppl 1992;5:147–56. Lüders HO, Lesser RP, Dinner DS et al. Localization of cortical function: new information from extraoperative monitoring of patients with epilepsy. Epilepsia 1988;29 Suppl 2:S56–65. Wyllie E, Lüders HO, Morris HH III et al. Subdural electrodes in the evaluation for epilepsy surgery in children and adults. Neuropediatrics 1988;19:80–6. Rosenow F, Lüders HO. Presurgical evaluation of epilepsy. Brain 2001;124:1683–700. Alarcon G, Binnie CD, Elwes RD et al. Power spectrum and intracranial EEG patterns at seizure onset in partial epilepsy. Electroencephal Clin Neurophysiol 1995;94:326–37.

17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.

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Blume WT, Young GB, Lemieux JF. EEG morphology of partial epileptic seizures. Electroencephal Clin Neurophysiol 1984;57: 295–302. Worrell GA, Parish L, Cranstoun SD et al. High-frequency oscillations and seizure generation in neocortical epilepsy. Brain 2004;127:1496–506. Jirsch JD, Urrestarazu E, LeVan P et al. High-frequency oscillations during human focal seizures. Brain 2006;129:1593–608. Weinand ME, Deogaonkar M, Kester M et al. Electrocorticographic factors associated with temporal lobe epileptogenicity. Pathophysiology 2000;7:33–9. Gotman J. Seizure recognition and analysis. Electroencephalogr Clin Neurophysiol Suppl 1985;37:133–45. Wieser HG. Data analysis. In Engel JJ, ed. Surgical Treatment of the Epilepsies. New York: Raven Press, 1987:335–60. Madhavan D, Kuzniecky R. Temporal lobe surgery in patients with normal MRI. Curr Op Neurol 2007;20:203–7. Mazars Y. Interpretation of the extinction phenomenon during the initial phase of focal cortical seizures. Rev Neurol 1950;82: 520–2. Mazars Y. Study of the rapid rhythmic hypersynchronism during epileptic focal cortical seizures. Rev Neurol 1950;82:522–4. Bickford RG, Klass D. Scalp and depth electrographic studies of electrodecremental seizures. Electroencephal Clin Neurophysiol 1960;12:236. Arroyo S, Lesser RP, Fisher RS et al. Clinical and electroencephalographic evidence for sites of origin of seizures with diffuse electrodecremental pattern. Epilepsia 1994;35:974–87. Lee SA, Spencer DD, Spencer SS. Intracranial EEG seizure-onset patterns in neocortical epilepsy. Epilepsia 2000;41:297–307. Lieb JP, Engel J Jr, Brown WJ et al. Neuropathological findings following temporal lobectomy related to surface and deep EEG patterns. Epilepsia 1981;22:539–49. Spencer SS. Substrates of localization-related epilepsies: biologic implications of localizing findings in humans. Epilepsia 1998;39:114–23. King D, Spencer S. Invasive electroencephalography in mesial temporal lobe epilepsy. J Clin Neurophysiol 1995;12:32–45. Mathern GW, Babb TL, Pretorius JK et al. The pathophysiologic relationships between lesion pathology, intracranial ictal EEG onsets, and hippocampal neuron losses in temporal lobe epilepsy. Epilepsy Res 1995;21:133–47. Babb TL, Lieb JP, Brown WJ et al. Distribution of pyramidal cell density and hyperexcitability in the epileptic human hippocampal formation. Epilepsia 1984;25:721–8.

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Textbook of epilepsy surgery Schiller Y, Cascino GD, Busacker NE et al. Characterization and comparison of local onset and remote propagated electrographic seizures recorded with intracranial electrodes. Epilepsia 1998;39:380–8. Engel J Jr, Crandall PH. Intensive neurodiagnostic monitoring with intracranial electrodes. In Gumnit RJ, ed. Intensive Neurodiagnostic Monitoring. Advances in Neurology. New York: Raven Press, 1986:85–106. Weinand ME, Wyler AR, Richey ET et al. Long-term ictal monitoring with subdural strip electrodes: prognostic factors for selecting temporal lobectomy candidates. J Neurosurg 1992;77:20–8. Spencer SS, Spencer DD, Williamson PD et al. Combined depth and subdural electrode investigation in uncontrolled epilepsy. Neurology 1990;40:74–9.

38. 39. 40. 41. 42.

Bernasconi A, Martinez V, Rosa-Neto P et al. Surgical resection for intractable epilepsy in ‘double cortex’ syndrome yields inadequate results. Epilepsia 2001;42:1124–9. Celesia GG. Organization of auditory cortical areas in man. Brain 1976;99:403–14. Sperling MR, O’Connor MJ. Comparison of depth and subdural electrodes in recording temporal lobe seizures. Neurology 1989;39:1497–504. van Veelen CW, Debets RM, van Huffelen AC et al. Combined use of subdural and intracerebral electrodes in preoperative evaluation of epilepsy. Neurosurgery 1990;26:93–101. Eisenschenk S, Gilmore RL, Cibula JE et al. Lateralization of temporal lobe foci: depth versus subdural electrodes. Clin Neurophysiol 2001;112:836–44.

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Stereoelectroencephalography P Kahane and S Francione

Introduction In the presurgical evaluation work-up of patients suffering from drug-resistant partial seizures, intracranial EEG has been in use for more than 50 years. This practice not only generated considerable historical and practical information, but also continues to hold an important role in the precise definition of the epileptogenic zone in a consistent percentage of patients. Invasive EEG, indeed, is still performed on 25–50% of patients at most epilepsy surgery centers, depending on the referral population. Among the broad group of invasive procedures, and more especially in the field of ‘depth recordings’, some conceptual and technical aspects make the stereoelectroencephalography (SEEG) very particular since, from the begining, it has been conceived by Talairach and Bancaud as a comprehensive methodology and not only as a diagnostic tool.

Theoretical basis Historical background The basic principle of Bancaud and Talairach approach was to study the seizures themselves, through what they named the ‘anatomo-electro-clinical correlations’.1–3 Under this term, they regarded the chronological occurrence of ictal clinical signs as crucial, reflecting the spatio-temporal organization of the epileptic discharge within the brain. Their clinical analysis of ictal events, beyond a simple description, consisted, on one hand of interpreting the symptoms according to documented cortical topology, and on the other hand of analyzing them chronologically to imagine a logical spatial evolution of the intracerebral discharge. Understanding this temporal dynamic of ictal symptoms with respect to brain anatomy implied that ‘ictal electroencephalographic changes must be recorded at the very point where they occur (anatomo-electrical relationships) and that their initial or secondary reverberations on the clinical picture (electro-clinical relationships) must be evaluated as the discharge spread’.2 Such an approach was rendered technically feasible thanks to the advent of atlases providing the spatial coordinates of most telencephalic structures, as well as the development of neurosurgical techniques that allowed to target and reach such coordinates4,5 (see Chapter 104). The selection of the structures to be explored was based on a very careful analysis of all the data – notably clinical – collected during the noninvasive presurgical investigations in order to formulate one or several hypothesis concerning the site(s) of

seizure onset, and the pathways of preferential ictal spread.1–3,6–8 The implantation strategy was then ‘custom-tailored’, and electrodes were placed according to the prior hypotheses, in a way that enabled to interpolate intracerebral EEG activity within the interelectrode space. The underlying concept was therefore very different from other intra-cerebral EEG procedures referred to as ‘depth recordings’9–11 the aim of which was primarily to ensure the side of seizure onset in temporal lobe epilepsies, or to differentiate frontal lobe seizures from temporal lobe seizures. Intracerebral targets were in such cases relatively standardized in order ‘to avoid biasing the exploration strategy in favor of one’s preferred localizing hypothesis’.12 It was clear, when considering the SEEG method, that if the pre-SEEG hypotheses were wrong, the placement of intracerebral electrodes would be inadequate, the interpretation of SEEG findings was likely to be erroneous, and surgical results would be probably poor.13 Conversely, if the pre-SEEG hypotheses were correct, the resulting implantation strategy would allow to help to identify the amount of brain tissue that must be ideally resected, and to reliably anticipate the patient’s postoperative outcome according to the surgical possibilities and limits. SEEG today Technically speaking, the SEEG method has evolved with time: ‘acute’ recordings has became ‘chronic’, electrodes have been reduced in size, electro-clinical correlations have been improved thanks to the advent of audio-video-EEG monitoring system, and intracerebral targets are currently assessed using MRI. Conceptually, ‘the song remains the same’, and a SEEG study cannot be performed without having previously hypothesized what the preferential origin and spread of the seizures could be.13–16 As for many epilepsy surgery centers, the overall proportion of our patients evaluated by invasive recordings has decreased over the last decade. However, the subset of patients who can benefit from the use of SEEG remains significant and, in our centers, approximately 40% of resective surgical procedures are performed so far after SEEG recordings.14 Schematically, such recordings are needed when noninvasively obtained data remain insufficiently concordant, when they are discordant or inconclusive, and when they suggest an early involvement of highly eloquent areas, providing that the questions derived from the noninvasive protocol are clear, and that the patient is likely to benefit from surgery. 649

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Implantation strategy Since there are no standard targets for electrode implantation, the selection of the structures to be explored must be determined individually, mainly on the basis of both clinical and scalp-EEG seizure pattern(s).1–3,6–8,13–15 This assumption is even true in lesional epilepsies where a SEEG study may remain indicated. In such cases, the presence of a lesion will influence the implantation strategy, as far as the relationships between the lesion itself and the region of seizure generation must be clarified. Nonetheless, the leading principle is still to investigate all the cortical areas, the ictal involvement of which is suspected on the main basis of ictal electro-clinical information. Yields of electro-clinical findings Today, evidence has accumulated on the diagnostic value of seizure symptoms, and many studies have been – and continue to be – conducted in this way. Most tend to attribute to isolated signs, as well as to clusters or evolution of a few signs, a lateralizing or localizing significance.17 This kind of clinical analysis, although helpful, remains very different from the working method that Talairach and Bancaud emphasized: in their mind, indeed, ictal clinical symptomatology must be viewed as a whole (this led to the notion of seizure pattern). Particularly, it was clear for them that seizure symptoms (and more particularly the ‘signal-symptom’), when taken individually, could lead to erroneous interpretation.1 The emergence of an identical clinical sign may result, indeed, from the ictal disorganization of cortex regions which, even if different, may have common subcortical projections. For instance, an ascending epigastric sensation, ‘typically’ of (mesio-)temporal lobe origin,18 may as well translate an ictal involvement of the insular cortex19 as that of the mesial prefrontal cortex,20 or be the first manifestation of a discharge circumscribed within a hypothalamic hamartoma.21 Additionally, symptoms of highly localizing value are rare and, even in such ideal condition, the localizing sign must be integrated chronologically to make an extrapolation of the anatomical origin of the seizure. Focal clonic jerks, for instance, which are the expression of the ictal involvement of motor cortex, will not have the same value at the beginning of an ictal episode initiated by paresthesia in the same body segment (strong probability that the perirolandic region was initially affected), than after the occurrence of auditory hallucinations (propagation of a posterior perisyslvian discharge to the motor strip), or than at the end of a fit beginning with a rising epigastric feeling followed by oroalimentary and gestural automatisms (no localizing value). Finally, the emergence of some signs of relatively poor localizing significance (e.g., gestural automatisms), especially in a late phase of the seizure, may only reflect the simultaneous or sequential dysfunction of several cortical areas – thus probably of several efferent systems – without giving any indication, per se, on seizure origin. A good example is given by the supposedly highly localising significance of ‘frontal’ hypermotor behavior, which have been recently described during seizures of temporal22 or insular origin.23 Nowadays, ictal clinical patterns are assessed at best by video-EEG monitoring, but careful attention must also be paid to the historical evolution of symptomatology. This latter may have evolved with time, so that auras or focal signs of high localizing significance may have disappeared during the

course of the disease, or still exist only in a few occasions but have not been documented during long-term video-EEG monitoring. The cortical areas to which these clinical manifestations refer will have to be taken into account for the adjustment of electrodes positioning. Although crucial, the localization hypothesis suggested by ictal clinical picture should be confirmed and completed by careful analysis of the concurrent ictal scalp-EEG discharge. This remains essential to confirm the clinical hypothesis when this latter is clear, but above all to improve it when ictal symptoms are ambiguous and fail to indicate a clear-cut localization or lateralization. In that respect, emphasis is put on the identification of the first ictal EEG change that occurs prior to the first clinical symptom, and more specifically on the identification of a well-localized low-voltage fast activity which is likely to reflect an underlying fast-synchronizing intracerebral EEG discharge. As a matter of fact, such a scalp EEG pattern has been recently found to be predictive of a good surgical outcome in frontal lobe epilepsy.24 However, a low-voltage discharge may not appear on the scalp recording, especially if it is well-limited and located deep in the cortex. In such a case, particular attention must be paid to a well-localized flattening of the EEG trace, or to the disappearance of well-localized interictal EEG abnormalities, which are both good indicators of the region of seizure origin. Altogether, these scalp-EEG patterns of seizure onset are particularly helpful for identifying the core region of the future implantation, but they cannot account for the whole brain area which is involved by the discharge. It is thus of particular importance to also evaluate the cortico-cortical propagation of the discharge, which is at best assessed by a careful analysis of the spatial evolution of the scalp-EEG discharge from the onset of the seizure to its end. Unfortunately, scalp-EEG discharges may quickly be widespread or bilateral, or multiregional, so that the preferential spread pattern may be particularly difficult to define. The recording of the patients seizures, although crucial, does not exempt one from analyzing interictal EEG abnormalities which may influence in part the final placement of the electrodes, particularly when their distribution does not match with the territories that are suspected to be involved by the seizures, or when ictal recordings are fairly informative due to movement artifacts, as during hypermotor seizures. Essential rules for electrodes implantation Although all the SEEG studies are designed, a priori, on the basis of patient’s individual characteristics, the analysis, a posteriori, of all our investigations shows that they can be schematically grouped in several implantation patterns, according to the main cortical regions that were targeted25 (see Chapter 104). However, the exact drawing of electrodes placement is never identical for one patient to another one, and it closely depends on all the noninvasive features previously collected (see below the illustrative case). As a rule, the position and number of intracerebral electrodes (Figure 73.2a) must be designed to address the following issues: 1. Demonstrating that brain regions suspected to be involved in seizure onset and early propagation (the ‘epileptogenic zone’) show the expected ictal pattern. This requires the suspected brain regions to be implanted (Figure 73.2b).

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Stereoelectroencephalography 2. Considering the possibility that this pattern might in fact reflect the propagation of an ictal discharge generated elsewhere. This requires a comprehensive review of such alternative hypothesis, and the intracerebral evaluation of part or all of the corresponding brain structures (depending on the number and the likelihood of these hypotheses) (Figure 73.2c). 3. Delineating the border of the ‘epileptogenic zone’ as precisely as possible, in order to perform the minimum cortical resection. This requires the placement of intracerebral electrodes in brain structures located outside the theoretical limits of the suspected ‘epileptogenic zone’ (Figure 73.2d). 4. Assessing whether the removal of the cortical areas involved in seizure generation will be possible or not. This requires the investigation of the eloquent areas that are of interest, relatively to the hypothetical ‘epileptogenic zone’, and with respect to the possible boundaries of the planned resection (Figure 73.2d). 5. Evaluating the precise relationships between an anatomical lesion (when present) and the ‘epileptogenic zone’. This requires to investigate, whenever possible, the epileptogenicity of the lesion itself and in any cases of the surrounding cortex, the number of the ‘lesional’ electrodes to use depending on the morphology, extent and anatomical location of the lesional process (Figure 73.2b).

Illustrative case This 32-year-old right-handed patient, without any familial nor personal antecedent of epilepsy, started having seizures at the age of 8 years. During childhood, the fits were initiated by auditory illusions associated with blurred vision, which were followed by a loss of contact and left oculo-cephalic deviation, possible fall, and rare secondary tonic-clonic generalisation. The episodes persisted until the age of 12 years when clobazam was associated to carbamazepine and phenobarbital. Around the age of 17, seizures recurred, beginning with a sensation of nausea in the stomach during which the patient was able to speak, followed by a loss of contact with gestural and verbal automatisms. Since then and despite numerous medications, seizures persisted with a mean seizure

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frequency of six to nine episodes per month, without any prolonged seizure-free intervals. Ictal symptomatology changed at the age of 21: seizures started with a sensation of pleasure (‘a spiritual pleasure’), rarely associated with an epigastric feeling or with a déjà-vécu impression. These auras could remain isolated without language disturbances, or could be followed by a global sensation of ‘switching off ’ (lowering of the sounds and visual blurring) as the prelude to the loss of contact, the features of which were not well described. At the age of 30, the patient came at the C. Munari Epilepsy Surgery Centre for presurgical evaluation. Neurological examination was normal and neuropsychological evaluation demonstrated a deficit in both verbal and visuo-spatial memory functions. The only persisting aura consisted in an inconstant and brief feeling of pleasure, which might precede the loss of contact with staring and a few gestural, verbal and oro-alimentary automatisms; the postical phase was characterized by deambulatory behaviors and complex verbal automatisms. Seizures could also occur in clusters of brief and pauci-symptomatic fits, during which the patient experienced a sort of ecstatic state with a clear spatio-temporal disorientation; he was still able to speak and had an almost correct working and social behaviour. MRI (Figure 73.1) showed in the right temporo-occipital junction a slightly expansive lesion involving the cortex of the collateral sulcus and the surroundings fusiform and lingual gyri. These gyri appeared thickened with a discrete hyposignal in inversion-recovery sequences and a clear and more widespread hypersignal in FLAIR images. The superior part of the lesion presented with a cystic component of less than 1cm in diameter. The diagnosis of tumor, possibly a dysembryoplastic neuroepithelial tumor, was suggested. No other MRI abnormalities were found, especially concerning the right hippocampus and the temporopolar region. Video-EEG monitoring showed, interictally, a clear asymmetry of background activity (8–9 Hz, mid amplitude) which appeared more regular and better represented over the left posterior regions. Slow waves and rare spikes were recorded over the right fronto-temporal region. Spikes frequency was increased during sleep, with a phase reversal over F8, but also T4 and T6. Occasionally, left temporal asynchronous spikes were also recorded. Five electro-clinical seizures were recorded during wakefulness. In all, the patient was able to warn and

(c)

Figure 73.1 Pre-operative MRI (patient of the illustrative case). a: axial view, inversion-recovery sequences; b: coronal view, inversion-recovery sequences; c: sagital view, FLAIR sequences.

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dialogue with the observer for the first 10 seconds. Then, the contact was impaired with staring, verbalization of a few stereotyped words, occurrence of a few activities of swallowing and discrete chewing. The episodes lasted less than 1 minute, at the end of which recovery of language function was total within a few seconds. EEG correlate was poor at the initial phase of the fit, but a clear rhythmic theta activity occurred while the patient became unresponsive: this activity mainly involved the right anterior temporal region, with a latter spread over the right parieto-central and left temporal regions. These anatomo-electro-clinical features led us to propose to the patient a SEEG investigation (Figure 73.2a), the main aims of which were to define the relationships between the lesion with its different components (Figure 73.2b), mesiotemporal lobe structures (Figure 73.2b), and the visual and auditory cortices (Figure 73.2c). The SEEG study aimed also at evaluating how the different parts of the temporal neocortex and the adjacent temporo-parietal and temporo-occipital regions could participate in seizure early spread.

Recording and stimulation procedures Thanks to many technical progresses such as the advent of long-term audio-video-EEG monitoring systems, most – if not all – SEEG studies are nowadays conducted extraoperatively in chronic conditions. Altough the monitoring systems utilized vary from one center to another, two main technical features are required to provide reliable information: the system must be able to sample the signal at a high frequency rate (at least 256 Hz, but recent work in patterns of seizure onset suggests potential benefit of using at least 512 Hz and even more), and to acquire the signal from at least 64 channels (but it is clear that this is a strict minimum, and twice, or even more, that number is optimal, and currently used). In our centers, we choose one of the contact sites in the white matter as reference and depth EEG activity is displayed using bipolar recordings between contiguous contacts. SEEG activity is

(b)

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Figure 73.2 Implantation of intracerebral electrodes (same patient as in Fig.1). a: SEEG scheme, lateral and frontal view of the skull; b, c, d: multiplanar reconstructions (sagittal, coronal and axial views) of the MRI performed with the implanted intra-cerebral electrodes. b: position of the electrodes exploring the suspected ictal onset zone, including the lesion (L) and the peri-lesional cortex located anteriorly (D) and posteriorly (E); c: position of the electrodes recording mesial temporal lobe structures (A: amygdala, B: anterior hippocampus, C: posterior hippocampus), the role of which in early propagation (or even onset) of the seizures had to be clarified; d: localisation of the other intra-cerebral electrodes utilised in this case for a complete definition of the cerebral structures involved in the primary and secondary organisation of ictal discharges: i) superior temporal gyrus (electrodes T and U) due to auditory illusions described in the patient’s history; ii) visual cortex (internal leads of electrodes F, O, V, K) both for clinical (blurred vision) and functional reasons; iii) lateral cortex of the temporo-occipital and temporo-parietal junctions since in our experience, such ‘pauci-symptomatic’ fits may result from an the ictal involvement of this extended neocortical region.

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Stereoelectroencephalography often recorded along with a limited number of EEG needle electrodes, the electrocardiogram is systematically monitored, and other parameters such as the electromyogram or the oculogram may at times be assessed. Recordings are performed under different conditions (waking, after sleep deprivation, or during night sleep when necessary), over a period of 1 to 3 weeks, with a gradual reduction of patient medication when necessary. Patients are continuously observed by a member of the epilepsy team in order to obtain a precise description of subjective patient experience at seizure onset, as well as to test awareness, language, muscle tone and sensory-motor functions. Particularly, attention is focused on the signs and symptoms which cannot be assessed by reviewing retrospectively the videotapes, and more especially on the initial subjective symptoms which may be forgotten at the end of the seizure. In our experience, it is not necessary to capture systematically a predefined number of ictal episodes, but it is mandatory that the fits recorded are similar to the patient habitual seizures, and well documented. Recording of several seizures, however, is usually necessary, particularly in those of patients in whom ictal symptomatology is fairly stereotyped. The aim is to be able to analyze the main elements of the clinical symptomatology before one can establish electro-clinical correlations. Electrical stimulations are performed for several days under continuous video-EEG control. The goals are the reproduction of the aura, the induction of an electroclinical seizure, and/or the localization of an eloquent cortical area that has to be spared during surgery. Following our standard clinical practice,26 stimulations are performed at 1 Hz and 50 Hz (depending on the level of excitability and on the type of clinical signs that one expects to elicit by stimulating a given structure) and applied between contiguous contacts at various levels of the electrode axis. Advantages and limits of the stimulation during SEEG procedure is the object of Chapter 71.

Interpretation of SEEG findings It is not possible to systematize, in this chapter, all the findings provided by a SEEG study, since each investigation is designed for a specific problem, and the number and type of structures evaluated vary according to the problem under investigation. Schematically, the interpretation of a SEEG study aims first at constructing a preoperative composite ‘drawing’ of the brain area to be removed (what we could call the ‘what-to-remove area’), which could be easily followed in the operatory theatre. The determination of this area depends above all on the study of the anatomo-electro-clinical correlations evidenced during the seizures themselves, also taking into account the features of subclinical discharges and of interictal abnormalities, as well as the effects of electrical stimulation. Seizure analysis Seizure analysis represents the principal guide of the whole SEEG approach, as it allows to define what the mentors of Sainte-Anne School named the ‘epileptogenic zone’, i.e., the ‘site of the beginning and of the primary organization of the epileptic seizures’.8 However, what was clear in Bancaud and Talairach’s

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minds from their earliest clinical experiences was that the topographic determination of the epileptogenic zone could not be based only on electrophysiological criteria: it depended on the study of electro-clinical correlations, this term underlining the importance to assess not only the precise anatomical location of the site of origin and early spread of the ictal discharges, but also how these SEEG changes gave rise to the clinical symptoms. Ictal onset In SEEG terminology, the ictal onset zone (‘site of the beginning ...,) can be defined as the cortical area(s) where the first clear ictal electrical change is recorded. The SEEG assessment of this area, however, depends on the spatial sampling of the SEEG investigation, so that caution is required to ascertain that the site of seizure origin has been unequivocally identified. Nevertheless, it is reasonable to attribute to the first clear ictal electrical change a reliable localizing significance, providing: (1) that this change occurs prior to the clinical onset of the seizure, and (2) that it manifests by a fast synchronizing discharge (low-voltage fast activity or recruiting fast discharge of spikes), the pattern and frequency of which may differ from one region to another one.27–29 The lack of one of these two criteria implies an incorrect SEEG investigation, so that the ictal onset zone, as well as the epileptogenic zone (which by definition should include the ictal onset zone), cannot be defined. In such condition, success or failure of surgery, if eventually performed, will not provide any valuable information. Conversely, the coincidence of clinical and relevant ictal electrical findings, and a fortiori the appearance of clinical onset after such ictal SEEG changes, both tend to indicate that the positioning of at least some electrodes is correct (Figure 73.3). Primary organization of the discharge The definition of the ictal onset zone, however, only helps in defining part of the epileptogenic zone, the main difficulty being then to evaluate ‘how much of the cortex contiguous to the site of origin is recruited into action to produce a clinical seizure’.30 Bancaud and Talairach assumed that this issue could be answered, at least in part, by considering also the cortical areas participating in early seizure spread (‘... the primary organization of the epileptic seizures’). Under this term, particular attention deserves the spatial extent of seizure discharges at the moment where the first clinical sign(s) occurs, as well as the coherence between the localization of the discharge and the (expected?) type of the concomitant symptom(s) (Figure 73.3). Also, attention must be paid on the types of SEEG changes that occur during seizure evolution: once again, emphasis is put on cortex areas that are able to generate fast synchronizing discharge, including not only those recruited successively from the ictal onset, but also those exhibiting such a fast activity de novo during the course of the initial discharge (Figure 73.3). In any cases, what must be considered as an ‘early’ or a ‘late’ SEEG change cannot be assessed in terms of seconds, or tens of seconds, so the repertoire of ictal patterns are rich and the propagation times variable. This probably explains why Talairach and Bancaud used preferentially the term of ‘primary organization of the epileptic seizure’ than the term of ‘early seizure spread’.

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Textbook of epilepsy surgery lctal onset Amygdala 2d T G (ant part) Hc (ant part) 2d T G (mid part) Hc (post part) Sup T Su (mid part) 2d T G (post part) 2d T G (post part) Lingual G (ant part) Collateral Su 3rd T G (post part) Lingual G (mid part) Lesion Sup T Su (post part) Fusiform G (post part) Mid O G (ant part) Lingual G (post part) Cuneus (ant part) Sup P G (post part) Calcarinian Cx Mid O G (post part) Calcarinian Cx Sup O G (ant part) Precuneus (post part) Precuneus (post part) IntraP Su Angularis G P cingulate G Supramarginalis G Sup T G (post part)

Primary organization

[A] [A] [B] [B] [C] [C] [F] [F] [D] [D] [D] [L] [L] [L] [L] [E] [K] [K] [K] [O] [O] [V] [V] [Q] [Q] [Q] [Q] [S] [S] [U] aura

Amygdala 2d T G (ant part) Hc (ant part) 2d T G (mid part) Hc (post part) Sup T Su (mid part) 2d T G (post part) 2d T G (post part) Lingual G (ant part) Collateral Su 3rd T G (post part) Lingual G (mid part) Lesion Sup T Su (post part) Fusiform G (post part) Mid O G (ant part) Lingual G (post part) Cuneus (ant part) Sup P G (post part) Calcarinian Cx Mid O G (post part) Calcarinian Cx Sup O G (ant part) Precuneus (post part) Precuneus (post part) IntraP Su Angularis G P cingulate G Supramarginalis G Sup T G (post part)

loss of contact

[A] [A] [B] [B] [C] [C] [F] [F] [D] [D] [D] [L] [L] [L] [L] [E] [K] [K] [K] [O] [O] [V] [V] [Q] [Q] [Q] [Q] [S] [S] [U]

Figure 73.3 SEEG recording of an electro-clinical seizure (same patient as in Fig.1,2).G: gyrus; Su: sulcus; T: temporal; Hc: hippocampus; P: parietal; O: occipital; 1st/2d/3rd: first/second/third; ant/post: anterior/posterior; sup: superior. Letters in brackets refers to the recording electrodes (see Fig.2). a: The seizure starts in the anterior part of the lingual lobule, an immediately perilesional structure, with a low voltage fast discharge (first arrow); 4 seconds later, this activity involves, in a slower way, the collateral sulcus, the mid part of the lingual lobule and the posterior part of the fusiform gyrus (small arrows); two seconds after, the fast discharge spread out of the borders of the peri-lesional area, involving the third temporal gyrus as well as the superior and mid occipital gyri. At that time, the hippocampal formation begins to exhibit a spiking activity. During all this period, the patient, who was talking with one of the observers, does not report any symptom but looks like watching around with an interrogative expression. Ten seconds after the ictal onset, he stares for a while before saying: ‘I guess I’m having an aura’. Immediately after he stops answering and obeying to the observer, even if he can continue looking at her. The electrical correlate of this sudden clinical modification is easily identified and consists, on one hand, in the abrupt acceleration of the low voltage fast discharge, especially over the lingual and fusiform gyri, and on the other hand in the sudden occurrence of a high amplitude spike-and-wave discharge within the hippocampus which seems to evolve independently. b: During the second part of the fit, the discharge is widely extended, involving almost all the explored structures.

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Stereoelectroencephalography Postictal findings Early postictal findings, although not clearly specified in Talairach and Bancaud’s work, are part of the analysis of any seizures recorded during SEEG investigation. Particular attention has been paid to those cortex areas exhibiting, at seizure termination, major attenuation and/or suppression of their background activity. Insofar, Toussaint et al.31 have recently reported that postictal SEEG suppression accurately localized the seizure onset zone in a majority of frontal lobe cases, while it appeared more widespread in temporal lobe patients, involving both areas of ictal onset and seizure propagation. Postictal spikes were, in this study, of relatively poor localizing significance, in accordance with other works.32 Certainly, postictal patterns have been neglected in the literature and further work is needed to set their actual role in the surgical decision. Subclinical discharges In any cortical location, a rhythmic activity or a fast activity mimicking an ictal discharge may develop focally without any accompanying symptoms. It is reasonable to attribute to such ‘subclinical seizure activities’ a high localizing significance, in as much as they have been correlated with an excellent outcome after surgery.33,34 However, even when this kind of paroxysmal activity is present on the traces, the recording of the fully developed electro-clinical seizures remains mandatory. Subclinical discharges, in fact, may differ in terms of morphology and/or location from the clinical ictal discharge, or may appear identical to the early part of a clinical seizure which later involves other cortical structures.35 Interictal abnormalities Lesional area In SEEG terminology, the lesional zone refers to the brain area which is revealed by an abnormal slow-wave activity or, in some cases, by a major alteration of background activity or by an electrical silence.6,7,13,36 These features, especially when caricatural, presume an underlying macroscopic alteration of the neural tissue, making common the anatomical overlapping of the electrically defined lesional zone with the ‘epileptogenic lesion’ (currently the most often revealed on MRI). Due to this good correlation, when slow-waves are present in the ‘negative MRI area’, neuroimaging evaluation should be improved in that specific region. However, the topographic distribution of the slow-waves does not always match with a lesion as assessed on pathological specimens. Thus, although the significance of such nonparoxysmals events remains unclear, it seems legitimate to carefully consider the area which exhibit continuous delta wave activity for the final surgical decision, even in the absence of a corresponding MRI anatomical lesion. Irritative area One of the cortical zones identified at the end of a SEEG study is the irritative zone, which includes the structures mainly involved by spike activity. Due to the abundance of these paroxysms and to their great variability in firing pattern and location, the definition of the irritative zone often represents a difficult diagnostic problem. In particular, the

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topographic relationships with the ‘epileptogenic zone’ must always be carefully evaluated since, in many occasions, the two zones can strongly differ in localization or show only a partial overlapping.13 In a surgical perspective, however, it would be a mistake to ignore the extent of interictal spikes, whether they are focal or not. Indeed, they can provide additional confirmation of localization, but also may even prove of more important localizing value than seizure recording. This is typically the case of Taylor’s focal cortical dysplasia (type II), whose peculiar interictal pattern could be considered as a good marker of the extent of the dysplastic cortex that needs removal to abolish the seizures.37–39 Particular attention has to be paid, moreover, to those spikes that do not disappear at seizure onset; this persistence, indeed, might suggest that they do not depend on a pathophysiological process common to the underlying area(s) of seizure onset, and therefore that they might be part of what Lüders and colleagues named the ‘potential seizure onset zone’.40 Intracerebral electrical stimulation Intracerebral electrical stimulations represent a mandatory part of a SEEG study, not only for localizing eloquent cortical areas, but also (and often mainly) for eliciting seizures.26,41,42 This latter application may prove very helpful in many controversial circumstances: (1) when spontaneous ictal discharges are widely extended from the onset of the seizure; (2) when they apparently arise ‘independently’ from different brain structures; (3) when regions initially silent at seizure onset seem to activate abruptly during the ictal discharge, showing in the further phases an asynchronous electrical build up that is different in terms of frequency and morphology from the primary seizure discharge. In these cases, induction of a complete and habitual seizure sequence by electrical stimulation militates for the inclusion of the stimulated structure in the surgical plan. Elicitation of auras may also help by identifying relay and subrelay areas that are essential for the final construction of ictal clinical picture, especially when those symptoms have disappeared in the course of the disease, or still exist occasionally and were not documented spontaneously. Even in this figure, however, the correct interpretation of elicited auras has to take into account, according to Talairach and Bancaud, the possibility of the activation of regions (cortical and subcortical) remoted from the stimulation site. Therefore, and mainly when a local ictal discharge has not been concomitantly elicited, caution is required when establishing a causal relation between a stimulated structure and the occurrence of a given symptom.3 The role of electrical stimulation for defining the ictal onset zone is detailed in Chapter 71.

Surgical implications Schematically, the ‘what-to-remove area’, wherever its location may be, can be defined either as focal, regional (lobar), multilobar, or multifocal. Surgery, in any cases, is designed according to the results of SEEG findings so that tailored resections are the rule rather than the exeption (see Chapter 104) (Figure 73.4).

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Figure 73.4 Tailored cortical resection (same patient as in Figures 70.1–70.3). Coronal Inversion Recovery (up) and sagittal FLAIR slices from the post-operatory (6 months) MRI study.

Focal discharges Discharges affecting only a well localized area do exist, showing as many clinical correlates as the combination of topographic and electrical features that one discharge may produce. This is true in temporal lobe epilepsy, where an ictal discharge can remain confined into the amygdala43 or the hippocampus,44 the most often without clinical accompaniment; but it is also a common finding in most cortical locations. In fact, one must be sure of the accuracy of the 3D spatial sampling of the SEEG investigation before defining as focal such an ictal discharge. As a consequence, very limited cortical resections are uncommonly performed on the basis of SEEG findings. It remains a peculiar finding, which is mainly seen in cases of focal epileptogenic lesions. However, small ‘epileptogenic zones’ may exist even in cryptogenic cases, as recently shown by the therapeutic effect of stereotactic radiofrequency lesion of a very restricted frontomesial epileptogenic ‘focus’ generating dyskinetic behavior and laughter.45 Lobar discharges In most patients, the area that has to be removed is localized inside the borders of a single lobe, even if ictal discharges may

affect initially different structures of the lobe. Therefore, relatively standardized cortical resections can be performed without taking into account some of the subtle variabilities that can be observed in electrophysiological terms and sequential involvement of different structures. This is even true in temporal lobe epilepsy where increasing evidences suggest that the classical subdivision between mesio-temporal and neocortical discharges is an oversimplification.29,46,47 In extratemporal epilepsies, similar considerations can be done but, due to the more limited experience in this field, the difficulty in the identification of clear cut and reproducible anatomo-clinical patterns is probably greater than in temporal lobe epilepsy.48–51 Multilobar discharges A few years ago, Claudio Munari and colleagues52 emphasized that in about 20% of patients studied by SEEG, the ‘epileptogenic zone’ included distinct (but interconnected) regions of different lobes of one hemisphere, and consequently should be defined as ‘multilobar’. This condition, though uncommon, has been reported in other studies,50,51,53–56 and does not represent a purely theoretical discussion: as demonstrated by Munari et al.,52 more than 80% of patients were cured when

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Stereoelectroencephalography the epileptogenic zone was completely (or almost completely) removed, while when the removal was clearly incomplete, the percentage of seizure-free patients dropped to 10%. Thus, the possibility that an epileptogenic zone may extend outside the boundaries of one lobe must be taken into account. For instance, when looking at surgical failures in temporal lobe epilepsy, a consistent percentage of patients are likely to suffer from ‘temporal plus’ epilepsy (Ryvlin and Kahane),57 so that identifying this ‘multilobarity’ might enable to tailor a more extensive corticectomy with a probably better surgical outcome. Multifocal discharges In our experience, the indication of depth recordings to understand whether the ‘epileptogenic zone’ is unifocal or multifocal is rare. In general, patients with electro-clinical evidence of different seizure types are excluded from surgery after the non-invasive phase of the evaluation. However, in a restricted and well-selected number of cases, especially when a lesion is present, the realization of a SEEG may help in establishing whether the different seizure types have a link in between. The results of the SEEG study performed in these conditions may allow to demonstrate that the different seizure types, although multifocal, are in fact part of a widely extended area which can be safely removed.58 Another striking example of this possibility is represented by patients in whom an hypothalamic hamartoma is associated with multiple seizure types, and in whom SEEG recordings demonstrated that laughing (or crying) attacks, the hallmark feature of the

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syndrome, were linked to ictal discharges confined to the hamartoma.21 Such examples are rare enough to be mentioned, so that caution is required whenever different kind of seizures have been clearly documented during scalp-EEG monitoring, and recognized by the patient and/or his family as the habitual seizures. Thus, in our experience, most of the true multifocal epilepsies defined during SEEG procedure are not expected from the non invasive protocol and, as a consequence, the idea of surgery is often abandoned, or eventually dictated by the possible efficacy of surgery on the predominant or more disabling seizure type.

Conclusions The SEEG is not a presurgical evaluation tool, but a complete methodology which emphasizes the importance to study the spatio-temporal dynamics of seizure discharges (the ‘epileptogenic zone’), and not only their starting point (the ‘ictal onset zone’). Obviously, it cannot be considered as the ideal method for defining the cortical areas that have to be removed to cure the patients. However it has survived the huge development of modern neuroimaging and other noninvasive localizing techniques, and has greatly helped our understanding of ictal clinical symptomatology of partial epileptic seizures. For these reasons, it remains a reliable way to assess the origin and extent of an epileptic discharge within the cortex, even in the absence of any neuroimaging abnormality.

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Bancaud J, Talairach J, Bonis A et al., eds. La stéréoencéphalographie dans l’épilepsie. Informations neuro-physio-pathologiques apportées par l’investigation fonctionnelle stéréotaxique. Paris: Masson, 1965. Talairach J, Bancaud J. Stereotaxic approach to epilepsy. Methodology of anatomo-functional stereotaxic investigations. Progr Neurol Surg 1973;5:297–354. Talairach J, Bancaud J, Szikla G, Bonis A, Geier S. Approche nouvelle de la neurochirurgie de l’épilepsie. Méthodologie stéréotaxique et résultats thérapeutiques. Neurochirurgie 1974;20(suppl 1):1–240. Talairach J, David M, Tournoux P, eds. L’exploration chirurgicale stéréotaxique du lobe temporal dans l’épilepsie temporale. Paris: Masson, 1958. Talairach J, Szikla G, Tournoux P et al. eds. Atlas d’anatomie stéréotaxique du télencéphale. Etudes anatomo-radiologiques. Paris: Masson, 1967. Bancaud J, Talairach J, Geier S, Scarabin JM, eds. EEG et SEEG dans les tumeurs cérébrales et l’épilepsie. Paris: Edifor, 1973. Munari C, Musolino A, Blond S et al. Stereo-EEG exploration in patients with intractable epilepsy: topographic relations between a lesion and epileptogenic areas. In: Schmidt D, Morselli PL, eds. Intractable Epilepsy: Experimental and Clinical Aspects. New York: Raven Press, 1986:129–46. Munari C, Bancaud J. The role of stereo-electro-encephalography (SEEG) in the evaluation of partial epileptic patients. In: Porter RJ, Morselli PL, eds. The Epilepsies. London: Butterworths, 1987: 267–306. Spencer SS. Depth elecroencephalography in selection of refractory epilepsy for surgery. Ann Neurol 1981;9:207–14. Olivier A, Gloor P, Quesney LF, Andermann F. The indications for and the role of depth electrode recording in epilepsy. Appl Neurophysiol 1983;46:33–6. Engel J Jr, Crandall PH. Intensive neurodiagnostic monitoring with intracranial electrodes. In: Gumnit R, ed. Intensive Neurodiagnostic Monitoring. New York: Raven Press, 1986:85–106.

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Gloor P. Preoperative electroencephalographic investigation in temporal lobe epilepsy: extracranial and intracranial recordings. Can J Neurol Sci 1991;18:554–8. Chauvel P, Vignal JP, Biraben A, Scarabin JM. Stereoelectroencephalography. In: Pawlik G, Stephan H, eds. Focus Localization. Berlin: Liga Verlag, 1996:135–63. Cossu M, Cardinale F, Castana L et al. Stereoelectroencephalography in the presurgical evaluation of focal epilepsy: a retrospective analysis of 215 procedures. Neurosurgery 2005;57:706–18. Isnard J. Drug-resistant partial epilepsy. Invasive electrophysiological explorations. Rev Neurol (Paris) 2004;160(Spec No 1):138–43. Kahane P, Minotti L, Hoffmann D, Lachaux JP, Ryvlin P. Invasive EEG in the definition of the seizure onset zone: depth electrodes. In: Rosenow F, Lüders HO, eds. Handbook of Clinical Neurophysiology, Vol.3. Presurgical Assessment of the Epilepsies with Clinical Neurophysiology and Functional Imaging. Amsterdam: Elsevier BV, 2004:109–33. Rosenow F, Hamer HM, Knake S et al. Lateralizing and localizing signs and symptoms of epileptic seizures: significance and application in clinical practice. Nervenarzt 2001;72:743–9. Henkel A, Noachtar S, Pfander M, Lüders HO. The localizing value of the abdominal aura and its evolution: a study in focal epilepsies. Neurology 2002;58:271–6. Isnard J, Guenot M, Sindou M, Mauguiere F. Clinical manifestations of insular lobe seizures: a stereo-electroencephalographic study. Epilepsia 2004;45:1079–90. Munari C, Quarato PP, Di Leo M et al. Surgical strategies for patients with supplementary motor area epilepsy: Grenoble experience. Adv Neurol 1996;70:379–403. Kahane P, Ryvlin P, Hoffmann D, Minotti L, Benabid AL. From hypothalamic hamartoma to cortex: what can be learnt from depth recordings and stimulation ? Epileptic Disord 2003;5: 205–17. Nobili L, Francione S, Cardinale F, Lo Russo G. Epileptic nocturnal wanderings with a temporal lobe origin: a stereo-electroencephalographic study. Sleep 2002;25:669–71.

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Textbook of epilepsy surgery Ryvlin P, Minotti L, Demarquay G et al. Nocturnal hypermotor seizures, suggesting frontal lobe epilepsy, can originate in the insula. Epilepsia 2006;47:755–65. Worrel GA, et al. Focal ictal beta discharge on scalp EEG predicts excellent outcome of frontal lobe epilepsy surgery. Epilepsia 2002;43:277–82. Munari C, Hoffmann D, Francione S et al. Stereo-electroencephalography methodology: advantages and limits. Acta Neurol Scan 1994;suppl 152:56–67. Kahane P, Tassi L, Francione S et al. Manifestations électro-cliniques induites par la stimulation électrique intra-cérébrale par ‘chocs’ dans les épilepsies temporales. Neurophysiol Clin 1993;22:305–26. Velasco AL, Wilson CL, Babb TL, Engel J Jr Functional and anatomic correlates of two frequently observed temporal lobe seizure-onsets patterns. Neurol Plast 2000;7:49–63. Wennberg R, Arruda F, Quesney LF, Olivier A. Preeminence of extrahippocampal structures in the generation of mesial temporal seizures: evidence from human depth electrode recordings. Epilepsia 2002;43:716–26. Chabardès S, Kahane P, Minotti L et al. The temporo-polar cortex plays a pivotal role in temporal lobe seizures. Brain 2005;128:1818–31. Rasmussen T. Surgical treatment of complex partial seizures: results, lessons and problems. Epilepsia 1983;24(suppl 1):65–76. Toussaint D, Moura M, Allouche L et al. Can early post-ictal activities help to better localise and lateralise the epileptogenic zone. Epilepsia 2005;46(suppl 6):324(abstract). Gotman J, Marciani MG. Electroencephalographic spiking activity, drug levels and seizure occurrence in epileptic patients. Ann Neurol 1985;17:597–603. Sperling MR, O’Connor MJ. Auras and subclinical seizures: characteristics and prognostic significance. Ann Neurol 1990;28:320–8. Tran TA, Spencer SS. Surgical outcome in patients with and without subclinical seizures: a comparative study. Epilepsia 1993; 34(Suppl 6):39. Bancaud J, Ribet MF, Chagot D. Origine comparée des paroxysmes de pointes ‘infra-cliniques’ et des crises spontanées dans l’épilepsie. Rev EEG Neurophysiol 1975;5:63–6. Munari C, Talairach J, Musolino A et al. Stereotactic methodology of functional neurosurgery in tumoral epileptic patients. Ital J Neurol Sci 1983;suppl 2:69–82. Chassoux F, Devaux B, Landre E et al. Stereoelectroencephalography in focal cortical dysplasia: a 3D approach to delineating the dysplastic cortex. Brain, 2000;123:1733–51. Tassi L, Colombo N, Garbelli R et al. Focal cortical dysplasia: neuropathological subtypes, EEG, neuroimaging and surgical outcome. Brain, 2002;125:1719–32. Francione S, Nobili L, Cardinale F et al. Intra-lesional stereo-EEG activity in Taylor’s focal cortical dysplasia. Epileptic Disord 2003;5(suppl 2):105–14. Lüders HO, Najm I, Nair D, Widdess-Walsh P, Bingaman W. The epileptogenic zone: general principles. Epileptic Disorders 2006;8(suppl 2):S1–S9. Bernier GP, Saint-Hilaire JM, Giard N, Bouvier G, Mercier M. Commentary: intracranial electrical stimulation. In: Engel J Jr ed: Surgical Treatment of the Epilepsies. New York: Raven Press, 1987:323–34. Landré E, Turak B, Toussaint D, Trottier S. Intérêt des stimulations électriques intracérébrales en stéréo-électroencéphalographie dans les épilepsies partielles. Epilepsies 2004;16:213–25.

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Munari C, Bancaud J, Bonis A et al. Rôle du noyau amygdalien dans la survenue des manifestations oro-alimentaires au cours des crises épileptiques chez l’homme. Rev EEG Neurophysiol 1979;9: 236–40. Munari C, Tassi L, Kahane P et al. Analysis of clinical symptomatology during stereo-EEG recorded mesio-temporal seizures. In: Wolf P ed. Epileptic Seizures and Syndromes. London: John Libbey, 1994:335–57. Chassagnon S, Minotti, Krémer S et al. Restricted frontomesial epileptogenic focus generating dyskinetic behaviour and laughter. Epilepsia, 2003;44:859–63. Bartolomei F, Wendling F, Vignal JP et al. Seizures of temporal lobe epilepsy: identification of subtypes by coherence analysis using stereo-electro-encephalography. Clin Neurophysiol 1999;110: 1741–54 Maillard L, Vignal JP, Gavaret M et al. Semiologic and electrophysiologic correlations in temporal lobe seizure subtypes. Epilepsia 2004;45:1590–9. Quesney LF, Constain M, Rasmussen T, Stephan H, Olivier A. How large are frontal epileptogenic zones? EEG, EcoG, and SEEG evidence. Adv Neurol. 1992;57:311–23. Talairach J, Bancaud J, Bonis A et al. Surgical therapy for frontal lobe epilepsies. Adv Neurol, 1992;57:707–32. Munari C, Tassi L, Francione S et al. Electroclinical semeiology of occipital seizures with occipital seizures with childhood onset. In: Andermann F, Beaumanoir A, Mira L, Roger J, Tassinari CA, eds. Occipital Seizures and Epilepsies in Children. London: John Libbey, 1993:203–211. Palmini A, Andermann F, Dubeau F et al. Occipitotemporal relations: evidence for secondary epileptogenesis. Adv Neurol 1999;81:115–29. Munari C, Francione S, Kahane P et al. Multilobar resections for the control of epilepsy. In: Schmidek HH, Sweet WJ (Eds.), Operative neurosurgical techniques, 3rd edn, vol. 2. Philadelphia: WB Saunders Company, 1995:1323–39. Munari C, Talairach J, Bonis A, Szikla G, Bancaud J. Differential diagnosis between temporal and ‘perisylvian’ epilepsy in a surgical perspective. Acta Neurochir 1980;suppl 30:97–101. Bancaud J, Talairach J. Sémiologie clinique des crises du lobe temporal (méthodologie et investigations SEEG de 233 malades). In: Crises épileptiques et épilepsies du lobe temporal. Proceedings of the VIIème Cours de Perfectionnement en Epileptologie, Rennes, 4–5 April 1991. Documentation médicale Labaz, tome II, 1991: 5–111. Bancaud J, Talairach J. Clinical semiology of frontal lobe seizures. Adv Neurol,1992;57:3–58. Kahane P, Huot JC, Hoffmann D et al. Perisylvian cortex involvement in seizures affecting the temporal lobe. In: Avanzini G, Beaumanoir A, Munari C, eds. Limbic seizures in children. London: John Libbey & Company Ltd, 2001: 115–27. Ryvlin P, Kahane P. The hidden causes of surgery-resistant temporal lobe epilepsy: extratemporal or temporal plus? Editorial review. Curr Opin Neurol 2005;18:125–7. Sivelle G, Kahane P, De Saint Martin A et al. La multilocalité des lésions dans la sclérose tubéreuse de Bourneville contreindique-t-elle une approche chirurgicale. Epilepsies, 1995;7: 451–64.

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DC recordings to localize the ictal onset zone A Ikeda

Introduction Interictal epileptic neuronal discharges were expressed as PDS (paroxysmal depolarization shift) and its pathophysiology has been revealed by abnomal channel activity of the cell membrane labeled as channelopathy, or by excitatory amino acid receptor abnormality, and so on. Furthermore, it is also pointed out that the glia performs important roles in buffering functions that help to maintain the uptake of potassium and glutamate, and other aspects of the extracellular circumstances of neurons.1,2 A change in the microenvironment of the neuron by glial dysfunction could be another important aspect of epileptogenesis. Since it is most likely that focal cortical epileptogenicity is almost always accompanied by gliosis, i.e., abnormally accumulated normal and abnormal glial cells, except for the functionally determined focal epilepsy such as benign rolandic epilepsy, dysfuction of the glia in epileptic focus could be one of the biggest modulating factors. Ictal direct current (DC) shifts reflect not only epileptic neuronal discharges but also passively depolarized glial activity following depolarization of the epileptic neurons, or the glia plays as an amplifier of the ictal DC shifts, as described below, and thus ictal DC recording could provide very important information about core epileptogenicity in patients with intractable partial epilepsy as surgical candidates. In this chapter, clinical application of ictal DC recording is described mainly by means of invasive recording techniques, and its usefulness for surgical candidates with intractable partial epilepsy is discussed.

Ictal DC shifts Generator mechanism and experimental epilepsy When EEG is recorded with an infinite time constant, slow potentials can be recorded as the DC shifts, which are believed to reflect (1) directly the physiological as well as (2) pathological activity of the central neurons and glia.3 DC shifts during generalized seizures induced by various drugs in experimental animals were studied by Goldring et al.4 in the 1950s, and clear negative shifts were associated with initial EEG changes consisting of paroxysmal fast activity. Field potentials recorded during interictal, epileptic activity are transient changes in neuronal membrane potential called PDS occurring in individual neurons.5,6 As the interictal

activity, it starts with steep depolarization which, having exceeded the membrane threshold, triggers a series of action potentials, followed by a plateau for 80 to 100 msec. It is then followed by steep repolarization and further hyperpolarization (Figure 74.1).7,8 As the ictal activity, simultaneous recording of intracellular and extracellular (field) potentials in experimental animals revealed that an intense depolarization of neuronal elements in the epileptic focus is associated with the intense DC negative shifts (Figure 74.2)9, and initially with high frequency discharges. In the 1940s, the experimental model of epilepsy was well developed also by topical application of penicillin, and the observation of slow ictal DC shifts was done by using the DC amplifier in 1965.10,11 In penicillin-induced seizures, DC negative shifts were associated with tonic seizure showing lowvoltage multiphasic pattern. The center of the focus had the surface negative shifts of the highest voltage, and the voltage became gradually smaller with increasing distance from the center. The shifts were positive in the area much further distant from the center.11 Epicortically recorded negative shifts had no reversal of the polarity beneath the center of focus by microelectrode analysis of the field. Maximum negativity was observed at a depth of 1–1.5 mm corresponding to layer V.12 Those findings suggest that the intense negative shifts at the center of the penicillin epileptic focus are related to intense depolarization of pyramidal neurons, i.e., PDS, in that area, and that nearly the entire length of the neurons is depolarized with the source of current flow lying in the axons and dendrites. On the other hand, DC shifts in seizures induced by strychnine had a reverse sign of polarity at 400 micron in depth from the surface, suggesting the different epileptogenicity of the pyramidal neurons from those of penicillin focus.13 The similar DC shifts were also observed in seizures at the hippocampus evoked by electric stimulation.14 Role of glia in ictal DC shifts In addition to intense depolarization of the epileptic neurons, it is also important that glial cell plays a significant role in generating slow cortical shifts.7 Glial cells are intermingled with neuronal structures, and the glial fibers are electrically coupled by low-resistance electrical junctions to build up an extended functional network as a ‘syncytium’.15 Glial cells do not generate action potentials or postsynaptic potentials. However, glial membrane potentials are not constant, and since action potentials of neurons are associated with the 659

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_

abnormal glial function, and (2) possible role of the glia in modulating epileptic activity in the seizure focus.

U

(a)

t Field potential

_ Action potentials

U

Membrane potential + U PDS (paroxysmal depolarization shifts)

(b)

Figure 74.1 EEG (a), and extracellular field potential and membrane potential changes (b) of pyramidal neurons during interictal activity elicited by topical application of penicillin to the cortical surface. The sweep speed in b is five times that in a. (Modified from ref. 7 with permission.)

extracellular potassium concentration increase, it causes depolarization of glial cells (Figure 74.3). If the potassium concentration does not affect the entire glial cell membrane and remains increased only locally, the potential gradients build up along the glial cells, giving rise to intra- and extracellular current flows similar to the ones described in reference to neuronal synaptic transmission. It is also shown that glial, as compared with neuronal, membrane potentials are more sensitive to changes in extracellular potassium concentration in the physiological ranges. Therefore, it is most likely that extracellular field potentials including DC shifts are amplified significantly by glial cells.16 Recently, furthermore, in experimentally produced cortical dysplasia (reactive gliosis), astrocytes surrounding the lesion showed a significant reduction in KIR (the activity of inwardly rectifying K+ channels) and compromised potassium buffering capacity for accumulated extracelluar potassium.2 It thus may suggest (1) the augmentation of the ictal DC shifts by the

Bilateral tonic posturing

Recording technique Clinically, equipments including amplifier and computer hard wares have been currently advanced, and the recent development of epilepsy surgery provided us with the opportunity to investigate ictal DC shifts in human epilepsy. Practically, the DC amplifier is not necessarily essential for recording slow shifts, but an AC amplifier with long time constant could be allowed to record slow shifts as long as the following three conditions are carefully considered from the methodological point of view: 1) the kind of metals used for the electrode, (2) the size of recording surface, and (3) input impedance of the amplifier. With regard to the property of the metal of which electrode is made, a nonpolarized or reversible electrode is essential to minimize electrode potentials which could distort slow potential signals. Currently available nonpolarized electrodes are made of Ag/AgCl. However, nonpolarized metals including Ag/AgCl are toxic to the brain tissue. Therefore, when used as intracranial electrodes, the only metals available are polarized or nonreversible ones, such as stainless steel, platinum, and gold. Each metal has its own electrode capacity as demonstrated by Cooper. (Figure 74.4)17 Among the nonreversible electrodes, platinum is better than either gold or stainless steel to slow potentials. Since the recording electrode could be represented by a series of resistance and capacitance (R-C circuit), it has the property of a low-frequency filter. Capacitance of electrodes, also combined together with the input impedance of the amplifier, acts as a low-frequency filter (LFF). Since the capacitance is proportional to the recording surface of the electrode, the large electrode surface such as subdural contacts minimally attenuates slow potentials; namely, LFF becomes open. On the contrary, depth electrodes which have a small contact surface may hardly record slow potentials.

Bilateral clonic twitching EEG & clinical end

A35–A1

A43–A1

A4–A1

B5–A1 1mV 10sec Figure 74.2 Subdurally recorded ictal DC shifts with the setting of time constant of 10 sec in a 48-year-old patient (right parietal lobe epilepsy). 2–3 Hz rhythmic activity at the A42 and 43 are suddenly replaced by high-frequency, low-amplitude activity and 4 sec later by electrodecremental pattern. A slow negative shift is selectively observed at A43 at that time, and then spread to A35 and B5. (Modified from ref. 18 with permission.)

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0 MP [mV] –40

K+ K+

661

K+ K+ K+ K+

Glia

K+

–80

K+

Glia

K+

t

(a) 0 MP [mV] –40

K+ K+

Neuron

Neuron

K+ –80 0 MP [mV] –40

K+ K+

Glia (b)

t

Glia –80 t

Figure 74.3 Functional linkage between neuronal and glial activities. Increased potassium concentration in the extracellular space close to the glial cell passively depolarizes glial membrane potentials (a). The similar situation in (a) for glial cells is produced by repetitive firing of neurons, and it leads to a sustained depolarization of the neighboring glial cell (b). (Cited from ref. 7 with permission.)

Previously, amplifiers used to have relatively small input impedance less than 1 Mohm, as in Cooper’s experiment in 1963 in Figure 74.4. Huge input impedance of more than 50 Mohm is currently available, which minimizes the effects of electrode potentials. Therefore, under the current recording conditions using an AC amplifier, platinum electrodes can record slow cortical potentials provided that widely-opened LFF, with huge input impedance of more than 50 Mohm, and large electrode contact surface are used. Since stainless steel electrodes recorded slow potentials as well as platinum

electrodes in our previous study,18 the difference electrode capacitance of metals can be overcome by the other factors described here. Therefore, Figure 74.5 represents the property of the metals under the recording condition adopted at that time, i.e., small input impedance (750 kohm) of the amplifier and wire electrodes with a small recording surface. Nevertheless, especially when attempts are made to record with scalp electrodes, the artifact contamination-like movements and galvanic skin responses are still always carefully taken into account, as mentioned later.19–22

VOLTAGE

10 Mv.

CURRENT

10 µA.

SILVER/SILVER CHLORIDE

Ch. 3-8

100 µV

PLATINUM

SILVER COPPER

1 sec

10 GAUGE 2MMS. BAND

input impedance 750korm GOLD

STAINLESS STEEL

Figure 74.4 Characteristics of various metallic electrodes to reproduce a 10 mV, 10 microA square wave input. It was recorded by using a DC amplifier with an input impedance of 750 kohm and electrodes of wire type. (Cited from ref. 17 with permission.)

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Textbook of epilepsy surgery (T.C. = 0.1sec) Fp1-A1 F3 C3 P3 O1 Fp2-A2 F4 C4 P4 O2 F7-A1 T3 T5 F8-A2 T4 T6

– 10sec.

+

100µV

EEG onset

(T.C. = 5sec)

EEG onset – 10sec.

100µV

+

Figure 74.5 Left: Ictal EEG pattern displayed with the conventional LFF setting of 1.0 Hz (time constant of 0.1 sec) recorded by scalp electrodes in a 9-year-old patient with intractable temporal lobe epilepsy. Background activity is first suppressed and a diffuse electrodecremental pattern occurs (as shown by an arrow labeled as EEG onset). Right: Ictal EEG pattern of the seizure shown on the left is displayed with the LFF setting of 0.03 Hz (time constant of 5 sec). A clear negative shift (shown by thick, short bars) started occurring exclusively at F7, F3 and T3, exactly at the time when the diffuse electrodecremental pattern appeared (as shown by an arrow labeled as EEG onset). The peak amplitude of the negative shifts is −300 µV. (LFF = low frequency filter.) (Cited from ref. 19 with permission.)

Scalp-recorded DC shifts in human focal epilepsy Usually scalp-recorded ictal DC shifts are not successfully recorded, because movements during clinical seizures could cause significant artifacts mainly due to the fluctuation of electrode potentials. Recent trials of scalp recording of ictal DC shifts in patients with focal epilepsy suggest its usefulness, although the degree of sensitivity varied between the studies.19–21 We recorded slow ictal negative shifts in four patients (three with neocortial epilepsy and one with temporal lobe epilepsy) who had more than ten seizures per day and thus, the incidence rate of ictal DC shifts were calculated. Scalprecorded ictal DC shifts were observed in 14–40% of all the recorded seizures and were restricted to 1–2 electrodes, very closely related to the onset of high frequency, low-voltage ictal activity (electrodecremental pattern) (Figure 74.5). Those seemed to be absent when the seizures were less intense among many recorded seizures.19,20 It was thus suggested that scalp-recorded ictal DC shifts were highly specific, but the low sensitivity was to be taken into account in clinical applications. Another group also demonstrated that scalp-recorded ictal slow DC shifts were always recorded in 35 recorded seizures from five patients with intractable mesial temporal lobe epilepsy (MTLE), using Ag/AgCl electrodes employing a DC amplifier,21 although their group pointed out the significant effects of non-neuronal generators for scalp-recorded slow shifts at the same time.22 For generalized epilepsy, slow shifts associated with spike and wave complexes were previously observed,23–25 mainly in patients with petit mal. Chatrian et al.26 carefully investigated slow negative shifts and concluded that these shifts occurred during the spike and wave complex paroxysms, and that they were generally unrelated to galvanic skin responses and were not generated by potential changes due to eye movements.

The slow negative shifts never preceded the appearance of spike and wave activity in the EEG, but occasionally would outlast the paroxysm for a brief time.

Ictal DC shifts with invasive electrodes in human partial epilepsy Subdural electrodes Currently invasive recording with subdural grid electrodes is widely used in epilepsy surgery in order to delineate an epileptogenic zone by analysis of ictal and interictal activity, and to map the eloquent zone by electric stimulation or various, sensory evoked potentials. When recording ictal activity in patients with extratemporal lobe epilepsy, intracranial ictal recordings often reveal diffuse or ill-defined ictal patterns, which make localization of the ictal onset zone difficult.27We have investigated ictal DC shifts accompanying clinical seizures from subdural electrodes chronically implanted in patients with intractable partial seizures mainly from the neocortical area. We concluded that, in addition to a careful interpretation of the conventional ictal EEG recording, an analysis of the ictal DC shift could be useful to better localize the ictal onset zone. In our laboratory, ictal DC shifts were investigated from more than 30 patients (mainly neocortical epilepsy and MTLE) with chronically implanted subdural grid electrodes in our laboratory (Figures 74.2, 74.6–74.9).18, 20, 28–31 Commercially available subdural grid electrodes of 3 mm in diameter and 1 cm center-to-center interelectrode distance were used. Electrodes made of platinum were used in all of the patients except for one (Patient 1 in Ikeda et al., 1996)18 in whom ones made of stainless steel were employed. For recording slow EEG shift, instead of DC amplifiers, AC amplifiers having an input impedance of 200 or 80 Mohm were used with a long time constant of 10 sec and high frequency filter

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* A2 A3 A4 A10 A9 EMG (Lt AT) _ 1mV(EEG) 5sec. +

Figure 74.6 Subdurally recorded ictal DC shifts associated with a simple partial seizure (supplementary motor seizure clinically) in a patient with intractable right frontal lobe epilepsy. Just after a large transient positive activity at the time of clinical seizure onset, as demonstrated by tonic EMG discharges from the tibialis anterior muscle (Lt. AT), negative shifts are localized exclusively at A3 and A10. These two electrodes belonged to the ictal onset zone defined by the conventional ictal EEG changes (high amplitude spiking in the later part of ictal period). An arrow indicates the ictal EEG onset, and an asterisk indicates the clinical onset in this figure and also in Figures 74.7–9. EEG is displayed with LFF setting of 0.016 Hz, also in this figure and Figures 74.7–9. (Cited from ref. 20 with permission.)

(HFF) of 100 Hz, and all signals were digitized and stored at a sampling rate of 200 Hz per channel. All subdural electrodes were referenced to one subdural electrode placed over the lateral convexity which, on stimulation, did not elicit any symptoms or show any ictal or interictal epileptiform discharges. As the results, with long-term follow-up of surgical outcome after surgery in our patient group, we analyzed ictal DC shifts in 24 patients with intractable partial epilepsy (19 of them with more than 1 year of follow-up period, mean of 3.9 ± 2.1 years) (16 with neocortical epilepsy and eight with

663

MTLE). The DC shifts were recorded in 23 out of 24 patients (96%) and were observed in 87% of recorded seizures on the average in each patient. The DC shifts predominantly occurred associated with electrodecremental pattern (11 patients: 48%) and with 10–15 Hz rhythmic fast activity (10 patients: 44%). Simple partial seizures associated with 2–4 Hz spike discharges were not associated with slow shifts except for one patient. The slow shifts were mainly negative in polarity. They occurred at or before the clinical onset in 16 patients (70%), and followed in seven patients (30%), most patients of the latter group had the diagnosis of MTLE. It was invariably located in a more restricted area as compared with the epileptogenic zone defined by conventional EEG finding. As seizure control among the 19 patients with more than 1 year of follow-up, 11 patients (58%) were for Class I (Class Ia: 7, Class Ib: 4), 6 (32%) for Class II, and 2 (11%) for Class III. Out of two patients in Class III, one (FLE) with four years of followup, belonged to Class I in the first 2 years, and another (PLE) with 3 years of follow-up, belonged to Class Ib in the first year. It was concluded that 1) subdurally recorded ictal DC shifts in humans were almost invariably recorded regardless of underlying etiology or epilepsy type, and that 2) the more restricted localization can aid in delineating ictal onset zone before surgery. Most of them had a good seizure control without surgical deficits probably because of resection of core epileptogenic zone by means of DC shifts, but some of them had a good seizure control only during initial 1 to 2 years. It may imply that 1) real, core epileptogenic zone was not detected in spite of DC recording, or that 2) those patients newly developed epileptogenicity after surgery.30 Another institute also provided the similar conclusion based on the suddurally recorded ictal DC shifts from the parahippocampal gyrus in five patients with MTLE.32 Judging from the basic experiments as described above, the ictal DC shifts seem to have a close relationship with the electrodecremental pattern seen in conventional EEG recording. These periods are frequently associated with paroxysmal

* B8 B9 B13 B14 B15 B18 B19 B20 EKG EMG (Rt Del) 5sec.

– 500µV (EEG) +

Figure 74.7 Ictal DC shifts were observed at B13,18 and 19 where conventional low amplitude fast activity occurred just 1–2 sec before the onset of DC shifts. It was recorded from a patient with left frontal lobe epilepsy. (Cited from reference 29 with permission.)

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* B13 B14 B15 B18 EMG (Lt AT) (Rt AT) _ 300µV 5sec. +

Figure 74.8 Ictal DC shifts were observed associated with about 1 Hz rhythmic activity in the conventional ictal pattern, but this occasion was less popular. It was recorded from a patient with right frontal lobe epilepsy. (Cited from ref. 19 with permission.)

low-amplitude, fast activity and usually they are also related with a very fast spreading of the ictal activity. Therefore, it is most likely that DC shifts seen with subdural electrodes in human epilepsy is an expression of highly synchronized PDSs of the pyramidal cells which occur in association with maximal intensity and rapid spreading of the ictal activity, leading to rapid involvement of extensive cortical areas. This highly synchronized PDSs of the pyramidal cells may occur relatively early during the ictus but may also occur later. DC shifts occur in close temporal relationship with this sudden seizure spread that could also be associated with a diffuse electrodecremental pattern. The fact that the DC shift is apparently more localized than the electrodecremental pattern and that these electrodecremental patterns in the conventional subdural EEG recording not infrequently occur just at the beginning of the seizures, especially in neocortical epilepsy, and also at least in the middle course of the ictal period at the parahippocampal gurus of MTLE, suggest that the DC shifts could greatly assist us in localizing the epileptogenic zone in human epilepsy.28 Other invasive electrodes Wieser et al.33 successfully recorded the ictal slow negative shifts from foramen ovale electrodes in patients with MTLE.

(The size of input impedance of the amplifier was not described.) In their results, DC records with foramen ovale electrodes were satisfactory during the initial ictal period if the beginning of the clinical seizure was not accompanied by gross movements of head or trunk, and a slow shift was observed even in cases in which spiking was restricted to a small volume of mesio-basal limbic structures and therefore not clearly visible in the simultaneous AC mode record (Figure 74.10).34 Therefore, they concluded that negative epicortical DC shifts recorded by the foramen ovale electrode are a sensitive indicator of epileptic activity within the underlying deeper structures, and that it is clinically useful at least to decide the side of ictal onset. Depth and epidural electrodes failed to record slow ictal DC shits in four patients with the LFF setting of 0.01 Hz on an AC amplifier with an input impedance of 20 Mohm, when they employed stainless steel electrodes with a small recording contact.35 However, recently, ictal slow shifts were investigated (LFF of 0.1 Hz) by means of depth electrodes placed in the hippocampus in 32 seizures of five patients with MTLE, and 84% of the seizures were associated with localized positive slow shifts at ictal onset, ranging from 1.5–11.5 sec. They concluded that ictal slow shifts at the onset of depth-recorded seizures is an excellent visual aid for localizing the epileptogenic focus.36 Clinical significance Ictal DC shifts represent sustained PDSs occurring in epileptic neurons, and thus reflect the nature of the neurons and adjacent glial cells in the epileptogenic area. When recorded in human epilepsy, especially, for presurgical evaluation by means of subdural grid electrodes, negative shifts were observed by currently available equipment: platinum electrodes using an AC amplifier with a very high input impedance (>50 Mohm) and opened LFF (< 0.016 Hz). The recorded slow cortical potentials can aid to delineate an epileptogenic area with high sensitivity and specificity, and thus provide additional information to the conventional ictal EEG findings. However, invasive recording with either depth or epidural electrodes may not record reliable slow shifts probably because recording conditions for DC shifts are not fulfilled technically. In patients with intractable partial epilepsy, especially of neocortical origin, cortical malformation including cortical

*

D3

EMG (Rt AT) _ 500µV(EEG) + 10sec

Figure 74.9 On rare occasion, ictal DC shifts were observed much after the onset of clinical and conventional ictal EEG pattern. It simply reflects that ictal DC shifts occur once a large population of neurons simultaneously discharge, and if it occurs later after the clinical onset, the onset of ictal DC shifts are then observed much after the clinical onset as shown in this figure. It was recorded from a patient with right parietal lobe epilepsy. (Cited from ref. 19 with permission.)

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129 RNA RFO

AC DC

LFO

AC DC

LNA –

5 s

AC: 100µV 0.5 – 70 Hz DC: 2mV DC – 1 Hz

Figure 74.10 AC and DC recordings with right- and left foramen ovale electrode (RFO, LFO) together with stereo-EEG from the right and left amygdalar nucleus (RNA, LNA) during a seizure induced by repetitive, single-pulse electrical stimulation of the right hippocampus in a patient with mesiobasal temporal lobe epilepsy. The arrow indicates the onset of seizure characterized by an olfactory aura. (Cited from ref. 34 with permission.)

dysplasia is one of the most prevalent and disabling causes. Cortical dysplasia or cortical malformation has been relatively well delineated by MRI FLAIR image recently, but frequently it is not visible even by the most powerful machine. It was recommended that the whole area of cortical dysplasia as revealed by MRI should be resected to obtain the best seizure control. Recently, it was shown that resection guided by MRI does not always stop seizures in these patients. Namely, the MRI negative area is also a very important zone for seizure generation in patients with focal cortical dysplasia.37,38 Usually, cortical dysplasia can generate very frequent interictal spikes that mimic ictal discharges because of its long-lasting repetitive discharges.39 In addition, some areas of cortical dysplasia generated scanty spikes or just irregular slow activity.40,41 Since epileptic spikes can reflect the dipoles generated in the cortical layers, cortical dysplasia would not always generate convenional spikes or dipoles, but only ill-defined ones, presumably depending on the degree of distortion of the cortical layers. Ictal DC shifts would be well defined even in cortical dysplasia where cortical layers were distorted, as long as epileptic firing neuronal pools and surrounding gliosis are preserved. In our patient series with subdural electrodes, only one patient so far who showed no ictal DC shifts had cortical dysplasia located within the white matter but not on the cortical surface at all. Ictal DC shifts usually provide information of epileptogenicity which is equally as useful as conventional ictal EEG changes, being thus regarded as redundant information in surgical candidates with very clear seizure focus. However, ictal DC shifts could provide very important information to delineate core epileptogenicity, especially in patients having cortical dysplasia invisible to MRI. In scalp recording in human focal epilepsy, little clinical application has been done so far. From the viewpoint of clinical practice, with currently available equipment as mentioned above, scalp-recorded ictal DC shifts were not sensitively recorded, but once recorded, high specificity may aid in localizing the epileptogenic zone even in scalp-recorded data for presurgical assessment.

High frequency ictal/interictal activity Since highly synchronized PDSs of the pyramidal cells occur at the beginning of seizures or relatively early during the ictus, DC shifts occur associated with an electrodecremental

pattern, i.e., low-amplitude very fast ictal activity. Highfrequency repetitive discharges of more than 100 Hz can also delineate the ictal onset zone in patients with neocortical epilepsy by means of invasive recording.42 Furthermore, discrete burst oscillation between 100 and 500 Hz (such as ripple for 100–200 Hz, and fast ripple for 250–500 Hz) was identified as interictal activity in the epileptogenic area mostly in animal experiments.43 Recently, in patients with both MTLE and neocortical epilepsy, this high frequency activity (100–200 Hz) was well defined in the primary seizure focus or very discrete focus, near the time of seizure onset, and thus it would delineate core epileptogenicity and common property of epileptogenicity regardless of etiology.44 Opening of an analysis window to both extremely slow and fast activity would be very important to add clinically useful information in invasive presurgical recording.

Summary and prospects Ictal DC shifts have been observed in the animal epilepsy experiments, and whose physiological significance was well suggested previously. However, clinical applications or studies in human focal epilepsy was infrequently done until recently, mainly because of the limitation of equipment, including amplifier and computer hardware, especially digital EEG systems. As suggested by animal experiments, at the beginning of seizures, ictal DC shifts most likely occur together as an expression of highly synchronized PDSs of the pyramidal cells which occur in association with maximal intensity and rapid spreading of ictal activity.5,6,10 It also strongly reflects glial function and dysfunction, i.e., passive depolarization as the result of massive depolarization of the epileptic neurons with accumulated extracellular potassium, and its impaired buffering function, respectively. Currently recording techniques have been advanced, and the recent development of epilepsy surgery provides us with the opportunity to investigate. On the other hand, new ictal EEG analysis techniques are required because conventional ictal EEG findings at times fail to localize an epiletogenic zone as seen in cortical dysplasia. Careful analysis of ictal DC shifts will lead us to valuable information with regard to epileptogenicity in human focal epilepsy. Although great technical advances enable us to record and analyze ictal DC shifts in patients having intractable

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partial epilepsy, the condition is not optimal for possible artifacts and unstable electrode potentials even in invasive recording situations, and much more in scalp recording. More suitable recording electrodes and relevant amplifier circuits for DC shifts would enhance clinical usefulness in the near future.

Acknowledgments This study was supported by a Research Grant for the Treatment of Intractable Epilepsy (19-1) from the Japan Ministry of Health, Labor and Welfare, and a Scientific Research Grant (C2) 18590935 from the Japan Society for Promotion of Sciences (JSPS).

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fMRI in the evaluation of the ictal onset zone K Hamandi and JS Duncan

Introduction Functional MRI (fMRI) encompasses the study of neural activity by measurement of alterations in the MRI signal caused by neuronally driven changes in blood oxygenation levels. Magnetic resonance spectroscopy (MRS) whilst also providing information on neuronal function is reviewed elsewhere (Chapter 88). fMRI has a number of advantages over other functional imaging techniques. (1) it is noninvasive, allowing repeated studies in the same patients, (2) the temporal resolution is such that a response to brief neural events can be captured, and (3) spatial resolution is of the order of a few millimetres. This allows the mapping of neural correlates of interictal discharges seen on surface EEG, i.e., the irritative zone during simultaneously acquired EEG and functional MRI (see Chapter 60). Imaging the ictal onset zone however may provide added insights into seizure generation and propagation. Major practical limitations exist. For robust analysis a seizure needs to be captured in its entirety during a scan session and subject motion is a serious confound in fMRI analysis.1,2 Nevertheless, a number of studies have been carried out in individual patients with frequent partial seizures.

Methodological considerations The increases in regional cerebral blood flow in response to neural activity, that forms the basis of many current functional imaging techniques, were recognized over a century ago.3 The extensive blood-flow increase during epileptic seizures was first described after direct visualization of macroscopic changes peroperatively.4,5 This can be captured with SPECT,6 PET,7 and gadolinium-enhanced MRI.8 The rate and spatial extent of the neuronally-driven blood flow increase greatly exceeds that of local oxygen consumption, resulting in a regional decrease in venous deoxyhaemoglobin levels. Oxy- and deoxyhaemoglobin have different magnetic properties.9 A time series of whole-brain images that are sensitive to changes in deoxyhemoglobin levels can be acquired using a fast image acquisition sequence–echo planar imaging (EPI).10 Each brain image or volume is typically acquired in approximately 3 sec. The haemodynamic response reaches a peak at around 5 sec from the onset of neural activity and returns to baseline over 20–30 sec and can be captured in its entirety with fMRI; thus providing an endogenous contrast

agent, termed the Blood Oxygen Level Dependent (BOLD) response.11 The terms ‘activation’ and ‘deactivation’ are operationally defined as increases or decreases in BOLD response, directly linked to neural activity. The signal-to-noise ratio in fMRI is low, a few percent at 1.5 Tesla. BOLD fMRI cannot be used to detect low-frequency state-related changes because of large intersessional variability and scanner noise characteristics. Together with a slow hemodynamic response function (HRF) relative to neural activity, the detection power of fMRI is limited to the narrow frequency band within which most conventional fMRI paradigms operate, i.e., active and rest states alternating, or events occurring, every 20–30 sec. Most commonly fMRI is used to map neural responses to a particular experimental task or stimulus. This is presented either as brief events or blocks, repeated over the course of an fMRI session (typically of 10- to 20-minute duration) to improve signal to noise. Advances in statistical analysis packages and computer processing power allow complex regression analyses to look for areas of significant correlation between the task or stimulus and the fMRI signal time course. A thresholded statistical map (the statistical parametric map or SPM) is used to show the spatial distribution of significantly correlated voxels. Clearly the experimental paradigms used in conventional fMRI studies are not possible in the study of ictal events with fMRI. Early reports of ictal fMRI used a number of exploratory analysis methods. These include visual inspection of image time series, cross-correlation analyses and variance maps; however these lack the robustness of a formal statistical framework. More sophisticated exploratory techniques are being developed, that do not rely on the statistical correlation of an experimental paradigm. These have not yet been applied to imaging seizures. They include principle component analysis (PCA) and independent component analysis (ICA) of fMRI data.12,13 Sources of noise in fMRI include subject motion, respiratory and cardiac effects, scanner noise (low-frequency drifts) and neuro-physiological confounds from changes in the subject’s resting state. Of these, subject motion will cause the greatest change in MRI signal. The type and timing of the motion with respect to the event of interest can have a greater effect than the actual extent of motion. Sudden motion, i.e., jerks, even on the submillimeter scale is sufficient to contaminate data and lead to false-positive activations if it is correlated with the event of interest.2 Similarly changes in heart rate or respiration that can accompany seizures can also affect MRI 667

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signal and confound data.14 Examination of voxel time series for temporal maxima, known as temporal clustering analysis, has been proposed as a means of identifying fMRI changes to interictal activity.15 However a close temporal relationship between subject motion as measured by realignment parameters (the six linear transformations used to realign successive scans to the same space) and the time points of voxels reaching their maximum temporal clusters has been shown.16 The spatial extent of fMRI activations is influenced by the voxel size, and spatial smoothing used during preprocessing to maximize signal to noise ratios. Typical voxel sizes are of the order of 3–5mm, with smoothing of 6–10mm. BOLD fMRI measures changes on the venous side of the circulation, such that large draining veins can result in false activations at a distance from the true neuronal activity.17,18 In the surgical setting errors in co-registration between functional and structural images can occur, in part due to the different distortions inherent in EPI and T1-weighted volumetric acquisitions.19 Where statistical analyses are used, the extent of an ‘activation’ is also influenced by the threshold at which the image is viewed. Finally the spatial extent of the decrease in deoxyhaemoglobin greatly exceeds that of the neural activity driving the haemodynamic changes, ‘watering the garden for the sake of one thirsty flower’.20

Comparison with PET, SPECT, and SEEG Notwithstanding the limitations outlined above, fMRI has a relatively high spatial resolution, of the order of several millimeter’s resolution, and a temporal resolution of several seconds. The correlates of brief neurological events can be captured in a way that is not possible with other neuroimaging techniques. Measuring changes in glucose metabolism or cerebral blood flow with PET has little to offer in directly imaging the ictal onset for the following reasons. For blood flow PET, the radioisotope H215O has a very short half-life, of around 2 min, such that only seizures occurring by chance at the time of prearranged scans could be captured. Glucose metabolism is measured with18 flouro-deoxy-glucose (18FDG). Although the half-life of the isotope18 FDG is around 2 hours, the brain uptake of tracer can take 30 to 45 minutes such that acquired images after injection made at seizure onset will be made up of an amalgam of ictal and postical activity, which compromises localizing value.7 SPECT (Chapter 79), despite its lower spatial resolution has significant advantages over both PET and fMRI in imaging seizures, and at the present time is the only potentially clinically applicable method of imaging seizure onset.21 The most commonly used SPECT tracers, 99mTc-hexamethylproplenamine (99mTc-HMPOA) and 99mTc-ethyl cysteinate dimmer (99mTc-ECD) are stable for several hours. The patient is monitored on the telemetry unit with an intravenous cannula in place and arrangements for isotope injection at the onset of a seizure. The isotope forms a stable bond once it crosses the blood–brain barrier. Patients can then be scanned some hours after the seizure when it is medically safer, and they are better able to lie still in the scanner. Any delay to tracer injection, and the time taken for tracer binding results

in activations in areas of seizure propagation rather than onset.22,23 The relatively low temporal and spatial resolution of SPECT necessitate a careful interpretation of results, taking into account delay to tracer injection from seizure onset, seizure duration, underlying pathology that may affect perfusion, as well as processing strategies used in analysing the images. Subtraction of ictal from interictal scans and coregistration with MRI (Subtraction Ictal SPECT Coregistered with MRI (SISCOM)) improves accuracy.21 EEG remains the optimum modality in studying seizure onset and propagation. However the distance of surface electrodes from the site of seizure onset, the filtering effects of skull and scalp and the lack of a unique solution due to the inverse problem, and rapid propagation of discharges confound dipole source localization.24 Intracranial recordings can overcome this,25 however they are highly invasive compared to functional imaging or surface EEG, and coverage is limited to the immediate vicinity of the implanted electrodes such that clear hypotheses regarding the location of the ictal onset zone are needed before their use.26 The search for a noninvasive imaging modalitiy that can identify the site of seizure onset for surgical resection, or better inform the placement of intracranial electrodes therefore continues.

Ictal fMRI studies Focal epilepsies A total of five case reports of fMRI of ictal activity in humans have been published (Table 75.1), in addition to a study using fMRI to image the preictal state. These are detailed below. Jackson et al. 27 used single-slice fMRI to obtain BOLD sensitive images in a 4-year-old child with Rasmussen’s encephalitis, and frequent motor seizures involving the right face. Images were obtained every 10s from a single slice in blocks of 10 min. Images were analyzed by subtracting baseline images from those acquired during seizures. Analysis was by way of visual inspection. No motion correction or formal statistical analysis was applied. Signal increases were seen in left hemisphere gyri in five clinical seizures. A similar change was also seen during a period that was not associated with a clinical seizure, felt to be subclinical activity. Whilst this case showed the potential of fMRI to detect seizure activity, the contribution of motion effects, caused by the single slice moving in and out of the imaging plane leading to the detected signal changes, remain a possibility. Detre et al.28 described fMRI activation with suspected subclinical seizure activity. The patient had right focal motor seizures, affecting the face. There was no simultaneous EEG recording during fMRI and there was no clinical evidence of seizure activity. Scans were acquired every 4 sec for 11 min. After standard preprocessing with realignment and spatial smoothing, images were displayed as an animated cine loop and inspected visually. Focal signal-intensity changes were seen in the posterior left frontal lobe, which correlated in both duration and spatial localization with ictal activity on EEG. The patient went on to intracranial implantation and surgery. A 1 cm2 area of cortex identified on corticography was resected; pathologic examination revealed chronic gliosis. The resected area, as seen on postoperative structural MRI, showed close spatial concordance with the area of fMRI

Morocz et al. 200333

Salek-Haddadi et al. 200231

30

Krings et al.

Self reporting by button press

Concurrent EEG

None

Clinical observation

Facial movement

Scanner 1.5T Philips Gyroscan Sequence Gradient echo PRESTO TE/TR 35/5000ms, 3.75×3.75mm, slice thickness 3.5mm flip angle 30°

Scanner 1.5T GE signa Sequence Single shot GE-EPI (TE/TR 50/4000 ms, 64×64 matrix, FOV 240mm, 16×5 mm slices no gap). Coverage: whole brain Time resolution: 4s Scanner 1.5T Phillips Gyroscan Sequence Multishot GE-EPI (TE/TR 35/2200ms Voxel size 3×5×5mm flip angle 35°) Coverage: Whole brain Time resolution: 2.2s Scanner: 1.5 GE signa Sequence: GE-EPI (TE/TR 40/3000 64×64 matrix, FOV 240, 21×5mm interleaved slices) Coverage: Whole brain Time resolution: 3 seconds

Scanner 1.5T Siemens SP4000 Sequence Multi shot FLASH (TE/TR 60/85ms, matrix 62×128. FOV 230mm, flip angle 40°

Functional MRI

SPM99, boxcar of inducing music versus non-seizure inducing music; and seizure sessions versus non-seizure sessions

SPM99 according to the general linear model. Modeling of ictal event as boxcar with motion parameters as nuisance covariates

Visual inspection of thresholded percentage change images and time courses from selected clusters

Visual inspection of thresholded percentage change images and time courses extracted from selected cluster. Concordant areas with 3-4% signal increases

Visual inspection of subtraction images and time courses extracted from subsequently selected areas

Analysis

L temporal signal increase during music induced seizures.

L fronto-temporal signal increase with subsequent prolonged undershoot before return to baseline

2 perilesional areas of signal increase and one of decrease, starting 60 seconds before the onset of the seizure

Area focal signal increase concordant with subsequently identified region on corticography

L hemisphere cortical signal increase

Main ictal fMRI finding

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28,29

4 year old male: right sided partial motor seizures of body and face Etiology Rasmussen’s encephalitis MRI L hemisphere thickened cortex with abnormal signal in grey matter Routine EEG Interictal: Widespread slow and occasional L parietal spikes. Ictal: Irregular slow waves over anterior frontotemporal regions preceded by twitching Sedation IV Diazepam 25 yr old male: R focal motor seizures of face Etiology cryptogenic MRI widespread left hemisphere atrophy Routine EEG Interictal: Increased theta during wakefulness Ictal: No definite ictal findings 62 yr old female, Jacksonian march L leg Etiology glioblastoma multiforme MRI R central space occupying lesion Routine EEG Ictal and interictal EEG normal 47 year old male, left frontotemporal electrographic seizure. Etiology cryptogenic MRI normal Routine EEG Interictal: Left frontotemporal spikes 48 yr old female, music induced complex partial seizures Etiology cryptogenic MRI normal Routine EEG Interictal: normal Ictal: left temporal theta and high frequency

Jackson et al.27

Seizure detection

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Detre et al.

Clinical data

Summary of case reports of ictal fMRI studies summarising patient details, data acquisition and analysis methods used and main findings

Reference

Table 75.1

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activation. Further cross-correlation analysis was used to examine time-dependent alterations in regional signal intensity that correlated with signal-intensity changes from this cortical seizure focus.29 Signal changes in the left ventrolateral thalamus showed a high degree of temporal correlation with signal changes in the left frontal cortical seizure focus, suggesting functional connectivity between the thalamus and the cortical focus. Krings et al.30 reported on a patient with a right frontal glioma. She was experiencing up to five events an hour at the time of the study. A 33-sec Jacksonian march involving the left leg with ‘calf shaking’ was imaged with fMRI. One hundred and two scans were acquired with a temporal resolution of 2.2 sec per scan, i.e., around 3 min of scanning. An automated image realignment algorithm was used to minimize the effects of interimage motion-related artifacts. For each voxel, the percent change in T2* signal fluctuations was calculated for each time point, against a baseline (mean of MR signal of the first 20 images of a given voxel). These were color coded on a thermal scale, overlaid onto an anatomical image and visualized by scrolling through the functional images in an animated loop. Only voxels exhibiting percentage signal changes larger than 1.5% from baseline were visualized to minimize random MR signal noise. Three perilesional areas with signal intensity changes related to seizure activity were seen with signal changes of between 2.2–3.5%. The temporal evolution of signal change in each of these regions differed, beginning at 60 seconds before (an increase of up to 2.2%), 30 sec before (a decrease of up to 3.5) and at the onset of the seizure (an increase of up to 3.1%). The last region was in the left foot area as determined by previous motor fMRI. It is not clear from the report whether changes of similar percentage changes were seen elsewhere in the brain at other times during scanning. A temporal resolution of 2.2 sec is too slow to allow imaging of the propagation of electrical activity. The authors conclude: the identification of cortical areas with different types of hemodynamic seizure-related changes may help in delineating seizure generators from areas with propagated activity, even if the propagation time is too fast to be detectable with fMRI. Salek-Haddadi reported a case of ictal fMRI based on an electrographic seizure recorded on simultaneous continuous EEG.31 The simultaneous recording of EEG during fMRI being necessary to fully correlate ictal activity with fMRI measures. A 47-year-old man with frequent partial and secondarily generalized seizures was scanned with continuous EEG and fMRI (EEG-fMRI) for 35 min (700 scans), as part of a study of interictal epileptiform discharges. An electrographic seizure, with a focus at F7/T3 of approximately 40 sec occurred early into the study. Images were realigned to the same space and spatially smoothed. fMRI data was analyzed according to the general linear model, with the recorded seizure as an effect of interest and the realignment parameters as nuisance covariates. An extensive area of activation was seen extending posteroinferiorly from the left insular gray matter, through the temporal lobe insula, along the superior and middle temporal gyri to the left fusiform gyrus; anteriorly to the left inferior frontal gyrus; and superiorly up to the left inferior parietal lobule. A smaller cluster was also evident within the gray matter of the ipsilateral

cingulate gyrus. The mean signal rise was 2.5% (maximum 5.5%) with a prolonged undershoot (Figures 75.1–3). The undershoot most likely represented more prolonged oxygen consumption, following the peak in blood flow response, than is seen in the normal physiological HRF. The authors stress the importance of a robust statistical framework for the analysis of ictal fMRI. Reflex epilepsies The reflex epilepsies32 although rarely, if ever considered for resective epilepsy surgery provide unique opportunities to study the epileptogenic zone with fMRI, given that ictal events can be induced during fMRI scanning; once appropriate ethical considerations and consent have been addressed. Morocz et al.33 studied a 48-year-old woman with music induced complex partial seizures. Scanning took place in blocks with previously identified ‘epileptogenic’ music alternating with music that was known not to induce seizures. Statistical analysis revealed two patterns of BOLD signal change, one related to the actual triggering of music-induced seizures in the left anterior temporal lobe, the right gyrus rectus and ventral frontal lobes, and the other related to exposure to the specific epileptogenic music in the orbitofrontal lobes only. The authors speculate that emotional processing of music in the orbito-frontal areas may have initiated the seizure cascade. Reading epilepsy is characterized by brief jaw jerks associated with EEG spikes when reading specific texts. Generalized seizures can follow if reading persists in the face of increasing jaw jerks. Archer et al.34 studied two patients with spike triggered fMRI and reading epilepsy. Subjects read text back projected onto a screen during fMRI scanning. EEG was recorded continuously and scanning was triggered 2.5 sec after the occurrence of an EEG spike to acquire one brain volume. An identical ‘rest’ volume was acquired after a 20-sec period of no spikes. fMRI of a standard reading task was also acquired using a 30-sec block design of reading text versus fixating on a cross hair. Spike versus rest scans were compared by means of an unpaired t-test. Reading-related spike activity was seen bilaterally in the inferior precentral gyrus, central sulcus, basal ganglia, and globus pallidus. Signal change of 2.5% in cortex and 1% basal ganglia was seen in association with jaw jerks and spikes. Koepp and Salek-Haddadi (unpublished work) studied nine patients with reading epilepsy using an MRcompatible system for scalp-EEG, submental EMG, lefthanded button press, and online audio recording to detect reading-induced orofacial myocloni (ORM). Language and motor (hand/mouth) mapping did not show any abnormalities, compared to normal subjects. One patient had abundant ORM in association with left-frontal spikes occurring on silent reading. In a further five patients, symptoms were only elicitable on reading aloud so events were selfindicated. Induced spikes or jaw jerks were associated with consistent activation patterns within left motor and premotor areas in five of these six patients, in Brodman area (BA) 47 in 2/6, in the striatum (4/6) and thalamus (2/6). Taken together these studies demonstrate the potential cortical and subcortical circuitry involved in reading induced seizures.35

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fMRI in the evaluation of the ictal onset zone (a)

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(b)

SPM{F7.479,288.6}

SPM{T294.5}

P 20 seconds),20 and a relatively high false positive rate (e.g., 1/hour) is tolerable.19,48 The detection algorithm described by Gotman18,19 was one of the first successful trending seizure detectors. It has been tested on both scalp and intracranial EEG recordings, and is now commercially available (see Stellate Section). Gotman noted that the majority of seizures contained paroxysmal, sustained rhythmic activity with a fundamental frequency between 3 and 29 Hz at some point during the event.18 Thus, the detection algorithm focused on detecting paroxysmal rhythmic activity within those frequencies. First, the EEG signal is low-pass filtered and decomposed into half-waves (elemental segments that are representative of the amplitude and frequency of the signal). Aggregate measures of the halfwaves within an epoch, such as the average amplitude, average duration, and coefficient of variation of the duration are extracted for each epoch. A detection occurs when the average half-wave amplitude in the current epoch is significantly greater than the background, and the coefficient of variation and average half-wave duration are within a specified range, indicative of rhythmic activity. The current epoch is defined by a short window (e.g., 2 seconds) and the background is defined by an extended window (e.g., 16 seconds, ending 12–20 seconds prior to the current epoch). This algorithm was further extended in 1990 to include a second ‘background’ segment after the current epoch (e.g., 8 seconds).19 The second background was included to reduce the number of false detections due to short events. Qu and Gotman (1993)21 later extended the algorithm again by incorporating false seizure detections from earlier monitoring sessions of an individual patient to further reduce the false-positive rate during subsequent sessions of the same patient. However, the limitation of all of these detection algorithms is that seizures consisting of irregular EEG with mixed frequencies as well as low-voltage fast events that are not followed by high-amplitude rhythmic activity can be missed. A similar trending seizure detection method was developed specifically for intracranial EEG recordings.48 This algorithm was designed to detect both high-frequency and high-amplitude activity. The absolute magnitude of sample-to-sample differences is calculated, where a large magnitude is indicative of a steep slope or rapid change in the signal. Within each 5-second epoch, the number of large magnitude differences is counted. A seizure is detected when a segment has an increased count compared to the running average counts of

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the background. The advantage of this system is that it detects high frequency activity very well. However, it may be insensitive to some low frequency events. Another implementation using the trending approach was reported by Osorio et al.12 This algorithm was developed specifically to detect seizures in real-time. In this algorithm, the signal is first filtered using a wavelet transform that is sensitive to power changes between 5 and 45 Hz. Then the signal is filtered using a non-linear median filter to rapidly detect changes while overlooking very brief signal changes. The final step compares the median power of the current epoch (2 seconds) to a background (30 minutes, smoothed with exponential forgetting). This algorithm results in earlier detection54 and shorter detection latencies (3.6–5 seconds)37 than the algorithms discussed above. It also includes several manuallyadjustable parameters associated with frequency band, filter percentile, background length, and patient-specific optimization. However, atypical seizures will still go undetected, which is a problem for patients who do not have a stereotyped electrographic seizure onset. Also, seizures that contain frequencies outside of the frequency range specified can go undetected.37 Preclassification-based seizure detection algorithms A second category of seizure detection algorithm leverages statistics derived from previously classified EEG to properly sort novel EEG into seizure and non-seizure categories. These prior data are used either to train a classification algorithm, such as an artificial neural network, or to provide a prior distribution for Bayesian methods. Preclassification-based algorithms differ from each other in two main facets: (1) the extracted EEG features used for detection and (2) the method used to classify the EEG. Feature extraction As with trending-based detection, the first step in a preclassification-based algorithm is to identify a feature or set of features upon which detection is determined. Relevant features can include statistics describing temporal features of the data, such as RMS amplitude,55 or measures of the frequency content.55–57 Three types of frequency analysis are commonly used in feature extraction: the Fourier transform, wavelet transform, and matching pursuit decomposition. Frequency analysis methods involve a tradeoff between time and frequency resolution. This tradeoff governs the method’s robustness to transient noise, ability to represent rhythmic behavior, and to some extent detection response time. The Fourier transform and its derivatives (e.g., short-term Fourier transform and fast Fourier transform) have long been used to analyze EEG frequency content.58 The Fourier methods are efficient and easy to implement. However, they are subject to broadband spectral interference in response to abrupt frequency changes because the time resolution is uniform across the frequency spectrum. This property negatively affects accurate characterization of EEG frequency in the presence of fast transients such as spiking.58,59 Wavelet-based frequency analysis provides excellent time resolution at higher frequencies and good frequency resolution at lower frequencies. Unlike Fourier analyses, where the signal is decomposed into sine and cosines, in wavelet analyses, segments of the signal are decomposed using a family of

finite functions called ‘wavelets’. In a family of ‘wavelets’, the primary waveform or ‘mother’ wavelet is scaled and shifted to form the ‘daughter’ wavelets, thus allowing for increased temporal resolution at higher frequencies. This property minimizes the broadband distortions due to brief spiking or sharp-wave transients seen in Fourier-based analyses. The discrete, wavelet transform is commonly used for EEG frequency analysis.10,60,61 Khan and Gotman62 compared a discrete wavelet-based trending detector to a prior Gotman trending detector, attaining equivalent sensitivity with an 86% decreased false-positive rate. Finally, the matching pursuit algorithm, a similar nonlinear signal decomposition method (further discussed in the Persyst Reveal Section), provides extensive flexibility in managing the time-frequency resolution trade-off, even within a single frequency band.55 The matching pursuit algorithm is robust against sharp transients and shows good frequency resolution within seizure EEG.55,57 Wilson et al.55 use matching pursuit in their commercialized Reveal algorithm, reporting satisfactory improvements in both accuracy and false-positive rate as compared to their previous fast-Fourier transform (FFT)-based detector.63 Classification The second step of preclassification-based seizure detection algorithms is to categorize novel EEG data based on the features of preclassified EEG. Three approaches are commonly used for classification: artificial neural networks (ANNs), support vector machines (SVMs), and Bayesian methods. Artificial neural networks describe a class of methods where ‘neural networks’ are trained to categorize EEG epochs as either seizure or non-seizure based on a manually preclassified set of EEG examples. The training or learning phase is typically an iterative process that generates rules to minimize the cost function or error. After the initial training, new EEG data are classified based on the rules created during the initial learning phase. Thus, the examples used in the training set are critical to the success of an ANN approach.64,65 In the Reveal algorithm, matching pursuit-based feature vectors are processed through both ANN-generated and hypothesis-driven rules. The algorithm achieved competitive sensitivity with exceptionally low false-positive rates.55 ANNs have also been used heavily in other automated seizure detectors over the last decade.63,65–68 Support vector machines use preclassified data to calculate a border that maximally separates the boundary cases of nonseizure EEG and seizure EEG. Novel data are then classified by where they fall relative to the defined border. In a patientspecific study, Shoeb et al.10 combined this classification method with a wavelet-based analysis to achieve competitive true-detection rates for novel EEG data with a relatively low false-detection rate. The group noted their SVM classifiers’ robustness to class-imbalanced training data, a property highly applicable to seizure detection due to the usual scarcity of seizure EEG relative to non-seizure EEG. Other theoretical advantages of the method include robustness to over-fitting, a guarantee of global optimization, and relatively low increase in model complexity with increasingly large feature vectors. The Bayesian method of seizure detection described by Saab and Gotman (2005)11 classifies novel EEG epochs by calculating the likelihood of the epoch being seizure data given prior probabilities from preclassified EEG data. This calculation assumes

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Automatic detection of epileptic seizures that the features in the data are independent, characterized by Gaussian distribution, and differentiable by class (e.g., have different mean and/or variance in seizure versus non-seizure EEG). When a novel EEG epoch is introduced, the formulation uses Bayes’ theorem to calculate the probability that an epoch belongs to the seizure class. If a measure based on that probability crosses an arbitrary threshold, it is classified as a seizure. This method also provides controls for balancing detector sensitivity against false-detection tolerance. The group observed sufficiently improved sensitivity to a previous method,19 and sufficiently fast execution time to merit further exploration of the classification method in real-time seizure detectors. Advantages and disadvantages Preclassification-based seizure detection algorithms offer certain advantages relative to trending-based algorithms. When employing the right technologies in a patient-specific context, excellent detector performance can be achieved at a low false-positive rate.10,55 Moreover, establishing these classification-based algorithms may require less manual manipulation of parameters than some trending-based detectors (e.g., half-wave), as rule and threshold development can occur mostly in the machine-based classifier. This family of methods also has disadvantages relative to trending algorithms. Shoeb et al.10 found that their preclassification-based detector performed poorly when used in a general clinical setting due to dissimilarity between training examples and new patient EEG data. Although this could also occur with most trending-based detection algorithms, the latter can be corrected by quickly altering trending parameters and thresholds whereas preclassification-based detectors may require training on possibly hours of data for each new patient, depending on their seizure rate. One group controlled for this effect by exclusively extracting normalized EEG features.11 Another disadvantage of these methods is that they can only detect those seizure types that have been previously observed and hand-classified in a training set, requiring additional training in the case of a patient’s newly observed seizure type. State-based algorithms A third category of seizure detection algorithms identifies a seizure state, irrespective of the recent background activity or previously categorized seizures. These algorithms are not dependent on the relative changes in the signal; rather they measure the absolute state of the current epoch and compare that state to a non-seizure state, which is either defined previously or acquired from the data. State-based detection algorithms operate by identifying the one feature or set of features (often non-linear) of the electrographic activity that is most representative of the seizure state. Several such features have been identified in the literature, including total energy, power, or variance,49,69 Lyapunov exponents,70 Kolmogorov entropy,71 and minimum description length.72 With this class of detection algorithms, detection may often occur seconds to minutes before the electrographic onset (as identified by the epileptologist). Therefore the distinction between seizure detection and seizure prediction becomes less clear, and these techniques are sometimes referred to as methods for ‘early’ seizure detection, seizure anticipation, or preseizure state detection.73

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The earlier methods to detect a change in state were based on the power or variance of the signal, either within a specific frequency band or across all frequencies. This method of detection is simple and requires minimum computational power. Detection occurs when power within a frequency band is above a threshold.69,74 In some cases changes in the accumulated energy occurred as early as 50 minutes before the electrographic onset.74 More elaborate state-based methods make use of nonlinear dynamics for seizure detection.70,75,76 These techniques focus on the change in the predictability or chaos of the neural system prior to or during the seizure. Iasemidis et al.70 proposed the use of the short-term Lyapunov exponent, a measure of the short-term predictability in a non-linear dynamic system. They found that during a seizure, the maximum short-term Lyapunov exponent is reduced, indicating decreased chaos and increased predictability of the system. The Kolmogorov entropy, another measure of the complexity of a dynamic system, describes the level of uncertainty about the future state of the system. As with the Lyapunov exponent, the Kolmogorov entropy has been shown to decrease prior to a seizure with detection of a trend as early as 40 minutes before the electrographic onset.71 Minimum description length is yet another way to define the complexity of the signal by estimating the minimum number of bits needed to describe the data.72 This method has been proposed for neonatal seizure detection, where seizures are typically very rhythmic, and therefore defined by a low minimum description length. Other similar measures such as correlation dimension73 and multidimensional probability evolution77 have also been proposed. For all of these non-linear dynamic methods, the main drawback is that they often require a large amount of stationary data to estimate parameters, and the computational complexity may be difficult to implement in real-time, particularly for ambulatory or implantable applications.

Clinical implementations Commercial seizure detection algorithms There are two major commercially available seizure detection systems; they are provided by Stellate Systems, Inc. (Montreal, Quebec, Canada), and Persyst Development Corporation (Prescott, Arizona). Stellate offers five different specialized seizure detectors: (1) a seizure onset detector, (2) a seizure pattern detector, (3) Icta-S for scalp EEG, (4) Icta-D for intracranial recordings, and (5) a newborn seizure detector. In addition to these stand-alone seizure detectors, several companies have incorporated Stellate algorithms into their EEG monitoring systems. Persyst offers their Reveal seizure detection algorithm. These commercially available algorithms employ a combination of the techniques and methods discussed above. All of these seizure detection algorithms can be run either on-line or off-line. Stellate The detection algorithms that are available in the Stellate package are summarized here; they are described in detail in several prior publications.11,18,19,51,78

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The Stellate seizure and onset pattern detector algorithm evaluates each EEG channel individually by comparing a brief (2 seconds) epoch sliding window with a background sliding window (15–16 seconds). The epoch and background windows are separated by a gap (12–20 seconds).19 The EEG signal is decomposed into half-waves and subsequent analysis is based on these half-waves. The seizure detector is triggered when several conditions are met:

amplifier saturation. Epochs containing excessive artifact, based on amplifier saturation and maximum amplitude excursion, are rejected. Several hand-coded and data-trained neural net functions are used to identify rhythmicity and seizure events based on features of the atoms and epochs. Additionally, a clustering function is applied to a moving 60-second window to group consecutive epochs based on similarity into background, seizure and offset sections. These functions are described below.

1. The epoch amplitude must exceed the background amplitude by a specified value. 2. A candidate detection must occur in the same or the following epoch on a specified number of channels. 3. The frequency of the candidate seizure must exceed a specified value. 4. The coefficient of variation within the epoch, which is inversely correlated with rhythmicity, must be below a specified value.

1. A hand-coded function computes a ‘rhythmicity’ value for each atom that is maximized when the atom half-waveamplitude, atom-half-wave-slope, atom-half-wave-count, and atom-duration are maximized. 2. A neural net function computes a ‘distinguished-fromwindow’ value that indicates how well an atom is distinguished from the window based on atom-amplitude, atom-duration, and atom-frequency. 3. A hand-coded function computes a ‘seizure-score’ for the epoch that is maximized when the previously computed rhythmicity and distinguished-from-window values are maximized. 4. A neural net function calculates a ‘seizure-candidate’ value based on seizure frequency and the seizure score. 5. A neural net function calculates a ‘seizure-is-perceived’ value based on the candidate seizure duration, the seizurecandidate value, and the absence of exceptionally high maximum amplitudes, indicative of artifacts. 6. A neural net function calculates a ‘composite-seizure-isperceived’ value based on the first- and third-best channels seizure-is-perceived values, as well as the amplitude and frequency differences between successive epochs.

The Icta-S algorithm is optimized for scalp EEG recordings. This algorithm is based on Bayes’ formula and uses features and probabilities developed from a training data set to probabilistically determine whether a seizure has occurred. Epochs of 2 seconds are compared with a 30-second baseline period, separated by 1 minute.11 Epochs with a high seizure probability affect the seizure probability of the following two epochs. As with the seizure and onset pattern detectors, amplitude, frequency, and coefficient of variation are used to identify candidate seizure epochs. The Icta-D algorithm is optimized for intracranial recordings, which contain more variability in patterns, amplitudes and frequencies. It differs from the Icta-S algorithm in that epochs of 4 seconds are compared with 2-minute baseline periods.78 Also, it was trained on intracranial data instead of scalp EEG. The neonatal seizure detector combines three detection algorithms: (1) detection of rhythmic discharges, (2) detection of multiple spikes, and (3) detection of slow rhythmic discharges. A spectral analysis method is used to detect rhythmic discharges of 0.5–10 Hz using overlapping 10-second epochs compared to 20 seconds of background, separated by a 60-second gap. Multiple spikes are identified within high-pass filtered, 10-second epochs. Only spikes above a specified threshold are counted and the number of spikes within a 10-second epoch must exceed a minimum value. Slow rhythmic discharges less than 0.5 Hz are detected using low-pass filtered EEG data and the same half-wave and trending-based analysis method as described in Gotman (1990),19 using overlapping 10-second epochs compared to a 20-second background, separated by a 60-second gap.51 Persyst Reveal The Persyst Reveal algorithm is described in detail by Wilson et al. (2004)55 and summarized here. In this algorithm, EEG data are filtered and downsampled to 32 Hz, restricting the maximum frequency analyzed to 16 Hz. Each channel of the data is segmented into 2-second epochs with a 1-second overlap. A matching pursuit decomposition is applied resulting in a set of Gabor ‘atoms’, describing the time-frequency evolution of each 2-second epoch; only the first two atoms are selected for the analysis. Epochs are also described by total RMS amplitude, maximum amplitude excursion, and summed duration of

NeuroPace® RNS™ system The NeuroPace RNS System is an implantable system capable of performing real-time seizure detection and responsive electrical stimulation (Figure 77.1, Figure 77.2). At this time, the system is being evaluated in clinical trials to assess the safety and efficacy of responsive neurostimulation for the treatment of medically intractable partial-onset epilepsy. The implantable components of the system include (1) a neurostimulator, which senses and stores electrographic activity, performs detection, and delivers electrical stimulation; and (2) chronically implanted depth and strip leads, which are used to sense and provide stimulation. The external components include (1) a Programmer, used to program detection and stimulation settings and retrieve stored information (e.g. electrographic activity) from the neurostimulator; and (2) a wand, which allows wireless communication between the neurostimulator and the Programmer. A patient data transmitter is also provided, to allow uploading and monitoring of device data between clinic visits. These data are uploaded via the Internet to a central patient data management system, and may be reviewed by physicians. Detection algorithm The detection algorithms implemented in the RNS Neurostimulator are designed to be computationally efficient and highly optimized in order to perform real-time seizure detection within the constraints of currently available

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Figure 77.1 Schematic illustration of the implanted RNS Neurostimulator, depth lead and cortical strip lead. The RNS Neurostimulator (inset) is designed to match typical skull thickness and curvature, and is intended for implant in a ferrule, or socket, placed in a craniectomy. Up to two leads may be used with the system; each may be a depth lead or cortical (subdural) strip lead, and each has four electrode contacts, which are used for sensing and providing stimulation. In order to provide early seizure detection and delivery of focal electrical stimulation, leads are positioned using standard neurosurgical techniques as close as possible to the seizure focus or foci.

implantable technology, such as limited power and processing capabilities. Three fundamental detection algorithms (or tools) are provided, which are based on the half-wave, line length, and area features extracted from the EEG. The detection tools are highly configurable and can be adjusted by the physician to optimize the sensitivity and specificity trade-off for each individual patient. The tools can also be combined to yield even more specific detection.

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The half-wave algorithm used in the RNS System is similar to that of Gotman (1982),18 and is used to detect spikes and rhythmic activity occurring in specific frequency ranges. The neurostimulator segments the EEG at local minima and maxima (excluding deviations smaller than a programmed threshold), resulting in half-waves the amplitude and duration of which are representative of the amplitude and frequency components of the EEG. Half-waves that exceed a physicianprogrammed amplitude and duration are counted; the number of these half-waves occurring within a given window length must exceed a certain threshold for detection to occur. The line length algorithm, described by Esteller et al. (2001),79 is similar to fractal-dimension measures and is used to identify changes in both amplitude and frequency. The line length is defined as the average of absolute sample-to-sample differences within a window. A short-term sliding window average is compared to a long-term sliding window average. The short-term window and long-term window durations can be configured to optimize detection of specific features. A detection occurs when the short-term measurement exceeds an absolute or relative threshold (Figure 77.3). A negative threshold can also be used to detect decreases in line length, which may represent a period of electrodecrement or decreased frequency. The area feature,80 is similar to an energy or power measurement81 and is used to identify changes in overall signal energy without regard for frequency. Area is defined as the average absolute area-under-the-curve within a window. As with line length, a short-term window average is compared to a longterm background window average, and detection occurs when positive or negative threshold is exceeded (Figure 77.3). The output of the half-wave, line length and area tools from the same or different EEG channels may be combined to identify specific electrographic events. In addition, the output of a tool may be assigned a persistence duration to facilitate detection of events in sequence. For instance, a seizure onset consisting of a series of spike-wave events followed by elevated gamma might be identified by a half-wave spike detector, given several seconds of persistence and a line-length detector sensitive to the increase in frequency.

Figure 77.2 Example of a possible seizure termination by responsive stimulation. The upper panel shows the FFT spectrogram and time series for a single cortical EEG channel. The lower panel shows a close-up of the time series around the time of termination. In the time series plots, detection is indicated by the vertical blue line and the ‘B’ label, and responsive stimulation is indicated by the vertical red lines and the ‘Tr’ labels (the first is partly obscured by the ‘B’ label). (See Color plates.)

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Figure 77.3 Demonstration of the line-length and area algorithms. The upper panel shows the FFT spectrogram and time series of a single cortical EEG channel at a seizure onset. The middle panel displays the data represented by the short-term (red) and long-term (blue) line length features. In this example, the short-term window is 2 seconds and the long-term window is 30 seconds. Detection occurs when the short-term trend exceeds the long-term trend (e.g., at ~59 seconds). The bottom panel displays the detection using the area algorithm. As with the line-length algorithm, detection occurs at ~59 seconds and redetection occurs at 70 seconds. Note that the line-length detection is sensitive to both changes in frequency and amplitude, whereas the area detection is sensitive to amplitude. (See Color plates.)

Advantages Implantable systems have the unique advantage of operating on a chronic, continuous and relatively artifact-free stream of electrographic data from an ambulatory subject. This information is valuable to both the clinician and researcher, and has been used to study such topics as circadian variation in the intracranial EEG.82 These data can be further used to optimize seizure detection for a given patient, or to control responsive stimulation delivered by the implantable device. In addition, bipolar signals recorded and analyzed by an entirely-implanted device are particularly resistant to external noise.

Moreover, the complexity of a device increases drastically as more channels are added. While in-hospital epilepsy monitoring may use grids of 64 or more contacts, implantable devices are currently limited to far fewer contacts and channels. This means that localization must be determined with some accuracy before use of an implantable device. It is expected that these boundaries will expand greatly as technology advances; however, implantable applications of seizure detection will always be constrained by the resources available in a small, chronically implanted device.

Conclusions Limitations of implantable technology These advantages do not come without limitations; at present implantable seizure detection is technologically constrained in comparison with methods proposed for off-line or nonimplantable applications. This is due to many factors, including limited power, computational restrictions, and limitations in electrode placement. An implantable device must either be rechargeable or possess a battery life on the order of years. In either case, the power available to perform seizure detection is strictly limited. This manifests as a limit on clock speed for the implantable microcontroller. Whereas current desktop computers may perform more than 109 operations per second, an implantable device may be constrained to fewer than 106 operations per second. Detection tools are constrained to those that may be reasonably implemented in low-power digital hardware. This may require discrete approximations to complex methods, such as line length for fractal dimension.

Automated seizure detection is a rich problem area for signal analysis. A range of algorithms have been developed for this purpose. Each of the approaches has its own strengths and weaknesses, owing to the complexities of seizure waveforms, tradeoffs between sensitivity and specificity, tradeoffs between accuracy and latency, and platform constraints. In this chapter, we have reviewed a number of computational algorithms for seizure detection. While the field has grown in leaps and bounds over the past three decades, there is still no single solution to the complex problem of automated seizure detection, and there may never be. As the field continues to develop along with the acceleration of computer technology, we expect advancement in the area ‘state-based’ or early seizure detection algorithms as well as significant progress in ambulatory and/or implantable detection systems. These developments will be invaluable to the understanding and treatment of epilepsy.

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van Drongelen W, Nayak S, Frim DM et al. Seizure anticipation in pediatric epilepsy: use of Kolmogorov entropy. Pediatr Neurol 2003;29:207–13. Celka P, Colditz P. A computer aided detection of EEG seizures in infants: a singular-spectrum approach and performance comparison. IEEE Trans Biomed Eng 2002;49:455–62. Jerger KK, Netoff TI, Francis JT et al. Early seizure detection. J Clin Neurophysiol 2001;18:259–68. Litt B, Esteller R, Echauz J et al. Epileptic seizures may begin hours in advance of clinical onset: a report of five patients. Neuron 2001;30:51–64. Lehnertz K, Widman G, Andrzejak R, Arnhold J, Elger CE. Is it possible to anticipate seizure onset by non-linear analysis of intracerebral EEG in human partial epilepsies? Rev Neurol (Paris) 1999;155:454–6. Le Van Quyen M, Martinerie J, Navarro V, Baulac AM, Varela FJ. Characterizing neurodynamic changes before seizures. J Clin Neurophysiol 2001;18:191–208. McSharry PE, He T, Smith LA, Tarassenko L. Linear and non-linear methods for automatic seizure detection in scalp electroencephalogram recordings. Med Biol Eng Comput 2002;40:447–61. Grewal S, Gotman J. An automatic warning system for epileptic seizures recorded on intracerebral EEGs. Clin Neurophysiol 2005;116:2460–72. Esteller R, Echauz J, Tcheng T, Litt B, Pless B. Line length: an efficient feature for seizure onset detection. In: Proc 23rd Annu Int Conf IEEE Eng Med Biol Soc 2001;2:1707–1710. Echauz J, Esteller R, Tcheng T et al. Long-term validation of detection algorithms suitable for an implantable device. Epilepsia 2001;42(suppl 7):35–6. Litt B, Esteller R, D’Alessandro M et al. Evolution of accumulated energy predicts seizures in mesial temporal lobe epilepsy. Proc 1st Joint BMES/EMBS Conf 1999;1:440. Duckrow RB, Tcheng TK. Daily variation in an intracranial EEG feature in humans detected by a responsive neurostimulator system. Epilepsia 2007;48:1614–20.

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‘Preictal’ predictors of epileptic seizures F Mormann, K Lehnertz, and CE Elger

Outline of the chapter Our understanding of the mechanisms that lead to the occurrence of epileptic seizures is rather incomplete. If it were possible to identify preictal precursors from the EEG of epilepsy patients, therapeutic possibilities could improve dramatically. First attempts to predict the occurrence of seizures from EEG time series were started in the 1970s. Studies on seizure prediction have since then advanced from preliminary descriptions of preictal phenomena and proof of principle studies via controlled studies to studies on continuous multi-day recordings. Following the mostly promising early reports, the recent years have witnessed a debate over the reproducibility of results and suitability of approaches. The current literature is inconclusive as to whether seizures are predictable by prospective algorithms. Prospective out-of-sample studies including a statistical validation are missing. Nevertheless, there are indications of a superior performance for approaches characterizing interactions between different brain regions by means of quantifying relations between signals from different recording sites. Prediction algorithms must be proven to perform better than a random predictor before prospective clinical trials involving seizure intervention techniques in patients can be justified. In this chapter we will critically review the literature from the emerging field of seizure prediction and discuss the problems and pitfalls associated with the design and evaluation of seizure prediction algorithms.

Introduction To epilepsy patients for whom complete seizure control can not be achieved, e.g., by medical or surgical treatment, it is the sudden, unforeseen way in which seizures strike ‘like a bolt from the blue’ that represents one of the most disabling aspects of the disease. Apart from the risk of serious injury, there is often a severe feeling of helplessness that has a strong impact on the everyday life of a patient. It is obvious that a method capable of predicting the occurrence of seizures could significantly improve the therapeutic possibilities1 and thereby the quality of life for epilepsy patients. A question of particular interest is whether apart from clinical prodromi, which are found only in some patients,2,3 characteristic features can be extracted from the continuous EEG that are predictive of an impending seizure. If it were possible

to reliably predict seizure occurrence from the EEG of epilepsy patients, therapeutic concepts could move from preventive strategies (e.g., long-term medication with AEDs) towards an on-demand therapy, e.g., by excretion of fast-acting anticonvulsant substances or by electrical or other stimulation in an attempt to reset brain dynamics to a state that will no longer develop into a seizure. In principle there are two different scenarios of how a seizure could evolve: It could either be caused by a sudden and abrupt transition in which case it would not be preceded by detectable dynamical changes in the EEG. Such a scenario would be conceivable for the initiation of seizures in primary generalized epilepsy. Alternatively, this transition could be a gradual change (or a cascade of changes) in dynamics which could in theory be detected. This type of transition could be more likely in focal epilepsies.4 Several seizure-facilitating factors are known. In the context of his ‘reservoir theory’, Lennox5 has defined seizure facilitation as the input of sensory, metabolic, emotional, or other yet unknown factors that ‘… fill up some reservoir until it overflows’, which in turn results in a seizure. Among others, state of consciousness, sleep deprivation, stress, disturbances of electrolytes and acid-base balance, sensory stimulation and exposure to drugs are factors known to facilitate seizures.6 Apart from the rare exception of sensoryevoked or reflex epilepsies, however, these factors are rather unspecific and highly variable since they depend on individual habits, susceptibility, and daily routine. Clinicians who care for patients with epilepsy have long known that individual patients can identify periods when seizures are more likely to occur, though they can rarely specify an exact time when seizures will happen. Reported prodromal symptoms include mood changes, irritability, sleep problems, nausea, and headache. There are also physiological studies in small numbers of patients, usually collected serendipitously before seizures, that support the existence of a preictal period. Weinand and coworkers7 detected a significant increase in blood flow in the epileptic temporal lobe starting 10 min before seizure onset that spread to both temporal lobes 2 min before seizure onset. Similarly, Baumgartner and colleagues8 demonstrated increased blood flow in the epileptic temporal lobe in two patients, 11 and 12 minutes respectively, before seizure onset. Using near-infrared spectroscopy in three patients, Adelson and co-workers9 reported an increase in cerebral oxygen availability that began more than 13.5 h, and was identified as early 691

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as 1.5 h, before documented seizure onset. Preictal changes in other variables, such as R-R interval on the ECG10–12 may also have predictive value, perhaps as epiphenomena related to seizure precursors, in some types of epilepsy. More recently, functional magnetic resonance imaging has demonstrated changes in perfusion prior to seizure onset.13 Knowledge about basic mechanisms leading to seizures has mainly been derived from animal experiments. Although there is a considerable bulk of literature on the topic, the underlying electrophysiological and neurobiochemical mechanisms are not yet fully explored. Moreover, it remains to be investigated to which degree findings from animal experiments can be transferred to human epilepsies. During recent years, a variety of potential ictogenic (seizure generating) mechanisms have been identified in experimental models of focal epilepsy, including alterations in synaptic and cellular plasticity and changes in the extracellular milieu. It is still a matter of debate, however, whether these mechanisms can be regarded as specifically ictogenic, apart from their critical role in normal brain function. On the level of neuronal networks, focal seizures are assumed to be initiated by abnormally discharging neurons (so-called bursters;14–18 see Yaari and Beck19 for an overview) that recruit and entrain neighboring neurons into a critical mass. This build-up might be mediated by an increasing synchronization of neuronal activity that is accompanied by a loss of inhibition, or by processes that facilitate seizures by lowering the threshold for excitation or synchronization. In this context, the term ‘critical mass’ might be misleading in the sense that it implies an increasing number of neurons that are entrained into an abnormal firing pattern. This mass phenomenon would be easily accessible to conventional EEG analysis which, to date, has failed to detect it. Rather, the seizure initiating process might better be visualized as a process in which an increasing number of critical interactions between neurons in a focal region and connected units in an abnormal functional network unfold over time. Based on these concepts, a number of studies have aimed at characterizing this collective neuronal behavior from the gross EEG in order to allow definition of a transitional preictal phase. In this chapter we will give an overview of the literature on this topic and the current state of this rather young research field and critically discuss some of the methodological problems and pitfalls involved in the design and testing of seizure prediction algorithms.

The history of seizure prediction For a better understanding of the practical problems in this field, in this section we categorize the literature on seizure prediction according to methodological standards. A chronological overview is given in Table 78.1. Early approaches After some early work on the predictability of seizures dating back to the 1970s,65 attempts to extract seizure precursors from the EEG were carried out by different groups using mostly linear approaches such as spectral analysis66–68 or pattern detection by analyzing spike occurrence rates.69–73

Preictal phenomena Following the advent of the theory of nonlinear systems in the 1980s, time series analysts became aware of seizure prediction as a potential field of application. In the early 1990s, Iasemidis and co-workers74 calculated the so-called largest Lyapunov exponent from the intracranial EEG of epilepsy patients by means of a moving window analysis and reported a decrease of this measure minutes before an epileptic seizure. Some years later, a French group of researchers reported a preictal decrease of a measure termed correlation density prior to seizures in a large group of patients.22 The same group developed another measure named dynamical similarity index, which quantified changes in dynamics relative to a constant reference window at the beginning of a preictal recording. They found changes in dynamics prior to seizures in both intracranial23,24 and scalp EEG recordings.28 Common to all these studies is that their focus of interest was entirely limited to the preictal period and that they did not include evaluation of interictal control recordings (i.e., periods from the seizure-free interval other than the presumed preictal period). By thus neglecting the issue of specificity, these studies rendered an incomplete evaluation of the investigated measures’ suitability for seizure prediction. Proof-of-principle studies Another group of studies tackled the issue of specificity by comparing preictal changes in dynamics to interictal control recordings, although the findings reported in these studies remained on an exemplary level. Navarro et al.36 used selected examples of five of their patients to show that drops in their similarity measure occurred more frequently before seizures than during the interictal EEG. In 2000, Mormann et al.25 reported changes in synchronization between different brain areas before seizures that were not found in exemplary seizure-free recordings. In two reviews of their own work, Le Van Quyen and co-workers31,32 referred to a submitted study including eight patients with neocortical epilepsy that seemed to confirm these findings. In 2003, Chávez et al.42 published exemplary results using phase synchronization analysis after band-pass filtering of the EEG and reported preictal changes in synchronization to occur predominantly in the beta band. Controlled studies on predictability In the first controlled studies comprising defined groups of patients with preictal and interictal control recordings, measures like the correlation dimension,20,21 dynamical entrainment29 (defined by the authors as the convergence of largest Lyapunov exponents in certain selected channels), accumulated signal energy,30,52 simulated neuronal cell models,37 or phase synchronization38,39 were shown to be suitable to distinguish interictal from preictal data. These studies were followed by a number of studies (mostly carried out on more extensive data bases) that found a substantially poorer predictive performance than presumable from earlier reports for the correlation dimension,47 the similarity index,46 and accumulated energy.51 Whether these measures performed at all better than random could not be answered by these studies since the statistical validation scheme applied did not include corrections for testing of multiple channels and seizures

Mormann et al.38

Navarro et al.36 Schindler et al.37

Le Van Quyen et al.31,32 Lehnertz et al.33 Protopopescu et al.34 Jerger et al.35

2003

2002

2002

2001

2001

iEEG

2001

Dynamical entrainment Accumulated energy Phase synchronization

Phase synchronization Correlation integral Dissimilarity measures Similarity index

Similarity index

Correlation dimension Correlation density Similarity index

Correlation dimension sEEG Dissimilarity measure iEEG 7 different measures s+iEEG Similarity index sEEG+FO Simulated neuronal cells iEEG Synchronization/ Correlation

iEEG

iEEG

2001

2001

iEEG

2000

2001

iEEG

2000

sEEG

iEEG

2000

2001

iEEG

1999

sEEG

iEEG

1998

2000

iEEG

1998

Lehnertz & Elger20,21 Martinerie et al.22 Le Van Quyen et al.23 Le Van Quyen et al.24 Mormann et al.25 Cerf et al.26

Characterizing measure

10

7

11

4

41

59

8

5

5

23

n.s.

7

2

9

13

11

16

Patients

14

15

41

12

46

95

n.s.

30

58

26

20

9

3

17

23

19

16

Seizures

31

144

53–142

1

261

>145

n.s.

>312

266

26–35

40

n.s.

4

11

15

13

21

Total EEG (h)

15

n.s.

12–60c

0

73.9

>115

n.s.

50

53.9

0

0

1.8

1.8

0

0

0

16.9

Interictal controls (h)

algorithmic

algorithmic

algorithmic

algorithmic

algorithmic

algorithmic

n.s.

statistical

statistical

algorithmic

algorithmic

statistical

algorithmic proof of principle

algorithmic

algorithmic

statistical

Type of analysis

yes

yes

no

yes

yes

yes

n.s.

yes

yes

no

yes

yes

no

no

no

no

yes

In-sample parameter optimization

no

no

yes

yes

yes

yes

n.s.

no

yes

yes

no

yes

yes

yes

yes

yes

yes

Retrospective best channel selection

no

no

no

no

no

no

no

no

no

no

no

no

no

no

no

no

no

Prospective

240

variable

90

3

60

n.s.

n.s.

180

variable

60

262.5

60

n.s.

20

20

20

30

86

100

83

100

95

47

77

90

91

96

100

100

100

94

83

89

94

Sensitivity (%)

0

n.s.

0.31c

n.a.

0

0

n.s.

0.12

n.s.

n.a.

n.a.

0

0

n.a.

n.a.

n.a.

0

Falsepositive Rate (FP/h)

yes

86 / 102h

Continued

no

no

no

no

no

no

no

no

no

no

no

no

no

no

no

no

Statistical validation of performance

83

8

2

n.s.

19

several min

19

49

7

52

n.s.

n.s.

4

6

3

12

Mean prediction Time (min)

12:52 PM

Hively et al.27 Le Van Quyen et al.28 Iasemidis et al.29 Litt et al.30

iEEG

Year

Type of EEG

Assumed preictal period (min)

Studies on seizure prediction and their relevant characteristics (see text). Adapted from Mormann et al. Curr Opin Neurol 2006 (in press)

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Authors

Table 78.1

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‘Preictal’ predictors of epileptic seizures 693

sEEG

iEEG

2003

2003

De Clercq et al.40 Niederhauser et al.41

iEEG

s+iEEG

sEEG

2003

2003

2003

Harrison et al.

2005

iEEG

iEEG

2005

55

iEEG

2005

D’Alessandro et al.53 Esteller et al.54

Gigola et al.

iEEG

iEEG

2004

2004

52

Maiwald et al.

Drury et al.

sEEG

iEEG

2003

2003

iEEG

2003

51

iEEG

2003

50

sEEG

2003

Hively & Protopopescu43 D’Alessandro et al.44 Iasemidis et al.45 Winterhalder et al.46 Aschenbrenner et al.47 Van Drongelen et al.48 Li et al.49

iEEG

2003

Chàvez et al.42

iEEG

2003

Mormann et al.39

Phase synchronization Similarity index Sign periodogram transf. Phase synchronization Dissimilarity measure Feature selection Dynamical entrainment Similarity index Correlation dimension Kolmogorov entropy Marginal predictability Marginal predictability Accumulated energy Accumulated energy Feature selection Accumulated energy Accumulated energy

Characterizing measure

5

4

2

4

21

14

8

5

21

21

5

4

41

2

5

a

12

18

Patients

b

51

42

19

b

13

88

44

24

5

88

88

28

46

46

6

31

n.s.

32

Seizures

311

294

177

26

588

59

37

5

588

588

214

n.s.

261

22

336

n.s.

117

Total EEG (h)

168

140

10.5

509

14.7

13.3

0

509

509

n.s.

160

73.9

9

335

0

49

Interictal controls (h)

statistical

algorithmic

algorithmic

statistical

algorithmic

statistical

statistical

algorithmic

algorithmic

algorithmic

algorithmic

algorithmic

algorithmic

algorithmic proof of principle

algorithmic

algorithmic

Type of Analysis

no

yes

no

yes

yes

no

no

yes

yes

yes

no

yes

yes

yes

yes

no

yes

In-sample parameter optimization

no

yes

no

n.s.

yes

no

no

no

yes

yes

no

yes

no

yes

yes

yes

no

Retrospective best channel selection

34

e

no

60

180

e

no

10 d

70

32

60

60

60

50

g

0

71

100/13

92

30

n.s.

n.s.

60

42 e

30

83 e

63

88

n.s.

94

0

81

Sensitivity (%)

180

10

60

90

2

60

240

yes

no

no

no

no

no

no

no

yes

no

d

no

no

no

no

no

Prospective

f

g

–

0.11

f

–

85

2/n.s.

n.s.

n.s.

30

n.s.

21

n.s.

n.s.

100

3

35

g

5–80 sec

–

4–221

Mean prediction time (min)

>>30

1.10/0.71

0

0.15

n.s.

n.s.

n.a.

0.10

0.15

0.17

f

0.28

0.02

n.s.

0.08

n.a.

0

Falsepositive rate (FP/h)

no

no

no

no

no

no

no

no

no

no

no

no

no

no

no

no

no

Statistical validation of performance

12:52 PM

Year

Type of EEG

Assumed preictal period (min)

3/19/08

Authors

cont’d

694

Table 78.1

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iEEG

iEEG

iEEG

iEEG

iEEG

iEEG

iEEG

2005

2005

2005

2005

2005

2005

2005

2005

Jouny et al.58

Le Van Quyen et al.59 Mormann et al.60 Kalitzin et al.61 Navarro et al.62 Chaovalitwongse et al.63 Harrison et al.64 20

10

13

3

5

5

2

1

2

2347

597

64b 960

227

>75

311

305

177

18

41

129

20

51

52

25

9

11b

n.s.

>404

0

n.s.

>107

25–120

n.s.

9

>8

statistical

algorithmic

algorithmic

statistical

statistical

algorithmic

statistical

statistical

algorithmic

n.s.: not specified; n.a.: not analyzed; iEEG: intracranial EEG; sEEG: surface EEG; FO: foramen ovale electrodes. a Selected out of a group of 10 patients. b Results listed are those obtained for out-of-sample testing data after in-sample optimization on training data. c Only from five selected patients. d Algorithm designed to run prospectively, but results are reported for training and testing data together. e Various predefined prediction horizons were analyzed. f Uncorrected false-positive rate including preictal periods. g Separate results reported for two different patients. h Separate results reported for two different measures. i Inconclusive validation: surrogate seizure times are not treated in the same way as original seizure times.

Dynamical entrainment Synchronization/ correlation Complexity/ synchrony Phase synchronization 30 different measures Phase clustering Similarity index Dynamical entrainment Correlation dimension yes

no

no

yes

yes

yes

no

no

no

no

no

yes

yes

yes

no

no

no

no

no

yes

no

no

90 / 15e

180

120

–

5–240e

variable

nod no

60

60

120

no

no

yes

0

69

64

n.s.

n.s.

69

0

22

82

–

0.15f

n.a.

n.s.

n.s.

n.s

–

–

0.15f

–

72

>13

–

–

187

–

–

78

no

yesi

no

no

yes

no

no

yes

no

12:52 PM

iEEG

iEEG

2005

3/19/08

Iasemidis et al.56 Jerger et al.57

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(cf. Schelter et al.).75 Around this time a controversy evolved regarding both the reproducibility of earlier studies40 and the problems and pitfalls associated with nonlinear measures used to characterize EEG time series.76–78

Conceptual issues

Continuous multiday recordings Around the turn of the millennium when mass storage capacity became more widely available, epilepsy centers were able to store the complete data acquired during presurgical monitoring without the necessity to select sample recordings. In 2005 a series of studies from different groups was published that were carried out on a set of five continuous multiday recordings provided by different epilepsy centers for the First International Collaborative Workshop on Seizure Prediction79 held in Bonn in April 2002. The aim of this workshop was to have different groups test and compare their methods on a joint data set. Results from the different groups for the most part showed a poor performance of univariate measures.53–55,58,60 A better performance was reported for bivariate measures.56,59,60 One of these studies found a discriminative power for interictal and preictal amplitude distributions for certain measures of synchronization that was shown to be significant using a rigorous statistical validation, while many univariate measures, including the correlation dimension, the Lyapunov exponent, and the signal energy, were not able to discriminate the preictal from the interictal period above chance level.60

Prediction, forecasting, or anticipation? In the strict sense of the words, prediction or forecasting of an event means the ability to determine in advance the time of its occurrence with a certain precision. The term anticipation on the other hand implies an uncertainty as to when exactly an event will occur. This latter concept better fits the design of seizure prediction algorithms which usually assume a seizure to occur within a certain time period after an alarm is issued without knowing its exact onset time. Throughout the literature, however, the three different terms are for the most part used interchangeably.

This section addresses issues that need to be resolved prior to designing a study on seizure prediction.

Prospective studies The first attempts to test seizure prediction algorithms in a prospective manner were carried out by Iasemidis et al.45 and D’Alessandro et al.53 The sensivity and specificity rates obtained were unacceptable for clinical implementation. Whether the performance of the algorithms was at all better than random was not investigated. A recent study by Chaovalitwongse et al.63 attempted such a validation based on a method proposed 2 years earlier,80 but the authors did not apply the exact same analysis procedure to the seizure times surrogates as to the original onset times so the results must be regarded as inconclusive.

The type of EEG: intracranial or surface recordings? While the majority of seizure prediction studies to date have been carried out on intracranial recordings, some studies have also used surface recordings (cf. Table 78.1). Intracranial recordings bear the advantage of a higher signal-to-noise ratio and a better spatial resolution, and the data can be considered mostly artifact free. They also bear the potential advantage of allowing to record directly from the seizuregenerating region. Surface recordings on the other hand are less invasive and could in principle be used in an ambulatory setting to monitor a patient’s seizure situation in his/her usual environment. This would, however, require a high compliance on part of a patient due to the impairment of constantly wearing an EEG cap. Furthermore, if seizure anticipation algorithms proved to be successful, they would most likely be implemented in an implantable, closed-loop warning or intervention system. The feasibility of such systems has already been proven by intracranial brain stimulation devices that are currently being tested in clinical trials for their ability to reduce seizure frequency. The usefulness of scalp EEG recordings for studies on seizure anticipation can therefore be regarded as rather limited compared to intracranial recordings.

Summary During the 1990s, a number of studies raised a high optimism about seizure prediction becoming feasible for clinical application in the near future. The focus of these studies, however, was limited to analyzing short and selected data segments, and numerous methodological caveats were disregarded. In the past 5 years many studies were published that questioned both the validity and reliability of these findings by showing that earlier optimistic results could not be reproduced. For the field of seizure prediction to advance towards clinical applications, it is inevitable that future studies on seizure prediction place a strong emphasis on sound methodology and include a rigorous statistical validation. In the next two sections of this chapter we will therefore address some of the methodological issues and caveats involved in the designing and testing of seizure prediction algorithms before pointing at possible future developments.

The events to be predicted: clinical or electrographical seizures? Another important issue is the selection of the ictal events that should be predicted by an algorithm.79 While the benchmark for clinical application would clearly be the forecasting of clinical seizure events, subclinical seizures today are mostly regarded not as a different entity, but as a milder variant of the same dynamical event that constitutes a clinical seizure. It is therefore arguable whether it is reasonable to exclude subclinical ictal events in a prediction algorithm. Nevertheless, most studies so far have restricted themselves to the analysis of clinical seizures. Similarly, the onset time of a seizure can be determined either from the first clinical signs or from the first visible EEG changes. Since there is often some uncertainty in the assessment of clinical symptoms, particularly in complex partial and absence seizures, it is reasonable to determine the seizure

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‘Preictal’ predictors of epileptic seizures onset electrographically, especially if intracranial recordings from the seizure onset zone are available. Algorithms that aim at an early detection of the electrographical seizure onset, which may occur several seconds before the first clinical symptoms should not be regarded as seizure prediction algorithms, but rather as early seizure detection algorithms (e.g., Osorio et al.).81 Data requirements and data completeness While it is on the one hand desirable to use data sets for analysis that contain a large number of seizures, it is also desirable to have a sufficient time interval between consecutive seizures, so they can be regarded as independent events. If seizures are too closely spaced (clustered seizures) it becomes difficult to separate the postictal period from a presumed preictal state (cf. Jouny et al.)58 as the exact duration of either of the two is unknown. Note in this context that the average seizure frequency in a monitoring unit of up to three events per day82 is about 30 times higher than a typical seizure frequency of three per month under normal circumstances.83 If a false prediction rate obtained in the epilepsy monitoring unit corresponded to a situation where every other alarm is a false alarm (positive predictive value of 50%), then the same false prediction rate under normal circumstances would result in only one out of 60 alarms being a correct warning (positive predictive value of 1.7%) (cf. Winterhalder et al.).46 EEG recordings used for studies on seizure prediction should ideally comprise EEG data recorded continuously over several days. Recording gaps due to diagnostic procedures during the presurgical work-up (e.g., structural MRI to verify electrode placement) are usually unavoidable and are not considered a major drawback. Since during the presurgical monitoring, patients are constantly undergoing changes that could have a confounding influence on characterizing measures of the EEG (e.g., tapering of medication), it is advisable to use all interictal control data available since a restriction to, e.g., the first 24 h of EEG could introduce a confounding bias.

Assessing the performance of a prediction algorithm In this section we will discuss some of the problems and pitfalls involved in the evaluation of an algorithm for seizure prediction. Moving window analysis In order to judge the relative merit of the different studies on seizure prediction published to date, it is necessary to realize how the performance of a seizure prediction technique is assessed. Most of the prediction techniques published up to now have certain common features: They use a moving window analysis in which some (linear or nonlinear) characterizing measure is calculated from a window of EEG data with a predefined length, then the subsequent window of EEG is analyzed, etc. The duration of these analysis windows usually ranges between 10 and 40 sec. Depending on whether the

697

employed measure is used to characterize a single EEG channel or relations between two or more channels, it is referred to as a univariate, bivariate or multivariate measure, respectively. The moving window analysis thus renders time profiles of a characterizing measure for different channels or channel combinations. Statistical vs. algorithmic approaches The study design used to evaluate these time profiles in a next step can be either statistical or algorithmic (cf. Table 78.1). A statistical design is retrospective by nature and usually compares the amplitude distributions of the characterizing measures from the interictal with those from the assumed preictal period in one way or another. The temporal structure of the time profiles is usually not preserved in this type of analysis. Such a design can be useful to investigate and compare the potential predictive performance of different characterizing measures under different conditions. An algorithmic analysis on the other hand uses a design that produces a time-resolved output, i.e., an output for every point of a time profile. With respect to practical application, the algorithm should ideally be prospective, i.e., its output at a given time should be a function of the information available at this time. Prediction algorithms usually employ certain thresholds. If the time profile of a characterizing measure crosses the threshold, the algorithm produces an alarm. This alarm can be either true or false, depending on whether it is actually followed by a seizure or not. For this distinction, it is necessary to define a prediction horizon, i.e., the period after an alarm within which a seizure is expected. If an alarm is followed by a seizure within the prediction horizon, it is classified as a true alarm (true positive), otherwise it is regarded as a false alarm (false positive). In addition, it may be useful to require a minimum time interval between an alarm and a seizure occurrence in order to count this alarm as a successful prediction if the algorithm is to be used for seizure prevention. This minimum intervention time can be introduced as an additional constraint. (Note that in the literature, sometimes different definitions are used for these quantities, e.g., one group has used the term ‘seizure occurrence period’ instead of prediction horizon and ‘seizure prediction horizon’ instead of minimum intervention time.)46,47,51 In studies that employ a statistical instead of an algorithmic design, the prediction horizon corresponds to the assumed preictal period. Sensitivity and specificity If a seizure is not preceded by an alarm within the prediction horizon, this will be counted as a false negative. A less trivial question is how to quantify true negatives. In principle, every single window of the moving window analysis that is outside the duration of the assumed preictal period (i.e., one prediction horizon prior to a seizure) and does not produce an alarm could be counted as a true negative. However, since sensitivity is usually quantified as the number of seizures with at least one alarm within the preceding prediction horizon divided by the total number of seizures, it is reasonable to define specificity based on the prediction horizon, too. If, for instance, the prediction horizon is 3 h, the sensitivity quantifies the fraction of correctly classified preictal 3-h segments, while the

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specificity measures the fraction of correctly classified (consecutive) interictal 3-h segments. In order to avoid any ambiguity in statistically quantifying the specificity of a prediction algorithm, most studies have instead reported specificity rates measured as false predictions per hour. Unfortunately, also for false prediction rates, different definitions are found in the literature. Several groups have determined false prediction rates by counting all false positives and dividing this number by the total duration of the analyzed recording.41,45,54,56,63 This definition ignores that for each seizure contained in the recording, there is a preictal period (i.e., the prediction horizon) during which every alarm is counted as a true prediction, and false predictions cannot occur by definition. Other groups have therefore used corrected false prediction rates that were calculated only for the interictal period.38,39,46,47,51 In this context it is important to realize that a reported false prediction rate cannot be judged independent from the prediction horizon since in a prospective prediction algorithm a false alarm will leave the patient mistakably awaiting a seizure for the duration of the prediction horizon. It is only after this duration that the patient will know if the alarm was a false warning or not. Consider as an example56 an algorithm with a 2-h prediction horizon that yields a sensitivity of 9/11 = 82% of predicted seizures and an uncorrected false prediction rate of 6/41h = 0.15/h. If we take into account that the uncorrected false prediction rate includes the preictal periods during which no false prediction can occur by definition, the corrected false prediction rate (assuming the preictal periods are nonoverlapping) is 6/19h = 0.32/h, thus more than twice as high. If we consider furthermore that after each false prediction, the patient needs to wait for 2 h before knowing if it was indeed a false prediction, the performance of our example (assuming that false predictions are not spaced closer than the prediction horizon) may leave a patient 6 × 2/19 = 63% of the interictal period waiting for a seizure that will not occur while still failing to anticipate every fifth seizure. An algorithm yielding the same results for a prediction horizon of 10 min would instead leave the patient in futile expectation of a seizure only in 3% of his/her seizure-free time. This example shows that a prediction rate should be judged in view of the prediction horizon used by the algorithm and that it is the product of these two quantities that should be compared across studies. A better way to assess the specificity of a prediction algorithm would be to report the portion of time from the interictal period (i.e., the interseizure-interval without the preictal period) during which a patient is not in a state of falsely awaiting a seizure. In general any algorithm can be tuned (e.g. by varying the alarm threshold) to yield a higher sensitivity at the cost of a lower specificity and vice versa. For a closed-loop intervention system, the desired relation between these two quantities will depend on the invasiveness of the intervention technique under consideration. If the intervention does not impair the patient, a higher false prediction rate will be tolerated up to the point where a constant intervention (such as a duty-cycle stimulation from implantable deep brain stimulation devices, cf. Vonck et al.)84 is possible that could be performed without a prediction algorithm.

The problem of in-sample optimization Another important issue in the evaluation of a prediction algorithm is the use of a posteriori information. For a prospective prediction algorithm, this type of information is not available. Two typical cases of using a posteriori information are found in the literature: (1) in-sample optimization of parameters of the algorithm and (2) a posteriori selection of one or more channels with optimum performance. In-sample optimization or training of parameters is present whenever parameters used for the calculation of the characterizing measure of the EEG or of the prediction algorithm itself are adjusted to produce optimal performance of the algorithm for a given set of data. Such an optimization is likely to result in an overestimated performance that will not be reproducible when applying the algorithm to other, out-of-sample testing data that was not used in the optimization process. In order to assess the true performance of a prediction algorithm, it is therefore inevitable to test it on out-of-sample data. Another way of using a posteriori information relates to the selection of channels that are able to discriminate an interictal from a preictal state. The great majority of studies have shown that out of the available number of recording channels, only a limited number carry information that can actually be used for the detection of a preseizure state, while the remaining channels are likely to increase the number of false detections without contributing to the detection sensitivity of an algorithm. The task at hand is to decide in advance which channels are best suited for the purpose. While many early studies reported preictal changes in channels within or close to the seizure onset zone,20–24 more recent ones found channels in more remote, in some cases even contralateral, areas to carry the relevant information.44,63,64,59,60 Several studies have attempted to tackle this problem by using the first few seizures to select the appropriate channels and/or parameters for the algorithm before trying to detect precursors of the seizures that follow.44,53,54,59 Such a procedure implies that the spatio-temporal dynamics preceding a seizure do not change from seizure to seizure. Iasemidis et al.45,56 designed an algorithm using a selection of channels that is readjusted after every seizure such that it would have been optimal for the seizure that has just occurred. Such a procedure is based on the implicit assumption that preictal dynamics change to a certain degree from seizure to seizure, but that the preictal dynamics of a seizure still depend on the dynamics of the previous one. If these algorithms reliably proved to be better than a random prediction, they could, in addition to being beneficial for patients, provide valuable clues for new theories on the mechanisms involved in ictogenesis. The need for statistical validation If an algorithm is designed to run prospectively, its quasiprospective out-of-sample performance can be tested retrospectively on continuous long-term recordings that were not previously used for parameter optimization or channel selection. Once this quasi-prospective performance (in terms of correct alarms and false alarms with respect to the given prediction horizon) has been assessed, it remains to be tested whether it is indeed superior to that of an algorithm working with random prediction. For this aim, Winterhalder and

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‘Preictal’ predictors of epileptic seizures collegues have designed a framework to assess the performance of such a random predictor.46,75 In retrospective statistical studies on predictability, however, it may be desirable to investigate and compare the potential predictive performance of different characterizing measures for various thresholds and parameters. In this case the use of a random predictor for statistical validation would require Bonferroni corrections for multiple testing that can be difficult to perform. Here the concept of seizure time surrogates as introduced by Andrzejak et al.80 can provide a means for statistical validation. In this process, artificial seizure onset times are generated by randomly shuffling the original inter seizureintervals. Using these surrogate seizure onset times instead of the original onset times, the EEG data is then subjected to the same algorithm or prediction statistics that was used for the original onset times. Only if the performance of the algorithm for the original seizure times is better than the performance for a number of independent realizations of the surrogate seizure times, can the null hypothesis, namely, that a given algorithm cannot detect a preseizure state with a performance above chance level, be rejected. The advantage of this type of statistical validation is that it can be applied to any type of analysis, algorithmic or statistical. A modification of this surrogate test has recently been proposed based on a constrained randomization of the time profile of the characterizing measure.85

Future perspectives Prospective out-of-sample algorithms with statistical validation The next problem that needs to be tackled by seizure anticipation algorithms is to design algorithms to run (quasi-) prospectively on unknown, out-of-sample data. If the algorithms require a training phase in which some seizures are used to adjust patient-individual parameters and perform a feature or channel selection, the requirements on the individual data sets increase since a larger number of seizures per individual data set will be needed. Performance results should be reported only for the testing data. Before addressing the question whether an obtained performance might be sufficient for clinical application, it needs to be tested whether a performance is at all better than chance. To this aim, methods for statistical validation are inevitable. These methods can be based either on bootstrapping techniques38,57,60,80,85 or on the performance of a random prediction process46,75 derived analytically. Mechanisms of ictogenesis While many studies on seizure prediction placed their emphasis on algorithmic prediction, their primary focus of interest was not directed towards the underlying mechanisms of seizure generation. A number of recent studies have attempted to increase our understanding of the dynamics of ictogenesis. Both in temporal lobe and neocortical epilepsies, high frequency oscillations were found to play a role in the initiation of epileptiform potentials and seizures.86–88 In another recent study on patients with temporal lobe epilepsy, the so-called phase demodulation of intracranial EEG recorded interictally during intermittent electrical stimulation was found to yield

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important clues for possible dynamical scenarios that lead to seizure onsets.61 Schiff and coworkers89 successfully used canonical discrimination analysis to search for dynamically distinct stages of epileptic seizures in humans. A further promising approach is to model EEG signals to gain a better understanding of the mechanisms of ictogenesis.90,91 For an excellent and detailed review on recent findings in quantitative EEG analysis, refer to Stam.92 Given the rather poor performance of the seizure prediction algorithms designed to date, it is likely that a better understanding of the mechanisms involved in seizure generation may stimulate the design of improved methods and algorithms. Confounding variables Another key to the improvement of algorithms could be a better understanding of the interictal period and all of its confounding variables that may influence the characterizing measures used in the algorithms and may thereby decrease the algorithm’s sensitivity or specificity. Studies on continuous multiday recordings have identified distinct circadian fluctuations of synchronization measures.85 Particularly different vigilance state, e.g., slow-wave sleep, seem to have a substantial influence on these measures. A further confounding influence on characterizing measures has been described for the blood levels of carbamazepine.93 Little is known to date about the influence of different cognitive or emotional states.94 Once the influence of these confounding variables is better understood, it can be taken into account by an algorithm to increase its predictive performance.

Conclusions The more rigorous methodological design in many recent seizure prediction studies has shown that many of the measures previously considered suitable for prediction perform no better than a random guess.55,60 On the other hand, evidence has accumulated that certain measures, particularly measures quantifying relations between recording sites as a correlate of interaction between different brain regions, yield a promising performance56,59,60 that ranges above chance level, as evidenced by rigorous statistical validation.60 The few studies that have used prediction algorithms in a quasi-prospective manner (i.e., without the use of a posteriori information) either did not include a statistical validation45,53,56 or did not apply it correctly.63 The design and evaluation of prospective seizure prediction algorithms involves numerous caveats that need to be regarded. The current literature allows no definite conclusion as to whether seizures are predictable by prospective algorithms. To answer this question, future studies need to rely on sound and strict methodology and include a rigorous statistical validation. The next necessary step in the field of seizure prediction will be to test on long-term recordings whether the prediction algorithms devised to date are able to perform better than a random predictor in a quasi-prospective setting on outof-sample data. This step is an indispensable prerequisite to justify prospective clinical trials involving invasive seizure intervention techniques based on prediction algorithms such as electrical brain stimulation in patients.

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Effect of anticonvulsant withdrawal on seizure semiology and ictal electroencephalography CT Skidmore and MR Sperling

Introduction Prior to performing epilepsy surgery, an intensive evaluation process is conducted to define the boundaries of the epileptogenic region. Characterizing seizure semiology and the EEG pattern of habitual seizures is a key component of this process. This is typically accomplished through monitoring in a videoEEG unit. It is important to ensure that all relevant seizure types are captured to ensure an accurate diagnosis. Moreover, it is important to make certain that the observed seizures have been accurately assessed, and that the observed EEG and behavioral characteristics are reliable. While the optimal number of seizures that should be recorded is uncertain, many strive to capture at least three typical seizures during hospital admission. This figure, however, depends upon the quality of the EEG recordings, results of other diagnostic testing, number of clinical seizure types, and other factors. While video-EEG monitoring can be accomplished during a brief hospital stay in many patients, those who have less frequent seizures (less then weekly) would require prolonged hospital stays. Since prolonged hospitalization can be emotionally taxing and injurious to patient finances, it is desirable to attempt to minimize hospital length of stay. In addition, there are external pressures from insurance companies for efficient monitoring stays, and the number of available video-EEG monitoring beds is limited. Therefore, any method that can shorten the length of stay can benefit patients, reduce the cost of presurgical investigations, and improve health care access. For these reasons, various techniques have been utilized in an attempt to temporarily increase seizure frequency, thereby shortening the hospital stay. The most common provocation maneuver is antiepileptic drug (AED) withdrawal. This is generally a safe and effective means for provoking seizures. This chapter will review the data regarding its effect on seizure semiology and ictal EEG.

Effect of AED withdrawal on seizure frequency Before assessing the effect of AED withdrawal on seizure semiology and ictal EEG, one must determine whether withdrawal truly provokes seizures. Marks et al.1 found a significant 702

increase in seizure frequency when AED levels were subtherapeutic or absent in a study of 35 patients. Marciani et al.2 reported the effects of AED withdrawal on seizure frequency in patients who were monitored on and off AEDs. In 12 of 17 patients who had no seizures on AED therapy, seizures were provoked by AED withdrawal, and in 16 of 23 patients who had baseline seizures there was a clear increase in seizure frequency. So and Gotman3 reported the seizure rate in three controls and in eight patients whose AEDs were withdrawn. They found a clear increase in seizure frequency during AED withdrawal in comparison with controls, whose seizures occurred less frequently. Several studies demonstrate that carbamazepine (CBZ) withdrawal increases both seizure frequency and the rate of occurrence of secondarily generalized seizures.4–9 Bromfield et al.10 demonstrated an increase in seizure frequency during phenytoin (PHT) withdrawal, Zhou et al.7 noted no change in seizure frequency during valproate (VPA) withdrawal, and Wang-Tilz et al.11 found an increased seizure frequency during lamotrigine (LTG) withdrawal. Based on these studies and many other reports in the literature, it seems apparent that AED withdrawal increases seizure frequency.

Effect of AED withdrawal on seizure semiology and ictal EEG Spencer et al.12 reported results in 25 patients who had intracranial EEG monitoring. They compared seizure semiology and ictal EEG before and after the withdrawal of AEDs. They identified four patients who had atypical semiology or ictal EEG onsets during the withdrawal phase; however these patients were already determined to have multifocal or bilateral epileptogenic zones during the baseline phase. One patient had atypical semiology and multifocal onsets, which was different from the baseline phase, however this patient failed surgery after excision of the region from which typical seizures emanated. He was found later to have seizures emanating from the contralateral hemisphere. They concluded that AED withdrawal successfully provoked typical seizures in the majority of patients, and that atypical seizures may suggest a latent multifocal predisposition that may not be surgically remediable. However, after this report Engel and Crandall13 reported a single patient who had an intracranial bitemporal

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Effect of anticonvulsant withdrawal on seizure semiology and ictal electroencephalography implant for seizure localization who had typical seizures emanating from the right temporal lobe and atypical seizures arising from the left temporal lobe. Based on the scalp evaluation and intracranial data he underwent a right temporal lobectomy and was seizure free for 4 years at the time of the report. They cautioned that atypical seizure semiology and ictal EEG data may be secondary to distant hyperirritability secondary to the primary epileptogenic focus or possible direct irritation from the implantation of the depth electrode. In addition to this patient they also commented on four additional patients who had atypical ictal EEG who ‘benefited from surgery’ and while atypical data is a poor prognostic sign, it should not be an absolute contraindication. Marciani and Gotman14 reported data from 14 patients who had typical seizures recorded with intracranial EEG while taking stable doses of medication and during drug AED withdrawal. Only one patient had a clinical seizure with altered semiology and ictal EEG onset compared to their baseline seizures. However, this seizure occurred after an insignificant change in a single AED dose and the patient then had several typical seizures during aggressive drug withdrawal. In the remaining patients, seizure semiology and ictal onset in the EEG were not affected by AED withdrawal, even during seizure clusters and secondary generalization. Marks et al.1 reported that five out of 35 patients had atypical clinical seizures during drug withdrawal. Two of these patients were thought to have multifocal disease, and the other 3 had atypical seizures both during the baseline and withdrawal phase, so AED withdrawal was probably not responsible for changes in ictal EEG findings. Seventeen of their patients had intracranial ictal data recorded while taking AEDs and during AED withdrawal. One patient who had a right temporal lesion had a diffuse ictal onset with the first seizure during drug withdrawal, but four other seizures recorded after this had focal onset. One patient missed several doses of clonazepam, apparently by mistake, which resulted in simultaneous neocortical and hippocampal onset. However, once the clonazepam was restarted all the remaining seizures had focal onset in the hippocampus. Bardy15 reported no change in seizure semiology in 11 patients undergoing AED withdrawal for video-EEG monitoring, and So and Gotman3 reported that while eight patients with intracranial EEG had more frequent and severe seizures during AED withdrawal, a variety of measures including latency of interhemispheric spread, seizure duration for a given seizure type (i.e., complex partial seizure), and localization were not affected. Based on these studies, it appears that the overwhelming majority of seizures occurring during AED withdrawal display typical semiology and ictal EEG. However, as noted by Engel and Crandall,13 the existence of atypical seizures should not necessarily prevent surgery from being carried out. Atypical seizures may signal the presence of a latent epileptogenic focus, but they may either be dependent upon the primary focus or be amenable to AED therapy should it persist after surgery.

Effect of specific AEDs on seizure semiology and the ictal EEG Most published data address the effect of withdrawal of older AEDs on seizure semiology and the ictal EEG.

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They do not address how withdrawal of most newer AEDs influence these features. With these constraints in mind, we will attempt to review the information available for each individual AED. Carbamazepine Duncan et al.9 and DeToledo et al.6 reported no new seizure types provoked by withdrawal of CBZ. These studies were limited though since they were based on clinical follow-up and not video-EEG monitoring. Zhou et al.7 studied 20 patients taking CBZ and undergoing video-EEG monitoring. They analyzed the presence of hypermotor features, oroalimentary automatisms, hand automatisms, ictal speech, and secondary generalized tonic and/or clonic signs before and after the withdrawal of CBZ, and noted an increased frequency, duration, and intensity of most ictal signs with CBZ withdrawal. However, the scalp ictal onset and initial seizure semiology was not altered by CBZ withdrawal. Spencer et al.12 evaluated eight patients with intracranial EEG before and after the withdrawal of CBZ. Three of these patients were determined to have multifocal or bilateral EEG onset in the baseline and CBZ withdrawal phases. None of the patients with unilateral focal onset had atypical clinical semiology or EEG onset. However two of the patients with multifocal disease had atypical EEG onset captured during drug withdrawal. Valproate Duncan et al.9 reported no new seizure types in 25 patients undergoing VPA withdrawal. However, this was an outpatient study without video-EEG correlation. Zhou et al.7 evaluated 13 patients taking VPA with video-EEG monitoring. They found no effect on seizure frequency or seizure intensity, but seizure duration was increased. They did report that the amounts of hypermotor components of the seizures were increased, but initial ictal signs and EEG onset were unchanged. Phenytoin Duncan et al.9 reported no new seizure types in 22 patients withdrawn from phenytoin (PHT) as outpatients. Spencer et al.12 reported two patients who were studied with intracranial EEG before and after PHT withdrawal. One patient had multifocal EEG onset and the other had bilateral EEG onset during baseline and withdrawal phases. Although new seizure types were not captured during the withdrawal phase, the patients did not have unilateral focal disease, and it is difficult to assess the effect of PHT withdrawal on ictal EEG and semiology. Phenobarbital/primidone Spencer et al.12 evaluated four patients on phenobarbital (PB) and one patient on primidone (PMD) with intracranial EEG before and after AED withdrawal. One patient on PB had focal ictal EEG onset and clinically typical seizures before and after withdrawal of PB. A second patient had a typical clinical seizure with EEG onset in the right temporal lobe in the baseline phase, but had atypical clinical and electrographic

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seizures during PB withdrawal. This patient was later found to have seizures emanating from the left hemisphere, as described previously. The other two patients had multifocal or bilateral disease and both had atypical seizures on EEG compared to the baseline phase. One of the patients also had atypical clinical seizures during drug withdrawal. Only one patient had seizures during the baseline and withdrawal phases on PMD, and this patient did not have any atypical seizures or ictal EEG onsets. Lamotrigine Wang-Tilz et al.11 noted an increased seizure severity and duration with LTG withdrawal, but no definite increased frequency of secondary generalized seizures. The ictal EEG onset and initial seizure semiology was not altered by LTG withdrawal.

Risks associated with AED withdrawal The concern about quality and character of seizures observed during drug withdrawal is more than matched by a concern about safety. If drug taper provokes more frequent and severe seizures, it may be associated with an increased risk of complication. Several possibilities exist, including secondary generalized tonic-clonic seizures, status epilepticus, neuronal injury, cognitive impairment, and bodily injury. Status epilepticus perhaps raises the most concern, but its incidence during controlled AED withdrawal in a hospital setting is apparently quite low. In several studies of patients monitored with video-EEG before and after AED withdrawal, there were no reported cases of status epilepticus.2,7,11,16,17 This could be due to the existence of protocols to treat seizure clusters and prolonged generalized tonic-clonic seizures early in their course, or due to under-reporting of status epilepticus. There are numerous reports of an increased incidence of seizure clusters during AED withdrawal, and some of these might fulfill criteria for status epilepticus. The incidence of clusters varies from study to study as do the definitions of a seizure cluster. Marks et al.1 defined seizure clusters as >3 seizures within a 48-hour period. They reported seizures clusters in four patients on stable AED therapy and in 18 patients during AED withdrawal of 35 patients. Yen et al.16 defined seizure clusters as >3 per 24-hour period, and reported that approximately 50% of their patients (n=102) experienced at least one seizure cluster during video-EEG monitoring with aggressive AED withdrawal. In our experience, status epilepticus can occur during drug taper, and the incidence ranges between half and one percent. We have observed tonic-clonic, tonic, complex partial, and absence status during drug withdrawal. In part, distinguishing between a seizure cluster and status epilepticus can be difficult, but when a series of seizures occur without full return of neurological function between the seizures,18 it is reasonable to diagnose status epilepticus. Hence, it is our belief that some patients who have been reported as having had seizure clusters probably had brief bouts of status epilepticus. Secondarily generalized seizures may either occur de novo or increase in frequency during drug withdrawal. These have

the potential of causing morbidity such as lacerations and other trauma, bone fractures, aspiration, and cognitive impairment. It is particularly concerning when patients with no prior history of secondarily generalized seizures or who have only rare secondarily generalized seizures have them during the evaluation. Most studies report an increase in the frequency of secondary generalized seizures during AED withdrawal.2,7,11,16 This appears to be especially true for CBZ withdrawal,2,4,7,8,11 but is also reported for phenytoin.2,4,10 The occurrence of new secondarily generalized seizures or the re-emergence of secondary generalized seizures in patients who had them rarely occurred in 9% of patients studied by Yen et al.16 and in 3/20 patients studies by Wang-Tilz et al.11 There is no data documenting that lamotrigine, valproate, or primidone withdrawal increase the frequency of secondarily generalized seizures,2,7,11 but it seems intuitive that it must happen at times; indeed, we have occasionally seen this phenomenon with these drugs at our institution. In contrast, Swick et al.17 found no correlation between AED withdrawal and the occurrence of secondary generalized seizures, and found that the only predictor of their occurrence was a prior history of secondary generalized seizures. However, this does not comport with the rest of the literature, nor our experience. Other complications are infrequent, but have occurred on occasion. We have observed a brachial plexus injury with persistent limb paresis after a de novo secondarily generalized seizure in one patient, several bone fractures, a few shoulder dislocations, bruising, and many severe tongue and cheek bites. In addition, after secondarily generalized seizures or clusters of complex partial seizures, many patients have reported memory defects that have lasted for up to several weeks. On the other hand, patients occasionally experience injury as a consequence of seizures when AED doses have not been altered. Therefore, how much drug taper increases risk cannot be known without a randomized study, which has never been performed and likely never will be done.

Conclusion AED withdrawal is an effective means of temporarily increasing seizure frequency in epilepsy monitoring units to ensure that an adequate number of seizures are recorded for diagnostic purposes. Drug withdrawal generally seems to lead to seizures that can be confidently analyzed as part of the presurgical evaluation process. Concerns that drug taper may provoke atypical seizures appear largely unjustified, and most data suggest that this phenomenon, if it occurs, is rare. Data regarding the effects of drug withdrawal is needed for many AEDs that came into use in the 1990s and afterward, but our clinical experience suggest that there is probably no difference compared with older drugs. The major disadvantage appears to be the provocation of seizure clusters and secondarily generalized seizures, which pose risk to the patient. Risk can be averted or reduced when epilepsy monitoring units employ clinical protocols for aggressive medical treatment when an unusual number of seizures or unusually severe seizure occurs. This may prevent the development of status epilepticus or injury. We advise that treatment be implemented automatically. Physicians should place orders in the hospital chart to initiate therapy once a certain predetermined seizure threshold is

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Effect of anticonvulsant withdrawal on seizure semiology and ictal electroencephalography reached in advance of problems developing, so that effective treatment is not delayed. Depending upon the type of seizure and how frequently seizures occur, one of several options can

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be used. Either one can prescribe a large dose of the oral agent that was being tapered, give an oral dose of a benzodiazepine, or administer an intravenous dose of a benzodiazepine.


5. 6.

7. 8.

Marks DA, Katz A, Scheyer R, Spencer SS. Clinical and electrographic effects of acute anticonvulsant withdrawal in epileptic patients. Neurology 1991;41:508–12. Marciani MG, Gotman J, Andermann F, Olivier A. Patterns of seizure activation after withdrawal of antiepileptic medication. Neurology 1985;35:1537–43. So N, Gotman J. Changes in seizure activity following anticonvulsant drug withdrawal. Neurology 1990;40:407–13. Costa M, do Campo SB, Brazil SP, Morris HH, Turnbill J. Carbamazepine and phenytoin withdrawal: acute effects on seizure frequence and type. Neurology 1997;48(Suppl. 2): A111(abst). White S, Balish M, Khan I, Theodore WH. Seizures during carbamazepine discontinuation. Epilepsia 1991;32(Suppl. 3): 13(abst). DeToledo JC, Ramsay RE, Lowe MR, Greiner M, Garofalo EA. Increased seizures after discontinuing carbamazepine: results from the Gabapentin monotherapy trial. Ther Drug Monit 2000; 22:753–6. Zhou D, Wang Y, Hopp P et al. Influence on ictal seizure semiology of rapid withdrawal of carbamazepine and Valproate in monotherapy. Epilepsia 2002;43:386–93. Malow BA, Blaxton TA, Stertz B, Theodore WH. Carbamazepine withdrawal: effect of taper rate on seizure frequency. Neurology 1993;43:2280–4.

9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

Duncan JS, Shorvon SD, Trimble MR. Discontinuation of phenytoin, carbamazepine, and valproate in patients with active epilepsy. Epilepsia 1990;31:324–33. Bromfield EB, Dambrosia J, Devinsky O, Nice FJ, Theodore WH. Phenytoin withdrawal and seizure frequency. Neurology 1989;39:905–9. Wang-Tilz Y, Tilz C, Wang B et al. Changes of seizures activity during rapid withdrawal of lamotrigine. Eur J Neurol 2005;12: 280–8. Spencer SS, Spencer DD, Williamson PD, Mattson RH. Ictal effects of anticonvulsant medication withdrawal in epileptic patients. Epilepsia 1981;22:297–307. Engel J, Crandall PH. Falsely localizing ictal onsets with depth EEG telemetry during anticonvulsant withdrawal. Epilepsia 1983;24:344–55. Marciani MG, Gotman J. Effects of drug withdrawal on location of seizure onset. Epilepsia 1986;27:423–31. Brady AH. Reduction of antiepileptic drug dosage for monitoring epileptic seizures. Acta Neurol Scand 1992;86:466–9. Yen DJ, Chen C, Shih YH et al. Antiepileptic drug withdrawal in patients with temporal lobe epilepsy undergoing presurgical video-EEG monitoring. Epilepsia 2001;42:251–5. Swick CT, Bouthillier A, Spencer SS. Seizure occurrence during long-term monitoring. Epilepsia 1996;37:927–30. Lowenstein DH. Status epilepticus: an overview of the clinical problem. Epilepsia 1999;40(Suppl. 1):S3–S8.

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Zone of electrical stimulation induced seizures in subdural electrodes R Schulz

Definition of zone of electrical stimulation induced seizures Electrical stimulation of the cortex can elicit afterdischarges (ADs), subclinical EEG seizure patterns, auras (SIA), and clinical seizures (SIS). Auras and clinical seizures can occur with nonhabitual or habitual symptomatology. Electrical stimulation takes place extraoperatively with implanted electrodes (subdural grid electrodes or depth electrodes), or intraoperatively by the neurosurgeon using stimulation electrodes. The area of responses can be defined as the zone of electrical stimulation induced seizures (ZESIS). The actual ictal onset zone as defined by spontaneous seizures is not always congruent with ZESIS so that ZESIS also includes cortex which is potentially epileptogenic, e.g., after the surgical removal of the actual seizure onset zone or pacemaker zone. From a historical perspective, SIA and SIS have been important in cortical localization since Fritsch and Hitzig discovered the irritability of the cortex using electrical stimulation in animals.1 Seizures were induced by electrical stimulation, by mechanical palpation of the brain during surgery, by local or systematic application of drugs, and by peripheral stimulation (e.g., photic stimulation). During the first decades stimulation concentrated on the motor cortex. Cortex outside the central region was mostly disregarded. Fritsch and Hitzig stimulated the motor cortex and elicited epileptic seizures with increased stimulation intensity. They strongly influenced Jackson who focused his studies on the semiology of unilateral motor seizures. Jackson argued that local symptoms like cloni of an arm imply a local lesion of the brain. Jackson also coined the term ‘variety of epilepsy’ for seizures characterized by ‘dreamy states’.2 Krause used the term ‘petit mal’ for seizures lasting only a few seconds regardless of the semiology, including auras, tonic seizures, and absences.3 Cushing assumed that the epileptogenic zone could be identified through auras elicited by electrical stimulation of the cortex when he wrote that in the future it would be possible ‘to pick out with an electrode areas of the brain from which the sensory aura of a focal convulsion has originated’ and speculated that this methodology would eventually lead toward ‘operative localization of subcortical irritative lesions of the immediate postcentral field.’ When mentioning subcortical lesions he was referring to lesions which cannot be detected by intraoperative inspection.4 706

Foerster was the first to use extensive stimulation outside the central cortex and reported on somatosensory, auditory, olfactory, gustatory, visual SIA, and prefrontal SIS.5 Foerster and Penfield reported the provocation of habitual seizures and auras by mechanical irritation and by stimulation with faradic current in a summery of 12 cases.6 In their stimulation studies, they carefully documented responses from the primary sensory and motor area and the occurrence of SIA and SIS. Furthermore, they outlined the visible epileptogenic lesion and the borders of the resections. In six of 12 cases (50%) the patient’s habitual seizure or aura was elicited by electrical stimulation. In two patients the cortical area with SIA or SIS was located within the epileptogenic lesion, in four patients the cortical area with SIA or SIS lay close to the epileptogenic lesion (1 cm or less). In all six patients the cortical area from which a habitual aura or seizure was elicited was resected together with complete removal of the epileptogenic lesion. Apparently Foerster assumed that the area with SIA was part of the epileptogenic zone which had to be resected to achieve seizure freedom. The initiative to develop epilepsy surgery further was taken by Penfield after the foundation of the Montreal Neurological Institute in 1934. In a study relating the Montreal experience, intraoperative stimulation reproduced habitual auras in 44 out of 80 patients (55%) with nontumoral parietal lobe epilepsy, in ten out of 25 patients (40%) with tumoral parietal lobe epilepsy7, and in 37% of 29 patients with occipital lobe epilepsy.8 Some of the patients with SIA are illustrated in detail in Penfield and Jasper’s compendium ‘Epilepsy and the functional anatomy of the human brain’.9 Penfield and Jasper9 considered SIA to be an important criterion for delineating the limits of resection: ‘Electrical stimulation is the original method of initiating focal cortical epileptic discharge, and is still one of the best.’ They carefully adjusted the stimulus intensity to initiate local discharges in a very restricted area of cortex: ‘Areas most susceptible to afterdischarges, especially if associated with the aura or onset of the patient’s seizure, indicate a hyperirritable cortex which may be the focus of spontaneous epileptic seizures.’ Penfield and Jasper also commented on SIA/SIS after spread from a distant source, suggesting that the SIA/SIS zone rarely leads to false assumptions about an epileptogenic region in silent cortex: ‘Volleys of nerve impulses arriving in a hyperirritable area of the cortex from different distant sources may serve to initiate epileptiform discharge in a manner similar to the direct stimulation of a hyperirritable cortex.’ In one of their

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Zone of electrical stimulation induced seizures in subdural electrodes documented cases, they commented that ‘distant stimulation had its effect by means of neuronal conduction along connecting pathways.’ But they mostly found a convergence of irritative and SIA/ SIS zone: ‘In the majority of cases, however, there is a close correlation between a spike focus and the area of susceptibility to prolonged afterdischarges. … There is also fairly good correspondence between the area of prolonged afterdischarges and the site from which the aura or onset of the attack was reproduced by electrical stimulation.’ In most cases the SIA zone was resected. In summary, Penfield and Jasper already discussed the present opinion of hyperirritable cortex – as documented by SIA/ SIS, afterdischarges, and interictal spikes – which in a minority of cases can also be triggered over a distance via connecting pathways of propagation. In 1954 Foerster, Penfield, and Jasper had used and had further developed the diagnostic means of the EEG in epilepsy surgery. Since that time brain imaging has considerably changed the diagnosis of the epileptogenic lesion so that preoperative, noninvasive detection is now possible in most cases in contrast to the previous reliance on EEG and, during surgery, inspection, electrocorticography, and assessment of SIA/ SIS.10,11 On the other hand, depth electrodes and subdural grid electrodes were essential in further contributing to the evolution of EEG and they now permit prolonged extraoperative evaluations with assessment of interictal and ictal EEG, mapping of functional cortex, and systematic registration of SIA, ADs, and SIS.

Defining ZESIS with subdural grid electrodes The technology and evaluation with subdural grid electrodes (SDE) in general have been outlined in Section 7 of this book. SIA and SIS occur as a by-product of electrical cortical stimulation for functional mapping. The stimulation current is increased in steps of 0.5–2 mA up to the maximum intensity of 15 mA or to the occurrence of functional responses, SIA or SIS. To discern accidental auras or seizures we usually only include SIA/SIS which occur more than once. To avoid eliciting a seizure after the first SIA at a given electrode we usually reduce the following stimulation current by 1 mA and stop the stimulation at this electrode after occurrence of the second SIA. SIA/SIS should occur without afterdischarges to exclude the triggering of remote cortical regions and make localization as precise as possible. On the other hand, the facilitation of pathways to a more distant pacemaker zone for auras and seizures indicates the irritability or epileptogenicity of all neurons involved. The threshold of afterdischarges (ADs) is low, especially in the primary motor and primary sensory areas (M1, S1),12 with easy triggering of a nonhabitual seizure semiology.13 The delineation of ADs and subclinical EEG seizure patterns is often not possible. Indeed, the EEG glossary of the International Federation of Clinical Neurophysiology defines ADs as EEG seizure patterns induced by electrical stimulation.14 Inoue and co-workers presented the EEG example of right temporal repetitive ADs with decreasing frequency, of 70 s duration, accompanied 30 s later by a contralateral, left

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temporal EEG seizure pattern and a habitual clinical seizure in a patient with left mesial temporal lobe sclerosis.15 In this case, the morphology of the EEG pattern with large-amplitude, low-frequency epileptiform discharges (similar to PLEDS), immediately after stimulation suggests ADs; the evolution of the frequency, however, suggests an EEG seizure pattern. The left temporal EEG seizure pattern was identical to the EEG pattern in spontaneous habitual seizures, clearly different to ADs. Obviously, there are gradual shifts in the epileptogenicity from ADs to clear-cut EEG seizure patterns. The threshold of ADs varies from day to day and even from stimulation to stimulation.16 To minimize ADs, antiepileptic medication is kept at a high level and often benzodiazepines are used. Afterdischarges, subclinical EEG seizure patterns, SIA, and SIS contribute to ZESIS. To our knowledge, systematic studies about the diagnostic value of ADs and stimulation-induced subclinical EEG seizure patterns in defining the epileptogenic zone do not exist. In a retrospective and prospective study of 31 patients, we evaluated the value of SIA in defining the extent of the epileptogenic zone.17 Sixteen of 31 patients (52%) had SIA. The epilepsy syndromes were classified as follows: frontal lobe epilepsy eight, parieto-occipital lobe epilepsy three, temporallobe epilepsy three, perirolandic epilepsy one, and nonlocalizable focal epilepsy one. In three patients the habitual first subjective sign of the seizure was not an aura in the strict sense of the term but a sensation of movement of an eye, a sensation of clonic jerks on one side of the mouth, or the inability to speak (aphasic seizure). SIA were elicited at one to 20 electrodes per patient (mean 4.8). SIA occurred on stimulation above the epileptogenic lesion in 75% of the patients (12 out of 16), in three patients 1 cm from the lesion, in one patient 2 cm from the lesion. The zone of SIA overlapped with the EEG seizure onset zone in 75% of the patients (12 out of 16); in three patients the EEG seizure onset zone was 1 cm away, and in the other patient SIA were located on the convexity of the cortex whereas the EEG seizure onset was on the mesial plate adjacent to the opposite limits of the lesion. Overlap of the SIA zone with the irritative zone of interictal spikes was observed in only 50% of the patients (eight out of 16). Relating surgical outcome to complete or incomplete resection of the epileptogenic lesion, the EEG seizure onset zone, the SIA zone, and the irritative zone of interictal spikes we found a significant correlation of surgical outcome only with the total removal of the epileptogenic lesion. Complete or incomplete resection of the EEG seizure onset zone, the SIA zone or the irritative zone did not permit prediction of the surgical outcome. However, the value of resecting the other zones in addition to the lesion could not be established because the number of patients was too small for statistical analysis with stepwise logistic regression. De Salles and co-workers reported a small series of 12 patients with invasive diagnosis using subdural strip electrodes. In eight patients cortical stimulation was performed.18 The authors argued that confirmation that with intracranial recordings was important for the final decision of resection, especially for the patient who experienced speech arrest, usual seizures and aura during cortical stimulation. …

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Cortical stimulation confirmed the seizure focus by inducing the usual seizures or aura in 75% of the patients undergoing electrical stimulation.

wakeful patient during surgery. The stimulation protocol has to take place within 1 hour or less, resulting in considerable time pressure so that SIA only rarely occur.

Surgical results were not mentioned in this study.

Conclusions Defining ZESIS intrasurgically Although extensive intrasurgical stimulation of the cortex for cortical mapping of eloquent areas was standard procedure in earlier days of epilepsy surgery, it is the exception nowadays and mostly confines itself to a definition of the language areas (Broca, Wernicke) or the primary motor cortex. The registration of SIA requires stimulation while the patient is awake. Anesthesia is demanding for both the patient and physician under these circumstances and as a consequence is applied only when the insertion of subdural grid electrodes is not possible and when functional mapping of language is necessary. The stimulation parameters are largely identical to extraoperative stimulation. We usually start at a current intensity of about 7 mA and increase in steps of 1–2 mA up to 15 mA. Instead of stimulation tweezers we use subdural strips so that the registration of ADs is also possible. After the occurrence of ADs stimulation is stopped to avoid the risk of SIS of the

The definition of ZESIS in SDE is usually a by-product of cortical mapping for language areas. The mapping of somatosensory and motor cortex is mostly done by SSEP and MEP during surgery and under considerable time pressure so that SIA/SIS rarely occur. Consequently only small evidence exists about the relative value of ZESIS versus other zones (e.g., lesion zone, irritative zone of interictal spikes or ictal EEG onset zone) with regard to postoperative seizure prognosis. Electrical stimulation is not undertaken merely for the definition of ZESIS because of possible complications of the implantation of SDE. On the other hand, neurologists and neurosurgeons will take the knowledge gained about a ZESIS together with other relevant information into consideration to delineate the borders of resection. A ZESIS in close vicinity to an epileptogenic lesion, with good convergence of the irritative and ictal onset zone, will be resected in most cases. A ZESIS with some distance to the epileptogenic lesion raises the doubt of propagation within a hyperconnective epileptogenic network and will often not be resected.

REFERENCES 1. 2. 3. 4. 5. 6.

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Fritsch G, Hitzig E. Ueber die elektrische Erregbarkeit des Grosshirns. Arch Anat Physiol Wiss Med 1870;300–32. Taylor J, ed. Selected Writings of John Hughlings Jackson. Volume 1: On Epilepsy and Epileptiform Convulsions. London; Staples Press: 1958:391. Krause F, Schum H. Die epileptischen Erkrankungen. 1 und 2. Hälfte. In:Krause F, ed. Die spezielle Chirurgie der Gehirnkrankheiten. Stuttgart: F Enke, 1931:103–4. Cushing H. A note upon the faradic stimulation of the postcentral gyrus in conscious patients. Brain 1909;32:44–53. Foerster O. Zur Pathogenese und chirurgischen Behandlung der Epilepsie. Zentralbl Chir 1925;52:531–48. Foerster O, Penfield W. Der Narbenzug am und im Gehirn bei traumatischer Epilepsie in seiner Bedeutung für das Zustandekommen der Anfälle und die therapeutische Bekämpfung derselben. Z f ges Neurol 1930;12:475–572. Salanova V, Andermann F, Rasmussen T et al. Parietal lobe epilepsy: clinical manifestations and outcome in 82 patients treated surgically between 1929 and 1988. Brain 1995;118: 607–27. Salanova V, Andermann F, Olivier A et al. Occipital lobe epilepsy: electroclinical manifestations, electrocorticography, cortical stimulation and outcome in 42 patients treated between 1930 and 1991. Brain 1992;115:1655–80. Penfield W, Jasper H. Epilepsy and the Functional Anatomy of the Human Brain. Boston: Little, Brown & Co, 1954. Sperling MR, Sutherling WW, Nuwer MR. New techniques for evaluating patients for epilepsy surgery. In: Engel J, ed. Surgical treatment of the epilepsies. New York; Raven Press: 1987:235–57.

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Kuzniecky RI, Cascino GD, Palmini A et al. Structural neuroimaging. In: Engel J Jr, ed. Surgical treatment of the epilepsies. 2nd edn. New York: Raven Press, 1993:197–209. Yazawa S, Ikeda A, Terada K et al. Subdural recording of Bereitschaftspotential is useful for functional mapping of the epileptogenic motor area: a case report. Epilepsia 1997;38:245–8. Schulz R, Lüders HO, Tuxhorn I et al. Localization of epileptic auras induced on stimulation by subdural electrodes. Epilepsia 1997;38:1321–9. Noachtar S, Binnie C, Ebersole J et al. A glossary of terms most commonly used by clinical electroencephalographers and proposal for the report form for the EEG findings. In: Deuschl G, Eisen A, eds. Recommendations for the Practice of Clinical Neurophysiology. Guidelines of the International Federation of Clinical Neurophysiology, 2nd edn. Amsterdam: Elsevier, 1999;21–2. (Electroenceph clin Neurophysiol (1999), suppl 52.) Inoue Y, Mihara T, Tottori T et al. Electrical stimulation of the contralateral mesial temporal structure induces an ipsilateral seizure pattern in mesial temporal lobe epilepsy. Epilepsia 1999; 40:1602–9. Lesser RP, Lüders HO, Klem G et al. Extraoperative cortical functional localization in patients with epilepsy. J Clin Neurophysiol 1987;4:27–53. Schulz R, Lüders HO, Tuxhorn I et al. Localization of epileptic auras induced on stimulation by subdural electrodes. Epilepsia 1997;38:1321–9. De Salles AA, Swartz BE, Lee TT et al. Subdural recording and electrical stimulation for cortical mapping and induc tion of usual seizures. Stereotact Funct Neurosurg 1994;62:226–31.

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SECTION 8 The epileptic lesion

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The epileptogenic lesion: general principles HM Hamer and S Knake

Concept of the epileptogenic lesion The most common cause of focal epilepsies is a morphological brain abnormality, the epileptogenic lesion. The concept of the epileptogenic lesion, however, is not without difficulties. Any alteration of the brain that can be identified by the pathologist could be considered an epileptogenic lesion but for the purposes of clinical practice, an epileptogenic lesion usually refers to a cerebral abnormality detected by invivo neuroimaging or by the surgeon. This concept was established with the introduction of CT scans but the development of magnetic resonance imaging (MRI) had the greatest impact on neuroimaging in epilepsy. The most frequent pathologies identified in partial epilepsy are hippocampal sclerosis (HS), vascular malformations, tumors, and malformations of cortical development (MCD). MCD constitute a large group of cortical malformations with distinct histopathological abnormalities revealing variable degrees of epileptogenicity. Establishing the etiology early in the course of epilepsies helps defining the prognosis and has the advantage to determine the possibility or even necessity of surgical treatment in the future. A potentially epileptogenic lesion detected by neuroimaging is predictive of good surgical outcome in frontal as well as in temporal lobe epilepsies.1–3 However, imaging of epilepsy patients can be challenging, since epileptogenic lesions frequently are small and difficult to detect. Moreover, their extent may be underestimated by MRI studies which is especially true in patients with MCD.2,4

most probably pathologic changes in the surrounding tissue due to hemosiderin deposits. On the other hand, postencephalitic lesions demonstrated by MRI were often widespread and even discordant to the seizure onset zone.5,6 This supports the observation that even incomplete removal of an assumingly epileptogenic lesion rendered a minority of patients seizure free.7 Not every lesion detected on structural imaging necessarily represents the epileptogenic lesion (Figure 81.1) and there is no definite way to predict by structural imaging to which extent the lesion identified on MRI overlaps with the epileptogenic cortex. Therefore, detailed video-EEG monitoring is required to establish the relationship between the structural lesion seen on imaging studies and the irritative and seizure onset zone. In selected cases, invasive recordings are necessary to achieve this goal. As a rule, the lesion can be considered epileptogenic, when irritative and seizure onset zone are overlapping with the lesion or are in the immediate neighborhood. If cortical areas which harbour the seizure onset zone but extend beyond the lesion are included in the resection, a better postoperative outcome was found as compared to simple lesionectomy.8 This confirms studies which showed that pure lesionectomy is associated with poorer outcome than ‘epilepsy surgery’ in a variety of etiologies.9 However, there are no convincing data to assume that the pathophysiology of epilepsy is the same for all different epileptogenic lesions nor is there reason to expect the postoperative prognosis to be the same.

Magnetic resonance imaging (MRI) Relationship between epileptogenic lesion and epileptogenic zone The presence of a structural lesion on imaging of epileptic patients usually implies that the epileptogenic zone comprises the lesion or lies in its immediate vicinity. However, the relationship between a lesion seen on imaging studies and the epileptogenic zone may be complex. Cortex extending far beyond the epileptogenic lesions seen on MRI studies, such as MCD or post-traumatic gliotic lesions, may appear normal on imaging but abnormal at a microscopic level and may be part of the epileptogenic zone. In noninfiltrating lesions, such as vascular malformations, the epileptogenic zone includes frequently the adjacent cortex. In cavernous hemangiomas, the main underlying mechanism for seizure generation is

MRI is clearly the most important imaging modality to detect structural cerebral abnormalities. Imaging strategy, quality and image interpretation have a major impact on the likelihood of detecting a lesion. Prior clinical and test information can assist in defining the possible location of the epileptogenic zone and should guide the MRI examination. Patients in whom a focal neocortical epilepsy is suspected should be imaged with a protocol that includes whole head thinsectioned high-resolution 3D T1-weighted and T2-weighted images and should also comprise a gradient echo T2 sequence. If mesial temporal epilepsy is suspected, the protocol should include high-resolution images scanned perpendicularly to the axis of the hippocampus to detect primary and secondary signs of hippocampal sclerosis. T1-weighted, T2-weighted and FLAIR sequences are usually employed. 711

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(a)

(b)

(c)

(d)

(e) Figure 81.1 35-year-old patient with medically refractory right hemispheric epilepsy leading to automotor seizures. Dual pathology was seen on MRI (hamartoma in the right amygdala (a, b), which was not detected on the first routine MRI and right parietal cavernous hemangioma (c, d). Video-EEG monitoring revealed right anterior temporal seizure patterns and interictal sharp waves exclusively recorded maximal in the right sphenoidal electrode which localized the seizure onset and irritative zone to the hamartoma. The patient remained seizure free after selective removal of the hamartoma (e).

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The epileptogenic lesion: general principles Scans through the rest of the brain should be analysed carefully to rule out dual pathology. Recent improvements in MRI have greatly increased the preoperative ability to identify epileptogenic lesions and to define their extent and nature. Image quality is generally enhanced by increasing the signal to noise ratio (SNR) available in a given scan time. The SNR can be improved in MRI by replacing the standard quadrature head coil by phased array (PA) surface coils and by going to field strengths higher than 1.5 T (Figure 81.2).10 These improvements increased lesion detection in patients with focal epilepsy.11 Phased array studies should particularly be considered in patients with focal epilepsies and medically refractory seizures. Additional developments in MRI techniques and image sequences, such as magnetisation transfer imaging,12 or double inversion recovery,13 have enabled further identification of abnormalities in patients in whom conventional MRI did not isolate a cause for focal seizures.14 Presurgical detection of brain lesions permit estimation of the spatial relationship of epileptogenic cortex to eloquent cortex and, if necessary, allow a more targeted placement of intracranial electrodes.11 Besides, the use of modern MRI in conjunction with stereotactic neurosurgery provides the opportunity to correlate the operating field with rendered views of the images acquired preoperatively and, thus, helps to tailor the resective procedure. However, there is still a subset of patients whose focal lesions will not be detected even by best quality neuroimaging and an experienced reader. Imaging research is directed to

713

such patients. Advanced techniques in postacquisition processing analysis such as diffusion tensor imaging,15,16 cortical thickness analysis,17 automated subcortical volumetry, cortical parcellation or statistic parametric mapping18–20 are innovative techniques whose potential to better define areas of structural brain abnormalities especially in so far ‘nonlesional’ patients is currently explored.

Electroencephalography In general, the EEG plays only an ancillary role to identify the nature of the epileptogenic lesion. There is one report that found interictal epileptiform discharges in patients with mesial temporal lobe epilepsy due to hippocampal sclerosis to be highly restricted to the anterior temporal region while patients with mesial temporal tumors showed more widespread interictal discharges.21 There is also evidence that continuous, rhythmic spiking on a slow background activity which is not associated with behavioral changes is characteristic although not pathognomonic for focal intrinsically epileptogenic cortical dysplastic lesions.2,22,23 Electroencephalography, however, is an essential tool to proof the epileptogenicity of a lesion seen on MRI (Figure 81.1). As mentioned above, the existence of a MRI-visible lesion in a patient with epilepsy does not proof its epileptogenicity. Video-EEG monitoring is necessary to demonstrate this relationship. Seizure semiology has to be consistent with the location of the lesion and the EEG defined irritative and seizure onset zone are usually required to overlap with the lesion or the immediate neighborhood. The same methodology is used when two or more lesions are detected in neuroimaging (Figure 81.1), such as patients with multiple cavernous hemangiomas or tuberous sclerosis. In selected cases invasive recordings are necessary to define the epileptogenicity of a lesion or the exact borders of the epileptogenic zone if the extent of the lesion is difficult to define by neuroimaging, such as in patients with MCD, or if it is unclear to what extent the adjacent cortex is responsible of the focal epilepsy.24

Magnetic resonance spectroscopy (MRS)

Figure 81.2 Ex vivo MRI of a healthy human brain, scanned at 7T using a 5-cm 1-channel surface-coil. The image is an average of four 1-hour runs of a 3D flash sequence (320 × 512 × 512, 120 µm isotropic voxel, TR/TE/flip 30 ms/4.5 ms/10 ms). The occipital pole and the superior part of the cerebellum are shown in great detail. In the occipital cortex, the stria of Gennari can be seen (arrowheads). The image quality and details give an outlook about future imaging possibilities, making it possible to detect even subtle pathologies. (Image courtesy of Lawrence L. Wald, PhD, A. A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Dept. of Radiology, Charlestown, MA.)

Magnetic resonance spectroscopy investigates cerebral metabolites, pH and some neurotransmitters. MRS provides an indirect, noninvasive tool to measure the integrity and function of neuronal tissue. Most clinical studies use 1H-MRS at 1.5 T scanners with spatial resolutions between approximately 1 and 8 cc depending on whether multivoxel or single voxel techniques are applied. 1H-MRS provides biochemical information about neuronal function (N-acetyl aspartate), membrane turnover (choline), total energy stores (creatine) as well as the presence of cerebral lactate.25 The sensitivity and specificity of pathological findings in MRS in patients with temporal lobe epilepsy ranges from 6026 to 90%27 with higher spatial resolution spectroscopic imaging techniques reporting greater sensitivity and specificity.28 Especially in patients with unremarkable structural imaging, MRS may be helpful to

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delineate the epileptogenic lesion. However, it has been reported, that the 1H-MRS signal may also be modified by recent seizure activity,29,30 by antiepileptic medication or by metabolic interventions such as the ketogenic diet.31,32,32 Therefore, results should always be interpreted with caution and in the clinical context. The usefulness of MRS in the presurgical evaluation has not yet been fully determined and its clinical application is still very limited.25

Positron emission tomography (PET) Positron emission tomography using desoxyglucose (FDGPET) demonstrates areas of reduced glucose metabolism, which are characteristic for the interictal state of the epileptogenic zone but usually extend beyond it.33 It may be useful in temporal lobe epilepsy for lateralization. However, results in extratemporal lobe epilepsy have been less favorable.4 FDGPET has been applied as an ancillary technique to identify the epileptogenic lesion in a certain subset of patients, such as patients with MCD or tumors unseen by MRI at its present state.34 More promising than FDG-PET may be PET studies which explore various neurotransmission related with epileptogenesis and thus, delineate better the extent of the epileptogenic zone. Benzodiazepine receptor ligands, such as flumazenil (FMZ), are found to be reduced in the epileptogenic zone and FMZ-PET images were more sensitive than FDG-PET to define the epileptogenic zone.4,35,36 FMZ-PET allowed lateralisation and localisation of seizure onset in MRI negative patients suffering from frontal lobe epilepsy.37 Tryptophan PET was reported in one study to differentiate between epileptogenic and nonepileptogenic tubers in patients with tuberous sclerosis.35 However, the lack of large multicentric and controlled studies, evaluating the impact of PET,

represents a major limitation to a better understanding of the clinical role and utility of PET in epilepsy.38

Conclusions MRI is generally the imaging technique of choice for identifying the structural basis of focal epilepsies. This is important for the diagnosis of focal epilepsies, the determination of therapeutic options and the prognosis in general39 as well as in respect to epilepsy surgery. Clinical and electrographic information on the possible location of the epileptogenic zone often helps to target imaging studies properly. Recent developments in MRI techniques and advanced postacquisition processing techniques further improved the sensitivity of MRI but there is still a subset of patients with focal epilepsy and unremarkable MRI. Not every lesion seen on imaging studies is epileptogenic and the relationship between the structural abnormalities on MRI and the epileptogenic zone can be complex. Therefore, correlation with clinical and electrophysiological data is mandatory. In addition, MRS and PET can help to define this relationship. The usefulness of novel MRI, MRS and PET techniques for assessment of patients MRI-negative with standard techniques is not clear yet because only few studies have directly compared the different imaging techniques in large samples or related the findings to postoperative outcome. Currently, a combination of different imaging modalities tailored specifically for each patient appears to be most appropriate to improve postoperative seizure control and reduce postoperative impairment through more accurate identification of the epileptogenic lesion, surrounding eloquent cortex, the epileptogenic zone, and vital connections between cortical areas. In addition to their use in the presurgical planning, these methods may reduce the need for invasive techniques in the future.

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Kuzniecky R, Murro A, King D et al. Magnetic resonance imaging in childhood intractable partial epilepsies: pathologic correlations. Neurology 1993;43:681–7. Palmini A, Gambardella A, Andermann F et al. Intrinsic epileptogenicity of human dysplastic cortex as suggested by corticography and surgical results. Ann Neurol 1995;37:476–87. Mosewich RK, So EL, O’Brien TJ et al. Factors predictive of the outcome of frontal lobe epilepsy surgery. Epilepsia 2000;41:843–9. Schauble B, Cascino GD. Advances in neuroimaging: management of partial epileptic syndromes. Neurosurg Rev 2003;26:233–46. Trinka E, Dubeau F, Andermann F et al. Successful epilepsy surgery in catastrophic postencephalitic epilepsy. Neurology 2000; 54:2170–3. Trinka E, Dubeau F, Andermann F et al. Clinical findings, imaging characteristics and outcome in catastrophic post-encephalitic epilepsy. Epileptic Disord 2000;2:153–62. Carreno M, Kotagal P, Perez JA et al. Intractable epilepsy in vascular congenital hemiparesis: clinical features and surgical options. Neurology 2002;59:129–31. Stefan H, Hammen T. Cavernous haemangiomas, epilepsy and treatment strategies. Acta Neurol Scand 2004;110:393–7. Weber JP, Silbergeld DL, Winn HR. Surgical resection of epileptogenic cortex associated with structural lesions. Neurosurg Clin N Am 1993;4:327–36. Grant PE. Imaging the developing epileptic brain. Epilepsia 2005;46(Suppl 7):7–14.

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Knake S, Triantafyllou C, Wald LL et al. 3 T phased array MRI improves the presurgical evaluation in focal epilepsies: a prospective study. Neurology 2005;65:1026–31. Rugg-Gunn FJ, Eriksson SH, Boulby PA et al. Magnetization transfer imaging in focal epilepsy. Neurology 2003;60:1638–45. Rugg-Gunn FJ, Boulby PA, Symms MR et al. Imaging the neocortex in epilepsy with double inversion recovery imaging. Neuroimage 2006; 31:39–50. Koepp MJ, Woermann FG. Imaging structure and function in refractory focal epilepsy. Lancet Neurol 2005;4:42–53. Eriksson SH, Rugg-Gunn FJ, Symms MR et al. Diffusion tensor imaging in patients with epilepsy and malformations of cortical development. Brain 2001;124:617–26. Knake S, Grant PE, Stufflebeam SM et al. Aids to telemetry in the presurgical evaluation of epilepsy patients: MRI, MEG and other non-invasive imaging techniques. Suppl Clin Neurophysiol 2004;57:494–502. Fischl B, Dale AM. Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci USA 2000;97:11050–5. Fischl B, Salat DH, Busa E et al. Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron 2002;33:341–55. Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage 1999;9:179–94. Fischl B, van der KA, Destrieux C et al. Automatically parcellating the human cerebral cortex. Cereb Cortex 2004;14:11–22.

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Hamer HM, Najm I, Mohamed A et al. Interictal epileptiform discharges in temporal lobe epilepsy due to hippocampal sclerosis versus medial temporal lobe tumors. Epilepsia 1999;40:1261–8. Gambardella A, Palmini A, Andermann F et al. Usefulness of focal rhythmic discharges on scalp EEG of patients with focal cortical dysplasia and intractable epilepsy. Electroencephalogr Clin Neurophysiol 1996;98:243–9. Rosenow F, Lüders HO, Dinner DS et al. Histopathological correlates of epileptogenicity as expressed by electrocorticographic spiking and seizure frequency. Epilepsia 1998;39:850–6. Lüders H, Awad I, Burgess R et al. Subdural electrodes in the presurgical evaluation for surgery of epilepsy. Epilepsy Res Suppl 1992;5:147–56. Knake S, Grant PE. Magnetic resonance imaging techniques in the evaluation for epilepsy surgery. In: Wyllie E, ed. The Treatment of Epilepsy: Principles and Practice. Philadelphia: Lippincott Williams and Wilkins, 2004. Connelly A, Van Paesschen W, Porter DA et al. Proton magnetic resonance spectroscopy in MRI-negative temporal lobe epilepsy. Neurology 1998;51:61–6. Meiners LC, van der GJ, van Rijen PC et al. Proton magnetic resonance spectroscopy of temporal lobe white matter in patients with histologically proven hippocampal sclerosis. J Magn Reson Imaging 2000;11:25–31. Hetherington HP, Pan JW, Spencer DD. 1H and 31P spectroscopy and bioenergetics in the lateralization of seizures in temporal lobe epilepsy. J Magn Reson Imaging 2002;16:477–83. Mueller SG, Kollias SS, Trabesinger AH et al. Proton magnetic resonance spectroscopy characteristics of a focal cortical dysgenesis during status epilepticus and in the interictal state. Seizure 2001;10:518–24.

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Ende GR, Laxer KD, Knowlton RC et al. Temporal lobe epilepsy: bilateral hippocampal metabolite changes revealed at proton MR spectroscopic imaging. Radiology 1997;202:809–17. Pan JW, Bebin EM, Chu WJ et al. Ketosis and epilepsy: 31P spectroscopic imaging at 4.1 T. Epilepsia 1999;40:703–7. Kuzniecky R, Hetherington H, Ho S et al. Topiramate increases cerebral GABA in healthy humans. Neurology 1998;51:627–9. Theodore WH, Fishbein D, Dubinsky R. Patterns of cerebral glucose metabolism in patients with partial seizures. Neurology 1988;38:1201–6. Hwang SI, Kim JH, Park SW et al. Comparative analysis of MR imaging, positron emission tomography, and ictal single-photon emission CT in patients with neocortical epilepsy. AJNR Am J Neuroradiol 2001;22:937–46. Chugani DC, Chugani HT, Muzik O et al. Imaging epileptogenic tubers in children with tuberous sclerosis complex using alpha[11C]methyl-L-tryptophan positron emission tomography. Ann Neurol 1998;44:858–66. Muzik O, da Silva EA, Juhasz C et al. Intracranial EEG versus flumazenil and glucose PET in children with extratemporal lobe epilepsy. Neurology 2000;54:171–9. Ryvlin P, Bouvard S, Le Bars D et al. Clinical utility of flumazenilPET versus [18F]fluorodeoxyglucose-PET and MRI in refractory partial epilepsy. A prospective study in 100 patients. Brain 1998;121(Pt 11):2067–81. Mauguiere F, Ryvlin P. The role of PET in presurgical assessment of partial epilepsies. Epileptic Disord 2004;6:193–215. Semah F, Picot MC, Adam C et al. Is the underlying cause of epilepsy a major prognostic factor for recurrence? Neurology 1998;51:1256–62.

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Magentic resonance imaging in epilepsy: mesial temporal sclerosis GD Cascino

Introduction Partial or localization-related epilepsy is the most common seizure disorder.1–3 Over 90% of the incident cases of epilepsy in adults experience partial seizure activity.1,2 The most frequently occurring seizure type in the adult patient is a complex partial seizure of mesial temporal lobe origin.1–3 Approximately 45% of patients with partial epilepsy will experience medically refractory seizures that are physically and socially disabling.1 A minority of patients who fail to respond to first-line antiepileptic drug (AED) therapy will be rendered seizure free with newer medical treatments introduced in the past decade.4–6 Less than 10% of patients will have a medically responsive seizure disorder if habitual seizures persist with the initial two or three AED medications. Epilepsy surgery is an effective and safe alternative form of therapy for selected patients with intractable partial epilepsy.1,2,7–12 Patients with medial temporal lobe epilepsy and lesional epilepsy may be favorable candidates for epilepsy surgery and have a surgically remediable epileptic syndrome.2,7,8 Surgical treatment compared favorably, i.e., more effective in reducing seizure tendency, to AED medication in a randomized controlled trial evaluating medical and surgical therapies in 80 patients with temporal lobe epilepsy. The majority of these patients experience a significant reduction in seizure tendency following surgical ablation of the epileptic brain tissue.7–16 The hallmark pathology of medial temporal lobe epilepsy is mesial temporal sclerosis (MTS).17,14,16–18 The surgically excised hippocampus in these patients almost invariably shows focal cell loss and gliosis.13,14,16–18 This entity is also referred to as hippocampal sclerosis, although, the pathological findings characteristically extend to the amygdala, subcortical white matter, and entorhinal cortex. Patients with lesional epilepsy may have a primary brain tumor, vascular anomaly or malformations of cortical development (MCD).10,11,14,15,18 The common surgical pathologies encountered in patients with lesional epilepsy include a low-grade glial neoplasm, gangliogliomas, dysembryoplastic neuroepithelial tumors (DNETs), cavernous hemangioma and focal cortical dysplasia.10,11 Individuals with mesial temporal sclerosis and lesional pathology usually have an abnormal structural magnetic resonance imaging (MRI) study and the seizure types are classified as substrate-directed partial epilepsy.2,10,18–20 Other MRI-identified structural abnormalities that may indicate the localization of the epileptic brain tissue include focal encephalomalacia related to a prior traumatic brain injury, cerebral infarction or intracranial 716

hemorrhage. The MRI in these individuals may detect a specific intra-axial structural abnormality that may suggest the likely site of seizure onset and the surgical pathology.20 MRI has a pivotal role in the selection and evaluation of patients for alternative forms of therapy.7,10,13,16–18 The rationale for the presurgical evaluation is to identify the site of ictal onset and initial seizure propagation, i.e., epileptogenic zone, and determine the likely pathological findings underlying the epileptic brain tissue.12,13 In patients with an MRI-identified foreigntissue lesion or unilateral mesial temporal sclerosis the purpose of the electroclinical correlation is essentially to confirm the epileptogenicity of the structural abnormality.13,15,16,18 The demonstration of concordance between the pathological substrate and the ictal onset zone indicates a highly favorable operative outcome in selected individuals. Approximately 80% of patients with a ganglioglioma, dysembryoplastic neuroepithelial tumor or cavernous hemangioma are rendered seizure free following surgical treatment.2,7,11,13–16,18 The operative strategy in these individuals usually includes excision of the foreign-tissue lesion and the epileptogenic zone. Over 90% of patients with these pathological findings will experience an excellent surgical outcome, i.e., auras only or rare nondisabling seizures.7 The operative outcome is distinctly less favorable in individuals with focal cortical dysplasia and other MCD.19 The most common operative strategy in patients with intractable partial epilepsy involves a focal cortical resection of the epileptogenic zone with an excision of the surgical pathology.10,11 The goals of surgical treatment are to render the individual seizure free and allow the patient to become a participating and productive member of society.1,2,9 This chapter will discuss the use of MRI in the evaluation of patients with medial temporal lobe epilepsy who are being considered for surgical treatment.

Magnetic resonance imaging MRI has been demonstrated to be the most sensitive and specific structural neuroimaging procedure in patients with partial or localization-related epilepsy.2,7 Importantly, MRI is a noninvasive technique that has no known biological toxicity and does not involve ionizing radiation.18 The presence of an MRI-identified structural abnormality may suggest the localization of the site of seizure onset.4–8 The high diagnostic yield of MRI to delineate foreign-tissue lesions, e.g., tumor or vascular malformation, has been confirmed.13 MRI findings have

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Magentic resonance imaging in epilepsy: mesial temporal sclerosis Table 82.1

717

Surgically remediable epileptic syndromes

Selected epileptic syndromes

MRI

SISCOM

Pathology

> 90% 100% 100% 80–90%

– – – –

MTS Ganglioglioma, glioma, DNET Cavernous hemangioma, AVM FCD

0%

75%

Gliosis, focal cell loss, none

Substrate-directed Medial temporal lobe epilepsy Lesional epilepsy: tumor Lesional epilepsy: vascular Lesional epilepsy: malformation Non Substrate-Directed Neocortical (extrahippocampal)

Adapted from Cascino GD. Advances in neuroimaging: Surgical localization. Epilepsia 2001; 42:3–12.

been used to select favorable candidates for epilepsy surgery, tailor the operative resection, and confirm the extent of corticectomy postoperatively.16 The sensitivity and specificity of MRI in patients with localization-related epilepsy has been confirmed.13 The high diagnostic yield of MRI to ‘reveal’ the common pathological alterations, e.g., post-trauma, vascular malformation, tumor, MCD has been demonstrated in patients undergoing epilepsy surgery. The optimal technique in adult patients with partial epilepsy must include coronal or oblique-coronal images using T1-weighted and T2-weighted sequences.15,16 The most common imaging alteration in the adult with intractable partial epilepsy is medial temporal lobe atrophy with a signal intensity change.15,16 Fluid attenuated inversion recovery (FLAIR) sequences have been shown to increase the sensitivity of MRI to indicate a signal change (personal communication: Dr Clifford Jack). Both magnetic resonance spectroscopy (MRS) and positron emission tomography (PET) have a high diagnostic yield in patients with temporal lobe epilepsy. These techniques may be most useful in patients with indeterminate structural MRI studies, e.g., no intra-axial abnormality of bilateral hippocampal atrophy. Patients with lesional epilepsy may have a primary brain tumor, vascular anomaly or a malformation of cortical development (MCD). The common surgical pathologies encountered in patients with lesional epilepsy include a low-grade glial neoplasm, cavernous hemangioma and focal cortical dysplasia. Individuals with mesial temporal sclerosis and lesional Table 82.2

pathology almost invariably have an abnormal structural magnetic resonance imaging (MRI) study and the seizuretypes are classified as substrate-directed partial epilepsy. The MRI in these individuals may detect a specific intra-axial structural abnormality that may suggest the likely site of seizure onset and the surgical pathology. The MRI seizure protocol at the Mayo Clinic Rochester includes: 1. Sagittal T1-weighted imaging with minimum echo time (TE) and 500 msec repetition time (TR) required for whole-head coverage with 5-mm thick contiguous sections; 2. Whole-head coronal three-dimensional volumetric spoiled gradient-echo (SPGR) acquisition is performed with minimum full TE and TR, 192 views, one repetition, 1.5 mm section thickness with 124 partitions, 22 cm field of view, and 45° flip angle; and 3. Coronal spin-echo (SE) imaging is performed with TE of 30 and 80 msec, TR greater than 2000 msec, 20-cm field of view, 4-mm section thickness and 2-mm intersection gap, and 192 views with one repetition. An oblique-coronal fluid attenuated inversion recovery (FLAIR) sequence is also obtained. The FLAIR sequence allows the pathological signal change to be differentiated from the physiological signal alteration related to cerebrospinal fluid. An enhanced study will be performed if a space-occupying lesion is detected in the unenhanced study.

Presurgical evaluation

Performed invariably

Performed variably

At selected centers

History and examination Routine EEG MRI head Video-EEG (extracranial) Neuropsychology

Video-EEG (intracranial) Electrocorticography FDG-PET Interictal-ictal SPECT Sodium amobarbital study

SISCOM MRS PET receptor studies Functional MRI MRI volumetry

Performed invariably: almost always obtained prior to epilepsy surgery. Performed variably: available at most epilepsy centers, used in selected candidates. Performed selected centers: not widely available. MRI: magnetic resonance imaging. PET: positron emission tomography. SPECT: single photon emission computed tomography. SISCOM: subtraction ictal SPECT co-registered to MRI. MRS: magnetic resonance spectroscopy.

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Medial temporal lobe epilepsy The three major categories of symptomatic partial epilepsy are as follows: (1) medial temporal lobe epilepsy; (2) lesional epilepsy; and (3) nonlesional neocortical epilepsy.1 Approximately 80% of patients with partial epilepsy have temporal lobe seizures.6 The epileptogenic zone in the temporal lobe involves the amygdalohippocampal complex in nearly 90% of patients.21 The pathological hallmark of medial temporal lobe epilepsy is MTS. 5,7 Surgically excised pathology in approximately 65% of patients with intractable partial epilepsy is MTS associated with focal neuronal loss with or without gliosis.5,7 A structural lesion underlying the epileptogenic zone is identified in approximately 30% of patients undergoing epilepsy surgery. Lesional pathology includes primary brain tumors, vascular malformations, and MCD. Mesial temporal sclerosis MRI findings in patients with MTS include hippocampal formation atrophy (HFA) and an increased mesial temporal signal intensity5,7,11,13–15 (Figures 82.1–82.3). Inspection of MRI will allow detection of 80–90% of the cases of MTS.5,7,11,13-15 The HFA atrophy is most obvious using the T1weighted image in the oblique-coronal plane.5,7 The signal intensity alteration can be identified using T2-weighted imaging or the FLAIR sequence in the oblique-coronal plane. The coronal or oblique-coronal planes are useful for MRI studies in patient MTS because of the capability to compare the two hippocampi for any side to side asymmetry.5,7,11,13,14 Potential limitations of visual inspection of the MRI in patients with suspected MTS includes the following: head rotation, symmetrical bilateral HFA, subtle unilateral HFA or signal intensity alteration. Most importantly, visual inspection is a subjective determination that is strongly dependent on the inspector’s expertise for appropriate interpretation. Threedimensional SPGR images are helpful since they are reformatted into true anatomic coronal plane.

Figure 82.1 MRI head: 3-Tesla T1-weighted pulse sequence in the oblique-coronal plane revealing atrophy of the left hippocampus. The pathological findings showed hippocampal neuronal loss. (Note: the left hippocampus is on the right side of the figure).

Figure 82.2 MRI head: 3-Tesla fluid attenuated inversion recovery sequence (FLAIR) in the oblique-coronal plane revealing a signal intensity alteration in the left hippocampus. The pathological findings showed severe gliosis. (Note: the left hippocampus is on the right side of the figure.)

MRI-based hippocampal formation volumetric studies have been developed to objectively determine the degree of hippocampal volume loss in patients with MTS.13,14,16–18 Absolute hippocampal volume measurements are performed using a standardized protocol with the results being compared to age-matched normal controls to assign abnormal values.13 A unilateral reduction in hippocampal volume has been shown to be a reliable indicator of the temporal lobe of seizure origin in patients with medically refractory partial epilepsy. Jackson et al. described T2 relaxometry to objectively determine the medial temporal lobe signal intensity.17 Quantitative MRI studies have limited clinical application because of the high diagnostic yield of visual inspection. The most important use of hippocampal formation volumetry and T2 relaxometry is for research studies. HFA correlates with an early age of seizure onset, a history of a febrile seizure of childhood, and

Figure 82.3 MRI head: 3-Tesla heavily T2-weighted pulse sequence in the axial plane shows unilateral hippocampal formation atrophy and a signal intensity alteration in the left hippocampus. The pathological findings showed hippocampal neuronal loss and gliosis. (Note: the left hippocampus is on the right side of the figure.)

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Magentic resonance imaging in epilepsy: mesial temporal sclerosis Table 82.3

MRI and surgical pathology

Table 82.4

MRI Pathology

T1

T2

FLAIR

Tumor AVM MCD MTS

+ ++ – –

++ ++ +/– +/–

+++ ++ + +

MRI and mesial temporal sclerosis

MRI Techniques HF atrophy Gad-DTPA – – – ++

++/– +/– – –

719

T2-relaxometry IR Visual atrophy IR + visual atrophy Hippocampal volumetry

Sensitivity 79% 86% 90% 93% 97%

Kuzniecky et al., 1997 T1: T1-weighted imaging sequence. T2: T2-weighted imaging sequence. FLAIR: fluid attenuated inversion recovery sequence. HF atrophy: hippocampal formation atrophy or volume loss. Gad-DTPA: gadolinium enhanced study. Tumor: primary brain tumor. AVM: vascular malformation. MCD: malformation of cortical development. MTS: mesial temporal sclerosis.

the diagnosis of medial temporal lobe epilepsy.13,14,16–18 A history of a neurologic illness in childhood, e.g., febrile seizure, head trauma, or meningitis, appears to be an important risk factor for the development of MTS.16 The duration of epilepsy and age at the time of surgery have not correlated with volumetric results in most studies.13,14,16 The identification of MTS in the surgically excised temporal lobe has been a favorable prognostic indicator of seizure control following epilepsy surgery.12 Nearly 90% of patients with unilateral hippocampal atrophy have been rendered seizure free.16 MRI is now recognized as being predictive of neurocognitive outcome in patients undergoing an anterior temporal lobectomy.18 Patients with normal left hippocampal volumes are at greater risk for experiencing a significant decline in cognitive performance following a left medial temporal lobe resection than those with left HFA.16–18 Magnetic resonance spectroscopy Proton (1H) MRS has been shown to be a reliable indicator of the temporal lobe of seizure origin in patients with medial temporal lobe epilepsy.28,29 1H MRS is highly sensitive in the lateralization of temporal lobe seizures by revealing a reduction in N-acetylated compound (NA) concentrations or abnormalities in the creatine (Cr)/NA or NA/choline ratios.28,29 The underlying pathogenesis for the metabolic changes are likely to be complex and may relate to focal neuronal loss, gliosis, or a functional alteration intimately associated with the frequency of seizure activity. The diagnostic yield of MRS is similar to structural MRI in patients with medial temporal lobe epilepsy related to MTS28. The detection of metabolic abnormalities by 1H MRS also correlates with the outcome following temporal lobectomy for intractable partial epilepsy.28,29 Preoperative metabolic abnormalities in the contralateral temporal lobe were predictive of operative failure. 1H MRS may be of particular benefit in patients with medial temporal lobe epilepsy and normal structural MRI studies.28,29 Proton spectroscopy may also lateralize the epileptic temporal lobe in patients with bilateral hippocampal formation atrophy. There is limited information regarding the diagnostic yield of 1H MRS in patients with

neocortical, extrahippocampal, seizures. The potential benefits of proton spectroscopy in patients with nonlesional extratemporal seizures remain to be determined. At present, 1 H MRS is an investigative diagnostic tool that is restricted to only selected epilepsy centers. Despite observations of focal metabolic abnormalities in selected patients with nonlesional extratemporal seizures, it is doubtful that this diagnostic innovation will have widespread use to demonstrate a localized abnormality in patients with nonsubstrate-directed partial epilepsy.

Conclusions The presurgical evaluation in patients with substratedirected partial epilepsy is designed to determine the epileptogenicity of the neuroimaging alteration. The rationale for the electrophysiological studies is essentially confirmatory in patients with unilateral MRI-identified mesial temporal sclerosis or an isolated foreign-tissue lesion. Video-EEG monitoring is performed in these individuals to confirm the diagnosis of a partial seizure disorder, establish the seizuretype, and determine the disabling effect of the ictal behavior. Functional neuroimaging procedures may not be necessary in patients with medial temporal lobe epilepsy or lesional epilepsy in the presence of a structural MRI abnormality that is concordant with the remainder of the presurgical evaluation. Both MRS and PET have a high diagnostic yield in patients with temporal lobe epilepsy. These techniques may be most useful in patients with indeterminate structural MRI studies, e.g., no intra-axial abnormality of bilateral hippocampal atrophy. In patients with nonsubstrate-directed partial epilepsy there are significant concerns regarding the localization of the epileptogenic zone. Chronic intracranial EEG monitoring may prove necessary in these patients, especially with extratemporal epilepsy. Identification of a localized SISCOM focus may be a reliable indicator of the ictal onset zone. SISCOM may reveal a localized region of cerebral hyperperfusion or hypoperfusion in up to 80% of patients with intractable partial epilepsy. The SISCOM findings are also predictive of operative outcome. Ultimately, a decision regarding surgical treatment must be based on a convergence of the neurodiagnostic evaluation. Electrophysiological studies invariably need to be performed to localize the ictal onset zone in these patients. Resection of the SISCOM focus may be necessary to significantly reduce the seizure tendency in patients with a localized abnormality that is concordant with the epileptic brain tissue.

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3. 4. 5. 6. 7. 8.

9. 10. 11. 12. 13. 14. 15. 16.

Dreifuss FE. Goals of surgery for epilepsy. In Engel J Jr, ed. Surgical Treatment of the epilepsies, 1st edn. New York: Raven Press, 1987:31–49. Cascino GD. Selection of candidates for surgical treatment of epilepsy. In: Cascino GD, Jack CR Jr, eds. Neuroimaging in Epilepsy: Principles and Practice. Boston: ButterworthHeinemann, 1996:209–18. Mattson RH. Drug treatment of uncontrolled seizures. Epilepsy Res (Suppl) 1992;5:29–35. Camfield P, Camfield C. Antiepileptic drug therapy: when is epilepsy truly intractable? Epilepsia 1996;37(Suppl 1):S60–5. Hauser W. The natural history of drug resistant epilepsy: epidemiologic considerations. Epilepsy Res (Suppl) 1992;5:25–8. Hauser A, Hesdorffer D. Prognosis. In: Hauser WA, Hesdorffer DC, eds. Epilepsy: Frequency, Causes and Consequences. New York: Demos,1990:197–243. Radhakrishnan K, So EL, Silbert PL et al. Predictors of outcome of anterior temporal lobectomy for intractable epilepsy: a multivariate study. Neurology 1998;51:465–71. Van Buren JM, Ajmone-Marsan C, Mustaga N et al. Surgery of temporal lobe. In: Purpura DP, Penry JK, Walter RD, eds. Neurosurgical Management of the Epilepsies. New York: Raven Press, 1975:155–96. Crandall PH. Postoperative management and criteria for evaluation. In: Purpura DP, Penry JK, Walter RD, eds. Advances in Neurology. New York: Raven Press, 1987:31–49. Cascino GD, Boon PAJM, Fish DR. Surgically remediable lesional syndromes. In: Engel J Jr, ed. Surgical Treatment of the Epilepsies, 2nd edn. New York: Raven Press, 1993:77–86. Awad IA, Rosenfeld J, Ahl H, Hahn JF, Lüders Ho. Intractable epilepsy and structural lesions of the brain: mapping, resection strategies, and seizure outcome. Epilepsia 1991;32:179–86. Engel J Jr, Ojemann GA. The next step. In: Engel J Jr, ed. Surgical Treatment of the Epilepsies, 2nd edn. New York: Raven Press, 1993:319–29. Cascino GD, Trenerry MR, So E et al. Routine EEG and temporal lobe epilepsy: relation to long-term EEG monitoring, quantitative MRI, and operative outcome. Epilepsia 1996;37:651–6. Cascino GD, Jack CR, Parisi J et al. Operative strategy in patients with MRI-identified dual pathology and temporal lobe epilepsy. Epilepsy Res 1993;14:175–82. Mosewich RK, So EL, O’Brien TJ et al. Factors predictive of the outcome of frontal lobe epilepsy surgery. Epilepsia 2000;41:843–9. Cambier DM, Cascino GD, So EL, Marsh WR. Video-EEG monitoring in patients with hippocampal atrophy. Acta Neurol Scan 2001; 103:1–7.

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Jackson GD. Visual analysis in mesial temporal sclerosis. In: Cascino GD, Jack CR, eds. Neuroimaging in Epilepsy: Principles and Practice. Boston: Butterworth-Heinemann, 1996:73–110. Cascino GD, Jack CR Jr, Parisi JE et al. MRI in the presurgical evaluation of patients with frontal lobe epilepsy and children with temporal lobe epilepsy: pathological correlation and prognostic importance. Epilepsy Res 1992;11:51–9. Palmini A, Andermann F, Olivier A et al. Focal neuronal migrational disorders and intractable partial epilepsy: results of surgical treatment. Ann Neurol 1991;30:750–7. Kuzniecky RI. Magnetic resonance imaging in cerebral developmental malformations and epilepsy. In Cascino GD, Jack CR Jr, eds. Neuroimaging in Epilepsy: Principles and Practice. Boston: Butterworth-Heinemann, 1996:51–63. O’Brien TJ, So EL, Mullan BP et al. Extent of resection of the ictal subtraction SPECT focus is an important determinant of epilepsy surgery outcome. Epilepsia 1996;37 (Suppl 5):S182. Spencer S. The relative contributions of MRI, SPECT and PET imagining in epilepsy. Epilepsia 1994;35:S72–89. Theodore WH. Positron emission tomography in the evaluation of epilepsy. In: Cascino GD, Jack CR Jr, eds. Neuroimaging in Epilepsy. Principles and Practice. Boston: Butterworth-Heinemann, 1996:165–75. Henry TR, Babb TL, Engel J Jr, et al. Hippocampal neuronal loss and regional hypometabolism in temporal lobe epilepsy. Ann Neurol 1994;36:925–7. Ho SS, Berkovic SF, Berlangieri SU et al. Comparison of ictal SPECT and interictal PET in the presurgical evaluation of temporal lobe epilepsy. Ann Neurol 1995;37:738–45. Sata Y, Matsuda K, Mihara T et al. Quantitative Analysis of benzodiazepine receptor in temporal lobe epilepsy: [125I]lomazenil autoradiographic study of surgically resected specimens. Epilepsia 2002;43:1039–48. Juhasz C, Chugani DC, Muzik O et al. Alpha-methyl-L-tryptophan PET detects epileptogenic cortex in children with intractable epilepsy. Neurology 2003;60:960–8. Cendes F, Caramanos Z, Andermann F, Dubeau F, Arnold DL. Proton magnetic resonance spectroscopy imaging and magnetic resonance imaging volumetry in the lateralization of temporal lobe epilepsy. Ann Neurol 1997;42:737–46. Kuzniecky R, Hugg JW, Hetherington H et al. Relative utility of 1 H spectroscopic imaging and hippocampal volumetry in the lateralization of mesial temporal lobe epilepsy. Neurology 1998;51:66–71.

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Magnetic resonance imaging in neurocutaneous syndromes D Moon and A Gupta

Introduction Neurocutaneous syndromes are commonly associated with epileptogenic brain lesion(s) that could be surgically resected for relief from refractory epilepsy. Their clinical recognition is of critical importance before surgical epilepsy planning for several reasons. First, recognition of a specific neurocutaneous syndrome will help to anticipate the pathological nature of the epileptogenic lesion(s) such as hamartomas in tuberous sclerosis complex (TSC) or a leptomeningeal angiomatosis in Sturge Weber syndrome (SWS). Additionally, a possibility of multiple bilateral lesions, that may be subtle, could be recognized and special MRI protocols may be done to fully appreciate the extent of brain lesions and scalp EEG findings. Second, screening for other organ and system involvement may be necessary before epilepsy surgery. For example, patients with SWS may have glaucoma, choroid angioma and chronic visual loss that may impact surgical planning of a brain lesion that is usually in the posterior quadrant. Third, some neurocutaneous disorders are familial, and genetic counseling is of paramount importance. Fourth, basic science studies using characteristic pathological substrates on the resected brain tissue from patients with neurocutaneous disorders have enhanced our understanding of the epileptogenesis. Most neurocutaneous syndromes are identifiable by physical examination, and brain MRI helps in confirming the presence of anticipated lesion(s). In this chapter, we will focus on brain MRI and important clinical findings in neurocutaneous disorders that are commonly associated with epilepsy.

Sturge-Weber syndrome (SWS) Sturge-Weber syndrome (SWS) or Sturge-Weber Dimitri syndrome is also known as encephalotrigeminal angiomatosis or encephalofacial angiomatosis. The majority of cases are sporadic mutations, and there is no clear inheritance pattern. Familial cases in which siblings have phenotypic presentation of SWS exist, but is estimated that these types of cases comprise less than 10% of all cases.1 Prevalence of SWS is estimated in one study to be 1 in 50 000.2 There is no known race or sex predilection. Seizures occur in 80% of SWS patients. Seizures usually begin in the first year of life, and are the most common presenting symptom of neurological involvement. Common clinical features include a facial capillary angioma (nevus flammeus or port-wine

stain) suggesting a possibility of an underlying ipsilateral leptomeningeal angioma and ocular choroidal angiomas. Skin findings in SWS The facial capillary angioma is in the cranial nerve V distribution. Usually it is in theV1 distribution with variable V2 and V3 involvement. Patients with V1 involvement are at risk for neuroocular lesions. Some experts feel that facial angioma is not a sine qua non, and up to 5% of patients with SWS do not have facial angiomas.3 In a minority of cases facial angiomas may be bilateral. Even when facial angiomas are bilateral intracranial involvement tends to be unilateral or dominant to one side.4 Eye findings in SWS Glaucoma is diagnosed in 15% of SWS patients at birth, 61% in the first year of life and 72% by the age of 5 years.5 Developmental anomalies in the anterior chamber and increased episcleral venous pressure are felt to be the inciting factors for glaucoma in SWS.6 Dilated episcleral and retinal vessels are present with V1 involvement. There is increased incidence of retinal detachment secondary to hemorrhages from the choroidal hemangiomas. Eye involvement may result in acute or chronic or acute on chronic visual loss that may not be readily apparent in a young infant without an opthalmological examination by an expert. Brain findings in SWS Key neuroimaging findings are cortical calcification (Figure 83.1), cerebral hemiatrophy with patchy parenchymal gliosis, choroid plexus hyperplasia, and leptomeningeal angiomatosis. Facial angioma and intracranial lesions are usually ipsilateral.7 The cortical calcifications show a gyriform pattern on unenhanced brain CT (Figures 83.1 and 83.2). This gyriform pattern, sometimes also referred to as ‘tram line calcification’, is best appreciated on bone window settings (Figure 83.1). In the normal brain windows the calcifications often appear as amorphous dense lesions (Figure 83.2). On brain MRI, calcified lesions are best visualized on gradient or susceptibility sequences where they exhibit gyriform susceptibility artifact (low signal areas Figure 83.3) similar to the pattern seen on brain. T1 images (Figure 83.4 and 83.5) show encephalomalacia in the area of the lesions. On administration

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Figure 83.1 Dense occipital cortical calcifications on head CT, bone window in a child with SWS.

of the intravenous gadolinium, T1 contrast images shows enhancement in this area reflecting the underlying venous anomaly, and of the hyperplastic chroid plexus in the ipsilateral atria of the lateral ventricles. Contrary to what might be anticipated intuitively, neither MR venography or MR angiography is helpful in assessing SWS (Figures 83.6–83.8). Neurological findings include hemianopsia that may not be appreciated or present at birth but tends to be recognized later in life. A subtle clue in a young infant may be gaze preference or ignoring the visual hemifield contralateral to affected size.8 In SWS, seizures may be followed by prolonged or persistent hemiparesis in the postictal period, suggesting the diagnosis of

Figure 83.3 Cortical susceptibility artifact reflecting MRI appearance of calcifications in the same SWS patient as 86.1 on MRI gradient echo sequence.

Figure 83.2 Dense cortical calcifications in same SWS patient on head CT, parenchymal window. Note that this is the same image as 86.1 but shows the appearance of more extensive calcifications because of windowing.

transient ischemic attacks or cerebral stroke.9 Fixed hemiparesis may develop. Hemianopsia is usually apparent by the time of hemiparesis.10 Intracranial angioma may also be bilateral, but one side tends to be dominant. Also SWS patients have angiomas of visceral organs such as kidneys, spleen, ovaries, intestine, adrenals, thyroid, pancreas, heart, thymus, lungs, and extremities. The latter with hypertrophy of the limbs is similar to or may be a subset of Klippel-Trenaunay-Weber syndrome.

Figure 83.4 Noncontrast T1 weight coronal MRI in a child with SWS showing volume loss in the underlying brain parenchymal in the affected right parietal and occipital lobes.

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Figure 83.6 MRA maximum intensity images (MIP) shows no abnormal signal to suggest vascular abnormality.

Figure 83.5 Post contrast coronal T1 images showing enhancing right pial angioma in the same patient as 86.4.

Pathophysiology in SWS The intracranial lesion is felt to be due to proliferation of leptomeningeal angioma in the subarachnoid space which causes shunting of blood away from brain tissue. Shunting and stasis of blood causes chronic ischemia resulting in

Figure 83.7 MRA individual source image shows no abnormal flow related enhancement (high signal) in the area of affected brain. There is susceptibility artifact in the area where there are gyriform cortical calcifications similar to the ones seen on the susceptibility scans.

gliosis, volume loss and calcification.11,12 Leptomeningeal angiomas could be bilateral in up to 14% of patients in one series from Mayo Clinic.13 Absence of superficial cortical veins and thrombosis of SSS has also been reported.14 Leptomeningeal angiomatosis is more obvious on gadolinium enhanced MRI than on a contrast enhanced CT.15 Xenon133 studies show decreased blood flow in the brain lesion even in patients without neurologic deficits suggesting chronic ischemia.16 Calcification in SWS is intracortical and noncontrast CT can be used to evaluate cortical calcifications in the later stages. Plain films show the classic ‘tram track’ pattern on calcification outlining the cortical gyri usually by the age of 2 years. Angiography usually shows enlargement of the deep cerebral veins, decreased or absent cortical veins, or early filling in 82% of patients.17

Figure 83.8 2-D time of flight MR venogram individual slice shows no abnormal flow related enhancement in the expected location of the cortical calcification in contrast to the normal high signal (bright) dural venous sinuses.

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Neurological morbidity in SWS Patients with SWS are more likely to have behavioral, social and intellectual issues than nonaffected siblings.18 Of SWS patients, 60–80% have some degree of mental retardation, and 47–60% are reported to have severe mental retardation in two studies.19,20 Bilateral hemispheric involvement usually shows increased severity of mental retardation.21 Intensity of seizures rather than age of onset or hemiparesis as correlated with the presence and severity mental retardation.22 Seizures are also very common in SWS, and various studies quote the incidence of seizures to be 75–90% in children with SWS.23–26 Of those SWS patients who will eventually have seizures, 75% develop seizures by the first year of life, and almost all by the age of 5 years. Only rarely, seizures may first present even in the second decade of life, as in a case report of one patient who presented with seizures at the age of 23 years.27 Bilateral hemispheric involvement increases risk of seizures.28 Seizures are usually partial motor (hemiclonic, hemitonic, or myoclonic) or secondarily generalized. Partial seizures involve contralateral extremeties to the intracranial (and usually the facial) lesion. A small number of patients may have primarily generalized tonic-clonic seizures. Some patients may experience a period of seizure remission but seizures may relapse later in life with increased frequency.29 In one study, there is a 50% incidence of prolonged seizures or status epilepticus.30 Epilepsy in SWS is usually difficult to treat. There are some data to suggest that prophylactic antiepileptic drug therapy is useful, even before the patients present with seizures.31 A trial of at least two antiseizure medications is usually given by most epileptologists before seizures are considered refractory.32 In SWS with refractory epilepsy, surgical options are usually promising. Presurgical evaluation should be promptly done in these patients. Surgical options include lesionectomy with removal of tissue including generous margins around the lesion or hemispherectomy type procedure of patients of SWS, 70–80% may be seizure free or significantly improved with rare aura or brief seizure after surgery. Lesionectomy is usually reserved for SWS patients who have no motor deficits (hemiparesis), who show a unilateral well-demarcated angiomatous lesion in the parieto-occipital region posterior to the perirolandic region on the brain MRI, and the scalp EEG shows epileptogenicity over the lesion.33 Hemispherectomy is usually recommended in patients with pre-existing severe hemiparesis that may be progressive, usually with an extensive lesion involving the sensory motor cortex on the brain MRI. The role of invasive recordings to salvage eloquent cortex or perform a more restricted surgery is controversial. Due to predominant posterior quadrant location of the lesions, a comprehensive eye examination and counseling for irreversible anticipated visual deficits is of great importance. Timing of surgery is important. A clinical course with worsening seizures, progressive hemiparesis, and relentless cognitive decline may occur in some patients with SWS. Early surgery is generally recommended for relief from catastrophic epilepsy and ensued encephalopathy from seizures and toxic doses of multiple antiepileptic medications.34 There is also a possible positive effect on cognitive development with early surgery.35

Tuberous sclerosis complex (TSC) Tuberous sclerosis complex (TSC) (Bourneville disease) is a multisystem genetic disease that is transmitted in an autosomal dominant pattern. Seizures are one of the most common presenting symptom in TSC, and most patients with TSC develop life-long refractory epilepsy. The prevalence is reported to be 1 in 10 000.36,37 There is no race or sex predilection and spontaneous mutation rate is 60%.38 Mutations in two genes have been identified in patients with TSC. TSC1 is located at chromosome 9q34 and encodes a protein called hamartin. TSC2 is located at chromosome 16p13.3 and encodes a protein called tuberin.39 Although located on different chromosomes, the two genes appear to code two proteins that work in the same biochemical pathway involved in cell differentiation and proliferation. Although most patients have mutations localizable to either TSC1 or TSC2, 15% of patients in a study by Dabora et al. did not have a lesion localizable to either gene.40 Sporadic mutations are more common in the TSC2 gene. TSC1 seems to have less severe phenotypic expression. Specifically, TSC1 patients appear to have fewer seizures, fewer intracranial lesions, and less severe mental retardation.41 Those patients in Dabora’s study who did not have a mutation localizable to either TSC1 or TSC2 had even a milder phenotypic presentation than the TSC1 patients. The classic Vogt triad of mental retardation, seizures, and adenoma sebaceum is only found in only 29% of TS patients.42 Diagnostic criteria for clinical diagnosis of TSC have been developed and are listed in Table 83.1. Interestingly, 7% patients with TSC1 or TSC2 mutation do not meet diagnostic criteria for TSC, and 15% of patients who meet the criteria for TSC do not have mutation in TSC1 or TSC2.43 Table 83.1

TS diagnostic criteria revised44

Major features Facial angiofibromas or forehead plaque Nontraumatic ungual or periungual fibromas Hypomelanotic macules (≥ 3) Shagreen patch (connective tissue nevus) Multiple retinal nodular hamartomas Cortical tuber Subependymal nodule Subependymal giant cell astrocytoma Cardiac rhabdomyoma, single or multiple Lymphangiomyomatosis Renal angiomyolipoma Minor features Multiple randomly distributed pits in dental enamel Hamartomatous rectal polyps Bone cysts Cerebral white matter radial migration lines Gingival fibromas Nonrenal hamartoma Retinal achromic patch Confetti skin lesions Multiple renal cysts Diagnosis ● Definite tuberous sclerosis complex is diagnosed by the presence of either two major features or one major feature plus two minor features. ● Probable tuberous sclerosis complex is indicated by one major feature plus one minor feature. ● Possible tuberous sclerosis complex is indicated by either one major feature or two or more minor features.

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Figure 83.9 Unenhanced brain CT of an 11-year-old child with TSC. Cortical tubers and white matter changes are seen in the left parietal lobe.

Brain involvement and neuroimaging in TSC

Figure 83.11 Brain MRI FLAIR sequence in a young adult with TSC showing multiple hyper-intense cortical tubers and linear and wedge-shaped white matter lesions.

This is associated with a variety of brain lesions, and these are: cortical tubers, white matter lesions, subependymal nodules (SEN), and subependymal giant-cell astrocytomas (SEGA).

Histologically, each of the four types of intracranial lesions are composed of clusters of giant cells with varying degrees of neuronal and astrocytic differentiation, and presence of cells that are transitional forms between these two types.45

Figure 83.10 Same child as in Figure 83.9. Ventral cuts on unenhanced brain CT show subependymal nodules and subcortical calcification in the left posterior frontal lobe. Additional cortical and white matter lesions are seen in the right parietal and frontal lobe. Hypodense nature of cortical and subcortical white matter lesions in TSC may be mistaken for remote insult, however the presence of multiple lesions and associated calcified SEN usually clarify the diagnosis.

Figure 83.12 Brain CT after administration of contrast in a 16year-old boy with multiple calcified subependymal nodules (SEN). In the left hemisphere, in addition to the calcified SEN, an enhanced soft tissue mass (SEGA) near the foramen of Monroe is seen. Note the lack of edema surroundings the intracranial masses. Also note the plaque-like areas of increased attenuation in the skin over the frontal bone compatible with cutaneous lesions.

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While brain CT is helpful in noticing calcified lesions in TSC, brain MRI is recommended as the neuroimaging procedure of choice to elicit the extent of all lesions. Cortical tubers are hyperintense on T2 and FLAIR sequences, and hypointense on T1 sequences in patients with mature myelination. In newborn and infants with immature myelination, the tubers are hyperintense to unmyelinated white matter on T1 sequences and appear hypointense on T2-weighted images. This effect of immature myelination on the brain MRI findings in infants with TSC is felt to be secondary to the increased water content in unmyelinated regions of the brain.46 Frontal lobe propensity for cortical tubers has been reported.47 Cortical tubers usually show decreased uptake of radioactive agent on Tc99mHMPAO interictal SPECT imaging.48 Similarly, there is hypometabolism on FDG (18-fluorodexy) brain PET.49 Brain PET may not be as reliable in infants due to normal low glucose metabolism in the brain.50 There is evidence to suggest that cortical tuber count and location is associated with increased risk of infantile spasms.51 There also appears to be a correlation between increased number of tubers, development of early seizures, and developmental delay.52 Magnetic resonance spectroscopy (MRS) shows decreased NAA/Cr ratio, increased choline to creatine ratio, increased myoinositol to creatine ratio, as well as lactate peak.53 There are three types of white matter lesions in TSC. These are, in the order of common occurrence; thin linear bands extending radially from the ventricular surface to cortical tubers, wedge-shaped bands with apices near ventricles, and amorphous lesions in the deep white matter. The white matters lesions also show predominance in frontal lobes.54 Subependymal nodules (SEN) are often near the caudate head or caudo-thalamic groove. They are variable in appearance. They do not usually obstruct CSF flow, but may uncommonly do so by mechanical pressure against the foramen of Monro. SEN may rarely enhance on gadolinium administration in a nodular or ring-like fashion, and enhancement is better appreciated at higher signal strengths.55 SEN are better seen on CT than MR because of the presence of calcification.56 SEGA are slow growing tumors. They are typically located near the foramen of Monroe and are believed to originate from SEN or tubers.57 However, rarely SEGA may also appear in other locations in the brain.58,59 Typically, there is no edema in the brain parenchyma adjacent to the SEGA. Most SEGA are benign, although there are rare cases of malignant degeneration. The symptoms of SEGA are mainly due to their location. TSC patients with SEGA often present with acute or chronic increased intracranial pressure suggesting chronic or intermittent obstruction at the level of the foramen of Monroe. Incidence of SEGA in various studies on TSC is reported to be 1.7–26%. A recent series in a moderate sized group of patients reported 8.2%.60 SEGA are generally iso- to hypo-intense to brain parenchyma on T1 and hyperintense on T2-weighted images. SEGA are heterogeneous in appearance. Flow voids may be identified within these lesions. They often have internal susceptibility artifact reflecting hemorrhage or calcification. They do show contrast enhancement, and in fact, SEGA should be suspected and periodic screening scans are indicated if SEN show enhancement.

Nonneurological lesion in TSC Patients with TSC have many visceral lesions including: cardiac rhabdomyomas, phakomas in the eyes (retinal hamartoma), renal cysts and angiomyolipomas, hepatic cysts and pulmonary leioangiomyomatosis. TSC patients may also have a multitude of cutaneous lesions such as hypomelanic macules (ash leaf spots), adenoma sebaceum (facial angiofibromas), forehead plaques, shagreen patches, and ungul or subungual fibromas.

Epilepsy and neurological manifestations in TSC Seizures are one of the most common presentation in TSC, and occur in up to 80% of patients with TSC.61 Most patients of TSC with seizures tend to present early in life, and 70% TSC patients develop epilepsy by the age of one year.62 Infantile spasms are most common type of seizures in infants with TSC. Depending on the location of the epileptogenic tuber(s), other types of seizures such as focal motor, grand mal, complex partial, and atypical absence seizures may occur.63 Most infants with infantile spasms progress to complex partial to generalized tonic-clonic seizures later in life.64 In rare TSC patients who develop seizures in later in teenage years or adulthood, partial seizures are most common.65 Seizures in TSC patients are often difficult to control. Of TSC patients, 50–65% have mild to moderate mental retardation. IQ appears to be bimodally distributed in patients with tuberous sclerosis.66 On the good side of the spectrum are a few patients who have no, or infrequent, seizures beginning after infancy with no, or mild, learning disabilities and an IQ that is lower than siblings without TSC. On the guarded side of the spectrum are TSC patients who present with infantile spasms or catastrophic epilepsy with onset before 12 months of age who end with moderate to severe mental retardation.67 Autism is commonly described in TSC patients, and is reported in 25–50% of patients.68,69 Patients with TSC also have other neuropsychiatric morbidity in the form of a high frequency of hyperactive and aggressive behavior, and, rarely, self mutilation.70 SEGA may grow and obstruct the CSF flow requiring tumor excision with or without placement of a ventriculo-peritoneal shunt. The first line treatment for seizures is antiepileptic medication. Vigabatrin has been found to be especially effective in the treatment for infantile spasms in TSC.71 There is a question whether it is more effective than ACTH treatment in the treatment of infantile spasms.72 While ACTH has acute and chronic steroid-related side-effects, Vigabatrin may cause irreversible peripheral field visual defects after long-term use.73 Besides other antiepileptic medications, ketogenic diet may be helpful in cases of otherwise intractable epilepsy.74 Vagal nerve stimulation has also been used in a few refractory patients who are not candidates for surgery.75 Surgery has proven to be an effective and promising option in many refractory cases of TSC. Detection of the solitary or predominant epileptogenic tuber(s) remains a challenge in patients with multiple closely located lesions, and is best achieved by carefully considering seizure semiology, scalp-EEG, and correlating with the brain MRI. Brain PET and ictal SPECT are less informative, although special radioactive PET agents have been touted to increase the yield to detect epileptogenic tuber(s).76,77

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Epidermal nevus syndrome (ENS)

Neurofibromatosis 1 (NF1)

This is a sporadic neurocutaneous disorder without any known familial cases. Somatic mutation is postulated as the underlying genetic mechanism. The defining cutaneous features of ENS are congenital epidermal nevi that are usually raised skin lesions that may be band-like, round, oval, or linear in configuration. Cutaneous lesions may be subtle to detect due to their skin like color and velvety appearance in infancy, however, they may become verrucous orange or brown later in life. A wide variety of epidermal congenital lesions have been linked to ENS, such as linear sebaceous nevus (of Jadassohn), nevus verrucosus, ichthyosis hystrix, nevus unius lateris, and inflammatory linear verruous epidermal nevus. The cutaneous lesions may differ somewhat in histology.78 Characteristically, the dermis is not involved, and there is thickening and hyperkeratosis of the epidermis with hyperplasia of the sebaceous glands. Besides cutaneous manifestations, there is a wide spectrum of clinical presentation involving multiple organs and systems.79 Pathogenesis of brain involvement is postulated to be vascular dysplasia and migrational anomalies.80,81 There is no consistent relationship between side of nevus and CNS abnormality.82 ENS patients may also have ocular, dental, and skeletal abnormalities.

Unlike SWS and TSC, only a small percentage of patients with NF1 (Von Recklinghausen’s disease) have seizures. The prevalence of seizures in NF1 varies from 4.2–7%.,85,86 The lower figure is just twice the prevalence in the general population. Seizures were due to tumors (hamartomas), cortical malformations and mesial temporal sclerosis.87 Other studies of NF1 patients with seizures report no structural lesions identified.88 Mental retardation is often present in those NF 1 patients who have seizures. Age of presentation varied from 4 days to over 20 years.89 There are occasional reports of seizures in NF2 patients which are likely due to the presence of localized effects of supratentorial meningiomas and meningioangiomatosis which occurs in NF2 patients.90,91

Epilepsy in ENS Various types of brain malformations and migration abnormalities are reported, however, classical involvement of the brain is in the form of hemimegalencephaly (17 out of 60 patients in Pavone’s study).83 Seizure onset is usually within the first year of life. Seizures in infancy are associated with significant hemispheric abnormalities.84 Seizures are usually daily, catastrophic, and fail to respond to medical treatment. Hemispherectomy is the treatment of choice in patients with hemimegalencephaly. Important considerations before epilepsy surgery in ENS patients include careful examination and investigations to elicit the clinical severity and organ/system involvement in a given patient, scalp-EEG and MRI to locate epileptogenic zone and also look for evidence of bilateral brain involvement, parental counseling, and weighing benefits/risks of early surgery, whenever possible. A case of ENS with pictures is described in Chapter 170.

Neurocutaneous melanosis (NM) This is a rare disorder in which patients have congenital cutaneous nevi and leptomeningeal melanosis leading to CNS manifestations. Precise incidence figure are unavailable, however, a 2.5% risk of developing NM with CNS involvement is quoted in patients with large congenital melanocytic nevi.92 This disease may be lethal early in life but some patients survival into their 20’s.93,94 Most common MR findings in NM patients is T1 shortening (increased signal) in the temporal lobe and infratentorial brain on noncontrast examinations.95 There is variable ventriculomegaly and there may be thickening of leptomeninges of brain and spine as demonstrated on contrast enhancement.96 Leptomeninges may appear to be normal on T1- and T2-weighted sequences. Usually there is leptomeningeal enhancement, however cases have been described without the leptomeningeal involvement.97 There may also be pachymeningeal (dural) involvement.98 Dermatologically, patients have multiple congential nevi, the largest of which typically measures greater than 5 cm. NM patients usually present with seizures or increased intracranial pressure. Cranial nerve palsy, hemiparesis, myelopathy, or psychiatric disorders may coexist. NM is believed to be a sporadic neurocutaneous disorder, and is not transmitted as a single gene disorder and does not have any sex predilection.

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Hunt A. Development, behaviour and seizures in 300 cases of tuberous sclerosis. J Intellect Disabil Res 1993;37(Pt 1):41–51. Elterman RD, Shields WD, Mansfield KA, Nakagawa J;US Infantile Spasms Vigabatrin Study Group. Randomized trial of vigabatrin in patients with infantile spasms. Neurology 2001;57(8):1416–21. Riikonen R. Infantile spasms: therapy and outcome. J Child Neurol 2004;19(6):401–4. McDonagh J, Stephen LJ, Dolan FM et al. Peripheral retinal dysfunction in patients taking vigabatrin. Neurology 2003;61(12):1690–4. Kossoff EH, Thiele EA, Pfeifer HH, McGrogan JR, Freeman JM. Tuberous sclerosis complex and the ketogenic diet. Epilepsia 2005;46(10):1684–6. Parain D, Penniello MJ, Berquen P et al. Vagal nerve stimulation in tuberous sclerosis complex patients. Pediatr Neurol 2001; 25(3):213–6. Lachhwani DK, Pestana E, Gupta A et al. Identification of candidates for epilepsy surgery in patients with tuberous sclerosis. Neurology 2005;64(9):1651–4. Jarrar RG, Buchhalter JR, Raffel C. Long-term outcome of epilepsy surgery in patients with tuberous sclerosis. Neurology 2004;62(3):479–81. Prayson RA, Kotagal P, Wyllie E, Bingaman W. Linear epidermal nevus and nevus sebaceus syndromes: a clinicopathologic study of 3 patients. Arch Pathol Lab Med 1999;123(4):301–5. Grebe TA, Rimsza ME, Richter SF et al. Further delineation of the epidermal nevus syndrome: two cases with new findings and literature review. Am J Med Genet 1993;47(1):24–30. Pavone L, Curatolo P, Rizzo R et al. Epidermal nevus syndrome: a neurologic variant with hemimegalencephaly, gyral malformation, mental retardation, seizures, and facial hemihypertrophy. Neurology 1991;41(2 Pt 1):266–71. el-Shanti H, Bell WE, Waziri MH. Epidermal nevus syndrome: subgroup with neuronal migration defects. J Child Neurol 1992;7(1):29–34. Gurecki PJ, Holden KR, Sahn EE et al. Developmental neural abnormalities and seizures in epidermal nevus syndrome. Dev Med Child Neurol 1996;38(8):716–23. Pavone L, Curatolo P, Rizzo R et al. Epidermal nevus syndrome: a neurologic variant with hemimegalencephaly, gyral malformation, mental retardation, seizures, and facial hemihypertrophy. Neurology 1991;41(2 Pt 1):266–71.

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Gurecki PJ, Holden KR, Sahn EE et al. Developmental neural abnormalities and seizures in epidermal nevus syndrome. Dev Med Child Neurol 1996;38(8):716–23. Kulkantrakorn K, Geller TJ. Seizures in neurofibromatosis 1. Pediatr Neurol 1998;19(5):347–50. Korf BR, Carrazana E, Holmes GL. Patterns of seizures observed in association with neurofibromatosis 1. Epilepsia 1993;34(4):616–20. Vivarelli R, Grosso S, Calabrese F et al. Epilepsy in neurofibromatosis 1. J Child Neurol 2003;18(5):338–42. Korf BR, Carrazana E, Holmes GL. Patterns of seizures observed in association with neurofibromatosis 1. Epilepsia 1993;34(4): 616–20. Korf BR, Carrazana E, Holmes GL. Patterns of seizures observed in association with neurofibromatosis 1. Epilepsia 1993;34(4):616–20. Kuchna I, Zabek M, Dambska M, Matyja E, Wierzba-Bobrowicz T. Neurofibromatosis type 2. Case report. Folia Neuropathol 1995:33(3):141–4. Ruggieri M, Iannetti P, Polizzi A et al. Earliest clinical manifestations and natural history of neurofibromatosis type 2 (NF2) in childhood: a study of 24 patients. Neuropediatrics 2005;36(1):21–34. Bittencourt FV, Marghoob AA, Kopf AW et al. Large congenital melanocytic nevi and the risk for development of malignant melanoma and neurocutaneous melanocytosis. Pediatrics 2000);106(4):736–41. De Andrade DO, Dravet C, Raybaud C et al. An unusual case of neurocutaneous melanosis. Epileptic Disord 2004; 6(3):145–52. Hubert JN, Callen JP. Incontinentia Pigmenti presenting as seizures. Pediatr Dermatol 2002;19(6):550–2. Frieden IJ, Williams ML, Barkovich AJ. Giant congenital melanocytic nevi: brain magnetic resonance findings in neurologically asymptomatic children. J Am Acad Dermatol 1994;31 (3 Pt 1):423–9. Kadonaga JN, Frieden IJ, Neurocutaneous melanosis: definition and review of the litature. J Am Acad Dermatol 1991;24:747–755. Byrd SE, Darling CF, Tomita T et al. MR imaging of symptomatic neurocutaneous melanosis in children. Pediatr Radiol 1997;27(1):39–44. Chu WC, Lee V, Chan YL et al. Neurocutaneous melanomatosis with a rapidly deteriorating course. AJNR Am J Neuroradiol 2003;24(2):287–90.

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Magnetic resonance imaging in epileptogenic neoplasms J Tamraz and Y Comair

Introduction Refractory epilepsy is a consistent health problem worldwide, affecting almost 1% of the population from which more than a quarter present a medically refractory form. Since the preliminary essays of in vivo magnetic resonance (MR) performed 25 years ago, its efficiency took an increasing major role in the diagnosis and the management of intractable epilepsy demonstrating the underlying structural abnormalities.1–3 Even in the idiopathic form of generalized epilepsy brain imaging may show related abnormalities. The Commission on Neuroimaging of the International League Against Epilepsy (ILAE) recommends4,5 that ‘… the ideal practice is to obtain structural neuroimaging with MRI in all patients with epilepsy, except in patients with a definite electroclinical diagnosis of idiopathic generalised epilepsy or benign epilepsy of childhood with centrotemporal spikes’. It also recommends that ‘… epilepsy surgery should never be contemplated without an MRI examination’. MR is actually a mature imaging technique and stands as the most accurate neuroimaging modality for the diagnosis of structural abnormalities related to epilepsy and the presurgical evaluation due to its inherent specific characteristics. In fact, MR due to its multiplanar ability allows the exploration of the patient in any oblique plane with a high-contrast resolution premitting to obtain an accurate differenciation of gray and white matter. The absence of beam hardening artifacts from bony structures such as those generated at the skull base vicinity, favors the exploration of tumoral processes located in the orbitofacial or temporal regions. The absence of ionizing radiation makes it the modality of choice for follow-up examinations, particularly in pediatric patients or post surgery or radiation therapy. MRI is a multiparametric technique that largely depends upon operator skills. It is an epilepsy specialist study. The choice of the appropriate pulse sequences contribute consistently to the final diagnosis. A minimum of T1- and T2-weighted sequences and a 3D-T1w volume acquisition with reformations and volume renderings are mandatory and recommended by the ILAE. The need for contrast administration, such as the paramagnetic Gadolinium chelates, is relatively limited usually restricted to the evaluation of intra-axial neoplastic processes and the leptom eningeal seeding and may be of some help in the differential diagnosis or in tumor grading.6 The search for an optimal cost/efficiency ratio requires the prescription of the most informative examination. The well-established sensitivity of 730

MRI in detecting structural abnormalities in refractory epilepsy averages (95% as compared to 32% for CT).7 MR is superior for identifying both the focus and the histopathologic substrate found at surgery. A combined approach may be needed for the detection of minute calcifications. However, CT remains useful in patients presenting absolute contraindications to MR exams as patients with pacemaker, vascular clips, neurostimulators, or other ferromagnetic devices. More sophisticated techniques, recently implemented on most available systems, may be used in addition to morphologic imaging: diffusion-perfusion to assess perfusion measurements and evaluate neovascularisation, diffusion tensor imaging (DTI) to obtain white matter tractography, functional imaging (fMRI) for mapping of brain functions, and in vivo spectroscopy (MRS), which may reveal subtle underlying biochemical abnormalities representing the effects or cause of the epileptic disorder. Note that fMRI activation is more widely available and of much higher spatial resolution than other functional techniques, improving particularly on higher field systems (3 Tesla magnets) and tend to become the powerful functional tool to detect metabolite disorders even supplanting PET for the localization of eloquent cortex most useful in the presurgical planning process.8–20 In apparently normal MR exams, functional imaging techniques such as ictal SPECT and/or interictal FDG-PET may show regional dysfunctions.

Neuroimaging technique of brain tumors In order to identify and recognize the underlying structural abnormality responsible for intractable partial epilepsy, a good knowledge of brain anatomy and the nature of the lesional processes that may potentially cause seizures, is necessary.21–25 These lesions are frequently subtle and may be easily overlooked or misdiagnosed.26 High spatial and contrast resolution thin coronal MR cuts off the brain and the temporal lobes should be performed on high field systems (1.5 or 3 Tesla). Brain referentials essential for neuroimaging Any precise topographical analysis of brain structures ought to be performed according to judicious and definite cerebral reference lines, based on reliable cutaneous, cranial and brain landmarks.22 In order to facilitate the neuro-anatomical

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Magnetic resonance imaging in epileptogenic neoplasms approach and optimize biometrical studies using MRI, two brain reference lines, the horizontal chiasmato-commissural line (Ch-Cp line) and the vertical commissural-obex line (CpOb line) perpendicular to the previous, are routinely used. These orthogonal reference planes suitable for multimodality imaging are used in brain imaging with highly reproducible anatomical results.22,27,28,31 The anatomical landmarks defining these reference lines are very easily found on a mid-sagittal MR scoutview (Figure 84.1a). The horizontal reference Ch-Cp line is defined as the line tangential to the superior border of the chiasmatic notch (Ch) anteriorly to join the inferior border of the posterior commissure (Cp) posteriorly. The consistency of the angle between this line and the bicommissural line serves to validate the choice of this pivotal line situated as it is at the mesodiencephalic junction. This plane has been shown to be truly horizontal oriented parallel to the parallel sulcus and consequently to the lateral fissure materializing a sylvian plane orientation of the brain cuts.27,28 The vertical reference Cp-Ob plane is defined as the line tangential to the anterior border of the posterior commissure (Cp) and joining the obex (Ob) at the caudal extremity of the calamus scriptorius on floor of the fourth ventricle (28) (Figure 84.1b). This Cp-Ob line materializing the great vertical axis of the brainstem has been demonstrated as the most reliable referential to obtain reproducible coronal cuts of the brain using MR.27,31 Coronal cuts are therefore best obtained with the Cp-Ob reference plane due to its perpendicularity to Ch-Cp plane and thus to the anterior-posterior axis of the first temporal and the lateral sulci, becoming particularly most suitable for the coronal study of the temporal lobes, the inferior frontal gyri and the perisylvian speech areas. Imaging protocol and methodology Accurate and reproducible brain reference planes as achieved using the Cp-Ob reference plane have to be used. The imaging

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protocol must include at least three pulse sequences: a sagittal T1-weighted gradient echo sequence useful for a morphological screening approach and for subsequent landmarking, followed by a coronal-oblique fast fluid attenuated inversion recovery (FLAIR) sequence according to PC-OB line and a 3D-T1 weighted volumetric acquisition with 128 partitions and 1.8 mm slice thickness. The near isotropic small voxel size obtained allow mutiplanar reformations and volume renderings with adequate spatial resolution. Additional T2-weighted and/or T2*-weighted pulse sequences in the axial or the coronal planes may be performed in special conditions.32 Beyond the routine examination protocol, more sophisticated and powerful imaging modalities available may be used to improve sensitivity in the diagnosis and the staging of primary intracranial tumors and to optimize the presurgical planning. Post-surgical follow-up of resected tumors and evaluation of the effects of adjuvant radiotherapy or chemotherapy are also promising. Functional aspects of MR Functional imaging applies to any technique that acquires time dependent imaging data. This includes flow, diffusion, perfusion, brain activation and MR spectroscopy.33–34 When combined and added to conventional MR technique these functional tools may increase the specificity of the positive diagnosis of brain tumors. A multifunctional approach may help to suggest the tumor grade, evaluate the tumor extension and the therapeutic response and precise the area to biopsy.35–39 Diffusion (DWI) and diffusion tensor imaging (DTI) While MR angiography and flow measure the movement of spins from voxel to voxel, MR is capable of measuring microscopic translational motion within each voxel. This motion can be the molecular diffusion of water and the microcirculation of blood in the capillary network, referred to as perfusion.

(b)

Figure 84.1 Cephalic reference planes suitable for neuroimaging. (a) Horizontal and vertical reference lines are used as referential coordinates for routine brain imaging: the chiasmatico-commissural line (Ch-Cp) joining the Chiasmal point to the Commissura posterior and the commissural-obex (Cp-Ob) line joining the Commissura posterior to the Obex, respectively. Both orthogonal orientations are compared to the bicommissural plane (Ca-Cp). (b) Anatomical correlation as obtained in the Cp-Ob coronal reference plane.

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Diffusion is the process by which molecules and other particles mix and migrate due to their random thermal motion. DWI is acquired using a specific bipolar gradient with very high strength to detect the slow molecular diffusion in the body. This bipolar gradient will cause a signal loss in the diffusing spins which depends on the diffusion coefficient and the B value. The B value is determined by the strength and duration of the gradients. High B values can eliminate the T2 effect and improve the visualisation of the white matter fibers. It is therefore possible to obtain maps of diffusion in the three different orthogonal directions or combine the three images into a single map of overall diffusion. With specific research software it is possible to calculate the diffusion tensor and deduce the actual direction of the diffusion and even obtain the direction of the neuronal axons. Diffusion is increased in area containing free water such as in edema and is decreased in case of hypercellularity as in solid tumors or in viscous necrotic areas found in an abcess, for instance. Increased diffusion appears as dark areas on DW images and as very bright on the ADC map. DTI may be useful to localize a tumor and evaluate its extent. This may be achieved either by the identification of an increase in diffusivity or a loss of anisotropy.40–42 Interpretation of tractography is improving due to advances in technology and could be more reliable on higher-resolution images as obtained on higher field systems (3 T). The need to compare between normal and diseased hemispheres is helpful.43 More work is still needed and the results are still debatable. Perfusion imaging Perfusion is the study of the net transport of magnetization into a volume of tissue. It can be performed either with endogenous or exogenous contrast agents.33 One way of achieving this is by injecting a bolus of contrast agent like Gadolinium (Gd) and acquiring rapidly, usually with EPI a series of slices through the region of interest, and then repeating the multislice acquisition at a rapid rate of the order of one per second. This repetition is performed from before the injection until about 30 seconds after the arrival of the bolus. The images are then analysed to look for variations in the arrival of the contrast agent between the pathological and normal regions. The analysis can be made in several ways: the negative enhancement integral which produces a map of the susceptibility effect caused by the flow of blood containing contrast; the mean time to enhance which produces a map based on the time of arrival of the contrast in different regions; and the positive enhancement integral which produces a map of the contrast enhancement rates based on the increase in SNR due to increased concentration of contrast material. Highly vascular high-grade gliomas usually show increased blood volume and blood flow with respect to normal brain. Conversely necrotic or cystic portions of the tumor show a decrease if not absence of perfusion.44,45 Reduced perfusion is also found in the peritumoral edema. Although lacking specificity, perfusion imaging may help in some circumstances to approach tumor grade. Low-grade astrocytomas may also show increased blood volume. Brain activation (fMRI) Brain activation can be studied either by direct methods, those that measure directly the electrical activity of neurons like

EEG (electrical effect) and MEG (magnetic effect), or by indirect methods, those that measure the hemodynamic response to the neuronal electrical activity, like 15O PET (blood flow) and fMRI (BOLD effect).33 The indirect method used by fMRI can be understood by following the chain of physiological events that describes it. When a set of neurons fire there is a local increase in glucose consumption which, in turn; produces an increase in oxygen consumption. This induces an increase in regional cerebral blood flow (rCBF) and an increase in regional cerebral blood volume (rCBV) with a consequent increase in blood velocity. In the blood there is a decrease in oxygen extraction fraction producing an increase in oxyhemoglobin and a decrease in deoxyhemoglobin. In this sequence of events the most common approach used in fMRI is the blood oxygen level dependent (BOLD) contrast. The decrease in deoxyhemoglobin, because of its high paramagnetism, produces a decrease in local microscopic field gradients which in turn produces an increase in T2*. This corresponds to an increase in signal which is measured by the MR equipment. The ideal sequence to use is a rapid sequence with T2* sensitivity which detects changes in magnetic field, usually a gradient echo EPI. fMRI has its own limitations both in spatial resolution and temporal resolution. To achieve optimal functional imaging it is important to have the highest possible magnetic field (1.5 T or 3.0 T), powerful and fast gradients and a powerful computer with adequate software to manipulate the image. Magnetic resonance spectroscopy (MRS) For almost two decades, in vivo magnetic resonance spectroscopy (MRS) has been a revolutionary technique in biomedical research. Today, it is a powerful tool in neurosciences giving noninvasive access to the chemistry of the human brain in health and in disease.34 MRS is a unique and powerful technique that has been applied to a number of brain diseases. It can be correlated with imaging and other clinical data for confirmation. It enables tissue characterization on biochemical levels. It is useful in the diagnosis and prognosis of diseases and mostly in the evaluation of the noninvasive monitoring of the response to treatment.46 The spectroscopy technique routinely used to assess brain tumors is the multivoxel acquisition modality, performed both with an intermediate TE of 144 ms which evaluates the choline level, the major metabolic abnormality in brain tumors, and with a short TE of 30 or 35 ms in order to detect myoinositol which may help tumor grading.51 The most salient findings are a decrease in NAA and Cr peaks and NAA/Cr ratio and an increase of Cho, lipids and lactate as well as Cho/Cr and Cho/NAA.49,50 Both 31P and 1H MRS have been used for diagnosis and therapy monitoring of brain tumors.47 Studying changes in tumortype-dependent metabolites is an area of active research.48–51 Lipids and lactate peaks correlate well with necrotic tumors. In vivo MRS is a complex technology that requires the simultaneous optimal adjustment of multiple parameters during an examination. The most critical task in MRS, however, is not spectral aquisition but rather spectral analysis. This latter is time demanding and necessitates appropriate knowhow in order to interprete the results, eliminate artifacts and quantitate data often by complex procedures and finally, statistically analyze the findings. The precise role of many identified metabolites is still unclear.

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Magnetic resonance imaging in epileptogenic neoplasms

Neuroimaging of developmental tumors Tumors are represented most frequently by gliomas of the astrocytic predominantly fibrillary but possibly protoplasmic type or of the oligodendroglial type, followed less commonly by the mixed neuronal-glial or neuronal tumors such as the ganglioglioma, gangliocytoma, and the dysembryoplastic neuroepithelial tumor (DNET). The majority of patients with DNETs or gangliogliomas are less than 20 years old. Tumor recurrence after surgery is usually low. Dysembryoplastic neuroepithelial tumors (DNET) Described in 1988 by Daumas-Duport52 and accepted into the 1993 WHO revision,53 DNETs show characteristic histologic features consisting of three cell lines: neuronal, astrocytic, and oligodendroglial. These uncommon tumors are highly associated with long-standing intractable epilepsy with onset in early childhood, before the age of 15 years in 85% of cases,20 with an average age of 9 years.54,55 DNET has been indicated in about 20% of medically refractive epilepsy in children and adolescents.52,56 Males are affected more than females. Diagnostic criterias include partial seizure activity before age of 20 with no associated focal neurologic deficits or congenital deficit, and a cortically-based tumor. DNETs are benign hemispheric mixed glial-neuronal tumor, predominantly cortical, very rarely deep in location, causing seizures as their earliest manifestations. They correspond to WHO gradeI lesions. These tumors are relatively rare with more than 300 cases reported. All reported cases are supratentorial.57,58 More than 60% of DNETs are found in the temporal lobes and involve the mesial structures preferentially and about 30% in the frontal lobes. Few are located in the parietal or occipital lobes, the basal ganglia, brainstem or cerebellum.

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Morphology and imaging Morphologically, these tumors are very superficially located, always involving and expanding the cortex despite a concurrent involvement of the subjacent white matter. The tumor gives rise to a macrogyriform aspect rather typically associated with a scalloping of the inner table of the skull vault in more than 50% of the cases.59,60 These neoplasms are heterogeneous with a multinodular microcystic appearance (Figure 84.2), but true intratumoral cystic formation is uncommon. Actually two varieties may be differenciated, a ‘macrogyric or megagyric’ form that causes gross expansion of the cortical ribbon and a ‘multinodular’ form. In the case of associated subcortical extension the tumor appear triangular in shape on coronal cuts.61 Associated edema is lacking and there is no mass effect. Calcifications are found in about 1/3 of the patients on CT.54 DNETs show many of the features of gangliogliomas and oligodendrogliomas. DNETs may be associated with adjacent cortical dysplasias and may occasionally occur in neurofibromatosis type I. Because of its benign nature, total resection with complete cure may be obtained. Hypodense to white matter on noncontrast CT, DNETs are hypointense to cortex on T1-weighted sequences on MR, becoming/hyperintense to adjacent cortex on PD-w and remaining hyperintense on T2-w and FLAIR, due to increased water content, but show no vasogenic edema. The characteristic microcystic architecture is demonstrated in almost 40% of cases on high resolution images using very long T1-w and T2w sequences at high fields.62 Cortical analysis and evaluation of DNETs and eventually associated cortical dysplasias may be highlighted using IR-T1-weighted sequence due to its higher contrast resolution. Subcortical extent of the lesion is observed in 30% of the cases.60 DNETs usually do not show contrast enhancement in more than 2/3 of the cases and show a patchy pattern in 20–40% of the cases.61 Peritumoral edema is almost absent. The differential diagnosis includes ganglion cell tumors and low-grade gliomas.63

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Figure 84.2 Dysembryoplastic neuroepithelial tumor. Coronal cuts showing a cortically based tumor involving the lateral temporal gyri and displaying highly suggestive multinodular appearance due to the presence of intracortical multiple tiny cysts (arrows), hyperintense to gray matter on PDw (a) and T2-w (b) images. The lesion expands the cortex with mild erosion of the inner table of the calvarium. There are no obvious mass effect, neither associated edema. No contrast enhancement was evidenced.

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Gangliocytomas and gangliogliomas Also called ganglioneuromas, most of these uncommon slowly-growing benign tumors are found in patients younger than 16 years old, affecting children and adolescents, but have been reported in patients ranging in age from a few months to 80 years old.64 Their incidence is slightly higher in males.65 The diagnosis is usually made in 80% of the cases before age 30 (20–30 years old) in patients presenting a long–standing epilepsy, most commonly partial complex seizures.65,66 In the pediatric population, the average age at diagnosis is 10 years old with seizures as the most frequent presenting symptom.65,67 Complete resection of the tumor usually cure seizures.67,70 Gangliocytomas are very rare mixed neuronal-glial tumors formed of neoplastic mature ganglion cells (WHO grade I). Gangliogliomas show the presence of mature ganglion cells with neoplastic glial cells (WHO grade I or II). The astrocytic component is either diffuse or pilocytic in nature. They represent together 1.3% of all brain tumors. The tumors may occur anywhere but are most commonly found in the temporal lobes and tend to spare the lateral neocortex.66,69–71 The other lobes involved are the parietal, the frontal, and the occipital lobes. When superficially located, the tumor may cause thickening of the cortical ribbon and cause a scalloping of the calvarium. Although benign, an aggressive behavior is found in about 10% of gangliogliomas which may undergo malignant degeneration.72,75 Association with cortical dysplasia may be found in 50% of the patients. Morphology and imaging Gangliogliomas and gangliocytomas are usually well-circumscribed small masses, solid or partly cystic in 25% of cases or almost cystic in about 50%. Intratumoral cysts are often multiple. There is usually no obvious mass effect and no or very mild, peritumoral vasogenic edema. In gangliogliomas, the tumor may involve the leptomeninges and the glial component of this mixed tumor may contribute to give a slight infiltrative appearance of the brain-tumor interface. Calcifications are common found in 40% of cases, sometimes of bizarre shape,70 but remain less frequent than in oligodendrogliomas but more than in juvenile pilocytic astrocytomas or in pleomorphic xanthoastrocytomas.70,71 It seldom presents as a brain ‘stone’ without associated soft-tissue neoplasm. They may be associated with mesial temporal sclerosis when located anteriorly. Peripheral tumors may erode the inner table of the skull as reported in about 5% of cases.74 The tumors may be associated with mesial-temporal sclerosis. Differential diagnosis between gangliogliomas and gangliocytomas is made on histopathology. Gangliogliomas are hypointense to cortex on T1-w sequences, but their cystic component may be isointense due to a high protein content. On PD-w images the solid portion of the ganglioglioma is hyperintense to the cortex with variable SI of the cystic component which may be even more hyperintense due to its high protein content. On T2-w images the solid portion of the gangliogliomas is mildly hyperintense to brain, less or equally to the cystic component and may show mild peritumoral edema (Figure 84.3). Calcifications may appear as areas of shortened T1 relaxation. IR-T1w sequence, due to its high contrast resolution, is a sensitive sequence, very useful in the investigation and the evaluation of cortical

dysplasias, mesial temporal sclerosis and superficial tumoral conditions such as gangliogliomas or gangliocytomas. Cortical analysis is highlighted. On CT, the solid portion of the tumors are isodense or hypodense showing calcifications in about 30% of the cases and a variable contrast uptake.75 Enhancement of at least the solid portion of gangliogliomas is variable either homogeneous or heterogeneous, usually mild and found in roughly half the cases, except in the case of malignant degeneration.65,69–71 The wall of the cystic component may show contrast enhancement. In peripherally developed tumors, differential diagnosis with DNETs and oligodendrogliomas may be difficult. Desmoplastic neuroepithelial tumors The desmoplastic infantile gangliogliomas (WHO grade I) and the desmoplastic astrocytomas of infancy are tumors encountered in infancy and early childhood, mainly in boys, and presenting similar features. Histopathologically these tumors are composed of both ganglionic and astrocytic cells with a desmoplastic stroma.76 Clinically, patients present with macrocephaly and partial complex seizures.76–78 These tumors show a benign clinical evolution and their complete excision may be curative.79 Morphology and imaging On imaging, the tumor presents as a usually very large cyst with an associated solid component adjacent to the leptomeninges containing the desmoplastic tissue.76,79,80 The mass shows a predilection to the frontal or the parietal lobes and tends to spare the occipital.81,82 The solid portion is iso- to hyperdense to gray matter on CT and is isointense to gray matter on T1-w and T2-w images on MR, enhancing intensely after contrast infusion, except for the walls of the cystic component.82 Desmoplastic neuroepithelial tumors should be differentiated from cystic astrocytomas and pleomorphic xanthoastrocytomas, the latter presenting similar imaging features but being found most frequently in adolescents and young adults, peripherally in the hemispheres and usually in the temporal lobe. Cystic astrocytomas are differentiated by the hypodense appearance of its solid component on CT and its long T2 signal intensity on MR. Hypothalamic hamartomas Hypothalamic or tuber cinereum hamartomas, are benign rare congenital slow-growing processes. Composed of disorganized heterotopic neuroepithelial cells, they are considered as non-neoplastic heterotopias. Found inferior to the hypothalamus originating usually from the tuberal region between the pituitary stalk and the mamillary bodies, or from the mamillary bodies.83 There is no sex predilection.84,86 The clinical presenting signs, usually present when tumor size exceeds 10 mm, are most frequently isosexual precocious puberty observed before age 2, whose pathogenesis is unclear, and less commonly gelastic epilepsy and hyperactivity.83,86–89 The characteristic gelastic seizures, although infrequent, result in spasmodic laughter. Many other types of seizures may be observed, partial complex, partial motor, atypical absences or even infantile spasms. Seizures would be mostly encountered with intrahypothalamic masses.88,90–92 Interconnections

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Figure 84.3 Ganglioglioma. Young adolescent male showing a well-demarcated rounded cortical-subcortical process involving the fusiform and inferior temporal gyri. The mass is homogeneously enhanced after contrast administration (a, b). Mass effect and edematous associated changes are mild (a) limited to an aspect of moderately expanded gyri with adjacent sulcal effacement.

between hamartomatous neurons to the limbic lobe could be one of the underlying causes generating seizure activity.85 Precocious puberty was present in 2/3 of patients and almost 50% presented gelastic or generalized seizures and behavioral disorders.83,87,89,92 Mental retardation is often associated in children.86 Diabetes insipidus, growth hormone secreting pituitary adenomas and obesity may be associated.83,93 Facial anomalies, heart defects or Laurence-Moon-Biedl syndrome have been reported as additional associated malformations. Presence of postaxial polydactyly suggests an autosomal dominant disorder, Pallister-Hall syndrome.94,95 Tumoral excision may improve patients with medically refractory seizures. Morphology and imaging Hypothalamic hamartomas are solid well–demarcated neoplastic processes of neuronal tissue, attached to the floor of the third ventricle posterior to the pituitary stalk. They are usually pedunculated, best shown on coronal cuts or sessile demonstrated on midsagittal cuts. They usually extend toward the suprasellar or the interpeduncular cisterns. They vary in volume from several millimeters to few centimeters. Very rarely the mass appear calcified but show no intratumoral hemorrhage.99 Typically the neoplasm does not infiltrate the adjacent neural tissues. Associated brain abnormalities may be found in the pediatric population such as callosal dysraphism, heterotopias, polymicrogyri.86,87 A clinical-topographical classification proposed, with a type I (a and b) concerning small pedunculated masses attached to the tuber (Ia) or the mamillary

body (1b), usually asymptomatic or presenting with precocious puberty, and a type II (a or b) in sessile hamartomas, larger than 1.5 cm associated with gelastic epilepsy.100 Axial CT usually fails to depict small sessile hamartomas attached to the floor of the third ventricle. Those visible are isodense to brain and well demarcated.96 Sagittal and coronal cuts using MR improve the diagnostic capability even in very small tumors. MR shows more characteristic imaging features (Figure 84.4). The hypothalamic mass is well delineated, round or ovoid, attached to the floor of the third ventricle or extending into its cavity. Its signal intensity is roughly similar to gray matter. Hypothalamic hamartomas are homogeneously isointense to gray matter on SE-T1w sequences becoming slightly more hypointense on GE-T1w images with IR-preparation. The tumors appear slightly hyperintense to brain on PDw sequences. On T2-w images hamartomas are moderately hyperintense or may remain isointense to brain in about 1/3 of the cases.85,98 The mass may appear heterogeneous, showing a hypointense central area on T1-w images and a hyperintense central area on T2-w images, surrounded by an isointense peripheral rim. MR spectroscopy tends to show a slight increase of the myoinositol peak and a small decrease of NAA peak, lower than within the thalami.98 Large cystic formation may infrequently be found. Calcifications may be found. Hypothalamic hamartomas as a rule do not enhance.)85 Hypothalamic glioma should be considered in the differential diagnosis.

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Figure 84.4 Hamartoma of the tuber cinereum. Huge well-delineated and pedunculated hypothalamic mass attached to the tuberal region of the floor of the third ventricle, between the pituitary stalk and the mamillary bodies as evidenced on the midsagittal T1-w cut (a) and developing within the interpeduncular and the upper prepontine cisterns. The tumor is homogeneous and roughly isointense to gray matter on T1-w (a) and slightly hyperintense on T2-w (b) sequences. The mass did not show any contrast enhancement.

Cortical hamartomas Corticosubcortical hamartomas are formed of mature but disorganized ganglion and glial cells. Discovered in patients presenting epilepsy but with a normal neurological examination. Usually solitary, brain hamartomas are commonly located in the mesial temporal lobe and may involve the hippocampal formation or in the frontal lobe. They are well-circumscribed masses with no mass effect on the adjacent cortex or sulci. Cortical dysplasia is often associated.17,18 The main differential diagnosis is the ganglioglioma. On MR imaging the lesion is usually homogeneous, isointense to gray matter on T1-w images, iso- to slightly hyperintense on T2-w images and becomes more or less hyperintense to gray matter on FLAIR sequences. A rim of hypointensity may be observed on T2-w surrounding the hyperintensity.99 The tumors generally do not enhance. Developmental cysts Arachnoidal mesial temporal cysts of developmental origin are usually found incidentally and infrequently in patients referred for seizures. These smoothly marginated cysts are commonly found within the choroidal fissure which appear enlarged. The size of the cystic mass is variable and may be

associated with variable mass effect upon the hippocampus. The cyst is well-delineated, ovoid in shape, fluid-filled, showing an homogeneous isointense signal intensity to CSF on all sequences. It never shows any peripheral contrast enhancement (Figure 84.5) but must be differentiated from cystic tumors arising in the mesial temporal lobe.

Neuroimaging of primary brain gliomas The overall incidence of intracranial tumors is estimated to reach 5 individuals per 100 000 population per year. The rate of brain tumors is much higher in older patients reaching roughly 40% per year per 100 000 population after age 80. Primary brain tumors represented by the gliomas correspond to almost half of all primary intracranial tumors in adults and roughly two-thirds of these in children less than 15 years old. Metastatic tumors, rare in childhood, represent in adults roughly 1/4 of all intracranial tumors in autopsy series. There is a topographic difference between intracranial tumors found in adults, and children. Almost 70% of brain tumors are supratentorial in location in adults, whereas roughly 70% are found in the posterior fossa in children.

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Magnetic resonance imaging in epileptogenic neoplasms Elements of histopathology and classification Gliomas may be divided into astrocytomas, oligodendrogliomas, and ependymomas corresponding respectively to the three types of glial cells, the astrocytes, oligodendrocytes, and the ependymal cells. Almost 5% of these neuroglial tumors are of a mixed type or ‘mixed gliomas’. Astrocytic tumors or ‘astrocytomas’ may be subdivided into five clinicopathological categories: 1) Diffuse astrocytomas representing more than 60% of all primary brain tumors are subdivided into three groups: low-grade diffuse astrocytomas (WHO grade II), anaplastic astrocytomas (WHO grade III), and glioblastomas multiforme (WHO grade IV); 2) Pilocytic astrocytomas (WHO grade I) found in childhood and usually circumscribed; 3) Pleiomorphic xanthoastrocytomas (WHO grade II) but showing some ‘malignant’ features on conventional criteria and usually circumscribed; 4) Desmoplastic astrocytomas, mixed neuronal-glial tumor, found in infancy; and 5) Subependymal giant cell astrocytomas typically found in tuberous sclerosis and usually circumscribed. The relationship with the neuroimaging aspect is critical as high grade astrocytomas show an enhancing core that may be necrotic centrally with surrounding edema. The enhanced part of the tumor correlates with neovascularity, hypercellularity and mitotic activity. Tumoral cells are found within the surrounding edematous area at least over 2 cm from the enhancing tumoral margin. Oligodendroglial tumors or ‘oligodendrogliomas’ are subdivided into: (1) oligodendrogliomas (WHO grade II) and (2) anaplastic oligodendrogliomas (WHO grade III). Mixed gliomas correspond to tumors showing a mixture of neoplastic astrocytic and oligodendroglial components. This pathological entity may be subdivided into two groups: (1) oligoastrocytomas (WHO grade II) more frequent of both varieties and (2) anaplastic oligoastrocytomas (WHO grade III).

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Signs and symptoms Patients with brain tumors may present variable neurological syndromes such as: generalized impairment of intellectual function with variable mental changes including emotional lability, inertia, psychomotor reduction, disturbance of memory, spatial disorientation and behavioral disorders; syndrome of increased intracranial hypertension with headaches usually mild, nocturnal and/or worse in the morning and of the pulsatile type, commonly bifrontal and bioccipital, accompanied by vomiting in almost 1/3 of the cases; generalized or focal seizures found in 20–50% of cases with the presence of an aura being suggestive and occurring most frequently in more than 2/3 of cases in slow-growing tumors as compared with fast-growing tumors in 30% of cases; specific neurological syndromes suggestive of specific tumors and localizations. Low grade diffuse astrocytomas Diffuse astrocytomas are poorly marginated neoplasms of varying potential which infiltrate the brain parenchyma. The appellation astrocytoma must be reserved to low-grade (WHO grade II) astrocytic tumors. These primary brain tumors account for 25–30% of all cerebral gliomas. The peak incidence occurs in young adults between ages 20 and 45 years in 60% of the cases (mean age of 34), after 45 years old it is about 30% and 10% before 20. They are unusual during the first decade and also in people older than 65. A slight male predilection is observed with a ratio M:F of 1.8:1. These are slowly-growing infiltrating tumors occurring anywere in the central nervous system but with a predilection to the cerebral hemispheres in adults following the path of white matter tracts without any associated significant damage, explaining the delayed symptomatology. These tumors are well-differentiated ‘benign’ but showing a great tendency for

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Figure 84.5 Developmental mesial temporal cyst of the choroidal fissure. Usually found incidentally and of small volume, arachnoidal cysts are found within the choroidal fissure. Commonly of small size, the cyst may be huge, as in this case, with significant mass effect on the hippocampal formation displaced superiorly and effacing the temporal lobe sulci. The cyst is smoothly marginated and appears isointense to CSF on all sequences. No contrast enhancement of the cyst wall and no mural nodule associated (b) as compared to T1-w precontrast parasagittal cut (a). Such cysts have to be differentiated from other cystic lesions that may develop in the mesial temporal lobe, such as glial parenchymal cysts, found in another patient with intractable epilepsy, arising in the white matter core of the parahippocampal gyrus expanded, with upward displacement of the body of the hippocampus.

Figure 84.5 cont’d (c). The cystic mass lack of contrast enhancement (d). A huge temporal-insular arachnoidal cyst associated with adjacent dysplastic cortex (e) shown on a 3D image of the brain, explained in another patient seizure activity.

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Magnetic resonance imaging in epileptogenic neoplasms malignant transformation or anaplasia. Many of these tumors show areas of different degrees of anaplasia.100,102 Histopathologically the tumors are formed of neoplastic astrocytes which are increased in number and size. Three major variants may be distinguished with respect to the related neoplastic cell type: (1) fibrillary astrocytomas, the most frequent variety formed of fibrillary astrocytes, elongated cells with little visible cytoplasm expressing GFAP; (2) gemistocytic astrocytomas, composed mainly of gemistocytic neoplastic astrocytes, plump cells with eosinophilic abundant cytoplasm expressing GFAP; (3) protoplasmic astrocytomas, a rare variant of stellate cells with small cell bodies and showing few or no stainable fibrils. Morphology and imaging Low-grade diffuse astrocytomas are commonly homogeneous infiltrating tumors, developed in the cerebral hemispheres in young adults or in children. They are found anywere in the cerebral hemisphere except in the occipital lobe. Ill-defined, they do not show clear-cut demarcation from the adjacent normal parenchyma as demonstrated on pathological specimen. It has been shown that the tumoral process due to its infiltrating nature may extend beyond the abnormality evidenced on imaging. The tumors tend to expand the anatomical structure involved which appear bulkier than normal or may infiltrate these structures without marked morphological changes or distortion of the normal anatomy. Occasionally invasion of the subarachnoid spaces may be shown but it is usually observed in case of malignant degeneration. These low-grade tumors usually lack of peritumoral vasogenic edema due to a normal blood–brain barrier. Presence of cytotoxic edema is unlikely as well. There are no vascular flow voids within the tumoral process and no evidence of intratumoral hemorrhage or necrosis. Calcifications which occur in about 15–20% of cases are seldom evidenced on MR as compared to CT. On CT such tumors tend to be isodense to hypodense. Using MR, the tumor is homogeneously isointense to hypointense to white matter on T1-w images becoming typically hyperintense to cortex and brighter than CSF, almost homogeneously, on PD-w images and hyperintense to white matter on T2-w and FLAIR images (Figure 84.6). Proton spectroscopy demonstrates an increase in Cho levels, a decrease in NAA levels and a mild elevation of Cr, but with nearly absence of lipid resonance peaks.101 Note that the spectrum of lowgrade gliomas may be similar to normal brain. Low-grade diffuse fibrillary astrocytomas (WHO grade II) usually do not show contrast enhancement and this may constitute the socalled ‘paradoxical’ diagnostic imaging feature. Note that enhancement is common in the circumscribed partly cystic pilocytic astrocytomas (WHO grade I) involving the mural nodule as in pleiomorphic xanthoastrocytomas and as in higher grade anaplastic astrocytomas (WHO grade III) or glioblastomas (WHO grade IV). Enhancement may be demonstrated during the course of the disease, mainly with tumor transformation. Note that recurrent low-grade gliomas usually show a more malignant form. Approximately 50% of glioblastomas show evidence of a pre-existing lower-grade astrocytoma. Note that enhancements do not correlate adequately with the histological grade of the tumor because anaplastic astrocytomas show variable behavior, including patchy enhancement or faint enhancement, or even no

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enhancement. Only half of the low-grade astrocytomas with characteristic imaging features prove to be low-grade tumors.102–104 The prognosis is variable as well because of frequent transformation into high-grade tumors either spontaneously or in recurrent tumors. Pilocytic astrocytomas Pilocytic astrocytomas, are circumscribed low-grade (WHO grade I) benign tumors, also called juvenile pilocytic astrocytomas or polar spongioblastomas.72 They represent 2–6% of all primary brain tumors and are as frequent as low-grade diffuse astrocytomas in epilepsy surgery series. Most astrocytic tumors of childhood are pilocytic astrocytomas. These tumors are relatively slow-growing neoplasms with a relatively favorable outcome. They are found primarily in childhood with a peak age of presentation between 5 and 15 years old and an equal incidence in both sexes in most series. A slight female predominance has been reported in a ratio less than 4:3. Seizures are a common presenting sign. Morphology and imaging Pilocytic astrocytomas are well-circumscribed yet encapsulated tumors which usually do not invade nor infiltrate the adjacent normal brain tissue as do most astrocytomas, but tend to expand the brain parenchyma. Most of these tumors tend to develop a cystic component and may show calcifications in almost 25% of cases. The overall suggestive gross aspect of the tumor is described as a fluid-filled proteinaceous cyst with a mural nodule. The mural nodule may be round or plaque-like. The wall of the cystic component is surrounded by a non-neoplastic gliotic tissue. Tumors with a pure solid component are infrequent. Multilobulated cystic mass is a more common finding. The tumors are most commonly located in the cerebellum, hypothalamus, thalamus, brainstem, and cerebral hemispheres. On CT, the mural nodule is usually isodense with eventually associated cytic component and calcifications. On MR, the tumor is isointense to white matter on T1-weighted sequences and hyperintense on T2-w. MR spectroscopy may show in addition a reduced NAA peak and an elevation of lactate and lipid levels.105,106 An intense homogeneous or heterogeneous enhancement of the tumor or its mural nodule is a characteristic feature and is invariably present. Note that the walls of the cystic component usually do not enhance (Figure 84.7). Contrast enhancement helps to differentiate it from a diffuse low-grade astrocytoma. Conversely it may lead to an erroneous diagnosis of a high-grade astrocytoma, especially in the cerebral hemisphere due to the possibility of associated vasogenic edema. Oligodendrogliomas and mixed gliomas Oligodendrogliomas are glial tumors arising from oligodendrocytes, usually slow-growing and developing in the cerebral hemispheres with a duration between symptoms and surgery ranging from 2 to 7 years. The presenting sign is most frequently a focal or generalized seizure found in 50–70% of cases. Signs related to intracranial hypertension with headaches are found in about 1/5 of cases. About 30% reduction in seizure frequency is observed after surgery.107,108

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(c) Figure 84.6 Low grade diffuse fibrillary astrocytoma (WHO grade II). MR shows a relatively well-demarcated temporal lobe mass expanding the pole with little associated edema and moderate mass effect on the mesial temporal region. The tumor is homogeneously hypointense to white matter on T1-w (a), hyperintense to gray matter on PD-w (b), T2-w (c), and FLAIR (d) sequences. The tumor infiltrates superiorly the sublenticular area and part of the insular lobe (d). No contrast uptake has been evidenced.

The overall 15-years, survival is about 25%109 improving to reach almost 70% in the pediatric population.108 Oligodendrogliomas are infiltrating usually well-defined tumors formed of cells resembling oligodendrocytes. Oligodendrogliomas account for 5–10% of all intracranial neoplasms and about 18% of all gliomas. They are found most commonly in adults in the fourth and fifth decades and are rare in infants or children found in about 6% of cases. A biphasic

age distribution of 6–12 years and 26–46 years is found.108,110 A slight male preponderance is observed with a 2:1 ratio. Histopathologically, oligodendrogliomas correspond to WHO grade II in well-differentiated tumors and WHO grade III for anaplastic tumors. The Kernohan and Saint-Anne/ Mayo classifications differentiate prognostically low-grade (1 and 2) from high-grade (grade 3 and 4) tumors. The classification is still debated. Oligodendrogliomas show a wide

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Figure 84.7 Pilocytic astrocytoma (WHO grade I). The tumor arising in the lateral temporal lobe demonstrates a characteristic cyst with mural nodule. The nodule is moderately hyperintense to the cortex on the T2-w axial image (a) and shows marked homogeneous enhancement on the T1-w lateral sagittal cut (b). Notice that the cystic component does not enhance with contrast.

variation ranging from well–differentiated to highly malignant lesions.111 Oligodendrogliomas are moderately cellular with a characteristic presence of intratumoral microcalcifications in 70% of cases which may also be found in the adjacent cortical area. Most neuropathologists require a preponderance of 75–90% of neoplastic oligodendrocytes within the tumor to be qualified as oligodendrogliomas, the remaining being considered as mixed gliomas. Morphology and imaging Oligodendrogliomas are supratentorial in location in 90–95% of the cases from which more than 50% up to 85% are located in the frontal lobe followed by the temporal, parietal and occipital lobes.109,112,113 The tumors tend to progressively grow toward the cortex infiltrating and expanding the corresponding gyri in a nondestructive manner similar to low-grade astrocytomas rather than centrally infiltrating the corpus callosum. The tumors develop and spread similarly to astrocytomas through white matter which appears largely expanded before symptoms are produced. The importance of infiltration is usually more limited than in diffuse astrocytomas. Blurring of the gray-white matter interface is caused by the propensity to invade the cortex and even the leptomeninges with secondary desmoplastic reaction. This superficial extent and slow growth often causes a remodeling of the inner table of the skull observed in 17% of cases.109 Meningeal gliomatosis and ventricular seeding are found in almost 10% of oligodendroglial tumors.113 Oligodendrogliomas are commonly fairly well-circumscribed tumors with poorly defined boundaries, showing little peritumoral edema. Some may appear

heterogeneous due to the intralesional presence of small cystic areas of degeneration (20%) and/or hemorrhages (20%) and / or calcifications (50–70%), the latter being best demonstrated on CT as dense or gyriform in shape commonly limited to the cortical areas and mimicking Sturge-Weber disease except that the brain is not atrophic. Calcifications may be to some extent depicted on MR using T2* gradient–echo sequences due to magnetic susceptibility, sensitive to the presence of iron frequently present within dystrophic calcifications. Most calcifications are isointense on T1-weighted and may become markedly hypointense on T2-weighted sequences. Anaplastic oligodendrogliomas appear as diffusely infiltrating tumors much less demarcated than oligodendrogliomas, with increased associated edema and mass effect. Occuring in adults in their fifties, they are found in the frontal lobes in 60% of cases and in the temporal lobe in roughly 30%. Their estimated incidence is unsettled due to less defined criteria for grading ranging from 20–50%. A variable heterogeneous aspect is found owing to the presence of necrotic or cystic areas, hemorrhages and calcifications, similar to that observed in other anaplastic gliomas. This variety respond well to chemotherapy. Mixed gliomas in which are demonstrated two neoplastic components are most frequently of the oligoastrocytic variety. These WHO grade II oligoastrocytomas are found in young adults with a mean age of 45 years, in the frontal and less frequently in the temporal lobes and show no significant imaging differences as compared to WHO grade II gliomas (Figure 84.8).

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(c) Figure 84.8 Mixed glioma (oligoastrocytoma, WHO grade II). Relatively well-delineated corticosubcortical tumor involving the superior part of the precentral gyrus extending medially into the paracentral lobule and anteriorly toward the superior frontal gyrus. The tumor is moderately hypointense to white matter on T1-w (a) images and appear roughly heterogeneous and moderately hyperintense on T2-w axial cuts (b). A slight sulcal effacement of the central sulcus is evidenced posteriorly. No associated edema not contrast enhancement were observed. The tumor is homogeneously hyperintense on FLAIR (c) sequence and best evaluated using 3D-T1w 2 mm contiguous slices acquisition (c) and volume renderings.

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Figure 84.8 cont,d (e), Useful for presurgical planning, as shown in this other young patient with a mass expanding part of the hand unit of the precentral gyrus (c, d, e).

On CT oligodendrogliomas appear as well-circumscribed cortico-subcortical hypodense, partly calcified masses in about 40%, showing hemorrhagic areas in 20%, and presenting cystic formations in 20% of.112,113 Sometimes a gyriform pattern of calcifications may mimic the changes observed in Sturge-Weber disease. On MR the tumor is remarkably hypointense to white matter or isointense to gray matter on T1-weighted images, hyperintense to cortex on PD-weighted images and hyperintense to white matter on T2-weighted or FLAIR images (Figure 84.9). In anaplastic oligodendrogliomas the aspect is more heterogeneous, showing small areas of necrosis. More infiltrating with a much less demarcated shape, they show a lower SI on T2-weighted sequences due to hypercellularity. Oligodendrogliomas may show contrast enhancement, usually mild and heterogeneous, reported in about 25% of cases on CT and almost 80% on MR.111 Anaplastic oligodendrogliomas may show nonspecific irregular ring-enhancement patterns. Enhancement may have a negative correlation with patient survival.114,115 In comparison with adults, oligodendrogliomas in children are less commonly calcified, enhance less frequently and show little peritumoral edema.108 Anaplastic astrocytomas and glioblastomas multiforme Malignant astrocytic tumors are represented by the anaplastic astrocytomas (WHO grade III) nd the glioblastomas (WHO grade IV). Anaplastic astrocytomas show a peak incidence in the fifth decade, with males more frequently affected than females with an almost 2:1 male-to-female ratio. They are slightly more frequent than low-grade fibrillary astrocytomas averaging 25% of gliomas. Almost 2/3 result from dedifferentiation of lowgrade gliomas. The median survival averages 2.5 years. Histopathologicaly anaplastic astrocytomas are diffuse fibrillary astrocytomas of intermediate form showing on preparations focal areas of anaplasia involving roughly half the cells and focal or diffuse increased cellularity by 50% or more. They typically display mitotic activity. The microcystic changes

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found in low-grade tumors are lacking here. They may arise de novo or develop from low-grade tumors by malignant transformation. Glioblastoma multiforme is the most frequent brain tumor in adults accounting for 50–60% of all astrocytic and 15–20% of all intracranial tumors. It is the most malignant of diffuse astrocytomas with a survival time of about 12 months. They usually arise as primary intracranial tumors but may develop as secondary tumors from low-grade diffuse or anaplastic astrocytomas. Glioblastomas are found at any age but most commonly in adults between ages 45 and 70 with/a mean of around 50 years old. They are rare in patients under age 30, with less than 3% reported.117 The incidence in men is more frequent than in women, about 2:1. They are found most often in the cerebral hemispheres. Histopathologically the diagnosis of glioblastoma is based on the presence of anaplastic glial cells, frequent mitotic activity, endothelial proliferation and hypervascularity, found peripherally or around the necrotic zones. Frequent areas of necrosis are usually found in the center of the tumor. Apparent multicentric tumors are reported in as many as 5–15% of cases, presumably due to the presence of multifocal zones of anaplasia within a pre-existing low-grade diffuse astrocytoma.116,118 Multiple glioblastomas are present as independent tumors in about 2.5–5% of cases.118 Widening of the extracellular spaces through vasogenic edema facilitates spreading of the neoplastic cells. Signs and symptoms: the clinical picture is similar in anaplastic astrocytomas to that presented in low-grade gliomas except for a shorter medical neurological history preceeding diagnosis and a higher mean age of 40 years old. The duration of the clinical history decreases dramatically in glioblastomas developed de novo, becoming as short as 3–6 months in almost half the cases as compared with those developing from pre-existing low-grade diffuse or anaplastic astrocytomas (4–5 years duration of the neurological history). In glioblastomas the symptomatology develops rapidly in a few weeks or months including generalized neurological symptoms and seizures followed by more definite lobar or callosal syndromes according to brain localization. The onset may even be sudden in 3–5%, pseudovascular in progression usually due to intratumoral hemorrhage or cystic formations within the tumor and leading to the development of focal cerebral signs. Glioblastomas show a very poor prognosis with less than 20% of patients surviving for 1 year and 10% beyond 2 years after the onset of clinical symptomatology. Younger patients, less than 45 years old, appear to have a better prognosis than the older presumably because of the higher frequency of secondary glioblastomas in such younger populations. Longer survival would be related to complete resection when possible. Morphology and imaging Anaplastic astrocytomas are morphologically often difficult to distinguish from low-grade astrocytomas but appear much more heterogeneous.103,104 As in diffuse fibrillary astrocytoma the tumor shows tendancy to infiltrate the anatomical structures involved without obvious distortion except for a relative enlargement of the corresponding gyri or the basal ganglia. Vascular proliferation and necrosis are lacking. Occasionally proliferation of tumor vessels may be observed with flow void foci. Note that anaplastic astrocytomas are found in half the

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Figure 84.9 Oligodendroglioma (WHO grade II). Superficial fairly well-circumscribed mass developing in the central lobe within the subcortical white matter rand abuting the cortex. The tumor is hypointense to gray matter on T1-w sequence (a) and hyperintense on PD-w (b) and T2-w (c) sequences. Almost no mass effect, peripheral edema no intratumoral calcifications were evidenced. A peripheral contrast enhancement is noticed (d).

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Magnetic resonance imaging in epileptogenic neoplasms cases of recurrent tumors due to malignant transformation. Peritumoral edema and mass effect may be found but remain a feature of glioblastomas. Frank intratumoral necrosis is absent. Anaplastic astrocytomas are usually heterogeneous tumors but may mimic a low-grade astrocytoma showing a homogeneous SI with slightly heterogeneous areas.102,104 Hypointense to white matter on T1-w images the tumor is hyperintense to cortex on PD-w images and appear hetereogeneously hyperintense to white matter on T2-w images and FLAIR. Proton

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spectroscopy has been reported in anaplastic astrocytomas to show an increase of Cho levels, a decrease of NAA levels and presence of lipid resonance peaks. Anaplastic astrocytomas show variable patterns of enhancement ranging from homogeneous to even nodular or patchy (Figure 84.10). Very occasionally a ‘ringlike’ pattern is found. The latter is more suggestive of a glioblastoma and should not be observed in anaplastic astrocytomas.103 Glioblastoma multiforme, the most aggressive and least differentiated variety of gliomas, occur most commonly in the

(b) Figure 84.10 Anaplastic astrocytoma (WHO grade III). Highly heterogeneous tumor infilltrating the frontal lobe and including areas of almost homogeneous signal intensity associated to more hyperintense areas on T2-w (a) or FLAIR (c) images. The tumor shows peritumoral edema and is associated with a pronounced mass effect on the lateral ventricles, collapsed and partly displaced posterolaterally (a). Significant patchy contrast enhancement is observed (c) extending toward the corpus callosum. Cavitary necrosis more suggestive of a glioblastoma is notably lacking.

(c)

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cerebral hemisphere located most frequently in the white matter, the epicenter of the tumor, of the frontal lobes, or temporal, and then parietal lobes. Some of these tumors are rather superficial in topography in contact with the leptomeninges and dura with possible subarachnoid seeding. Cortical infiltration may occur giving rise to a thickened appearance of gyri surrounding a necrotic area in the subjacent white matter. Glioblastoma commonly appear as an irregular almost wellcircumscribed mass with highly suggestive central necrosis as compared to the anaplastic type, surrounded by relatively large areas of peripheral edema. The cellular peripheral zone is highly vascularized showing a microvascular proliferation corresponding to the zone of ‘ring’ enhancement. The large areas of intratumoral necrosis secondary to destruction of tumoral tissue may correspond to as much as 90% of total tumoral volume and appear as characteristic of primary glioblastomas, being absent in anaplastic astrocytomas. Hemorrhagic changes are common in the central portion of the tumor. Calcifications are very rare. Mass effect associated

to peritumoral edema may be prominent with sulcal effacement or ventricular displacement or collapse. Sharply circumscribed tumors may be observed (Figure 84.11). Glioblastomas show a high propensity to rapidly expand along the white matter tracts to invade adjacent areas of the cerebral white matter or spread in the internal capsule or the fornix. This pattern of spread is facilitated by widening of the extracellular spaces through vasogenic edema. The tumor may also typically extend through the corpus callosum in almost 75% of cases and even cross the midline to reach the contralateral hemisphere with a ‘butterfly’ appearance. The latter aspect may also be encountered in lymphomas except that lymphomas exhibit a hypointense SI on T2 due to their hypercellularity. Glioblastomas may show subependymal or leptomeningeal spread in 5% of cases, best demonstrated after contrast enhancement. Glioblastoma multiforme are markedly heterogeneous tumors showing on T1-w images a heterogeneously hypointense signal intensity to white matter with even more

(a) Figure 84.11 Glioblastoma multiforme (WHO grade IV). Highly heterogeneous aggressive tumors, appearing as almostcircumscribed, arising in the white matter of the temporal lobe, including areas of cavitary necrosis, which is the hallmark of glioblastomas as compared to anaplastic astrocytomas (a,b).

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Figure 84.11 cont’d The tumor is heterogeneously hyperintense on FLAIR sequence (a, double arrows) showing a prominent enhancement (b, arrow) with an irregular ringlike pattern after Gd administration (b). Peritumoral vasogenic edema is pronounced (a, arrow and b, triple arrows) with important mass effect on the adjacent ventricular atrium almost collapsed and displaced anteriorly and medially. Extension to the leptomeninges (b, double arrows) and adjacent sulcal effacement may be observed as well. The tumor aspect may be misleading and appear as a well-circumscribed more homogeneous mass roughly well separated from the vasogenic edema as in an other patient (c,d).

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hypointense intratumoral necrotic zones, unless including hemorrhagic areas which may be hyperintense due to the presence of paramagnetic methemoglobin. On PD-w images the tumor is hyperintense to white matter with areas of central necrosis that could show a more hyperintense SI than the solid part due to its high protein content and the presence of blood breakdown products such as extracellular methemoglobin, surrounded by extensive peritumoral vasogenic edema. T2-w images show a variably heterogeneous signal intensity of the solid portions of the tumor that may be mildly hyperintense to brain and/or may show iso- to hypointense areas due to tumoral hypercellularity. Serpentine fow void structures corresponding to vessels related to tumoral angiogenesis are also found. FLAIR sequence shows mild hyperintensity to normal brain tissue with variable intensity of the intratumoral necrotic areas associated to markedly hyperintense SI of the peritumoral vasogenic edema. Tumors may show a well-circumscribed appearance roughly well separated from the vasogenic edema (Figure 84.11). Proton spectroscopy has been reported in glioblastomas to show an increase in Cho levels, a decrease in NAA and the presence of peaks of lactate and lipids. A significant correlation has been observed between higher grade glial tumors and mobile lipid resonance peaks at 1.3 ppm. Glioblastoma multiforme always show a heterogeneous enhancement more sensitive with MR than with CT. Most commonly the enhancing pattern is irregular, ring-like, highly heterogeneous with variable thickness and a shaggy inner margin more conspicuously shown with delayed scans, surrounding the area of necrosis which do not enhance. Contrast enhancement correspond to the tumoral process but do not delimitate the outer tumoral boundary as shown on pathology. The nonenhancing surrounding edema has been demonstrated to include microscopic tumors. The extent of such microscopic adjacent peritumoral zone appear to be usually limited to 2 cm, an area which corresponds to the zone of tumor recurrence as observed in more than 85% of cases. It may extend to more than 2 cm and exceed 3 or 3.5 cm in 17–27% of cases according to imaging studies with pathological correlations to stereotactic biopsies. The imaging aspect may mimic other malignant tumors such as anaplastic oligodendrogliomas, metastases, lymphomas, or other processes as radiation necrosis, cerebritis and abscesses. An abcess typically shows hypoperfusion as compared with high-grade gliomas which demonstrate a high perfusion. On diffusion-weighted images, abcesses show a bright signal intensity due to restricted diffusion, while necrotic areas of glioblastomas show a low or an isosignal on diffusion. On MRS the presence of a peak at 0.9 ppm corresponding to cytosolic amino acids is highly suggestive of an abcess. Note that Cho peak, the most specific marker of brain neoplasms may not be evidenced in tumors with significant necrosis. In lymphomas DWI shows similar high signal intensity. Hypoperfusion would be more suggestive of lymphoma probably due to elevated nucleus/cytoplasm ratios. MR spectroscopy will demonstrate the presence of suggestive significant high peaks in lipids associated to a decrease of NAA and Cr levels. Metastases may be differentiated and evidenced using MRS which demonstrates an almost absence of NAA and Cr peaks in the tumor and no elevation of Cho within the peritumoral area of vasogenic edema.119 Conversely, high Cho levels peritumorally indicates infiltration of brain

parenchyma by the tumoral process associated to edema. Radiation necrosis, eventually observed within 6 months, may demonstrate on multivoxel MRS similarly and with a greater sensitivity than PET, an increase in lipids and lactate peaks along with a decrease in Cho level or may show a normal spectrum.47 Conversely in the case of elevation of Cho levels and Cho/NAA ratios in irradiated brain, tumor recurrence should be suspected.46 Necrotic areas present in postradiation therapy or in postchemotherapy, show a drop in brain metabolites but an increase in lipids and lactate and disclose a large peak between 0 and 2 ppm related to cell necrosis. Note that administration of steroids may modify the absolute levels but do respect the ratio values of brain metabolites. Pleiomorphic xanthoastrocytomas Pleiomorphic xanthoastrocytomas, introduced in the 1993 WHO revision53 are very rare circumscribed astrocytic tumors accounting for less than 1% of all gliomas and demonstrating marked cellular pleomorphism.120 They are usually found in adolescents and young adults and children in the first or second decades with no sex predilection at a median age of 14 years old with a longstanding history of seizures, as in dysembryoplastic neuroepithelial tumors.121–123 Pleiomorphic xanthoastrocytomas, classified as WHO grade II, are special variants of astrocytomas.124 Considered as slow-growing lowgrade tumors typically arising peripherally from the subpial astrocytes with predilection for a location within the temporal and parietal lobes, they may progress to a more aggressive behavior over time with transformation into a malignant glioma in more than 1/3 of cases.125 Because of such potentiality the tumors are never better than grade II. Morphology and imaging Thought to arise from subpial astrocytes, the morphological aspect on imaging is suggestive. The tumor is characteristically a well-circumscribed peripheral mass showing cystic components with a solid mural nodule similar to the appearance of pilocytic astrocytomas and tends to develop at the surface of the cerebral hemisphere, often extending superficially to the pial surface of the brain which may show meningeal thickening and arachnoid spread in more than 2/3 of cases.126 Cystic components, some of which very large, are found in 50% of the cases (Figure 84.12). Calcifications are infrequent. The neoplasm may be associated with a scalloping of the inner table of the cranial vault. Imaging features are suggestive, even if rarely diagnostic.127–129 On CT, the mass is isodense to gray matter. On MR imaging, pleiomorphic xanthoastrocytomas show an isointense signal intensity or a mixed signal intensity to gray matter on T1-weighted and T2-weighted images and a hyperintense signal intensity on FLAIR. The solid portion of the tumor commonly enhances homogeneously or heterogeneously and may show a dural tail sign.126 Cyst walls show variable contrast uptake.130 Hemorrhagic foci and calcifications are rare and associated vasogenic edema minimal if not absent. These tumors may be differentiated from astrocytomas which are hypodense on CT and are more hypointense on T1-w and more hyperintense on T2-w images, due to their higher water content, but need to be differentiated from desmoplastic neuroepithelial tumors in infants and from gangliogliomas or oligodendrogliomas in children.

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Figure 84.12 Pleiomorphic xanthoastrocytoma (WHO grade II). Huge multilobulated largely cystic fluid-filled mass with a relatively very small well-defined mural nodule superficially located adjacent to the cortical ribbon and showing a strong homogeneous enhancement (b) with a dural tail sign. Slight and limited contrast uptake involves the cyst walls. The morphological features are similar to pilocytic astrocytomas. The mass is isointense to gray matter on T1-w and PD w (c) or T2-w (a, d) sequences.

Gliomatosis cerebri Recognized as a separate histopathological neoplasm by the WHO53 most cases of gliomatosis cerebri are considered by most neuropathologists as representing an unusual extensive infiltration of the brain by a diffuse astrocytoma.131,132 It is usually found in young adults with no sex predilection in their twenties to forties. Morphology and imaging Gliomatosis cerebri are very rare diffuse glial tumor (WHO grade III or IV) infiltrating the cerebral hemispheres in 2/3 of

cases, uni- or bilaterally, and extending over more than one lobe which appear enlarged. The centrum semiovale is infiltrated in over 2/3 of cases and the cortex in less than 20%, followed by the brainstem in about half, the thalami in 40% and the basal ganglia in 30%. Leptomeningeal spread occurs in about 1/5 of the cases.133 Age at diagnosis shows a peak incidence between 40–50 years old. Imaging features of gliomatosis cerebri include an isodense to hypodense appearance on CT but it is best imaged using MR, which is much more sensitive in depicting the neoplasm and evaluating its wide extension.134 The neoplastic expansion along the anatomic

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pathways is multilobar and often bihemispheric distorting rather than destroying the brain parenchyma in the manner of low-grade gliomas. Involvement of the white matter core is predominant with blurring of the gray-white matter junction (135). This ill-defined tumor is homogeneously isointense to hypointense on T1-weighted sequences and hyperintense on T2. Enhancement, usually faint, is observed in less than half of

(a)

the cases and mass effect is usually moderate (Figure 84.13). Prognosis is poor. Subependymal giant cell astrocytomas Subependymal giant cell astrocytomas are low-grade (WHO grade I) astrocytic tumors associated in more than 90% of

(b) Figure 84.13 Gliomatosis cerebri (WHO grade III). Extensive tumoral process infiltrating the fronto-temporo-insular lobes in a young adult, associated with enlargement of the related gyri and moderate mass effect on the midline structures and the ventricular cavities displaced contralaterally. Note the predominant involvement of the white matter core with blurring of the gray-white matter interface (a,b) and the propensity to expand along the anatomical pathways such as the external and extreme capsules (b) or the temporal stem (c) in the manner of a low-grade glioma. This diffuse ill-defined glial tumor is hypointense on T1-w images (a), and hyperintense on T2-w (b) and FLAIR (c) images. Almost no contrast uptake is noticed (a).

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it or the adjacent parenchyma and does not show subarachnoid seeding (Figure 84.14). The tumor is covered by an intact layer of ependyma. Irregular calcifications may be commonly found. It may be rarely an isolated finding, a ‘forme fruste’ of Bourneville’s disease. The tumor is hypodense to isodense on CT showing calcifications. On MR the tumor is rounded or ovoid, presenting a heterogeneous signal intensity usually hypointense to isointense on T1-weighted images and hyperintense on T2weighted images.139,140 Associated subependymal nodules and tubers, best visualized on MR, are usually evidenced in Bourneville’s patients. The tubers are centrally hypointense to white matter or isointense on T1-weighted images, but appear hyperintense in infants as compared with unmyelinated white matter. On SE-T2w or FLAIR images, the tumor is hyperintense to white matter. Note that in the case of associated calcified subependymal nodules or cortical tubers, GE-T2*w sequence is helpful for depicting the calcified portions due to the magnetic susceptibility differences with adjacent brain tissue. Calcifications may show a hypointense SI on SET2w and may even appear as bright areas on T1-w images. Subependymal nodules of more than 1 cm particularly if symptomatic should to be considered as subependymal giant cell astrocytomas.140 Although cortical-subcortical tubers and subependymal hamartomatous and glial nodules within the white matter usually do not show contrast enhancement, subependymal giant-cell astrocytomas characteristically strongly enhance uniformly.140 Note that enhancement of a subependymal nodule must be followed up with MR in order to rule out an eventual transformation into a giant cell astrocytoma. Regional parenchymal invasion or rapid growth is highly suspect of anaplastic transformation. Although benign, spontaneous intratumoral hemorrhage may occur leading to death.

cases with Bourneville’s disease, a phakomatosis including cutaneous, visceral, and central nervous system manifestations. Almost 10–15% of these patients will develop, usually in their teens or twenties, the characteristic subependymal giantcell astrocytoma.136,137 The average age at diagnosis is 10 years old.138 The clinical presentation is commonly hydrocephalus. Histologically, these tumors are similar to the subependymal hamartomas found in tuberous sclerosis137 which is a genetically determined and familial disease transmitted in an autosomal dominant mode with low penetrance. Its incidence is evaluated as being 1:100–150 000 patients or may even be as high as 1:10–20 000. There is no sexual or racial preponderance. Clinically, patients with tuberous sclerosis present a classic triad of cutaneous angiofibroma (90%), appearing at 1–5 years old, in the nasolabial folds or extending to the cheeks and the malar region (butterfly appearance); myoclonic seizures and hypsarrhythmia (80%), and mental deficiency (about 60%) of variable severity. Tuberous sclerosis is characterized in the CNS by the presence of disseminated hamartomas or tubers consisting of nodules of disorganized cortical tissue containing atypical giant bizarre neurons and astrocytes. The subjacent white matter contains few myelinated fibers and fibrillary gliosis. Morphology and imaging The giant-cell astrocytoma is a slowly-growing well-demarcated tumor typically subependymal and almost always found in the lateral ventricle near the foramen of Monro, frequently causing an obstructive hydrocephalus with an ipsilateral or bilateral ventricular enlargement. This morphologic and topographic appearance is almost pathognomonic when associated with other features of tuberous sclerosis. The mass is fixed to the head of the caudate nucleus but does not infiltrate

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Figure 84.14 Subependymal giant-cell astrocytoma (WHO grade I). Intraventricular rounded mass found in association with tuberous sclerosis and developed in the lumen of the frontal horn of the lateral ventricle, at the foramen of Monro (arrow). It appears attached to the caudate nucleus which is not infiltrated. The mass is well demarcated including small cystic formations (a). It appears heterogeneously hyperintense to white matter on the T2-w coronal cut (a) and enhances intensely as shown on the parasagittal T1w cut (b), overlying the interventricular foramen. Note the ipsilateral ventricular enlargement and the mass effect on the third ventricle (double arrows).

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6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

19. 20. 21. 22.

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Brooks BS, King DW, El Gammal T et al. MR imaging in patients with intractable complex partial epileptic seizures. Am J Neuroradiol 1990;11:93–9. Bronen RA. Epilepsy: the role of MR imaging. AJR 1992;159:1165–74. Andermann F. Brain structure and epilepsy: the impact of modern imaging. Am J Neuroradiol 1997;18:302–6. Commission on Neuroimaging of the International League Against Epilepsy. Recommendations for neuroimaging of patients with epilepsy. Epilepsia 1997;38:1255–6. Commission on Neuroimaging of the International League Against Epilepsy. Guidelines for neuroimaging evaluation of patients with uncontrolled epilepsy considered for surgery. Epilepsia 1998;39:1375–6. Breslau J, Jarvik JG, Haynor DR et al. MR contrast media in neuroimaging: a critical review of the literature. Am J Neuroradiol 1999;20:670–5. Bronen RA, Fulbright RK, Spencer DD et al. Refractory epilepsy: comparison of MR imaging, CT, and histopathologic findings in 117 patients. Radiology 1996;201:97–105. Knowlton RC, Laxer KD, Ende G et al. Presurgical multimodality neuroimaging in electroencephalographic lateralized temporal lobe epilepsy. Ann Neurol 1997;42:829–37. Connelly A, Van Paesschen W, Porter DA et al. Proton magnetic resonance spectroscopy in MRI-negative temporal lobe epilepsy. Neurology 1998;51:61–6. Achten E, Santens P, Boon P et al. Single voxel proton MR spectroscopy and positron emission tomography for lateralization of refractory temporal lobe epilepsy. Am J Neuroradiol 1998;19:1–8. Binder JR, Swanson SJ, Hammecke TA et al. Determination of language dominance using functional MRI: a comparison with the Wada test. Neurology 1996;46:978–84. Benson RR, Fitzgerald DB, Lesueur LL et al. Language dominance determined by whole brain functional MRI in patients with brain lesions. Neurology 1999;52:798–809. Detre JA, Maccotta L, King D et al. Functional MRI lateralization of memory in temporal lobe epilepsy. Neurology 1998;50:926–32. Righini A, de Divitiis O, Prinster A et al. Functional MRI: primary motor cortex localization in patients with brain tumors. Comput Assist Tomogr 1996;20:702–8. Negendank WG, Sauter R, Brown TR et al. Proton magnetic resonance spectroscopy in patients with glial tumors: a multicenter study, J Neurosurg 1996;84:449–58. Resta M, Palma M, Dicuonzo F et al. Imaging studies in partial epilepsy in children and adolescents. Epilepsia 1994;35:1187–93. Wolf H, Campos M, Zentner J et al. Surgical pathology of temporal lobe epilepsy. Experience with 216 cases. J Neuropathol Exp Neurol 1993;52:499–506. Zentner J, Hufnagel A, Wolf H et al. Surgical treatment of temporal lobe epilepsy: clinical, radiological, and histopathological findings in 178 patients. J Neurol Neurosurg Psychisatry 1995; 58:666–73. Spencer SS. The relative contributions of MRI, SPECT, and PET imaging in epilepsy. Epilepsia 1994;35(suppl 6):72–89. Kuzniecky RI, Jackson GD. Neuroimaging in epilepsy. In: Magnetic Resonance in Epilepsy. New York, NY: Raven, 1995;27–48. Duvernoy H, Cabanis EA, Iba-Zizen MT, Tamraz J, Guyot J. The Human Brain Surface Three-dimensional Sectional Anatomy and MRI Wien, New York: Springer-Verlag 1991. Tamraz J, Comair Y. Cephalic reference lines suitable for neuroimaging in: Atlas of Regional Anatomy of the Brain Using MRI, chapter 2. Berlin, Heidelberg, Springer-Verlag, New York: 2000;330 pp, (reprint 2005, 2nd ed in preparation). Tamraz J, Brain Anatomy. Structural neuro-imaging, part IV, In: Lüders HO, Comair Y, eds Epilepsy Surgery. 2nd edn Parke-Davis, 2001. Talairach J, Szikla G, Fournier P, Atlas d’anatomie stéréotaxique du télencéphale. Etudes anatomoradiologiques. Paris:Masson 1967. Comair J, Tamraz J. Cortical anatomy: normal and abnormal subcal and gyral patterns, chapter 6. In: Willey E ed., The Treatment of Epilepsy: Principles and Practice, 3rd edn. Lippincott Williams and Wilkins, 2000. Raymond AA, Fish DR, Sisodiya SM et al. Abnormalities of gyration, heterotopias tuberous sclerosis, focal cortical dysplasia, microdysgenesis, dysembryoplastic neuroepithelial tumour and dysgenesis of the archicortex in epilepsy. Clinical, EEG and neuroimaging features in 100 adult patients. Brain 1995;118:629–60.

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Textbook of epilepsy surgery Lee Y, Van Tassel P, Bruner JM et al. Juvenile pilocytic astrocytomas: CT and MR characteristics. Am J Neuroradiol 1989;10:363–70. Rizk T, Mottoloese C, Bouffet E et al. Cerebral oligodendrogliomas in children: an analysis of 15 cases. Childs Nerv Syst 1996; 12:527–9. Razack N, Baumgartner J, Bruner J: Pediatric oligodendrogliomas. Pediatr Neurosurg 1998;28:121–9. Shaw EG, Scheithaure BW, O’Fallon JR et al. Oligodendrogliomas: the Mayo Clinic experience. J Neurosurg 1992;76:428–34. Tice H, Barnes PD, Goumnerova L et al. Pediatric and adolescent oligodendrogliomas. Am J Neuroradiol 1993;14:1293–300. Daumas-Duport C, Monsaingeon V, Blond S. Serial stereotactic biopsies and CT scan in gliomas: correlative study in 100 astrocytomas, oligo-astraocytomas and oligodendrocytomas. J Neurooncol 1986;4:317–28. Lee YY, Van Tassel P. Intracranial oligodendrogliomas: imaging findings in 35 untreated cases. Am J Neuroradiol 1989;10:119–27. Ludwig CL, Smith MT, Godfrey AD et al. A clinicopathological study of 323 patients with oligodendrogliomas. Ann Neurol 1986;19:15–21. Daumas-Duport C, Tucker ML, Dolles H et al. Oligodendrogliomas part II: A new grading system based on morphological and imaging criteria, J. Neurooncol. 1997;34:61–78. Daumas-Duport C, Varlet P, Tucker ML et al. Oligodendrogliomas, part I: patterns of growth, histological diagnostic, clinical and imaging correlations: a study of 153 cases. J. Neurooncol. 1997;34:37–59. Barnard RO, and Geddes JF. The incidence of multifocal gliomas: a histologic study of large hemisphere sections. Cancer 1987;60:1519. Artico M, Cervoni L, Celli P, Salvati M, Palma L. Supratentorial glioblastoma in children: a series of 27 surgically treated cases. Childs Nerv Syst 1993;9:7–9. Burger PG, Vogel FS, Green SB et al. Glioblastoma multiforme and anaplastic astrocytoma: pathologic criteria and prognostic implication. Cancer 1985;56:1106–11. Sijens PE, Knopp MV, Brunetti A et al. 1H MR spectroscopy in patients with metastatic brain tumors: a multicenter study. Magn Reson Med 1995;33:818–26. Kepes JJ Pleomorphic xanthoastrocytoma: the birth of a diagnosis and a concept. Brain Pathol 1993;3:269–74. Kepes JJ, Rubinstein LJ, Eng LF. Pleomorphic xanthoastrocytoma: a distinctive meningocerebral glioma of young subjects with relatively favorable prognosis: a study of 12 cases. Cancer 1979;44:1839–52. Allegranza A, Ferraresi S, Bruzzone M et al. Cerebromeningeal pleomorphic xanthoastrocytoma: report on four cases: clinical radiologic and pathological feature (including a case with malignant evolution). Neurosurg Rev. 1991;14:43–9.

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Magnetic resonance spectroscopy in patients with epilepsy MA McLean, M Koepp, and FG Woermann

Introduction Magnetic resonance spectroscopy (MRS) offers a unique opportunity to assay noninvasively the concentrations of metabolites in the brain in vivo. In epilepsy, this information can be used to aid diagnosis of the epileptogenic lesion, optimization of the extent of a surgical resection, or prediction of postoperative outcome. MRS may give important insights into the mechanisms of seizure generation and termination, and into the pharmacodynamics of antiepileptic drugs, and may thus help in deciding which patients may tolerate particular drugs.

Principles of MRS The principles underlying the technique are the same as for MRI discussed in previous chapters. A magnetic nucleus in an applied magnetic field can be induced to emit signal at a specific frequency, which depends on its electronic environment (specifically, on the electronegativity of the chemical bonds in which it takes part). These frequencies can be analyzed as a spectral fingerprint, to tell us what chemicals are present. MRS is an insensitive technique: typically only metabolites present at concentrations of about 1 mM or higher are detectable in vivo. Not all isotopes are magnetic, and not all magnetic isotopes produce signal which is equally easy to detect. The most commonly studied isotopes in epilepsy are 1H and 31P. Proton MRS The 1H nucleus (a single proton), although both abundant and relatively sensitive in NMR terms, initially presented problems to study via MRS: techniques needed to be developed to exclude the strong signals arising from water and macromolecules (lipids and proteins) in order to study the more interesting small metabolites (amino acids, sugars, etc.). Such techniques are now available to suppress the water peak,1 and to reduce and/or spatially exclude the macromolecule signal. Spatial exclusion (known as outer volume suppression, or OVS) is needed because of the very intense lipid signals arising from the scalp. Macromolecule signals can also be reduced by taking advantage of their short T2 relaxation (by acquiring at echo times >100 ms) or their short T1 (by preceding the acquisition with an inversion pulse). If the delay between inversion and acquisition is short, the lipid signal

may be nulled;2 if it is long, the metabolite signal may be nulled, and the resultant macromolecule signal may be subtracted from a spectrum without inversion to yield a clean metabolite signal.3 Following these technical advances, 1H has become by far the most widely studied nucleus in clinical MRS. The metabolites studied are shown in Figure 85.1. At long echo times, signal is primarily present from N-acetyl aspartate (NAA), creatine plus phosphocreatine (Cr) and choline-containing compounds (Cho). As described previously, at this echo time of 144 ms the macromolecule signal (MM) has decayed completely, giving a flat baseline from which metabolite peak areas can be measured. Following hypoxic insults, some seizures, or more rarely in normal brain, an inverted doublet signal can be observed from lactate at 1.33 ppm. At shorter echo times (e.g., 30 ms as shown), the MM peaks interfere with quantification not just at the frequencies below 2 ppm, but throughout the spectrum. Additional interesting peaks can be detected from myoinositol (Ins) and glutamate and glutamine (Glx), but sophisticated modelling is necessary to distinguish them from the overlapping peaks,4 and baseline determination remains a major source of error. Localization techniques Localization is needed for 1H-MRS, not merely to exclude scalp lipid signal, but to compare different tissues and locations in the brain (e.g., left vs. right hippocampus as shown in Figure 85.2). Localization makes use of frequency-selective excitation, where the rf pulses are accompanied by gradients. In imaging, this is used to excite a single slice for 2D images. In spectroscopy, we often choose to do slice-selective excitation in three orthogonal planes to excite a cuboid volume at their intersection. This is called single voxel (SV) MRS. The three rf pulses used are chosen to create either stimulated echoes (STEAM) or spin echoes (PRESS). The other common localization tool is phase encoding, as used in imaging. This is known as spectroscopic imaging (MRSI), sometimes called chemical shift imaging (CSI). Sometimes we use both 3D localization (e.g., PRESS) and MRSI, to acquire a spectroscopic image of a cuboid volume, rather than over the whole slice (Figure 85.3). This aids in the exclusion of the intense scalp lipid signal. Analysis methods Since the areas of metabolite signals are directly proportional to their concentrations in the tissue, we can use MRS to estimate 755

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Textbook of epilepsy surgery overlap with each other and with broad underlying macromolecule resonances. Therefore it is generally desirable to fit such spectra using automated routines which can take this broad baseline into account, and which incorporate information on the whole complicated spectral fingerprint of each metabolite of interest. The most commonly used spectral packages are LCModel4 and MRUI (www.mrui.uab.es). Finally, metabolite concentrations differ in gray matter, white matter, CSF and lesions, so it is desirable to estimate the proportion of each in the excited volume. Metabolite content of CSF can be assumed to be negligible,5 and that of lesions would generally be expected to be lower than normal tissue for most metabolites. In gray matter, we and others have found significantly higher content of glutamate plus glutamine, creatine, and myoinositol than in white matter.6

NA

Cr

Ins

4

Cho

Glx

3

MM

2 Frequency (ppm)

1

0

Figure 85.1 Sample proton spin-echo (PRESS) spectra from human frontal lobe in vivo, at long (144 ms, solid line) and short (30 ms, dotted line) echo times.

metabolite concentrations. However, since there are so many elements of the proportionality constant that are difficult or impossible to determine (e.g. characteristics of the coil hardware), we generally can only calculate a concentration relative to a known or assumed standard. For example, we can scan a solution of 50 mM creatine and compare the area of the peak we measure to the area of the peak we measure in vivo. Then we can correct for differences in machine gains, the volume of tissue excited, relaxation properties, etc., to obtain an estimate for the concentration in vivo. Alternatively, sometimes only the ratio of one peak to another is reported, e.g., NAA/Cr, or NAA/(Cr+Cho). This has the advantage that any temporal, spatial, or inter-subject differences in machine performance cancel out. However, such ratios can vary in different tissues in the brain, or in disease, in ways that are not always easy to interpret. Even the measurement of peak areas is not trivial, especially in short echo-time spectra, since many peaks of interest

3.5

Metabolite-specific spectroscopy Only three to five metabolites are clearly visible in a conventional proton spectrum (perhaps up to seven can be estimated with spectral modelling at short echo times). If our metabolite of interest cannot be resolved from overlapping molecules, we must turn to more sophisticated methods. One possibility is to perform 2D spectroscopic studies. If we collect data not merely at a single echo time, but at a series of incremented echo times, then we can perform a Fourier transform across this second time dimension to produce a second frequency dimension. Any coupled peaks in the spectrum are modulated at different echo times, so they appear spread out across the second frequency dimension. There are a number of slightly different techniques that use this approach: the most common are J-resolved PRESS7 and localized correlation spectroscopy (L-COSY).8 The main advantage of 2D techniques is that uncoupled signal is retained, so that, in theory, the entire metabolic content of the tissue can be determined from a single acquisition. The main disadvantage is that the spectral resolution in the second frequency dimension is often insufficient to fully resolve overlapping peaks. Another approach with more potential specificity is spectral editing.9 This is a difference technique: we collect one spectrum where we have manipulated a small range of frequencies, another spectrum where we have not, and we look at

3.0 2.5 2.0 Frequency (ppm)

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Figure 85.2 Proton spectra (using PRESS localization with an echo time of 30 ms and repetition time of 3 s) from the ipsi- and contralateral hippocampi of a patient with hippocampal sclerosis and epilepsy. Left: anatomic image showing the positions of the voxels studied. Middle: spectrum from ipsilateral hippocampus. Right: spectrum from contralateral hippocampus.

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Magnetic resonance spectroscopy in patients with epilepsy

Cr

NAA

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Figure 85.3 Long-echo-time (144 ms) MRSI in vivo at 3 Tesla: 20 × 20 phase encoding steps were acquired, but only those which fell inside the volume selected using PRESS are shown. The spectra from each voxel were fit using LCModel to obtain semiquantitative maps of N-acetyl aspartate, creatine, and choline.

the difference between them. There are still potential problems when multiple peaks in the same range pass through the spectral filter, or ‘co-edit’, but more complicated subtraction schemes can be developed to get around this limitation.10 A more fundamental problem is motion: if it occurs, the subtraction will no longer cancel the unwanted resonances. A final technique used to observe coupled peaks is multiple-quantum (MQ) filtration. If we create a MQ coherence, we can use gradients to filter out the uncoupled spins, which are not able to enter this state. The ratio between two gradients applied is chosen to select the desired coherence: the most common is a double quantum filter (DQF). This has been used to study GABA11 and glutathione12 in the brain. Phosphorous MRS 31 P is the 100% abundant isotope of phosphorus, an important atom in biological systems. Its resonances can be detected by tuning the scanner into a frequency range roughly 60% lower than that of proton, although many clinical scanners are not equipped to transmit and receive signal over such a wide range (‘broadband’) of frequencies. The methods for studying 31P are similar to those for proton, with two main exceptions. The first is that the T2 relaxation times are much shorter: about 10–30 ms. Therefore 31P is unsuitable for spin-echo or stimulated-echo experiments, because the signal would have decayed away during the echo time. Instead, nonecho localization schemes such as ISIS13 may be preferred. The second major difference is that phosphorus signal is modulated by nearby protons. These heteronuclear splittings can complicate the spectral signal considerably, particularly the phosphomonoester (PME) and phosphodiester (PDE) peaks. Therefore, decoupling may be applied: this selectively saturates signal at the proton frequency, so that it no longer affects the 31P signal. Visible metabolites The three resonances of adenosine triphosphate (ATP) are detectable in virtually every soft tissue in the body (Figure 85.4). They are not coupled with any protons, but they are coupled with each other: the gamma and alpha peaks are split into doublets by the beta peak, and the beta peak is split into a triplet with intensity ratios 1:2:1. The concentration of ATP tends to

remain stable in living tissues, unless the bioenergetics are very severely compromised. This stability is generally maintained by a store of phosphocreatine (PCr). This singlet (i.e., uncoupled) peak dominates spectra from skeletal muscle, and can be observed to radically reduce during exercise. In brain and other internal organs it is less prominent, but also less subject to reduction, except in hypoxic/ischaemic insults. It may reduce during seizures, as discussed below. The singlet peak of inorganic phosphate (Pi) can also be detected. It has the interesting property that its chemical shift is dependent upon the local concentration of hydrogen ions, so that its distance from the PCr peak may be used as a noninvasive internal pH meter.14 Similarly, the chemical shift of β-ATP can be used to monitor the concentration of free magnesium ions. The other peaks visible in the phosphorus spectrum are broad signals assigned collectively as phosphomonoesters (a)

PCr

PDE

Pi γ

PME

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−25.00

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Figure 85.4 Seven peaks are characteristically identifiable in the 31P-MR spectrum from a normal human brain. In order of decreasing chemical shift, these peaks are assigned to phosphomonoesters (PME), inorganic phosphate (Pi), phosphodiesters (PDE), phosphocreatine (PCr) and g, a, and b nucleotide triphosphate (g, a, and bNTP). These signals were quantified in the time domain using the AMARES algorithm included in the MRUI software program (a), with the residual shown (b) (courtesy of Prof B. Puri).

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(PME) and phosphodiesters (PDE). These are thought to be associated primarily with membranes.

Clinical applications of MRS MRS in temporal lobe epilepsy In the presurgical evaluation of patients with TLE, the potential value of 1H-MRS (or -MRSI) depends on the method’s ability to detect lateralized metabolic changes not only in clear-cut cases of hippocampal sclerosis, but also in patients with normal MRI (‘MRI-negative’); it depends on the method’s ability to lateralize abnormality in the presence of bilateral EEG or MRI changes and to contribute to the detection of dual pathology; ultimately, the clinical value of 1H MRS in this patient group is based on studies correlating presurgical measurements with post-surgical seizure and neuropsychological outcome. Proton MRS in hippocampal sclerosis In patients with hippocampal sclerosis, the typical finding in the epileptogenic hippocampus is a reduction of NAA and an elevation of Cr and Cho (or corresponding changes of ratios like NAA/Cr, NAA/Cr+Cho or Cr/NAA) relative to normal control subjects; the contralateral hippocampus may be normal or show a lesser degree of abnormality. In a series of 100 consecutive TLE patients, the NAA/Cr values were abnormally low in at least one temporal lobe in all but one patient and were abnormally low bilaterally in 54%.15 The asymmetry between right and left NAA/Cr ratios lateralized 92% of patients in concordance with lateralized ictal EEG findings. More abnormalities were detected using MRS than with MR volumetry, but only a few patients with postoperative outcome were reported in this study. Prediction of postoperative outcome The literature is discordant on the issue of predicting outcome with MRS. There is a restricted number of MR spectroscopic studies describing more than 20 operated adult TLE patients and providing individual MRS and outcome data.16–22 A recent meta-analysis23 aiming to assess the additional preoperative value of 1H-MRS further included smaller studies (with 7–17 operated patients). Combining those studies on patients with TLE which allowed correlation of individual MRS data and seizure outcome according to the Engel Classification, unilateral MRS changes were reported to have a predictive value of 82% for good postsurgical outcome (Engel I+II). TLE patients with unilateral MRS abnormality had a markedly better chance of becoming seizure free compared to patients with bilateral abnormalities (odds ratio 4.891, CI = 1.965–12.172).23 One study of 24 TLE patients included in this meta-analysis showed that unilateral abnormality in hippocampal 1H MRS (in 61%) did not predict, and bilateral abnormalities (in about 30%) did not preclude, good surgical outcome.16 The predictive value of bilateral MRS abnormalities (for unfavorable outcome) is even less clear. Bilateral temporal MRS abnormalities have been observed to a varying degree in different studies in 0–70% of patients.24 In 21 patients with bilateral hippocampal atrophy, discriminant 1H-MRSI features associated with favorable post-surgical seizure outcome

were: concordant 1H-MRSI lateralization, a greater side-toside asymmetry of NAA/Cr, and an absence of contralateral posterior NAA/Cr reduction.18 However, in patients with preoperatively low NAA ratios contralateral to the seizure onset, a postoperative metabolic normalization on the nonoperated side was observed.25–27 It led to the view that a decrease of NAA does not necessarily represent neuronal loss, but that NAA might be a putative reversible, thus functional, marker.28 Bilateral MRS abnormalities might also affect neuropsychological prognosis. Patients with right sided TLE and with additional MRS abnormalities in the left temporal lobe performed worse on neuropsychological tests of episodic verbal memory compared to patients with right sided TLE and ipsiand unilateral MRS changes.29 Whether this particular combination of two independent markers for bilaterality has clinical significance remains questionable. Proton MRS in temporal lobe epilepsy without MR abnormalities (‘MR-negative’) Some TLE patients with apparently normal MRI (‘MRI-negative’) were the subject of feasibility studies30 or part of studies correlating typical MRS changes (low NAA ratios ipsilateral to the seizure onset with a relatively low degree of contralateral abnormality) with good post-surgical outcome.15,21,31–33 In 15 MRI-negative, but operated, TLE patients a single 1H-MRSI study came to conflicting results.34 This study curiously showed a greater degree of ipsilateral NAA/Cr changes in patients that were not seizure free after surgery. Extending this finding to the contralateral side, these results still confirmed the generally acceptable view that subjects with bilateral metabolic abnormalities might have seizure foci that extended beyond the ipsilateral hippocampus. Against all expectations, MRI-negative patients who were ‘well lateralized’ by NAA (i.e., ipsilateral NAA ratios lower than contralateral ratios) had worse surgical outcomes than patients who were ‘poorly lateralized’.35 A possible explanation for this solitary finding of a poor correlation between lateralization with NAA and surgical outcome, is that TLE patients with normal MRI may represent a different syndrome than TLE with hippocampal atrophy. In other studies, 1H MRS described a metabolite profile in the hippocampi of MRI-negative TLE patients that was in fact different from patients with hippocampal sclerosis, with an increase in glutamate and glutamine and a less marked decrease in NAA than was seen in hippocampal sclerosis.34,36 Another explanation for a poor correlation between lateralization with NAA and surgical outcome in MRI-negative patients with TLE was put forward in a study correlating presurgical 1H MRS, post-surgical histopathology and outcome.19 In 13 patients with TLE, subtle histopathological signs of cortical malformations in the resected temporal lobes were found: six of them with concomitant hippocampal sclerosis (dual pathology) and seven without. The MRI-negative subgroup had a worse surgical outcome and showed more marked bilateral and/or contralateral MRS abnormalities possibly representing more widespread subtle developmental changes. Proton MRS in dual pathology These and other extrahippocampal or extratemporal abnormalities in patients with mesiotemporal/hippocampal sclerosis are called ‘dual pathology’. Dual pathology is rarely

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Magnetic resonance spectroscopy in patients with epilepsy identified in a hypothesis-driven way allowing the targeted placement of regions of interest. 1H-MRS/MRSI could only contribute to the detection of these changes when single voxels or single MRSI slices were placed outside the hippocampus and/or outside the temporal lobe or by the use of multislice 1H-MRSI.37 Making a virtue of technical necessity, some MRS studies placed their voxels outside the mesial temporal lobe due to the difficulty in sampling such small structures and the difficulty in achieving an adequately homogeneous magnetic field owing to the magnetic susceptibility effects at the tissue-air interface near the petrous bone. MRS measurements in the superior temporal lobes and inferior insular cortex lateralized 45% of TLE patients with a low extrahippocampal temporal lobe NAA/Cr.21 Using multislice 1H-MRSI in combination with tissue segmentation, significantly lower NAA in ipsi- and contralateral frontal gray and nonfrontal white matter compared with controls was found, although not correlated to outcome.37 Further studies by the same group found that TLE was associated with extrahippocampal reductions of NAA/(Cr+Cho) in several lobes consistent with those brain areas involved in seizure spread and that temporal and extratemporal NAA/(Cr+Cho) reductions might be helpful for focus lateralization.38 Widespread abnormalities of ratios were found not only in TLE, but also in extratemporal lobe epilepsy.39 Even in normal controls, large differences in metabolite concentrations were seen between posterior lateral temporal lobe (predominantly subcortical white matter) and the posterior mesial temporal lobe, most notably lower creatine, Glx, and myoinositol, and higher NAA/(Cr + Cho) in the lateral than mesial temporal lobe; this pattern was similar to that previously seen for gray/white matter differences in the frontal, parietal, and occipital regions.40 It remains to be seen whether widespread MRS changes in TLE are specific and have prognostic value. Brain GABA and glutamate-glutamine (Glx) in temporal lobe epilepsy In adult patients with complex partial seizures, poor seizure control was found to be associated with low brain GABA levels measured with 1H-MRS within a 14-cm3 volume in the occipital lobe, i.e., outside of the epileptic focus,41 although other studies did not find a correlation between GABA and seizure control or recent epileptic seizures.42 In one study, low GABA/Cr seemed even to lateralize the hemisphere with the seizure onset zone and predicted increases of the GABA/Cr signals after successful antiepileptic treatment with vigabatrin.43 Acute and/or longstanding GABA increases were shown with different antiepileptic drugs, like gabapentin, lamotrigine, topiramate, and vigabatrine,44–46 but not with carbamazepine, phenytoin, or valproate.47 Increased intracellular glutamate content in epileptic human hippocampus may also contribute to the epileptogenic nature of hippocampal sclerosis.48 Short-TE MRS studies in patients with TLE showed an increase in the overlapping peaks of glutamate and glutamine in MRI-negative patients with TLE.35,36 Phosphorous MRS in temporal lobe epilepsy Results from the few studies using 31P-MRS in TLE are controversial. 31P-MRS studies of the anterotemporal lobes of patients with medically refractory TLE showed that the pH was significantly more alkaline and the inorganic phosphorous concentration was greater on the side of the epileptogenic focus.49–51

759

Differences in intracellular pH between controls and patients were not observed in other studies, although some bilateral, but lateralizing, phosphorus metabolite abnormalities were found (e.g., the phosphocreatine/inorganic phosphate ratio was reduced in the epileptogenic temporal lobe).52,53 The decline in energetics (reduced ATP/Pi, both ipsilateral and contralateral)53 has been discussed as a seizuremediated imbalance, because successful treatment of the seizures might reverse the contralateral impairment.54 Further study is needed correlating presurgical 31P-MRS with postsurgical 31P-MRS and seizure outcome. Summary: MRS in temporal lobe epilepsy Although 1H-MRS/-MRSI has been advocated as part of a cluster or a sequence of clinical tests prior to epilepsy surgery in TLE, its contribution to the overall validity of the cluster or sequence remains to be determined. Influential epilepsy surgery programs with early enthusiasm for 1H-MRS/-MRSI (‘NAA/Cho is an excellent marker for localizing the epileptogenic zone in TLE’, Ng et al., 1994) abandoned this noninvasive but tedious method as part of their presurgical evaluation of patients with TLE (H. Luders, personal communication). Is it time to reconsider? MRS in extratemporal neocortical epilepsy Studies correlating presurgical 1H-MRS/-MRSI data with post-surgical seizure outcome in patients with extratemporal neocortical epilepsy seem not to be available in this increasingly important patient population. It remains to be seen whether 1H-MRS/-MRSI can help to select those candidates whose extratemporal neocortical epilepsy can be treated successfully by epilepsy surgery. Proton MRS in frontal lobe epilepsy In the relatively large frontal lobes, the use of a restricted region-of-interest approach (single voxel or single slice) might reduce the sensitivity of 1H-MRS/-MRSI for the localization or the lateralization of the epileptogenic region. Mean NAA/Cr in the epileptogenic frontal lobe was found to be decreased compared to the contralateral homologous region;55,56 however, widespread, even bilateral frontal lobe NAA/Cr changes have also been described.57 50% of patients with extra-TLE had NAA/Cr reduction outside the clinical and EEG-defined primary epileptogenic area.18 In individual patients, correct lateralization varied between 50 and 100%. Using reduced frontal lobe NAA/Cr, four out of seven patients were correctly lateralized.58 Comparing MRSI in patients with MCD and in ‘MRI-negative’ patients with neocortical epilepsy, localization of the focus was correct in 70% of the patients with an MRI-visible malformation and in 60% of the patients with normal MRI.59 Phosphorous MRS in frontal lobe epilepsy There are preliminary findings in patients with frontal lobe epilepsy awaiting replication in larger patient populations. Studying eight patients with frontal lobe epilepsy, interictal alkalosis and decreased phosphomonoester levels in the epileptogenic region compared to the contralateral frontal lobe were found.60

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MRS in neocortical epilepsies due to malformations of cortical development Some proton magnetic resonance spectroscopy studies have been performed in patients with malformations of cortical development (MCD), although without correlation to postsurgical outcome. A decrease in NAA (concentrations or ratios) was the most frequent finding in individual MCD and in group comparisons.61–66 Using quantitative short echo time 1H-MRSI, abnormal metabolite concentrations in MCD, perilesional tissue and brain tissue remote from MCD were demonstrated in patients with localization-related epilepsy.64 These findings support the concept of widespread abnormalities in patients with apparently focal MCD. Spectroscopic abnormalities do not necessarily represent widespread structural changes as described earlier in MCD,67,68 but might demonstrate dysfunction. Measurements of individual metabolites were abnormal in some malformations and normal in others, suggesting metabolic heterogeneity.64 Even within a single MCD, metabolically normal regions were interspersed with metabolically abnormal regions.66 Categorizing MCD based upon the step at which fetal cortical development was likely first disturbed (as proposed by Barkovich)69 might reduce the variability of MRS results in MCD. NAA/Cr was shown to be most markedly reduced in MCD secondary to very early disturbances during stem cell formation.62 This ratio was variably reduced in heterotopic gray matter (MCD due to a later developmental step, abnormal migration) and normal in polymicrogyria.62,71 Whether MR spectroscopy can contribute to the distinction between low-grade gliomas and focal MCD (especially FCD), remains unclear. Promising results from group comparisons (less NAA in tumours compared to MCD) await replication and prospective translation to clinical practice in individual patients.71 Prototypically in epilepsy patients with tuberous sclerosis, the presence of multiple bilateral lesions can make it difficult to identify a single lesion responsible for intractable epileptic seizures. Using MRS, a lactate peak was detected in the regions

corresponding to an epileptic focus in some patients72, but this was not a universal finding (Figure 85.5). MRS in neocortical epilepsies without MR abnormalities (‘MR-negative’) The usefulness of multislice 1H-MRSI in combination with tissue segmentation for the identification of the epileptogenic focus, was extended from patients with MCD to MRI-negative patients with neocortical epilepsy.38 MRSI correctly identified the lobe containing the epileptogenic focus as defined by EEG in 65% of the patients with neocortical epilepsy. MRSI localization of the focus was correct in 70% of the patients with an MRI-visible malformation and in 60% of the patients with normal MRI. Of the patients, 15% had metabolically abnormal brain regions outside the epileptogenic lobe, and 35% of the patients had evidence for secondary hippocampal damage.38 It remains to be seen whether these changes have prognostic value and whether these widespread abnormalities are specific, as they are also found in temporal lobe epilepsy.39 Summary: MRS in extratemporal neocortical epilepsy In contrast to the numerous 1H-MRS of TLE, there are only a few reports in other types of localisation-related epilepsies. These studies suggest that the potential of correct seizure focus lateralisation is less than in TLE. MRS in children with epilepsy Metabolite concentrations change with early brain maturation, and this differs between different brain regions,69 which complicates investigations of infants and young children. In older children and adolescents with TLE, 1H-MRS of mesial temporal lobe regions showed similar results compared to adults. Abnormally low NAA/Cho+Cr was seen in 75%; 55% were correctly lateralized; bilateral abnormalities were seen in 45%.73 These results were extended to young TLE patients who showed no abnormality on specialised structural MRI investigation.30

Figure 85.5 Left panel: MRI of a young patient with tuberous sclerosis with a large calcified tuber in the left pericentral region. Right panel: MR spectra (TR 1.5 s, TE 135 and 270 ms) showing low NAA and relatively high Cho as described recently in a larger series of patients with TS.72 Note the presence of spectral distortion around 2.9 ppm, and that the SNR is lower than would be expected for a voxel of this size: both effects are presumed to be due to the presence of calcification, which degrades spectral quality.

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Magnetic resonance spectroscopy in patients with epilepsy Comparing children with TLE and a history of complex febrile convulsions and children without any history of complex febrile convulsions, changes in the metabolite ratios were detected to a similar degree (60%).74 MRS-detectable neuronal dysfunction throughout the temporal lobes of children with TLE was already as severe at the time of diagnosis as it was in patients with long-standing intractable TLE.75 Whether longitudinal MRS studies might help to clarify the role of febrile convulsions in the pathogenesis of TLE remains unclear. The most frequent pathology in children undergoing epilepsy surgery is malformation of cortical development (MCD). Heterogeneous MRS findings in MCD have been reviewed in an earlier paragraph of this chapter. In pediatric epilepsy surgery, extensive resections (multilobar resections, hemispherotomies) are more frequent than in adults. Whether MRS can help to characterize the contralateral hemisphere and to define it as normal, remains unclear. In single cases of MRS investigations in hemimegalencephaly, the normalappearing hemisphere was mildly affected (decreased NAA in white matter).76 There are case reports describing MRS results in catastrophic epilepsy, i.e., childhood epilepsy with very frequent seizures and the loss of neurological or neuropsychological function (‘epileptic encephalopathy’). In these patients, MRS measurements at a single time point should be treated with caution considering the possibility of fluctuating metabolite profiles related to seizure activity. In an 8-year-old boy with Rasmussen’s encephalitis, five MRS examinations were performed over 9 months.77 Following complex partial status, MRS showed a reduction in N-acetyl aspartate, total creatine and choline. Subsequent scans showed complete resolution of these metabolite abnormalities, followed later by development of further abnormal metabolite values. In this case, lactate and Glx were elevated after status. In hemimegalencephaly, another cause of catastrophic epilepsy, a single case study reports signs of progression of MRS measures of glial proliferation after one year (reduced NAA and elevated myoinositol).78 In Sturge-Weber syndrome, a vascular malformation underlying catastrophic epilepsy, NAA was reduced in the ipsilateral gadolinium-enhanced volume of interest compared to a similarly placed contralateral volume.79 A focal area of elevated choline without significant alteration of NAA might characterize the early pathophysiological manifestation of Sturge-Weber syndrome.80 In pediatric neuroimaging, MRS has some role in diagnosis and follow-up of encephalopathies due to metabolic diseases,69 which might be the cause of epileptic seizures. In the neuronal ceroid lipofuscinoses (NCL), probably the most common progressive metabolic encephalopathies of childhood associated with seizures, MRS might help to distinguish different subtypes. Infantile NCL was characterized by a complete loss of NAA, a marked reduction of Cr and Cho, and an elevation of myoinositol and lactate in both gray and white matter; reduced NAA and elevated Lac were also detected in gray and white matter of late infantile NCL; in contrast to the infantile forms, juvenile NCL exhibited normal metabolic profiles.81,82 In late infantile NCL, proton MR spectra revealed progressive changes, with a reduction of NAA and an increase of myoinositol and Glx; myoinositol became the most prominent resonance.83

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Decreased NAA, sometimes increased Cho and myoinositol, but mainly the presence of lactate can also be found in peroxisomal or mitochondrial disease. For example in Zellweger syndrome, a peroxisomal disease, widespread bilateral MCD might be associated with decreased NAA and an abnormal signal consisting of lactate and lipids.84 Lactate has been detected in young patients with mitochondrial encephalopathies, but as with all other means used to diagnose rare disorders, MR spectroscopy does not depict elevated lactate in all cases.85 Lactate is usually not seen in spectra of normal adult brain. Lactate was detected, however, in all 35 normal control infants at 31–42 wk of gestational plus postnatal age studied at 2.4 T, making the use of MRS to diagnose abnormal lactate in this very young age range difficult.86 Future research MRS will benefit substantially from the increased availability of higher magnetic field strength scanners. The gain in SNR will allow shorter acquisition times, better spatial resolution, or a combination of both. The dispersion of individual peaks contributing to a spectrum will also increase, allowing separation of metabolite peaks that would otherwise not be distinguishable. These improvements should allow both more precise quantification of common metabolites, and assessment of a broader range of metabolites. Future developments in MRS may enable the technique to benefit the investigation of seizure generation by correlating metabolite changes with interictal discharges or monitoring progression of neuronal damage due to ongoing seizure activity. In induced seizures in animals NAA ratios were reduced,87 but have been observed to increase initially during the ictal phase.88 Lactate/Cr ratios were observed to increase ictally, being elevated up to 24 hours after a seizure and returning to the baseline levels within 7 days in induced status in animals.88 Increase in lactate ratios in kainic-acid treated rats was prevented by cycloheximide pretreatment, suggesting that in situ lactate increase is a marker of seizure-induced neuronal damage. In human studies NAA levels were not changed after complex partial seizures and absences.15 Significant increases in lactate/Cr during and soon after complex partial seizures were reported, but this was not seen during absence seizures. Castillo et al.89 demonstrated increased lipids/lactate in the hippocampus of patients within 24 hours of their last seizure. The increase in lactate in these studies was maximal over the area of the seizure focus and this might explain the absence of change of lactate distant to the seizure focus. The rise in lactate seen following secondarily generalized tonic clonic seizures in two patients implies a spread of seizure activity into the frontal lobe. In the first study using magnetization transfer (MT) MRS in patients with epilepsy, we recently observed that the MT effect on choline was reduced after seizures, while choline concentrations remained unaltered.90 We hypothesise this is due to membrane perturbation as a consequence of seizure activity, possibly due to NMDA receptor activation, which has been shown to induce choline release from membranes by inhibition of phosphatidylcholine synthesis. The future lies in the development of new MRS acquisition techniques and the refinement of existing ones. Increasing the

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speed of MRS protocols would facilitate their validation in larger numbers of patients, which is an essential step in the more widespread application of the technique in clinical evaluation.

Conclusion

changes are reversible with treatment. However, in children as in adults with epilepsy, ‘the cornerstone of neuroimaging remains anatomic; the physiologic data (from spectroscopy, diffusion, or perfusion) should always be interpreted in association with anatomic neuroimaging, as well as knowledge of the patient’s history, clinical exam, and laboratory data’ (from the preface of Barkovich, 2005).69

There is no doubt that MRS detects relevant metabolite changes in patients with TLE. There are indications that these


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16. 17. 18.

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Kantarci K, Shin C, Britton JW et al. Comparative diagnostic utility of 1H MRS and DWI in evaluation of temporal lobe epilepsy. Neurology 2002;58:1745–53. Antel SB, Li LM, Cendes F et al. Predicting surgical outcome in temporal lobe epilepsy patients using MRI and MRSI. Neurology 2002;58:1505–12. Willmann O, Wennberg R, May TW, Pohlmann-Eden B. The role of 1 H magnetic resonance spectroscopy in preoperative evaluation for epilepsy surgery. A meta-analysis. Epilepsy Res 2006;71: 149–58. Cendes F, Knowlton RC, Novotny E et al. Magnetic resonance spectroscopy in epilepsy: clinical issues. Epilepsia 2002;43 (suppl 1):32–9. Hugg JW, Kuzniecky RI, Gilliam FG et al. Normalization of contralateral metabolic function following temporal lobectomy demonstrated by 1H magnetic resonance spectroscopic imaging. Ann Neurol 1996;40:236–9. Cendes F, Andermann F, Dubeau F et al. Normalization of neuronal metabolic dysfunction after surgery for temporal lobe epilepsy. Evidence from proton MR spectroscopic imaging. Neurology 1997;49:1525–33. Serles W, Li LM, Antel SB et al. Time course of postoperative recovery of N-acetyl-aspartate in temporal lobe epilepsy. Epilepsia 2001;42:190–7. Kuzniecky R, Palmer C, Hugg J et al. Magnetic resonance spectroscopic imaging in temporal lobe epilepsy: neuronal dysfunction or cell loss? Arch Neurol 2001;58:2048–53. Incisa della Rocchetta A, Gadian DG, Connelly A et al. Verbal memory impairment after right temporal lobe surgery: role of contralateral damage as revealed by 1H magnetic resonance spectroscopy and T2 relaxometry. Neurology 1995;45:797–802. Connelly A, Van Paesschen W, Porter DA et al. Proton magnetic resonance spectroscopy in MRI-negative temporal lobe epilepsy. Neurology 1998;51:61–6. Connelly A, Jackson GD, Duncan JS et al. Magnetic resonance spectroscopy in temporal lobe epilepsy. Neurology 1994;44:1411–17. Cendes F, Andermann F, Preul MC, Arnold DL. Lateralization of temporal lobe epilepsy based on regional metabolic abnormalities in proton magnetic resonance spectroscopic images. Ann Neurol 1994;35:211–16. Ende GR, Laxer KD, Knowlton RC et al. Temporal lobe epilepsy: bilateral hippocampal metabolite changes revealed at proton MR spectroscopic imaging. Radiology 1997;202:809–17. Woermann FG, McLean MA, Bartlett PA et al. Short echo time single-voxel 1H magnetic resonance spectroscopy in magnetic resonance imaging-negative temporal lobe epilepsy: different biochemical profile compared with hippocampal sclerosis. Ann Neurol 1999;45:369–76. Suhy J, Laxer KD, Capizzano AA et al. 1H MRSI predicts surgical outcome in MRI-negative temporal lobe epilepsy. Neurology 2002;58:821–3. Simister RJ, Woermann FG, McLean MA et al. A short-echo-time proton magnetic resonance spectroscopic imaging study of temporal lobe epilepsy. Epilepsia 2002;43:1021–31. Mueller SG, Suhy J, Laxer KD et al. Reduced extrahippocampal NAA in mesial temporal lobe epilepsy. Epilepsia 2002;43: 1210–16. Mueller SG, Laxer KD, Cashdollar N et al. Identification of abnormal neuronal metabolism outside the seizure focus in temporal lobe epilepsy. Epilepsia 2004;45:355–66. Li LM, Cendes F, Andermann F et al. Spatial extent of neuronal metabolic dysfunction measured by proton MR spectroscopic

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imaging in patients with localization-related epilepsy. Epilepsia 2000;41:666–74. McLean MA, Woermann FG, Simister RJ, Barker GJ, Duncan JS. In vivo short echo time 1H-magnetic resonance spectroscopic imaging (MRSI) of the temporal lobes. Neuroimage 2001;14:501–9. Petroff OA, Rothman DL, Behar KL, Mattson RH. Low brain GABA level is associated with poor seizure control. Ann Neurol 1996;40:908–11. Simister RJ, McLean MA, Barker GJ, Duncan JS. A proton magnetic resonance spectroscopy study of metabolites in the occipital lobes in epilepsy. Epilepsia 2003;44:550–8. Mueller SG, Weber OM, Duc CO et al. Effects of vigabatrin on brain GABA+/Cr signals in focus-distant and focus-near brain regions monitored by 1H-NMR spectroscopy. Eur J Neurol 2003;10:45–52. Petroff OA, Hyder F, Rothman DL, Mattson RH. Topiramate rapidly raises brain GABA in epilepsy patients. Epilepsia 2001;42:543–8. Petroff OA, Mattson RH, Behar KL et al. Vigabatrin increases human brain homocarnosine and improves seizure control. Ann Neurol 1998;44:948–52. Kuzniecky R, Ho S, Pan J et al. Modulation of cerebral GABA by topiramate, lamotrigine, and gabapentin in healthy adults. Neurology 2002;58:368–72. Petroff OA, Rothman DL, Behar KL et al. Effects of valproate and other antiepileptic drugs on brain glutamate, glutamine, and GABA in patients with refractory complex partial seizures. Seizure 1999;8:120–7. Petroff OA, Errante LD, Rothman DL et al. Neuronal and glial metabolite content of the epileptogenic human hippocampus. Ann Neurol 2002;52:635–42. Laxer KD, Hubesch B, Sappey-Marinier D, Weiner MW. Increased pH and inorganic phosphate in temporal seizure foci demonstrated by 31P-MRS. Epilepsia 1992;33:618–23. Hugg JW, Laxer KD, Matson GB et al. Lateralization of human focal epilepsy by 31P magnetic resonance spectroscopic imaging. Neurology 1992;42:2011–18. van der Grond J, Gerson JR, Laxer KD et al. Regional distribution of interictal 31P metabolic changes in patients with temporal lobe epilepsy. Epilepsia 1998;39:527–36. Chu WJ, Hetherington HP, Kuzniecky RJ et al. Is the intracellular pH different from normal in the epileptic focus of patients with temporal lobe epilepsy? A 31P NMR study. Neurology 1996;47:756–60. Kuzniecky R, Elgavish GA, Hetherington HP et al. In vivo 31P nuclear magnetic resonance spectroscopy of human temporal lobe epilepsy. Neurology 1992;42:1586–90. Simor T, Chu WJ, Hetherington HP. Tailored temporal lobectomy induced improvements in 4.1 T 31PNMR SI generated phosphorous metabolite indices in temporal lobe epilepsy. In: Proceedings of the International Society of Magnetic Resonance in Medicine. Vancouver, British Columbia;1997:33. Garcia PA, Laxer KD, van der Grond J et al. Proton magnetic resonance spectroscopic imaging in patients with frontal lobe epilepsy. Ann Neurol 1995;37:279–81. Lundbom N, Gaily E, Vuori K et al. Proton spectroscopic imaging shows abnormalities in glial and neuronal cell pools in frontal lobe epilepsy. Epilepsia 2001;42:1507–14. Stanley JA, Cendes F, Dubeau F et al. Proton magnetic resonance spectroscopic imaging in patients with extratemporal epilepsy. Epilepsia 1998;39:267–73. Kikuchi S, Kubota F, Akata T et al. A study of the relationship between the seizure focus and 1H-MRS in temporal lobe epilepsy and frontal lobe epilepsy. Psychiatry Clin Neurosci 2000;54:455–9. Mueller SG, Laxer KD, Barakos JA et al. Identification of the epileptogenic lobe in neocortical epilepsy with proton MR spectroscopic imaging. Epilepsia 2004;45:1580–9. Garcia PA, Laxer KD, van der Grond J et al. Phosphorus magnetic resonance spectroscopic imaging in patients with frontal lobe epilepsy. Ann Neurol 1994;35:217–21. Kuzniecky R, Hetherington H, Pan J et al. Proton spectroscopic imaging at 4.1 Tesla in patients with malformations of cortical development and epilepsy. Neurology 1997;48:1018–24. Li LM, Cendes F, Bastos AC et al. Neuronal metabolic dysfunction in patients with cortical developmental malformations: a proton magnetic resonance spectroscopic imaging study. Neurology 1998;50:755–9. Simone IL, Federico F, Tortorella C et al. Metabolic changes in neuronal migration disorders: evaluation by combined MRI and proton MR spectroscopy. Epilepsia 1999;40:872–9. Woermann FG, McLean MA, Bartlett PA et al. Quantitative short echo time proton magnetic resonance spectroscopic imaging study of malformations of cortical development causing epilepsy. Brain 2001;124:427–36.

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Kaminaga T, Kobayashi M, Abe T. Proton magnetic resonance spectroscopy in disturbances of cortical development. Neuroradiology 2001;43:575–80. Mueller SG, Laxer KD, Barakos JA et al. Metabolic characteristics of cortical malformations causing epilepsy. J Neurol 2005;252: 1082–92. Sisodiya SM, Free SL, Stevens JM et al. Widespread cerebral structural changes in patients with cortical dysgenesis and epilepsy. Brain 1995;118:1039–50. Woermann FG, Free SL, Koepp MJ et al. Voxel-by-voxel comparison of automatically segmented cerebral gray matter – a raterindependent comparison of structural MRI in patients with epilepsy. Neuroimage 1999;10:373–84. Barkovich AJ. Evaluation of brain development using physiologic MRI techniques – MR spectroscopy. In: Barkovich AJ, ed. Pediatric Neuroimaging 4th edn. Philadelphia: Lippincott, Williams and Wilkins, 2005:55–61. Widjaja E, Griffiths PD, Wilkinson ID. Proton MR spectroscopy of polymicrogyria and heterotopia. AJNR 2003;24:2077–81. Vuori K, Kankaanranta L, Hakkinen AM et al. Low-grade gliomas and focal cortical developmental malformations: differentiation with proton MR spectroscopy. Radiology 2004;230:703–8. Yapici Z, Dincer A, Eraksoy M. Proton spectroscopic findings in children with epilepsy owing to tuberous sclerosis complex. J Child Neurol 2005;20:517–22. Cross JH, Connelly A, Jackson GD et al. Proton magnetic resonance spectroscopy in children with temporal lobe epilepsy. Ann Neurol 1996;39:107–13. Holopainen IE, Valtonen ME, Komu ME et al. Proton spectroscopy in children with epilepsy and febrile convulsions. Pediatr Neurol 1998;19:93–9. Miller SP, Li LM, Cendes F et al. Neuronal dysfunction in children with newly diagnosed temporal lobe epilepsy. Pediatr Neurol 2000;22:281–6. Hanefeld F, Kruse B, Holzbach U et al. Hemimegalencephaly: localized proton magnetic resonance spectroscopy in vivo. Epilepsia 1995;36:1215–24. Wellard RM, Briellmann RS, Wilson JC et al. Longitudinal study of MRS metabolites in Rasmussen encephalitis. Brain 2004;127: 1302–12. Kruse B, Pouwels PJ, Christen HJ et al. Proton magnetic resonance spectroscopy of linear nevus sebaceus syndrome. Pediatr Neurol 1998;18:176–80. Moore GJ, Slovis TL, Chugani HT. Proton magnetic resonance spectroscopy in children with Sturge-Weber syndrome. J Child Neurol 1998;13:332–25. Lin DD, Barker PB, Kraut MA, Comi A. Early characteristics of Sturge-Weber syndrome shown by perfusion MR imaging and proton MR spectroscopic imaging. AJNR 2003;24:1912–25. Brockmann K, Pouwels PJ, Christen HJ et al. Localized proton magnetic resonance spectroscopy of cerebral metabolic disturbances in children with neuronal ceroid lipofuscinosis. Neuropediatrics 1996;27:242–8. Sitter B, Autti T, Tyynela J et al. High-resolution magic angle spinning and 1H magnetic resonance spectroscopy reveal significantly altered neuronal metabolite profiles in CLN1 but not in CLN3. J Neurosci Res 2004;77:762–9. Seitz D, Grodd W, Schwab A et al. MR imaging and localized proton MR spectroscopy in late infantile neuronal ceroid lipofuscinosis. AJNR 1998;19:1373–7. Groenendaal F, Bianchi MC, Battini R et al. Proton magnetic resonance spectroscopy (1H-MRS) of the cerebrum in two young infants with Zellweger syndrome. Neuropediatrics 2001;32:23–7. Lin DD, Crawford TO, Barker PB. Proton MR spectroscopy in the diagnostic evaluation of suspected mitochondrial disease. AJNR 2003;24:33–41. Penrice J, Cady EB, Lorek A et al. Proton magnetic resonance spectroscopy of the brain in normal preterm and term infants, and early changes after perinatal hypoxia-ischemia. Pediatr Res 1996;40:14–16. Petroff OA, Prichard JW, Ogino T et al. Combined 1H and 31P nuclear magnetic resonance spectroscopic studies of bicucullineinduced seizures in vivo. Ann Neurol 1986;20:185–93. Najm IM, Wang Y, Hong SC et al. Temporal changes in proton MRS metabolites after kainic acid-induced seizures in rat brain. Epilepsia 1997;38:87–94. Castillo M, Smith JK, Kwock L. Proton MR spectroscopy in patients with acute temporal lobe seizures. AJNR 2001;22:152–7. Flügel D, McLean MA, Simister RJ, Duncan JS Magnetisation transfer ratio of choline is reduced following epileptic seizures. NMR Biomed 2006;19:217–22.

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Post-processing of the magnetic resonance imaging to better define structural abnormalities S Knake, F Rosenow, and PE Grant

Introduction Magnetic resonance imaging (MRI) has become one of the most important tools in the pre-surgical evaluation of patients with medically resistant focal epilepsies. The importance of detecting a concordant lesion on MRI is reinforced by the impact it has on predicting surgical outcomes.1,2 In many patients with medically intractable focal epilepsies that are MRI negative a focal cortical dysplasia (FCD) is later detected histopathologically. On MRI FCD are often characterized by a combination of increased cortical thickness, increased T2 signal within the dysplastic cortex and blurring of the gray and white matter junction. However, the visual identification of these abnormal characteristics may be difficult and time consuming, even for the experienced reader, because the changes on MR are subtle and the lesions may be only a few millimeters in size. Additional challenges include determining the full extent of the FCD and the secondary changes in brain structure and organization that may occur. New imaging techniques and post-processing methods have the potential to detect subtle lesions undetected in previously MRI-negative patients3–5 and the ability to better define full impact on brain structure and organization. This chapter presents a brief overview of postprocessing techniques currently in use, both clinically and experimentally, to diagnose, plan treatment, and increase our understanding of the neuropathology of focal epilepsies: Advanced brain imaging technologies now provide a means to investigate disease specific morphological changes in their full spatial and temporal complexity. New imaging techniques have the potential to uncover patterns of altered structure and function that cannot be detected by visual inspection alone.

Analyzing the cortex 2D and 3D reformatting Planar brain surface reformations Curvilinear reformatting of the 2D images is used to reconstruct the images into thin, curved slices where the distance from the surface of the hemispheric convexities is kept constant.6 These reformations (‘pancake views’) aid in the visual detection of subtle cortical lesions (Figure 86a.1). To create these images, isotropic 1 mm, three-dimensional (3D) MRI data sets are postprocessed using a curved multiplanar reformatting technique.3 764

These images preserve the spatial relation of adjacent cortex areas and surface structures in one view.8 This technique can increase the reader’s ability to detect cortical abnormalities compared to standard imaging planes.9 Surface rendering Gyral folding patterns, although quite variable normally, can be significantly altered in a variety of diseases. Sulcal pattern anomalies have been identified in schizophrenia and epilepsy10–12 and visually obvious gyral folding anomalies have been reported in patients with cortical dysplasias.8 Subtle gyral folding abnormalities may not be identified on twodimensional images. A 3D reconstruction of the cortical surface can aid in the identification of gyral folding abnormalities associated with cortical dysgenesis.14 Volumetric Analysis Voxel-based morphometry Voxel-based morphometry (VBM) can be performed as a semiautomated or automated procedure carried out on MRI data acquired at high resolution in a three-dimensional (whole-brain) format, typically a T1-weighted MRI volume data set (MPRAGE, 3DFLASH, 3DSPGR) that is normalized and segmented using algorithms from SPM99 (Statistical Parametric Mapping Software, Wellcome Department of Imaging Neuroscience, London). The distribution of gray and white matter is analyzed on a voxelwise basis and compared with a normal database of healthy subjects. The volumetric T1-weighted scans are used and a stereotactic normalization, segmentation, smoothing is performed before an automated statictic voxel-based comparison of T1-differences is performed.15 VBM has been used in previous studies in a variety of populations including healthy adults, patients with various forms of dementia, and schizophrenic patients to identify regions of cerebral abnormality as well as to determine how these regions correlate with neuropsychological function.16 Some groups have used this methods to better define the epileptogenic lesion.17–19 One of the advantages of this method is the automated, user-independent determination of gray-scale differences in each voxel that allows large amounts of data to be processed in a reasonable time frame. VBM analyses the whole brain voxel by voxel without the selection of predefined regions of interest that are based on a priori hypothesis.

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Figure 86a.1 Cortical flat map of a T1-weighted MR datatset of a 34-year-old right-handed woman with left frontal lobe epilepsy due to focal cortical dysplasia (FCD) (Taylor type 2). The area of FCD is represented by a difference in cortical folding and a subtle blurring of the sulci (see circle). We have used the technique in a 34-year-old patient with left central cortical dysplasia. Planar reconstruction images show the blurring in the depth of the cortical sulcus as demonstrated in Figure 86a.7.

The disadvantage of this method is that the accuracy is based on the voxel size and subtle differences, smaller than the voxel size cannot be detected. The performed stereotactic normalization is only a rough correction of global differences, subtle differences of individual brains might not be registered correctly and might have an influence on the result. Atlas based segmentation Fischl and Dale22 have developed an automated technique for assigning neuroanatomical labels to each voxel in an MRI volume. The technique is based on probabilistic information that is estimated automatically for each voxel based on a manually labeled training set and is embedded in the Freesurfer program (CorTechs Labs, La Jolla, CA, USA). In contrast to several existing segmentation procedures the program assigns one of 37 labels to each voxel, including left and right caudate, putamen, pallidum, thalamus, lateral ventricles, hippocampus, and amygdala. The classification technique employs a surfacebased registration procedure that seems robust to anatomical variability, including the ventricular enlargement typically associated with neurological diseases and aging.23 The technique has to be comparable in accuracy to manual labeling, and of sufficient sensitivity to robustly detect changes in the volume and tissue of noncortical structures in epilepsy patients.23,24 We have used the program to automatically label brains of patients with cortical dysplasia and periventricular heterotopia. The program labeled dysplastic cortex as ‘cortex of unknown origin’. The technique therefore seems to be a useful approach to direct the eye of the radiologist reading the film (Figure 86a.2).

Figure 86a.2 Automated segmentation of a T1-weighted 3D MRI (mprage) of a 42-year-old right-handed patient with left periventricular heterotopia. The program detected the heterotopiua that were labeled as gray matter of unknown origin (see arrowheads).

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Quantitative tissue characterization Huppertz et al.25 have used three novel VBM techniques in SPM for texture analysis of 3D MRI which may improve lesion detection by enhancing image properties not readily accessible by visual analysis. To better identify focal cortical dysplasia, they created 3D maps called ‘thickness image’, ‘extension image’, and ‘junction image’, which characterize three different features of FCD, i.e., abnormal thickness of the cortical ribbon, abnormal extension of gray matter into the white matter, and blurring of the gray-white matter junction (see Figure 86a.3). These methods were applied to the MRI data of 25 epilepsy patients with histologically proven FCD. In each of the new feature maps the locations of the five highest maxima (corresponding to the maximum deviations from the mean of the normal database) were automatically determined and compared with the sites of the lesions in the conventional MR images or – in case of cryptogenic epilepsy – with the resection areas in the post-operative MRI. This approach was able to identify 15/25 lesions in the

thickness image and 18/25 lesions in the junction and extension image, respectively. With all feature maps combined, 23 out of 25 dysplastic lesions were identified. Among these cases there were also four patients in whom the dysplastic lesion itself or at least an essential part of it had not been recognized on conventional MR images despite acquisition and assessment in a tertiary epilepsy center.25,26 These novel VBM techniques may facilitate the detection and localization of FCD and increase the diagnostic yield of MR imaging. Another method of tissue characterization is to perform multiflip, multiecho FLASH sequences to quantitate T1, T2, and PD at each voxel in the brain. Combined with an atlas, this allows tissue classification and detection of differences that occur with disease. Cortical thickness analysis The human cortical surface is extensively folded so that twothirds is in the sulci. Accurate manual determination of the

MPRAGE

1 Extension Image

2 Junction Image

3 Thickness Image

Figure 86a.3 Voxel-based 3D MRI analysis in an 18-year-old female patient with FCD Palmini 2b and SPS, CPS and SGTCS since the age of 2 years: Following the principles of voxel-based morphometry a T1-weighted MRI volume data set (MPRAGE) is normalized and segmented using algorithms of SPM2 (Statistical Parametric Mapping Software, Wellcome Department of Imaging Neuroscience, London). Then, the distribution of gray and white matter is analyzed on a voxelwise basis and compared with a normal database consisting of the MR images of over 50 healthy subjects. Based on this analysis, 3-dimensional maps called ‘extension image’, ‘junction image’, and ‘thickness image’, are created which characterize three different features of FCD, i.e., the abnormal extension of gray matter into the white matter (1), blurring of the gray-white matter junction (2), and slightly abnormal thickness of the cortical ribbon (3). (Courtesy of HJ Huppertz, Swiss Epi Center, Zurich.)

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Figure 86a.4

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Cortical thickness analysis of the cortex of a 38-year-old right-handed patient with right pericentricular heterotopia.

cortical thickness is labor intensive, time consuming and usually focuses on a priori selected regions of interest. In recent years, semiautomated techniques for analyzing cortical thickness have been developed.23,27 Using this technique, diseasespecific differences in cortical thickness have been detected in patients with Huntington’s disease and in aging.28,29 These intravoxel interpolation methods detect differences in cortical thickness that cannot be appreciated visually and are below the resolution of the image voxel. Cortical thickness measures have the potential to increase the diagnostic yield of MRI and to increase our understanding of the extent and location of cortical involvement associated with different epilepsy syndromes.3 For example, in four patients with periventricular heterotopia we detected cortical thinning in the ipsilateral temporal lobe, concordant with the seizure semiology (see Figure 86a.4). Tools analyzing the cortical thickness may also help delineate the anatomical extent of epileptogenic cortical lesions. If validation is possible, this technique could provide a more accurate and regionally specific description of normal and abnormal cortex. Kotini et al. report the findings of increased cortical thickness in the affected cortex in a patient with unilateral perisylvian syndrom.30 This technique may be especially beneficial for detecting unexpected widespread cortical pathology or in focusing the visual inspection for lesions in MRI-negative patients with focal epilepsies.3 By using semi-automated tools, user-dependent inaccuracies are avoided. Currently, these cortical thickness measures rely on the ability to automatically detect a normal gray-white junction in a fully myelinated brain. Therefore, these measures are limited to subjects over approximately 2 years of age. Lesions with blurred gray-white junction are typically detected but the measured thickness of the cortex may be inaccurate due to the poorly defined gray-white junction. Gyral folding Quantitative analysis of 2D surfaces in 3D Techniques like planar or 3D reformation of the brain focus on the visual detection of gyral and sulcal differences. However, the identifiation of subtle changes may require quantitative analysis of the brain curvature and comparison to previously established populations of normals. To perform quantitative analysis of surface properties a topologically correct 2D surface in 3D must be created. As it turns out, the cortical surface is folded in on itself in a way that makes it almost

impossible to create a topologically correct surface from the existing volumetric MR data. This occurs because gyral surfaces touch, making it hard to resolve boundaries in an automated fashion. The gray-white surface in comparison does not have this property and therefore it is much easier to construct topologically correct 2D surfaces from this interface. The graywhite boundary is the surface area through which connections exit or enter from gray matter and therefore the characteristics of this interface have implications for cortical and whitematter organization. Only a few centers have begun to quantify properties of these surfaces. Quantities that are calculated include surface areas, local curvature and its components, local Gaussian curvature, local fractal dimension, and wavelet decompositions. Our preliminary data of normal neonatal brain development suggest that the gyri develop in a very regular manner, resulting in conserved curvature properties. We believe that these techniques hold great potential for defining normal growth trajectories and differentiating normal from abnormal brain development. It addition, these methods may improve our ability to detect global changes that occur with congenitial malformations or persistent seizures. Different techniques have been used describe differences in cortical gyrification in patients with shizophrenia31 and in Williams syndrome,32 Ronan et al.33 have used stereology. Quantitative examination of human cerebral gyrification has been applied to detect abnormal gyrification in schizophrenia on healthy brains using the isoperimetric ratio (IPR) as an index of cerebral gyrification. The IPR is a dimensionless ratio defined as surface area corrected for volume allowing for a robust and reliable quantification cerebral gyrification.33

Analyzing subcortical structures and white matter Automated subcortical labelling and volumetry Accurate manual segmentation techniques are labour intensive, time consuming and tedious. Automated techniques have the potential to make cerebral volumetrics part of a routine clinical assessment, but they currently require validation and standardization before this potential can be realized. The identification of anatomical substructures is based on tissue classification by classifying different gray-level intensities in different voxels. Fully automated analysis tools have been

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developed to label different MRI substructures in an unbiased, user-independent fashion.22,23,34 Previous studies have shown that volumetry might help identifying the epileptogenic lesion. Especially in patients with temporal lobe epilepsy, volumetry seems superior to pure visual MRI inspection in correctly lateralizing the hippocampal pathology.11 We have used the technique developed by Dale and Fischl23,34,35 to automatically segment the brain in patients with medically refractory epilepsies due to cortical dysplasia. Areas of cortical dysplasia were identified correctly and tissue was classified as ‘grey matter of unknown origin’ in the respective ares (Figure 86a.2). Magnetic resonance diffusion imaging Diffusion-weighted imaging and ADC maps Diffusion imaging is based on changes in the diffusion properties of water molecues in diseased brain tissue: ‘Diffusion’ describes the random microscopic translational motion (Brownian motion) of water molecules.36 Unrestricted diffusion of freely diffusing molecules is spherical, with the radius of the sphere increasing as the square root of the time of diffusion. Diffusion behavior in a highly organized system like the human brain is more complex and restricted and is determined by multiple variables such as fiber crossings, myelinization, ischemia, and neuronal cell density. Diseases of the central nervous system are often accompanied by changes in diffusion. The application of diffusion imaging on patients with epilepsies has been used to postictally identify areas of transient postictal changes.35,37,38 Acute postictal changes have also been reported in areas distant from the EEG focus, often near the corpus callosum or the splenium.39,40 Diffusion imaging has been used interictally to study patients with focal epilepsies: Wieshmann et al. showed significantly reduced diffusion in sclerotic hippocampi as compared to the nonsclerotic side.36,41 Diffusion tensor imaging The phenomenon of a restricted diffusion is of particular interest to studies that evaluate the integrity of white matter and of fiber tracts. Like DWI, DTI uses the diffusion properties of water in the brain. With standard DTI, in addition to an ADC map from DWI, one also acquires a map that is a measure of the directional bias of diffusion. DTI therefore provides information about the rate, magnitude, and directionality of water diffusion in the brain. DTI contrast is associated with water diffusion and is influenced by microstructural factors such as myelin and other fiber components. A normalized metric of white matter integrity, termed ‘fractional anisotropy’ (FA) is computed from the diffusion properties within a voxel. Similar metrics have been used to detect white-matter pathology in epilepsy and neurodegenerative diseases.42–46 Specifically, the more tightly packed and coherent the white matter tract, the more likely the diffusion is dominated by fewer versus many directions, the greater will be the FA value, resulting in a brighter signal intensity on an FA map. The signal abnormality in the DTI scan is presumed to reflect alterations in tissue properties, including decreased myelination or changes in the number of myelinated nerve fibers.45 DTI is presently being explored as a research tool.

Figure 86a.5 Comparison of fractional anisotropy (FA) maps of 14 patients with left temporal lobe epilepsy due to hippocampal sclerosis and healthy normal controls. Statistically significalnt differences in white-matter organization, measured in FA, are presented co-registered on the anatomical T1-weighted image. Diffences mainly occur in the ipsi- and contralalteral temporal stem and the ipsilateral frontal lobe.

Information of WM integrity provided by DTI could be very useful in the characterization and quantification of epilepsyassociated brain damage and might be used as a marker of disease severity and progress. Our preliminary studies show decreased FA values in the ipsilateral and contralateral temporal stem as well as in the frontal lobe of patients with mesial temporal lobe epilepsy (TLE) (Knake et al., unpublished data) (Figure 86a.5). In addition to determining the coherence of white matter tracts, DTI can be used to estimate fiber orientation in the brain. To visualize fiber direction, images are color coded according to the direction of the diffusion and then superimposed on an image aquired without diffusion weighting (B0-image) (Figure 86a.6). The green codes for anterior to posterior vectors, blue for superior to inferior, and red for left to right.48 Although it seems that DTI can identify networks and anatomical tracts, it is uncertain at present, if DTI is able to delineate relevant tracts with sufficient reliability. Voxelsize, artefacts and a variety of technical issues make it difficult to extract fiber directionality from water diffusion.36

Conclusions Improved imaging technique and sequences as well as improved accuracy in data registration and the use of fully automated techniques will have a huge impact on standard MR imaging in the pre-surgical evaluation in future. However, most techniques are new and have to be validated in large, prospective studies. It would be desirable to combine functional imaging techniques like EEG, fMRI and MEG with new structural imaging techniques to better define the epileptiogenic lesion, the irritative zone and the seizure onset zone, in respect to the eloquent cortex.

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Figure 86a.6 Diffusion tractology image. Left corticospinal tracts (blue), interhemispheric connections (green), calculated from high-resolution diffusion tensor sequence at 3 T using custom built software by Drs Ruopeng Wang, Greg Sorensen, and colleagues at the HST A.A. Martinos Center for Biomedical Imaging. The directional bias of the diffusion can provide information about the structure of underlying white-matter tracts. Analysis techniques under development may enable statistical measures of connectivity which, in turn, may further our understanding of cerebral malformations and seizure propagation.

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Figure 86a.7 MEG data of a 17-year-old right-handed boy suffering from right hemispheric epilepsy (referred by Dr G. Holmes, Children’s Hospital, Boston). During the investigation several MEG-only spikes but no spikes were recorded on EEG. Magnetic source imaging of all recorded MEG spikes (right side) mapped the IED to the right posterior temporal lobe. Dynamic SPM of one IED shows that the spike is spreading from right posterior temporal to the right frontal region within 16 msec. (Image courtesy of Dr Hideaki Shiraishi, Department of Pediatrics, Hokkaido University, Graduate School of Medicine.)


5. 6.

7. 8. 9. 10.

Kuzniecky R, Burgard S, Faught E, Morawetz R, Bartolucci A. Predictive value of magnetic resonance imaging in temporal lobe epilepsy surgery. Arch Neurol 1993;50:65–9. Mosewich RK, So EL, O’Brien TJ et al. Factors predictive of the outcome of frontal lobe epilepsy surgery. Epilepsia 2000;41:843–9. Knake S, Grant PE. Stufflebeam SM et al. Aids to telemetry in the presurgical evaluation of epilepsy patients: MRI, MEG and other noninvasive imaging techniques. J Clin Neurophysiol 2004. (in Press) Knake S, Grant PE. Magnetic resonance imaging techniques in the evaluation for epilepsy surgery. In: Wyllie E, ed. The Treatment of Epilepsy: Principles and Practice. Philadelphia: Lippincott Williams and Wilkins, 2004: (in press). Grant PE. Structural MR imaging. Epilepsia 2004;45 (Suppl 4):4–16. Rugg-Gunn F, Duncan J. Three-dimensional analysis of MRI. In: Daube JR, Mauguiere F, eds. Presurgical Assessment of the Epilepsies with Clinical Neurophysiology and Functional Imaging. Amsterdam: Elsevier, 2004:513–29. Hattingen E, Hattingen J, Clusmann H et al. Planar brain surface reformations for localization of cortical brain lesions. Zentralbl Neurochir 2004;65:75–80. Scheef L, Hoenig K, Urbach H et al. Curved-surface projection: an alternative method for visualizing functional MR imaging results. AJNR Am J Neuroradiol 2003;24:1045–8. Hattingen E, Hattingen J, Clusmann H et al. Planar brain surface reformations for localization of cortical brain lesions. Zentralbl Neurochir 2004;65:75–80. Kikinis R, Shenton ME, Gerig G et al. Temporal lobe sulco-gyral pattern anomalies in schizophrenia: an in vivo MR three-dimensional surface rendering study. Neurosci Lett 1994;182:7–12.

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Cook MJ. Mesial temporal sclerosis and volumetric investigations. Acta Neurol Scand Suppl 1994;152:109–14, discussion. Fu et al.1998. Sobira et al.1995. Ashburner and Friston Sisodiya SM, Free SL, Fish DR, Shorvon SD. Increasing the yield from volumetric MRI in patients with epilepsy. Magn Reson Imaging 1995;13:1147–52. Gale SD, Baxter L, Roundy N, Johnson SC. Traumatic brain injury and grey matter concentration: a preliminary voxel based morphometry study. J Neurol Neurosurg Psychiatry 2005;76:984–8. Bernasconi N, Duchesne S, Janke A et al. Whole-brain voxel-based statistical analysis of gray matter and white matter in temporal lobe epilepsy. Neuroimage 2004;23:717–23. Colliot O, Bernasconi N, Khalili N et al. Individual voxel-based analysis of gray matter in focal cortical dysplasia. Neuroimage 2006;29:162–71. McMillan AB, Hermann BP, Johnson SC et al. Voxel-based morphometry of unilateral temporal lobe epilepsy reveals abnormalities in cerebral white matter. Neuroimage 2004;23:167–74. Keller SS, Wilke M, Wieshmann UC, Sluming VA, Roberts N. Comparison of standard and optimized voxel-based morphometry for analysis of brain changes associated with temporal lobe epilepsy. Neuroimage. 2004;23:860–8. Huppertz HJ, Grimm C, Fauser S et al. Enhanced visualization of blurred gray-white matter junctions in focal cortical dysplasia by voxel-based 3D MRI analysis. Epilepsy Res 2005;67:35–50. Fischl B, Liu A, Dale AM. Automated manifold surgery: constructing geometrically accurate and topologically correct models of

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Textbook of epilepsy surgery the human cerebral cortex. IEEE Trans Med Imaging 2001;20: 70–80. Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage. 1999;9: 179–94. Fischl B, Sereno MI, Dale AM. Cortical surface-based analysis. II: Inflation, flattening, and a surface-based coordinate system. Neuroimage. 1999;9:195–207. Huppertz HJ, Grimm C, Fauser S et al. Enhanced visualization of blurred gray-white matter junctions in focal cortical dysplasia by voxel-based 3D MRI analysis. Epilepsy Res 2005;67:35–50. Kassubek J, Huppertz HJ, Spreer J, Schulze-Bonhage A. Detection and localization of focal cortical dysplasia by voxel-based 3-D MRI analysis. Epilepsia 2002;43:596–602. Fischl B, Dale AM. Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci USA 2000;97:11050–5. Rosas HD, Liu AK, Hersch S et al. Regional and progressive thinning of the cortical ribbon in Huntington’s disease. Neurology 2002;58:695–701. Salat DH, Buckner RL, Snyder AZ et al. Thinning of the cerebral cortex in aging. Cereb Cortex 2004;14:721–30. Kotini A, Camposano S, Hara K et al. Cortical thickness in a case of congenital unilateral perisylvian syndrome. Neurol Clin Neurophysiol 2004;2004:4. Vogeley K, Tepest R, Pfeiffer U et al. Right frontal hypergyria differentiation in affected and unaffected siblings from families multiply affected with schizophrenia: a morphometric MRI study. Am J Psychiatry 2001;158:494–6. Schmitt JE, Eliez S, Bellugi U, Reiss AL. Analysis of cerebral shape in Williams syndrome. Arch Neurol 2001;58:283–7. Ronan L, Doherty CP, Delanty N, Thornton J, Fitzsimons M. Quantitative MRI: a reliable protocol for measurement of cerebral gyrification using stereology. Magn Reson. Imaging 2006;24: 265–72. Fischl B, Salat DH, Busa E et al. Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron 2002;33:341–55. Fischl B, van der KA, Destrieux C et al. Automatically parcellating the human cerebral cortex. Cereb Cortex 2004;14:11–22.

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Connelly A. MR Diffusion and perfusion imaging in epilepsy. In: Kuzniecky R, Jackson GD, eds. Magnetic Resonance in Epilepsy. San Diego: Elsevier Academic Press, 2005:315–32. Szabo K, Poepel A, Pohlmann-Eden B et al. Diffusion-weighted and perfusion MRI demonstrates parenchymal changes in complex partial status epilepticus. Brain 2005;128:1369–76. Jansen FE, Braun KP, van Nieuwenhuizen O et al. Diffusionweighted magnetic resonance imaging and identification of the epileptogenic tuber in patients with tuberous sclerosis. Arch Neurol 2003;60:1580–4. Oster J, Doherty C, Grant PE, Simon M, Cole AJ. Diffusionweighted imaging abnormalities in the splenium after seizures. Epilepsia 2003;44:852–4. Jansen FE, Braun KP, van Nieuwenhuizen O et al. Diffusionweighted magnetic resonance imaging and identification of the epileptogenic tuber in patients with tuberous sclerosis. Arch Neurol 2003;60:1580–4. Wieshmann UC, Clark CA, Symms MR et al. Water diffusion in the human hippocampus in epilepsy. Magn Reson Imaging 1999;17:29–36. Salat DH, Tuch DS, Hevelone ND et al. Age-related changes in prefrontal white matter measured by diffusion tensor imaging. Ann NY Acad Sci 2005;1064:37–49. Wieshmann UC, Symms MR, Parker GJ et al. Diffusion tensor imaging demonstrates deviation of fibres in normal appearing white matter adjacent to a brain tumour. J Neurol Neurosurg Psychiatry 2000;68:501–3. Thivard L, Lehericy S, Krainik A et al. Diffusion tensor imaging in medial temporal lobe epilepsy with hippocampal sclerosis. Neuroimage. 2005;28:682–90. Arfanakis K, Hermann BP, Rogers BP et al. Diffusion tensor MRI in temporal lobe epilepsy. Magn Reson Imaging 2002;20:511–19. Rugg-Gunn FJ, Eriksson SH, Symms MR, Barker GJ, Duncan JS. Diffusion tensor imaging of cryptogenic and acquired partial epilepsies. Brain 2001;124:627–36. Salat DH, Tuch DS, Greve DN et al. Age-related alterations in white matter microstructure measured by diffusion tensor imaging. Neurobiol Aging 2005;26:1215–27. Grant PE. Imaging the developing epileptic brain. Epilepsia 2005;46 (Suppl 7):7–14.

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Multimodal image processing in pre-surgical planning C Vollmar, S Noachtar, and PA Winkler

Introduction to the multimodal image processing approach As described in Chapter 47, the definition of the epileptogenic zone is the key challenge in pre-surgical evaluation of epilepsy. The epileptogenic lesion and the seizure onset zone will typically be included in the epileptogenic zone. However, it is known that they may reflect only the core of the epileptogenic zone and that the irritative zone, the symptomatogenic zone or even the functional deficit zone can further contribute to epileptogenicity and can also define an additional part of the epileptogenic zone. In most chronic focal epilepsies, all these zones are partially overlapping, with different spatial extent and a complex mutual relationship between them. Additionally, most of these zones are not visualized directly by any imaging modality, but images reflect various physiological tissue characteristics and different aspects of epileptogenicity. Interpreting diagnostic images in the pre-surgical evaluation of epilepsy includes the task of assigning individual imaging findings to the theoretical zones described above: a regional hyperperfusion shown in an ictal SPECT study may reflect the seizure onset zone only, or spread to the symptomatogenic zone can already be involved. This judgment will be based on the exact time of injection in relation to seizure onset, EEG findings, seizure semiology and other information on the clinical context. The presence of any structural lesion can further influence the regional perfusion. Facing the complexity of this mutual relationship between different imaging modalities, a precise topographic correlation of all available diagnostic modalities is helpful. Image coregistration and the combination with a three-dimensional reconstruction of the patient’s individual cortical anatomy can assist the interpretation of each single modality and finally support a conclusive interpretation with the aim to individually define the epileptogenic zone for resection. To transfer imaging findings from original or postprocessed images into the operating theatre, it is necessary to provide some guidance, which allows a reliable correlation of images with the real brain. The use of navigation systems is possible1, however epilepsy surgery often includes large craniotomies, causing a significant brainshift, due to loss of CSF or distortions during the course of an extensive resection.2,3 A significant brain shift also occurs after removal of a subdurally implanted grid,

which is typically the occasion to proceed with the resection of the epileptogenic zone. To overcome this issue, we focussed on the topography of the cerebral venous system to provide anatomical landmarks for planning and tailoring cortical resections. The specific shape of the superficial venous anatomy is fixed to cortical anatomy via the arachnoid trabecular system.4,5 This makes superficial cortical veins a reliable anatomical landmark, overcoming the trouble of brainshift. Finally this allows for a precise intraoperative localization of previously identified structures like subcortical lesions or the seizure onset zone or eloquent cortex, even in extensive craniotomies. The aim of this chapter is to provide the reader with a short overview of techniques for multimodal image correlation, applicable in the pre-surgical evaluation of epilepsy. The specific contribution of multimodal image processing to the definition of the epileptogenic zone and for planning individually tailored cortical resections will be illustrated in several clinical examples.

Requirements Increasing computing performance makes the technical basis for multimodal image processing available to a wide community. All the images in this chapter were created on a standard Personal Computer (Intel Pentium IV, 1.8 GHz CPU, 512 MB RAM), equipped only with an additional consumer class (‘gamer’) graphic acceleration card. Improvements in diagnostic imaging, like the invention of 3 T MRI scanners or multislice CT scanners, allows the acquisition of datasets with a higher spatial resolution, resulting in bigger image datasets being processed. However, this development coincides with a continuous increase in computing power and storage capacity of personal computers. In practical terms this means, a standard personal computer in the $ 1000 category has always been sufficient for multimodal medical image processing for the last few years, and most likely there will be no need for a higher investment during the next few years. Searching the internet for ‘medical image processing’ will provide a broad bandwidth of possible software packages, including free and commercial products. The decision on which software to use should be based on previous experience in your department, since all available software packages require some period of time for training. It is important to mention, that most of the software is marketed for research 771

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purpose only, and not for clinical patient care. This reminds us that every single step of image processing is a possible source of errors, and that clinical decisions should never be based on image processing results, without confirmation by the clinical context. The decision, how much image processing is allowed to contribute to clinical decision underlies the physician’s responsibility. Typically, the involvement will increase over time, with more experience and confidence in the image processing procedures. Another issue for image processing is the comfortable accessibility of digital image data. In a fully digitized hospital, employing modern network infrastructure and a PACS system, it will be easy to collect and process image data from several departments. However, with a less advanced infrastructure it is just a bigger effort, to export, convert, and transfer image data from different modalities and departments, yet image processing can still be performed.

Image acquisition The basis for multimodal imaging is typically a T1-weighted, high-resolution volume acquisition MRI dataset. It serves as the primary dataset for all further image registration procedures, and also provides the anatomical basis for all further localizations, including the three-dimensional reconstruction of the patient’s cortical surface. At the University of Munich Epilepsy Centre we use a sagittally acquired fast gradient echo T1 sequence, providing isotropic 1 mm3 pixels (‘mprage’ on Siemens MRI-scanners or ‘FSPGR’ on General Electric scanners). An image matrix of 256 × 256 pixels and a slice thickness of 1 mm are entirely sufficient to depict the patient’s individual cortical anatomy; however, the higher resolution that is becoming available with higher field strengths can further improve the image quality. Besides this anatomic basis dataset, a number of additional sequences will be acquired, following established protocols for epilepsy, or driven by specific questions from the clinical context. There are no specific requirements to allow further processing of additional MRI sequences. Limiting the slice thickness to not more than 4 mm warrants a minimum image quality after reformatting of images and will improve the reliability of image registration. For visualization of the superficial cortical veins, we currently use a contrast enhanced 2D-Time-of-Flight-Angiographysequence with a 512 × 256 matrix and 2 mm slice thickness. However, comparable results have also been achieved with different angiography sequences. In nuclear medicine, SPECT and PET images can usually be acquired by routine protocols; most departments will create transverse datasets with isotropic pixels of about 3 × 3 × 3 mm3 which can perfectly be used for further image processing.

Image coregistration The first step in multimodal image processing is image coregistration. This term describes the procedure of spatially aligning two different image datasets in a way that both studies show the same anatomic structure in every pixel. One dataset is defined as ‘primary’ or ‘reference’ and is left unchanged. The ‘secondary’ dataset is then transformed, to match the reference. Since the transformation and resampling of the secondary

dataset requires interpolation, a modest loss of image quality is possible. For this reason, typically the higher resolution data like MRI is defined as ‘reference’, and the lower resolution data like PET is transformed to match the MRI. The minimal necessary transformation to align two threedimensional datasets from one patient is a ‘rigid body’ transformation, and uses six degrees of freedom: translation and rotation along the three perpendicular axes of a coordinate system. The scaling and internal configuration of both datasets remains unchanged. For image registration from different individuals or for the registration of an individual dataset to a normative template, a ‘nonrigid transformation’ might be necessary, which includes additional scaling or stretching of the datasets. These nonrigid transformations are based on complex algorithms and contain several sources of artificial influence on the image data. Currently this limits their use in clinical routine; nonrigid transformations are primarily applied for group comparisons in research settings. In the pre-surgical evaluation of an epilepsy patient, the rigid body transformation of several imaging modalities will be sufficient to achieve the image registration, necessary for multimodal correlation of different imaging findings. However, even a rigid body transformation has to be verified to estimate the accuracy of the procedure, before its results are allowed to influence clinical decisions.6 A rigid body image registration can be performed either automatically or manually. Automatic image registration All automatic methods are based on comparable principles, which will be illustrated briefly using the example of the ‘pixel uniformity registration’, also known as Woods’ algorithm7 as a representative method. The first step in this method is a classification of the primary modality, e.g. an MRI, into several groups of pixel values. The idea is that each of these pixel groups should represent an ‘organ’ or an anatomically defined structure. When matching this group of pixels with a second modality, e.g. a PET, it is obvious that the PET pixel values will be different in these defined ‘organs’. Also there will not be a linear relationship between an ‘organs’ pixel values in each modality. However, at least the ‘organ’ is supposed to show homogenous pixel values, also in the second modality. With this assumption, the uniformity of pixel values in the second modality, within each pixel class of the first modality is analysed. An improvement of this uniformity is assumed to represent a better registration. Therefore, this uniformity is defined as a measure for the quality of a registration. The last step is now to optimize this measure of quality. The aim is to find the transformation of the secondary dataset that leads to the best possible pixel uniformity, according to the above definition. This is usually achieved with an iterative optimization process, which is a trial-and-error approach initially, changing the transformation parameters arbitrarily and recalculating the measure of quality. Parameter changes that improve the quality of the registration are recognized by the optimization algorithm and the next changes will be guided by previous achievements. This iterative procedure is repeated, until a predefined threshold is reached, or until a maximum number of iterations have been performed. Most automated methods for image registration can be broken down into these three steps: First, some kind of classification or segmentation of the primary datasets is performed.

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Multimodal image processing in pre-surgical planning Secondly a measure of the quality of the registration is defined, typically including some correlation of pixel values between the two datasets. It is assumed, that an optimization of this error measure reflects an improved registration. Thirdly, this error measure has to be optimized, typically by an iterative approach. Each of these three steps can be modified and optimized independently, in order to improve automatic image registration. However, despite all the major improvements in the field of automated image registration, all automatic algorithms are inevitably still prone to errors when used in the clinical setting of epilepsy surgery. From a clinical point of view, divergences between different imaging modalities are exactly what we expect from a multimodal pre-surgical evaluation. In a patient with normal MRI, we perform a PET scan, because we expect the patient’s pathology to be apparent by a change in glucose metabolism or receptor density, in spite of a normal MRI. This is the clinical reason why we perform the PET scan. For an automated algorithm this discrepancy will be regarded an error, worsening the measure of registration quality and the algorithm will try to correct this ‘mismatch’. The possible work to identify those regions manually from an image dataset and exclude them from the automated registration algorithm is significant. Manual image registration On the other hand, there is the possibility to perform image registration manually. This typically means that a user interface is provided to the operator to perform the registration by hand. Usually the primary dataset is displayed as grayscale image in the background and is superimposed by the second dataset, using a transparent colour encoding, isolines or alternating display patterns. The user then has to shift and rotate the secondary dataset manually in all three orientations, until the best fit has been achieved visually. This is an interactive process, including a final visual control by scrolling through the whole dataset, to ensure an adequate registration quality. This manual approach has several advantages, which is the reason why we only perform manual image registration in clinical routine at the University of Munich Epilepsy Centre. Many ‘automated’ methods for image registration require a significant amount of user interaction to prepare the automatic procedure. The removal of the skull from images, or the manual identification of ‘regions of interest’, are often necessary tasks. The time spent in such preparations of the data quickly amounts to several minutes. Furthermore, one can hardly trust an algorithm blindly, and every automated image registration has to undergo some plausibility check by the physician. The minimum check a physician has to perform, is scrolling through the whole registered dataset to check the registration accuracy. This check will typically take a few minutes. Both of these steps are not necessary if the registration has been performed manually under permanent visual control of the user. In the case of suboptimal image quality in either modality, the physician can identify the more reliable areas, or the areas of more clinical interest, and then focus on these areas during the manual image registration procedure. Not only technical artifacts, but also discrepancies in the imaging findings, can

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easily be detected and interpreted by the physician, who knows the clinical context. An automatic algorithm usually does not know how to handle such difficulties, and is likely to fail. Finally, it could be shown, that the achieved accuracy of manual registration is superior to that of automated algorithms, when analyzing the registration of MRI and ECDSPECT.6 An accuracy of 1.5 mm could be achieved manually, and the effect of user- dependency could be shown to be negligible. Similar results have been achieved for registration of other modalities to an MRI dataset, namely PET, CT and MR-angiography, with errors between 0.9 and 1.5. Even the total processing time is lower for manual image registration, taking into account the above-described preprocessing and quality checks for automated algorithms. A manual registration can usually be performed in less than five minutes.

Image segmentation and 3D reconstruction Image registration alone already allows a correlation of imaging findings from two different modalities. However, datasets are still only analyzed in 2D slices, not in the context of the patient’s individual cortical anatomy. Visualization of the cortical surface requires a threedimensional rendering of an anatomical MRI dataset. Usually some manual image preprocessing is required before 3D rendering can be performed, namely the segmentation of the brain to separate it from skull and skin. This processing step can be performed automatically or manually. Our preliminary experience with automated segmentation algorithms showed that they work fine at the lateral convexity of the brain and can provide sufficient segmentation within minutes. However, in clinical routine, these algorithms are often limited by artifacts, e.g. skull base susceptibility artifacts or artefacts from eye movement, which typically appear at the level of the temporal lobes. Separating the dura from the cortical surface is also a challenge for automated algorithms, especially in images from patients with a history of previous neurosurgery or meningitis. Fully manual image segmentation, on the other hand, is the most time consuming step in 3D image processing. To manually segment a high resolution MRI of the brain, a trained user will need 15–30 minutes, depending on the characteristics of the dataset, software and user skills. Even the use of supportive tools, like interpolation of the segmentation or automated edge detection, barely reduces the total processing time. As with image registration, we also perform image segmentation manually at the University of Munich Epilepsy Centre. A time-saving compromise can be, to segment only the hemisphere of interest and leave the other side unsegmented. Other than segmenting the whole brain to display the patient’s cortical anatomy, in some cases it is reasonable to also segment pathological findings from other MRI sequences or from other modalities. For example, FLAIR images can show focal signal increase in cortical dysplasia or may help to delineate the extent of structural lesions such as posttraumatic gliosis, and can reasonably be segmented for further visualization. In complex cases, the segmentation and colouring of anatomical landmarks such as the precentral gyrus can be helpful.

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After the segmentation of the brain surface, we perform 3D volume rendering in order to display the cortical surface three dimensionally. Volume rendering applies for each pixel transparency settings, defined by a colour table, which is specifically adjusted to the underlying MRI sequence. Pixel values for gray and white matter will typically be displayed almost opaque, while lower values for CSF or higher values for fat will be displayed more transparent or completely invisible. This allows for some tolerance with the brain surface segmentation, because thin layers of dura will only slightly change the appearance of the underlying gyri. In case other image modalities show subcortical findings, then the overall transparency of the 3D rendering can be increased, to improve the view to the depth of the dataset. On the other hand, this procedure will reduce the quality of the superficial cortical anatomy. For visualization of subdural or depth electrodes from a CT scan, no segmentation is necessary. Since the metal electrodes have a higher X-ray density than any tissue, a simple threshold technique with a cutoff at 2300 Hounsfield units can usually isolate the electrodes for further visualization.8 Some subdural electrodes can be more difficult to display, if by chance the thin platinum contacts are positioned almost parallel to the CT slice orientations. This can happen to temporo-basal or fronto-orbital electrodes, typically resulting in lower pixel values in the CT scan which requires an adjustment of the threshold value. Once the invasive electrodes are visualized, all results from EEG recording and cortical stimulation can also be localized in the image data.

Image arithmetic For some images, further processing has to be performed, before the final results can be defined and included in the multimodal visualization. The most common application of arithmetic calculations performed on image datasets is the subtraction of ictal and interictal perfusion SPECT, as described in the chapters on SPECT scans.9 It is important to keep in mind, that such a subtraction is prone to different influences. The amount of injected activity may vary between both SPECT studies, requiring a normalization of the datasets’ count rate before subtraction. After subtracting the interictal ‘baseline’ image from the ictal image, a ‘difference’ image is created, showing the specific change in perfusion at the time of injection. This image can now be displayed with different thresholds, modifying the extent of change that is visualized. Typically, the most prominent change in perfusion can be found in the seizure onset zone; however, areas of seizure spread, like the symptomatogenic zone or parts of the irritative zone may also be involved. A later time of ‘ictal’ injection might result in an actual postictal scan, showing a reduced blood flow. In this case, the postictal image would then be subtracted from the interictal scan. The knowledge of the clinical context of the tracer injection, is vital to handle the images adequately, and this requires a close interaction between different involved departments. In some cases, the regional hyperperfusion can be prominent enough to be displayed without subtracting the interictal scan; in others, it might be beneficial to combine both and add the subtraction result to the whole ictal scan. Whichever way is chosen to calculate and visualize the relevant findings, it is important to always check the original data, to confirm the plausibility of any postprocessing result.

Illustrative case reports After this technical introduction, illustrative case reports should demonstrate the relative contribution of each imaging modality, and of image processing, in the pre-surgical evaluation of epilepsy patients. Patient 1 M.R. is a 32-year-old male patient, suffering from frontal lobe epilepsy since the age of 15. He suffers from tonic seizures of the face, evolving to left sided tonic and clonic seizures, eventually further evolving to hypermotor or automotor seizures and GTCS. At the time of pre-surgical evaluation, the seizure frequency on medication was 18 per month. Initial MRI studies were normal, an FDG-PET scan revealed extensive right temporal and right frontal hypometabolism. Video-EEG monitoring with surface electrodes was performed, and showed interictal spikes and polyspikes, in the right frontal region, and continuous right frontal slowing. Ictal EEG showed consistent right frontal seizure patterns. Therefore, the patient was considered for epilepsy surgery and scheduled for implantation of subdural electrodes to prepare a right frontal resection. Additionally, a Flumazenil-PET scan was acquired in order to localize the seizure onset zone. The scan showed a circumscribed reduction in GABA-A receptor density (white arrow) in the right frontoorbital cortex (coronal slices through the frontal lobes, Figure 86b.1a). The right frontal lobe was extensively covered with subdural electrodes, as shown in the right lateral view in Figure 86b.1b. Visualization of the electrodes was carried out by image registration of an anatomic T1-weighted MRI scan and a postimplantation CT scan and then combined 3D volume rendering. Figure 86b.1c is a combined image registration of the same MRI, the electrodes and the colour encoded Flumazenil-PET scan (inferior view to temporal lobes and orbitofrontal cortex). It shows the right fronto-orbital reduction in GABA-A receptor density (dark blue area) and its good correlation with the seizure onset zone as recorded from invasive EEG (black electrodes). An ECD-SPECT scan was performed to visualize the regional hyperperfusion during a seizure, and it revealed a prominent hyperperfusion in the lateral right frontal lobe (Figure 86b.1d). Image fusion with MRI (Figure 86b.1e) allowed anatomic localization of the hyperperfusion (red spot). Figure 86b.1f shows the corresponding 3D rendering, localizing the hyperperfusion to the most posterior portion of the middle frontal gyrus. Since early spread of seizure activity and the maximal frequency of interictal spikes were also recorded from this area, it was decided to include this region in the resection. The detailed 3D view and corresponding equivalent intraoperative photograph (Figure 86b.1g and 1h) show a perfectly matching cortical anatomy. The posterior border of the frontal lobe resection was marked by a black cord intraoperatively and it includes the inferior portion of the central region(Figure 86b.1h). The photograph also shows a prominent artery and vein, crossing the border of the resection. Vascular anatomy was not included in the pre-operative imaging procedure at the time, but this example shows how helpful it would have been for the resection planning.

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Figure 86b.1 Patient 1. Flumazenil-PET (coronal slices) showing reduced GABA-A receptor density in the right frontoorbital region (a). Subdural electrodes were implanted (b), confirming right frontoorbital EEG seizure onset (black electrodes), overlapping with the PET hypointense area (blue) (c). Ictal SPECT showed marked hyperperfusion (d) in the right middle frontal gyrus (e,f,g). This area was included in the resection (h). (See Color plates.)

Patient 2 A.F. is a 45-year-old female patient, who developed posttraumatic left temporal lobe epilepsy as a consequence of head trauma at the age of 17. Ten years after a car accident, she suffered from epigastric auras, dialeptic seizures, and automotor seizures with an increasing frequency (ten per month at time of admission). T1-weighted MRI showed a posttraumatic defect in the left temporal neocortex (white arrow, Figure 86b.2a, sagittal, transverse and coronal view). Video-EEG monitoring with surface electrodes confirmed left temporal origin of the seizures. Recurring postictal aphasia was indicative of a close topographic relation between the seizure onset zone and language relevant areas. Consequently, subdural

electrodes were implanted, to localize the seizure onset precisely and to perform cortical stimulation for the identification of eloquent areas. Figure 86b.2b shows the implanted electrodes and their relation to the posttraumatic defect, which was labeled in orange (derived from FLAIR images). Figure 86b. 2c shows the results of the invasive evaluation, with a seizure onset zone (black electrodes) on the posterior border of the lesion, and an overlap with speech relevant areas (yellow electrodes). Because speech representation was very extensive in this case, and since we know, that inferior temporal language areas are usually accessory areas, it was decided to include this electrode in the resection. Motor responses were elicited from the red electrodes. The gray electrodes indicate

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Figure 86b.2 Patient 2. T1-weighted MRI showed a posttraumatic defect in the left inferior temporal gyrus (a), with adjacent gliosis, apparent as FLAIR hyperintensity (orange in b,c,d). Subdural electrodes were implanted (b), localising the seizure onset (black electrodes) and language relevant areas (yellow electrodes, c). Venous MR-angiography revealed a prominent anastomotic vein of Labbé that had to be preserved during the resection (d). (See Color plates.)

interictal spiking. However, the maximum of interictal spikes was recorded from the mesio-temporal stripe electrodes (not visible in this lateral view), and justified a complete resection of the anteromesial temporal lobe. The newly developed technique to visualize the superficial cortical veins, showed a prominent anastomotic vein of Labbé, which had to be preserved, crossing the planned area of resection (Figure 86b. 1d). Additionally, an accessory duplicate vein of Labbé was present in this case, a common variation already described by Labbé in 1868.10 Therefore, resection was limited to the part of the temporal lobe anterior to the vein. An additional topectomy of the seizure onset zone between both, the first order and the accessory veins of Labbé was also carried out (white resection line).

Patient 3 M.V. is a 44-year-old secretary, who suffered from short bilateral tonic seizures at night since childhood. Occasionally, she would also experience astatic seizures and GTCS. Initial MRI studies

were normal, EEG showed rare interictal polyspikes in the right frontal region. At time of admission for epilepsy surgery, a new MRI was performed and 3 mm T1-weighted inversion recovery images (Figure 86b.3a) showed a circumscribed blurring of the cortical band with a corresponding slight increase in FLAIR signal (Figure 86b.3b) in the medial aspect of the dorsal superior frontal gyrus, close to the margin, on the left side. These findings confirmed the clinical hypothesis of a focal cortical dysplasia (FCD). However, the reconstruction of the superficial veins (Figure 86b.3) showed a complex formation of draining veins over the FCD, making the implantation of subdural electrodes more difficult. From the venous topography, it was obvious that the craniotomy had to be extended towards the frontal pole, to allow for an implantation of electrodes in the medial surface of the frontal lobe, circumventing by the bridging veins Figure 86b.3d shows the localization of the medial electrodes, covering the FCD in a view to the medial surface of the left hemisphere. EEG Seizure onset in the region of the FCD could be confirmed (black electrodes). Cortical stimulation identified

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Multimodal image processing in pre-surgical planning

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Figure 86b.3 Patient 3. Repeat MRI identified a focal cortical dysplasia in T1 (a) and FLAIR (b) images. Surgical access to the lesion (orange) was complicated by an intricate formation of cortical veins (blue), one of them also draining parts of the primary motor cortex (arrow). Preservation of this vein was crucial in order to avoid venous infarction. (See Color plates.)

motor (red), sensory (green) and speech (yellow) relevant eloquent areas. A critical aspect of the venous anatomy is the drainage of the central region. A prominent vein (white arrow in Figure 86b.3c), draining the central region, which includes the right hand primary motor area was draining anteriorly and passing through the caput- medusa- like configuration of veins over the FCD. This vein had to be preserved, to avoid venous infarction of the central region. Part of the implanted grid electrode had already been cut off to avoid compression of this fragile venous configuration. The resection was a tricky surgical procedure, since it had to remove the complete FCD, reaching down to the cingulate gyrus, without sacrificing the adjacent lateral eloquent cortex, and without damaging the critical vein draining a part of the central region. This case shows how the reconstruction of superficial cortical veins helped in planning the implantation of invasive electrodes, as well as the resection itself. Also, the risk of a planned resection and the chances for complete removal of the target can be estimated more reliably. This combination of lesion localization and venous reconstruction allowed the veins to serve as robust anatomic landmarks, guiding the surgeon to the target region on the medial surface.

Summary Defining the epileptogenic zone and defining the borders of a neocortical resection are the key challenges in epilepsy surgery. A wide range of different imaging modalities is included in the pre-surgical evaluation of epilepsy patients. It is beneficial to use all the available information from MRI, PET, SPECT, and CT scans. However, 2D images are usually not sufficient to precisely evaluate the topographic relationship between different imaging modalities. Multimodal image processing, including 3D reconstructions of the patients, individual cortical anatomy, allows a true anatomical correlation of all integrated relevant imaging findings. This approach is helpful for the interpretation of single imaging findings and in the individual planning of cortical resections. The visualization of the superficial cortical veins can serve as brainshift-resistant anatomic landmark and therefore allows the transfer of diagnostic information into the operating theatre. Furthermore, the information about the venous anatomy can help to avoid complications such as venous infarction and improves the estimation of the individual risk benefit ratio of epilepsy surgery.


Wurm G et al. Evaluation of neuronavigation in lesional and non-lesional epilepsy surgery. Comput Aided Surg 2003;8(4):204–14. Hill DL et al. Measurement of intraoperative brain surface deformation under a craniotomy. Neurosurgery 1998;43(3):514–26; discussion 527–8. Roberts DW et al. Intraoperative brain shift and deformation: a quantitative analysis of cortical displacement in 28 cases. Neurosurgery 1998;43(4):749–58; discussion 758–60. Di Chiro G. Angiographic patterns of cerebral convexity veins and superficial dural sinuses. Am J. Roentgenology 1962;87:308–21. Duvernoy HM, Delons, Vannson JL. Cortical blood vessels of the human brain. Brain Res Bull 1981;7(5):519–79.

6.

7. 8. 9. 10.

Pfluger T et al. Quantitative comparison of automatic and interactive methods for MRI-SPECT image registration of the brain based on 3-dimensional calculation of error. J Nucl Med 2000;41(11):1823–9. Woods RP, Mazziotta JC, Cherry SR. MRI PET registration with automated algorithm. J Comput Assist Tomogr 1993;17:536–46. Winkler P.A, et al. Usefulness of 3-D reconstructed images of the human cerebral cortex for localization of subdural electrodes in epilepsy surgery. Epilepsy Res 2000;41(2):169–78. O’Brien T et al. Subtraction ictal SPET co-registered to MRI in partial epilepsy: description and technical validation of the method with phantom and patient studies. Nucl Med Commun 1998;19(1):31–45. Bartels RH, van Overbeeke JJ. Charles Labbé (1851–1889). J Neurosurg 1997; 87(3):477–80.

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SECTION 9 The functional deficit zone

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The functional deficit zone: general principles C Baumgartner and E Lehner-Baumgartner

Definition The functional deficit zone is defined as the brain area that shows abnormal functioning in the interictal period. This abnormal functioning can be due to the effects of a structural lesion and/or due to the functional consequences of the persisting epileptic condition. The location and extent of the functional deficit zone can be assessed directly with the neurological examination and neuropsychological assessment (including the Wada test) and indirectly using surrogate markers of abnormal functioning including electroencephalography (EEG), magnetoencephalography (MEG) as well as functional neuroimaging tools like single-photon-emission-tomography (SPECT), positron-emission-tomography (PET), magnetic resonance spectroscopy (MRS) and functional magnetic resonance imaging (fMRI).

Neurological examination and neuropsychological assessment In the early days of epilepsy surgery careful neurological examination was the only way to localize the epileptogenic lesion and the epileptogenic zone. However, even in the age of modern neurophysiology and neuroimaging, the clinical examination should precede the use of these techniques in order to exploit their full diagnostic potential. Careful neurological examination can reveal abnormal function, be it behavioral, motor, or sensory. Characteristics of the dysfunction often pave the way for a topographical diagnosis.1 Nevertheless, neurological deficits are only present in a minority of surgical candidates because many cortical regions may be dysfunctional without causing abnormalities in the neurological examination, i.e. clinically silent.2 Several different causes can be responsible for neuropsychological dysfunctions in patients with focal epilepsy: ●

●

A circumscribed structural lesion responsible for the patient’s epilepsy, i.e., the epileptogenic lesion. Here, location and type of the lesion are decisive for the profile of neuropsychological impairment. Structural lesions remote from the seizure-onset zone, for instance in a patient with multiple lesions due to cerebral trauma. Approximately 10% of patients who survive severe traumatic brain injury will develop epilepsy. While memory

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and attention/information processing speed and efficiency are typically the cognitive domains most severely affected by head injury, intellectual, language, and perceptual skills tend to be relatively preserved.3 Diffuse brain damage causing both the patient’s epilepsy and neuropsychological impairment. Neuropsychological deficits can also occur in patients suffering from focal epilepsy with normal MRI scans. This patientgroup constitutes about 20–30% of surgical candidates. Functional disturbances can arise remote from the epileptogenic lesion, i.e., lateral temporal or extratemporal dysfunctions in patients with mesial temporal lobe epilepsy. Functional disturbances can be caused by interictal epileptiform discharges, also referred to as ‘transient cognitive impairments (TCI) caused by interictal epileptiform EEG discharges’.4 While interictal epileptiform EEG discharges may cause additional and independent transient cognitive impairments, their incidence is as low as 2.2%5 and their effect is usually small to moderate and limited to transient mechanistic cognitive processes (alterness and mental speed).4 Functional disturbances can be the consequences of seizures, i.e., circumscribed postictal neuropsychological deficits.6, 7 Antiepileptic drugs can cause generalized, but also specific neuropsychological dysfunctions. Thus, topiramate can cause verbal dysfunctions which can be difficult to distinguish from dysfunctions as a consequence of the functional deficit zone in patients with seizures arsing adjacent to speech cortex.8

The concept of the functional deficit zone should be restricted to neuropsychological impairments caused either directly or indirectly by the epileptogenic zone. However, the segregation of the various causes of neuropsychological deficits can be difficult and requires an astute and experienced neuropsychologist. Depending on the location of the epileptogenic zone several distinct neuropsychological profiles can be distinguished.9–11 In patients with temporal lobe epilepsy, the most important neuropsychological symptoms consist of materialspecific or even non-specific deficits in episodic memory due to hippocampal dysfunction.9 While impairment of episodic verbal memory can be consistently found in left temporal lobe epilepsy, the relationship between figural or visuospatial memory deficits and right temporal lobe epilepsy is far less consistent. This could be explained by confounding of figural memory with 781

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verbalization, sex differences, as well as by atypical language representation and suppression of right hemispheric functions due to crowding phenomena.10 Within the temporal lobe a differentiation between mesial and lateral temporal lobe dysfunction is frequently possible by the assessment of verbal learning versus verbal memory. While lateral temporal dysfunction affects primarily verbal learning, mesial temporal structures are critical for verbal memory.12 In addition, naming difficulties can be frequently found in patients with temporal lobe epilepsy. While deficits in visual confrontation naming indicate inferotemporal dysfunction, auditory confrontation naming requires inferotemporal and lateral temporal structures.13 Finally, patients with temporal lobe epilepsy and more specifically patients with mesial temporal lobe epilepsy frequently suffer from considerable generalized cognitive impairments (intelligence, academic achievement, language, and visuospatial functions) indicating an extension of the functional deficit zone beyond the temporal lobes to frontal lobe structures.14 Thus, frontotemporal dysfunctions frequently can be found in patients with temporal lobe epilepsy.12 While prefrontal lobe functions such as attention and executive functions are frequently spared in patients with temporal lobe epilepsy, the occurrence of frequent secondarily generalized tonic-clonic seizures poses the patients at risk for global intellectual as well as specific impairment of prefrontal lobe functions. These neuropsychological deficits were associated with a prefrontal hypometabolism on [18F]FDG-PET which therefore can be considered as a surrogate marker of the functional deficit zone.15 Seizure-freedom after successful epilepsy surgery may lead to a normalization of this prefrontal hypometabolism and the corresponding neuropsychological impairments indicating the dynamic nature of the functional deficit zone.16 The complexity and diversity of frontal lobe functions and the intense connections between the frontal and the temporal lobes explain the variability of neuropsychological dysfunctions in patients with frontal lobe epilepsy. While frontal lobe epilepsy patients show little if any impairments of general intelligence and memory, some but not all patients show deficits in executive functions, psychomotor speed and attention.17–19 The neuropsychological characteristics of parietal and occipital lobe epilepsies have not been well characterized in larger groups of patients. Lesions of the parietal lobe may cause visual associative agnosia, hemineglect, visuospatial and constructive disorders, apraxia as well as linguistic deficits.9 However, these symptoms are rarely found in patients with chronic epilepsies most probably due to compensatory mechanisms especially in patients with seizureonsets early in life. More often impairments are diffuse and often mimic frontal or temporal dysfunction.20 The neuropsychological profile of patients with idiopathic occipital lobe epilepsies does not systematically differ from that of normal controls.21

The intra-carotid-amobarbital procedure or Wada test The goals of the intracarotid-amobarbital procedure or Wada test include language and memory lateralization.22 In epilepsy

patients, atypical language lateralization, i.e., right hemispheric or bilateral representation, is more likely than in normal controls.23,24 The determinants for atypical language dominance include early injuries, lesions adjacent to speech cortex and finally the epileptic process per se. Thus, early left hemispheric injuries occurring before the age of 5 years result in an interhemispheric reconstitution of language functions to the right hemisphere,25 while later injuries – when language becomes gradually lateralized – cause contralateral language reorganization more seldom.24 In mesial temporal lobe epilepsy, left-sided speech occurred in 76% of left-sided and in 100% of right-sided patients. Atypical language representation was also associated with a higher spiking frequency and sensory auras representing an ictal involvement of lateral temporal structures indicating the influence of interictal and ictal epileptic activity on language lateralization.26 The rationale of the Wada memory test consists of anesthetizing mesial temporal structures which should simulate the potential mnestic effects of the proposed surgery in a crude way.22 Injection of the hemisphere contralateral to the epileptogenic zone usually results in impaired memory performance due to the functional deficit of the affected temporal lobe. The functional status of the diseased temporal is also referred to as ‘functional adequacy’ and can be considered as a marker of the functional deficit zone of the ipsilateral temporal lobe. If the temporal lobe, which is planned to be resected, supports significant memory function (i.e., high functional adequacy), a greater memory decline should be anticipated because functionally intact tissue is removed. Anesthetization of the hemisphere ipsilateral to the epileptogenic zone, on the contrary, tests the functional integrity of the contralateral ‘healthy’ temporal lobe also referred to as ‘functional memory reserve’. A poor performance after ipsilateral injection thus would indicate an extension of the functional deficit zone to the contralateral temporal lobe and also would suggest poor memory performance after surgery. Both functional adequacy and functional reserve are therefore important predictors for post-operative memory performance.27 Patients with a strong asymmetry of memory performance, i.e., impaired memory ipsilateral to the epileptogenic focus and intact memory contralaterally, are those at the lowest risk for post-operative memory decline. In the case of symmetric Wada scores, functional adequacy will determine memory decline in patients with bilaterally good performance, whereas functional reserve will be decisive in patients with bilaterally poor performance. Especially in left temporal lobe epilepsy, high functional adequacy poses a major risk on post-operative memory decline. The highest risk for post-operative memory decrease is present in patients with unexpected asymmetry in Wada test performance, i.e., better performance after contralateral injection.27 Some patients may fail the Wada memory component without developing a significant memory decline after surgery,28 whereas others pass the Wada test and still experience a significant post-operative memory loss.29,30 Nevetheless, failures of the Wada memory component can be considered as a risk factor for postoperative memory decline and always have to be viewed in the context of the results of other investigations.27 The Wada test was found to be a clearly superior predictor of seizure laterality in comparison to neuropsychological

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The functional deficit zone: general principles testing.31 Functional asymmetries as assessed by Wada memory scores were significantly correlated with structural asymmetries as measured by hippocampal volumetry on MRI.32-34 Wada memory scores showed a significant negative correlation with the degree of hippocampal cell loss indicating that a severely damaged hippocampus could not support memory after contralateral amobarbital injection. 35–37 Furthermore, the Wada test has been used to predict post-operative seizure control.

Interictal EEG and MEG Slow wave activity can be classified according to its distribution as focal or generalized, according to its persistence as intermittent or continuous and according to its morphology as rhythmic or polymorphic.38 While continuous slowing (CS) on interictal EEG is usually caused by a structural lesion, intermittent rhythmic slowing (IRS) can be considered as the EEG/MEG marker of the functional deficit zone and often can be seen in the absence of structural lesions. Temporal interictal rhythmic delta activity (TIRDA) – characterized by trains of 50–100 µV sinusoidal or sawtoothed 1–4 Hz activity localized predominantly over anterior temporal regions – was found in 45 of 127 recordings of patients with epilepsy with complex partial seizures. Because TIRDA often occurred in association with anterior temporal spikes or sharp waves particularly during sleep, TIRDA was considered as an accurate interictal indicator of epilepsy with complex partial seizures.39 In a study reviewing 12 198 EEG recordings, TIRDA was present in 33 records of 27 patients and was associated with sharp waves either in the same record (23 patients) or on previous occasions (3 patients). All patients suffered from seizures and 23 patients from welldocumented epilepsy with complex partial seizures.40 Concerning its localizing significance, TIRDA was strongly associated with temporal lobe epilepsy, although it was infrequently seen also in extratemporal epilepsy. Temporal intermittent polymorphic delta activity (TIPDA), on the contrary, occurred at an equal rate in both temporal lobe and extratemporal epilepsy.41 In a series on patients with medically refractory focal epilepsy undergoing prolonged video-EEG monitoring, TIRDA was present in 52 out of 129 patients (40.3%) and showed a significant correlation with mesial and mesio-lateral TLE, mesial temporal sclerosis, interictal epileptiform discharges localized over the anterior temporal regions and 5–9 Hz temporal ictal discharges. Therefore it was concluded that TIRDA can be considered as an EEG marker of an epileptogenic zone involving mesial temporal structures.42 The lateralizing significance of slow wave activity in temporal lobe epilepsy was investigated in several studies. In patients with unilateral seizure-onsets, exclusively or predominately unilateral delta waves occurred ipsilateral to the seizure-onset zone in 46 out of 56 patients (82%) and never were seen contralaterally.43 Conversely, in patients with lateralized arrhythmic delta waves the concurrence with the side of seizure onset was 90% with delta waves in one EEG and 100% with delta waves in ≥ 4 EEGs.43 In mesial temporal epilepsy, the lateralizing accuracy of delta waves was studied in relation to spikes and hippocampal atrophy as assessed by volumetric measurements in 56 patients – 35 patients had unilateral (group I) and

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21 had bilateral hippocampal atrophy with lateralized predominance (group II). Unitemporal trains of delta waves lateralized the side of hippocampal atrophy with equal accuracy as interictal spikes (delta: 29 of 32 patients (92%) in group I and 12 of 19 of patients (63%) in group II; spikes: 85% or 28 of 33 patients (85%) in group I and 13 of 20 patients (65%) in group II). Delta waves and spikes occurred together in >85% of cases. Delta activity almost always occurred ipsilateral with unilateral spiking (19 of 21 of patients (90%) in group I and seven of eight of patients (88%) in group II) and bilaterally independently with bilateral spiking (six of nine of patients (67%) in group I and ten of ten patients (100%) in group II). Furthermore, spiking and delta activity were never in disagreement with respect to lateralization. It was concluded that intermittent delta waves are a reliable indicator of the epileptogenic focus and presumably reflect the epileptogenic process rather than the underlying structural pathology.44 The correlation of intermittent slow wave activity with other markers of the functional deficit zone, namely with hypometabolism on interictal [18F]FDG-PET and functionality on fMRI was investigated in several studies. In the first study, 16 of 28 patients (57%) had lateralised IRS with a maximum over the temporal regions which was always ipsilateral to the resection and significantly correlated with hypometabolism in the lateral temporal neocortex on [18F]FDG-PET, but not to mesial temporal sclerosis or any other pathology.45 The authors suggested that IRS should be conceptualised as a distinct electrographic phenomenon directly related to the epileptogenic abnormality and that the lateral temporal hypometabolism may delineate a field of reduced neuronal inhibition which can receive interictal and ictal propagation.45 In the second study on 40 patients with intractable temporal lobe epilepsy, the severity of temporal lobe hypometabolism on [18F]FDG-PET was significantly correlated with the amount of delta activity in the interictal EEG, independently of MRI findings.46 Therefore, common pathophysiologic mechanisms for metabolic and electrical dysfunction in temporal lobe epilepsy were suggested.46 Finally, activation of malformations of cortical development (MCDs) by simple (sensomotor, visual) or complex (language, memory) functional magnetic resonance imaging (fMRI) paradigms was assessed in 28 patients with focal epilepsy and MCDs. Besides an influence of the type of MCD, both focal neurological signs and focal EEG slowing independently were correlated with MCD inactivity.47 Magnetoencephalography (MEG) which measures the weak magnetic field induced by neuronal currents has the advantage of a better spatial resolution as compared with scalp-EEG.48 In one study, one or more sites of focal lowfrequency magnetic activity (LFMA) were detected in 29 of 33 patients and showed a 48.5% specificity with respect to the presumed epileptogenic region. LFMA was in agreement with the final consensus as often as was ictal scalp-EEG, and was exceeded in specificity overall only by invasive ictal EEG.49 In 29 patients with mesial temporal lobe epilepsy, LFMA with maximum amplitude over the temporal area was found in 17 patients (58.6%); it always occurred ipsilateral to the side of resection and the side of MEG interictal spike sources. Dipolar sources of LFMA were found in the posterior superior temporal region in the majority of cases and, occasionally, in mesial temporal structures.50

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Functional neuroimaging with SPECT and PET Functional neuroimaging techniques like SPECT and PET provide additional and independent information to structural neuroimaging during persurgical evaluation. While the recent developments of PET tracers aim to measure abnormalities of neurotransmission underlying neuronal hyperexcitability and thus could possible directly visualize the epileptogenic zone,51 the classical SPECT and PET tracers measure regional cerebral blood flow, oxygen consumption and glucose metabolism associated with epileptic dysfunction and therefore can be considered as surrogate markers of the functional deficit zone. SPECT ligands most commonly used in epilepsy, i.e., 99m Tc-Hexamethyl-propyleneamine (99mTc-HMPAO) and 99m Tc-ethyl cysteinate dimer (99mTc-ECD), are markers of regional blood flow. Both tracers are lipophilic, generally pass the blood–brain barrier on their first pass through brain tissue, become trapped and exhibit little subsequent redistribution. In temporal lobe epilepsy, interictal SPECT shows a regional temporal hypoperfusion ipsilateral to the epileptogenic zone in 40–50%, while 5–10% of studies are falsely lateralizing.52 These results concur with PET studies demonstrating an uncoupling of glucose metabolism and blood flow resulting in significantly higher sensitivity and specificity of glucose metabolism for the lateralization of the epileptogenic zone in temporal lobe epilepsy.53 Thus, interictal SPECT is of limited value and inferior to interictal [18F]FDG-PET for the localization of the functional deficit zone. [18F]FDG has been the most widely used PET tracer used during pre-surgical evaluation. While [18F]FDG crosses the blood brain barrier before phosphorylation in the cell compartment, unlike glucose-6-phosphate it does not enter into further steps of the Krebs glycolysis cycle, but accumulates in the intracellular compartment and thus directly reflects the energy demand of the brain cells.51 The mechanisms underlying interictal glucose hypometabolism are not fully understood. While glucose consumption occurs primarily at the synapse, reduced regional metabolism appears to reflect a decrease in glucose influx from reduced glucose transport across the blood brain barrier which correlates with subsequent reduced phosporlyation.54 Possible mechanisms of reduced interictal glucose metabolism include (1) atrophy and partial volume effects; (2) neuronal loss; (3) hypometabolic macro- or microscopic lesions; (4) decreased synaptic activity (diaschisis), (5) deafferentation due to reduced numbers of synapses, (6) postictal metabolic depression, (7) inhibitory mechanisms of seizures.51 Converging evidence has been accumulated that interictal hypometabolism represents a reversible functional state for several reasons. First, an increase of glucose metabolism can be observed during ictal PET scans in the interictal hypometabolic zone. Second, interictal hypermetabolism can be reverted by the application of a specific GABAA receptor agonist (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), THIP. After THIP injection, the increase of glucose metabolism in the hypometabolic focus was larger than the mean increase in the whole brain. Within the hypometabolic focus, this increase was significantly higher in regions with the lowest basal metabolic levels. This metabolic response in the hypometabolic

focus suggests that GABAA receptors are up-regulated or at least preserved in temporal lobe epilepsy. Furthermore, GABAA receptor mediated inhibition apparently increases the metabolic demand and therefore the hypothesis that hypometabolism is caused by increased inhibition becomes questionable.55,56 Third, hypometabolic zones surrounding the epileptogenic zone pre-operatively showed a normalization of glucose metabolism after successful surgery.16, 57, 58 This normalization of glucose metabolism was paralleled by an improvement in neuropsychological functioning.16 The sensitivity of [18F]FDG-PET varies according to etiology and location of the epileptogenic zone.51 In temporal lobe epilepsy, the sensitivity ranged between 65–90% in early studies encompassing patients with varying etiologies. This figure is closer to 60% in patients with normal MRI scans and closer to 90% in studies with newer scanners.52 In a prospective study in patients with hippocampal atrophy on MRI, sensitivity approached 100%.59 In frontal lobe epilepsy with normal MRI scans, abnormalities on [18F]FDG-PET are found in only 50% of patients.51 The differing sensitivities of [18F]FDG-PET according to the location of the seizure onset zone, the finding that hypometabolism on [18F]FDG-PET was not related to the epileptogenicity of cavernous angiomas60 and the low indicence of hypometabolism in new onset temporal lobe epilepsies,61,62 indicate that hypometabolism is not directly related to the epileptogenic process itself, but rather may reflect the functional and maybe structural consequences of repeated seizures. This is in line with some studies which found a correlation between hypometabolism and epilepsy duration as well as age at epilepsy onset, although these results could not be replicated by other authors.51 Although the lateralizing value of [18F]FDG-PET approaches 100% in temporal lobe epilepsy, bitemporal hypometabolism – which is usually less pronounced on the side contralateral to the epileptogenic zone – can be found in up to 32% of patients with unilateral temporal lobe epilepsy using statistical parameter mapping.63 Conversely, bitemporal hypometabolism was indicative of bilateral independent seizure onsets in approximately 50% of patients, especially when involving the inferior temporal gyrus. Moreover, bitemporal hypometabolism was associated with a more rapid contralateral seizure spread, a longer disease duration and worse memory performance during the Wada test and therefore could reflect an advanced stage of the disease process, characterized by a breakdown of the inhibitory mechanisms in the contralateral hemisphere.64 The localizing significance of PET within the hemisphere or lobe of seizure onset is far less well-defined than its lateralizing value. In temporal lobe epilepsy, this is already intuitively clear from the usually widespread hypometabolism involving – besides the temporal lobe – also the ipsilateral frontal and parietal neocortex, ipsilateral subcortical structures such as the thalamus and the striatum as well as the contralateral cerebellum.52 Recent studies suggested that lateral temporal hypometabolism is correlated with extrahippocampal structural changes including white matter changes in the anterior temporal lobe,65 temporal neocortical microscopic cortical dysplasia66 or temporal polar signal changes on MRI scans.67 Furthermore, some specific patterns of hypometabolism may help to differentiate mesial from lateral temporal lobe

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The functional deficit zone: general principles epilepsy. Whereas hypometabolism is more prominent in lateral than in medial structures both in medial and lateral temporal lobe epilepsy, a hypometabolism in the medial temporal structures is found less frequently in lateral temporal lobe epilepsy than in medial temporal lobe epilepsy. Furthermore, the extent of hypometabolism is significantly larger in medial temporal lobe epilepsy.63 Several studies correlated the functional deficit zone defined by interictal [18F]FDG-PET with the irritative zone and the seizure-onset zone defined by EEG. A consistent unilateral spike focus concurs with a lateralized hypometabolism on PET in over 90% of the cases. However, bilateral independent spikes can occur in the presence of unilateral hypometabolism.51 Several studies compared the location and extent of hypometabolism on [18F]FDG-PET with the location of the irritative zone defined by EEG and MEG dipole modeling of interictal spikes.68–70 While dipole sources usually were contained within the extended hypometabolic zone on [18F]FDG-PET, dipole localizations did not concur with the degree of hypometabolism within this hypometabolic zone.68,70 This is accordance with a study which found a poor agreement between stereoEEG localizations of the irritative zone and [18F]FDG-PET quantitative measures of regional metabolism.71 In temporal lobe epilepsy and lesional epilepsy, the seizureonset zone defined by intracranial EEG usually is contained within the functional deficit or hypometabolic zone on [18F]FDG-PET. On the contrary, in nonlesional neocortical and especially in nonlesional extratemporal epilepsy, the localizing value of [18F]FDG-PET in comparison to intracranial EEG seems to be limited. In a series of 41 patients with nonlesional temporal epilepsy including 16 with frontal lobe epilepsy, 11 with neocortical temporal lobe epilepsy, seven with occipital lobe epilepsy, four with parietal lobe epilepsy, and three with multifocal onsets, [18F]FDG-PET correctly predicted the lobe of seizure-onset zone on intracranial EEG in only 42.9% of the cases.72 [18F]FDG-PET analyzed by statistical parametric mapping correctly localized the epileptogenic lobe in 15 of 22 patients (68.2%) with nonlesional neocortical temporal lobe epilepsy, but only in three of 11 patients (27.3%) with nonlesional extratemporal epilepsy.73 Furthermore the degree of hypometabolism does not correlate with the location of seizure-onset on stereo-EEG.71 The question whether the presence of hypometabolism on [18F]FDG-PET and its restriction to the epileptic temporal lobe are necessary and sufficient prerequisites for a good surgical outcome after temporal lobectomy remains controversial. Whereas several studies identified a temporal hypometabolism as good prognostic sign independently of hippocampal atrophy on MRI,74 other studies failed to verify such an association.75 Hypometabolism on [18F]FDG-PET also has been correlated with other measures of the functional deficit zone, namely EEG and neuropsychological parameters. The correlation between slowing or background depression on stereo-EEG and quantitative measures of regional metabolism on [18F]FDG-PET was poor.71 Regional hypometabolism on [18F]FDG-PET was associated with corresponding circumscribed neuropsychological deficits. Relative reductions in glucose metabolism of the left lateral temporal lobe and the left thalamus independently predicted verbal memory impairments in temporal lobe epilepsy patients.76 Prefrontal hypometabolism which was more

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frequent in patients with left temporal lobe epilepsy and a history of secondarily generalized seizures correlated with impairments of neuropsychological ‘frontal lobe measures’, including verbal and performance intelligence measures.15 The results of [18F]FDG-PET – especially medial temporal metabolism – significantly correlated with Wada memory scores.77,78 Finally, pre-operative [18F]FDG-PET was predictive for postoperative memory performance in patients with left-sided temporal lobe epilepsy. Patients with no/mild asymmetry in temporal lobe metabolism exhibited significantly greater verbal memory decline compared with patients with moderate/severe hypometabolism.79

Proton magnetic resonance spectroscopy Magnetic resonance spectroscopy (MRS) allows noninvasive in vivo detection and quantification of various brain metabolites.80,81 1H or proton spectroscopy which measures N-acetyl aspartate (NAA), choline (Cho) and creatine (Cr) can be regarded as a surrogate marker of the functional deficit zone. NAA – a mitochondrial neuronal compound – is generally considered as a marker of neuronal density and viability. Cho which is bound to cell membranes, myelin and complex brain lipids indicates membrane damage and gliosis. Cr, finally, is used as an internal reference for other metabolites, because it is a relative stable compound and a marker for cell density of glial and neuronal cells.82 In epilepsy, abnormalities of proton spectroscopy typically consist of (1) a reduced NAA/Cr or NAA/(Cho+Cr) ratio or (2) a reduced NAA signal without significant changes in Cho and Cr signals.82, 83 These MRS abnormalities reflect neuronal and glial dysfunction rather than neuronal cell loss as has been shown in a study comparing metabolic dysfunction measured by MRS and hippocampal volume loss detected by MR volumetry.84 This concept is further supported by a recovery of the NAA signal remote from the epileptogenic zone after successful epilepsy surgery.85–88 Proton spectroscopy correctly lateralized the epileptogenic zone in 86% of patients with various forms of temporal lobe epilepsy89, in 61% of patients with nonlesional temporal lobe epilepsy90 and in 97% of patients with mesial temporal lobe epilepsy.91 Proton spectroscopy can be used to differentiate patients with temporal and extratemporal epilepsies92 as well as patients with mesial and neocortical temporal lobe epilepsy93 although these discriminations were less accurate than lateralization. In neocortical epilepsy, multislice MRS imaging in combination with tissue segmentation correctly localized the epileptogenic zone in 70% of patients with an MRI-visible malformation and in 60% of patients with normal MRI.94 Proton spectroscopy is extremely sensitive for the detection of metabolic dysfunction. In one study on 100 patients with temporal lobe epilepsy, MRS was abnormal in 99 of 100 patients, while volumetric amygdala-hippocampal measurements were abnormal in only 86 of 98 patients.89 These results were essentially confirmed in a subsequent study were no correlation was found between the degree of hippocampal volume loss and the NAA/Cr ratio indicating that the two techniques examine distinct pathophysiologic processes.91

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Moreover, metabolic dysfunctions are usually found in widespread regions extending beyond the epileptogenic zone. In one study, 38% of patients with temporal lobe epilepsy and 50% of patients with extratemporal lobe epilepsy had NAA/Cr reductions outside the clinical and EEG-defined epileptogenic area.95 In mesial temporal lobe epilepsy, comparisons between individual brain regions revealed trends toward lower NAA/(Cr + Cho) ratios in many areas of the ipsilateral and, to a lesser extent, the contralateral hemisphere outside the hippocampus and the temporal lobe, suggesting a diffuse impairment.96 In patients with mesial and nonlesional temporal lobe epilepsy, reduced NAA/(Cr + Cho) ratios were found in the ipsilateral temporal and parietal lobes and bilaterally in the insula and the frontal lobes consistent with those brain areas involved in seizure spread.97,98 Metabolic abnormalities of the contralateral temporal lobe were observed in 33% of patients with nonlesional temporal lobe epilepsy90 and in 54% of patients with various forms of temporal lobe epilepsy.89 MRS was more sensitive for the detection of bilateral involvement than MR volumetry in both studies.89,90 Nevertheless, the reduction of the NAA ratios seems to be greater in the epileptogenic region as compared with nonepileptogenic regions.99 The MRS defined functional deficit zone was correlated with the irritative and the seizure-onset zone in several studies. One study found a moderate level of concordance between the distribution of proton spectroscopy and interictal EEG abnormalities, while proton spectroscopy identified abnormalities contralateral to the predominant seizure focus more often than EEG.100 In nonlesional temporal lobe epilepsy, NAA/Cho was significantly decreased in the MEG spike zone indicating that functional abnormalities can be detected in vivo in radiographically normal-appearing cortex exhibiting abnormal excitability.101 In patients with mesial temporal lobe epilepsy, there was a significant correlation between the asymmetry indexes of interictal epileptiform discharges recorded on foramen ovale electrodes with the asymmetry index of NAA/Cr ratios within medial temporal structures.102 Finally, regional metabolic alterations on proton spectroscopy were correlated with electrophysiological abnormalities recorded by depth electrodes and with structural lesions in patients with temporal lobe epilepsy103 and frontal lobe epilepsy.104 NAA/(cho+cr) ratios were significantly lower in regions involved in SEEG electrophysiological epileptic abnormalities, while regions without electrophysiological abnormalities showed normal ratios. No differences between the metabolic profiles of the irritative and the seizure-onset zone were found. The metabolic alterations included, but also extended beyond, the structural lesions indicating that metabolic abnormalities are linked to interictal and ictal epileptiform activities rather than to structural alterations.103,104 Proton spectroscopy was useful to predict seizure control after epilepsy surgery in temporal lobe epilepsy,105 mesial temporal lobe epilepsy106–108 and MRI-negative temporal lobe epilepsy.109 Furthermore, proton spectroscopy may provide information on the individual best type of surgery.108 The relationship between metabolic dysfunction on proton spectroscopy and other methods assessing the functional deficit zone was addressed in several studies. There was no correlation between interictal background delta activity as assessed by quantitative EEG and abnormalities

seen on proton spectroscopy.110 Controversial results were found for the comparison of proton spectroscopy with [18F]FDG-PET. While in one study [18F]FDG-PET was more sensitive than proton spectroscopy for the lateralization of the seizure-onset zone in temporal lobe epilepsy ([18F]FDGPET: 87% vs. proton spectroscopy: 61%),90 in two other studies [18F]FDG-PET and proton spectroscopy showed an identical lateralization accuracy of 76%111 resp. 85%,112 although in general proton spectroscopy was more sensitive than [18F]FDG-PET in depicting metabolic abnormalities.111 In a recent study on patients with mesial temporal lobe epilepsy, hippocampal metabolic disturbances as measured by [18F]FDG-PET and by proton spectroscopy did not correlate which was explained by differential effects of disturbed cellular energy metabolism on mechanisms of glucose use and biosynthesis of NAA.113 Several studies related proton spectroscopy to neuropsychological testing. In mesial temporal lobe epilepsy, materialspecific memory deficits and memory performance during the WADA test were correlated significantly with hippocampal metabolic dysfunction, visual confrontation naming was selectively associated with left hippocampal metabolic function, whereas performance on a facial recognition task was correlated with right hippocampal metabolic function.114–117 In patients with unilateral mesial temporal lobe epilepsy, reduced left hippocampal NAA/Cr ratios were more sensitive to predict verbal memory impairments than hippocampal volumetric measurements.118 Furthermore, some studies indicate that pre-operative MRS findings may be useful to predict memory decline after epilepsy surgery.115, 117, 119

Functional magnetic resonance imaging (fMRI) fMRI offers a unique technique for the assessment of the functional deficit zone because it not only allows to visualize areas of functional deficits, but also provides information where in the brain the remaining functions are actually represented. Thus, fMRI gives insights in mechanisms of compensation, shift and plasticity. The primary contrast mechanisms used for fMRI are blood oxygenation level-dependent (BOLD) contrast and perfusion contrast obtained by using aterial spin labeling (ASL) which uses magnetically labelled arterial blood flow water as a flow tracer. Because BOLD contrast is easier to obtain and generally provides a higher signal-to-noise ratio for task-specific activation, it has been widely adopted as the method of choice for imaging regional brain activation.120 BOLD contrast is based on the fact that brain areas actively engaged during functional activation experience a local increase in cerebral blood flow. The amount of blood flow increase exceeds the associated increase in local cerebral oxygen consumption resulting in a localized increase in the ratio of oxyhemoglobin (which is diamagnetic, i.e. its effect on T2-relaxation is negligible) to deoxyhemogelobin (which is paramagnetic, i.e., it accelerates the rate of T2-relaxation) which can be visualized using a variety of pulse sequences, including routine gradient-echo sequences and gradient-echo echoplanar sequences, which particularly emphasize T2*-effects.120, 121 For the assessment of

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The functional deficit zone: general principles the functional deficit zone, fMRI language and memory lateralization and localization can be used. Focal epilepsy can be associated with a disruption in normal language organization resulting in a high incidence of atypical language dominance (bilateral or right hemisphere) in epilepsy patients as compared to normal controls (epilepsy group: 78% left hemisphere dominance, 16% bilateral symmetric language representation, 6% right hemisphere dominance; normal subjects: 94% left hemisphere dominance, 6% bilateral symmetric language representation, none right hemisphere dominance) which was especially evident with early brain insults and weak right hand dominance.24 In another study, 33% of patients with left-sided temporal lobe epilepsy showed bilateral or right hemispheric language lateralization which was significantly higher as compared to patients with right-sided temporal lobe epilepsy suggesting considerable plasticity of language representation in the brains of patients with intractable epilepsy.122 However, it is difficult to infer intra- versus inter-hemispheric language reorganization on the basis of the vicinity of early pathology to classical language areas, because in a recent study lesions in or near Broca’s area were not associated with inter-hemispheric language reorganization in four out of five cases, but with perilesional activation within the damaged left hemisphere. Paradoxically, lesions remote from the classical language areas were associated with nonleft language lateralization in four out of five cases.123 fMRI showed excellent agreement with the Wada test for language lateralization in several studies.122,124–128 Concordance was usually best in left hemisphere dominant patients ranging from 91 to 100%, lower in patients with right hemisphere dominance (range: 67–100%) and worst in patients with bilateral hemisphere dominance ranging from 50 to 75% although the numbers in these latter groups were small.122,125,126 Furthermore, agreement was better in left-sided temporal with 97% than in left-sided extratemporal epilepsy with only 75%.127 fMRI was predictive for post-operative confrontation naming deficits after left anterior lobectomy showing 100% sensitivity and 73% specificity.129 fMRI also has been evaluated as an alternative to intraoperative cortical stimulation mapping for the localization of critical language areas in the temporoparietal region.130 Correspondence between functional magnetic resonance imaging and intraoperative cortical stimulation mapping depended heavily on statistical threshold and varied between patients and tasks (i.e., verb generation, picture naming, verbal fluency, and sentence comprehension). Whereas fMRI correctly detected all critical language areas with high spatial accuracy (sensitivity of 100%), fMRI activity was found also at noncritical language sites with an overall specificity was 61%. Although fMRI cannot replace intraoperative cortical stimulation mapping at the present time, it can be used to optimally plan this procedure and increase its safety. fMRI can be used to visualize asymmetries in the lateralization of memory activation in patients with temporal lobe epilepsy and therefore can serve as a marker of the functional deficit zone. While mesial temporal lobe structures are activated symmetrically in normal controls during various memory encoding tasks, a decreased activation was seen ipsilateral to the seizure focus in patients with unilateral temporal lobe epilepsy.131–134 Verbal encoding engaged the right mesial

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temporal lobe in left mesial temporal lobe epilepsy, whereas nonverbal encoding engaged the left mesial temporal lobe in right mesial temporal lobe epilepsy.134 In patients with left mesial temporal lobe epilepsy, an extensive left prefrontal activation was seen during memory encoding and retrieval which was not evident in normal controls.135 In nonamnesic patients with left hippocampal sclerosis, verbal memory encoding was associated with reorganisation to the right hippocampus and parahippocampal gyrus, while it involved activation of the left hippocampus in normals. The additional presence of left amygdala sclerosis resulted in reorganisation for encoding of emotional verbal material to the right amygdala.136 These findings indicate both a functional deficit of the diseased temporal lobe and a functional shift to the nonaffected temporal lobe or to extratemporal structures indicating a high degree of plasticity of medial temporal lobe functions. fMRI memory lateralization concurred with the results of neuropsychological testing133 and of intracarotid amobarbital testing.132,134,137 The degree of verbal memory encoding activity in the left mesial temporal lobe was inversely related to the extent of verbal memory loss after left anterior temporal lobectomy and provided the strongest independent predictor of memory outcome after surgery in a multiple regression analysis.138 In right mesial temporal lobe epilepsy, the pre-operative asymmetry index of memory-fMRI, consisting of retrieval from long-term memory induced by self-paced performance of an imaginative walk, significantly correlated with post-operative changes in memory retention: Reduced activation of the mesiotemporal region ipsilateral to the epileptogenic region correlated with a favorable memory outcome after right-sided anterior temporal lobectomy.139 Finally, in patients with both left and right temporal lobe epilepsy, a greater post-operative memory decline was observed with increased pre-operative activation ipsilateral to the seizure focus using a complex visual scene-encoding task.137

MEG language lateralization and localization MEG language lateralization obtained by various language paradigms including a word recognition task,140 a silent reading task141 as well as a verb generation and picture naming task142 showed a high degree of concordance with the Wadatest ranging between 89 and 95%. MEG may also be used for intrahemispheric language localization where excellent agreement with direct cortical stimulations could be achieved in selected cases.143,144 Finally, MEG was useful to study interand intrahemispheric language reorganization in patients with temporal lobe epilepsy.145–147

Conclusions The functional deficit zone provides information on the functional deficits associated with focal epilepsies. These functional deficits manifest themselves as neurological and neuropsychological abnormalities. Surrogate markers of the functional deficit zone include interictal EEG and MEG as well as functional neuroimaging tools like SPECT, PET, MRS and

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fMRI. When assessing the functional deficit zone mechanisms of neuronal compensation, shift and plasticity have to be taken into account, which in turn are influenced by epilepsy variables including age at insult and epilepsy onset, as well as duration, activity and severity of disease. Fixed and reversible functional deficits can be distinguished. The former are caused by structural lesions, most often the epileptogenic lesion; the latter represent consequences of the epileptogenic process per se, vary according to epileptic activity and can be reverted by successful surgical treatment. Thus, the functional deficit zone has to be considered as a dynamic concept. The various surrogate markers of the functional deficit zone measure different parameters of functional deficit and differ concerning their sensitivity. Therefore, the extension of the functional deficit zone varies according to the investigational

technique applied. The functional deficit zone usually is spatially more extended than the epileptogenic zone. With the currently available techniques there is only a poor correlation between the local degree of functional abnormality and of epileptogenicity. Therefore, the functional deficit zone can only lateralize and localize the epileptogenic zone on a lobar, but not on a sublobar level. This could be improved by measuring dysfunctions more closely related to epileptogenicity. Nevertheless, the functional deficit zone provides important information during pre-surgical evaluation complementary to the five other zones (irritative zone, seizure-onset zone, ictal symptomatogenic zone, epileptogenic lesion, epileptogenic zone), can be used to derive prognostic information on postoperative seizure control and most importantly is critical to predict the post-operative functional status.

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Textbook of epilepsy surgery Hugg JW, Kuzniecky RI, Gilliam FG et al. Normalization of contralateral metabolic function following temporal lobectomy demonstrated by 1H magnetic resonance spectroscopic imaging. Ann Neurol 1996;40:236–9. Cendes F, Andermann F, Dubeau F, Matthews PM, Arnold DL. Normalization of neuronal metabolic dysfunction after surgery for temporal lobe epilepsy. Evidence from proton MR spectroscopic imaging. Neurology 1997;49:1525–33. Serles W, Li LM, Antel SB et al. Time course of postoperative recovery of N-acetyl-aspartate in temporal lobe epilepsy. Epilepsia 2001;42:190–7. Vermathen P, Ende G, Laxer KD et al. Temporal lobectomy for epilepsy: recovery of the contralateral hippocampus measured by (1)H MRS. Neurology 2002;59:633–6. Cendes F, Caramanos Z, Andermann F, Dubeau F, Arnold DL. Proton magnetic resonance spectroscopic imaging and magnetic resonance imaging volumetry in the lateralization of temporal lobe epilepsy: a series of 100 patients. Ann Neurol 1997;42:737–46. Knowlton RC, Laxer KD, Ende G et al. Presurgical multimodality neuroimaging in electroencephalographic lateralized temporal lobe epilepsy. Ann Neurol 1997;42:829–37. Kuzniecky R, Hugg JW, Hetherington H et al. Relative utility of 1H spectroscopic imaging and hippocampal volumetry in the lateralization of mesial temporal lobe epilepsy. Neurology 1998;51:66–71. Li LM, Caramanos Z, Cendes F et al. Lateralization of temporal lobe epilepsy (TLE) and discrimination of TLE from extra-TLE using pattern analysis of magnetic resonance spectroscopic and volumetric data. Epilepsia 2000;41:832–42. Vermathen P, Ende G, Laxer KD et al. Hippocampal N-acetylaspartate in neocortical epilepsy and mesial temporal lobe epilepsy. Ann Neurol 1997;42:194–9. Mueller SG, K DL, Barakos JA et al. Identification of the epileptogenic lobe in neocortical epilepsy with proton MR spectroscopic imaging. Epilepsia 2004;45:1580–9. Li LM, Cendes F, Andermann F, Dubeau F, Arnold DL. Spatial extent of neuronal metabolic dysfunction measured by proton MR spectroscopic imaging in patients with localization-related epilepsy. Epilepsia 2000;41:666–74. Vermathen P, Laxer KD, Schuff N, Matson GB, Weiner MW. Evidence of neuronal injury outside the medial temporal lobe in temporal lobe epilepsy: N-acetylaspartate concentration reductions detected with multisection proton MR spectroscopic imaging – initial experience. Radiology 2003;226:195–202. Mueller SG, Suhy J, Laxer KD et al. Reduced extrahippocampal NAA in mesial temporal lobe epilepsy. Epilepsia 2002;43:1210–6. Mueller SG, Laxer KD, Cashdollar N et al. Identification of abnormal neuronal metabolism outside the seizure focus in temporal lobe epilepsy. Epilepsia 2004;45:355–66. Stanley JA, Cendes F, Dubeau F, Andermann F, Arnold DL. Proton magnetic resonance spectroscopic imaging in patients with extratemporal epilepsy. Epilepsia 1998;39:267–73. Maton B, Gilliam F, Sawrie S et al. Correlation of scalp EEG and 1H-MRS metabolic abnormalities in temporal lobe epilepsy. Epilepsia 2001;42:417–22. Shih JJ, Weisend MP, Lewine J et al. Areas of interictal spiking are associated with metabolic dysfunction in MRI-negative temporal lobe epilepsy. Epilepsia 2004;45:223–9. Park SA, Kim GS, Lee SK et al. Interictal epileptiform discharges relate to 1H-MRS-detected metabolic abnormalities in mesial temporal lobe epilepsy. Epilepsia 2002;43:1385–9. Guye M, Le Fur Y, Confort-Gouny S et al. Metabolic and electrophysiological alterations in subtypes of temporal lobe epilepsy: a combined proton magnetic resonance spectroscopic imaging and depth electrodes study. Epilepsia 2002;43:1197–209. Guye M, Ranjeva JP, Le Fur Y et al. 1H-MRS imaging in intractable frontal lobe epilepsies characterized by depth electrode recording. Neuroimage 2005;26:1174–83. Eberhardt KE, Stefan H, Buchfelder M et al. The significance of bilateral CSI changes for the postoperative outcome in temporal lobe epilepsy. J Comput Assist Tomogr 2000;24:919–26. Kuzniecky R, Hugg J, Hetherington H et al. Predictive value of 1H MRSI for outcome in temporal lobectomy. Neurology 1999;53:694–8. Li LM, Cendes F, Antel SB et al. Prognostic value of proton magnetic resonance spectroscopic imaging for surgical outcome in patients with intractable temporal lobe epilepsy and bilateral hippocampal atrophy. Ann Neurol 2000;47:195–200. Spencer DC, Szumowski J, Kraemer DF et al. Temporal lobe magnetic resonance spectroscopic imaging following selective

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amygdalohippocampectomy for treatment-resistant epilepsy. Acta Neurol Scand 2005;112:6–12. Suhy J, Laxer KD, Capizzano AA et al. 1H MRSI predicts surgical outcome in MRI-negative temporal lobe epilepsy. Neurology 2002;58:821–3. Bernasconi A, Cendes F, Lee J, Reutens DC, Gotman J. EEG background delta activity in temporal lobe epilepsy: correlation with volumetric and spectroscopic imaging. Epilepsia 1999;40:1580–6. Achten E, Santens P, Boon P et al. Single-voxel proton MR spectroscopy and positron emission tomography for lateralization of refractory temporal lobe epilepsy. AJNR Am J Neuroradiol 1998;19:1–8. Park SW, Chang KH, Kim HD et al. Lateralizing ability of singlevoxel proton mr spectroscopy in hippocampal sclerosis: comparison with mr imaging and positron emission tomography. AJNR Am J Neuroradiol 2001;22:625–31. Knowlton RC, Abou-Khalil B, Sawrie SM et al. In vivo hippocampal metabolic dysfunction in human temporal lobe epilepsy. Arch Neurol 2002;59:1882–6. Martin RC, Sawrie S, Hugg J et al. Cognitive correlates of 1H MRSI-detected hippocampal abnormalities in temporal lobe epilepsy. Neurology 1999;53:2052–8. Pauli E, Eberhardt KW, Schafer I et al. Chemical shift imaging spectroscopy and memory function in temporal lobe epilepsy. Epilepsia 2000;41:282–9. Kikuchi S, Kubota F, Hattori S, Oya N, Mikuni M. A study of the relationship between metabolism using 1H-MRS and function using several neuropsychological tests in temporal lobe epilepsy. Seizure 2001;10:188–93. Hanoglu L, Ozkara C, Keskinkilic C et al. Correlation between 1H MRS and memory before and after surgery in mesial temporal lobe epilepsy with hippocampal sclerosis. Epilepsia 2004;45:632–40. Sawrie SM, Martin RC, Knowlton R et al. Relationships among hippocampal volumetry, proton magnetic resonance spectroscopy, and verbal memory in temporal lobe epilepsy. Epilepsia 2001;42:1403–7. Incisa della Rocchetta A, Gadian DG, Connelly A et al. Verbal memory impairment after right temporal lobe surgery: role of contralateral damage as revealed by 1H magnetic resonance spectroscopy and T2 relaxometry. Neurology 1995;45:797–802. Detre JA. fMRI: applications in epilepsy. Epilepsia 2004;45 Suppl 4:26–31. Binder JR, Achten E, Constable RT et al. Functional MRI in epilepsy. Epilepsia 2002;43(Suppl 1):51–63. Adcock JE, Wise RG, Oxbury JM, Oxbury SM, Matthews PM. Quantitative fMRI assessment of the differences in lateralization of language-related brain activation in patients with temporal lobe epilepsy. Neuroimage 2003;18:423–38. Liegeois F, Connelly A, Cross JH et al. Language reorganization in children with early-onset lesions of the left hemisphere: an fMRI study. Brain 2004;127:1229–36. Binder JR, Swanson SJ, Hammeke TA et al. Determination of language dominance using functional MRI: a comparison with the Wada test. Neurology 1996;46:978–84. Gaillard WD, Balsamo L, Xu B et al. Language dominance in partial epilepsy patients identified with an fMRI reading task. Neurology 2002;59:256–65. Rutten GJ, Ramsey NF, van Rijen PC, Alpherts WC, van Veelen CW. FMRI-determined language lateralization in patients with unilateral or mixed language dominance according to the Wada test. Neuroimage 2002;17:447–60. Woermann FG, Jokeit H, Luerding R et al. Language lateralization by Wada test and fMRI in 100 patients with epilepsy. Neurology 2003;61:699–701. Powell HW, Duncan JS. Functional magnetic resonance imaging for assessment of language and memory in clinical practice. Curr Opin Neurol 2005;18:161–6. Sabsevitz DS, Swanson SJ, Hammeke TA et al. Use of preoperative functional neuroimaging to predict language deficits from epilepsy surgery. Neurology 2003;60:1788–92. Rutten GJ, Ramsey NF, van Rijen PC, Noordmans HJ, van Veelen CW. Development of a functional magnetic resonance imaging protocol for intraoperative localization of critical temporoparietal language areas. Ann Neurol 2002;51:350–60. Bellgowan PS, Binder JR, Swanson SJ et al. Side of seizure focus predicts left medial temporal lobe activation during verbal encoding. Neurology 1998;51:479–84. Detre JA, Maccotta L, King D et al. Functional MRI lateralization of memory in temporal lobe epilepsy. Neurology 1998;50:926–32.

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Jokeit H, Okujava M, Woermann FG. Memory fMRI lateralizes temporal lobe epilepsy. Neurology 2001;57:1786–93. Golby AJ, Poldrack RA, Illes J et al. Memory lateralization in medial temporal lobe epilepsy assessed by functional MRI. Epilepsia 2002;43:855–63. Dupont S, Van de Moortele PF, Samson S et al. Episodic memory in left temporal lobe epilepsy: a functional MRI study. Brain 2000;123(Pt 8):1722–32. Richardson MP, Strange BA, Duncan JS, Dolan RJ. Preserved verbal memory function in left medial temporal pathology involves reorganisation of function to right medial temporal lobe. Neuroimage 2003;20 Suppl 1:S112–9. Rabin ML, Narayan VM, Kimberg DY et al. Functional MRI predicts post-surgical memory following temporal lobectomy. Brain 2004;127:2286–98. Richardson MP, Strange BA, Thompson PJ et al. Preoperative verbal memory fMRI predicts post-operative memory decline after left temporal lobe resection. Brain 2004;127:2419–26. Janszky J, Jokeit H, Kontopoulou K et al. Functional MRI predicts memory performance after right mesiotemporal epilepsy surgery. Epilepsia 2005;46:244–50.

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Hirata M, Kato A, Taniguchi M et al. Determination of language dominance with synthetic aperture magnetometry: comparison with the Wada test. Neuroimage 2004;23:46–53. Bowyer SM, Moran JE, Weiland BJ et al. Language laterality determined by MEG mapping with MR-FOCUSS. Epilepsy Behav 2005;6:235–41. Simos PG, Papanicolaou AC, Breier JI et al. Localization of language-specific cortex by using magnetic source imaging and electrical stimulation mapping. J Neurosurg 1999;91:787–96. Kober H, Moller M, Nimsky C et al. New approach to localize speech relevant brain areas and hemispheric dominance using spatially filtered magnetoencephalography. Hum Brain Mapp 2001;14:236–50. Breier JI, Castillo EM, Simos PG et al. Atypical language representation in patients with chronic seizure disorder and achievement deficits with magnetoencephalography. Epilepsia 2005;46:540–8. Pataraia E, Billingsley-Marshall RL, Castillo EM et al. Organization of receptive language-specific cortex before and after left temporal lobectomy. Neurology 2005;64:481–7. Pataraia E, Simos PG, Castillo EM et al. Reorganization of language-specific cortex in patients with lesions or mesial temporal epilepsy. Neurology 2004;63:1825–32.

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Mesial temporal lobe epilepsy and positron emission tomography A Mohamed and MJ Fulham

Introduction Positron emission Positron emission tomography (PET) is a molecular imaging technique that uses radiolabeled compounds to image molecular interactions in vivo. PET relies on the nature of positron decay. The positron was first conceived by Dirac in the late 1920s and discovered experimentally in 1932. The positron is the antimatter counterpart to the electron and has the same mass as an electron but a positive charge. PET scanners detect photons, which are released when a positron emitting radionuclide, such as fluorine-18, carbon-11, and oxygen-15 emit positrons, which then undergo annihilation after a collision with electrons. The commonly used positron emitting isotopes and their half-lives are shown in Table 88.1. A key benefit of PET is the ability to quantify molecular events in vivo. This depends in part on the ability of PET to measure the tracer concentration in the region of interest, to account for photon attenuation by the body and to apply a mathematical model, which describes the kinetic behavior of the process of interest. PET instrumentation Positron annihilation is a unique form of radioactive decay where two photons (gamma rays with an energy of 511 keV) are emitted at 180 degrees to one another. Scintillation crystals (or detectors) detect these gamma rays and they are regarded as true events when they are detected simultaneously or ‘coincidentally’. These detectors produce light output, which is detected and magnified by photomultiplier tubes. Logic circuits localize precisely where the annihilation event occurred. High-speed timing circuits provide temporal localization. This time window for coincidence detection is typically 6–12 nsec. Photons outside this time window are considered as single events and discarded by the coincidence circuit. Compared with most radioisotopes used in nuclear medicine, PET ligands emit photons with much higher energies. Hence, PET detectors require greater stopping power. The scintillation crystals may be made of sodium iodide (NaI), bismuth germinate (BGO) and more recently lutetium oxyorthosilicate (LSO) and gadolinium orthosilicate (GSO). The absorption efficiency of BGO is greater than LSO but the latter has five times more light output. Additionally, the decay time for LSO compared with BGO is lower at 40 nsec as opposed to 300 nsec. Consequently, it takes less a 792

shorter period of time to obtain the necessary scintillation events (counts) for image generation with LSO. The first human PET study was carried out in 1977 using 18-F-fluorodeoxyglucose (FDG) and was ‘primitive’ by today’s standards.1 These tomographs were generally restricted to large universities and devoted mainly to neuroscience research. They were slow and had poor spatial resolution but nevertheless they were regarded as a great advance because for the first time ‘function’ rather than just anatomy of the brain could be depicted. Instrumentation advances coupled with faster techniques to acquire data, corrected for attenuation and reconstructed the massive amounts of data that came with the addition of more than one image plane. This allowed the introduction of this technology into clinical practice rather than just basic research. The next major advance and arguably the most important advance in medical imaging over the past decade, was the development of the PET/CT scanner. Townsend2 developed the combined PET/CT scanner in the late 1990s and the first commercial PET/CT devices were installed in 2001. The PET/CT combines a helical CT, which provides anatomical data and as well allows for correction of varying degrees of photon attenuation by different tissues. The PET device is attached to the ‘back end’ of the CT scanner. CT and PET studies are carried out sequentially and this allows for good registration between the anatomical (CT) and the functional (PET) data, such that the two images that are produced can be overlain to provide a ‘fused’ image (Figure 88.1). The introduction of the faster PET detectors (LSO, GSO) into these devices, volume acquisitions (3D) and CT attenuation has resulted in a dramatic shortening of scan time. At our institution prior to PET/CT a brain acquisition using FDG on a PET-only device took approximately 60 mins. The same study with our current PET/CT scanner (LSO Biograph Duo, Siemens, Hoffman Estates, IL, USA) takes only 10 minutes. FDG PET ligands are produced when ions are accelerated in a cyclotron to high speeds and directed to bombard a ‘target’. The ensuing nuclear reaction in the target produces the positron emitter, which can then incorporated into a specific compound. In the case of FDG, fluorine-18 is incorporated into an analogue of glucose, deoxyglucose that can describe glucose metabolism in the body in vivo. FDG is the most commonly used PET isotope in the assessment of refractory epilepsy. In the early years

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Mesial temporal lobe epilepsy and positron emission tomography Table 88.1 Radionuclide 11

Carbon Nitrogen 15 Oxygen 18 Fluorine 13

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Positron emitting isotopes Half life 20.3 minutes 9.97 minutes 124 seconds 110 minutes

of neuroscience research with PET, 15O was also used; this ligand when attached to water (15O-H2O) labels blood flow but the signal to noise ratio with this ligand is far inferior to FDG and it is not routinely used in PET centers. Patient preparation for FDG-PET Patients are asked to fast for approximately 6 hours prior to the scan. They are instructed to avoid caffeine and caloric beverages but may drink water in this period. A clinical history is obtained before the PET procedures commence. It is important to determine the seizure frequency, in particular, the timing and type of the last. This is because seizures can induce postictal glucose hypometabolism, which can persist for many hours after a seizure. This hypometabolism can be focal or generalized and present outside the epileptogenic zone. In addition, it is important to determine the patient’s medication history as sedatives, major tranquillisers and steroids can reduce cerebral glucose metabolism. Before injection of FDG, a blood sugar level is measured; a level of less than 150 mg/dL is desirable. An elevated BSL results in a technically poor PET scan because FDG uptake competes with glucose for the surface membrane protein (glucose transporter – [GLUT]), which facilitates glucose and deoxyglucose transport into cells.3 An intravenous cannula is placed, usually in an arm vein prior to isotope injection. Typically, 10 mCi of FDG is injected intravenously. Patients then rest quietly and remain awake during the ‘uptake period’ as FDG equilibrates in the brain. This ‘uptake period’ is typically 45 minutes. Activity and speech are limited during this time to minimize physiologic uptake into ‘active’ areas of the brain. FDG is safe and there are no known contraindications or side effects. Imaging is initiated approximately 40 minutes following isotope injection. EEG monitoring prior to and after isotope injection is recommended to detect seizures, which at times may confound the interpretation of the scan.

Interpretation of FDG-PET studies Interictal FDG-PET in mesial temporal sclerosis (mTLE) The overall aim of functional imaging in mTLE is to map the site of seizure generation – the so-called ‘epileptogenic zone’. FDG uptake in the brain represents synaptic activity 4 together with glutamate-mediated uptake of the ligand into astrocytes.5 The first FDG-PET studies in epilepsy were done in the early 1980s and the typical findings that were reported by the early investigators were extensive and marked glucose hypometabolism of the involved temporal lobe6–9 where severe mesial temporal sclerosis (MTS) was usually found (Figure 88.2). However, over the past decade the pattern of glucose hypometabolism in

Figure 88.1 FDG-PET/CT of patient LS, a 23-year-old female with MTS. Top image, FDG-PET, middle image, co-registered CT, bottom image, PET/CT-fused images. Images show reduced glucose metabolism in the right anteromesial temporal structures including the amygdala, hippocampus and temporal pole (arrows).

MTS appears to have changed.10 The extensive glucose hypometabolism of the entire temporal lobe is now more commonly replaced by a more restricted region of glocose hypometabolism in to the anteromesial temporal structures, including the hippocampus, amygdala, temporal pole, entorhinal and anterior fusiform cortices (Figure 88.1).

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Textbook of epilepsy surgery partial seizures. Such head motion has its own problems for image interpretation but generally complex partial seizures (CPS) and generalized motor seizures will mean that the scan has to be aborted. Nevertheless, if the ictal event can be captured with imaging, the PET findings can be extremely valuable in seizure localization. The typical findings are focal, markedly increased glucose metabolism at the site of seizure onset 19,20 (Figure 88.3) and there may be ipsilateral increased metabolism in the basal ganglia and crossed cerebellar hypermetabolism due to increased efferent input to the contralateral cerebellar hemispheres via the cortico-ponto-cerebellar (CPC) pathway. The more problematic issue is when the patient has a seizure in the uptake period whilst awaiting the scan. If EEG monitoring is done prior to the scan acquisition it may provide valuable localising data but the practical issue is to whether to continue with the scan acquisition. Given that the static FDG-PET scan represents glucose metabolism over the entire uptake period and the study acquisition, a seizure produces a mixed interictal-ictal-post ictal scan where there may be regions of increased and decreased metabolism. However, the patient has already been injected with isotope and so our practice is to continue with the scan. If the scan results are problematic then we suggest that the study is repeated at a later date.

Figure 88.2 FDG-PET in a 35-year-old man with severe hipppocampal atrophy on MR and left temporal lobe seizures showing severe glucose hypometabolism in the entire left temporal lobe.

Subtle or marked glucose hypometabolism can also be seen in ipsilateral extra temporal structures including the thalamus, basal ganglia, frontal, parietal and occipital cortices and sometimes the contralateral cerebellar hemisphere.11,12 These patterns of associated hypometabolism reflect the extra temporal connections of the seizure focus involved in the epileptogenic circuit. In the temporal lobe, the hypometabolic region involves the grey matter, which is involved in the initial ictal electrophysiologic discharges seen with intracranial monitoring.13,16 Occasionally, glucose metabolism may be normal in the involved temporal lobe.10 The reason for this is unclear but it may relate to differences in instrumentation and periscan ictal events that can increase glucose metabolism. In addition, the mesial temporal structures can be hypometabolic secondary to extra temporal neocortical epilepsy, in particular, due to seizure spread from the ipsilateral occipital lobe.17,18 This change in pattern of involvement may reflect the earlier identification of patients with mTLE through the more widespread availability of surgical epilepsy programs and the advances in MR imaging. Ictal FDG-PET Ictal FDG-PET scans are difficult to obtain, in part, because of the half-life of FDG and the difficulty in predicting a seizure. Furthermore, they are problematic as there is always some degree of movement associated with all but simple

Visual versus quantitative analysis Experience plays a large part in interpretation of PET scans and an extensive review of normal subjects is necessary to appreciate normal variation prior to the attempted interpretation of clinical cases. Co-registration programs that relate structural information to PET images allow a more precise anatomical localization of the lesion but this problem has been partially addressed with PET-CT. The limitations of qualitative visual analysis of PET images also apply to its quantitative analysis. With these limitations in mind, a few studies suggest that quantification enhances the clinical utility of FDG-PET21,22 and may prevent misinterpretation of normal right and left variation.23 However, in our experience quantification of studies, although a useful research tool, adds little to the clinical interpretation of PET studies. The routine quantification of clinical PET studies in every case of epilepsy is also tedious and is not practical in most centers. Effect of blood glucose and anticonvulsants on FDG-PET Endogenous molecules that compete with the ligand in the biological process can increase noise or reduce ligand tissue uptake. High blood glucose levels interfere with FDG uptake and lead to studies with poor signal-to-noise ratio. Antiepileptic medications produce a global reduction in cerebral metabolism in particular the deep nuclei and cerebellum24–27 but this is not as marked as major tranquilisers and corticosteroids.28 Chronically administered barbiturates, phenytoin, carbamazepine and valproate have all been shown to globally reduce absolute values of cerebral glucose metabolism but not to alter interregional ratios of metabolism.29,30 Valproic acid reduces glucose metabolism by up to 10% and cerebral blood flow by up to 15%. The degree of glucose hypometabolism is not related to the serum valproate level and is similar to that of carbamazepine (10%) and phenytoin (11.5%). The reductions in cerebral glucose metabolism

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seizures in small cerebral volumes or deep structures may not be detected with surface EEG.35

Figure 88.3 Ictal FDG-PET in a patient with right mesial temporal epilepsy who had a prolonged seizure in the uptake period showing markedly increased glucose hypometabolism in the right hippocampus (arrows).

is more pronounced with barbiturates (27%), diazepam (20%) or the combination of valproate and carbamazepine.26,27,31,32 Artifacts Common artefacts that the reader should be familiar with may arise from partial volume effects, incorrect attenuationcorrection, motion and seizures in the periscan period. Partial volume is an artefact common to all tomographic imaging. If a structure is smaller than the detection threshold permitted by a scanner’s spatial and contrast resolution, its functional activity will be averaged together with that of the activities of adjacent structures. Small structures may lose border detail if their contours are complex. Computer simulations show partial volume errors can cause up to a 15% change in the apparent size of an object in the PET image.33 Incorrect attenuation correction can lead to false increases or decreases in the perceived tracer uptake. The most common mechanism for this in current PET-CT devices is head movement. The relationship of the scan to seizure activity is extremely important as discussed previously. Continuous EEG monitoring should be performed prior to the scan, during the uptake phase and when practical during scan acquisition to exclude unintentional ictal scanning which could lead to misinterpretation of FDG images.34 However, it is important to note that surface EEG monitoring does not provide a complete solution to this problem, as subclinical electrographic

Current role of FDG-PET in assessment of mTLE Interpretation of the literature on the role of FDG-PET in mTLE presents a formidable challenge to even experienced users of functional imaging. This in part relates to the different hardware/software methodologies, interpretation skills and variable emphasis on different investigation algorithms in the various centers. Further, local expertise across all facets (EEG, MR imaging, PET, SPECT) is usually not readily available in all centers. Although the studies in mTLE, which have compared FDG-PET to other imaging modalities, were done using older generation scanners, a number of reports have identified that interictal FDG-PET is more sensitive than volumetric MR imaging in identifying the temporal lobe of seizure origin.36,37 FDG-PET also provides valuable information in patients with nonlocalizing surface ictal EEG, which can then reduce the need for intracranial EEG studies.23 However, FDG-PET does not provide additional information when hippocampal atrophy is present on MR imaging.38 The concordance between MR and FDG-PET is also associated with a better post-surgical seizure outcome.39 However, false lateralization on FDG-PET, confirmed by depth EEG, can occur in a small percentage of patients.6,22,40,41 Ictal HMPAO SPECT and interictal PET are probably equivalent for the lateralization of mTLE, although ictal SPECT generally requires hospital admission, cessation of medications and is more labor intensive and expensive when compared to an outpatient procedure.42,43 In the comparison of FDG-PET to proton MR spectroscopy (MRS) there is little difference in lateralizing seizure onset according to the available data, although falsely lateralization is more common with MRS (6 vs. 3%) and expertise in MRS is restricted to only a few centers.44,45 Della Badia et al. has suggested that the combination of sleep EEG and MR imaging may be more cost-effective as outpatient screening tools.46 It is our experience that the widespread availability of MR imaging at 1.5 T has meant that the need for routine FDG-PET scanning in mTLE has diminished. FDG-PET is now more directed to cases where there are discordant data and in this situation FDG-PET may be lateralizing and in this setting patients have a good post-surgical outcome.47,48 FDG-PET may also be used to prognosticate on postoperative memory deficits (see below). Pathophysiology of glucose hypometabolism with FDG-PET Although it is over 25 years since the first interictal FDG-PET studies were done in the study of epilepsy the pathophysiology of the glucose hypometabolism in mTLE remains unknown. Various mechanisms have been suggested including neuronal loss, diaschisis, postictal depression and other epilepsy-related phenomena. There is no correlation between cortical metabolism on preoperative FDG-PET and neuronal density of resected hippocampi in mTLE.49 There is also a lack of correlation between hippocampal volume loss and the degree of temporal glucose hypometabolism.50 Diaschisis was described by Von Monakow over a century ago to explain a disconnection between functionally related parts of the nervous system.51 In the 1980s the most common example of this was the reduction in blood flow and

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metabolism in the contralateral cerebellar hemisphere (‘crossed cerebellar diaschisis’ – CCD), which was noted in patients with hemispheric or deep white matter strokes due to interruption of the cortico-ponto-cerebellar (CPC) pathway when PET scanning was used as a research tool.52 However, despite the reduced metabolism and blood flow in the contralateral cerebellar hemisphere there were no obvious associated neurological signs. The most common example of CCD today is that seen with FDG-PET scans done in patients with brain tumors. Whilst this effect may in part explain the remote hypometabolism in extra temporal sites where there are known connections from the mesial temporal structures, it cannot be the sole mechanism and there is difficulty with this mechanism in explaining the marked neocortical temporal hypometabolism that is sometimes seen. Dlugos et al. reported a correlation between hilar cell densities and the degree of glucose hypometabolism in the deep nuclei, which suggests that there may be functional changes in neurons and their associated circuits in relation to seizure spread.53 Still other investigators have hypothesized that interictal spikes at sites inaccessible to surface EEG may explain the reduction regional glucose metabolism54 and this is partly supported by depth EEG recordings.55 These remote sites of regional glucose hypometabolism return towards normal after successful surgery for MTS.56 But rather than an effect of diaschisis, Bartenstein et al. linked these findings to downregulation of opiate receptors.57 The exact cause of glucose hypometabolism in mTLE remains unknown. The evidence so far suggests that it is due to a combination of factors and that neuronal loss does not adequately explain the reversible and functional changes seen with FDG-PET. Interictal FDG-PET in early temporal lobe disease Investigators have studied FDG-PET in early mTLE to understand the underlying cause for the glucose hypometabolism seen in focal epilepsy. There are conflicting data in the literature. There is evidence that temporal hypometabolism may already be present at the onset of mTLE. In a cross sectional study of pediatric patients with refractory mTLE, the incidence of FDG-PET hypometabolism was similar to that of the adult population.58 These findings would also be in agreement with studies in adult patients that have failed to detect an association between the lifetime frequency of seizures and the severity of temporal lobe glucose hypometabolism on PET59 or hippocampal atrophy on MR imaging.60 There have been examples of patients with severe temporal glucose hypometabolism where hippocampal volumetric measurements were normal.60 These data support the postulate that glucose hypometabolism represents the severity of the underlying epilepsy syndrome, rather than simply an effect of repeated seizures. Other authors have argued that the degree of glucose hypometabolism may worsen with continuing seizure activity.61 They cite prospective imaging studies62 and studies done in children with new onset temporal epilepsy.63 However, none of these studies have been longitudinal and the results may reflect a mixed cohort, some of whom may have a more benign epilepsy syndrome. The evidence with FDG-PET in early TLE parallels that of clinical experience. That is, the natural history of refractory mTLE is different from mTLE which is easily controlled by

anticonvulsants. It is not surprising that abnormal glucose metabolism may be present early in patients with refractory disease.

Clinical aspects of mTLE and FDG-PET FDG-PET and seizure semiology There is a weak association between seizure semiology and the pattern of interictal glucose hypometabolism. Early animal and clinical FDG-PET studies described temporal hypometabolism together with limbic auras, automatisms and posturing that are typical findings with mTLE.8,64,65 A quantitative study by Savic et al.18 confirmed that the topographical pattern of interictal glucose hypometabolism in mTLE was not only a reflection of regions involved in seizure generation but also included regions of the cerebrum involved in seizure expression. Limbic auras or staring spells without other motor manifestations were limited to the ictal onset zone. However, these authors found more widespread areas of glucose hypometabolism in patients with more complex motor behaviors during the seizure. Patients with motor automatisms, thrusting movements, head turning or swinging of the extremities had more widespread hypometabolism in the limbic structures, often involving the contralateral side. Posturing during the seizure was associated with hypometabolism in the dorsolateral frontal and/or motor cortex. In subjects with secondary generalized seizures there was cerebellar and parietal lobe hypometabolism in addition to the abnormalities described above. The pattern of glucose hypometabolism in the temporal lobe may be also used to distinguish patient with mTLE from patients with neocortical temporal lobe epilepsy. Ipsilateral insular and temporal neocortical hypometabolism is more pronounced in patients with neocortical temporal lobe epilepsy when compared to mTLE.66,67 Also patients with neocortical temporal lobe epilepsy who describe an acoustic aura can be differentiated from mTLE by reductions in glucose metabolism primarily involving temporo-perisylvian locations.67 FDG-PET and interictal epileptic abnormalities There are conflicting reports on the relationship between the frequency of interictal temporal EEG spikes and severity of glucose hypometabolism on PET. This may be due to the different patient groups studied; evolution of PET technology; relative sophistication of MR imaging and PET equipment and the scanning protocols. Early studies did not find a relationship between interictal scalp and depth EEG spikes and the severity of temporal lobe hypometabolism9 but this group may have been studied much later in the natural history of mTLE. In addition, continuous focal slowing or focal suppression of barbiturateinduced beta activity during the PET study did not correlate with the severity of temporal lobe hypometabolism. More recent studies suggest that FDG-PET hypometabolism may reflect not only a permanent functional deficit but also a transient regional cerebral dysfunction related to the occurrence of interictal spikes.68,69 Some researchers have found a relationship between interictal EEG abnormalities and the severity of glucose hypometabolism. In another study

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Mesial temporal lobe epilepsy and positron emission tomography there was a significant negative correlation between asymmetry in glucose hypometabolism in temporal lobes and total number of interictal spikes recorded.55 Investigators have also shown a concordance between temporal lobe glucose hypometabolism and regional slow activity recorded over temporal electrodes 70 and the amount of delta activity in the interictal EEG that is independent of MR findings.71 However, none of these studies accounted for the seizure frequency around the time of the PET study. This is an important issue because patients with more frequent interictal epileptic discharges often have more frequent seizures. Without controlling for seizure frequency around the time of the PET study, it is difficult to conclude that a reversible diaschisis from interictal epileptic activity results in neuronal dysfunction that in turn leads to abnormal glucose metabolism. At present there is no evidence that there is a strong relationship between interictal discharges and the severity of glucose hypometabolism on PET. FDG-PET and ictal epileptic discharges Early studies showed a good relationship between the site of focal hypometabolism and the epileptic focus determined by the combined results of all electrophysiological studies.7 These findings then led to performing anterior temporal lobectomies without chronic intracranial recordings as a routine part of clinical practice provided there were no discordant data.13 In mTLE, the zone of intracranially recorded electrographic ictal onset is almost always located in the region of glucose hypometabolism on FDG-PET.72 This regionalization of the ictal onset zone has been borne out in more recent studies. The area of glucose hypometabolism is usually larger than the pathological abnormality and may even be present in the absence of any MR scan abnormality.38 There are also subtle differences between epilepsies of mesial temporal origin versus those from the lateral neocortex on FDG-PET.72 Patients with mTLE as a group have the lowest FDG uptake in the entire temporal lobe when compared to patients with lateral or mesio-basal temporal seizure origin but there is no discernible correlation between the degree of hypometabolism and the location of EEG-defined epileptogenic zone.21 FDG-PET has superior sensitivity and specificity when compared to scalp EEG in mTLE.13 These data are old and more recent studies have not been done but one would expect an improved performance with the new generation of scanners. FDG-PET is as accurate as MR imaging in identifying the temporal lobe of onset in patients with bitemporal epilepsy73 and can provide lateralizing data in patients with a nonlocalized surface ictal EEG23 or nonlateralized MR findings.48 However, occasionally both metabolic and electrophysiological techniques can produce false positive as well as false negative results.7 FDG-PET and neuropsychological outcome and intracarotid amobarbital memory testing (ICAMT) There are limited studies that have investigated the distribution of FDG-PET abnormalities, the temporal structures involved and neuropsychological measures. A number of general rules have emerged from these studies: patients with mTLE and left temporal hypometabolism perform poorly on verbal memory tasks and those with right temporal

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hypometabolism perform less well in visual memory tasks;74,75 left thalamic and left lateral temporal hypometabolism are independently associated with impairment of delayed verbal recall76 and more severe left hemispheric hypometabolism on FDG-PET is associated with poorer overall cognitive performance in patients with left hemisphere language dominance.76 FDG-PET has shown the mesial temporal region to be a dominant and leading area for lateralizing Wada memory dominance.77 In one study 65% of patients with TLE and glucose hypometabolism on FDG-PET had impaired memory on the ICAMT and memory impairment contralateral to the temporal glucose hypometabolism was never found.78,79 FDG-PET is also useful to help predict postoperative memory loss. Patients with mild to no glucose hypometabolism on the left side have a significantly greater verbal memory decline following a left temporal lobectomy when compared with those with findings of moderate to severe hypometabolism (89 versus 33%). However, there does not appear to be a significant relationship between the extent of PET hypometabolism and memory outcome for right anterior temporal lobectomy patients.80 FDG-PET and seizure outcome following surgery FDG-PET can be predictive of postoperative seizure outcome and neuropsychological deficits following temporal lobectomy for mTLE but may be less useful in patients with bitemporal epilepsy. Studies that have examined the relationship of FDG-PET to outcome of temporal lobectomy independent of EEG findings have found that asymmetries in glucose metabolism in the temporal lobes of at least 15% can be predictive of good post surgical outcome.22,81 The prognostic value of the exact location of glucose hypometabolism within the temporal lobe is more controversial. Some data suggests that patients with mesial temporal glucose hypometabolism on PET have a high probability of becoming seizure free postoperatively.82,83 However, other studies have indicated that lateral22,81 or polar temporal hypometabolism84 are better predictors of a seizurefree postoperative course. Despite these conflicting results these studies provide us with a number of other important findings: (i) the high correlation between temporal hypometabolism and seizure outcome is independent of the pathologic diagnosis83 (ii) a 100% lateralization by depth EEG, nonlateralized PET scan and MR imaging do not indicate poor surgical outcome;6,73 (iii) unilateral temporal lobe hypometabolism is ‘falsely lateralized’ in approximately 1–2% of patients (iv) prior intracranial surgery, including depth electrode placement, can produce temporal hypometabolism that is falsely lateralized.13 Although bilateral temporal hypometabolism is a relative contraindication to surgery,12 FDG-PET is as sensitive and specific as volumetric MR in patients with bitemporal epilepsy. However, in these patients, a lateralizing PET that is convergent with depth EEG recordings and MR imaging73 does not increase the probability of successful postoperative seizure outcome. FDG-PET and pathology As described earlier cell loss in the mesial structures is only one component in the pathophysiology of glucose hypometabolism.

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It is not surprising that reduced glucose metabolism on FDG-PET corresponds closely with the presence of a histologic lesion in the mesial temporal lobe that, rarely, may not be detected on MR imaging.48 However, as already discussed, glucose hypometabolism on PET does not correlate with the degree of neuronal loss in surgical specimens13,49,85–87 or hippocampal atrophy on MR imaging.50 FDG-PET is also very sensitive in patients with mTLE and a concomitant pathology located outside the hippocampus, i.e., ‘dual pathology’. Alien-tissue lesions, including ganglioglial, oligodendroglial, and astroglial tumors, occur in 10–20% of patients who undergo surgery for temporal lobe epilepsy. Up to 91% of patients with dual pathology have abnormal PET scans88 where they may also have a different distribution of glucose hypometabolism. For example in the subgroup of patients with dual pathology who have microscopic temporal cortical dysplasia and concurrent MTS there is more prominent lateral temporal metabolic dysfunction compared with isolated MTS.89

with FDG-PET where there are clear-cut MR findings of MTS, the more sensitive FMZ-PET does not provide any additional clinical information. By the same token, where hippocampal volumetry fails to show hippocampal atrophy, reduced binding on FMZ-PET as with FDG-PET, may provide evidence for functional impairment.10,96 However it is important to note that transient and falsely lateralized abnormalities with FMZPET can occur in patients with normal MR imaging.97 Both visual and quantitative assessments of FMZ-PET are very sensitive where there is a coexistent cortical lesion in addition to MTS.98,99 In patients with microdysgenesis where the MR images are normal, some authors have also found increased binding on FMZ-PET in the white matter and periventricular region and have postulated that it may represent benzodiazepine receptors on heterotopic neurons.100–102 These authors did not confirm their postulate by a pathological study. Opiate receptors C-carfentanil PET binds to the mu opiod receptors, which are increased in the temporal neocortex, but decreased in the amygdala on the side of the epileptic focus.103 On the other hand, 11 C-diprenorphine binding – that reflects mu as well as nonmu opiate subtypes – is not different among regions of affected and nonaffected temporal lobes in patients with unilateral TLE. One possible explanation of this increase in mu opioid receptors in the lateral neocortex without an overall increase of opioid receptor binding includes an up-regulation of mu receptors in response to epileptic activity and down-regulation or occupation of kappa opioid receptors.104 This reduced binding of opioid receptors appears to persist after surgical removal of the epileptic focus.57 The studies done so far in mTLE suggest that this ligand is of limited clinical value. 11

Other PET ligands Several other PET ligands have been developed over the last two decades that have provided insights into the pathophysiology of epilepsy. These include 15O-water, ligands that bind to benzodiazepine, cholinergic, opiate, serotonin, and monoamine oxidase receptors together with agents to identify protein synthesis and positron-labeled anticonvulsants. [11C] Flumazenil (FMZ) FMZ is a competitive central benzodiazepine receptor antagonist. Histopathologic and autoradiographic studies of surgically removed sclerotic hippocampi have shown reduced neuronal counts, central benzodiazepine receptor (cBZR) densities and a reduction of cBZR density per remaining neuron.90 There is a reduction of available cBZR on remaining neurons in MTS detected in vivo by using FMZ-PET. After correction for grey matter atrophy there is reduced FMZ binding, which suggests that a reduction in cBZR binding is not solely due to hippocampal atrophy or neuronal loss.91 These changes are not permanent and may be in part due to the effects of seizures on projection areas from the mesial temporal lobe.92 Comparison FMZ-PET with FDG-PET in defining the ictal onset zone FMZ-PET studies when compared with FDG-PET have shown a less extensive reduction in cortical binding (Figure 88.4) but are as sensitive in localizing the temporal lobe of seizures onset.93–95 It has been postulated that unlike more widespread glucose hypometabolism seen with FDG-PET, the FMZ-PET changes may be more specific to the epileptogenic zone (Figure 88.4). Ryvlin et al.10 studied a series of patients with partial epilepsy the majority whom had temporal lobe epilepsy. An abnormal FMZ-PET was found in 94% of patients with temporal epilepsy in which 81% also had concordant MR abnormalities. There were a small number of patients who had a positive FMZ-PET with a normal FDG-PET and vice versa. False lateralization occurred rarely with FMZ-PET. However, as

Cholinergic receptors Cholinergic receptors have been imaged using [76Br] 4-bromodexetimide (BDEX) or [11C] N-methyl-4-piperidyl benzylate (NMPB). With mTLE BDEX there is a reduction in binding in the temporal lobe ipsilateral to the seizure focus.105 Highly restricted zones of reduced activity in the anteromesial temporal regions are seen with NMPB106 – similar to the distribution seen with FMZ-PET. These findings have also been reproduced using SPECT ligands.107 Monoamine oxidase type B (MAO-B) receptors Deprenyl is an irreversible inhibitor of MAO-B with a very high affinity for the enzyme. In the brain, MAO-B is preferentially located in astrocytes and there is histological evidence for increased binding of MAO-B enzyme in sclerotic hippocampi. PET with 11C-deuterium-deprenyl in patients with temporal epilepsy showed increased binding in its ipsilateral mesial temporal lobe.108 However, 11C-deuterium-deprenyl PET adds little to FDG-PET in patients with TLE.109 N-Methyl-d-Aspartate (NMDA) receptors 11 C-(S)-N-methyl ketamine that binds NMDA receptors in the brain may have a 9–34% reduction of tracer radioactivity in

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(a)

(b)

(c)

Figure 88.4 Patient LS from Figure 88.1. with left mesial temporal sclerosis and temporal lobe seizures. Row A,MR images. Arrows showing increased signal and atrophy in the right hippocampus on T2-weighted images. Row B,FDG-PET. Arrows showing marked anteromesial glucose hypometabolism. Row C,FMZ-PET. Arrows showing a more restricted area of reduced ligand binding in the right hippocampus when compared to the FDG-PET images.

the temporal lobes of ictal onset; very similar to the metabolic pattern seen on PET scans with FDG-PET.110 However, only a few patients have been studied with this technique and its role in clinical assessment is at present uncertain. Serotonin receptors and metabolism Studies exploring the serotonergic mechanisms in animal models of epilepsy and human surgical specimens have shown increases in serotonin and its metabolites in epileptic tissue.111,112 Patients with severe mTLE have reduced 5-HT1A serotonin receptor binding in the mesial temporal lobe and its limbic connections. There is decreased binding of the PET ligand [18F] FCWAY to the

5HT1A receptor in both mesial and lateral temporal regions ipsilateral to the epileptic focus113 together with the ipsilateral anterior cingulate, insula and lateral temporal cortex, contralateral hippocampus and the raphe nuclei.114 These findings have been echoed by another ligand that is an antagonist of the 5-HT1A receptor – 4-(2Vmethoxyphenyl)-1-[2V-(N-2-pirydynyl)-p-fluorobenzamido]-ethylpiperazine (MPPF).115 Assuming that these findings are not due to the effect of anticonvulsant medications, they can be explained by increased endogenous serotonin release that results in agonist-mediated down-regulation of 5HT1A receptors in the hippocampus. PET with alpha [11C] methyl-l-tryptophan (AMT) has been used to examine serotonin synthesis and has revealed an

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increase in AMT uptake in the hippocampus.116 The increased AMT uptake in the hippocampus has been speculated to be the result of serotonergic fiber sprouting.117 Although there have been limited studies of many ligands in temporal lobe epilepsy research in this area continues. None of the above ligands apart from perhaps FMZ have found a clinical place in the assessment of patients with mesial temporal epilepsy. However, even FMZ has not gained widespread clinical use due to its limited availability and little additional benefit when compared to FDG. This may reflect the fact that in temporal lobe epilepsy there is not only a change in the distribution of receptors but also altered function of the remaining receptors that will require new methodologies to investigate.

Conclusion The current clinical role of FDG-PET/CT appears to be in the nonlesional cases of mTLE or where there is discordance between the MR and EEG data. Although instrumentation has improved markedly over the past decade and scan times are shorter, it should be emphasized that patients with mTLE are subject to dynamic changes in the periscan period. Accurate accounts of seizure frequency and EEG recordings around the time of the scan are essential to correct interpretation. Although many ligands have been used over the past decade, FMZ shows the most promise but in the extra temporal seizure disorders. A ligand that is able to map the seizure onset remains elusive.

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show only mild hippocampal damage. Archives of Neurology 2001;58(6):933–9. Matheja P, Kuwert T, Ludemann P et al. Temporal hypometabolism at the onset of cryptogenic temporal lobe epilepsy. European Journal of Nuclear Medicine 2001;28(5):625–32. Jokeit H, Ebner A, Arnold S et al. Bilateral reductions of hippocampal volume, glucose metabolism, and wada hemispheric memory performance are related to the duration of mesial temporal lobe epilepsy. Journal of Neurology 1999;246(10):926–33. Gaillard WD, Kopylev L, Weinstein S et al. Low incidence of abnormal (18)FDG-PET in children with new-onset partial epilepsy: a prospective study. Neurology 2002;58(5):717–22. Engel J Jr, Wolfson L, Brown L. Anatomical correlates of electrical and behavioral events related to amygdaloid kindling. Annals of Neurology 1978;3(6):538–44. Engel J Jr, Rausch R, Lieb JP, Kuhl DE, Crandall PH. Correlation of criteria used for localizing epileptic foci in patients considered for surgical therapy of epilepsy. Annals of Neurology 1981;9(3):215–24. Bouilleret V, Dupont S, Spelle L et al. Insular cortex involvement in mesiotemporal lobe epilepsy: a positron emission tomography study. Annals of Neurology 2002;51(2):202–8. Wunderlich G, Schuller MF, Ebner A et al. Temporal lobe epilepsy with sensory aura: interictal glucose hypometabolism. Epilepsy Research 2000;38(2–3):139–49. Chee MW, Morris HH III, Antar MA et al. Presurgical evaluation of temporal lobe epilepsy using interictal temporal spikes and positron emission tomography. Archives of Neurology 1993;50(1):45–8. Olson DM, Chugani HT, Shewmon DA, Phelps ME, Peacock WJ. Electrocorticographic confirmation of focal positron emission tomographic abnormalities in children with intractable epilepsy. Epilepsia 1990;31(6):731–9. Koutroumanidis M, Binnie CD, Elwes RD et al. Interictal regional slow activity in temporal lobe epilepsy correlates with lateral temporal hypometabolism as imaged with 18FDG-PET: neurophysiological and metabolic implications. Journal of Neurology, Neurosurgery & Psychiatry 1998;65(2):170–6. Altay EE, Fessler AJ, Gallagher M et al. Correlation of severity of FDG-PET hypometabolism and interictal regional delta slowing in temporal lobe epilepsy. Epilepsia 2005;46(4):573–6. Henry TR, Sutherling WW, Engel J Jr et al. Interictal cerebral metabolism in partial epilepsies of neocortical origin. Epilepsy Research 1991;10(2–3):174–82. Benbadis SR, So NK, Antar MA, Barnett GH, Morris HH. The value of PET scan (and MRI and Wada test) in patients with bitemporal epileptiform abnormalities. Archives of Neurology 1995;52(11):1062–8. Boivin MJ, Giordani B, Berent S et al. Verbal fluency and positron emission tomographic mapping of regional cerebral glucose metabolism. Cortex 1992;28(2):231–9. Harris IM, Fulham MJ, Miller LA. The effects of mesial temporal and cerebellar hypometabolism on learning and memory. Journal of the International Neuropsychological Society 2001;7(3):353–62. Rausch R, Henry TR, Ary CM, Engel J Jr, Mazziotta J. Asymmetric interictal glucose hypometabolism and cognitive performance in epileptic patients. Archives of Neurology 1994;51(2):139–44. Hong SB, Roh SY, Kim SE, Seo DW. Correlation of temporal lobe glucose metabolism with the Wada memory test. Epilepsia 2000;41(12):1554–9. Salanova V, Markand O, Worth R. Focal functional deficits in temporal lobe epilepsy on PET scans and the intracarotid amobarbital procedure: comparison of patients with unitemporal epilepsy with those requiring intracranial recordings. Epilepsia 2001;42(2):198–203. Salanova V, Morris HH III, Rehm P et al. Comparison of the intracarotid amobarbital procedure and interictal cerebral 18-fluorodeoxyglucose positron emission tomography scans in refractory temporal lobe epilepsy. Epilepsia 1992;33(4):635–8. Griffith HR, Perlman SB, Woodard AR et al. Preoperative FDG-PET temporal lobe hypometabolism and verbal memory after temporal lobectomy. Neurology 2000;54(5):1161–5. Theodore WH, Gaillard WD, Sato S, Kufta C, Leiderman D. Positron emission tomographic measurement of cerebral blood flow and temporal lobectomy. Annals of Neurology 1994;36(2):241–4. Delbeke D, Lawrence SK, Abou-Khalil BW, Blumenkopf B, Kessler RM. Postsurgical outcome of patients with uncontrolled complex partial seizures and temporal lobe hypometabolism on 18FDGpositron emission tomography. Investigative Radiology 1996;31(5):261–6.

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Textbook of epilepsy surgery Manno EM, Sperling MR, Ding X et al. Predictors of outcome after anterior temporal lobectomy: positron emission tomography. Neurology 1994;44(12):2331–6. Dupont S, Semah F, Clemenceau S et al. Accurate prediction of postoperative outcome in mesial temporal lobe epilepsy: a study using positron emission tomography with 18-fluorodeoxyglucose. Archives of Neurology 2000;57(9):1331–6. Engel J Jr, Brown WJ, Kuhl DE et al. Pathological findings underlying focal temporal lobe hypometabolism in partial epilepsy. Annals of Neurology 1982;12(6):518–28. Theodore WH, Katz D, Kufta C et al. Pathology of temporal lobe foci: correlation with CT, MRI, and PET. Neurology 1990;40(5):797–803. Radtke RA, Hanson MW, Hoffman JM et al. Temporal lobe hypometabolism on PET: predictor of seizure control after temporal lobectomy. (see comment). Neurology 1993;43(6):1088–92. Salanova V, Markand O, Worth R. Temporal lobe epilepsy: analysis of patients with dual pathology. Acta Neurologica Scandinavica 2004;109(2):126–31. Diehl B, LaPresto E, Najm I et al. Neocortical temporal FDG-PET hypometabolism correlates with temporal lobe atrophy in hippocampal sclerosis associated with microscopic cortical dysplasia. Epilepsia 2003;44(4):559–64. Johnson EW, de Lanerolle NC, Kim JH et al. ‘Central’ and ‘peripheral’ benzodiazepine receptors: opposite changes in human epileptogenic tissue. Neurology 1992;42(4):811–15. Koepp MJ, Hand KS, Labbe C et al. In vivo [11C]flumazenil-PET correlates with ex vivo [3H]flumazenil autoradiography in hippocampal sclerosis. Annals of Neurology 1998;43(5):618–26. Savic I, Blomqvist G, Halldin C, Litton JE, Gulyas B. Regional increases in [11C]flumazenil binding after epilepsy surgery. Acta Neurologica Scandinavica 1998;97(5):279-86. Henry TR, Frey KA, Sackellares JC et al. In vivo cerebral metabolism and central benzodiazepine-receptor binding in temporal lobe epilepsy. Neurology 1998;43(10):1998–2006. Savic I, Ingvar M, Stone-Elander S. Comparison of [11C]flumazenil and [18F]FDG as PET markers of epileptic foci. Journal of Neurology 1993;Neurosurgery & Psychiatry. 56(6):615–21. Szelies B, Weber-Luxenburger G, Pawlik G et al. MRI-guided flumazenil- and FDG-PET in temporal lobe epilepsy. Neuroimage 1996;3(2):109–18. Szelies B, Weber-Luxenburger G, Mielke R et al. Interictal hippocampal benzodiazepine receptors in temporal lobe epilepsy: comparison with coregistered hippocampal metabolism and volumetry. European Journal of Neurology 2000;7(4):393–400. Ryvlin P, Bouvard S, Le Bars D, Mauguiere F. Transient and falsely lateralizing flumazenil-PET asymmetries in temporal lobe epilepsy. Neurology 1999;53(8):1882–5. Csaba J. Positron emission tomography in presurgical localization of epileptic foci. Ideggyogyaszati Szemle 2003;56(7–8):249–54. Juhasz C, Nagy F, Muzik O et al. [11C]Flumazenil PET in patients with epilepsy with dual pathology. Epilepsia 1999;40(5):566–74. Hammers A. Flumazenil positron emission tomography and other ligands for functional imaging. Neuroimaging Clinics of North America 2004;14(3):537–51.

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Hammers A, Koepp MJ, Hurlemann R et al. Abnormalities of grey and white matter [11C]flumazenil binding in temporal lobe epilepsy with normal MRI. Brain 2002;125(Pt 10):2257–71. Hammers A, Koepp MJ, Richardson MP et al. Grey and white matter flumazenil binding in neocortical epilepsy with normal MRI. A PET study of 44 patients. Brain 2003;126(Pt 6):1300–18. Mayberg HS, Sadzot B, Meltzer CC et al. Quantification of mu and non-mu opiate receptors in temporal lobe epilepsy using positron emission tomography. Annals of Neurology 1991;30(1):3–11. Duncan JS. Positron emission tomography receptor studies in epilepsy. Revue Neurologique 1999;155(6–7):482–8. Dupont S, Semah F, Loc’h C et al. In vivo imaging of muscarinic cholinergic receptors in temporal lobe epilepsy with a new PET tracer: [76Br]4-bromodexetimide. Journal of Nuclear Medicine 1999;40(6):935-41. Pennell PB. PET: cholinergic neuroreceptor mapping. Advances in Neurology 2000;83:157–63. Mohamed A, Eberl S, Fulham MJ et al. Sequential 123I-iododexetimide scans in temporal lobe epilepsy: comparison with neuroimaging scans (MR imaging and 18F-FDG-PET imaging). European Journal of Nuclear Medicine & Molecular Imaging 2005;32(2):180–5. Kumlien E, Bergstrom M, Lilja A et al. Positron emission tomography with [11C]deuterium-deprenyl in temporal lobe epilepsy. Epilepsia 1995;36(7):712–21. Kumlien E, Nilsson A, Hagberg G, Langstrom B, Bergstrom M. PET with 11C-deuterium-deprenyl and 18F-FDG in focal epilepsy. Acta Neurologica Scandinavica 2001;103(6):360–6. Kumlien E, Hartvig P, Valind S et al. NMDA-receptor activity visualized with (S)-[N-methyl-11C]ketamine and positron emission tomography in patients with medial temporal lobe epilepsy. Epilepsia 1999;40(1):30–7. Louw D, Sutherland GR, Glavin GB, Girvin J. A study of monoamine metabolism in human epilepsy. Canadian Journal of Neurological Sciences 1989;16(4):394–7. Pintor M, Mefford IN, Hutter I et al. Levels of biogenic amines, their metabolites, and tyrosine hydroxylase activity in the human epileptic temporal cortex. Synapse 1990;5(2):152–6. Toczek MT, Carson RE, Lang L et al. PET imaging of 5-HT1A receptor binding in patients with temporal lobe epilepsy. (see comment). Neurology 2003;60(5):749–56. Savic I, Lindstrom P, Gulyas B et al. Halldin C, Andree B, Farde L. Limbic reductions of 5-HT1A receptor binding in human temporal lobe epilepsy. Neurology 2004;62(8):1343–51. Merlet I, Ostrowsky K, Costes N et al. 5-HT1A receptor binding and intracerebral activity in temporal lobe epilepsy: an [18F]MPPF-PET study. Brain 2004;127(Pt 4):900–13. Natsume J, Kumakura Y, Bernasconi N et al. Alpha-[11C] methyl-L-tryptophan and glucose metabolism in patients with temporal lobe epilepsy.(see comment). Neurology 2003;60(5):756-61. Juhasz C, Chugani DC, Muzik O et al. Alpha-methyl-L-tryptophan PET detects epileptogenic cortex in children with intractable epilepsy. Neurology 2003;60(6):960–8.

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PET in neocortical epilepsies HT Chugani, C Juhász, E Asano, and S Sood

Summary ●

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PET techniques have contributed to the clinical management of epilepsy. In extratemporal lobe epilepsy, glucose metabolism PET guides placement of intracranial electrodes. Dynamic metabolic changes occur with persistent epilepsy. Flumazenil PET is useful in detection of ‘dual’ pathology, more precise localization of the epileptogenic zone, defining perilesional epileptogenic cortex, and possibly identifying ‘secondary epileptic foci’. α-[11C]methyl-L-tryptophan (AMT) PET can differentiate between epileptogenic and nonepileptogenic tubers in tuberous sclerosis complex. AMT-PET can localize the epileptic focus in lesional and occasionally in nonlesional epilepsy. In cases of failed epilepsy surgery, AMT-PET may identify residual epileptogenic cortex for a second surgery.

Introduction Positron emission tomography (PET) is a noninvasive functional imaging tool which can be used to measure regional uptake and affinity of ligands or metabolic substrates in brain and other organs. In epileptic disorders, PET scanning has been applied both in the clinical setting and also to investigate basic mechanisms associated with epileptogenicity and seizure propagation. The commonest clinical application of PET is in the evaluation of patients with intractable epilepsy for surgical treatment. In such instances, PET scanning can assist in the selection of appropriate surgical candidates, localize epileptogenic brain regions, evaluate the integrity of brain areas outside the epileptic focus, and even predict postoperative cognitive dysfunction in some patients. In this review, we summarize the findings of previous PET studies which have investigated clinical applications in patients with neocortical epilepsies with the aim of defining epileptogenic cortex for surgical resection. The application of PET in mesial temporal lobe epilepsy has been discussed in the previous chapter.

PET tracers used in neocortical epilepsy The most widely available PET tracer for presurgical evaluation of both adults and children with intractable focal epilepsy

is 2-deoxy-2-[18F]fluoro-D-glucose (FDG), which is used to measure glucose utilization in various brain regions and, in the interictal state, shows decreased metabolism (hypometabolism) in the vicinity of the epileptic focus. It is important to monitor the EEG during the PET tracer uptake period, since an active focal epileptiform discharge present on the EEG may be associated with local hypermetabolism, even on the interictal PET scan. In such instances, the relative hypometabolism on the contralateral (normal) side may be mistakenly interpreted as an interictal epileptic focus, an interpretation that would lead to false lateralization of the focus.1 Of the receptor ligand PET tracers, the most commonly used in epilepsy is [11C]flumazenil (FMZ) which binds to GABAA receptors.2–8 It should be pointed out that in clinical studies with FMZ-PET, patients taking benzodiazepine drugs have generally been excluded, but the effects of drugs that result in allosteric interactions with GABAA receptors have not been well studied. Although quantification of FMZ-PET images can be performed using a three-compartmental model9 or a simpler two-compartmental model,10 a disadvantage is the requirement of arterial blood sampling to define the input function. However, experience has shown that visual as well as objective detection of focal cortical and subcortical abnormalities for clinical purposes can be reliably achieved using FMZ activity images that do not require arterial blood sampling. Comparison of focal FMZ abnormalities in patients with neocortical epileptic foci showed that summed FMZ activity images obtained between 10 and 20 min after tracer injection represented excellent agreement between FMZ activity and the quantitative ‘volume of distribution’ images.11 In our center, we also use alpha-[11C]methyl-L-tryptophan (AMT) which measures tryptophan metabolism12–14 for epilepsy surgery evaluation. AMT is an analog of tryptophan (the precursor of serotonin), and is converted in the brain to α[11C]methyl-serotonin, which is not a substrate for the degradative enzyme monoamine oxidase, and therefore accumulates in serotonergic terminals. Obviously, patients taking medications that affect tryptophan or serotonin metabolism should not undergo AMT-PET scan. Other PET tracers with the potential for detecting epileptic brain regions include radiolabeled ligands which bind to opioid receptors,15 histamine H1 receptors,16 monoamine oxidase type B enzyme,17 N-methyl-D-aspartate receptors,18 peripheral-type benzodiazepine receptors,19 and serotonin 1A receptors.20 Among these, only the few that have been applied in the study of intractable neocortical epilepsy will be described in further detail below. 803

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Extratemporal lobe epilepsy Unlike temporal lobe epilepsy, in which there is a ‘standard’ lobectomy procedure, extratemporal lobe resections are quite variable and range from small topectomies to unilobar or multilobar cortical resections. Defining the location and extent of even the primary epileptic focus (let alone secondary foci) can be quite challenging, particularly in frontal lobe epilepsy, which constitutes 20–30% of all partial epilepsies and the majority of extratemporal lobe epilepsy.21–25 In a review of surgical outcome from 10 epilepsy surgery centers worldwide,26 only 45% of 805 patients undergoing extratemporal cortical resections became seizure free. The success rate is even worse when no structural lesion can be identified on MRI.27–29 For example, Schiller et al.30 reported that of the nonlesional patients subjected to chronic intracranial EEG monitoring, only 22% became seizure free after surgery. Even with the many advances in neuroimaging techniques (reviewed in Kuzniecky & Knowlton, 2002,31) current success rates for extratemporal lobe epilepsy surgery remain modest at the 50–60% range.32–34 Nonlesional extratemporal lobe epilepsy When the MRI scan fails to show a focal structural abnormality in extratemporal lobe epilepsy, the epileptologist is guided only by seizure semiology and scalp-EEG findings for the placement of intracranial electrodes, an approach that is fraught with sampling errors and may lead to surgical failure. In such instances, PET often provides important localizing data that can be compared to EEG localization and guide intracranial electrodes placement, thus increasing the confidence of the epilepsy surgery team (Figure 89.1). Using a high resolution PET scanner in a predominantly pediatric population, a sensitivity of 92% in the detection of frontal lobe epileptic foci with FDG-PET, and a specificity of 62.5% were demonstrated.35 In an adult population with nonlesional

neocortical epilepsy, however, the sensitivity was 42.9%.36 Unfortunately, the consistent observation of large areas of glucose hypometabolism on PET extending beyond the primary epileptogenic region has precluded the use of FDG PET to define precisely the boundary of the epileptogenic zone for surgical resection, although it remains a very valuable tool for lateralization and general localization of epileptogenic brain regions.37–39 This is supported by a recent study, which found that localization data obtained by FDG PET and interictal EEG tended to predict a seizure-free outcome.34 The large areas of glucose hypometabolism seen in patients with partial epilepsy are more often seen in cases of chronic epilepsy than in patients with recent onset epilepsy.40,41 Indeed, in a PET study of 40 children with newly diagnosed partial epilepsy with normal MRI, only eight (20%) showed focal cortical hypometabolism on FDG-PET.41 More recently, we measured changes in the extent of cortical hypometabolism defined by an asymmetry-based method and projected on the 3Dreconstructed cortical surface in 15 children who underwent two consecutive FDG-PET scans 7–44 months apart.42 Change in seizure frequency between the two PET scans correlated positively with the change in the extent of cortical glucose hypometabolism (r = 0.81, p < 0.001; corrected for interval time between the two scans). Patients with persistent or increasing seizure frequency (≥1 seizure per day) showed extension of hypometabolic cortex over time (Figure 89.2). In contrast, patients whose seizures were characterized as 30 on the Beck Depression Inventory–II, what can it be, other than a MDE? While this statement is probably correct, a MDE may be the expression of more than one type of mood disorder, each with a different prognosis and treatment strategy (see the section on mood disorders in this chapter). As in the case of structured interviews, most of the screening instruments were developed for the screening of symptoms in patients with primary psychiatric disorders and not in patients with epilepsy. The only exception is the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E)55 (see below). In addition two screening instruments for the identification of symptoms of depression, the Beck Depression Inventory-II (BDI-II) and the Center for Epidemiologic Studies-Depression Scale (CES-D) have been recently validated in patients with epilepsy.56 Clearly, the use of screening instruments for psychiatric research in epilepsy must be used in conjunction with a structured psychiatric interviews designed to establish a DSM-IV-TR diagnoses; only then do these screening instruments yield meaningful data as they permit regular re-screening to measure changes in severity of symptomatology. The most frequently used screening instruments in adults include the following. Screening of general psychiatric symptoms Adult Self-Report Inventories-4: The Adult Self-Report Inventories are symptom inventories that can be used as a

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Pre-surgical psychiatric evaluations: risk factors for post-surgical deficits guide for conducting clinical interviews.57 They include the behavioral symptoms of more than two dozen psychiatric disorders described in the DSM-IV. There are parallel versions of the Adult Self-Report Inventories that are designed to obtain information from both patients and significant others. These inventories take approximately 15 to 20 minutes to complete. Items are grouped according to diagnostic categories. Hopkins Symptom Checklist (SCL-90 Revised): The SCL-90 is used to evaluate a broad range of psychopathology. It consists of 90 items and usually can be completed in less than 30 minutes.58 The scoring system includes nine symptom scales (somatization, obsessive-compulsive behavior, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism) and three global indexes. This scale has documented validity and has been used in many treatment studies of mood disorders and schizophrenia. Minnesota Multiphasic Personality Inventory: It consists of a self-report personality inventory with ten clinical scales (hypochondriasis, depression, hysteria, psychopathic deviance, male-female, paranoia, psychasthenia, schizophrenia, mania, and social introversion) and three validity scales. The administration time is about 40 to 90 minutes.59 Depressive symptoms Beck Depression Inventory-II (BDI): The BDI-II is the most commonly used self-rating scale for depression.60 There are 21 items scored on a scale from 0–3 according to how the patient feels at the current time. The scale is sensitive to change and has been used in clinical drug trials. As stated above, the BDIII has been recently tested in 205 patients with epilepsy from five epilepsy centers and was found to have a high sensitivity and specificity as a screening instrument of major depressive episode.56 The Center for Epidemiologic Studies-Depression Scale (CES-D): It is a composite of 20 items, rated from 0 (rarely) to 4 (most or all of the time). It can yield scores from 0–60, with scores >16 being suggestive of depressive illness. This scale has also been recently validated for its use in patients with epilepsy.56 Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). This is a new self-rating instrument that consists of only six items but which was specifically developed to screen for the presence of major depressive episodes in patients with epilepsy, while minimizing the risk of overlap with adverse antiepileptic drug effects or preexisting cognitive problems.55 Completing this instrument only takes 3 minutes or less and a score >14 is suggestive of the presence of a major depressive episode. Anxiety symptoms Hospital Anxiety and Depression Scale:61 This scale is specifically developed for use in patients with medical comorbidity, and consists of 7-item self-rated subscales for both depression and anxiety. Beck Anxiety Inventory (BAI):62 The BAI is a 21-item selfreport measure of anxiety severity. The scale consists of 21 items, each describing a common symptom of anxiety over the past week on a 4-point scale ranging from 0 (Not at all) to 3 (Severely–I could barely stand it). The items are summed to obtain a total score that can range from 0–63. Goldberg’s Depression and Anxiety Scales:63 The instrument consists of nine questions assessing mood and anxiety

831

over the previous month, and the full set of nine questions need to be administered only if there are positive answers to the first four. The scales are devised specifically to be used by nonpsychiatrists in clinical investigations. Scores are from 0–9. Hamilton Anxiety Rating Scale (HAM-A or HARS):64 This scale is a 14-item clinical interview scale (not selfreported) measuring somatic and psychic anxiety symptoms. The responses include five degrees of severity ranging from 0 (None) to 4 (Frequent and severe symptomatology). This instrument should be used with caution in patients with epilepsy, given the large number of somatic symptoms included in this scale which in patients with epilepsy can result from adverse effects of AEDs potentially yielding false positive suggestions of more severe anxiety symptomatology. Obsessive-compulsive symptoms Yale-Brown Obsessive Compulsive Scale (Y-BOCS): This is the most widely used scale for rating obsessive-compulsive symptoms. It includes a symptom checklist as well as a ten-item scale that is rated by clinicians. It has been shown to be a highly reliable instrument that is sensitive for measuring changes in the severity of obsessive-compulsive symptoms.65 Self-Report measures for children and adolescents include: Child Symptom Inventories (CSI-4): The Child Symptom Inventories are screening instruments for the behavioral, affective, and cognitive symptoms of more than a dozen DSM-IV childhood disorders. There are Child Symptom Inventories for three different age groups: Early Childhood Inventory-4 (ages 3 to 5 years), Child Symptom Inventory-4 (ages 5 to 12 years), and Adolescent Symptom Inventory-4 (ages 12 to 18 years). There is a self-report measure for adolescent patients: Youth’s Inventory-4 (ages 12 to 18 years).66 Child Behavior Checklist (CBCL): Developed by Thomas M. Achenbach, this scale evaluates pathologic behaviors and social competence in children ages 4 to 16 years. Forms are available for teachers, parents, and children. It is one of the most widely used scales for both clinical use and research.67 Children’s Depression Inventory (CDI): This is a 27-item self-report questionnaire that can be given to 7- to 17-yearolds. It is currently one of the most widely used instruments for monitoring depression in children. Each question includes three statements of increasing severity.68 Multidimensional Anxiety Scale for Children (MASC): This is a scale for children and adolescents designed to assess symptoms of anxiety. The 39 items are scored on a scale from 0–3 as follows: 0 = never true about me; 1 = rarely true about me; 2 = sometimes true about me; 3 = often true about me.69 Connors’ Parent/Teacher Rating Scales: This scale identifies behavior problems through parent and teacher report and particularly symptoms of ADHD. It is available in three versions: a 93-item version, a 48-item version, and a ten-item screening version. It is used in children ranging in age from 3 to 17 years.70 Leyton Obsessional Inventory-Child Version (LOI-CV; Short Form): This questionnaire is a 20-item inventory with ‘yes/no’ responses adapted from the adult version to assess obsessivecompulsive symptoms.71

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Should patients with pre-surgical psychiatric disorders be excluded from epilepsy surgery? The short answer is no, as long as they can cooperate with the presurgical evaluation and they can understand the risks of the surgical procedures and the likelihood of achieving a seizure-free state. As discussed in detail in chapter 142, epilepsy surgery is associated with a significant improvement of pre-surgical psychiatric disorders, including remission of depression and anxiety disorders in approximately 50% of patients.11,13, 47 A pre-surgical psychiatric evaluation is important in these patients as it can be predictive of the risk of developing postsurgical psychiatric complications (see chapter 142). Indeed, a pre-surgical lifetime history of depression has been identified as the strongest predictor of post-surgical psychiatric complications presenting as exacerbation or recurrence of latent pre-surgical psychiatric disorders. Various studies have also identified an association between pre-surgical psychiatric disorders and a worse post-surgical seizure outcome (see chapter 142). Thus, in the setting of a pre-surgical psychiatric disorder, discontinuation of AEDs post-surgically may be discouraged to avert seizure recurrence. The biggest controversy centers on the consideration of epilepsy surgery in patients with psychotic disorders. In general, patients with chronic psychosis are less likely to be referred to epilepsy surgical programs because of the assumption that they cannot cooperate with the pre-surgical evaluation. This assumption, however, has been proven to be erroneous time and again. Also, there has been a concern that psychotic disorders may worsen following epilepsy surgery. As stated above, IPOE is more benign than the primary schizophreniform disorders and hence poses less problems for the patient to be able to cooperate with the necessary tests of the pre-surgical evaluation. A review of the literature in Chapter 144 shows that the impact of ATL on the post-surgical course of the psychotic disorder has varied from unchanged (in a

majority of cases) to improved psychotic status and/or level of functioning. For example, among 74 patients who underwent an ATL, Jensen and Larsen found 11 patients who had experienced a psychotic disorder pre-surgically.72 The surgical procedure had no impact on the course of psychotic disorder. On the other hand, in a small series of five patients with a chronic psychotic disorder who underwent an ATL, Reutens et al., reported an excellent seizure outcome in all patients and while the seizure-free state did not modify the actual psychotic disorder post-surgically, it facilitated their level of functioning.73 Marchetti et al. reported a series of six patients with pre-surgical interictal psychosis who underwent an ATL.74 Five of the six patients achieved a seizure-free outcome and there was no worsening of their psychotic disorder, with relative improvement in the mental conditions of five patients. In summary, the presence of a comorbid psychotic disorder should not be an ‘automatic’ reason for exclusion for epilepsy surgery.

Concluding remarks Pre-surgical psychiatric evaluations are of the essence to ensure that any psychiatric comorbidity has been properly identified and the appropriate treatment has been started to avert or minimize the development of post-surgical psychiatric complications. While most epilepsy surgery rely on neuropsychological evaluations to screen for comorbid psychiatric disorders, there is a great risk that comorbid psychiatric disorders will go undetected and untreated. As mentioned above, the psychiatric disorders of patients with refractory epilepsy are often atypical in their presentation and screening instruments are unlikely to provide an objective picture. Epilepsy centers need to incorporate a psychiatrist into their epilepsy team. Unfortunately, the economic barriers of today’s healthcare environment limits the availability of access to psychiatrists in general and epilepsy programs may need to cover the costs of having a psychiatrists available in their team.


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Kanner AM. Depression in epilepsy: prevalence, clinical semiology, pathogenic mechanisms and treatment. Biol Psychiatry, 2003; 54:388–98. Jacoby A, Baker GA, Steen N et al. The clinical course of epilepsy and its psychosocial correlates: findings from a UK community study. Epilepsia 1996;37:148–61. O’Donoghue, MF, Goodridge DM, Redhead K et al. Assessing the psychosocial consequences of epilepsy: a community-based study. Br J Gen Pract 1999;49(440):211–14. Ettinger A. Reed M, Cramer J Epilepsy Impact Group. Depression comorbidity in community-based patients with epilepsy or asthma. Neurology, 2004; 63:1008–14. Elkin T, Shea MT, Watkins JT et al. National Institute of Mental Health treatment of depression collaborative research program. General effectiveness of treatment. Arch Gen Psychiatry 1989; 46:971–82. Charney DS, Berman RM, Miller HL. Treatment of depression. In: Schatzberg AF, Nemeroff CB, eds. Textbook of Psychopharmacology, 2nd edn. Washington, DC: American Psychiatric Association Press, 1998:705–32. Paykel ES, Ramana R, Cooper Z et al. Residual symptoms after partial remission; an important outcome in depression. Psychol Med 1995;25:1171–80. Mendez MF, Cummings J, Benson D et al. Depression in epilepsy: significance and phenomenology. Arch Neurol 1986;43:766–70. Kraepelin E. Psychiatrie, vol 3. Leipzig: Johann Ambrosius Barth, 1923. Bleuler E. Lehrbuch der Psychiatrie, 8th edn. Berlin: Springer, 1949. Gastaut H, Roger J, Lesèvre N. Diffèrenciation psychologique des èpileptiques en fonction des formes èlectrocliniques de leur maladie. Rev Psychol Appl 1953;3:237–49. Blumer D, Altshuler LL. Affective disorders. In: Engel j, Pedley TA, eds. Epilepsy: A Comprehensive Textbook, vol II. Philadelphia: Lippincott-Raven, 1998:2083–99. Kanner, AM, Kozak AM, Frey M. The use of sertraline in patients with epilepsy: is it safe? Epilepsy Behav 2000;1(2):100–5. Jones JE, Herman BP, Berry JJ et al. Clinical assessment of Axis I psychiatric morbidity in chronic epilepsy: a multicenter investigation. J Neuropsychiatry Clin Neurosci. 2005;17(2):172–9. Robertson MM. Suicide, parasuicide, and epilepsy. In: Pedley T, Engel. J, eds. Epilepsy: A Comprehensive Textbook. Philadelphia: Lippincott-Raven; 1997. Vazquez B, Devinsky O. Epilepsy and anxiety. Epilepsy Behav 2003;4(Supplement 4):S20–25. Edeh J, Toone B. Relationship between interictal psychopathology and the type of epilepsy. Br J Psychiatry 1987;151:95–101. Pariente PD, Lepine JP, Lellouch J. Lifetime history of panic attacks and epilepsy: an association from a general population survey. J Clin Psychiatry 1991;52:88–9. Diagnostic and Statistical Manuel of Mental Disorders, 4th edn. Washington, DC: American Psychiatric Press, 2000. Rutter M, Graham P, Yule W. A Neuropsychiatric Study in Childhood. Philadelphia: JB Lippincott, 1970. McDermott S, Mani S, Krishnaswami S. A population-based analysis of specific behavior problems associated with childhood seizures. J Epilepsy 1995;8:110–18. Slater E, Beard AW, Glithero E. The schizophrenia-like psychoses of epilepsy. Br J Psychiatry 1963;109:95–150. Dongier S. Statistical study of clinical and electroencephalographic manifestations of 536 psychotic episodes occurring in 516 epileptics between clinical seizures. Epilepsia 1959/1960; 1:117–42. Kanner AM, Stagno S, Kotagal P, Morris HH. Postictal psychiatric events during prolonged video-electroencephalographic monitoring studies. Arch Neurol 1996;53:258–63. Logsdail SJ and Toone BK. Postictal psychosis. A clinical and phenomenological description. Br J Psychiatry 1988;152:246–52. Devinsky O, Abrahmson H, Alper K et al. Postictal psychosis: a case control study of 20 patients and 150 controls. Epilepsy Res 1995; 20:247–53. Umbricht D, Degreef G, Barr WB et al. Postictal and chronic psychoses in patients with temporal lobe epilepsy. Am J Psychiatry 1995;152(2):224–31. Lancman ME, Craven WJ, Asconape JJ, Penry JK. Clinical management of recurrent postictal psychosis. J Epilepsy 1994;7:47–51. Kanemoto K, Kawasaki J, Kawai J. Postictal psychosis: a comparison with acute interictal and chronic psychoses. Epilespia 1996;37:551–6. Christodoulou C, Koutroumanidid M, Hennessy MJ et al. Postictal psychosis after temporal lobectomy. Neurol 2002;59(9):1432–5.

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Kanner AM, Soto A. Ictal recordings in postictal psychosis and postictal depression. Neurol 1998;50:4(Suppl 4):A397. Kanner AM, Tilwalli S, Byrne R. Psychiatric and neurologic predictors of post-surgical psychiatric complications following a temporal lobectomy. Neurol 2005;64:(Suppl):1:A–358. First MB, Spitzer RL, Gibbon M et al. Structured Clinical Interview for DSM-IV Axis I Disorders. New York, NY: State Psychiatric Institute, Biometrics Research, 1995. Kessler RC, Andrews G, Mroczek D et al. The World Health Organization Composite International Diagnostic Interview-Short Form (CIDI-SF). Int J Meth Psych Res 1998;7:171–85. Endicott J, and Spitzer RL. A diagnostic interview: the Schedule for Affective Disorders and Schizophrenia. Arch Gen Psychiatry, 1978;35:7:837–44. Robins LN, Helzer JE, Croughan J et al. National Institute of Mental Health Diagnostic Interview Schedule. Its history, characteristics and validity. Arch Gen Psychiatry 1981;38:4:381–9. Sheehan DV, Lecrubier Y, Sheehan KJ et al. The MiniInternational Neuropsychiatric Interview (MINI): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry, 1998;59(Suppl 20):22–33. Kaufman J, Birmaher B, Brent D et al. Schedule for affective disorders and schizophrenia for school-age children: present and life-time version. In: Handbook of Psychiatric Measures. Washington, DC; American Psychiatric Association, 2002:296–302. Weissman MM, Wickramaratne P, Adams P et al. Brief screening for family psychiatric history: the family history screen. Arch Gen Psychiatry 2000;57:675–82. Gilliam FG, Barry JJ, Meador KJ et al. Rapid detection of major depression in epilepsy: a multicenter study. Lancet Neurol 2006;5(5):399–405. Jones JE, Herman BP, Woodard JL et al Screening for major depression in epilepsy with common self-report depression inventories. Epilepsia. 2005;46(5):731–5. Gadow KD, Sprafkin J. The Symptom Inventories: An Annotated Bibliography. Stony Brook, NY: Checkmate Plus, 1998. Derogatis LR, Cleary PA. Confirmation of the dimensional structure of the SCL-90: a study in construct validation. J Clin Psychol 1977;33:981–9. Hathaway SR, McKinley JC. The Minnesota Multiphasic Personality Inventory Manual, revised edn. New York: Psychological Corporation, 1989. Beck AT, Ward CH, Mendelson M et al. An inventory for measuring depression. Arch Gen Psychiatry 1961;4:561–71. Zigmond AS, Snaith RP: The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand 1983;67:361–70. Beck AT, Steer, RA. Manual for the Beck Anxiety Inventory. San Antonio, TX: Psychological Corporation, 1990. Goldberg D, Bridges K, Duncan-Jones P, Grayson D. Detecting anxiety and depression in general medical settings. Brit Med J 1988;297:897–9. Hamilton M: The assessment of anxiety states by rating. Br J Med Psychol 1959; 32:50–55. Goodman WK, Price LH, Rasmussen SA et al. The Yale-Brown Obsessive Compulsive Scale, I: development, use, and reliability. Arch Gen Psychiatry 1989;46:1006–11. Nolan EE, Volpe RJ, Gadow KD et al. Development, gender and comorbidity differences in clinically referred children with ADHD. J Emotion Behav Disord 1999;7:11–20. Achenbach TM, Edelbrock CS. Child Behavior Checklist. Burlington, VT: TM Achenbach, 1986. Kovacs M. Children’s Depression Inventory (CDI). Psychopharmacol Bull 1985;21:995–8. March J. Manual for the Multidimensional Anxiety Scale for Children (MASC). Toronto, Ontario: Multi-Health Systems, 1998. Conners CK. The Conners’ Ratings Scales. Austin, TX: Pro-Ed, 1985. Berg C, Rapoport J, Flament M. The Leyton Obsessional InventoryChild Version. J Am Acad Child Psychiatry 1986;25:84–91. Jensen I, Larsen JK. Mental aspects of temporal lobe epilepsy: follow-up of 74 patients after resection of a temporal lobe. J Neurol Neurosurg Psychiatry 1979;42:256–65 Reutens DC, Savard G, Andermann F, Dubeau F, Olivier A. Results of surgical treatment in temporal lobe epilepsy with chronic psychosis. Brain 1997;120:929–36. Marchetti RL, Fiore LA, Valente KD et al. Surgical treatment of temporal lobe epilepsy with interictal psychosis: results of six cases. Epilepsy Behav. 2003;4(2):146–52.

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Pre-surgical neuropsychological workup in children and intellectually disabled adults with epilepsy U Gleissner and C Helmstaedter

Introduction Due to several factors, children and intellectually disabled adult patients are more difficult to analyze neuropsychologically than other patients with epilepsy. There are similarities between both groups – for example behavioral problems often complicate the assessment of cognitive functions in both children and intellectually disabled adults – but there are also differences. For instance, the assessment of children needs to be sensitive to the developmental increases in cognitive skills, while floor effects in intellectually disabled patients can prevent an adequate mapping of performance changes. Therefore, children and intellectually disabled patients will be addressed in separate sections. The chapter summarizes technical problems of the neuropsychological assessment in children and intellectually disabled patients and provides an overview of test issues. First, special features that must be considered in the neuropsychological assessment of children and commonly used tests will be introduced and we will discuss matters of interpretation. Then, information concerning intellectual disability in patients with epilepsy will be provided as well as methods for the pre-surgical neuropsychological assessment. The final topic for discussion will address why a localizational interpretation of the neuropsychological profile in these patients is only of minor relevance in pre-surgical diagnostics.

Neuropsychological assessment of children The goal of neuropsychological pre-surgical testing in children and adolescents is to provide a detailed assessment of the individual’s cognitive functioning that serves as a basis for estimating and judging post-operative changes. The following objectives have been summarized by Oxbury.1 1. Confirmation of lateralization and localization of the epileptogenic area. 2. Prediction of risk to memory and other cognitive functions as well as long-term cognitive development. 3. Educational and rehabilitation issues and potential. As we will see, the individual fit of these goals depends on the age and developmental level of the child. The neuropsychological assessment of pediatric patients is complicated by certain 834

methodological and interpretational difficulties related to brain development and by patient intrinsic features which include lower cooperation and a frequent occurrence of behavioral problems. An overview of special features that have to be considered in the neuropsychological assessment of children is provided in Table 92.1. Methodological aspects Test selection The components of a neuropsychological evaluation assess linguistic, attentional, memory, executive, sensory, perceptual, motor and higher cognitive functions. Table 92.2 lists commonly used tests well suited for the assessment of specific cognitive domains, academic achievement and behavioral problems in children and adolescents and provides information on the age range of their norms. Please note that the table is not comprehensive. Baron2 recently provided a broad collection of tests and normative data in child neuropsychology. Other comprehensive test surveys that are not specifically designed for children were compiled by Spreen and Strauss,3 Table 92.1 Special features in the neuropsychological assessment of children Methodological aspects Test selection should consider the following aspects: ● Applicability of tests across a larger age range ● Suitability of tests for a specific age level ● Adequacy and topicality of age norms Observation of the patient is a valuable additional source of information. Anamnesis of parents or another caregiver is essential. Interpretation of test results must relate to developmental expectations. Patient intrinsic features Ability-achievement discrepancy is likely because of ● Lower level of cooperation and motivation particularly in younger children ● Increase of behavioral problems Brain development ● Increased potential for reorganization/ plasticity ● Possibility of a ‘growth into the deficit’ ● Possibility of functional changes during development

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Pre-surgical neuropsychological workup in children and intellectually disabled adults with epilepsy and Lezak.4 A very useful overview is also given in Anderson et al.5 Standardized neuropsychological test batteries such as the Halstead-Reitan Neuropsychological Test Battery for Children (9–14 years)6; the Luria-Nebraska Neuropsychological Battery – Children’s Revision (8 years and older)7; and the NEPSY (3–12 years)8 ensure a comprehensive assessment and usually rely on adequate normative data. However, their fixed format lacks the flexibility needed in order to tailor the assessment to the individual patient and often not all of the subtests are reliable for assessing the specific problems of patients with focal epilepsy. Many neuropsychologists therefore prefer a ‘self-made’ set of tests that are proven to be sensitive for the preand post-operative course of focal deficits in epileptic patients. When selecting a test, one must consider that test translations

Table 92.2

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and culturally-specific, adequate age norms are not available for each country and that differences in the educational system may prevent the transfer of norm data between countries. A variation of the preferred tests is therefore found in the different countries. However, also within English-speaking countries, a great variety of tests was revealed by a comparison of the assessment methods used by neuropsychologists who work with children at different epilepsy surgery centers.1 Neuropsychological tests should be selected in such a way that they are suited for a specific age level. Most abilities improve as the child grows older and it is essential to have tests that comprise adequate age norms. On the other hand, a test should be applicable across a larger age range in order to assess the course of illness and treatment effects in the individual child.

Common neuropsychological tests for the assessment of different functional domains

Function

Test

Age range

Attention

Trail-Making-Test for Children (Reitan & Wolfson, 1993) Continuous Performance Tests (Conners’ Continuous Performance Test, TOVA...) Visual Cancellation Tests (d2-Test of attention, Cancellation of Targets Test..) Test of Everyday Attention for Children (Manly et al., 1999) Clinical Evaluation of Language Fundamentals-3 (Semel et al., 1995) Children’s Token Test (Di Simoni, 1978) Peabody Picture Vocabulary Test-III (Dunn & Dunn, 1981) Boston Naming Test (Kaplan et al., 1983) Controlled Oral Word Association Test (Gaddes & Crocket, 1975; Anderson & Lajoie, 1996)

7–13 years Variable Variable 6–15 years 6 years–adult 6–13 years 2.5 years–adult 6–12 years 7–13 years

Wide Range Achievement of Memory and Learning (Sheslow & Adams, 1990) Rivermead Behavioural Memory Test for Children (Wilson et al. 1991) Rey Auditory Verbal Learning Test, several parallel forms (Rey,1964) California Verbal Learning Test for Children, one alternate form (Fridlund & Delis 1994) Story Recall (Christensen, 1979; Anderson & Lajoie, 1996) Digit Span (Isaacs & Vargha-Khadem 1989; Wechsler 1991; Anderson & Lajoie 1996) Rey-Osterrieth Complex Figure a: Recall (Rey, 1941; Forrester & Geffen, 1991; Anderson & Lajoie, 1996; Kolb & Wishaw, 1996) Corsi Block-Span (Milner, 1971; Anderson & Lajoie, 1996) Benton Visual Retention Test, three parallel forms (Benton, 1982) Rey Osterrieth Complex Figure: Copy (Kolb & Wishaw 1990) Motor free visual perception test-3 (Colarusso & Hammill, 2002) Block Design and Object Assembly of the Wechsler Scales (Wechsler 1991) Maze Tests (Porteus, 1965, Milner 1965, Wechsler 1991) Tower of London (Shallice 1982) Digits backwards (Isaacs & Vargha-Khadem 1989) Trail Making Test (Reitan 1969) Wisconsin Card Sorting Test (Heaton 1981; Chelune & Baer 1986) Children’s Category Test (Boll T 1992) Tests for manual motor sequencing and coordination Purdue Pegboard (Gardner & Broman 1979) Finger Tapping (Finlayson & Reitan, 1976)

5–17 years 5–11 years 7–13 years 5–16 7–13 years 6 years–adult 6 years–adult

Language

Learning/Memory General Verbal stimuli

Nonverbal stimuli

Visuospatial functions Executive and Motor Functions

Academic functions Behavior and Mood

Family functioning a

Wide Range Achievement Test (reading, spelling, arithmetic) (Jastak & Wilkinson 1994) Wechsler Individual Achievement Test (Wechsler 1993) Achenbach Child Behavior Checklist (Achenbach 1991) Adolescent Psychosocial Seizure Inventory (Batzel et al. 1991) Conners’ Behavioural Rating Scales–Revised (Conners 1997) Specific scales for the assessment of depression, anxiety, autism, conduct disorder,... Parenting Stress Index (Abidin 1995)

7–13 years 8 years–adult 6–15 years 4 years–adult 6 years–adult Various 7–13 years 7–15 years 7–13 years 6–12 years 6–13 years No norms available 5–15 years 6–14 years 5 years–adult 5–19 years 2–18 years 12–19 years 3–17 years Variable 3 months– 10 years

Full references and more detailed descriptions of the tests can be found in refs. 2,3,and 5. The Taylor Complex Figure as a parallel form of the Rey Osterrieth Figure is probably a bit easier.

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It is important, that tasks are not too complex but yield information about functioning within specific functional domains. If possible, one should favor tests that include alternate versions, since neuropsychological testing in children treated with epilepsy surgery includes retesting after surgery. This is particularly relevant for tests that evaluate learning and memory. The type of assessment and the choice of instruments depends on the age as well as the maturational and cognitive level of a child. It can thus be adequate to evaluate a 10-year–old child with moderate intellectual disability using a test developed for preschool children. Global intellectual functioning provides a background for the interpretation of the test profile in patients with focal epilepsy who are candidates for surgical treatment. Better than functions in individual domains, intelligence provides information about intellectual disability and this can be a clue in determining the etiology. Furthermore, intelligence is still the best predictor of school achievement. A measure of intelligence should therefore be included in the neuropsychological examination, although intelligence tests are usually insensitive indicators of common but subtle neuropsychological dysfunctions in these patients and they are largely insensitive to surgical effects. Table 92.3 provides an overview of tests for the assessment of intelligence or developmental level. The Wechsler Intelligence Scales are probably the most popular measures of general intellectual ability. There are versions for preschool children (WPPSI-III) and for school children

Table 92.3 Tests for the assessment of intelligence or developmental level Test

Age range

Bayley Scales of Infant Development II (Bayley, 1993) McCarthy Scales of Children’s Abilities (McCarthy, 1972) Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III, Wechsler, 2002) Stanford-Binet Intelligence Scalea (SB-IV, Thorndike et al., 1985) Kaufman Assessment Battery for Childrenb (KABC, Kaufman & Kaufman, 1987) NEPSY (Korkman et al., 1998) Coloured Progressive Matricesc (CPM, Raven 1995) Wechsler Intelligence Scale for Childrend (WISC-III, Wechsler 1991) Standard Progressive Matricesc (SPM, Raven 1996) Kaufman Adolescent and Adult Intelligence Teste (KAIT, Kaufman & Kaufman 1982)

1–42 months

a

2 1⁄2–8 1⁄2 years 2 1⁄2–7 years 3 months 2 yrs–adulthood 2 1⁄2–12 1⁄2 3–12 years 4–11 1⁄2 years 6–16.11 years 8–80 years 11–85 years.

The SB-IV is particularly apt to assess gifted children. The KABC includes an achievement scale. c The Raven’s Progressive Matrices keep verbal instructions to a minimum and require nonverbal reasoning, they are relatively culturally unbiased. d The WISC-III differentiates between verbal and nonverbal intelligence. e The KAIT differentiates between fluid and crystallized intelligence. Full references and more detailed descriptions of the tests found in refs. 2,3,and 4. b

(WISC-III) and these tests have been translated in to a multitude of languages. Abbreviated forms have been developed for screening purpose.9 For infants, the Bayley Scales of Infant Development–II are probably the most popular method for assessing the current developmental level. For those patients who speak a foreign language or for language-impaired patients (e.g., deaf-mute or aphasic patients) tests of nonverbal reasoning (e.g., CPM, SPM) or nonverbal subscales of common intelligence tests (e.g., the performance scale of WISC-III) can be applied. Interpretation of test results In a child that is referred for the purpose of pre-surgical diagnostics, the neuropsychologist interprets the obtained data in the context of a comprehensive understanding of brain-behavior relationships. This interpretation varies depending on the age of the patient. In very young children or children with severe intellectual disability, the neuropsychological evaluation mainly aims to assess the global developmental level to set a baseline for follow-up. Answers to localization-related questions can normally not be given for those patients. In school children (6–12 years), neuropsychological patterns that exhibit specific profiles with strengths and weaknesses of localizing or lateralizing value can sometimes be recognized. Neuropsychological factors in the adolescent (> 12 years) are assumed to be very similar to those found in adults and neuropsychological patterns are often of localizing or lateralizing value. Specific deficits can be taken to strengthen or confirm or amplify other findings of the presurgical diagnostics, especially if an intracarotid amytal test has confirmed left hemisphere language dominance. General guidelines for a localizational interpretation are: 1. Selective deficits in language associated functions (e.g., expressive or receptive language, vocabulary, semantic fluency, verbal memory) point to impairments in functions of the language dominant hemisphere. 2. Selective deficits in visuospatial functions (e.g., visuoconstruction, visual perception, visual memory, mental rotation) point to impairments in functions of the nonlanguage–dominant hemisphere. 3. Predominant memory deficits are associated with temporal foci. 4. Predominant executive deficits are associated with frontal foci (see also Table 92.4). The performance on psychological tests is reported in percentiles, standard scores or developmental/mental age scores. Mental age scores have a descriptive appeal, but it must be kept in mind that they are only on an ordinal-scale level and that the meaning of differences systematically shrink with age: a 5-year-old child functioning with a mental age of a 3-year-old might be quite impaired, while a 14-year-old functioning at a 12-year-old level might be only moderately behind. Percentile scores have an advantage over mental age scores because they maintain their meaning at different ages. However, they are also on an ordinal scale level and the unit of measure varies across the range (e.g., a 20-point difference is insignificant in the middle but very meaningful near the tail of the distribution). Standard score scales (e.g., z-, IQ-, T-Scores) report scores in standard deviation (SD) units from the

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Pre-surgical neuropsychological workup in children and intellectually disabled adults with epilepsy Table 92.4

Studies on cognitive functions in pediatric patients with focal epilepsy

Study

N

Measure

Results concerning group differences

Adams et al.64

16 LTLE 12 RTLE

LTLE declined in verbal memory after surgery.

Cohen et al.65

12 LTLE 12 RTLE 14 ETLE 28 TLE; 18 IGE, 13 LTLE 16 RTLE 12 FLE 12 TLE

WMS, RCFT, TROG/Grammar test, Shortened Token Test Comprehensive Children’s Memory Scale Signoret’s Memory Battery Scale

Jambaque et al.66 Beardsworth & Zaidel67 Lendt et al.47

Culhane-Shelburne et al.68

12 FLE 15 TLE

Gleissner et al.42

26 LTLE 26 RTLE 16 FLE 8 TLE 8 GEA 16 FLE 8 TLE 8 GEA 17 LTLE 18 RTLE 25 FLE, 32 TLE 13 GEA

Hernandez et al.69 Hernandez et al.70 Mabott & Smith71 Nolan et al.72

837

Memory for faces Verbal fluency, Mazes, VLMT, DCS-R WISC-R, Motor coordination Reaction times, Corsi Block Design Digits, Token Test, Letter cancellation TOVA, TOL, CVLT WRAML, Twenty Questions Test, Stroop Color-Word test, VABS VLMT, DCS-R Purdue Pegboard, Self-ordered pointing task, motor coordination, WCST, TOL, Verbal Fluency. CVLT, CPT, WISC-III RCFT, CBCL CAVLT, RCFT face recognition WRAML

LTLE impaired in verbal memory. RTLE impaired in nonverbal memory. LTLE lower performance in verbal tasks. RTLE defective visual memory. RTLE < LTLE in memory for faces. FLE more impaired in motor coordination, FLE higher IQ-level. FLE deficits in planning and executive functions and mal-adaptive functioning. TLE deficits in memory. LTLE had a significant decline in verbal memory after surgery. FLE deficits in planning, impulse control, fluency, and motor coordination. FLE were more impaired in attention, impulse control, working memory, perceptual organization, and behavior than the other groups. Significant post-operative difference in memory for faces (RTLE < LTLE). TLE more impaired in memory than FLE.

The table illustrates the fact that several studies observed functional deficits in children often associated with a focal epilepsy similar to those reported in adult patients. Therefore, the table is not comprehensive; it presents only a selection of studies on cognitive functions in pediatric patients with focal epilepsy. CAVLT = Children’s Auditory Verbal Learning Test; CBCL = Child Behavior Checklist; CPT = Continuous Performance Test; CVLT = California Verbal Learning Test; DCS-R = Diagnosticum für Cerebralschädigungen-Revision; FLE = frontal lobe epilepsy; GEA = generalized epilepsy with absences; IGE = idiopathic generalized epilepsy; LTLE = left temporal lobe epilepsy; RAVLT = Rey Auditory Verbal Learning Test; RCFT = Rey Complex Figure Test; RTLE = right temporal lobe epilepsy; TOVA = Test of Variables of Attention; TLE = temporal lobe epilepsy; TMT = Trail Making Test; TOL = Tower of London; VABS = Vineland Adaptive Behaviour Scales; VLMT = Verbal Learning and Memory Test; WCST = Wisconsin Card Sorting Test; WISC-R = Wechsler Intelligence Scale for Children–revision; WISC-III = Wechsler Intelligence Scale for Children–third version; WMS = Wechsler Memory Scale; WRAML = Wide Range Assessment of Memory and Learning.

normative sample’s mean. To understand and interpret standard scores, one must know the mean and SD of the scale on which it is based (e.g., 100 ± 15 for IQ-scores, 50 ± 10 for T-Scores). Standard scores allow for a more direct comparison of the different measures in the different age groups. A deficit is usually assumed if the test result is more than one SD below the mean. A deficit is specific if it is more than one SD below the test results in other functions. Thus, if a child exhibits memory problems, but also has difficulties in attentional, visuospatial and language functions, one would not diagnose a prominent temporal lobe dysfunction, but would rather assume diffuse functional damage. On the other hand, average verbal memory functions in an epileptic child with otherwise above average results might be considered as an indicator for a left temporal lobe dysfunction. It should be kept in mind that neuropsychology never diagnoses epilepsy. Classifying test results into a cognitive pattern does not prove a causal relation with epilepsy. However, if a cognitive pattern with weaknesses and strengths is consistent with a focal deficit in the context of general assumptions about brain organization and if it is consistent with other, particularly functional findings (e.g. EEG, functional

imaging), it is of course plausible to assume that the performance is influenced causally by the disease. Intelligence tests usually do not localize or lateralize to specific brain regions or hemispheres. It is tempting, but not justified by empirical evidence, to interpret a difference of the verbal and performance IQ of the Wechsler Intelligence Scale for Children (WISC-III) or between the scales of simultaneous and sequential processing of the Kaufmann-Assessment Battery for Children (K-ABC) in terms of lateralization. Subtests of intelligence tests often cross multiple domains. However, if it is possible to decide the cause of a child’s failure, this can provide valuable localizing information within the general context of the other tests. For instance, the ‘picture arrangement’ subtest of the Wechsler intelligence test requires that the child sorts cartoon pictures to make sensible stories. This can be impaired because of slow speed, a deficit in visual-motor integration, an impulsive mental style, or a comprehensional or conceptual deficit. Asking a child to tell the story helps one understand why a child fails the task. But please note that a real process approach during testing (i.e., determining what a child needs for successful performance as a means of determining which cognitive processes are not fully

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operational) – although very useful in neuropsychological training and rehabilitation – cannot be applied in the field of pre- and post-operative evaluations because this would distort the results of the retest. The observation in a face-to-face interaction provides indispensable additional information. For instance, as a basic function, an attentional problem can lower the performance in all of the other tests, but relevant attentional tasks can also be failed due to an impairment in the other processes. In practice, the psychologist will rely not only on the test results but also on his clinical observation of the child’s alertness, his ability to focus on the task in hand, reactions to distracting stimuli, and the ability to sustain effort throughout time. The interpretation of performance will therefore rely not only on the profile of the test results but also on the observation of the child during the examination and on information given by the caregivers and other relevant persons (e.g., teachers). Brain maturation One of the main differences between an adult brain and that of child or adolescent, is that the child/adolescent brain is still engaged in significant developing processes. The enormous changes that occur, including an overproduction of dendrites and synapses and their consecutive pruning during the first years of life, are well known. The sequence in which the cortex matures shows parallels to the cognitive and behavioral development.10 Regions subserving primary functions, such as sensory and motor systems, mature earliest. Temporal and parietal association cortices associated with basic language skills and attention mature next. Higher-order association areas, such as the prefrontal and lateral temporal cortices which integrate sensorimotor processes and modulate attention and language processes, mature last. However, it has become clear in recent years that the process of postnatal brain maturation is long and lasts at least into early adolescence. Although the total brain size is approximately 90% of its adult size by age six, the gray and white matter subcomponents of the brain continue to undergo dynamic changes throughout adolescence. Data from recent longitudinal studies which use modern imaging tools as magnetic resonance imaging (MRI), functional MRI (fMRI), and diffusion tensor imaging indicate that, while white matter volume increases in a roughly linear pattern until approximately young adulthood, gray matter has an inverted U-shaped pattern with a regional variation.11 Developmental curves for the gray matter of the frontal and parietal lobes peaked at about age 12, the temporal lobe at about age 16, and the volume in the occipital lobe continued to increase through age 20. Ongoing maturation of the temporal lobes during adolescence is also indicated by electroencephalographic and postmortem studies.12,13 At least three possible implications of this immaturity for the neuropsychological evaluation of pediatric patients with epilepsy have to be discussed: 1. The function of a specific neural area may change over time. Several studies indicated that children recruit more diffuse prefrontal regions when performing executive tasks, and that the pattern of activity within brain regions with task-related activity becomes more focal or finetuned with age, whereas brain regions with task-unrelated

activity decrease in activity with age.14 However, similar results were obtained in adult learning studies.15 Thus, it is likely that task-related activation of more extended or different areas in children is due to differences in training or strategy. A regional qualitative change of functions during development would not be economic and does not fit with the assumption that learning and experience guide cerebral development processes. Therefore, we regard it unlikely that functional brain organization is qualitatively fundamentally different in children. 2. Due to brain maturation, the extent of an impairment may not become obvious until the underlying brain structure is fully mature. Table 92.4 provides a selection of studies reporting neuropsychological results in children with focal frontal or temporal lobe epilepsy with functional associations similar to those reported in adults. Of course, this does not exclude the possibility that those functional deficits might strengthen when the children grow up. A deficit can also become more imposing when daily tasks become more demanding. The demands for self-organizational abilities, for instance, are relatively low at school because school provides a highly organized structure. The issue of a ‘growth into the deficit’ can be answered only in a longitudinal design. In their longitudinal study, Bjoernaes et al.16 found some evidence that children may experience a greater decline of intellectual functioning than adults over the years of a severe epilepsy. However, the adult patients also had a significantly longer duration of epilepsy and started with a significantly lower performance at the time of the first test. There are a few single case reports about children with frontal damage, whose deficits were not apparent until they were grownup.17 However, in the literature one gets the impression that this is the exception rather than the rule. 3. Brain damage in infants and children may produce different effects because it can alter the basic functional brain organization. When interpreting test results, it is essential to keep in mind that brain damage in infants and children can more easily alter the basic functional brain organization than in adults. The preservation of language functions seems to be particularly important for the brain. A reorganization of visuospatial functions with a suppression of language functions has not yet been described but a suppression of nonverbal functions in patients with an interhemispheric reorganization of language is a robust finding.18,19 Language is usually thought to be lateralized by the age of 6 years. After the age of 5, the potential for language to reorganize from the left to the right hemisphere appears to decrease rapidly.23 A high incidence of atypical (i.e., right- or bilateral) language representation in patients with early left hemisphere insult has been well documented.18,20 Atypical language due to a damage beyond adolescence is very rare and probably reflects a genuine right hemisphere participation in language. In patients with epilepsy, it is presumed that not only lesions but also epileptic dysfunction can cause a language shift. Thus, a relatively small lesion which is not necessarily proximal to classic anterior or posterior language areas associated with epileptic activity can be sufficient for an interhemispheric transfer.21 Characteristic features of adult patients with atypical language dominance are left-hemispheric

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ith dr a An C om wal xi ou s/ pla So Dep ints re c ss Th ial ou Pro ed At ght ble te Pr ms nt io obl e n Pr ms ob D el lem in In qu s te rn Ag enc Ex ali e g te zin res g rn si Pr on al iz in obl e g Pr ms ob To lem ta lS s co re

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Patient intrinsic difficulties Behavioral problems As both chronic illness and CNS disorders are risk factors for behavioral problems, the frequency of behavioral disorders is much higher for patients with epilepsy. The prevalence of behavioral problems is below 10% for the general childhood population. In pediatric patients with epilepsy, rates between 30% and 50% have been reported for behavioral problems, while rates of approximately 20% have been reported for children with other chronic physical illness not involving the central nervous system (i.e., diabetes mellitus or cardiac disease).28 Behavioral problems include anxiety, aggression,

% 50 45 40 35 30 25 20 15 10 5 0

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The assessment of language representation can be more difficult in children than in adults. The determination of language representation by the IAT (Intracarotid Amytal Test) is more often applied in adults than in pediatric patients. The IAT temporarily inactivates one hemisphere by the injection of sodium amytal or, more recently, also with brevimytal by a catheter through the internal carotid artery. Difficulties in performing the angiographic portion of the procedure in conscious children are frequent and sedation interferes with language testing. Although IAT language testing has been successfully obtained in children as young as seven years of age,24 children under ten years of age and intellectually disabled patients are sometimes not able to cooperate actively in the IAT situation.25 The same is principally true for language assessment with fMRI, although there have been attempts to develop child-friendly functional magnetic resonance imaging paradigms for children too young or too impaired to execute an active task.26 The baseline testing used to get the child familiarized with the procedure, and use of a pediatric protocol with simpler pictures and familiar words is recommended also in the IAT in order to maximize cooperation and the validity of the results. Near-infrared spectroscopy (NIRS), transcranial magnetic stimulation (TMS) and contrast transcranial Doppler sonography (CTCDS) provide interesting and valuable options for assessing language dominance in children, but these methods do not yet show a breakthrough. It is still widely assumed that less dysfunction will result from a brain lesion if a child is younger at the time of a neurological insult, because plasticity processes can counterbalance the damage. This believe came up mainly because early hemispherectomized children often showed a respectable development and school achievement after surgery, but the general assumption is not true in light of the present data. An early cure of epilepsy can result in an impressive developmental catch-up, but early damage during the first two years of life in general is destructive for cognitive development and often results in global intellectual impairment.27 Interhemispheric functional reorganization probably is an emergency solution for the brain. The resulting performance level for the rescued function is not unimpaired and it is not without cost as has been shown by the suppression of nonverbal functions in patients with an interhemispheric language reorganization.

oppositional behavior, autistic features, depression, and hyperactivity. Behavioral problems can already be observed in children with new-onset seizures.29 Risk factors for behavior problems in childhood epilepsy include neurologic dysfunction, side-effects of antiepileptic medication, seizure variables as an early onset and a higher frequency and a stronger severity of seizures.30,31 No significant associations have been found with the side and site of epilepsy.32 The family environment variables (e.g. family stress, family mastery, and extended social support) are also significant predictors of behavioral problems in childhood epilepsy.33 Symptoms of depression, reported in approximately one-quarter of children and adolescents with epilepsy,34 were correlated with a negative attitude toward seizures, lower satisfaction with family relationships and no internal locus of control. This points to the relevance of early educational programs that should support the family and the patient in order to reduce the risk of depression and anxiety. Behavioral problems are diagnosed by a combination of the anamnesis of the patient and the parents, the observation of the patient during the examination and standardized questionnaires (see Table 92.3). The Child Behavior Checklist (CBCL35) and the Conners Behavioral Rating Scales36 are among the most widely used instruments for assessing behavioral problems. They provide parent-, teacher-, and self-ratings. The CBCL is introduced as an example. It consists of 120 items that describe specific behavioral and emotional problems, plus two open-ended items for reporting additional problems. Also included are scales for measuring social problems, anxiety and depression, somatic complaints, attention problems, thought problems, delinquent and aggressive behavior. On a superordinate level, a score for Internalizing Problems (e.g., anxiety, depression), a score for Externalizing Problems (e.g., aggression, delinquent behavior), and a Total Problem score can be derived. The newest form (ASEBA) is for children between 1.5 and 5 years.37 Children with epilepsy exhibit prominent problems, particularly in the scale of internalizing problems and in the subscale indicating attention problems (Figure 92.1, see also ref 29). It should be noted that for children with epilepsy, it is important to consider, that a few items describe the consequences of a chronic illness or aspects of

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damage, an early onset of epilepsy, atypical hand dominance, a predominance of extratemporal lesions and a strong deficit in nonverbal memory. The same characteristics have been described also in children.19,22,23

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Figure 92.1 Child Behaviour Checklist : % with deviant performance (T-Scores ≥ 67 for the subscales, ≥ 60 for the superordinate scales) in our unselected clinical population of pediatric patients (in between 526 and 539).

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seizure semiology rather than the behavior problems. Oostrom et al.38 found that rescoring the CBCL by seven ambiguous items∗ reduced the percentage of patients trespassing the clinical cut-off score considerably in newly diagnosed patients while rescoring had no effect in healthy children. A recent study in pediatric epilepsy patients who were assessed pre-operatively and one year after successful surgical treatment indicated the CBCL as a valid assessment tool in children with epilepsy73. The parents of children with epilepsy should nevertheless be instructed that seizure should not be included in the ratings to avoid a confusion of behavior problems with seizure semiology. Post-operatively, impressive improvements of behavioral disorders have been reported.39,30 Post-operative behavioral improvements can often explain the positive changes in school and social life as reported by the parents despite no obvious improvements in the neuropsychological examination. Guidelines for a valid neuropsychological assessment of children A reliable and valid assessment implies that a child has put forth appropriate effort. Some guidelines that optimize a valid neuropsychological assessment of children are briefly outlined here; a comprehensive description is available in Baron.2 Testing is often stressful for the child and produces anxiety especially at the beginning when the structure of the situation and the examiner are still unfamiliar. At the beginning of the test, informal conversations about a special interest or favorite activity increase the child’s comfort level and allow the examiner to formulate initial clinical impressions. The purpose of testing should be explained as should information about what will happen during the session and how long it will approximately take. This will reassure the child. It should be emphasized that the child tries his best but failures are unavoidable, because some tasks are designed to push the test-taker to his limits and no child will always be correct. Children are often reassured when told that a hard item is actually intended for an older child. Praise should be given for the effort that the child made. Difficult tasks should not be given at the beginning, if it is compatible with a standardized sequence of the tests. Suitable first tests are drawings or simple verbal or motor tasks if they do not emphasize an expected weakness. A low level of cooperation and motivation can be expected particularly in children with conduct disorder, attention deficit disorder, and in younger children. In the latter, attentional persistence and tolerance to failure are limited and the children are less able to comprehend the relevance of the situation. This is probably one reason why intelligence measures during early childhood and preschool measures are far less predictive of later functioning than assessments taken during middle childhood. Highly active children require considerable structure and guidance from the examiner and it can be necessary to set firm limits for those patients. Informing the child that if the examination is not completed, there will be another visit might sufficiently motivate a defiant child to continue. If the child is extremely resistant, it might be appropriate to terminate and continue another time. It is absolutely crucial that the examiner adjusts to the individual child to optimize the child’s motivation. ∗The items are Nr. 13 “confused, seems to be in a fog”, Nr. 17 “Daydreams”, Nr 46 “Nervous movements or twitching”, Nr. 80 “Stares blankly”, Nr. 84 “Strange behaviour”, Nr. 107 “Wets during the day”, and Nr. 108 “Wets the bed”.

Predictors of post-operative neuropsychological outcome in pediatric patients with epilepsy As in adults, the location and extent of surgery in children influences the neuropsychological outcome. However, due to additional factors such as ongoing maturational changes and physiological and functional plasticity, the impact of epilepsy surgery on brain functions could depend also on the maturational stage of the child at the time of epilepsy onset and the time of surgery. Early surgery may prevent the disturbance of brain development by epileptic activity and enable the brain to recover more completely from the consequences of the surgery due to structural and functional plasticity. All in all, the available data indicate that early surgery in pediatric patients is beneficial.40–43 It has been observed in individual patients that a cognitive decline was stopped or that development was advanced by successful seizure control after surgery.44 However, group data on cognitive outcome after epilepsy surgery indicate that surgery is usually not followed by markedly improved intellectual development, but there seem to be fewer additional deficits induced by surgery and a better recovery than in adults.45 With respect to temporal lobe resections, studies which have found no evidence of post-operative decline outweigh those studies revealing a loss.46 Risk factors for a post-operative memory decline are a left-sided resection, a higher pre-operative performance, a shorter post-operative retest interval and a longer duration of epilepsy. One study investigating the cognitive outcome after frontal surgery observed improvements in measures of memory and attention. Seizure outcome was not a predictor of cognitive outcome in this study.47 After a hemispherectomy, the intellectual functions usually remain unchanged,48 although more positive results could probably be obtained if the assessment of psychosocial features (e.g., level of integration in the family, at school or at work) would be assessed instead of the IQ. Etiology seems to be a relevant factor for the pre-operative level and the postoperative course.49 Very favourable results have been obtained with regard to the post-operative cognitive development for patients with Sturge-Weber-Syndrome and an early epilepsy74 Patients with hemimegalencephaly have a worse outcome than other etiological groups probably due to the presence of bilateral structural and epileptic anomalies.43 An earlier age at the time of surgery has been shown to be prognostically good in patients with hemispherectomy.43,40 For those patients undergoing a callosotomy, behavioral improvement is one of the major surgical benefits.50 In the series of Sauerwein et al.41 only mild or moderate mental deficiency before surgery was the most reliable predictor of postoperative cognitive gains. The age at the time of surgery had an effect on the course of recovery from post-operative sequelae – patients younger than 13 years recovered more rapidly and more completely and had almost no disconnection deficits in simple tactile interhemispheric transfer tasks. All patients aged 13 years and older displayed permanent disconnection signs. Bilateral language and dissociated language dominance patterns can be considered an exclusion criteria for a callosotomy. It should be considered that developmental gains may need longer periods to accumulate. Freitag and Tuxhorn51 observed a significant increase in the developmental quotient after surgery for preschool children only after a follow-up interval of 2–3 years. Westerveld52 reported that a longer post-operative retest interval (range 5–60 months) was a significant predictor for a gain in performance IQ.

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Neuropsychological pre-surgical workup in intellectually disabled adult patients Intellectual disability (ID) is found more frequently in patients with medically intractable epilepsy than in the normal population. Its prevalence has been estimated at 35% for those patients with an early onset of epilepsy.53 It should be noted that the term ‘mental retardation’ has become stigmatizing and should be avoided. ID is pragmatically defined as a measured IQ of greater than two standard deviations below the mean (IQ ≤70), such that approximately 2 – 3% of the population would be defined as intellectually disabled. Further diagnostic criteria are according to DSM-IV, an onset of ID before age 18 and significant limitations in adaptive functioning in at least two skill areas (e.g., communication, home living, social/interpersonal skills). According to the diagnostic manuals, there are four severity grades of intellectual disability (see Figure 92.2). Intelligence tests (see Table 92.2) are not suited for assessing more severe ID, since IQ test scores usually end between 10 and 50. Therefore, it is useful to also apply a measure of adaptive functioning, usually in the form of a semistructured interview with the parent or caregiver. Instruments which assess functional capacities in a wide array of domains including daily living skills, communication skills and socialization are the Vineland Adaptive Behavior Scales-II (VABS-II,)54 and the second edition of the American Association of Intellectual disability Adaptive Behavior Scales.55 Pre-operative neuropsychological diagnostics refer not only to the absolute level of performance, but also to the diagnostic information given by the pattern of strengths and weaknesses in the cognitive profile. In the majority of intellectually disabled patients, many functions are equally impaired and the test results often indicate a diffuse functional impairment without a performance minimum of localizing value. More often, a performance maximum in a single function indicates relative functional integrity of a region, but this is, of course, of minor relevance from a pre-surgical diagnostic point of view. Finding tests for the assessment of specific neuropsychological

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functions in patients with ID is more difficult. Although most of the neuropsychological tests listed in Table 92.3; can be applied to patients with mild intellectual disability (e.g., Boston Naming Test, semantic fluency, recognition form of the Benton Visual Retention Test), the floor effects often prevent an adequate mapping of performance changes. Therefore, it might be more appropriate for the documentation of the post-operative course in patients with ID to compare raw scores rather than standard scores. Application of tests originally designed for children can be considered to quantify performance in intellectually disabled patients who can not cope with the test versions for adults. Behavioral problems are more frequent in intellectually disabled patients and can further complicate the neuropsychological examination. A health-related quality of life questionnaire (e.g., QOLIE-89)56 should also be used, to optimize mapping of the post-operative outcome. A proxy report form can be used in those patients, who are not able to fill out the questionnaire themselves. Patients with epilepsy and intellectual disability are often difficult to treat. Drug resistance is more frequent in patients with intellectual disabilities. In a long-term study conducted by Huttenlocher and Hapke,57 70% of the patients who had an IQ F5>F3). The frequency was once every 30–60 seconds during awake and once every 5–10 seconds during sleep (Figures 100.1 and 100.2). In addition, bursts of bifrontal, max left (FP1>F3>F5) paroxysmal fast activity, of 3–5 seconds duration, were seen during sleep, once every 10 minutes approximately. Thirty seizures were recorded during EMU stay, mainly during stage I and stage II sleep. Seizure semiology was very similar in all seizures: the patient suddenly woke up, sat up in bed and displayed high amplitude movements of trunk and arms (as if he was trying to reach for objects) and repeated vocalizations, with lack of response. Seizures’ duration ranged between 30–60 seconds. The patient recovered quickly, without postictal confusion. He was amnestic for all that happened during the seizures. Ictal EEG showed a generalized electrodecremental pattern, followed by fast paroxysmal activity (15 Hz/10 mV) over the left frontal region (max Fp1>F3>F5>Fp2>Fz). After 4–8 seconds, this activity evolved to a higher voltage theta rhythm (5–7 Hz/40-60 mV) which was lateralized over the left hemisphere, soon obscured by muscle artifact. After the seizures, focal continuous slowing was evident over the left frontal region. Injection of radioisotope for ictal SPECT happened 22 seconds after seizure EEG onset. MRI showed a dysplastic lesion over the medial part of the left superior frontal gyrus and the polar portion of the orbital region, compatible with cortical dysplasia (Figure 100.2): Ictal SPECT co-registered with MRI showed increased perfusion over the more anterior and mesial part of the malformation of cortical development (Figure 100.3). Neuropsychological study showed intellectual level in the low-medium range. There was some psychomotor slowing in fine visuomanual coordination tasks and execution of movement sequences, together with slowing and fluctuations in verbal learning ability. Psychiatric evaluation showed mildly depressed mood without obvious need for antidepressant drugs. All physicians attending the conference agreed that the patient had medically intractable left frontal epilepsy with hypermotor seizures due to cortical dysplasia over the left frontal region (Figure 100.4). It was clear that the patient had medically intractable epilepsy and that his seizures were significantly interfering with his daily life. The neurorradiologist and the neurosurgeon were asked about the proximity of the lesion to the expected location of Broca’s area. Both concluded that the lesion was outside this area, and the neurosurgeon concluded he could safely resect the abnormal region on MRI. The patient and his family were informed about the procedure, possible benefits, and risks of surgery. He was given an approximately 60% chance of seizure cessation. The malformation was resected. Pathology showed heterotopic neurons

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Figure 100.1

Repetitive frontopolar spikes.

Figure 100.2

Repetitive frontopolar spikes.

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Figure 100.3 Coronal T1-W image showing malformation of cortical development over the left mesial frontal region.

and balloon cells. The patient has been seizure free since surgery. There was a temporary behavior abnormality (the patient was apathetic, with lack of inititative, and unwilling to get up and move) for 6 or 7 days after surgery. This seemed to resolve after discharge, and he has currently returned to his normal life. Case 2 B.P.A. is a 32-year-old left-handed woman with seizures since the age of 27. She had no significant risk factors or family history of epilepsy. Seizures were characterized by an aura described as ‘nervousness, together with a warm rising sensation’. Rarely she felt an auditory aura (beep in her ears, which she could not further localize). The aura was followed by a change in facial expression and clenching of both fists, without clear oral or manual automatisms. There was partial loss of awareness. At times, however, she was able to follow simple commands at the beginning of the seizure and the family stated that she was able to speak intelligibly during seizures, although sometimes the content of the sentences was inappropiate. Seizures lasted 1–2 minutes and thereafter she was slightly confused for another 4 minutes. She had never had a secondarily generalized seizure. Seizure frequency was initially one every 10 days, but had progressively increased in spite of treatment with antiepileptic drugs. Seizures happened on a daily basis when she was first referred to us. She had failed treatment with carbamazepine, topiramate, and lamotrigine. She currently was treated with oxcarbazepine (1200 mg per day) and clobazam (20 mg per day).

Figure 100.4 SISCOM showing hyperperfusion over the cortical dysplasia in the left mesial frontal region.

She was admitted to the Epilepsy Monitoring Unit in 2004. Right temporal sharp waves were seen, with a maxium over the middle temporal region (T4>FT8>FT10), once every 5 minutes (Figure 100.5). In addition there were left anteriotemporal sharp waves (max FT9>F9>T7, TP7), seen less frequently (once every 20 minutes of recording) (Figure 100.6). Five seizures were recorded, which were characterized by changing in facial expression, loss of awareness, and subtle oral automatisms, with ictal speech. There was no postical dysphasia. Seizures were nonlateralized on surface EEG, being characterized by irregular theta slowing over both temporal regions (Figure 100.7). Isotope for ictal SPECT was injected after 40 seconds of EEG onset. The MRI showed a lesion in the white matter of the right temporal lobe compatible with cavernoma (Figure 100.8). There were no alterations in morphology or signal intensity of both hippocampi. Gradient sequence did not identify signs of bleeding in any other locations. Ictal SPECT co-registered with MRI showed increased focal perfusion over the mesial and basal region of both temporal regions, more pronounced on the left side (Figure 100.9).

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Figure 100.5

Right anterior and middle temporal sharp waves.

Figure 100.6

Left anterior temporal sharp waves.

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Figure 100.7

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Ictal surface EEG. Nonlateralized theta.

Wada test showed right hemisphere dominance for language (she became mute after right carotid injection, while she continued to talk after left injection), with good functional memory reserve on the left side. Neuropsychological study showed intellectual level in the normal range, with a subtle deficit in verbal fluency tasks (mainly with semantic clues), a slightly inferior than expected performance in naming and a slow verbal learning curve. No alterations in memory were seen. All these subtle difficulties suggested an initial involvement of dominant temporal structures. Psychiatric evaluation showed mild depression. During the patient management conference it was concluded that the patient had medically intractable temporal lobe epilepsy, probably secondary to cavernous angioma located on the right temporal neocortex. However there was some concern that the seizure onset zone had not been adequately lateralized during the pre-surgical evaluation (the pattern on surface EEG was bitemporal, and also the ictal SPECT co-registered with MRI suggested a bitemporal ictal onset). In addition, ictal speech suggested seizure onset in the nondominant hemisphere which was discordant with the findings in the Wada test. After discussing risks and benefits, it was concluded that the patient would be offered video-EEG with placement of foramen ovale electrodes (FOE) to better lateralize the seizure onset zone. The possibility that seizure onset could not be accurately recorded with the FO electrodes if arising from the temporal neocortex was also discussed. The patient agreed to the semi-invasive evaluation. Interictal EEG showed abundant epileptiform activity over the contacts which were closest to the mesial structures on the right side (Figure 100.10). Seizure onset was also in the right temporal mesial region (Figure 100.11). The patient was discussed again in another patient management conference and the best surgical technique was discussed.

Everybody agreed that she should have a lesionectomy, leaving the right hippocampus in place, in view of its normal apperance in MRI, to avoid memory loss. The patient underwent resection of the cavernoma in April 2005. She has been seizure free since then. Neuropsychological evaluation has shown no memory decline.

Figure 100.8 T2-Weighted coronal MRI image showing right temporal covernoma.

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Figure 100.9

SISCOM showing increased perfusion over both temporal lobes, more pronounced on the left side.

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Figure 100.10

Interictal EEG with foramen ovale electrodes showing repetitive spikes over the right contacts.

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SECTION 13 Surgical techniques for placement of intracranial electrodes

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Anesthesia for epilepsy surgery M Lotto and A Schubert

Introduction Epilepsy surgery adds a level of complexity to the anesthetic care of the neurosurgical patient. Anesthetic selection significantly impacts surgical procedures which require intraoperative mapping of the epileptic foci or identification of eloquent tissue during resection of epileptogenic tissue. Designing an anesthetic that can produce varying depths of patient sedation and the patient participation necessary for speech and motor mapping requires forethought, skill and occasionally luck. In addition, anesthetic agents have a wide variation and sometimes confusing profile of proconvulsant and anticonvulsant effects that must be taken into consideration. There are also significant pharmacologic interactions between anticonvulsant medications and anesthetic drugs. Developing an anesthetic care plan that facilitates the patient’s best interests and the intraoperative goals of the surgeon and neurophysiologist requires intimate knowledge of the pharmacology of the patient’s antiepileptic medications and the anesthetic agents. Good communication between the anesthesiologist, surgeon and neurophysiologist is critical in achieving patient safety and a successful procedure. This chapter presents an overview of the anesthetic care of the epileptic patient undergoing epilepsy surgery, with a focus on the pharmacology of common anesthetic agents and how these drugs impact both epileptic surgical procedures and perioperative events in epileptic patients.

Pharmacology of anesthetic agents Given the modification of neuronal transmission generated by anesthetic agents, it is not surprising that these drugs can have significant effects on CNS excitation events. However, the literature describing the pro- versus anticonvulsant effects of many anesthetic agents can be confusing and seemingly contradictory. One may produce reports which implicate the same drug in both precipitation and termination of seizure activity.1,2 The mechanisms behind the conflicting convulsant effects of these agents are not completely understood. However, several authors attempted explanation by proposing that the ratio of affected inhibitory or excitatory neurons in both the cortical and subcortical brain structures varies with depth of sedation. EEG recording supports altering activation and inhibition of the cerebral cortex with administration of anesthetic agents. During light sedation reveals cortical activation with higher frequency beta activity which then progresses to slow wave activity as sedative/anesthetic depth increases.3

Some of the confusion may also be attributed to the method of documentation of epileptic activity used in the case reports of anesthetic drug related seizure activity. Several induction agents, such as propofol and thiopental, have been demonstrated to induce myoclonic activity not associated with EEG excitatory activity4; while others agents (etomidate, methohexital) have been shown to generate both myoclonus and EEG documented epileptiform activity in patients.5 Sedative hypnotic agents As a group, these agents have the greatest variation and most confusing profile as far as effects on epileptogenic activity. Most of the agents can generate neuroexcitatory effects when used at low doses, and neurodepressive effects when used at higher doses. Motor stimulatory phenomena, such as myoclonus, opisthotonus, and tonic clonic activity may occur with varying frequency in both epileptic and nonepileptic patients during induction with these agents, however, only a few actually produce cortical electrical activity suggestive of seizures. Methohexital, etomidate and ketamine are known to activate EEG seizure activity when administered to patients with a history of epilepsy.6,7 Motor activity may not occur with the induction of abnormal spike wave activity. Both etomidate and methohexital have been used to assist with activation of ictal foci during intraoperative electrocorticography.8,9 These agents may also generate nonepileptic myoclonic activity during induction which can be mistaken for epileptic convulsions. Etomidate has a dichotomous effect on seizure thresholds, producing EEG confirmed epileptic activity when used as an induction agent in epileptic patients, as well as producing burst suppression and breaking status epilepticus when administered in higher doses.10,11 Ketamine appears to have a dose dependent threshold for seizure generation, with most reported cases of clinical seizure activity occurring when doses greater than 4 mg/kg are administered.12 Despite an early report of seizure induction with propofol injection, propofol has demonstrated a good safety record and low epileptogenic potential when used in patients undergoing epilepsy surgery. The anticonvulsant properties of propofol are fairly well established, although the antiepileptic effect may be shorter acting after discontinuation of propofol than thiopental.13,14 The short acting antiepileptic nature of propofol can be useful for sedation during epileptic procedures, generating fewer seizures in between monitoring periods than neurolept anesthesia.15 However, propofol has also been observed to decrease the frequency of epileptogenic spikes and to quiet existing seizure foci, particularly in the lateral and 923

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mesial temporal areas.16 In addition, propofol may generate beta EEG activity obscuring spike wave activity for up to 20 minutes following discontinuation of the infusion.17,18 See Figure 101.1. Therefore, propofol infusions should be discontinued 20–30 minutes prior to electrocorticography (ECoG) monitoring to facilitate successful location of the ictal foci.19 Barbiturates and benzodiazepines have substantiated anticonvulsive properties and are recommended for treatment of refractory status epilepticus.20 Volatile inhalational agents and N2O The epileptogenic potential of isoflurane, desflurane, and halothane appears low, and there have been no reported seizures when used in isolation.21 However, there are rare reports of myoclonic activity with a normal EEG. Convulsions with spike and wave activity on EEG have been reported with combinations of isoflurane and N2O.22,23 Although N2O has been associated with seizure generation when used to supplement other agents, it appears to be fairly inert in both the development and treatment of seizure activity in humans.24 Both N2O and isoflurane have been used for many years at multiple institutions with a good safety record in epileptic patients. Enflurane, used either with or without nitrous oxide, has been the most frequent offender with reports of intraoperative and postoperative myoclonus and EEG demonstrated epileptiform activity in both epileptic and nonepileptic patient populations.7,8,24–27 The incidence of EEG spike wave production with enflurane appears to be dose dependent. The end tidal concentration that triggers maximum epileptiform activity is reduced during hypocapnia. Enflurane has fallen out of favor as new inhalational agents have become available and it is currently rarely used clinically in the United States. Enflurane should be avoided in patients with a history of epilepsy, unless the desired effect is triggering seizures during ECoG. Sevoflurane, but not desflurane has been reported to generate convulsions as well as electrical spike waves in both epileptic and nonepileptic patients.21,28 Similar to enflurane, the frequency of spike wave activity with sevoflurane increases with dose escalation and hyperventilation.

Analgesics The effects of opioids on seizure threshold vary with opioid drug class. Synthetic opioids such as alfentanil, fentanyl, sufentanil, and the more recently introduced remifentanil are commonly used in neurosurgical anesthesia due to the short duration of action and ability to minimize cortical effects through continuous infusion. Synthetic opioids have been reported to have some proepileptic properties; however, the potency of seizure production is unclear. Bolus doses of synthetic opioids, such as alfentanil and remifentanil have been demonstrated to increase spike wave activity in the interictal foci of patients undergoing intraoperative EcoG.29,30 In fact, bolus doses of these agents may be useful in ECoG to facilitate location of the ictal cortex through stimulation of spike wave phenomenon with concomitant depression of background EEG. Fentanyl has been associated with epileptiform electrical activity in subcortical nonictal cortical tissue, therefore the author prefers to avoid the dosing range in which epileptogenic properties have been observed (17–25 µg/kg).31 The clinical history of the use of synthetic opioids in large numbers of epileptic patients undergoing ablative procedures suggest that synthetic opioids can be used safely in this patient population without significant increase in the risk of perioperative seizures. The neurostimulatory effects of the long-lived meperidine metabolite, normeperidine have been well documented. Normeperidine can accumulate with chronic oral or parenteral administration of the drug. The normeperidine metabolite is renally excreted and can accumulate to neurotoxic doses more rapidly in patients with renal insufficiency.32 Convulsions may occur in both epileptic and nonepileptic patients receiving repeated administration of meperidine. Concurrent administration of meperidine with anticonvulsants may increase the first pass metabolism of meperidine to normeperidine, making it a significant risk for epileptic patients treated with anticonvulsant medications.33 Morphine and hydromorphone used at clinically relevant doses do not appear to have significant proconvulsant activity.24

A9 - A10 A11 - A12 A13 - A14 A15 - A16 A17 - A18 A19 - A20 300 µV 1 SEC.

Figure 101.1 Beta-EEG activation 10 min after propofol injection (right temporal and central convexity). Reprinted with permission from Ebrahim ZY et al. Anesth Analg 1994;78:275–9.

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Anesthesia for epilepsy surgery

Muscle relaxants Chronic anticonvulsant therapy with phenytoin and/or carbamazepine can result in reduction of the duration of effect of nondepolarizing neuromuscular blockers, including pancuronium, vecuronium, rocuronium, atracurium, and cis-atracurium.34–36 The etiology of the phenomenon was initially contributed to induction of hepatic enzymes leading to faster breakdown of muscle relaxant agents. However, the resistance to nonhepatically metabolized agents such as atracurium and cis-atracurium suggest additional effects on metabolism and possible competitive interactions between neuromuscular blockade and anticonvulsants at the neuromuscular junction.37

Anesthetic goals Goals of anesthetic management In providing perioperative care for the patient undergoing epilepsy surgery, the anesthesiologist aims to give a continuum of critical care throughout the perioperative period. Intraoperatively, the common goals of neurosurgical anesthesia apply, including adequate brain relaxation for surgical manipulation, good systemic blood pressure control, and timely emergence from anesthesia to allow for early postoperative neurologic examination of the patient. Procedures requiring seizure induction for epileptic foci monitoring require avoidance of inducing a prolonged epileptogenic event or patient injury during an intraoperative tonic clonic event. In treating unintentional seizure activity the anesthesiologist weighs the therapeutic goals of seizure control against the potential for oversedation or interference with critical electrocortical monitoring.

Preoperative evaluation and preparation Seizure history The nature and manifestations of the patient’s seizures should be inquired about preoperatively. Epileptic activity can occasionally be difficult to discriminate from psychomotor behavior sometimes displayed during emergence delirium. Familiarity with the patient’s seizure pattern promotes recognition and awareness of perioperative seizures. In all cases, the anesthesiologist should maintain a high degree of suspicion for an epileptic etiology in a patient who has prolonged emergence, poor responsiveness, or repetitive motor movements in the postoperative period. Associated medical conditions Most patients presenting for epilepsy surgery are relatively young and fit from the cardiovascular and respiratory standpoint. Any patient with a significant end organ dysfunction or complex past medical history should have a comprehensive preoperative anesthetic evaluation prior to surgery. Open craniotomy is considered a moderate risk procedure (indicating a less than 5% risk of cardiac events) with regards to its taxing effects on the cardiovascular system of the patient.38 Several rare medical conditions associated with epilepsy may present significant challenges to the anesthesiologist.

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Patients with neurofibromatosis may have intracranial tumors, airway compromise from tumors involving the respiratory tract or from cranial nerve involvement. Pulmonary status may be compromised from chronic aspiration syndrome, pulmonary fibrosis, and pulmonary hypertension. Medication history Medication history is important for preoperative laboratory test selection and predicting intraoperative drug interactions. Antiepileptic agents have been demonstrated to have significant impact on the dose response curve for both nondepolarizing muscle blockers and opioids. Both phenytoin and carbamazepine are associated with resistance to nondepolarizing neuromuscular blockade37 and elevated liver function tests. The direct relationship between the number of anticonvulsants a patient receives, and the dose of fentanyl required for intraoperative anesthetic maintenance39 further suggests that anticonvulsant therapy predisposes resistance to opioids. Elevations in hepatic enzymes are prevalent (gamma-glutamyl transpeptidase is elevated in 75% and alanine aminotransferase in 25% of patients receiving anticonvulsant therapy).40 Asymptomatic laboratory abnormalities should not cause cancellation of the surgery, since elevated liver function tests are almost always a predictable result of anticonvulsant therapy. Sedation and lethargy are common side effects of many antiepileptic agents including newer therapies such as Lamotriqine and oxcarbazepine and may potentiate the central nervous system (CNS) depressant effects of anesthetics. Carbamazepine may cause a severe depression of the hemopoietic system and cardiac toxicity in rare cases. This drug’s metabolism is materially slowed by erythromycin and cimetidine, drugs which may be administered during the perioperative period. Valproic acid therapy results in dose related thrombocytopenia and platelet dysfunction.41 A bleeding time obtained preoperatively is indicated to assess the potential for increased perioperative bleeding. Phenobarbital, phenytoin, or valproic acid may theoretically increase the possibility of halothane hepatitis since they induce its hepatic metabolism.42 Recent craniotomy Small case series suggest significant pneumocephalus may be seen in post-craniotomy patients for up to 1 month after surgery.43 Avoidance of nitrous oxide in patients who have had recent placement of intracranial electrodes would thus be prudent. Psychologic preparation Preoperative consultation and discussion of expectations has a significant impact on the anxiety of the patient undergoing neurological surgery. Planned intraoperative corticography or awake craniotomy should always be preceded by a realistic description of what the patient will experience including expected discomforts, level of cooperation and tasks that will be performed for speech and memory testing, and the possibility of events that may require rapid interventions including conversion to general anesthesia. It is important that the anesthesiologist develop an excellent rapport with the patient during the preoperative period. The interview should include

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an assessment of the patient’s ability to cooperate during a planned awake procedure. Patients who are too young, are mentally impaired, have personality disorders, behavioral problems, or difficult airways should not be considered for ‘awake’ craniotomy. The age cut-off utilized at the authors’ institution is variable based on the adolescent’s maturity. Children under 14, however, rarely tolerate this procedure awake. Because intraoperative electrocorticography commonly requires significant reduction in the dose of sedative hypnotic agents for adequate EEG monitoring, patients should be prepared for the possibility of intraoperative awareness even when this procedure is performed under a general endotracheal anesthetic technique. The patient should be reassured that this experience is usually described as a painless awareness of voices or other sensations. Patients and their families need to understand that this is expected and that other risks such as perioperative seizure, nausea, vomiting, and airway compromise exist.

Intraoperative anesthetic approach Diagnostic surgical procedures for intractable epilepsy Placement of epidural (‘peg’) electrodes requires multiple burr holes and can be a lengthy procedure depending on the number of electrodes to be placed. ‘Depth’ electrodes exploring subcortical regions of the brain require stereotactic placement. The procedure is usually uneventful and not associated with significant bleeding. A general anesthetic is most frequently used at the authors’ institution. Unless otherwise indicated for medical co-morbidity, only routine noninvasive monitoring is employed. Implantation of subdural grid electrodes requires a full craniotomy. In our institution, this procedure does not generally involve EEG recording or stimulation as this is done postoperatively in the epilepsy monitoring unit. Therefore, we employ a standard anesthetic technique without special consideration for suppression of EEG components. As with any full craniotomy procedure, significant bleeding may occur from dural sinuses. This requires good IV access (two large-gauge IVs) and an arterial cannula. The anesthetic regimen should be constructed to allow rapid emergence for timely neurologic assessment. The electrode plates to be implanted are quite bulky and require brain shrinkage with mannitol and hyperventilation. One should be aware, hyperventilation to facilitate surgical exposure may precipitate seizure activity. It should be used only as necessary, with increased reliance on ancillary measures such as mannitol and/or loop diuretics. Furthermore, patients with complex partial seizures may have reduced CO2 reactivity of cerebral blood flow when compared to normal controls.44

Resection of epileptogenic brain regions under general anesthesia The anesthetic goals for these surgeries will depend upon the need to use intraoperative ECoG for seizure foci localization. Resection of epileptic foci under general anesthesia without the use of ECoG has goals similar to those of most open craniotomy procedures. These goals are to ensure lack of awareness,

immobility and hemodynamic stability, to facilitate brain relaxation, ensure rapid emergence so that neurologic status can be assessed and to avoid perioperative seizures. Benzodiazepine premedication can be given if EEG recording is not planned. Multiple studies have investigated the potential benefits of one anesthetic technique over another for providing hemodynamic stability, good brain relaxation and rapid emergence for evaluation of the patient’s neurologic examination. Many anesthetic combinations have been used with success. Recent studies suggest total intravenous anesthesia (TIVA) with propofol may have the benefit of providing lower intracranial pressures and better brain relaxation when compared to isoflurane or sevoflurane administered at >0.5 minimum alveolar concentration (MAC) in patients undergoing craniotomy with intracranial mass lesions.45 However, these benefits may be less clinically significant when lower MAC doses of volatile agent are used.46 Use of the ultra-short acting opioid remifentanil more consistently allow for rapid emergence and early neurologic examination than other opioids.47–50 Remifentanil has also been associated with better brain relaxation than fentanyl; however, this has not been a consistent finding in comparison studies.51–52 No prospective studies have been adequately powered to determine the impact of anesthetic technique on neurologic outcome after craniotomy. Additional goals for anticipated use of intraoperative ECoG include avoidance of drugs that will interfere with monitoring of seizure spikes and preventing unwanted generalization of interictal spike wave activity. Barbiturate and benzodiazepine premedication should be avoided as seizure threshold may be elevated, making EEG recording of epileptogenic activity more difficult. Antihistamines can activate seizure foci in these patients and should likewise be avoided as premedicants. Despite an isolated report of N2O-related diminution of epileptic foci during intraoperative electrocorticography,44 N2O can be used for these procedures. The use of low concentrations of isoflurane, sevoflurane (for induction of pediatric patients) or desflurane is permissible, provided these agents can be eliminated well before the onset of corticography. When no potent inhaled anesthetics are in use, scopolamine or droperidol can be substituted to prevent intraoperative recall with virtually no effect on the EEG. Alternatively, narcotic dosing is increased. Mild to moderate hypocapnia (PaCO2 = 30–35 mmHg), however, is often necessary to assist in brain volume control and brain relaxation. Isoflurane may decrease the frequency and spatial distribution of epileptogenic spikes, although it is unclear whether this effect persists at low concentrations.53 An intubation dose of short-acting barbiturate during induction is not contraindicated, but should be avoided later in the case, as should intravenous lidocaine. If cortical motor area stimulation is necessary, particular attention to the management of neuromuscular blockade and anesthetic dosing is appropriate. As a general rule, neuromuscular blockade must be minimal to allow motor stimulation. If moderate residual neuromuscular block persists, a small dose of anticholinesterase can be administered to achieve complete reversal. Occasionally, intraoperative EEG recording fails to reveal seizure spikes. After consultations with a surgeon and an electroencephalographer, doses of methohexital (10–50 mg increments),8,25 alfentanil (50 µg/kg)26 or etomidate (0.2 mg/kg)7

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Anesthesia for epilepsy surgery may be administered to help activate dormant foci. However, controversy exists over the correlation of seizure spikes elicited with these drugs to pathologic epileptogenic foci.

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Patients are best placed in the full lateral position to allow adequate access to the airway and avoid back or pressure point pain after prolonged positioning. The authors common approach to positioning these patients is to administer bolus doses of short acting sedation titrated to patient comfort levels (propofol 10–20 mg) during the placement of the local block and Mayfield head holder (if used) then allowing the patient to become conscious enough to cooperate in finding the most comfortable head and body position for the procedure. Although some surgeons choose to use a pin-type head holder to minimize head movement, the holder is not attached to the bed but is placed on a foam doughnut for comfort. Sudden movement is certainly undesirable during craniotomy, but it must be an anticipated event during awake craniotomy even with the best anesthetic technique. Patients may have confusion while emerging for the testing portion of the procedures and seizures may occur from mapping or from the patients’ underlying condition. Immobilization of the head may be dangerous in these situations. Excellent access to the patient’s face and extremities is required. The drapes need to be appropriately tented to allow a clear view of the patient’s face for both patient safety and adequate sensorimotor and speech and memory testing. Pillows are placed between the patient’s legs, between the back and the back support and in front of the patient allowing them to ‘hug’ the pillow. Potential pressure points are padded with foam or soft blankets. Drapes are carefully taped out of the way to allow good access to the face. Figure 101.2 demonstrates a configuration for operating room setup which the authors have found useful to facilitate the process. The development of short acting, rapidly titratable intravenous agents has made total intravenous anesthetic (TIVA) a more popular choice over the traditional neurolept anesthesia for the awake craniotomy procedure.56 Until recently the authors used a combination of propofol (75–150 µg/ kg/min) and alfentanil (0.25–0.75 µg/kg/min) or fentanyl (0.5–1 µg/kg/hr). These agents were then discontinued

Awake craniotomy for epilepsy surgery Awake craniotomy for resection of seizure focus is performed when tissue resection requires mapping of eloquent cortical tissue located proximal to the ictal foci. The technique may also be used to avoid anesthetic related interference with intraoperative ECoG. The anesthetic technique for awake craniotomy is more aptly described as variable depth anesthesia with periods of wakefulness. Various institutions and anesthetists have reported on favored techniques for ‘Awake’ craniotomies including periods of general anesthesia using a laryngeal mask airway or endotracheal intubation, or deep sedation with discontinuation of anesthesia for the period of speech or memory testing.54,55 Despite the development of multiple approaches to the problem, the awake craniotomy remains one of the more challenging anesthetics to provide and no method is without its pitfalls and limitations. Factors which support a successful procedure include: selection of a patient appropriate for the procedure, preoperative psychologic preparation of the patient, positioning which will be comfortable for the patient for an extended period of time, and a short surgical duration. There is no prospective data to suggest one approach is preferable to another. The following techniques represent the favored technique of the authors. Regardless of the anesthetic technique used, excellent scalp local anesthesia is required for patient comfort. Escalating the patient’s sedation to supplement an inadequate scalp block should be avoided as this will needlessly increase the risk of airway obstruction and oversedation during cognitive testing. Girvin described the technique which is utilized for local scalp anesthesia during craniotomy.17,27

Anesthesia machine

A Microscope Surgical drapes

IV pole

S

S Instrument table N

Figure 101.2 Operating room setup for right-sided craniotomy performed for the awake patient. Note the arrangement of the surgical drapes, which ensures access to the patient’s face. Reprinted with permission from Schubert A. Clinical Neuroanesthesia Boston, MA: Butterworth-Heinemann Publishers, 1997;4,66.

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15–20 minutes prior to the testing period. During testing, the authors preferred to reduce, but not eliminate the opioid infusion to maintain an analgesic background. For the last several years a newer anesthetic agent, dexmedetomidine has gained some favor due to its unique property of inducing a sedation more akin to natural sleep with minimal respiratory effects.57 Dexmedetomidine is given as a loading dose of 1 mcg/kg over 10 minutes and then infused at 0.6 mcg/kg/hr for the remainder of the procedure. A second agent is often required for adequate sedation during cranial flap opening and then discontinued for the testing period. The authors prefer to use a low-dose propofol infusion (25–75 mcg/ kg/min) that can be titrated to the desired sedation depth to supplement dexmedetomidine. Other authors have reported good experience with remifentanil combined with dexmedetomidine.58 Propofol is discontinued 15–20 minutes prior to intraoperative stimulation of motor, and speech areas to allow adequate time for patient emergence. Experience with dexmedetomidine has demonstrated that some patients require more intense effort to be roused from dexmedetomidine sedation (a physical stimulus such as sternal rub and calling of their name). However, once roused and engaged, the patient remains able to cooperate with cognitive testing. At least one institution has reported difficulty with cognitive testing in patients receiving dexmedetomidine during Wada testing. It is possible the excessive sedation was due to the use of additional sedative agents, such as benzodiazepines in combination with dexmedetomidine. Dexmedetomidine is known to have a significant second drug effect and the sedative effect will be greater when used in combination with other sedative agents.59 Frequently, surgical resection proceeds while the patient completes verbal tasks or reads from a large-print book (speech area assessment) or squeezes the tester’s hand (motor area assessment). Resection is stopped or modified at the first sign of speech difficulty or weakness. During cortical stimulation, the patient may be distressed by strange sensations and involuntary movements. Reassurance and comforting words go a long way, but occasionally mild sedation is also provided. More seriously, a seizure may be precipitated which requires prompt termination as well as assurance of a patent airway and adequate ventilation. Following the completion of the cognitive testing, sedation is then again deepened to the point of unresponsiveness as necessary.

Adverse events Sedation techniques for ‘awake’ craniotomy are associated with a significant incidence of complications, which can be managed safely under the management and close scrutiny of the experienced anesthesiologist. The traditional neurolept sedation regimen was associated with a 16% rate of convulsions, an 8% incidence of nausea and vomiting and at least a 2% rate of conversion to general anesthesia.54 Contrary to neuroleptanalgesia, propofol sedation techniques are almost completely devoid of intraoperative seizure risk. Yet, transient respiratory depression is much more prevalent with propofol compared to neurolept or dexmedetomidine-based techniques, where it is virtually absent.54

Seizure activity (especially with direct cortical stimulation) can be treated with propofol (0.75–1.25 mg/kg), or thiopental (1.0–1.5 mg/kg) depending on the need for subsequent EEG recording. At the end of the procedure, benzodiazepines and phenytoin may also be used.

Cerebral hemispherectomy On occasion, the seizure foci are so diffuse as to require resection of substantial portions of an entire cerebral hemisphere. Frequently, this procedure is performed in children and can be associated with significant morbidity and mortality, related to massive blood loss, electrolyte and metabolic disturbances, coagulopathy, cerebral hemorrhage, and seizures. Hemispherectomy requires a very large craniectomy, which increases the chance of bleeding and tearing of dural sinuses. Air embolism also has been reported and may lead to serious morbidity. Recently, three different surgical techniques (anatomical, functional, and lateral) for hemispherectomy were compared. Lateral hemispherectomy was associated with the lowest intraoperative blood loss, the shortest intensive care stay, and the lowest complication rate. Functional hemispherectomy had the highest rate of reoperation, while patients undergoing anatomical hemispherectomy had the longest hospital stays, greatest requirement for CSF diversion and highest postoperative fever. Patients with cortical dysplasia had the largest intraoperative blood loss.60 Continuous monitoring of blood pressure by arterial catheter is required, as is central venous access and monitoring of cardiac filling pressure. Brian et al.61 report a series of ten patients, ages 3 months to 12 years, whose intraoperative blood replacement amounted to 1.5 blood volumes, on average. Seven of ten patients developed a coagulopathy intraoperatively, requiring administration of platelets and/or fresh frozen plasma. Progressive hypokalemia requiring replacement occurred in 40%. Hypothermia and metabolic acidosis was observed in 50%. Urine output was a poor indicator of volume status because of frequent massive glycosuria. Zuckerberg et al.62 report several children under 5 years who developed severe decreases in cardiac index, bradycardia, increased systemic vascular resistance (SVR), and an alveolar to arterial gradient suggestive of neurogenic pulmonary edema after hemispherectomy with extensive subcortical resection. Removal of the endotracheal tube at the conclusion of the case is fraught with the danger and should be carefully reconsidered in each patient. Postoperative hemodynamic instability is common and the airway may be compromised by seizure activity. Early postoperative recovery is best accomplished in an intensive care environment. As has been reported in adults,63 children undergoing major brain resection become hypercoagulable as early as during dural closure.64 While the clinical significance of this finding is debated, thrombotic complications should be anticipated.

Emergence and postoperative management The incidence of complications after intracranial neurosurgery remains substantial.65 Nausea and vomiting occur in 30–50%,

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Anesthesia for epilepsy surgery the incidence of neurologic deterioration is 8–10%, of which approximately one-half is permanent. Respiratory morbidity occurs in 3–8%, while cardiovascular complications were found in 5–19% of patients. While epilepsy patients are generally healthy from the cardiovascular perspective, seizures, impaired mental function and the effect of large craniotomy procedures with substantive brain resection can combine to put patients at significant postoperative risk. Because of preoperative tapering of anticonvulsants and perioperative drug interactions, patients may be at higher risk of developing postoperative seizures. Anticonvulsant blood levels need to be checked frequently and doses adjusted accordingly to continue appropriate maintenance of anticonvulsant therapy postoperatively. When a seizure occurs, adequacy of oxygenation and ventilation must be assured by appropriate measures to secure airway patency. The first step should be ventilation with 100% oxygen via bag/mask. If necessary, the airway is secured by tracheal intubation. In adults, the seizure may be stopped with a small (1–2 mg/kg) dose of thiopental, lorazepam 2–5 mg, diazepam 5–10 mg administered over 2–3 minutes, or midazolam 2–4 mg. If seizure activity recurs, phenytoin is begun at 50 mg/minute to a total dose of 20 mg/kg, assuming the patient has not previously been treated with phenytoin. Intractable status

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epilepticus is treated with general anesthesia using isoflurane, barbiturates, or propofol. Antiepileptic medications are associated with drowsiness and lethargy. It is our clinical experience that epilepsy patients emerge from anesthesia more slowly than neurologically normal individuals. Intraoperative loading of phenytoin for treatment of seizures may increase the risk of delayed emergence from general anesthesia. This tendency can be exacerbated in epilepsy patients with mental handicaps who are also on therapy with the anticonvulsants mentioned. During the course of aggressive medical therapy and in the postoperative period, phenytoin and carbamazepine blood levels may increase into the toxic range.66 Intracranial bleeding occurs in a small percentage of patients, so that neurological status must be closely and continuously monitored during recovery. Coughing and systemic hypertension should be avoided and promptly treated so as not to precipitate or aggravate intracranial bleeding. Prophylactic administration of antinauseants is effective67 and advisable. Other postoperative neurologic complications of temporal lobe surgery include memory and visual field deficits. Patients with temporary subdural grid electrode implants may suffer cerebral edema68 occasionally necessitating emergency re-exploration.

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Drummond JC, Iragui-Madoz VJ, Alksne JF, Kalkman CJ. Masking of epileptiform activity by propofol during seizure surgery. Anesthesiology 1992;76:652–4. Awad IA, Nayel MH. Epilepsy surgery: introduction and overview. Clin Neurosurg 1992;38:493–513. Ebrahim ZY, Schubert A, Van Ness P et al. The effect of propofol on the electroencephalogram of patients with epilepsy. Anesth Analg 1994;78:275–9. Walker M. Status epilepticus: an evidence-based guide. BMJ 2005;331:673–7. Vakkuri AP, Seitsonen ER, Jantti VH et al. A rapid increase in the inspired concentration of desflurane is not associated with epileptiform encephalogram. Anesth Analg 2005;101:396–400. Hymes JA. Seizure activity during isoflurane anesthesia. Anesth Analg 1985;64:367–8. Harrison JL. Postoperative seizures after isoflurane anesthesia. Anesth Analg 1986;65:1235–6. Modica PA, Tempelhoff R, White PF. Pro- and anticonvulsant effects of anesthetics (Part I). Anesth Analg 1990;70:303–15. Wyler AR, Ritchey ET, Atkinson RA, Hermann BP. Methohexital activation of epileptogenic foci during acute electrocorticography. Epilepsia 1987;28:490–4. Cascino GD, Sharbrough FW, So EL et al. Intraoperative alfentanil hydrochloride in temporal lobe epilepsy: correlation with MRI-based volume studies. Epilepsia 1992;33:85. Girvin JP. Neurosurgical considerations and general methods for craniotomy under local anesthesia. Int Anesthesiol Clin 1986;24:80–114. Watts AD, Herrick IA, McLachlan RS et al. The effect of sevoflurane and isoflurane anesthesia on interictal spike activity among patients with refractory epilepsy. Anesth Analg 1999;89:1275–81. Wass CT, Grady RE, Fessler AJ et al. The effects of remifentanil on epileptiform discharges during intraoperative electrocorticography in patients undergoing epilepsy surgery. Epilepsia 2001;42:1340–4. Cascino GD, So EL, Sharbrough FW et al. Alfentanil-induced epileptiform activity in patients with partial epilepsy. J Clin Neurophysiol 1993;10:520–5. Tempelhoff R, Modica PA, Bernardo KL, Edwards I. Fentanylinduced electrocorticographic seizures in patients with complex partial epilepsy. J Neurosurg 1992;77:201–8. Szeto HH. Accumulation of normeperidine, an active metabolite of meperidine, in patients with renal failure of cancer. Ann Int Med 1977;86:738–41.

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Textbook of epilepsy surgery Stambaugh JE Jr, Wainer IW. Drug interaction: meperidine and chlorpromazine, a toxic combination. J Clin Pharmacol 1981; 21:140–6. Spacek A, Neiger FX, Krenn CG et al. Rocuronium-induced neuromuscular block is affected by chronic carbamazepine therapy. Anesthesiology 1999;90:109–12. Tempelhoff R, Modica PA, Jellish WS, Spitznagel EL. Resistance to atracurium-induced neuromuscular blockade in patients with intractable seizure disorders treated with anticonvulsants. Anesth Analg 1990;71:665–9. Richard A, Girard DC, Boudreault D et al. Cisatracurium-induced neuromuscular blockade is affected by chronic phenytoin or carbamazepine treatment in neurosurgical patients. Anesth Analg 2005;100:538–44. Ebrahim ZY, Bulkley R, Roth S. Carbamazepine therapy and neuromuscular blockade with atracurium and vecuronium. Anesth Analg 1988;67:S55. Eagle KA, Berger PB, Calkins H et al. ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery – executive summary a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to update the 1996 guidelines on perioperative cardiovascular evaluation for noncardiac surgery). Circulation 2002;105:1257–67. Tempelhoff R, Modica PA, Spitznagel EL Jr. Anticonvulsant therapy increases fentanyl requirements during anaesthesia for craniotomy. Can J Anaesth 1990;37:327–32. Wall M, Baid-Lambert J, Buchanan N, Farrell G. Liver function tests in persons receiving anticonvulsant medications. Seizure 1992;1:187–90. Gidal B, Spencer N, Maly M et al. Valproate-mediated disturbances of hemostasis: relationship to dose and plasma concentration. Neurology 1994;44:1418–22. Nomura F, Hatano H, Ohnishi K et al. Effects of anticonvulsant agents on halothane-induced liver injury in human subjects and experimental animals. Hepatology 1986;6:952–6. Reasoner DK, Todd MM, Scamman FL, Warner DS. The incidence of pneumocephalus after supratentorial craniotomy. Observations on the disappearance of intracranial air. Anesthesiology 1994;80:1008–12. Artru AA, Lettich E, Colley PS, Ojemann GA. Nitrous oxide: suppression of focal epileptiform activity during inhalation, and spreading of seizure activity following withdrawal. J Neurosurg Anesthesiol 1990;2:189–93. Peterson KD, Landsfeldt U, Cold GE et al. Intracranial pressure and cerebral hemodynamic in patients with cerebral tumors: a randomized prospective study of patients subjected to craniotomy in propofol-fentanyl, isoflurane-fentanyl, or sevoflurane-fentanyl anesthesia. Anesthesiology 2003;98:329–36. Todd MM, Warner DS, Sokoll MD et al. A prospective, comparative trial of three anesthetics for elective supratentorial craniotomy. Propofol/fentanyl, isoflurane/nitrous oxide, and fentanyl/nitrous oxide. Anesthesiology 1993;78:1005–20. Coles JP, Leary TS, Monteiro JN et al. Propofol anesthesia for craniotomy: a double-blind comparison of remifentanil, alfentanil, and fentanyl. J Neurosurg Anesthesiol 2000;12: 15–20. Balakrishnan G, Raudzens P, Samra SK et al. A comparison of remifentanil and fentanyl in patients undergoing surgery for intracranial mass lesions. Anesth Analg 2000;91:163–9.

49. 50.

51. 52. 53. 54. 55. 56. 57. 58. 59.

60. 61. 62. 63. 64. 65. 66. 67.

68.

Gerlach K, Uhlig T, Huppe M et al. Remifentanil-propofol versus sufentanil-propofol anaesthesia for supratentorial craniotomy: a randomized trial. Eur J Anaesthesiol 2003;20:813–20. Sneyd JR, Whaley A, Dimpel HL Andrews CJ. An open, randomized comparison of alfentanil, remifentanil and alfentanil followed by remifentanil in anaesthesia for craniotomy. Br J Anaesth 1998; 81:361–4. Gelb AW, Salevsky F, Chung F et al. Remifentanil with morphine transitional analgesia shortens neurological recovery compared to fentanyl for supratentorial craniotomy. Can J Anaesth 2003;50:946–52. Guy J, Hindman BJ, Baker KZ et al. Comparison of remifentanil and fentanyl in patients undergoing craniotomy for supratentorial space-occupying lesions. Anesthesiology 1997;86:514–24. Ito BM, Sato S, Kufta CV, Tran D. Effect of isoflurane and enflurane on the electrocorticogram of epileptic patients. Neurology 1988;38:924–8. Archer DP, McKenna JM, Morin L, Ravussin P. Conscious-sedation analgesia during craniotomy for intractable epilepsy: a review of 354 consecutive cases. Can J Anaesth 1988;35:338–44. Sarang A, Dinsmore J. Anaesthesia for awake craniotomy – evolution of a technique that facilitates awake neurological testing. Br J Anaesth 2003;90:161–5. Silbergeld DL, Mueller WM, Colley PS et al. Use of propofol (Diprivan) for awake craniotomies: technical note. Surg Neurol 1992;38:271–2. Coursin DB, Coursin DB, Maccioli GA. Dexmedetomidine. Curr Opin Crit Care 2001;7:221–6. Bekker AY, Kaufman B, Samir H, Doyle W. The use of dexmedetomidine infusion for awake craniotomy. Anesth Analg 2001;92:1251–3. Bustillo MA, Lazar RM, Finck AD et al. Dexmedetomidine may impair cognitive testing during endovascular embolization of cerebral arteriovenous malformations: a retrospective case report series. J Neurosurg Anesthesiol 2002;14:209–12. Cook SW, Nguyen ST, Hu B et al. Cerebral hemispherectomy in pediatric patients wit epilepsy: comparison of three techniques by pathological substrate in 115 patients. J Neurosurg 2004;100:125–41. Brian JE Jr, Deshpande JK, McPerson RW. Management of cerebral hemispherectomy in children. J Clin Anesth 1990;2:91–5. Zuckerberg AL, Tobin JR, Fleisher L et al. The physiopathological consequences of cerebral hemispherectomy in children. Anesthesiology 1993;79:A1187. Abrahams JM, Torchia MB, McGarvey M et al. Perioperative assessment of coagulability in neurosurgical patients using thromboelastography. Surg Neurol 2002;58:5–11. Goobie SM, Soriano SG, Zurakowski D et al. Hemostatic changes in pediatric neurosurgical patients as evaluated by thrombelastograph. Anesth Analg 2001;93:887–92. Manninen PH, Raman SK, Boyle K, el-Beheiry H. Early postoperative complications following neurosurgical procedures. Can J Anaesth 1999;46:7–14. Kofke WA, Tempelhoff R, Dasheiff RM. Anesthesia for epileptic patients and for epilepsy surgery. In: Cottrell JE, Smith DS, eds. Anesthesia and Neurosurgery. St. Louis: Mosby, 1994:495–524. Madenoglu H, Yildiz K, Dogru K et al. Randomized, double-blind comparison of tropisetron and placebo for prevention of postoperative nausea and vomiting after supratentorial craniotomy. J Neurosurg Anesthesiol 2003;15:82–6. Onal C, Otsubo H, Araki T et al. Complications of invasive subdural grid monitoring in children with epilepsy. J Neurosurg Anesthesiol 2003;98:1017–26.

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Placement of subdural grids F Salazar and WE Bingaman

Brief history It is often said that the history of epilepsy surgery began on 25 May 1886, when Victor Horsley operated on a patient of John H. Jackson at the National Hospital for the Paralyzed and Epileptic at Queen’s Square in London. This patient was a man of 22 years with focal motor seizures that were caused by a depressed skull fracture, the consequence of a trauma he had suffered 15 years earlier.1 The first cortical electrical stimulation studies in humans can be traced back to work done by Robert Bartholow in Ohio. In 1874, he had in his care a patient with a large cranial defect exposing her cerebral hemispheres. Needles were inserted into the dura mater and, upon closing the circuit, right arm and leg muscular contractions were observed.2 In 1893, Krause performed the first documented case of intraoperative electrical stimulation of the human cerebral cortex to determine locations of cerebral function and epileptogenic foci as a guide to cortical resection.2 The first intraoperative electrocorticogram was produced by Foerster and Altenburger in 1934. By the early 1950s, direct electrical activity measurement from the human cerebral cortex during surgery was extensively used and considered an indispensable technique in the evaluation of surgical candidates to define the irritative zone2. However, chronic intracranial recordings were not reported until 1939 when Penfield used epidural single contact electrodes in a patient with an old left temporo parietal fracture and whose pneumoencephalography disclosed diffuse cerebral atrophy3. The use of subdural grid arrays became more popular after several publications during the 1980s demonstrated their safety and efficacy4–6. Before that time most invasive techniques involved epidural electrodes or intraoperative recordings.

Materials and design Subdural electrode grids consist of stainless steel or platinum contacts embedded in a thin matrix of biologically inert but flexible material such as Silastic® or Teflon®. By design, each contact and its connecting wire are electrically isolated so as to provide precise anatomic localization of seizure foci.7,8 These wires extend to insulated cables that attach to an extracranial amplifier. The shape and size of each subdural electrode grid varies from simple strips, consisting of a single row with usually four to eleven contacts to rectangular or square arrays of

16 to 64 electrodes. The distance between electrodes is approximately 10mm. The diameter of the electrode contact varies between 2 and 5 mm. It is very important that the material in which the electrodes are embedded is flexible and thin permitting the array to adopt the shape of the brain it is covering.9 The embedding material should be clear in order to facilitate its placement over specific brain areas and also to define the relationship of the contacts with the underlying vessels and other anatomical landmarks such as sulci and gyri. Minimizing the total volume of the electrode array is essential to avoid increased intracranial pressure from mass effect. Variability in shape and size of the electrodes permits tailoring their use to the specific clinical situation. Custom designed arrays of subdural electrodes have been configured for placement in specific anatomical locations. For example, to record from interhemispheric brain regions, rows of electrodes arranged in curvilinear fashion were designed to follow the average curvature of the corpus callosum. The plate is designed with contacts on both sides to record from the ipsilateral mesial cortex and the contralateral mesial region through the falx.7

Indications and advantages Epilepsy surgery is based on the principle that resection of an epileptogenic focus can result in seizure freedom. The epileptogenic zone is defined as the area of brain necessary and sufficient to generate seizures.9 Accordingly, accurate localization of the epileptogenic zone and its relationship to eloquent cortex is crucial for the success of epilepsy surgery.10–18 In certain clinical situations, invasive electrode recordings allow for accurate localization of the epileptogenic zone and mapping of functional cortical regions. The most common indications for intracranial electrodes include lateralization or localization of epilepsy and localization of functional/eloquent cortical information. In the first case, preoperative noninvasive studies and semiology often suggest focal epilepsy but scalp electroencephalography (EEG) is unable to adequately localize or lateralize the epileptogenic zone.14,19 Subdural grids have particular advantages: they can be in place long enough to record both spontaneous seizures and interictal activity during various stages of arousal, and they have applicability for mapping of cerebral function extraoperatively.9,20,23 These characteristics allow tailored cortical resections around areas of higher function while minimizing 931

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Table 102.1 Major indications for implantation of subdural grids Determination of extent and distribution of the epileptogenic zone. 䊊䊊

䊊䊊䊊

Normal imaging data. Epileptogenic zone that is more widespread than the structural lesion. Absolute noncongruence of preoperative data. Epileptogenic zone versus structural lesion. Multiple lesions or multifocal interictal epileptiform activity.

Determination of the relationship of the epileptogenic zone to eloquent cortex. 䊊䊊

Cortical stimulation Somatosensory evoked potentials.

the risk of permanent neurological deterioration.21,22 Intraoperative electrocorticography, as compared with chronically implanted subdural grids, is a limited option because it only provides information restricted to interictal activity. When used in patients under general anesthesia, it is believed that anesthetic agents may influence EEG activity by altering the thresholds of after discharges and motor responses creating a misleading electroencephalographic picture. Additionally, intraoperative functional mapping often requires a cooperative patient that can tolerate being awake during surgery under local anesthesia. This is particularly difficult in the pediatric population. Indications for invasive video-EEG monitoring can be divided in two overlapping groups (see Table 102.111–15).

Disadvantages and limitations Disadvantages of subdural invasive monitoring include increased surgical risks, financial costs, and limitations in the ability to access deep cortical regions. It requires two surgical procedures, the first to implant the electrodes and the second for removal of electrodes followed by resection of the epileptogenic zone. The amount of cerebral cortex exposed is often extensive requiring larger craniotomies and increasing the risk for complications. Implantation of a foreign body in the brain has increased potential of causing intracranial mass effect and infection. Additionally, hospital cost and length of stay are increased. Because of these factors, invasive monitoring should not be routinely undertaken as an ‘exploratory procedure’ to identify a focal epilepsy (the noninvasive preoperative evaluation should identify a focal epilepsy and approximate location of the epileptogenic zone). Subdural grids should be used if it is believed that their use will alter the ultimate surgical strategy and outcome. An attempt must be made to place adequate electrodes so that the predicted site of seizure origin and its boundaries are sampled. Limitations in both the area and regions of cortex to be covered exist. In specific cortical areas such as the interhemispheric, basal temporal, and basal frontal surfaces the grids are placed without direct visualization. This makes precise cortical coverage difficult and more risky. The use of intraoperative stereotaxis can improve the accuracy by displaying the grid’s implanted position on the 3D reconstruction of the

cortical surface. This allows the surgeon to adjust grid position intraoperatively. The relatively common presence of bridging veins in these regions is a limiting factor for safe implantation of grids. Additionally, in the interhemispheric region it is common to find adhesions that makes grid placement difficult. Finally, subdural grid coverage of the mesial temporal lobe structures is not optimal since the grids/strips are placed in the subtemporal region without direct visualization and likely record from the parahippocampal gyrus and not the hippocampus directly.24 Other limitations of subdural grid implantation are the number of available channels for recording with the EEG system in the hospital. Some systems can handle only 64 channels unlike other systems record up to 200 channels thus allowing the implantation of more electrodes over wider cortical areas. Despite this, only limited coverage of cortical regions can be sampled and preoperative surgical planning is necessary to maximize the chances of covering the ictal onset zone with the electrodes.

Surgical technique Video of subdural grids placement (DVD) Placement of subdural grid electrodes is carried out by means of a standard neurosurgical craniotomy under general anesthesia.20 Our preference is to use mannitol (0.5–1.0gr/kg), hyperventilation, and optimal head positioning at the beginning of skin incision in order to obtain adequate brain relaxation and sufficient subural space for placement of the plates. Before prepping, the skin incision should be planned to allow adequate brain exposure and room to tunnel the electrode wires. Localization can be performed with simple craniometric measurement in accompaniment of magnetic resonance imaging (MRI), or frameless navigation can be used as a localizing aid.25 The scalp and bone flaps should be of generous proportions, exposing areas of cortex needing coverage and taking into account the requirements of any definitive surgical procedure.26 The use of stereotactic navigation and direct inspection of cortex and identification of gyri allows optimal grid placement according to the preoperative plan. The goal of surgery is to maximize the chance of fully documenting seizure foci and to be able to identify functionally important cortex by brain mapping techniques. Thus, the location of electrodes is a synthesis of the preoperative information and the surgical limitations on the amount of cortex that can or needs to be covered.27 Once the brain is exposed, the plates are inserted with smooth bayonet forceps, directing them towards the desired cortical region using a steady stream of irrigation allowing it to slide smoothly over the surface of the brain and preventing trauma. The grids can be ‘slid’ beyond the edges of the craniotomy to cover adjacent areas, including basal temporal, basal frontal and interhemispheric regions. Areas of resistance may include bridging cortical veins or adhesions that should be avoided to prevent hemorrhage. Whenever possible the electrodes should be placed under direct visualization to prevent this complication. Occasionally, when large plates are used over the convexity, there is a tendency for them to buckle. This can be overcome by dividing the grid along lines of electrodes to give a better fit over the brain. If the grids are cut to a smaller size to fit in the region of interest, edges should be carefully trimmed to avoid electrode injury and cortical laceration.28

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Care must also be taken to ensure that the edges of large grids do not compress and impede the outflow of major draining vessels such as the vein of Labbe or Trolard as they enter the dural venous sinuses.29 Care should be taken when implanting electrodes in patients with mass lesions, in reoperations (there are usually adhesions of the dura to the cortex), and in areas of encephalomalacia (grids may be difficult to secure). Prior to closure the electrode positions should be confirmed with the neurologist. Once in place, the electrode cables are secured to the dura with suture. A digital photograph of the brain is taken; this provides a reference between gyral anatomy and electrode placement that cannot be obtained with three dimensional reconstructed scans (Figure 102.1). A watertight dural closure around the electrode cables reduces the possibility of cerebrospinal fluid leakage. Hitch stiches are used to reduce the risk of extradural bleeding. The leads should exit without kinking in the bone edges. Electrode leads are tunneled a minimum of 10 cm from the craniotomy margin and attached to the skin with a purse-string suture. The bone flap is replaced and secured to minimize the risk of electrode movement during seizures. It is important to appropriately identify each plate and record the intended position in the patient’s chart. Computer software has been developed to aid the surgeon intraoperatively in the placement of the subdural grids. A standard preoperative stereotactic volume acquisition MRI with scalp fiducial markers in place is obtained, and co registered to the patient intraoperatively after positioning with rigid head fixation. The pointing tool is then used to register the positions of as many exposed electrodes as possible, and using specialized computer software the grid is displayed as pseudocolored spheres on the volume surface reconstruction of the brain. This allows the surgeon to have immediate intraoperative feedback demonstrating the anatomic position of the subdural grid.30,31

transferred to the Epilepsy Monitoring Unit where the electrodes are connected for continuous digital EEG recording along with video imaging. Intravenous antibiotics are prescribed throughout the entire monitoring period. Following removal of the subdural grids at least one of the plates is sent for culture (even in the absence of signs of infection). In cases of positive cultures, antibiotics are continued based on these results and the clinical condition of the patient. Corticosteroid therapy is administered during the first 48 hours after surgery to reduce cerebral swelling and help with postoperative pain. In some patients severe headache can develop after surgery requiring use of intravenous analgesics. Postoperatively, any change in the level of consciousness or neurological function is evaluated with computed tomography (CT) scanning. The period of implantation is variable with a range between 9–26 days and an average of 12 days.21 In general, patients with extra temporal seizure foci require more recorded seizures than patients with temporal foci. Traditionally, the method of localizing implanted electrodes is based on a skull X-ray after implantation and from this an electrode map is drawn on a standard hard-copy template of the brain. In this map, electrodes involved in interictal epileptiform activity, ictal onset, and spread patterns can be marked along with the functional brain map obtained during cortical stimulation and evoked potentials (Figure 102.2). The main limitation of this method is the difficulty correlating the electrode positions to precise sulcal and gyral cortical surface anatomy. The clinical value of subdural electrodes can be further enhanced by postimplantation MRI co-registration and 3D visualization of the electrode position in relation to the cortical surface on the MRI.32 This allows a more precise understanding of the anatomic relationships between the ictal onset zone, eloquent cortex, and the underlying brain anatomy. For this, a stereotactic computed tomography (CT) scan is obtained immediately postimplantation to verify electrode location and to supplement drawings or photographs made intraoperatively. The preoperative MRI is fused with the postoperative CT scan in order to obtain a 3D reconstruction of the brain and the relationship of the grids with the particular anatomy of the patient.33 Postoperative MRI is avoided because of safety concerns as it has been shown that the oscillating magnetic field can induce electrical currents in any metallic implants and potentially cause heating and/or electrical damage to the brain cortex.34 Unfortunately, CT scan images show extensive streak artifact which is especially pronounced with alloy grids. Although MRI imaging allows for better visualization of the electrodes, the risk of possible complications outweigh the benefits.8 Upon return to the operating room, the surgeon must be careful to avoid movement of the subdural grids as they are exposed. Once exposed, the cortical resection takes place using the grids as a reference with the interictal, ictal, and functional cortex information. Additionally, stereotactic navigation can be used to further correlate electrode position based on post implantation CT.35

Postoperative management

Complications

The patient is sent to a neurosurgical intensive care unit (ICU) for the first postoperative night. The next day the patient is

Subdural monitoring with grid electrodes has historically been shown to have low permanent morbidity (0–3%) compared

Figure 102.1 Intraoperative photography showing subdural grid electrodes after implantation before closing the dura.

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Brain Map-Right

Brain Map-Right

C

C

RAM

A B

B Interictal RPH F

Ictal (1-26P)

1: Mesial Temporal Every 2-10s: 45% RAH

E

RAM

RPH

2: Orbito-Frontal D2, 6- 15 Runs lasting 2-30s: 45% SWC simultaneous on A

G

F

Onset D: 6,2>9 15 PF RAH

E

RAM

Spread to E10 (P3, P5, P6, P10) Spread to mesial temporal (P3,P5)

G

3. Lateral Temporal rare: 10%

D

(a)

(b) Cental Sulcus from MRI

Brain Map-Right

C

A B Cortical Stimulation

Left Hand Sensory

F

RPH RAH E RAM

Left Hand Motor

G

Left Face Sensory Left Face Motor Negative Motor Stim with no symptoms

(c) Figure 102.2 (a) Brain map showing the relative position of the subdural and intracerebral electrodes and the recorded interictal activity. (b) Brain map showing the relative position of the grids and the recorded seizure activity of its electrodes. (c) Brain map showing the cortical stimulation map.

with depth electrodes (3–6%) since, as mentioned previously, there is no intraparenchymal passage.36 Adverse events caused by subdural grid implantation can be categorized as either surgical or neurological. For purposes of this chapter, emphasis is placed on the surgical and neurological complications related to the implantation of the grids separate from the resective stage. Resections performed after the monitoring period can also cause neurological complications, either transient or permanent. These sequelae can be variable depending on the amount of cortex resected, and are predicted based on the information obtained during the stimulation period. Risk factors for complications are: greater number of implanted electrodes, longer duration of monitoring, dominant side grid insertion, and earlier age at time of monitoring.37 One of the most common complications is cerebrospinal fluid leakage. Transient cerebrospinal fluid (CSF) leakage through the electrode exit site has been reported to be between 13 and 31% of the patients despite careful watertight dural closures, adequate subcutaneous tunneling, and tight skin closure.29,38,39 This occurs most frequently after motor seizures or bouts of vomiting. Our current practice is to check the dressing

regularly for any signs of cerebro spinal fluid leakage, to suture any active leak at the bedside, and to apply topical sterile skin adhesive, though the clinical utility of this practice is unknown. Use of a lumbar drain has been reported to significantly reduce the incidence of CSF leak,40 although not routinely used at our institution due to concern of downward cerebral herniation. Infectious complications are also reported in several invasive monitoring series. Postoperative wound infections after clean neurosurgical procedures have been quoted to range from 0.6–11%. Meningitis has been reported in 0.34–2% of patients.41 Considering these percentages, a 6–8% rate of infection is not unrealistic for a procedure that leaves several foreign bodies implanted with cables exiting the scalp for seven or more days. Factors that have been reported to increase the incidence of infection are greater number of electrodes, exiting cables, or exit sites. The duration of recording following implantation is also found to correlate significantly with infection rate; duration exceeding 14 days is more likely to result in an infectious complication.38 This can occur acutely during the monitoring period or chronically after

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Placement of subdural grids removal of the grids. During the invasive video-EEG evaluation period, wound infection, meningitis or epidural abscess can appear. Except for cases with superficial localized wound infection, the grids should be removed and aggressive intravenous antibiotic treatment initiated immediately. Subsequently, the treatment plan is modified based on culture results and clinical response. Osteomyelitis is a rare complication that has been described in 3% of the patients;29 it usually is a late infection, occurring weeks or months after the initial surgery that requires removal of the bone flap and treatment with intravenous antibiotics. Brain abscess has also been described as a potential complication, but its incidence is very low.42 Bacteria that have been isolated in patients with clinically relevant infections have included different species of Staphylococcus, Streptococcus, Bacillus, and Diptheroid mainly.37 Cerebral edema and intracranial mass effect is a potentially serious complication. Factors that favor its development are patients with multiple plates, presence of intracranial mass lesions, and pediatric patients.37 Its precise incidence is not well defined because many times the only manifestation is headache with or without nausea that is successfully treated with analgesics and antiemetics. Severe cases leading to somnolence or stupor, focal neurological deficit, brain shift, or impending herniation are infrequent and require immediate removal of the electrodes. Large duraplasties and hinging the bone with sutures have been reported to prevent clinically significant cerebral edema in some patients. Also, some centers report on leaving the bone flap out during the monitoring period to avoid this complication.43 One of the most concerning complications with invasive monitoring is intracranial hemorrhage. As opposed to depth electrodes, intracerebral bleeding is a rare occurrence during placement of subdural grids. It is related more to venous occlusion or laceration of cortex caused by the edges of the plates. Subdural hematomas can be more frequently encountered and its incidence has been described around 8%; they can lie between the cortex and grids or superficial to the electrodes.42,44,45 These could be a cause of deficient recording, may induce seizures or change the epileptiform activity, and also can contribute to intracranial mass effect and neurological deterioration. As a result of the requirement for large craniotomies and two surgical procedures these patients have a significant risk for blood loss during surgery and may require blood transfusion. This is more frequently observed in patients with interhemispheric electrodes implanted where its location in relationship to venous structures enhances the risk of bleeding. Accidental removal or displacement of grids is a potential complication that can be seen more commonly in patients with severe motor seizures or during periods of postictal confusion were the exiting cables can be pulled. If there is any suspicion of displacement, an immediate skull X-ray and a CT scan should be performed in order to evaluate movement of the grids or possible hemorrhage. When the information obtained during the monitoring demonstrates that the ictal onset zone is at the edge of a grid or is suspected to be in an area not covered by the grids, repositioning of the plates may be necessary in order to obtain adequate coverage of the area of interest. In selected

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patients where invasive monitoring fails to identify the site of seizure origin, reinvestigation can sometimes achieve localization of the seizure onset and allow a successful surgical treatment.46–48 Due to the relatively prolonged period of reduced activity in these patients, other serious complications such as deep venous thrombosis, pulmonary embolism, pneumonia, and other sequelae of immobility can develop. Appropriate diagnostic and therapeutic measures should be initiated.

Outcomes In evaluating outcomes after application of subdural grids, several important factors should be mentioned. First, it has been reported that patients selected for intracranial monitoring with subdural grids are less likely to have excellent outcomes because of their inherent complexity (non concordant preoperative data, non lesional MRI, and/or close relationship with eloquent cortex).49–53 Second, this population of patients is heterogeneous and the analysis process itself is dynamic and changes over time. Third, in many cases, the invasive monitoring is a combination of subdural grids and strips, depth electrodes, and scalp electrodes which makes comparison of techniques difficult.54,55 Another important variable is the amount of resection performed: resection of the ictal onset zone plus interictal epileptiform abnormalities, only the ictal onset zone, or limited resection of the ictal onset zone. The area of resection is often limited by the presence of eloquent cortex or by dominant draining veins. Because of these factors, reported outcomes after subdural grid evaluation are difficult to interpret. In a recent Cleveland Clinic series of patients with normal preoperative MRI no differences in outcome were identified with or without the use of subdural grids, but the authors suggest that the invasive testing helped to devise a surgical strategy and allowed surgical treatment to patients who would not otherwise been candidates.56 Despite adequate and prolonged invasive monitoring with subdural grids, up to 10% of the patients are found not to be candidates for surgical resections. In most of these cases, the epileptogenic zone is overlapping with eloquent cortex that if resected will cause severe permanent neurological deficit. At other times, it is found that the ictal onset zone is widespread or cannot be localized thus impeding surgical treatment.

Conclusions Subdural grid placement is a useful technique that helps to localize areas of epileptogenicity and to map functional brain cortex in order to aid in the planning of cortical resections for the treatment of medically resistant epilepsy in patients whom otherwise will not be candidates for surgical intervention or patients with increased risk of neurological deficit. Despite its usefulness, it is a costly and risky procedure that should be limited to highly selected patients with severe refractory epilepsy and should be attempted in tertiary centers with the appropriate experience in video-EEG monitoring and by a surgeon with experience in these techniques.

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Wolf W. History of epilepsy surgery: introduction. In: Luders HO, Comair Y, eds. Epilepsy Surgery. Philadelphia: Lippincot Williams and Wilkins, 2000:19–21. Lüders JC, Lüders HO. Contributions of Fedor Krause and Otfrid Foester to epilepsy surgery. In Lüders HO, Comair Y, eds. Epilepsy Surgery. Philadelphia: Lippincot Williams and Wilkins, 2000:23–33. Almeida AN, Martinez V, Feindel W. The first case of invasive EEG monitoring for the surgical treatment of epilepsy: historical significance and context. Epilepsia, 2005;46(7):1082–5. Wyllie E, Lüders HO, Morris HH et al. Subdural electrodes in the evaluation for epilepsy surgery in children and adults. Neuropediatrics. 1988;19:80–6. Levy WJ, Hahn JH, Lüders HO et al. Chronic cortical electrode array for seizure investigation. Child Brain 1982;9:48–52. Lüders H, Hahn J, Lesser RP et al. Basal temporal subdural electrodes in the evaluation of patients with intractable epilepsy. Epilepsia 1989;30:131–42. Ebner A and Lüders HO. Subdural electrodes. In: Lüders HO, Comair YG, eds. Epilepsy Surgery. Philadelphia: Lippincot Williams and Wilkins, 2000;593–6. Silberbusch, MA, Rothman MI, Bergey GK et al. Subdural grid implantation for intracranial EEG recording: CT and MRI appearance. Am J Neuroradiol 1998;19:1089–93. Lesser RP, Gordon B, Fisher R et al. Subdural grid electrodes in surgery of epilepsy. In: Lüders HO, ed. Epilepsy Surgery. New York: Raven Press, 1992;399–408. Carreno M, Lüders HO. General principles of presurgical evaluation. In: Lüders HO, Comair Y eds. Epilepsy Surgery. Philadelphia; Lippincot Williams and Wilkins, 2000;185–99. Engel J Jr, Wieser HG, Spencer D. Overview: surgical therapy. In: Engel J Jr, Pedley TA, eds. Epilepsy a Comprehensive Textbook. Philadelphia: Lippincot-Raven Publishers, 1997:1673–6. Lüders HO, Awad IA. Conceptual considerations. In: Lüders HO, ed. Epilepsy Surgery. New York: Raven Press, 1992:51–62. Wyllie E, Lüders HO, Morris HH et al. Clinical outcome after complete or partial cortical resection for intractable epilepsy. Neurology 1987;37:1634–41. Hamer HM, Morris HH. Indications for invasive videoelectroencephalographic monitoring. In: Lüders HO, Comair YG, eds. Epilepsy Surgery. Philadelphia: Lippincot Williams and Wilkins, 2000:559–66. Duchowny MS, Jayakar P. Indications for invasive video electroencephalographic evaluation: special considerations in children. In: Lüders HO, Comair YG, eds. Epilpesy Surgery. Philadelphia: Lippincot Williams and Wilkins, 2000:567–72. Cukiert A, Sousa A, Machado E et al. Paradigms for subdural grids’ implantation in patients with refractory epilepsy. Arq Nueuropsiquiatr 2000;58:630–6. Uematsu S, Lesser R, Fisher R et al. Resection of the epileptogenic area in critical cortex with the aid of a subdural electrode grid. Stereotactic Func Neurosurg 1990;54:34–45. Cukiert A, Buratini JA, Machado E et al. Results of surgery in patients with refractory extratemporal epilepsy with normal or nonlocalizing magnetic resonance findings investigated with subdural grids. Epilepsia 2001;42:889–94. Najm IM, Bingaman WE and Lüders HO. The use of subdural grids in the management of focal malformations due to abnormal cortical development. Neurosurg Clin N Am 2002;37:87–92. Fabinyi G. Operative diagnostic methods in the treatment of epilepsy. In: Kaye AH, Black PMcL, eds. Operative Neurosurgery. New York: Churchill Livingston, 2000. Behrens E, Zetner J, van Roost D et al. Subdural and depth electrodes in the presurgical evaluation of epilepsy. Acta Neurochirugica (Wien) 1994;128:84–7. Swartz BE, Rich JR, Dwan PS et al. The safety and efficacy of chronically implanted subdural electrodes: a prospective study. Surg Neurol 1996;46:87–93. Matsumoto R, Nair D, LaPresto E et al. Functional conectivity in the human language system: a cortico-cortical evoked potential study. Brain 2004;127:2316–30. Shimizu H, Suzuki I, Ohta Y et al. Mesial temporal subdural electrode as a substitute for depth electrode. Surg Neurol 1992;38: 186–91. Murphy M, O’Brien TJ, Morris K et al. Multimodality image-guided epilepsy surgery. J Clin Neurosci 2001;8:534–8. Adelson PD, Black PMcL, Madsen JR et al. Use of subdural grids and strip electrodes to identify a seizure focus in children. Ped Neurosurg 1995;22:174–80.

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Rosenow F, Lüders HO. Presurgical evaluation of epilepsy. Brain. 2001;124:1683–700. Bruce DA, Bizzi JW. Surgical technique for the insertion of grids and strips for invasive monitoring in children with intractable epilepsy. Child Nerv Sys 2000;16:724–30. Onal C, Otsubo H, Araki T et al. Complications of invasive subdural grid monitoring in children with epilepsy. J Neurosurg 2003;98:1017–26. Hadar EJ, LaPresto EL and Bingaman WE. Image-guided epilepsy surgery. In: Germano IM, ed. Advanced Techniques in Imageguided Brain and Spine Surgery. New York: Thieme, 2002:156–61. Murphy MA, O’Brien TJ, Cool MJ. Insertion of depth electrodes with or without subdural grids using frameless stereotactic guidance systems – technique and outcome. Br J Neurosurg 2002;16: 119–25. Winkler PA, Vollmar C, Krishnan KG et al. Usefulness of 3-D reconstructed images of the human cerebral cortex for localization of subdural electrodes in epilepsy surgery. Epilepsy Res 2000;41: 169–78. Boonyapisit K, Najm I, Klem G et al. Epileptogenicity of focal malformations due to abnormal cortical development: direct electrocorticographic-histopathologic correlations. Epilepsia 2003;44(1): 69–76. Davis L, Spencer D, Spencer S et al. MRI imaging of implanted depth and subdural electrodes: is it safe. Epilepsy Res 1999;35: 95–8. Morris K, O’Brien TJ, Cook MJ et al. A computer-generated stereotactic virtual subdural grid to guide resective epilepsy surgery. Am J Neuroradiol. 2004;25:77–83. Rydenhag B and Silander HC. Complications of epilepsy surgery after 654 procedures in Sweden, September 1990–1995: a multicenter study based on the Swedish National Epilepsy Surgery Register. Neurosurgery 2001;49:51–79. Hamer HM, Morris HH, Mascha EJ et al. Complications of invasive video-EEG monitoring with subdural grid electrodes. Neurol 2002;58:97–103. Simon SL, Telfeian A, Duhaime AC. Complications of invasive monitoring used in intractable pediatric epilepsy. Ped Neurosurg 2003;38:47–52. Onal C, Otsubo H, Araki T et al. Complications of invasive subdural grid monitoring in children with epilepsy. J Neurosurg 2003;98:1017–26. Weinand ME, Oommen KJ. Lumbar cerebral spinal fluid drainage during long-term electrocorticographic monitoring with subdural strip electrodes: elimination of cerebro spinal fluid leak. Seizure 1993;2:133–6. Wiggins GC, Elisevich K, Smith BJ. Morbidity and infection in combined subdural grid and strip electrode investigation for intractable epilepsy. Epilepsy Res 1999;37:73–80. Lee W, Lee JK, Lee SA et al. Complications and results of subdural grid electrode implantation in epilepsy surgery. Surg Neurol 2000;54:346–51. Vives KP, Lee S, McCarthy K et al. Intracranial monitoring. In: Winn HR, ed. Youmans Neurological Surgery. Philadelphia: Saunders, 2003:2551–63. Fountas KN, King DW, Jenkins PD et al. Nonhabitual seizures in patients with implanted subdural electrodes. Stereotactic Func Neurosurg. 2004;82:165–8. Wennberg R, Gross D, Quesney F et al. Transient epileptic foci associated with intracranial hemorrhage in patients with subdural and epidural electrode placement. Clin Neurophysiol 1999;110:419–23. Awad IA, Nayel M, Lüders HO. Second operation after the failure of previous resection of epilepsy. Neurosurgery 1991;28: 510–18. Schwartz TH, Spencer DD. Strategies for reoperation after comprehensive epilepsy surgery. J Neurosurg 2001;95:615–23. Siegel AM, Roberts DW, Thadani VM et al. The role of intracranial electrode reevaluation in epilepsy patients after failed initial invasive monitoring. Epilepsia 2000;41:571–80. Lesser RP, Arroyo S. Subdural electrodes. In: Niedermeyer E, Lopes da Sliva F, eds. Electroencephalography: Basic Principles, Clinical Applications, and Related Fields, 5th Edn. Philadelphia: Lippincott Williams & Wilkins, 2005:777–90. Benbadis S, Wyllie E, Bingaman WE. Intracranial electroencephalogrphy and localization studies. In: Wyllie E, ed. The Treatment of Epilepsies, 3rd edn. Philadelphia: Lippincott Williams & Wilkins, 2001:1067–75.

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Benbadis SR. Invasive EEG. In Lüders HO, ed. The Epileptic Seizure: Pathophysiology and Semiology. New York: WB Saunders, 2000:49–53. Jayakar P. Invasive EEG monitoring in children: when, where, and what? J Clin Neurophysiol 1999;16:408. Cukiert A, Buratini JA, Machado E et al. Seizure’s outcome after cortical resections including the face and tongue rolandic areas in patients with refractory epilepsy and normal MRI submitted to subdural grids’ implantation. Arq Neuropsiquiatr 2001;59: 717–21.

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Mihara T and Baba K. Combined use of subdural and depth electrodes. In: Lüders HO, Comair YG, eds. Epilepsy Surgery. Philadelphia: Lippincot Williams and Wilkins, 2000:613–21. Brekelmans GJ, van Emde Boas W, Velis DN et al. Comparison of combined versus subdural or intracerebral electrodes alone in presurgical focus localization. Epilepsia 1998;39: 1290–301. Chapman K, Wyllie E, Najm I et al. Seizure outcome after epilepsy surgery in patients with normal preoperative MRI. J Neurol Neurosurg Psychiatry 2005;76:710–13.

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Placement of depth electrodes L Mulligan, K Vives, and D Spencer

Background

Planning

The first step to eradicating chronic seizures is to accurately identify the seizure focus. Although imaging has improved dramatically in recent years, there are still patients whose seizure focus defies noninvasive localization as described earlier in this text, and who must proceed to intracranial electrode evaluation. Intracranial recordings can be done by a variety of means, including subdural grid and strip electrodes, epidural electrodes, and depth electrodes. Depth electrodes, electrodes that actually enter the substance of the brain and pass to deep structures, were first used for the evaluation of epilepsy in 1950 and then more consistently in the United States since the early 1970s.1 They are still used now either alone or, more commonly, in concert with subdural strip electrodes (SDSEs) and subdural grid electrodes (SDG) for chronic recording for as long as a month if necessary to capture an adequate number of ictal events. The electrodes are also useful for recording interictal activity and studying the pattern of seizure spread. Depth electrodes offer the advantage of being able to record from deep structures (i.e., the hippocampus, hypothalamus, deep frontal lobes) where there is inadequate coverage provided by subdural electrodes. They can also be used to record activity from the neocortex through which they pass, though the sampling area is quite limited. Similarly, they can be stimulated to map for function, although are usually far less useful than subdural strip or grid electrodes for that purpose.

There are several common scenarios where depth electrodes prove useful (Table 103.1), however, the frequency and extent of their use varies from institution to institution. Their use in focal versus survey studies, temporal versus frontal studies and in re-operative cases will be discussed below. The special cases of sampling from other deep structures will also be discussed.

Materials Over the years, the structure and materials for depth electrodes have evolved substantially. While the early electrodes were rigid, most electrodes implanted currently are flexible (Figure 103.1), usually with a semi-rigid stylet to help prevent errant placement. They are often implanted through a guide cannula to further improve the accuracy of placement. The electrodes, usually 1–1.5 mm in diameter, come in a variety of configurations with arrays of 4–10 individual contacts with spacing from 5–10 mm between the center of each. The most commonly used material now for the contacts is platinum, though stainless steel, nickel-chromium and gold have all been used.2 Silver and copper are toxic to brain tissue and cannot be employed. The outer casing is usually polyurethane which houses the individual wires for each contact. The electrodes can also be configured to allow for the performance of microdialysis, useful for research applications. 938

Temporal lobe studies Patients that have temporal lobe epilepsy confirmed on scalp-EEG with MRI findings of mesial temporal sclerosis, appropriate semiology, and concordant PET and neuropsychological data do not require invasive monitoring. Those patients can usually go directly to resection with a high degree of success. Patients that do require invasive monitoring fall into one of several categories. The most common scenario is a patient that appears to have apparent temporal lobe epilepsy but has a normal MRI or discordant phase I and II evaluation data that do not confirm location or laterality or imply bilaterality. In that instance, one reasonable approach would be to place depth electrodes in both hippocampi and subdural, subtemporal strips around both temporal lobes. This can be performed through 2–4 burr holes or small troughs. The depth electrodes can be placed in one of two principle orientations: either longitudinally or orthogonally. Longitudinal electrodes are passed posteriorly to anteriorly starting from a paramedian occipital start point and traversing the long axis of the hippocampus. Orthogonally placed electrodes are passed perpendicularly to the cortical surface via the middle or inferior temporal gyrus into the mesial structures. These orthogonal approaches are typically designed utilizing one anterior electrode placed into the pes/amygdala area and another into the body of the hippocampus. Either method can be combined with subdural strip or grid electrodes and the purpose of the intracranial study largely determines the best approach. Two other common scenarios involving the temporal lobe are (1) patients that are suspected to have extrahippocampal temporal lobe epilepsy or (2) patients with well lateralized epilepsy, but the lobar location of the seizure is still in question and the medial temporal lobe remains suspect. In these cases, a detailed study is usually designed to find the extent of the epileptogenic zone and its relationship to critically functional cortex. A large grid is often used over the cortex in combination with subdural strips and depth electrodes (Figure 103.2). This type of study usually requires a large craniotomy.

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directly exposing and dissecting the interhemispheric fissure. In other patients, the suspicion of medial frontal onset may be lower, but a limited sampling of the interhemispheric ares is indicated; in this situation, depth electrode coverage of the anterior cingulate and supplementary area can be utilized (Figure 103.3). Care is taken to avoid primary motor and language cortices when planning the entrance sites – often coregistration of preoperative fMRI can be utilized to further define these areas. Subdural strip coverage of the orbitofrontal and fronto-polar areas is also unreliable. Depth electrodes can easily be used to provide coverage of these areas as well (Figure 103.4). Fortunately, medial occipital coverage can typically be gained by directing posterior subtemporal strips posterior to the collusum and pineal area.

Deep structures

Figure 103.1 Intracranial electrodes. Arrow – depth electrode with microdialysis membrane.

Rather than making an additional burrhole to pass the electrodes from an occipital approach, depth electrodes are typically passed in an orthogonal orientation often by making a small hole in the grid though which the electrode(s) can be passed. Multiple electrodes can be passed into different portions of the amygdala and hippocampus to further refine localization as described above.

Extratemporal epilepsy Another common category is patients with nonlesional extratemporal epilepsy. The placement of depth electrodes in these patients is usually done in order to sample areas where subdural strip coverage is either difficult or unreliable. In patients with frontal lobe epilepsy where there is a high suspicion that the medial frontal lobe is involved, interhemispheric subdural strip coverage is typically planned. Due to draining veins, these strips typically cannot reliably be placed without

Table 103.1 Common scenarios where depth electrodes prove useful Study type

Structures sampled

Temporal lobe studies Frontal lobe studies

Hippocampus and amygdala Anterior cingulate, orbitofrontal and supplementary motor areas Areas where adhesions prevent subdural strip monitoring Hypothalamic hamartoma, periventricular gray heterotopias

Reoperative studies Deep lesions

Several groups have reported successfully recording both ictal and interictal activity from hypothalamic hamartomas3,4 and from periventricular gray matter heterotopias.5,6 An example of this type of case is illustrated in Figure 103.5. The technique and placement of electrodes in this situation is not different that in others. Gray matter heterotopias may also be an indication that the overlying cortex may be abnormal thus making subdural cortical recordings in these corresponding areas, important. Likewise, it is often the case that depth electrode recording can supplement surface recordings in cases of large cortical dysplastic lesions, even those that come to the surface.

Technique There are several viable techniques for inserting depth electrodes: framed stereotaxis, frameless neuronavigation, freehand passage, and endoscopically assisted. Framed stereotaxis is certainly the time-honored standard. Any number of systems are useful, including the Brown-Roberts-Wells (BRW), the Cosman-Roberts-Wells (CRW), the Leksell frame and others. Pillay et al. studied the accuracy of the BRW and CRW systems and found them to be consistently within 2 mm of the target.7 Similarly, Ross et al.8 reported 100% accuracy of electrode placement with the Leksell frame using MRI. Framed stereotaxis is particularly useful for bilateral survey studies. It allows for the placement of bilateral longitudinal hippocampal electrodes without the need for repositioning. To perform a framed placement of hippocampal depth electrodes, the frame is usually placed the morning of surgery under local anesthesia and possibly light sedation. The patient is then scanned usually with fine cut MRI often using SPGR sequencing. MRI gives a more detailed anatomical image than CT and allows better visualization of blood vessels along the proposed trajectory, but CT has also been shown to be a viable alternative. CT theoretically introduces less error and is more rapidly acquired. Van Roost et al.1 placed 212 longitudinal hippocampal depth electrodes using CT guided framed stereotaxis followed by postoperative MRI for evaluation of placement. They found that 97% of hippocampal head contacts and 96% of hippocampal body contacts were in or

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(c)

(b)

(d)

Figure 103.2 Reconstructions of electrode positions superimposed on preoperative MRI scans. A – anterior medial temporal depth electrode. B – posterior medial temporal depth electrode. C – electrode entrance sites (arrows) in context of the rest of the study on a lateral view. D – a view from below of the subtemporal strip electrodes.

immediately abutting the target.1 Others have performed fusion of the two modalities in an effort maintain the excellent detail afforded by MRI while reducing any error introduced by magnetic reasonance.9 Once the scan is obtained, the patient is taken to the operating suite and the surgical planning can be performed on a navigation system. Great care is taken to define a trajectory that avoids major blood vessels and brings as many contacts as possible through the length of the hippocampus and into the amgydala. A 10-contact electrode is often chosen for this purpose. A burr hole is recommended, rather than a twist-drill hole, so that surface vessels can be identified and avoided. A rigid cannula is usually passed along the proposed trajectory, sometimes several millimeters short of the final target, and then the electrode is passed through that with its stylet still in place. Once it has reached target, the cannula and the stylet are removed and the electrode can then be tunnel several centimeters from the insertion site and secured with a stitch to the scalp. Once the depth electrodes are placed, burr holes can be made in the temporal areas to pass subdural strip electrodes. If only depth and strip electrodes are inserted, those can actually be removed at the bedside upon completion of monitoring without returning to the operating room.

Frameless systems can be employed with some minor customized adaptations to perform the same procedures. Mehta et al.10 and Murphy et al.11 both report on their experience with commercially available systems. Longitudinal and orthogonal electrode placement was performed and found to be accurate. Mehta et al.10 showed with postoperative imaging that the electrodes were on average 3 mm from the intented target site, but only 0.4 mm ±0.9 mm from the anatomic structure of interest. Not surprisingly, they also found the orthogonal electrodes to have a lesser degree of error than the longitudinally oriented electrodes. Frameless navigation is particularly useful for detailed studies when orthogonal electrodes are to be placed can be placed through the grid at to target various locations within the amygdala and hippocampus. Using a stabilizing arm, the electrodes can be passed through a cannula in nearly identical fashion to a framed system. If the depth electrodes are passed through a large subdural grid, the electrode is typically secured to the grid and the patient must return to the operating room for their removal. Frameless navigation offers a great deal more flexibility in the design of a cranial flap as there is no frame to hinder the approach. There are several other benefits as well. First, the scanning can be done the day before the surgical procedure. Imaging can be

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Placement of depth electrodes (a)

(b)

(c)

(d)

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Figure 103.3 Reconstructions of electrodes trajectories for medial frontal monitoring. A – coronal reconstruction of a left anterior cingulate (AC) depth electrode. B – coronal reconstruction of a supplementary motor area (SMA) depth electrode. C – interhemispheric reconstruction of the above mentioned electrodes. Arrows point to the SMA and AC depths. D – left lateral view of the same depths. Upper arrows indicate the AC and SMA depths. Inferior arrows also demonstrate the medial temporal lobe depths.

acquired and a surgical plan devised prior to taking the patient to the operating room. This allows for a rapid start of the case on the day of surgery. Furthermore, application of the frame can be quite distressing to the patient and this step is obviated. Freehand application of orthogonal depth electrodes has also been reported with acceptable accuracy. Davies et al.2 placed 15 electrodes in 12 patients and found that their average closest contact was 0.8 mm from target, with 11⁄15 actually being in or abutting the hippocampus and all were capable of capturing ictal events. It is not a viable technique, however, for longitudinal placement and theoretically has a higher risk

Figure 103.4

of hemorrhage as vessels along the trajectory cannot be accounted for. It does, however, reduce operative time and the need for additional imaging. Finally, Song et al.12 describe a combination of frameless navigation and neuroendoscopy for the placement of longitudinal hippocampal depth electrodes. Using frameless stereotaxis, a trajectory is developed for introduction of the endoscope into the atrium of the lateral ventricle. Then, under endoscopic visualization, the electrode is passed into the temporal horn along the hippocampus, without actual penetration of the tissue. Plain film radiography is used intraoperatively to

Coronal and sagittal reconstructions of an orbitofrontal depth electrode.

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(a)

(b)

Figure 103.5 Use of depth electrode monitoring of a periventricular heterotopia. A – axial T1 weighted MR with arrow pointing to the heterotopia. B – reconstruction of the path of the depth electrode used to monitor electrographic activity.

verify an appropriate trajectory. CSF pulsations do not appear to degrade the recordings. Because the electrode does not actually traverse tissue, this method offers the advantage that the non-resected hippocampus is not injured. Although the clinical significance is not known, it certainly confers a theoretical advantage. Once the electrodes are placed, they are tunneled several centimeters and secured by a suture to the scalp. Purse string sutures are also placed around each electrode to decrease the leakage of CSF. A generous head wrap is applied and the patient is taken to the ICU for overnight observation. Postoperative imaging is usually obtained the next day to document the actual location of the electrodes. Post placement imaging is routinely performed to assess the accuracy of the electrode placement. While plain film can certainly demonstrate at least gross localization, MRI yields the most detailed information and lends itself to three dimensional reconstruction programs. Davis et al.13 performed a study to verify the safety of MRI with respect to the scanning of electrodes made from stainless steel, platinum, and nickel-chromium alloy. Placement of 143 depths, 688 subdural strips, and 38 subdural grids was evaluated on a 1.5 T MRI unit. T1, T2, and spoiledgradient sequences were obtained and no patient had an adverse neurological event. The patient is typically maintained on antibiotics only for 24 hours and steroids are tapered off over 3–4 days. On postoperative day 1, the patient is transferred to the epilepsy monitoring unit to continue recording. The above discussion was directed mostly at the placement of depth electrodes into the hippocampus. Depth electrodes can be used in a number of different locations including in perilesional areas, deep frontal lobes, the hypothalamus, the thalamus, and the subthalamic nucleus. The technique for insertion remains essentially the same just with different targeting. Most experience with these alternative locations, especially the deeper locations is with framed systems. As with any surgery, the decision to proceed must weigh the potential gains versus the potential risks. The overall risk

associated with depth electrode placement is 1–4% with most risk falling into one of two categories: hemorrhage or infection. In preparation for surgery, aspirin and nonsteroidal antiinflammatory medications are stopped and for patients on valproic acid, a bleeding time is assessed. If it is prolonged, the medicine is stopped, due to its documented adverse influence of platelet function. Specific surgical technique may also reduce the risk of hemorrhage. Using a burr hole where the cortical vessels can be adequately visualized and coagulated is safer than using a small twist-drill hole. Improved intraoperative imaging and guidance is beneficial as well. The entire tract along which the electrode is to be placed can be assessed for the presence of vessels. Additionally, limiting the number of electrodes to that which is truly essential reduces the numbers of passes through the brain and thus reduces the risk of hemorrhage as well. The risk of hemorrhage with permanent sequela ranges from 0–0.8% and hemorrhages without permanent deficit occurred approximately 0–4%.9 With regard to infection, the rate is approximately 0–4%.9 Some institutions prophylax their patients with intravenous or oral antibiotics for the duration of implantation. However, there is not convincing data to support that practice,14 so many simply perform standard perioperative dosing, and discontinue antibiotics after twenty four hours. Another technique that reduces infection is ensuring that each lead is individually tunneled several centimeters from the incision and a purse string suture is placed around the lead to minimize CSF leak. Most infections can be successfully treated with removal of the leads coupled with intraventous antibiotics. Cerebritis and abscesses are extremely rare. Of note, two cases of Jakob-Creutzfeld have been reported, so electrodes should not be reused. Some controversy does exist about the ability of depth electrodes to provide information that subdural strip electrodes cannot. Spencer et al.15,16 noted that 168 of 181 temporal lobe seizures presented in the hippocampal depth electrode in advance of presentation in the subdural strip, sometimes by as much as 70 seconds. It was further noted, however,

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Placement of depth electrodes that 21 of 105 events captured with the hippocampal electrode, never appeared in the SDSEs. Twelve of those events were simple partial seizures, but even nine complex partial events were missed. Based on that they reported that depth electrodes were approximately 20% more sensitive that subdural strip electrodes in detecting mesial temporal seizures.15 Seizures from patients with bilateral strip and depth electrodes were also analyzed for spread pattern and it was noted that the pattern of spread never showed epileptiform activity in the contralateral neocortex prior to the ipsilateral neocortex, thus in their data, the SDSE never provided falsely lateralizing data.15–18 Ultimately, they felt a combination of subdural strip and depth electrodes were most effective as the sdse were useful in detecting the uncommon patient with neocortical temporal lobe or extratemporal lobe epilepsy and they were useful for studying spread patterns that are sometimes prognostically relevant. Sperling and O’Connor19 did report rare instances of falsely lateralizing data from SDSEs when compared to depth electrodes. Davies et al.2 however, found that although the depth electrode may detect mesial temporal seizures slightly earlier by 2–3 seconds, that no novel information was gleaned from the depths and that every seizure did appear in the SDSE.2 Eisenshenck, et al.20 noted that false localization did occur between depth subdural electrodes in approximately 15% of seizure events, but was seen when the subdural electrodes were placed suboptimally and specifically, lateral to the collateral sulcus. With regard to SDSE placement, Cohen-Gadol and Spencer21 note that a newer technique for placement may provide more accurate information. Instead of placing the strips subtemporally perpendicular to the long axis of the lobe, placement is in the anterior-posterior axis around the temporal pole just underneath the lesser wing of the sphenoid. This passage provides extensive mesial coverage. It has yet to be confirmed that this SDSE provides sufficiently similar data to hippocampal depth electrodes to be used in their place. To justify the use of invasive monitoring, there has to be a substantial number of patients that have localizable seizure foci and that ultimately go on to have excellent seizure control following resection. Ross et al.8 reported on their results over three years comparing their temporal lobe epilepsy patients that did and did not require invasive monitoring. They found of 50 patients on whom they performed invasive monitoring with combined depth and subdural electrodes, 37 were found to be good candidates for temporal lobectomy, 36 underwent the surgery, and 69% were seizure free following resection. In comparing that to their patient population who underwent lobectomy without invasive monitoring, 70% of that group was seizure free. So the results of resection were nearly identical

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and because of intracranial monitoring, they were able to offer resection and ultimately seizure control to a substantially larger group of patients. Although most studies comparing subdural and depth electrodes involve the mesial temporal structures, there are case reports of extratemporal lobe epilepsy where depths were critical for detection. Privitera et al.22 report the case of a patient with MRI occult focal cortical dysplasia that was not detected by subdural electrodes that was subsequently detected by depth electrodes. The patient was found to have an epileptogenic area approximately 2 cm below the sensory cortex with depth electrodes that did not demonstrate abnormalities on the overlying subdural electrodes. Following resection of the area detected by the depth electrode, the patient experienced a 95% reduction in seizures. More recently, depth electrodes have been used in less conventional ways. With interest in deep brain stimulation for epilepsy management increasing, depth electrodes have found new used. Dinner et al.23 performed a study on four patients by implanting bilateral subthalamic nucleus (STN) depth electrodes and simultaneously recording scalp and STN activity. They found that activity, both interictal and ictal, recorded from scalp EEG was also represented in the ipsilateral STN which may ultimately lead to novel treatment options.

Future Currently, depth electrodes, or perhaps more properly probes, sample the electrical activity of structures with the brain or are also used for microdialysis in order to examine the concentrations of substances in the CSF. Centers are looking at a number of different devices to add to these probes to gather other types of information about the tissue of interest. Probes for pH, oxygenation, calcium and enzyme-linked probes for a number of different molecules are either being designed or are being used in investigations. Additionally, research is being done to provide ‘smart’ electrodes that house their own pre-amplifiers, analog to digital converters, wireless broadcast mechanisms and power sources. Phase 3 studies are also underway for implantable devices that continuously sample EEG activity and provide electrical stimulation to interrupt seizure activity through both subdural strips and depth electrodes (Neuropace, La Jolla, CA). Until an efficient means becomes available to monitor the electrical, magenetic and/or chemical changes in 3D space from a remote location, it is likely that depth electrodes will continue to play an instrumental role in the investigation of patients with epilepsy.

REFERENCES 1.

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Van Roost D, Solymosi L, Schramm J, van Oosterwyck B, Elger CE. Depth electrode implantation in the length axis of the hippocampus for the presurgical evaluation of the medial temporal lobe epilepsy: a computed tomography-based stereotactic insertion technique and its accuracy. Neurosurg 1998;43(4):819–27. Davies KG, Phillips BLB, Hermann BP. MRI confirmation of accduracy of freehand placement of mesial temporal lobe depth electrodes in the investigation of intractable epilepsy. Br J Neurosurg 1996;10(2):175–8.

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Fukuda M, Kameyama S, Wachi M et al. Stereotaxy for hypothalamic hamartoma with intractable gelastic seizures: technical case report. Neurosurgery 1999;44:1347–50. Kahane P, Ryvlin P, Hoffmann D et al. From hypothalamic hamartoma to cortex: what can be learnt from depth recordings and stimulation? Epileptic Disord 2003;5:205–17. Kothare SV, VanLandingham K, Armon C et al. Seizure onset from periventricular nodular heterotopias: depth-electrode study. Neurology 1998;51:1723–7.

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Textbook of epilepsy surgery Li LM, Dubeau F, Andermann F et al. Periventricular nodular heterotopia and intractable temporal lobe epilepsy: poor outcome after temporal lobe resection. Ann Neurol 1997;41:662–8. Pillay PK, Barnett G, Awad IA. MRI-guided stereotactic placement of depth electrodes in temporal lobe epilepsy. Br J Neurosurg 1992;6:47–53. Ross DA, Brunberg JA, Drury I, Henry TR. Intracerebral depth electrode monitoing in partial epilepsy: the morbidity and efficacy of placement using magnetic resonance image-guided stereotactic surgery. Neurosurgery 1996;39(2):327–34. Blatt DR, Roper SN, Friedman WA. Invasive monitoring of limbic epilepsy using stereotactic depth and subdural strip electrodes: surgical technique. Surg Neurol, 1997;48:74–9. Mehta AD, Labar D, Dean A et al. Frameless stereotactic placement of depth electrodes in epilepsy surgery. J Neurosurg 2005;102:1040–5. Murphy MA, O’Brien TJ, Cook MJ. Insertion of depth electrodes with or without subdural grids using frameless stereotactic guidance systems – technique and outcome. Br J of Neurosurg 2002;16(2):119–25. Song JK, Abou-Khalil, Konrad PE. Intraventricular monitoring for temporal lobe epilepsy: report on technique and initial results in eight patients. J Neurol Neurosurg Psychiatry 2003;74:561–65. Davis LM, Spencer DD, Spencer SS, Bronen RA. MR imaging of implanted depth and subdural electrodes: is it safe? Epilepsy Res 1999; 35:95–8. Wyler AR, Walker G, Somes G. The morbidity of long-term monitoring using ubdural strip electrodes. J Neurosurg 1991;74:734–7.

15. 16.

17. 18. 19. 20 21 22. 23.

Spencer SS, Spencer DD, Williamson PD, Mattson R. Combined depth and subdural electrode investigation in uncontrolled epilepsy. Neurology 1990;40:74–9. Spencer SS, Williamson PD, Spencer DD, Mattson RH. Human hippocampal seizure spread studied by depth and subdural recording: the hippocampal commissure. Epilepsia 1987;28(5): 479–89. Spencer SS, So NK, Engel JJr et al. Depth electrodes. In Engel JR, ed. Surgical Treatment of the Epilepsies, 2nd ed. New York: Raven Press, 1993. Spencer SS. Intracranial recording. In: Spencer SS, Spencer DD, eds. Contemporary Issues in Neurological Surgery: Surgery for Epilepsy. Cambridge, MA: Blackwell Scientific Publications, 1991. Sperling MR, O’Connor MJ. Comparison of depth and subdural electrodes in recording temporal lobe seizures. Neurology, 1989; 39:1497–504. Eisenschenk S, Gilmore RL, Cibula JE, Roper SN. Loateralization of temporal lobe foci: depth versus subdural electrodes. Clin Neurophysiol 2001;112:836–44. Cohen-Gadol AA, Spencer DD. Use of an anteromedial subdural strip electrode in the evaluation of medial temporal lobe epilepsy. Technical note. J Neurosurg 2003;99(5):921–3. Privitera MD, Yeh HS, Blisard K, Sanchez N. Detection of epilectogenic focal cortical dysplasia by depth, not subdural electrodes. Neurosurg Rev 2000;23:49–51. Dinner DS, Neme S, Nair D. et al. EEG and evoked potential recording from the subthalamic nucleus for deep brain stimulation of intractable epilepsy. Clin Neurophysiol 2002;113:1391–402.

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Stereoelectroencephalography D Hoffmann, GL Russo, and M Cossu

Historical aspects of stereoelectroencephalography (SEEG) The first successful attempts to record intracerebral electrical activity date back to the first half of the past century. In those decades, during which the technique of intraoperative recording from the cerebral cortex in epileptic patients had been developed by Penfield and Jasper,1 intracerebral electrodes began to be placed with the aim to record from subcortical structures, mainly in order to elucidate the role of basal nuclei in ‘petit mal’2,3 as well as to investigate cases with presumed ‘centrencephalic’ seizures.4,5 In several studies electrodes were placed using a rough ‘free hand’ technique, which resulted in largely imprecise targeting of intracerebral structures.6–8 Furthermore, despite a trend towards chronic recording was progressively developing, the primary goal of inserting intracerebral electrodes was to record interictal stationary spike discharges, in this way depending on the same concepts established for intraoperative electrocorticography. Some new essential issues were addressed by two crucial methodological landmarks in the development of presurgical evaluation of epileptic patients, namely the employment of stereotactic approaches for the targeting of intracranial structures and the introduction of the concept of Epileptogenic Zone (EZ). Stereotactic devices for use in humans were designed in 1947 by Spiegel and Wycis,9 and their employment in recording from deep brain structures is reported since 1950.10 Stereotactic placement of intracerebral electrodes gained popularity and it was reported for the evaluation of temporal lobe epilepsy in the early 1960s.11 Meanwhile, in the Neurosurgical Unit of the Saint-Anne Hospital in Paris, France, stereotactic investigations of epileptic patients with intracerebral electrodes were inspired to a newly elaborated concept: epileptic seizures were regarded to as a dynamic process, with a spatialtemporal, often multidirectional, organization, which is best defined referring to a 3-dimensional arrangement.12–15 The site of origin and of primary organization of this dynamic process in focal epilepsies, whose surgical removal results in control of seizures, was defined as the EZ. With these premises, the Saint-Anne group developed the methodology of stereoelectroencephalography (SEEG),16,17 which enabled to address the complex requirements of defining in the 3D space and time the organization of the ictal discharges by tailored ‘explorations’ (arrangements of intracerebral electrodes). These were aimed to the verification of a previously formulated coherent hypothesis as to localization of the EZ, based upon available anatomo-electro-clinical findings

peculiar of each single case (see also Chapter 78, KahaneFrancione). For these purposes, several needs should be satisfied: the electro-clinical definition of epilepsies must rely on the recording of spontaneous seizures, and not be limited to recording of static interictal electrical abnormalities; the structures presumed to be involved in the ictal electrical onset and in the primary and secondary organization of the ictal discharge should be previously defined, included in the plan of exploration and surgically reached with the precision of the stereotactic technique; unlike the early studies with intracerebral electrodes, a primary role was assigned to the exploration of cortical structures, since the dynamic organization of the ictal discharges was presumed to follow cortical trajectories. For this latter purpose, owing to the interindividual variability of cortical anatomy, the stereotactic localization of different cortical areas required an approach based on a statistically built up proportional reference system which used the intercommissural line, as identified by contrast ventriculography, as the baseline landmark. This approach enabled to incorporate the anatomy of each single patient into a flexible anamorphotic reference system.18 Furthermore, stereotactic and stereoscopic tele-angiography provided excellent definition of the gyral and sulcal anatomy of the brain,19,20 and allowed to plan avascular trajectories for electrode placement through a double grid mounted on the custom-made Talairach’s frame.21 Since the pioneering experience of the Paris group, the development of modern neuroradiology and of image-fusion techniques have progressively increased the safety of the methodology and the accuracy of stereotactic targeting of intracerebral structures.22,23 Nevertheless, the baseline concepts of a single ‘stereotactic environment’, where electrophysiological, morphological and functional information may be imported and entered in a dynamic process of correlation to define the 3-dimensional organization of an epileptic discharge, are still topical in the current era of SEEG and they have been relevant for the development of modern epilepsy surgery and stereotactic neurosurgery.24–26

Indications In our centers, approximately 40% of resective surgical procedures in patients with drug-resistant focal epilepsy have been performed so far after chronic intracranial EEG monitoring with stereotactically implanted intracerebral electrodes (SEEG). Nevertheless, this proportion is progressively decreasing, and in the last two years it has dropped to less than 35%. This is the result of the growing experience of the teams 945

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dedicated to selection of patients and of the refinement of available diagnostic tools, mainly in the field of neuro-imaging, which enabled to reduce the indications to invasive diagnostic procedures. From a general point of view, invasive recordings are indicated whenever the non-invasive investigations fail to correctly localize the epileptogenic zone. This is the result of a varying degree of incoherence among anatomical, electrical and clinical findings, which is peculiar for every given patient. Although this means that indications to a SEEG exploration are usually customized to the requirements of single cases, a retrospective analysis of our experience allows to group the indications into different patterns of anatomo-electro-clinical incoherence that configure the need for invasive monitoring.27 This issue is extensively detailed in Chapter 76 by Kahane–Francione.

The implantation strategy should be addressed to record from the regions considered the most likely origin of the discharge (including the lesion, if present) as well as from all the structures possibly involved in the organization of the discharge through the more common pathways of propagation, as suggested by available electro-clinical findings. Furthermore, one should arrange the exploration taking into consideration also possible alternative hypothesis of localization, with number and sites of additional electrodes consistent with the likelihood of these hypothesis. The aim to obtain all the possible information from the SEEG exploration should not be pursued at the expense of an excessive number of electrodes. The possible involvement of eloquent regions in the ictal discharge requires their judicious coverage, with the twofold goal to assess their role in the seizure organization and to define the boundaries of a safe surgical resection.

Planning

Patterns of explorations The SEEG methodology emphasizes a tailored strategy of exploration, which results from the anatomo-electro-clinical features of every case, therefore rejecting a standardized arrangement of electrodes. Nevertheless, a posteriori, a number of typical patterns of coverage are clearly recognizable, and some illustrative examples of the more frequent of them will be herein detailed. Cases of temporal lobe epilepsy with consistent anatomoelectro-clinical findings are usually operated on after noninvasive investigations. SEEG recordings may be required in patients in whom the supposed epileptogenic area, though probably involving the temporal lobe, is suspected to extend also to extratemporal areas (so called ‘temporal plus’ epilepsies).28 In these cases, the main implantation patterns point to disclose a preferential spread of the discharge to the insulo-opercular complex,29,30 to the temporo-parieto-occipital junction (Figure 104.2), or to the anterior frontal cortex. Sampling of extratemporal areas must be wide enough to provide

General principles The available noninvasive anatomo-electro-clinical data are reviewed to formulate a coherent hypothesis of localization of the EZ and to plan a consistent tailored strategy of exploration. This decisional process requires a good experience in the interpretation of electro-clinical patterns of focal seizures, as well as a detailed knowledge of the functional anatomy of the brain, including that of both intra- and interhemispheric connections. Furthermore, one has to take into account the intrinsic peculiarities of multilead intracerebral electrodes, which, despite a limited coverage of the cortical surface compared to subdural strips or grids, enable an accurate sampling of the structures encountered along its trajectory, from the entry site to the final impact point. In this way, the investigation may include lateral and mesial surface of the different lobes, fissural and deep-seated cortices, as well as different kinds of lesions (Figure 104.1).

Figure 104.1 Left: pre-implant Gadolinium-enhanced T1-weighted coronal slice showing a nodular heterotopia at the right temporo-occipital junction (arrow). Right: T1-weighted 3D post-implantation MRI, coronal slice at the same level, showing an intracerebral electrode sampling the lateral cortex, the lesion and the cortex mesial to ventricular trigone. The electrode artifact generated in this sequence (as well as in the MRIs appearing in the following figures) is three-fold thick (2.5 mm) compared with the actual thickness of the electrode (0.8 mm). Single contacts on the length of the electrode are easily recognizable.

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Figure 104.2 Lateral (A) and antero-posterior (B) views of the stereotactic sketch, according to the bicommissural reference system, of a left inferior temporal-parietal SEEG exploration. Electrodes are indicated with either circled dots or dashed lines labelled by upper case letters. C-F: T1-weighted 3D post-implantation MRI, where the arrangement of electrodes is shown in some sagittal slices. G–M: same MRI, coronal slices.

information also to identify a possible extratemporal origin of the seizures that could not have been anticipated with certainty according to scalp EEG and clinical findings. Owing to the large volume of the frontal lobe, one can expect that a high number of electrodes is required for an adequate coverage of this region. In most patients, however, taking into account ictal clinical data and the related surface EEG expression, such a very large sampling can be avoided, and the exploration is focused on (but not restricted to) a more limited portion of the frontal lobe. The suspicion of an orbito-frontal epilepsy, for instance, often requires to investigate both the gyrus rectus and the orbital cortex (using oblique electrodes that also evaluate the frontal pole), the lateral fronto-basal cortex, the anterior cingulate gyrus (including Brodmann areas 32 and 24), and the anterior portion of the temporal lobe (Figure 104.3). In the same way, seizures that are thought to arise from the mesial wall of the premotor

cortex are evaluated by targeting at least the rostral and caudal part of the supplementary motor area (SMA), the pre-SMA, different portions of the cingulate gyrus, as well as the primary motor cortex, mainly for functional mapping purposes (Figure 104.4). Proceeding this way, hypothesis-based sampling often allows localization of the seizure onset zone in the frontal lobe, and in some cases may allow to identify very small epileptogenic regions.31 Occasionally, frontal lobe explorations may be bilateral, but almost always very asymmetric, because the question of the ‘affected side’ is usually addressed to before placement of electrodes. Rolandic electrodes are placed when MRI shows anatomical abnormalities within or close to this region and/or when its involvement in the EZ may be suspected, with the aim to evaluate the rolandic participation to the ictal discharge and to obtain a functional mapping by intracerebral electrical stimulations. This is not infrequently required when seizures

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Figure 104.3 Lateral (a) and antero-posterior (b) views of the stereotactic sketch, according to the bicommissural reference system, of a right fronto-orbital and anterior temporal SEEG exploration. Electrodes are indicated with either circled dots or dashed lines labelled by upper case letters. The contoured and shaded area corresponds to a focal cortical dysplasia detected at MRI, incorporated into the stereotactic space by co-registering the 3D MRI to the stereotactic angiography. c–f: T1-weighted 3D post-implantation MRI, where the arrangement of electrodes is shown in some sagittal slices. g: pre-implant coronal T2-weighted FLAIR MRI image, showing the hyperintense dysplastic lesion on the mesial aspect of the anterior portion of right frontal lobe. h–m: coronal slices of post-implantation 3D MRI. Box h shows sampling of the lesion by the internal contacts of electrodes ‘L’, ‘G’ and ‘O’ (see the stereotactic scheme).

are suspected to start in the frontal or parietal lobes and to propagate subsequently to the perirolandic areas. In the central region, intracerebral electrodes are particularly helpful to sample the depth of the rolandic fissure, as well as the descending motor and ascending sensory pathways. In the posterior quadrant of the hemisphere, placement of electrodes limited to a single lobe is extremely uncommon, due to the frequent simultaneous involvement of several occipital, parietal and posterior temporal structures, as well as to the possible multidirectional spread of the discharges to supra- and infra-sylvian regions. However, though multidirectional, posterior discharges often show a preferential spreading

pattern that has to be adequately assessed by employing implantation strategies which mainly focus on parietal, occipital and temporal areas (Figure 104.5).

Technical aspects Stereotactic neuroradiology In all patients a cerebral stereotactic stereoscopic teleangiogram,20 by injection of the appropriate vessels through catheterization of the femoral artery, is obtained after placement of the Talairach frame by transosseous pins and under general anesthesia.

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Figure 104.4 Lateral (a) and antero-posterior (b) views of the stereotactic sketch, according to the bicommissural reference system, of a left fronto-parietal SEEG exploration. Electrodes are indicated with either circled dots or dashed lines labelled by upper case letters. c–g: T1-weighted 3D post-implantation MRI, coronal slices, showing the arrangement of some of the intracerebral electrodes. h–l: same MRI, sagittal slices. m: preimplant T2-weighted FLAIR sagittal sequence, showing a precentral mesial focal cortical dysplasia, which was sampled by internal contacts of electrodes ‘E’, ‘J’ and ‘L’.

The X-ray sources are placed at 5 m distance from the patient’s head in order to obtain nearly distortion-free images in the lateral and anterior-posterior views. Two series of angiograms are obtained by both an orthogonal and a slightly oblique incidence (±6 degrees) of the X-rays. The coupled vision of corresponding phases of the two series enables a stereoscopic 3-dimensional effect, which is particularly helpful to distinguish vascular structures in different anatomical planes. Furthermore, 3D MR images (spoiled gradient echo T1-weighted gadolinium-enhanced sequence, slice thickness 1 mm, no gap, matrix 512 × 512) are imported in a computerassisted neuronavigational module (STP 4.0, Leibinger/Fischer, Freiburg, Germany, or Voxim, IVS, Chemnitz, Germany) and co-registered with angiographic images. In this way, a stereotactic diagram may be plotted, which includes arterial and

venous vessels, anatomical structures and possible lesions within the same geometrical referential space (Figure 104.6). This direct stereotactic localization procedure is employed in order to plan avascular trajectories for electrodes intended to reach well defined intracerebral structures. Placement of electrodes Placement of intracerebral electrodes is performed usually in a separate procedure (in order to dedicate all the time required to the accurate planning of trajectories), under general anesthesia and following refixing the frame exactly in the same position as for the previous stereotactic arteriographic study. Several thousands of commercially available, platinumiridium, semiflexible multilead intracerebral electrodes

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Figure 104.5 Lateral (a) and antero-posterior (b) views of the stereotactic sketch, according to the bicommissural reference system, of a left temporo-occipito-parietal SEEG exploration. Electrodes are indicated with either circled dots or dashed lines labelled by upper case letters. c–l: T1-weighted 3D post-implantation MRI. The electrode arrangement is shown in eight axial slices.

(diameter 0.8 mm; 5–18 contacts of 1.5 mm length, 2 mm apart) have been implanted so far in our Centers, the number of electrodes per patient ranging from 3 to 20 (mean 12 ± 3 electrodes/patient). The exploration is unilateral in most cases; bilateral (but not symmetrical) explorations account for less than 20% of the procedures. Antibiotics (cephamezine, 1–2 gr i.v. depending on patient’s weight in a single bolus) are routinely administered at anesthesia induction. Electrodes may be successfully placed by either orthogonal (i.e., perpendicular to the frame ‘midline’ plane or, less frequently, to the ‘coronal’ plane of the frame itself) or oblique trajectories in all the cerebral lobes. Targeting of deep-seated

or mesial structures such as the amygdala, hippocampus, cingulated gyrus, calcarine cortex is feasible, as well as excellent sampling of the insular cortex by electrodes inserted through the supra- or infra-sylvian opercula or by a retro-insular trajectory with a fronto-polar entry point (Figures 104.7–104.10). For the implantation of each electrode, a skull percutaneous trephination is performed with a 2.3 mm twist drill, guided through metallic double grids. Alternatively, a computerassisted robotized tool holder fully dedicated to stereotactic procedures (NeuroMate, Integrated Surgical Systems, Davis, CA, USA) which enables practically infinite degrees of freedom, is employed to insert electrodes with complex obliquities.

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Removal of electrodes Once monitoring is completed, electrodes are withdrawn. In most patients local anesthesia is employed, though sedation may be required in less cooperative patients and children. The plastic caps are removed, then each electrode is gently withdrawn and accurately inspected in order to check its integrity. Once all the hollow pegs have been unscrewed, a skin suture is applied to each electrode entry site and a sterile medication applied. The patient is usually discharged the day after.

Functional mapping

Figure 104.6 The lateral view of this stereotactic scheme shows several anatomical structures incorporated into the stereotactic space. The different structures are imported from the stereotactic skull X-ray film (bone profiles, black lines), from the stereotactic angiograms (profile of the insular vessels and of the sylvian fissure, dotted and dashed red line; some mesial and dorso-lateral arteries, red lines; a mesial vein, blue line) and from a co-registered 3D MRI (profiles of the ventricular cavities, violet; profile of the hippocampus, pink). The bicommissural referential system (thick black lines) has been drawn on the sagittal midline MRI slice and imported in the stereotactic space as previously described. (See Color plates.)

The dura is perforated by low-current monopolar coagulation. Minor leakage of cerebro-spinal fluid is often observed at this stage, but it does not require particular attention. Titanium hollow pegs (external diameter 2.5 mm), for the insertion and the fixation of the electrodes, are then screwed to the skull. A rigid stylet (diameter 0.8 mm) is then advanced through the peg as far as the established target under fluoroscopic control, in order to trace the intracerebral track of the electrode. After removal of the stylet, the electrode is inserted and advanced to the target. A plastic cap fixes the electrode to the peg and prevents possible CSF leakage. EEG signal provided by all implanted electrodes is checked in the operating room, enabling replacement of malfunctioning electrodes, which is however an uncommon occurrence. The cables are sutured to the skin and a sterile medication is applied. The patient is then awakened from anesthesia and moved to the recovery room. Intensive video-EEG monitoring usually starts the day following implantation, with the purpose of recording patient’s habitual ictal manifestations. After an adequate number of seizures is obtained, the patients undergo the sessions of intracerebral electrical stimulations (see below). Mean duration of video-SEEG monitoring approximates 10 days. An MRI with implanted electrodes is obtained in all cases, in order to define the actual position of each electrode contact. Nevertheless, local artifacts generated by the electrodes may prevent the accurate anatomical location of each individual electrical contact. This technical problem can be overcome by image fusion of post-implantation MRI or CT scan and preoperative 3D MRI investigation.

High- and low-frequency intracerebral electrical stimulations, delivered to pairs of contiguous contacts, have the two-fold goal to induce habitual ictal manifestations and to provide a functional map of the implanted regions.32–34 For these issue see also the chapter by Minotti. Intracerebral electrical stimulations performed for functional purposes enable the identification of regions related to different critical functions: primary somatomotor and somatosensory, visual, acoustic, and speech. Positive responses consist of either objective clinical events (e.g., clonic jerks of circumscribed body districts, errors in naming or reading, tachyphemia) or subjective manifestations (dysesthesic sensations, positive or negative visual and acoustic phenomena) concurrent with electrical stimulations. For primary sensorymotor functions low-frequency stimulations (frequency 1 Hz, duration of single stimulus 2–3 msec, current intensity 0.4– 3 mA) are preferred.32 In most cases, positive responses may be obtained from stimulations both in grey and white matter, thus allowing to map critical pathways extensively. Speech and visual areas are mapped using a combination of low and high-frequency (frequency 50 Hz, duration of single stimulus 1 msec, current intensity 1–3 mA) stimulations. Low-frequency stimulations are usually adequate in inducing subjective acoustic changes, the effect of high frequencies resulting often unpleasant for the patient. Chronic intracerebral seizure monitoring coupled with functional mapping is crucial in distinguishing between patients with early ictal involvement of highly eloquent regions, who should be excluded from surgery, and those with later spread of the discharge to these structures, who can be operated on with limited surgical risks and with predictable benefit on seizures. Functional mapping allows to anticipate potentially acceptable postoperative deficits, such as visual field defects in posterior temporal, occipital and parietal resections, as well as to evaluate the risk-to-benefit ratio of excisions close to more critical regions, such as sensory-motor and language areas. Though similar functional information can be obtained also from acute intraoperative electrical cortical stimulation, the following points must be stressed. First, chronic SEEG intracerebral electrical stimulations makes mapping of both cortex and fibres feasible, allowing to plan safer resections also in potentially critical subcortical areas. Second, availability of functional information before and not during surgery allows the patient to participate in the discussion of the riskto-benefit balance in a relaxing and comfortable setting. Third, intraoperative electrocorticography only exceptionally results in spontaneous seizures recording, which is essential in evaluating the actual ictal involvement of eloquent areas.

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Figure 104.7 T1-weighted 3D post-implantation MRI. In the sagittal slice at the level of the left mesial temporal structures electrodes sampling the amigdala (*) and hyppocampus ($) are highlighted. The coronal slices are parallel to the trajectories of the two electrodes.

SEEG-guided thermo coagulation Though SEEG is merely a diagnostic tool, the employment of this technique for possible therapeutic purposes has been suggested.35 Following a complete SEEG monitoring, intracerebral electrodes may be used to generate focal lesions of the SEEG-defined EZ. A thermocoagulation with a diameter of 5–7 mm is produced by a radiofrequency generator connected to adjacent electrode contacts. By these means, a variable

number of lesions may be produced in the cortical areas selected according to the SEEG data, with no relevant morbidity. Preliminary results are encouraging, with 15% of patients seizure free and 40% with significant improvement after the procedure.35 This technique, though deserving further evaluation in order to assess its feasibility, safety and efficacy, has been proposed as a possible option in cases with a limited and well-confined EZ, or when resective surgery is contraindicated.

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Figure 104.8 The sagittal slice of the T1-weighted 3D post-implantation MRI details electrodes sampling the parietal portion of the cingulated gyrus (*,$) and the anterior portion of the lingual gyrus (&). In the lower row the same electrodes are shown in coronal slices.

Morbidity Severe intracerebral hemorrhage is the most feared complication of intracerebral electrode placement.36 Talairach and Bancaud,16 in a series of 560 cases, report three cases (0.5%) operated on for removal of intracerebral hematomas which

developed after SEEG implantation. It is not clear whether these authors observed other cases with intracranial bleeding which did not require surgical treatment, but it is unlikely that such cases were diagnosed by the neuroradiological techniques available in the pre-CT scan or MRI era, even if mild neurological impairment was evident following implantation

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Figure 104.9 The sagittal slice of the T1-weighted 3D post-implantation MRI details electrodes sampling the superior (*) and inferior ($) lips of the left calcarine fissure. In the lower row, the same electrodes are shown in the coronal slices (left and centre). A different trajectory has been employed for an additional electrode which encroaches the calcarine fissure with an entry point in the parietal parasagittal cortex (right).

of intracerebral electrodes. The MNI group experienced one subdural bleed out of 170 cases (0.6%) investigated with intracerebral electrodes.37 Mortality has also been associated to such complication. Engel et al.,38 in a series of 140 patients, reported two deaths (1.4%) from intracerebral hemorrhage. In a series of 100 SEEG cases one death secondary to an intracerebral clot (1%) has been reported in a patient under anticoagulant treatment for deep vein thrombosis.39

The morbidity associated to the SEEG technique described in the present chapter has been recently reported.27 Out of 215 procedures in 211 patients, complications of different nature occurred in 12 SEEG procedures, for an overall incidence of morbidity as high as 5.6%. There were three acute symptomatic intracerebral hemorrhages which required emergency surgical evacuation, five asymptomatic intracranial bleedings detected at postimplantation MRI, one obstructive

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Figure 104.10 Sagittal (left) and coronal slices of a T1-weighted 3D post-implantation MRI, showing an electrode (*) placed in the insular cortex with a fronto-polar entry point.

hydrocephalus due to a clot in the aqueduct in a patient with a platelet disorder, one symptomatic brain abscess, one focal cortical edema and one retained broken electrode. In two cases (0.9%) a permanent motor deficit resulted from massive intracerebral bleeding. No death occurred in that series.

SEEG-guided resection The contribution of SEEG in addressing the decision whether to operate or not, the choice of an adequate surgical strategy, and the results of SEEG-guided resections may vary among different epilepsy surgery teams. The results of resective surgery performed relying on the SEEG methodology described in this chapter have been previously reported.27 Temporal lobe resections have been performed in approximately 25% of the studied patients. In several of these cases the indication to SEEG recording was formulated in the previous decade and, as experience of the teams has increased with time, the rate of temporal lobe resections performed after SEEG has currently dropped to 16%, with invasive tests having been reserved to temporal lobe cases with atypical ictal clinical features40 (or with poorly localizing ictal EEG. In most patients (75%) SEEG indicated an extratemporal or multilobar ictal onset, a proportion which is comparable to other studies,41,42 though several reports on invasive EEG tests show a preponderance of temporal lobe epilepsies over other localizations.43–46 Overall surgical results on seizures show that 56% of our patients operated on after SEEG investigation are in Engel’s47 class I, with 44% of them being completely seizurefree (Engel’s classes Ia and Ic). These proportions conflict with the much more favourable results obtained in patients operated on after noninvasive evaluations (in our experience, 83% in class I and 69% completely seizure-free). It has been reported that employment of invasive EEG predicts a non-favourable outcome on seizures, compared with surgery performed after a noninvasive workup,48 a finding which probably reflects the particular complexity of patients who need intracranial monitoring. In a number of patients, ranging close to 13% in our centers, SEEG findings may provide contraindications to resective surgery for different reasons. First, bilateral or multifocal ictal onsets of the epileptic discharge may be detected, a situation

which per se does not match a fundamental prerequisite of the surgical treatment of focal epilepsies by resective procedures. Second, coupling electro-clinical monitoring to functional mapping may disclose that not-resectable highly functional cortex is involved by the ictal onset or by the early spread of the discharge. Third, SEEG may fail to define the EZ, indicating that the previously elaborated hypothesis of localization was incorrect. The literature reports a 10–20% rate of poor localization after invasive recordings.49,50 In this regard, no consensus exists on whether such patients should be considered for repeated invasive tests or not. In our experience, the few patients who received a double exploration before surgery had, at their first evaluation, ictal SEEG evidence of an EZ partially covered by the exploration at the margins of the electrode arrangement, which was therefore corrected in the second step.

Clinical example This 22-year-old man with a negative familial history of epilepsy was born after a complicated pregnancy with repeat threats of miscarriage. Seizures started at 6 years of age, and prevailed during wakefulness. Administration of carbamazepine resulted in control of seizures for 2 years. Ten months following withdrawal of therapy seizures relapsed, and they persisted despite attempts with different antiepileptic drugs. Progressively, seizures became more frequent during sleep, occurring during wakefulness only occasionally. The patient was awakened by a subjective manifestation of discomfort at his left upper limb associated to a feeling of constraint at his throat which prevented him from speaking. Stiffening of the left upper limb, apnea, bilateral eyelid blinking and a complex hyperkinetic behavior occurred after the subjective phase. Postictally, no focal deficits were observed. A high seizure frequency was reported, with many episodes every night. Neurological examination was normal. Scalp video-EEG monitoring disclosed a possible right anterior onset of seizures. Brain MRI demonstrated a possible focal cortical dysplasia in the right frontal lobe (Figure 104.11). According to anatomo-electro-clinical considerations, which suggested an early ictal involvement of areas exceeding the anatomical limits of the lesion, a tailored SEEG exploration was indicated. In particular, the presence of early subjective symptoms

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Figure 104.11 T2-weighted FLAIR MRI sequence shows a hyperintense cortical lesion in the anterior portion of the right inferior frontal sulcus (arrow) in both coronal (top) and sagittal (bottom) slices.

pertaining to the visceral domain suggested the possible involvement of the opercular-insular region. In this tailored SEEG exploration intracerebral electrodes covered dorsolateral, mesial (including different portions of the cingulated gyrus), polar, opercular and orbital aspects of the right frontal lobe, the anterior and posterior portions of the right insular cortex and the lesion disclosed at MRI (Figure 104.12). Epileptiform interictal activity, often consisting of rhythmic paroxysmal discharges with no clinical correlates, was recorded from the insular and fronto-opercular cortices (electrodes I and R, deep leads of electrode Z). Ictal discharges, recorded during 18 spontaneous seizures, originated in the same regions, with subsequent spread to the anterior cingulated gyrus (internal leads of J) and posterior-mesial superior frontal gyrus (supplementary motor area, internal leads of M) (Figure 104.13). The lesion showed only a delayed and marginal involvement in the discharge. Intracerebral electrical stimulations of the internal leads of electrode R (opercular cortex) and of insular leads of electrodes I and Z evoked symptoms identical to those experienced during habitual fits, with concomitant electrical discharges in the same sites of the spontaneous seizures. Therefore, surgical resection of the fronto-central operculum, extended as far as the posterior aspect of the lesion, and of the suprasilvian portion of the insular cortex was performed (Figure 104.14). Histology of the ‘lesional’ specimen was positive for a cytoarchitectural focal cortical dysplasia, with no relevant alterations having been found in the opercular and insular specimens. It should be stressed, however, that removal

of the insular cortex resulted in fragmentation of the specimens, which probably did not allow an adequate histological evaluation. One year after surgery, the patient is seizure free.

Summary ●

●

●

●

●

Stereotactic placement of intracerebral multilead electrode for chronic EEG recording of seizures (SEEG) was introduced in the second half of the last century by the group of Saint-Anne Hospital in Paris, France, for the presurgical evaluation of patients with drug-resistant focal epilepsy. SEEG explorations are indicated whenever the noninvasive tests fail to adequately localize the Epileptogenic Zone (EZ). Currently, approximately 35% of our operated-on patients require a SEEG evaluation. Arrangement of electrodes in SEEG explorations is tailored according to the peculiar needs of each patient, and it is therefore customized to verify a predetermined hypothesis of localization of the EZ based on pre-SEEG anatomo-electro-clinical findings. Multilead intracerebral electrodes are designed to sample cortical structures on the lateral, intermediate and mesial aspect of the hemisphere, as well as deep-seated lesions. Planning of avascular electrode trajectories is performed employing stereoscopic teleangiograms of the pertinent vessels obtained in stereotactic conditions, co-registered to 3D T1-weighted gadolinium-enhanced MRI to improve

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(a)

(c)

(f)

(d)

(g)

(e)

(h)

K X M E

N

J F

I

R

H G

L

Z

O

X K

(b)

J

M E N F R H I L G

Z

O

Figure 104.12 a–b: stereotactic scheme showing the electrode arrangement in this SEEG exploration. Electrodes are indicated with either circled dots or dashed lines labeled by upper case letters. The contours of the lesion, incorporated in the stereotactic space by co-registering the stereotactic angiogram and the 3D MRI, are detailed in the lateral view (double-dotted line). Electrodes ‘L’, ‘G’, and the external contacts of ‘Z’ sample the lesion. The insular cortex is sampled by the internal contacts of electrodes ‘Z’, ‘I’, and ‘R’. In the post-implant 3D T1weighted MRI, sagittal (c–e) and coronal slices (f–h) provide further details on the structures explored by intracerebral electrodes.

Insula Central operculum Insula Precentral operculum Insula Frontal pole Gyrus rectus Lateral orbital cortex Gyrus rectus Anterior gingulated sulcus Anterior cingulated sulcus Anterior F2/F3 sulcus Anterior F3 Anterior mesial F1 Lesion Lesion Anterior cingulated gyrus Anterior F3 Precentral cyngulated gyrus Intermediate F1 Intermediate mesial F1 Intermediate F1/F2 sulcus Intermediate F2 Intermediate mesial F2 Intermediate F2 Posterior mesial F1 Posterior F1 Posterior mesial F1 Posterior F2 Central cingulated gyrus Inferior precentral gyrus Time coder

Figure 104.13 Early electrical activity during a spontaneous seizure in a synthetic montage of intracerebral EEG traces. The ictal discharge originates in the insular and opercular cortices, with subsequent involvement of the postero-mesial portion of the superior frontal gyrus (F1) and of precentral cingulated gyrus. The lesion does not show prominent ictal involvement. F2 = middle frontal gyrus; F3 = inferior frontal gyrus.

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Figure 104.14 Postoperative T1-weighted Inversion Recovery MR images, coronal (left row) and sagittal (right row) slices, obtained six months after surgery, demonstrating resection of the right fronto-central operculum and of the suprasylvian portion of the insular cortex.

●

the targeting of the desired structures. Pre-SEEG stereotactic neuroradiology and electrode implantation are usually performed in separate procedures. Electrodes are removed once video-SEEG monitoring is completed. Intracerebral electrical stimulations are used to better define the EZ and to obtain a detailed functional mapping of critical cortical and subcortical regions, which enables to perform safer surgical resections in eloquent areas.

●

●

Surgical morbidity of SEEG is reasonably low, and it mainly consists of intracerebral bleeding. Permanent post-SEEG neurological impairment is observed in less than 1% of the procedures. In approximately 75% of cases, SEEG evaluation enables to guide extratemporal or multilobar resections. SEEG-guided resective surgery may yield excellent results on seizures, with 56% of operated on patients in Engel’s Class I.

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Penfield W, Jasper H. Epilepsy and the Functional Anatomy of the Human Brain. Little Boston: Brown and Co; 1954. Kirikae T, Wada J. Electrothalamogram of petit-mal seizures. Med Biol 1951;20:253. Spiegel EA, Wycis HT. Diencephalic mechanisms in petit-mal epilepsy. Electroencephalogr Clin Neurophysiol 1951;3:473–5. Williams D, Parsons Smith G. The spontaneous electrical activity of the human thalamus. Brain 1949;72:450–82. Jung R, Reichert T. Heines KD. Zur Technik und Bedeutung der operativen Elektrocorticographie und subcorticalen Hirnpotentialableitung. Nervenarzt 1951;22:433–6. Dodge HW, Holman CB, Sem Jacobsen CW et al. Technic of depth electrography. Mayo Clin Proc 1953;28:147–55. Delgado JMR. Use of intracerebral electrodes in human patients. Electroencephalogr Clin Neurophysiol 1956;8:528–30. Ribstein M. Exploration du cerveau humain par electrodes profondes. Electroencephalogr Clin Neurophysiol 1960;Suppl. 16:1–129. Spiegel EA, Wycis HT, Marks M, Lee AJ. Stereotaxic apparatus for operations on the human brain. Science 1947;106:349–50. Spiegel EA, Wycis HT. Thalamic recordings in man with special reference to seizure discharges. Electroencephalogr Clin Neurophysiol 1950;2:23–39. Crandall PH, Walter RD, Rand RW. Clinical applications of studies on stereotactically implanted electrodes in temporal-lobe epilepsy. J Neurosurg 1963;20:827–40. Bancaud J. Apport de l’exploration fonctionnelle par voie stéréotaxique à la chirurgie de l’épilepsie. Neurochirurgie 1959;5:55–112. Bancaud J, Dell MB. Techniques et methodes de l’exploration fonctionnelle stéréotaxique des structures encéphaliques chez l’homme (cortex, sous-cortex, noyaux gris centraux) Rev Neurol 1959;101:220–1. Talairach J, Bancaud J, Bonis A et al. Functional stereotaxic exploration of epilepsy. Confin Neurol 1962;22:328–31. Bancaud J, Talairach J, Bonis A et al. La stereo-electro-encephalographie dans l’epilepsie. Paris: Masson, 1965. Talairach J, Bancaud J. Stereotaxic approach to epilepsy. Methodology of anatomo-functional stereotaxic investigations. Progr Neurol Surg 1973;5:297–354. Talairach J, Bancaud J, Szikla G et al. Approche nouvelle de la neurochirugie de l’epilepsie. Méthodologie stérérotaxique et résultats thérapeutiques. Neurochirurgie 1974;20 (Suppl 1):1–240. Talairach J, Tournoux P. Co-planar Stereotaxic Atlas of the Human Brain: 3-Dimensional Proportional System: An Approach to Cerebral Imaging. Stuttgart-New York: Georg Thieme Verlag, 1988. Szikla G, Bouvier G, Hori T. In vivo localization of brain sulci by arterio graphy: a stereotactic anatomoradiological study. Brain Res 1975;95:497–502. Szikla G, Bouvier G, Hori T, Petrov V. Angiography of the Human Brain Cortex. Berlin: Springer, 1977. Talairach J, Szikla G. Application of stereotactic concepts to the surgery of epilepsy. Acta Neurochir 1980;Suppl 30:35–54. Heyman D, Menegalli-Boggelli D, Lajat Y. Adaptation of the Talairach technique to the evolution of medical imaging. Stereotact Funct Neurosurg 1997;68:59–63. Devaux B, Nataf F, Meder JF et al. Prospects and future: evolution of stereotactic methodology for planning. Neurochirurgie 2001;47:253–9. Pecker J, Talairach J. Surg Neurol 1980;14:241–2. Chauvel P. Contribution of Jean Talairach and Jean Bancaud to epilepsy surgery. In: Lüders HO, Comair YG eds. Epilepsy Surgery, 2nd ed. 5–41 Philadelphia: Lippincott Williams & Wilkins 2001:35–41. Kelly PJ. Stereotactic navigation. Jean Talairach and I. Neurosurgery 2004;54:454–63. Cossu M, Cardinale F, Castana L et al. Stereo-EEG in the presurgical evaluation of focal epilepsy: a retrospective analysis of 215 procedures. Neurosurg 2005;57:706–18. Ryvlin P, Kahane P. The hidden causes of surgery-resistant temporal lobe epilepsy: extratemporal or temporal plus? Curr Opin Neurol 2005;18:125–7.

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Isnard J, Guenot M, Ostrowsky K et al. The role of the insular cortex in temporal lobe epilepsy. Ann Neurol 2000;48:614–23. Kahane P, Huot JC, Hoffmann D et al. Perisylvian cortex involvement in seizures affecting the temporal lobe. In: Avanzini G, Beaumanoir A, Munari C, eds. Limbic Seizures in Children. London: John Libbey & Company, 2001:115–27. Chassagnon S, Minotti, Krémer S et al. Restricted frontomesial epileptogenic focus generating dyskinetic behaviour and laughter. Epilepsia 2003;44:859–63. Szikla G, Talairach J. Coordinates of the rolandic sulcus and topography of cortical and subcortical motor responses to low frequency stimulation in a proportional stereotaxic system. Confin Neurol 1965;26:471–5. Kahane P, Tassi L, Francione S et al. Manifestations électrocliniques induites par la stimulation électrique intracérébrale par ‘chocs’ dans les épilepsies temporales. Neurophysiol Clin 1993;22: 305–26. Munari C, Kahane P, Tassi L et al. Intracerebral low frequency electrical stimulation: a new tool for the definition of the ‘epileptogenic area’? Acta Neurochir 1993;Suppl 58:181–5. Guenot M, Isnard J, Ryvlin P et al. SEEG-guided RF thermocoagulation of epileptic foci: feasibility, safety, and preliminary results. Epilepsia 2004;45:1368–74. Sperling MR. Depth electrodes. In: Lüders HO, Comair YG, eds. Epilepsy Surgery 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 2001:597–611. Espinosa J, Olivier A, Andermann F et al. Morbidity of chronic recording with intracranial depth electrodes in 170 patients. Stereotact Funct Neurosurg 1994;63:63–5. Engel JJ, Crandall PH, Rausch R. The partial epilepsies. In: Rosenberg RN, Grossman RG eds. The Clinical Neurosciences. New York: Churchill Livingstone, 1983:1349–80. Guenot M, Isnard J, Ryvlin P et al. Neurophysiological monitoring for epilepsy surgery: the Talairach SEEG method. Stererotact Funct Neurosurg 2001;77:29–32. Nobili L, Cossu M, Mai R et al. Sleep-related hyperkinetic seizures of temporal lobe origin. Neurology 2004;62:482–5. Lee WS, Lee JK, Lee SA et al. Complications and results of subdural grid electrode implantation in epilepsy surgery. Surg Neurol 2000;54:346–51. Önal C, Otsubo H, Araki T et al. Complications of invasive subdural grid monitoring in children with epilepsy. J Neurosurg 2003;98:1017–26. Rosenbaum TJ, Laxer KD, Vessely M, Smith WB. Subdural electrodes for seizure focus localization. Neurosurgery 1986; 19:73–81. Van Veelen CWM, Debets RMC. Functional neurosurgery in the treatment of epilepsy in the Netherlands. Aspects of presurgical evaluation and contribution of subdural and stereotactically implanted depth electrodes in the Dutch Workgroup for Functional Surgery. Acta Neurochir 1993;124:7–10. Brekelmans GJF, van Emde Boas W, Velis DN et al. Comparison of combined versus subdural or intracerebral electrodes alone in presurgical focus localization. Epilepsia 1998;39:1290–301. Henry TR, Ross DA, Schuh LA, Drury I. Indications and outcome of ictal recording with intracrebral and subdural electrodes in refractory complex partial seizures. J Clin Neurophysiol 1999;16:426–8. Engel JJ, Van Ness PC, Rasmussen TB, Ojemann LM. Outcome with respect to epileptic seizures. In: Engel JJ, ed. Surgical Treatment of the Epilepsies. New York:Raven Press, 1993:609–22. Janszky J, Jokeit H, Schulz R et al. EEG predicts surgical outcome in lesional frontal lobe epilepsy. Neurology 2000;54:1470–76. Siegel AM, Jobst BC, Thadani VM et al. Medically intractable, localization-related epilepsy with normal MRI: presurgical evaluation and surgical outcome in 43 patients. Epilepsia 2001;42:883–8. Berg AT, Vickrey BG, Langfitt JT et al. The multicenter study of epilepsy surgery: recruitment and selection for surgery. Epilepsia 2003;44:1425–33.

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SECTION 14 Cortical mapping and electrocorticography

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General principles of cortical mapping by electrical stimulation SU Schüle, C McIntyre, and HO Lüders

Introduction History of electrical stimulation of the human brain The modern objective of resective epilepsy surgery is the complete removal (or disconnection) of the area of cortex indispensable for the generation of clinical seizures without causing a permanent neurological deficit.1 Electrical cortical stimulation (ECS) has been one of the essential tools not only to instigate the beginning of epilepsy surgery but also to develop the concepts of modern epilepsy surgery. The localization of brain function with ECS heralded the first brain surgeries and at the same time the idea that seizures may arise from an identifiable ‘discharging lesion’.2 Until the first half of the nineteenth century, the brain was believed to function as a single unit.3 Opposing views, introduced by Frank Joseph Gall, who observed that a patient with a fencing coil wound in the frontal lobe of the brain suffered from speech disturbance, were dismissed.4 In 1861, Pierre Paul Broca, a prominent French surgeon, reported that a localized lesion in the third convolution of the left frontal lobe of man was responsible for expressive aphasia.5,6 John Hughlings Jackson (1864), influenced by the work of Bravais (1827) and Todd (1856) on postictal hemiparesis, supported Broca’s observation and introduced the concept of focal epilepsy as a ‘discharging lesion’ of the brain.2,7–9 Jackson conceived that during a focal motor seizure there is a discharge in the gray matter of the brain which begins at a local point and spreads from that point, producing a march of outward phenomena.10 Experimental evidence to Jackson’s ideas was provided by Fritsch and Hitzig (1870) who performed the first direct electrical stimulation of mammalian cortex. When they applied galvanic current through bipolar electrodes to the anterior half of the canine cerebral hemisphere, they obtained movement of muscle groups in the opposite half of the body.11 Fritsch and Hitzig used voltaic current, i.e., direct current, polarizing the nerve cells and producing undifferentiated twitches. A few years later, Ferrier employed Faradic stimulation, i.e., alternating current, thereafter used by all investigators, and provided incontrovertible evidence for functional localization.12 In the following decades, animal studies using electrical cortical stimulation revolutionized the understanding of brain function and allowed the description of the supplementary motor area,13,14 the primary auditory and olfactory cortex,12,15 and the visual area, corroborated by the results of experimental lesions.16 Grünbaum and Sherrington were able to separate the pre-Rolandic area for motor function from the post-Rolandic

area for sensory function in anthropoids and discovered the frontal eye field.17 Direct stimulation of the human brain to produce sensory or motor responses was first performed in 1874. A ‘feeble minded’ American woman in Cincinnati, Ohio, granted her neurosurgeon, Roberts Bartholow, permission to insert wires through the granulation tissue overlying the crater of an abscess in the left cerebral convexity.18 The ability to map human brain function with electrical stimulation revolutionized brain surgery and led to the first resective epilepsy surgeries by Macewen, Bennett, and Horsley.19–22 However, epilepsy surgery remained focused on the symptomatogenic motor cortex and was associated with significant postoperative deficits, and consequently fell more and more out of favor when Bromide (1857) and Phenobarbital (1912) became widely available as an effective medical treatment for epilepsy.23–27 At the beginning of the 20th century, Feodor Krause in Berlin was the only surgeon who continued to perform craniotomies on Jacksonian epilepsy in a larger number of patients.28,29 Krause introduced faradic stimulation to map the human cortex during surgery, which until then had been used only in animal studies. His work continued to focus on the central motor area and he published the first detailed map of the primary motor area (Figure 105.1). His goal was not only to define and resect the symptomatogenic area with the help of ECS but to delineate the cortex from which the habitual (motor) seizures could be induced with weak current. He thought the area of increased irritability to stimulation represented ‘das primaer kramfende Zentrum’ (the primary convulsing center) which should be included in the resection. Advancements in anesthesia permitted Cushing to perform an awake craniotomy eliciting a sensory response from the postcentral region in humans.30 In Breslau, Ottfried Foerster continued the detailed mapping of the human cortex using local anesthesia so that the patient could report subjective responses during the operation (Figure 105.2).31–34 He was the first to describe ‘erregbare’ (excitable) or ‘epileptogenic’ regions outside the central area, and reported on stimulation induced somatosensory, auditory, olfactory, gustatory, visual, and prefrontal symptoms. (Figure 105.2). Foerster operated in various areas of the brain and correlated the results of ECS with the immediate and ‘nachhaltigen’ (long-term) deficits after resection.32,34 Foerster’s seminal work coincided with the discovery of the EEG35 and he reported the first series of intraoperative cortical EEG records together with Altenburger in 1935.36 Wilder Penfield, after spending time with Sherrington, Cushing, and Foerster, extended the work of Foerster through 963

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Einwärtsrollen und Abdduction des Oberschenkels

Streckung Streckung und innenDorsal Quadraceps- der 4 letzStreckung der groβen Zehe rotation Plantarflexion stretching contraction ten Zehen des Fuβes des Fuβes im Grundgelenk, Beugung der des Fuβes übrigen Zehen, Supination der Planta pedis

Schulterhochziehen (Accessoriuswirkung)

Sulcus centralis Streckung

Hochheben, Abduction des Oberarmes (Deltoideus contraction) Supination Des Vorderarmes Pronation Spreizung Des 4 letzten Finger Beugung Streckung Streckung Zeigefinger Beugung Beugung des gestreckten Zeigefingers im Grundgelenk Streckung des kleinen Fingers Abduction des kleinen Fingers

Ulnarflexion Volnarflexion des Handgelenkes Radialflexion Dorsalflexion Beugung Streckung des Daumens Opposition Adduction Isolierter Krampf des Daumens

Kontralaterales Ober-und Unterlid

Mundwinkel nach oben ver Mundwinkel

Unterlippe direkt seitlich Kinn stark seitlich

des Ellenbogengelenkes

Beugung

Mm. zygomatici et levator labii superioris

M.pterygoideus externus

Masseter

Mundwinkel stark nach unten

Figure 105.1 The first published map of the human motor cortex by Feodor Krause, 1911.

a more detailed mapping of cortical areas subserving speech, hearing, vision, and further refined cortical representation of sensory and motor function. The work of Penfield lead to the mapping of a posterior and superior language area, the vestibular cortex, the secondary sensory area, autonomic areas, simple, and complex psychic responses, and negative motor areas.37,38 ‘Dreamy states’ associated with stimulation of the uncus were first described by Jackson. Penfield realized the

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high prevalence of intractable epilepsy arising from the temporal lobe and pioneered temporal lobe surgery for these patients.39 His initial limited antero-lateral approach was influenced by the perioperative interictal EEG findings using intraoperative electrocorticography with grids over the lateral temporal region.40 Clues from experimental animal studies and stimulation responses during surgery, however, began to point to the mesial and inferior parts of the temporal lobe as

ti onen

Figure 105.2 Foerster and Penfield’s map of the human cortex, 1930.

trales optisches Scotom

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General principles of cortical mapping by electrical stimulation the origin of the epileptic attack. Subsequent surgical series included the mesial structures in the resection improving the outcome significantly.41–43 In the minds of Talairach and Bancaud in France, Penfield’s localization approach could only be truly applied through EEG recording directly from the involved brain structures allowing not only interictal but also ictal recordings. This goal was accomplished in 1959 when Talairach introduced a stereotactical method to accurately place numerous intracerebral electrodes which could be left in place for several days, followed by recording of electrical activity from involved cerebral structures during the course of a seizure.44,45 Similar to Krause, Foerster, and Penfield, the French school emphasized the usefulness of electrically induced seizures to delineate the epileptogenic network to be included in the resection. In North America, extraoperative ictal recording became feasible by the work of Ajmone-Marsan and Van Buren who introduced subdural strip electrodes in temporal lobe epilepsy.46 Epidural grid electrodes were introduced by Goldring, but proved to be less useful for simultaneous cortical mapping.47,48 Subsequently, large array subdural plates which permitted not only invasive ictal recording but also detailed extraoperative mapping were developed.49,50 The extraoperative mapping with ECS allowed the verification of Penfield’s intraoperative results, and, with less interference by anesthesia and time constraints, lead to a revised map of eloquent language areas, and a more detailed description of the supplementary sensorimotor area, the negative motor area, and the secondary sensory cortex.51–54 Definition of eloquent cortex by electrical stimulation Epilepsy surgery is based on the assumption that human functions are localized in discrete anatomical modules and that there are areas of the brain which can be resected without causing noticeable deficits.55 Historically, electrical cortical stimulation was the first experimental technique which established the concept of functional brain localization. Based on the results of ECS the human brain was divided in ‘eloquent’ and ‘silent’ areas and it became soon apparent that the effect of stimulation was able to predict functional outcome after surgical resection. Response to electrical stimulation includes not only positive (motor) signs which can be readily observed, but also subjective symptoms reported by the patient and negative signs which become only apparent to the patient and the examiner while testing specific functions. Classical areas of eloquent cortex defined by electrical cortical stimulation include: ● ● ● ● ● ● ● ●

Primary motor area (Figure 105.3) Primary sensory area Supplementary sensory motor area Secondary sensory area Language areas (Figure 105.4) Visual cortex Auditory cortex Negative motor area

Additional areas of functional localization based on ECS have been described but are not predictably obtained: the cortical representation of olfactory, gustatory, vestibular, autonomic, and nociceptive function.56 Elementary emotional

965

SSMA SNMA

M1

S1

PNMA

Figure 105.3 Diagram showing the location of the primary motor area (M1), the primary sensory area (S1), the primary (PNMA) and supplementary negative motor area (SNMA), and the supplementary sensorimotor area (SSMA).

responses, e.g., fearful sensations, are well localizable to the amygdala and bilateral resections are associated with noticeable impairment in the perception of fear.57 More complex psychic responses seem to occur predominantly in patients with epilepsy including the déjà vu and deja vecu experience seen during stimulation of the temporoparietal association cortex.37 Negative signs associated with the localization of discrete cognitive functions have been mapped with electrical cortical stimulation, e.g., Gerstman syndrome over the dominant angular cortex.58 However, except in unusual situations, it is impossible (because of time constraints) to check at any given electrode for interference of more than two or three specific functions. In other words, in the absence of a positive response, the possibility that stimulation of an electrode interferes with a function that was not tested for cannot be excluded. Absence of a response does not exclude functional localization for other reasons: the stimulus intensity may be insufficient to interrupt function or the area stimulated is too limited to interrupt function in larger functional networks. Notably, memory in the temporal lobes and executive function in the frontal lobes cannot be predicted by ECS and intracarotid amobarbital injection, neuropsychological evaluation, and functional MRI seem better tools for predicting preoperatively cognitive outcome in resective surgeries involving these areas. However, despite its shortcomings, electrical stimulation remains the gold standard for presurgical functional mapping, particularly in patients requiring invasive evaluations, providing the surgeon with the most accurate correlation of ictal onset and eloquent cortex. Dispensable versus indispensable cortex Eloquent cortex as defined by ECS may have the highest correlation with postoperative functional outcome but has to be validated with the results of surgical resections. The resection of eloquent areas may lead to no recognizable or only a temporary deficit, or may provoke a permanent, noticeable impairment for the patient or the physician during testing.

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Textbook of epilepsy surgery SPEECH AREAS A

Anterior

P

Posterior

S

Superior Basal Temporal

S

P A

Figure 105.4 Diagram showing the location of the anterior, posterior, basal temporal language areas and Penfield’s superior language area.

The benefit of neurosurgical resections often outweighs the risk of a minor or temporary deficit, but permanent deficits are usually not acceptable for most adult patients. Influenced by Foerster, Penfield introduced the terms ‘dispensable’ and ‘indispensable’ eloquent cortex to differentiate between these areas of the brain.37,59 Indispensable eloquent cortex:

function on long-term follow-up.66,67 The basal temporal language area in the dominant hemisphere can lead to a temporary naming deficit which usually resolves long-term. Dispensable eloquent cortex: ● ● ●

●

● ● ●

Primary motor area (corresponding to the distal portion of upper and lower extremity) Primary sensory strip Primary visual area Anterior and posterior language areas

Resections involving the primary motor, sensory and visual cortex are mostly associated with a permanent and functionally significant deficit.59 These areas can be reliably mapped with ECS and show a well-defined contralateral somatotopic response. The language areas seem to safely allow resection up the gyrus adjacent to the functional sites based on ECS. However, there are reports that for the posterior language cortex resections closer than 1 cm to sites with stimulation-induced naming errors may increase the risk for a postoperative deficit.60 We have not been able to confirm these observations. Other motor areas with a positive response during ECS, the premotor cortex (possibly also including the frontal eye field) and the supplementary motor area, can often be resected without significant permanent impairment and in the context of intractable epilepsy or tumor surgery may be considered dispensable.61,62 However, resection of these areas may produce significant acute deficits and more detailed postsurgical testing may reveal permanent but subtle changes in motor coordination or eye movement control.63–65 Besides, most reported cases only refer to partial resections and it is unclear if more extensive resections could result in more significant permanent deficits. Besides, resection of the face motor area which has a bilateral cortical representation has mostly a good recovery of

● ● ●

SSMA Primary auditory cortex (Heschl’s gyrus) Brodman’s area 6 (probably including the frontal eye field) Face area of Brodman’s area 4 Secondary sensory cortex Basal temporal language area

Subjective factors may play a role of what constitutes a dispensable eloquent area: unilateral resection of the primary auditory cortex will not lead to any noticeable deficit for many of us, but certainly impair an orchestra conductor depending on the ability of dichotic listening. The permanent deficit after resection of the supplementary motor cortex may be subtle, however, the immediate consequences with contralateral weakness and mutism are dreaded by patient and surgeon. Age-dependant cortical plasticity has a strong impact on recovery and may allow extensive hemispheric resections with at least partial recovery in children and may become a consideration in catastrophic hemispheric epilepsy. Predicting postoperative functional deficits in areas silent to cortical stimulation is even more complex. Most of the frontal lobe cortex, except for motor and premotor cortex, the anterior language area in the dominant and the negative motor area in the dominant and non-dominant hemisphere show no response to electrical stimulation.66 The same is true for the parietal lobe caudal to the postcentral sulcus in the nondominant hemisphere. Experience has shown that limited surgical resections of these silent cortical areas are usually not associated with any neurological deficits.68,69 Resection of the ‘nociferous’ epileptic brain, a term used by Penfield, may actually lead to improvement in cognitive function.37,70 However, it is less defined to what extent larger surgical resections

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General principles of cortical mapping by electrical stimulation of silent cortical areas are permissible without behavioral consequences.71 Whereas limited unilateral frontal resections are well tolerated, bilateral lesions of the frontal lobes will produce a typical frontal lobe syndrome.72–74 In other words, socalled silent areas most probably are involved in functions for which the brain has extensive capacity for compensation either by using adjacent cortex (when only small areas of cortex are resected) or due to bilateral representation of these functions. The fact that no deficits are detected even when the brain is inactivated acutely by electrical stimulation implies that these silent areas of the brain have extremely flexible compensation mechanisms that are immediately effective. In addition, whatever defect the excision might have produced in a completely normal individual can not to be determined. Therefore, the risk of cognitive decline can only partially be predicted by the size, location, dominance, and preoperative functional deficit.

Neurophysiological effect of electrical stimulation of the cortex Electric field generated by cortical stimulation The electric field generated by clinical cortical stimulation electrodes is a three-dimensionally complex phenomenon that depends on the stimulation parameters and the electrical conductivity of the surrounding medium. Experimental measurements of the field are difficult to perform, but detailed theoretical models can be constructed to study both the potential distribution in the brain and the neural response to the stimulation.75,76 These studies show that the strength of the field directly transmitted to the brain is strongly regulated by the relative position of the electrode contact to the cortical surface, and the presence of CSF between the contact and the cortex. The high conductivity of CSF can shunt current flow around the brain, instead of through the brain, thereby increasing the stimulus amplitude necessary to generate a behavioral response. The voltage distribution generated in the brain is the starting point for understanding the neural response to extracellular stimulation. The first derivative of the voltage distribution is related to the current density. The second derivative of the voltage distribution is related to membrane depolarization and hyperpolarization.77,78 The stimulation induced membrane polarization interacts with voltage-gated ion channels, and given the appropriate conditions, can result in the generation of propagating action potentials that underlie the clinically observable behavioral response. The electric field is applied to the complex three-dimensional geometry of the surrounding neural processes (i.e., axons and dendrites). Each neuron (or neural process) surrounding the electrode will be subject to both depolarizing and hyperpolarizing effects from the stimulation.77–81 As a result, a neuron can be either activated or suppressed in response to extracellular stimulation in different ways and in different neural processes depending on its positioning with respect to the electrode and the stimulation parameters. Neural response to cortical stimulation When electrically stimulating the brain, three general types of neurons can be affected by the applied field: local cells, afferent

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inputs, and fibers of passage. Local cells represent neurons that have their cell body in close proximity to the electrode (i.e., cortical pyramidal neurons). Afferent inputs represent neurons that project to the region near the electrode and whose axon terminals make synaptic connections with local cells. Fibers of passage represent neurons where both the cell body and axon terminals are far from the electrode, but the axonal process of the neuron traces a path that comes in close proximity to the electrode. Each of these classes of neurons can be activated by stimulation with extracellular sources. And, experimental measurements indicate that local cells, axon terminals, and fibers of passage have similar thresholds for activation when stimulating with extracellular sources.82 However, activation of each different class can result in substantially different physiologic and/or behavioral output. Therefore, it is important to understand the factors that regulate the neural response to applied electric fields so accurate inferences about anatomical structures or physiological mechanisms involved in stimulation can be made. Most work addressing the neural response to extracellular electric fields concentrates on the direct effects of the stimulation on individual neurons. When neurons are directly activated by extracellular electric fields, action potential initiation takes place in the axon because it is the most electrically excitable part of the neuron.80,81 However, the threshold for indirect, or trans-synaptically evoked excitation (or inhibition) of local cells, is similar to the threshold for direct excitation of local cells. Indirect excitation (or inhibition) of local cells is the result of stimulation induced release of neurotransmitters from the direct activation of afferent inputs by the stimulus pulse. This stimulation induced trans-synaptic activity can be predominantly excitatory, predominantly inhibitory, or any relative mix of excitation and inhibition depending on the types and numbers of afferent inputs activated. Therefore, the interpretation of the effects the stimulation on the neural output of local cells is made up of two components: 1) The direct effect of the extracellular electric field on the local cell, and 2) The indirect effect of the stimulation induced trans-synaptic excitation and/or inhibition. In general, the indirect effects of extracellular stimulation of local cells result in a biphasic response of a short period of depolarization followed by a longer period of hyperpolarization. This biphasic response is the result of the interplay between the time courses of the traditionally fast excitatory synaptic action and the traditionally slow inhibitory synaptic action. The role of indirect effects on the output of local cells can be enhanced with high frequency stimulation. If the interstimulus interval is shorter than the time course of the synaptic conductance, the indirect effects will summate. Because inhibitory synaptic action traditionally has a longer time course than excitatory synaptic action the effect of this summation is hyperpolarization of the cell body and dendritic arbor of the local cell. This hyperpolarization can limit the neuronal output when stimulating at high frequencies. However, because action potential initiation takes place in the axon of local cells in response to the direct effects of the stimulation, local cells can still fire action potentials in response to each stimulus pulse given that the stimulus amplitude is strong enough.76,83,84

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Effects of stimulation parameters on cortical stimulation The complexities of the neural response to applied electric fields are further complicated by the vast array of stimulation hardware and stimulation parameter options available. Stimulation pulse generators are either current-controlled or voltage-controlled. Voltage-controlled pulse generators are more simplistic in design, but the current delivered to the tissue is regulated by the electrode impedance, which may be variable.85 And, the shape of the stimulus waveform transmitted to the tissue under voltage-controlled stimulation is distorted by the electrode capacitance.86 Therefore, current-controlled stimulators are suggested for scientific investigation or clinical situations where long-term consistency of stimulation delivery is required. Once a stimulus pulse has been generated, the physical dimensions of the electrode contact can substantially impact the shape of the resulting electric field and subsequent neural response to stimulation. Microelectrodes enable focal stimulation of targeted populations of neurons, but their small surface areas limit the amount of charge that can be safely delivered to the tissue.87,88 Macroelectrodes enable stimulation of large volumes of tissue and are commonly used in clinical contexts, but their neural and spatial specificity of stimulation is limited. However, the focus of stimulation can be manipulated by simultaneously activating multiple contacts. Detailed computer models of the electric field generated by clinical epidural, subdural, and deep brain electrode designs have been generated.75,76,84,89 These results show that bipolar stimulation or current steering with any number of anodes and cathodes can substantially change the shape of the electric field in the tissue. The stimulus waveform plays an important role in the neural response to extracellular stimulation. Square waves are typically used in clinical settings; however, sinusoids or any other arbitrary waveform can also be implemented. One of the fundamental requirements of a clinical stimulation device is to use biphasic stimulus waveforms to limit stimulation induced tissue damage.87,88 In addition, the axon represents the most excitable part of a neuron, so extracellular stimulation of fibers of passage, afferent inputs, and local cells are all regulated by the response of the axon to the stimulation.80,81 In turn, the strength-duration properties of extracellular stimulation have a relatively short time constant of ~100 µs. Therefore, to maximize the stimulating influence of the injected charge, a pulse duration of 100–200 µs is suggested. Typically, anodal stimulation preferentially excites neural elements perpendicular to the electrode surface, and cathodal stimulation excites those with a direction component parallel to its surface. When stimulating bipolarly, the excitation of neural elements parallel to the bipole axis is additionally facilitated.84 Manipulating the shape of the stimulus waveform can also be used to improve the neural selectivity of the stimulation. In general, local cells will be preferentially activated with anodic pulses, and fibers of passage will be preferentially activated with cathodic pulses.90 Comparison of stimulation with subdural and depth electrodes Both subdural and depth electrodes, are usually made of nonferromagnetic platinum electrodes which allow postoperative verification of placement not only with two-dimensional

Table 105.1 electrodes

Stimulation parameters: Subdural and depth

Polarity Stimulated electrode Stimulus intensity Duration of stimulus Frequency Duration of train

Subdural

Depth

Biphasic Monopolar or bipolar 1–15 mA (Grass S88) 1–17.5 mA (Grass S12) 1–20 mA (Ojeman) 0.3 ms 50 Hz 5s

Biphasic Bipolar 1–3 mA 1–3 ms 50 Hz 95% reduction of monthly seizure frequency. 62% of patients undergoing pure MST fell into this ‘excellent’ category for simple and partial seizures and 71% had an excellent response as regards generalized seizures. Simple partial seizures were seen to increase in 15–20% of the total group of patients and outcome was better in the presence of focal lesions and worse in progressive or diffuse pathologies. This analysis is a worthy attempt to bring together the sporadic and sometimes anecdotal reports of MST in the surgical

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Multiple subpial transections treatment of epilepsy but sadly can draw no significant conclusions other than MST ‘can be considered a viable and effective approach to uncontrolled seizures arising in functionally critical cortical areas’. Because of the interest in patients with Landau–Kleffner syndrome, which is discussed below, there has been much interest in the application of MST to the pediatric population. Blount et al. have reported the results in 30 cases accrued over a four year period, in whom 26 had MST combined with resection and four had MST alone.17 The surgical strategy applied was to resect the epileptogenic zone and therefore invasive recordings were performed in 23. Outcome was 42% of patients who had resection and MST were Engel Class I and a further 42% Engel II and III. In all there was evidence of motor impairment when primary motor cortex was transected but there was no evidence of any permanent deficits. This outcome is very similar to a comparable adult series although the functional recovery appears superior in the pediatric group.18,19

Specific seizure types Epilepsia partialis continua When epilepsia partialis continua (EPC) affects the sensorimotor cortex the effects can be disabling and painful and severely affect quality of life. When distinct structural lesions are present it may be possible to carry out a successful resection using a combination of pre- and intra-operative functional information. This is not, however, possible in all cases and therefore when the pathology is diffuse or progressive with as yet little or no neurological deficit then MST may be the only realistic option. There have been five descriptions in the literature of MST being used for EPC in a total of five clinical cases. In one case MST was used in conjunction with resection;20 another with disconnection21 while in another22 it was used as a prelude to invasive recording and focal resection. Molyneux et al.23 have reported a patient with lifethreatening complications due to medical treatment of EPC was significantly improved with MST. Despite a negative 0.5 T MRI the underlying pathology from a biopsy taken at the time of surgery was found to be cortical dysplasia. Follow up at eleven years following MST finds the patient had three seizures in the previous year and is working, whilst there have been several years completely free from seizures. A further unreported case from the same institution involves a patient with Rasmussen’s encephalitis who had painful sensori-motor EPC with no neurological deficit in whom MST in primary sensori-motor cortex produced a dramatic clinical improvement and at 11 years follow up is having approximately four seizures per year. Infantile spasms There has been increasing recognition that infantile spasms may be associated with underlying focal pathology which may be surgical remediable, with associated improvement in developmental progress.24–26 Chuang et al. have described two children (22 months and three years) in whom MST was carried out over an area localized by intraoperative electrocorticography.27 There was an appreciable reduction in spasms in both cases but neither became seizure free. In one case cortical

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dysplasia was seen on biopsy and in the other the picture was strongly suggestive of dysplasia due to the asymmetric spasms and localized epileptogenic zone. It could be therefore argued that these cases would have been suitable for a potentially curative resective or disconnective procedure. Patil in describing his series of MST performed on both hemispheres included two patients with infantile spasms, one of whom was seizure free whilst the other was not improved.28

Specific syndromes and clinical settings Landau–Kleffner syndrome with or without autistic features Landau–Kleffner syndrome is an acquired epileptic aphasia with female predominance following previously normal development and the clinical picture is one of a progressive deterioration of speech, which may be associated with clinical seizures but more typically clinical seizures are less prevalent but EEG abnormalities exist most commonly in the temporal lobe. The neurophysiological findings may include electrical status epilepticus in sleep (ESES). The severity of the clinical syndrome and the natural history of the disorder can vary considerably and the classical picture may be complicated by other features such as autism.29 Although the condition may remit spontaneously within 2–3 years, there is evidence that continuing ESES lasting longer than 36 months and a younger age at onset are associated with poorer long term outcome. In addition, even when speech does return there is frequent evidence of impairment both of speech and memory. Morrell30 described his experience with 14 children with LKS who underwent MST in Wernicke’s area, lateralization being achieved by EEG, methohexitone suppression test, sodium amytal test, and dipole mapping. All surgically treated subjects were developmentally normal prior to the acquisition of LKS and had the condition for a minimum of 2 years. Unilateral MST was carried out under electrocorticographic control with the Sylvian fissure being opened where deemed necessary and in two cases an additional anterior temporal resection was performed. In seven cases ‘normal’ speech returned, in five there was a marked improvement in speech whilst in the remaining three there was no change. Changes in speech were usually seen progressively over the first six months following surgery and other gains seen with longer follow up. The presence of persistent EEG abnormality following MST was associated with a poorer outcome. Grote et al.31subsequently reported the outcome of a further series of surgically treated patients from a total of 80 patients with LKS. Eighteen patients were operated upon of whom 14 were available for follow up. This study included 10 of the patients from Morrell’s original group, four having been excluded on the basis of progressive or bilateral problem. A much more detailed analysis of outcome was available with two patients suffering significant peri-operative morbidity, one child showing a significant decline expressive and receptive language function and only 4 of 14 patients were recorded as returning to normal school. Nonetheless 50% showed a significant improvement in one or other domain tested following surgery.

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Figure 122a.8

Intra-operative electrocorticography recordings in patient with Landau–Kleffner syndrome before and after MST.

Irwin et al.32 have described five patients with LKS treated with MST over an eight year period. Despite what appears to be an identical surgical procedure the outcome with respect to language was poor with no patient recovering age appropriate language. There was however, a significant reduction in clinical seizures and also an improvement in behavior, with loss of defiant aggressive behavior, improvement in attention span and reduction in hyperactivity. No child had a return of fluent speech but in two patients there was a significant improvement in behavior. This experience is shared in the series from Toronto17 and in our own series of 10 patients undergoing MST for LKS in whom three showed an improvement of receptive language function and two an improvement of expressive language function. It is not clear why the results described by Morrell and Grote have not been replicated in these two further studies. In Morrell’s original paper children with autistic regression in association with LKS were not included. Certainly other authors have recognized a great deal of variability of the clinical picture with many patients either showing signs of delayed language before regression or failure to acquire language.33–35 There are also clear links with features of autistic regression as one third of autistic patients undergo language regression under the age of three years and surgical series show evidence of lesions particularly in the right temporal lobe in patients with seizures and autism.36 Nass et al.37 have described seven cases in whom there were improvements in receptive language and also behavior although these were not always sustained. Neville et al38 have described the response following surgical treatment in two patients with autistic regression one treated with temporal lobectomy and the other with MST, both of whom showed improvements in communication. Patil has reported five cases who showed apparent post operative improvement but this outcome was not quantified

objectively.39 Szabo et al.40 have described five cases of epilepsy surgery in autistic regression with improvement but not relief of the autistic features. Finally, early onset of seizures has been linked with autistic regression and this might support the argument for early referral to surgical centers and the as yet unproven hypothesis that early surgery might minimize the development of autistic regression.41 Whilst clearly MST remains a surgical option in the management of LKS,42 the families of patients need to be carefully counselled as to the expected outcome on the basis of the clinical information available. The outstanding questions of the timing of the procedure in the clinical course of the syndrome and its true clinical efficacy remain unanswered and will require a prospective audit of cases with careful pre- and postoperative evaluation both electroclinically and from the language and behavioral standpoint. The relationship between LKS, autistic regression, and epileptiform activity is a complex one35 and thus the effect of MST on autistic regression also requires further evidence and remains the subject of discussion.39 Rasmussen’s encephalitis Due to the preservation of cortical function afforded by MST it is a surgical option when there is little or no neurological deficit, particularly for the dominant hemisphere.43 Despite the likely palliative nature of the procedure in the presence of progressive pathology, it may have a role in the management of Rasmussen’s encephalitis and has been described as such by a number of authors. Reviewing the major published series it appears that a approximately 19 patients with Rasmussen’s encephalitis have undergone MST,11,15,19,43–45 although two reports from the same center may duplicate cases. Whilst the long-term results are inevitably poor the temporary palliation

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Multiple subpial transections afforded may improve quality of life significantly and obviate the need for a hemispherectomy both in the short and long term. Bilateral independent seizure foci Patil et al. have described their experience of 61 patients in whom they have performed MST to multiple areas in both hemispheres.28 Seventeen of these patients had an additional resection carried out, although these tended to be small and indicated only when there were persistent discharges detected on intraoperative electrocorticography after extensive MST had been performed. Each procedure lasted for between 10 and 12 hours and there was an interval of between 5 and 7 days between the surgeries to each hemisphere. The clinical seizure types consisted most of complex partial seizures (50 cases) but included Lennox–Gastaut (3 cases) infantile spasms (2 cases), and myoclonic seizures (2 cases). The number of lobes of the brain operated upon ranged from two to eight. Although transient hemiparesis and dysphasia were observed in one patient and there were two peri-operative complications and one patient died from a massive post operative GI bleed, no lasting neurological deficits were seen. Seizure outcome was Engel Grade I in 52% and Grade II in a further 8%. There was no further clinical detail of functional or neuropsychological outcome. This is obviously an apparently impressive response to MST but further outcome data is required before such a procedure could be widely adopted although the authors have demonstrated the safety of this procedure in a potentially difficult to treat patient group. Focal pathologies One of the confounding factors in being able to gauge the efficacy of MST has been its frequent use in combination with cortical resection. The rationale has usually been that either the structural abnormality or neurophysiological abnormality extends into eloquent cortex rendering complete excision of either focus impossible. Even when eloquent cortex is not encroached upon it has been argued that MST to the neurophysiological abnormality beyond the structural abnormality may improve seizure outcome. Certainly there is scientific evidence that the tissue surrounding structural lesions such as dysembryoplastic neuroepithelial tumours and gangliogliomas may be abnormal and epileptogenic.46 In addition as we learn more about the patterns of abnormality of cortical migration and the abnormal circuitry that lies within and around these lesions, it is increasingly apparent that the epileptogenic zone may extend beyond the structural abnormality, supporting the hypothesis for additional MST.47 There is reported evidence that resecting the epileptogenic zone in addition to the anatomically evident pathology improves seizure outcome48 but similarly in the current era of MRI and intraoperative guidance excellent results can be achieved without careful intraoperative neurophysiological guidance.49 A series from the Toronto group appears to show no additional benefit in 16 cases where MST was applied in conjunction with focal resection in cases of focal cortical dysplasia.50 In order to prove the additional benefit of MST a large prospective study would be required with considerable funding to support it.

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Current questions concerning MST Because of the fragmented and sometimes repetitive data presented for MST it is difficult to draw firm conclusions as to its role and efficacy. There is no doubt that it remains an immensely innovative procedure and there is evidence that seizures are reduced following surgery in many patients who would otherwise not be considered to be surgical candidates. However, like other palliative procedures such as callosotomy and vagal nerve stimulation it is not possible to accurately predict preoperatively who is likely to benefit from surgery. There are currently a number of questions that need to be asked of MST. Does MST achieve its anatomical goal? If the gyral folding of the cerebral cortex were to be smoothed out, then the incisions made over the crowns of the gyri would provide a very incomplete isolation of the cortex into discrete islands of the desired volume; a fundamental thesis of the procedure cannot therefore be achievable. Even with the addition of transections down into the sulci and opening of the major gyri a significant portion of the cortex will remain anatomically and neurophysiologically connected. In addition the thickness of the cortex varies according to anatomical location, varying from 2 mm in the calcarine cortex to 4 mm in the precentral region and also tending to be thinned towards the depths of a sulcus.51 Furthermore a number of pathological conditions may result in either thickening52 or thinning of the cortical mantle and therefore the intragriseal transections may either incompletely cut through thickened cortex or extend into the white matter when the cortex is atrophic, resulting in either incomplete disconnection or damage to white matter tracts. Whilst the former may be rectified by further transections if the intraoperative electrocorticography shows persistent electrical abnormality, the latter will be irreversible and may explain some unexpected post operative functional deficits. Does MST achieve its physiological goal? When transections are carried out in eloquent cortex the functional results strongly support the hypothesis of preservation of function. Whilst the results are not free of morbidity such morbidity as does occur is frequently linked to a clear explanation such as the presence of subcortical hemorrhage and others may be explained by the variation in cortical thickness as explained above.51 A single post operative functional PET study has demonstrated functional activity in an area in which MST had previously been carried out.53 There was also suggestion of recruitment of other areas and this would be supported by the prospective study of functional motor recovery following MST.54 Similarly the results with respect seizure outcome are also supportive of the hypothesis of the critical area required for seizure propagation and support the animal data. Nonetheless the increasing understanding of the aberrant physiological circuits present in certain pathologies such as focal dysplasias55,56 and the very rapid spread of seizures, suggest that the physiology of this pathology is significantly different from normal cortex and therefore the underlying thesis may not apply.57

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Is there a place for MST in addition to resection? In certain pathologies the outcomes for anatomical resection are excellent and therefore determining the added efficacy of MST is extremely difficult. Morrell himself suggested that in dominant temporal lobe resections improved outcome could be achieved by combining MST with resection.15 This approach may be justified when there is a structural lesion rather than mesial temporal sclerosis due to the possibility of incomplete lesional resection or more widespread pathology. Examination of the pathological specimens from ‘en bloc’ temporal resections from the Maudsley group revealed concomitant ‘dual pathology’ in the form of mesial temporal sclerosis in 33% and evidence of dysplasia in 25%; although outcome did not appear to be dependent upon extent of resection.58 MST as a procedure was conceived in the era prior to the consistent MRI detection of mesial temporal pathology and in view of the excellent results of a Spencer type procedure this approach does not seem to be justified, unless its addition might result in broadening the numbers of patients suitable for surgery. Why has MST not been more widely applied? MST was conceived in an era of epilepsy surgery when many structural lesions causing epilepsy could not be identified. In addition much weight was placed on pre- and intra-operative electrophysiological studies, with a great deal of experience of the latter being available. In the MRI era, targeted resections of pathology causing epilepsy is now both feasible and followed with excellent results. In addition, whilst the major epilepsy centers continue to have experience of intraoperative electrocorticography, the field of epilepsy surgery and the numbers of centers performing it have increased dramatically. The emphasis on neurophysiology in many centers has reduced and the availability of intraoperative electrocorticography is not widespread. The debate over the ‘structural’ or ‘functional’ approach to the investigation and management of epilepsy has, at times, been a heated one59 but there is little doubt that the increasing impact of structural imaging has broadened the scope and availability of epilepsy surgery considerably. It is likely that MST will remain a procedure for complex epilepsy centers and indeed experience should be concentrated in major centers so that the appropriate studies can be performed. Can a multi-center study of the efficacy of MST be carried out? On review of the data on MST there is a lamentable lack of consistent data that can be compared in an objective way. This is because of the combination of MST with resections and disconnections, the varied pathologies treated, an inconsistent approach to reporting outcome and the lack of any quality of life data. The only way in which a multi-centre trial will be effective is if a distinct entity, such as pure Landau–Kleffner syndrome, is looked at and if MST is assessed on its own merits in the absence of resection or disconnection. The ILAE subcommission for pediatric epilepsy surgery in its Appendix 1 has indicated that MST is the surgical treatment of choice for Landau–Kleffner but the evidence to support this appears confused.42 The commissions’ main document stresses the

importance of a careful pre- and postoperative assessment of all pediatric cases so that outcome data can be standardized. However, even in major centers such cases as are suitable for MST are rare and the accumulation of cases may simply be an impossible task. Does MST have a future? The introduction of any new surgical procedure is usually followed by a period of increased usage and then a decline, when the indications, outcome and complications become clearer. Due to its very limited clinical application the period of accrual for MST has taken longer than most and the surge of interest in surgery for epilepsy based on anatomical imaging has done nothing to help its cause. The excellent results of focal resection without additional MST make its role in focal pathology very limited. In true MRI negative cases when the epileptogenic focus appears well localized to eloquent cortex and the deficit offered by resection is unacceptable, then MST clearly does still have a role. A recent paper from Japan has put forward a new innovative role for MST in the management of seizures of hippocampal origin.60 Twenty-one patients underwent a minimally invasive procedure in which access was obtained into the temporal horn through the temporal stem and then transections carried out in the hippocampal formation, using a modified ring-type transector. The objective of this approach was to reduce neuropsychological deficits in patients who were highly functioning. Seizure outcome was reported in 17 cases with 82% seizure free at one year, comparable with resective techniques. Neuropsychological data

Figure 122a.9

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Multiple subpial transections was only available in eight patients and only in one of these was there evidence of deficit in post-operative testing which resolved at six month follow up. It is not clear whether all of these cases were in the dominant hemisphere (12 of the total series had dominant temporal resections) but in any event the neuropsychological outcome is encouraging and further results in term of seizure outcome and neuropsychology are now needed to see if this technique has a role in the surgical armamentarium. The description of this final innovative surgical application for MST brings us full circle to Prof. Morrell once more. Much of his laboratory and clinical research was directed to the concepts of secondary epileptogenesis in man and the possibility of mirror foci.61 The intriguing possibility now arises for bilateral temporal surgery to be possible, for if bilateral mesial temporal foci can be targeted without neuropsychological

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deficit, then a whole group of patients will potentially become suitable surgical candidates.

Summary Multiple subpial transection is a technique whose role has yet to be clarified. The surgical series reported present a confused picture due to the widely disparate subjects, pathologies and methods of reporting outcome. There is evidence that it does cure seizures in some cases and give good palliation in others. Without careful multi-center trials it will be difficult in the future to establish clearly its clinical indications. It remains an inspired piece of translational science and is likely to remain in the armamentarium of the epilepsy surgeon for the foreseeable future.

REFERENCES 1. 2. 3.

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Morrell F, Kanner AM, de Toledo-Morrell L, Hoeppner T, Whisler WW. Multiple subpial transection. Adv Neurol 1999;81:259–70. Powell TP, Mountcastle VB. The cytoarchitecture of the postcentral gyrus of the monkey Macaca mulatta. Bull Johns Hopkins Hosp 1959;105:108–31. Powell TP, Mountcastle VB. Some aspects of the functional organization of the cortex of the postcentral gyrus of the monkey: a correlation of findings obtained in a single unit analysis with cytoarchitecture. Bull Johns Hopkins Hosp 1959;105:133–62. Lueders H, Bustamante LA, Zablow L, Goldensohn ES. The independence of closely spaced discrete experimental spike foci. Neurology 1981;31(7):846–51. Sperry RW, Miner N. Pattern perception following insertion of mica plates into visual cortex. J Comp Physiol Psychol 1955;48(6):463–9. Sperry RW, Miner N, Myers RE. Visual pattern perception following sub-pial slicing and tantalum wire implantations in the visual cortex. J Comp Physiol Psychol 1955;48(1):50–8. Morrell F, Whisler WW, Bleck TP. Multiple subpial transection: a new approach to the surgical treatment of focal epilepsy. J Neurosurg 1989;70(2):231–9. Spencer SS, Schramm J, Wyler A, O’Connor M, Orbach D, Krauss G et al. Multiple subpial transection for intractable partial epilepsy: an international meta-analysis. Epilepsia 2002;43(2):141–5. Whisler WW. Treatment of epilepsy with multiple subpial transection: an acute histological analysis in human subjects. Epilepsia 1997;38(2):258–9. Rougier A, Sundstrom L, Claverie B, Saint-Hilaire JM, Labrecque R, Lurton D et al. Multiple subpial transection: report of 7 cases. Epilepsy Res 1996;24(1):57–63. Mulligan LP, Spencer DD, Spencer SS. Multiple subpial transections: the Yale experience. Epilepsia 2001;42(2):226–9. Schramm J, Aliashkevich AF, Grunwald T. Multiple subpial transections: outcome and complications in 20 patients who did not undergo resection. J Neurosurg 2002;97(1):39–47. Kaufmann WE, Krauss GL, Uematsu S, Lesser RP. Treatment of epilepsy with multiple subpial transections: an acute histologic analysis in human subjects. Epilepsia 1996;37(4):342–52. Pierre-Louis SJ, Smith MC, Morrell F, Whisler WW, Clasen RA, Cochran E. Anatomical Effects of multiple subpial transection. Epilepsia 1993;2008:104S. Morrell F, Whisler WW. Multiple subpial transection. In: Shorvon SD, Dreifuss F, Fish DR, Thomas D, eds. The Treatment of Epilepsy 1996:739–50. Engel J Jr (ed). Outcome with respect to epileptic seizures. Surgical treatment of the epilepsies. Raven Press; 1993 609–21. Blount JP, Langburt W, Otsubo H, Chitoku S, Ochi A, Weiss S et al. Multiple subpial transections in the treatment of pediatric epilepsy. J Neurosurg 2004;100(2 Suppl Pediatrics):118–24. Pacia SV, Devinsky O, Perrine K, Luciano DJ, Vazquez B, Doyle WK et al. Multiple Subpial Transection for intractable partial seizures: seizure outcome. J Epilepsy 1997;10:86–91.

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Pondal-Sordo M, Diosy D, Tellez-Zenteno JF, Girvin JP, Wiebe S. Epilepsy surgery involving the sensory-motor cortex. Brain 2006;129(Pt 12):3307–14. Ma X, Liporace J, O’Connor MJ, Sperling MR. Neurosurgical treatment of medically intractable status epilepticus. Epilepsy Res 2001;46(1):33–8. D’Giano CH, Del CG, Pomata H, Rabinowicz AL. Treatment of refractory partial status epilepticus with multiple subpial transection: case report. Seizure 2001;10(5):382–5. Ng YT, Kim HL, Wheless JW. Successful neurosurgical treatment of childhood complex partial status epilepticus with focal resection. Epilepsia 2003;44(3):468–71. Molyneux PD, Barker RA, Thom M, van PW, Harkness WF, Duncan JS. Successful treatment of intractable epilepsia partialis continua with multiple subpial transections. J Neurol Neurosurg Psychiatry 1998;65(1):137–8. Caplan R, Guthrie D, Mundy P, Sigman M, Shields D, Sherman T et al. Non-verbal communication skills of surgically treated children with infantile spasms. Dev Med Child Neurol 1992;34(6):499–506. Kang HC, Jung DE, Kim KM, Hwang YS, Park SK, Ko TS. Surgical treatment of two patients with infantile spasms in early infancy Brain Dev 2006;28(7):453–7. Shields WD, Shewmon DA, Chugani HT, Peacock WJ. Treatment of infantile spasms: medical or surgical? Epilepsia 1992;33 Suppl 4:S26–S31. Chuang MF, Harnod T, Wang PJ, Chen YH, Hsin YL. Effect of multiple subpial transection on patients with uncontrolled atypical infantile spasms. Epilepsia 2006;47(3):659–60. Patil AA, Andrews RV, Johnson M, Rodriguez-Sierra JF. Is epilepsy surgery on both hemispheres effective? Stereotact Funct Neurosurg 2004;82(5–6):214–21. Robinson RO, Baird G, Robinson G, Simonoff E. Landau–Kleffner syndrome: course and correlates with outcome. Dev Med Child Neurol 2001;43(4):243–7. Morrell F, Whisler WW, Smith MC, Hoeppner TJ, de ToledoMorrell L, Pierre-Louis SJ et al. Landau-Kleffner syndrome. Treatment with subpial intracortical transection. Brain 1995;118 (Pt 6):1529–46. Grote CL, Van SP, Hoeppner JA. Language outcome following multiple subpial transection for Landau-Kleffner syndrome. Brain 1999;122(Pt 3):561–6. Irwin K, Birch V, Lees J, Polkey C, Alarcon G, Binnie C et al. Multiple subpial transection in Landau-Kleffner syndrome. Dev Med Child Neurol 2001;43(4):248–52. Canitano R, Luchetti A, Zappella M. Epilepsy, electroencephalographic abnormalities, and regression in children with autism. J Child Neurol 2005 Jan;20(1):27–31. Canitano R. Epilepsy in autism spectrum disorders. Eur Child Adolesc Psychiatry 2007;16(1):61–6. Ballaban-Gil K, Tuchman R. Epilepsy and epileptiform EEG: association with autism and language disorders. Ment Retard Dev Disabil Res Rev 2000;6(4):300–8.

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Taylor DC, Neville BG, Cross JH. Autistic spectrum disorders in childhood epilepsy surgery candidates. Eur Child Adolesc Psychiatry 1999;8(3):189–92. Nass R, Gross A, Wisoff J, Devinsky O. Outcome of multiple subpial transections for autistic epileptiform regression. Pediatr Neurol 1999;21(1):464–70. Neville BG, Harkness WF, Cross JH, Cass HC, Burch VC, Lees JA et al. Surgical treatment of severe autistic regression in childhood epilepsy. Pediatr Neurol 1997;16(2):137–40. Palac SM, Kanner AM, Andrews R, Patil AA. Should Epilepsy Surgery Be Used in the Treatment of Autistic Regression? Epilepsy Behav 2002;3(2):113–21. Szabo CA, Wyllie E, Dolske M, Stanford LD, Kotagal P, Comair YG. Epilepsy surgery in children with pervasive developmental disorder. Pediatr Neurol 1999;20(5):349–53. Humphrey A, Neville BG, Clarke A, Bolton PF. Autistic regression associated with seizure onset in an infant with tuberous sclerosis. Dev Med Child Neurol 2006;48(7):609–11. Cross JH, Jayakar P, Nordli D, Delalande O, Duchowny M, Wieser HG et al. Proposed criteria for referral and evaluation of children for epilepsy surgery: recommendations of the Subcommission for Pediatric Epilepsy Surgery. Epilepsia 2006;47(6):952–9. Smith MC. Multiple subpial transection in patients with extratemporal epilepsy. Epilepsia 1998;39 Suppl 4:S81–S89. Hufnagel A, Zentner J, Fernandez G, Wolf HK, Schramm J, Elger CE. Multiple subpial transection for control of epileptic seizures: effectiveness and safety. Epilepsia 1997;38(6):678–88. Sawhney IM, Robertson IJ, Polkey CE, Binnie CD, Elwes RD. Multiple subpial transection: a review of 21 cases. J Neurol Neurosurg Psychiatry 1995;58(3):344–9. Aronica E, Redeker S, Boer K, Spliet WG, van Rijen PC, Gorter JA et al. Inhibitory networks in epilepsy-associated gangliogliomas and in the perilesional epileptic cortex. Epilepsy Res 2007;74(1):33–44. Duchowny M, Jayakar P, Levin B. Aberrant neural circuits in malformations of cortical development and focal epilepsy. Neurology 2000;55(3):423–8. Kameyama S, Fukuda M, Tomikawa M, Morota N, Oishi M, Wachi M et al. Surgical strategy and outcomes for epileptic patients with focal cortical dysplasia or dysembryoplastic neuroepithelial tumor. Epilepsia 2001;42 Suppl 6:37–41.

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Bourgeois M, Sainte-Rose C, Lellouch-Tubiana A, Malucci C, Brunelle F, Maixner W et al. Surgery of epilepsy associated with focal lesions in childhood. J Neurosurg 1999;90(5):833–42. Hader WJ, Mackay M, Otsubo H, Chitoku S, Weiss S, Becker L et al. Cortical dysplastic lesions in children with intractable epilepsy: role of complete resection. J Neurosurg 2004;100(2 Suppl Pediatrics):110–7. Jones SE, Buchbinder BR, Aharon I. Three-dimensional mapping of cortical thickness using Laplace’s equation. Hum Brain Mapp 2000;11(1):12–32. Lawson JA, Birchansky S, Pacheco E, Jayakar P, Resnick TJ, Dean P et al. Distinct clinicopathologic subtypes of cortical dysplasia of Taylor. Neurology 2005;64(1):55–61. Leonhardt G, Spiekermann G, Muller S, Zentner J, Hufnagel A. Cortical reorganization following multiple subpial transection in human brain – a study with positron emission tomography. Neurosci Lett 2000;292(1):63–5. Moo LR, Slotnick SD, Krauss G, Hart J. A prospective study of motor recovery following multiple subpial transections. Neuroreport 2002;13(5):665–9. Cepeda C, Andre VM, Levine MS, Salamon N, Miyata H, Vinters HV et al. Epileptogenesis in pediatric cortical dysplasia: the dysmature cerebral developmental hypothesis. Epilepsy Behav 2006;9(2):219–35. Kriegstein AR. Constructing circuits: neurogenesis and migration in the developing neocortex. Epilepsia 2005;46 Suppl 7:15–21. Turkdogan D, Duchowny M, Resnick T, Jayakar P. Subdural EEG patterns in children with taylor-type cortical dysplasia: comparison with nondysplastic lesions. J Clin Neurophysiol 2005;22(1):37–42. Hennessy MJ, Elwes RD, Honavar M, Rabe-Hesketh S, Binnie CD, Polkey CE. Predictors of outcome and pathological considerations in the surgical treatment of intractable epilepsy associated with temporal lobe lesions. J Neurol Neurosurg Psychiatry 2001;70(4):450–8. Stevens JM. Epilepsy: structural or functional? AJNR Am J Neuroradiol 1996;17(2):243. Shimizu H, Kawai K, Sunaga S, Sugano H, Yamada T. Hippocampal transection for treatment of left temporal lobe epilepsy with preservation of verbal memory. J Clin Neurosci 2006;13(3):322–8. Morrell F, Toledo-Morrell L. From mirror focus to secondary epileptogenesis in man: an historical review. Adv Neurol 1999;81:11–23.

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Nonresective surgical procedures and electrical or magnetic stimulation for epilepsy treatment mutiple hippocampal transection H Shmizu

Introduction Temporal lobe epilepsy is known to be one of the most drug resistant epilepsy in adulthood. However, surgical treatment of temporal lobectomy is very effective in seizure control with around 70% success rate.1 Temporal lobectomy was established in the 1950s 2–4 and has been widely applied to intractable temporal lobe epilepsy. In spite of good seizure outcome, postoperative memory impairment has been a longstanding unresolved problem.5–7 If the epileptic focus exists in the left medial temporal area and the preoperative MRI demonstrates no atrophy of the hippocampus, resection of the hippocampus brings about worsening of verbal memory in most cases.8 This ominous complication cannot be avoided even if the most selective resection of the medial structures, selective amygdalohippocampectomy, is employed.9 To cope with this complication, we applied the principle of multiple subpial transection (MST)10 to the hippocampus. The neuronal structure of the hippocampus is significantly different from that of the cerebral cortex.11 However, the rationale of MST, disrupting the horizontal interneuronal connections and preserving vertical connection fibers, can be also applicable to the pyramidal layer of the hippocampus. We applied this new method, multiple hippocampal transection, to patients with intractable temporal lobe epilepsy without hippocampal atrophy on preoperative MRI. We have so far obtained excellent surgical results with regard to preservation of verbal memory and control of seizures.12

Rationale for this method Multiple subpial transection is an established surgical method to surgically treat eloquent areas, particularly as the motor or speech area, with preservation of cortical functions. The basic concept of MST is to interrupt interneuronal connections, most important for genesis of epileptic discharges, and to preserve vertical projecting fibers, critical connections for cortical functions. We hypothesized that if the pyramidal layer of the

hippocampus can be treated in the same way as in MST, epileptogenic discharges from the hippocampus might be eliminated. For this purpose, an adequate access route to the hippocampus without disrupting the memory circuit must be found. There are two neuronal pathways important for the hippocampus: the polysynaptic intrahippocampal pathway and the direct intrahippocampal pathway. The latter is the most important connection for verbal memory in humans.11 The input fibers of the direct hippocampal pathway mainly originate from the inferior temporal association cortex (area 37) and reach the entorhinal cortex through the perirhinal cortex. Therefore, access routes to the hippocampus through the temporal basal area will disrupt this pathway. Experimental data from monkeys, using a behavioral test known to most relevantly represent human amnesia, indicated that bilateral section of the temporal stem does not impair the memory function.13 Based on this experimental data, we developed the following surgical route to the hippocampus, which can preserve the neuronal connections to memory function. A small corticotomy is placed on the superior temporal gyrus within 4.5 cm from the temporal tip and the gray matter is aspirated along the sylvian fissure to reach the temporal stem. As the temporal stem constitutes the roof of the inferior ventricle, the hippocampus can be easily accessed by sectioning the temporal stem (Figure 122b.1). Although the temporal stem can be also accessed by directly dissecting the sylvian fissure and aspirating the lower part of the superior temporal gyrus as employed in selective amygdalohippocampectomy, the visual field thus obtained is too narrow and too deep to perform very subtle manipulation of hippocampus transection. As the pyramidal cell layer of the hippocampus is within 2 mm from the surface, we devised a ring transector 2 mm in diameter. To transect the CA4 and the dentate gyrus, deeper transection is necessary. As the pyramidal cell layer descends into the subiculum at the lateral corner of the hippocampus, deep transection is also necessary to transect this CA1 area (Figure 122b.2). Based on these anatomical relations, a ring 1149

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corticotomy

STG cm

4.5

Figure 122b.1

transector 4mm in diameter is designed for transection of the bilateral corners of the hippocampus. At the posterior part of the hippocampus, the transverse diameter becomes smaller, so an oval-shaped transector with 4×2mm diameter is applied to transect the lateral corners without intruding the mid portion of the hippocampus (Figure 122b.3).

Surgical procedure Under general anesthesia, the patient is placed supine on the operating table with the head tilted almost horizontal to the opposite side. Skin incision and the extent of craniotomy are the same as for ordinary anterior temporal lobectomy. The bone window is widened as much as possible to expose the temporal pole and basal areas. After dural incision, around 2 cm corticotomy is placed on the superior temporal gyrus along the superior sylvian veins. The posterior end of the corticotomy is confined within 4.5 cm from the temporal tip to prevent postoperative speech disturbance. If moderate size arteries cross the corticotomy line, the arachnoid membrane

av

CA2

2 mm

CA3

iv

f

dg 4 mm CA1 ce 4 mm

CA4 sbc

Figure 122b.2

around the arteries and their small branches are dissected or severed and the main arteries are translocated out of the corticotomy area to keep normal cerebral circulation of the left temporal pole. It is very important to precisely open the inferior ventricle without injuring the hippocampal surface. The optimal point of the ventricular opening is the medial posterior portion of the ventricle, just above the choroid plexus around the hippocampal body. For this purpose, the operating table is adjusted as the patient’s head is up and rotated to the opposite side. The ideal trajectory of the temporal stem suction is directed at 45° inward from the center of middle fossa (Figure 122b.4). Three types of electrodes (Figure 122b.5) are applied to the amygdala, the hippocampal head and the posterior part of the hippocampus to record electrocorticography (ECoG) over these areas and determine the extent of surgical procedure. If the amygdala does not show any independent epileptic discharges, only its surface is pared off to obtain am ample space for manipulating the hippocampal head. If ECoG otherwise documented active independent epileptic discharges from the amygdala, it is resected in the same way as in anterior temporal lobectomy. Generally, the hippocampus shows very active spike discharges. They are sometimes confined to the head or observed throughout over the entire hippocampus (Figure 122b.6). Based on ECoG data, the extent of hippocampal transection is determined. The alveus, white fiber bundle covering the hippocampal surface, is extremely tough and should be incised with microscissors for inserting a ring transector. The incisions lines are designed 5mm apart as in MST and parallel to the hippocampal digitation marks at the hippocampal head (Figure 122b.7). If vessels (usually small veins) cross the incision lines, they are electrically coagulated with bipolar forceps. To transect the pyramidal cell layer, which is within 2mm from the surface, a ring transector 2mm in diameter is inserted through the incision lines of the alveus. At both lateral ends of the hippocampus, a larger ring transector 4mm in diameter is employed to completely transect the end folium at the medial portion and the CA1 pyramidal cell layer descending to the subiculum at the lateral border. In the posterior part of the hippocampus, the transverse diameter is smaller and a 4 × 2 mm oval-shaped ring transector is used for transection of the bilateral corners.

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2 mm ring

4 mm ring

oval ring with 4x2 mm diameter

Figure 122b.3

Center of the middle fossa

Figure 122b.4

Once hippocampal transection is accomplished, ECoG is repeated over the entire hippocampus. This time, an amygdala electrode is also placed over the hippocampal head and residual spikes are carefully examined. Generally, active epileptic discharges from the hippocampus beautifully disappear as far as transection covers entire epileptic areas (Figure 122b.8). If residual spikes are detected in an untreated posterior part, transection is extended posteriorly. When spikes do not disappear over transected areas, each transection line is carefully examined to check whether they cover the full length of the hippocampal surface. If all of the transection lines are complete and yet synchronized small spikes or sharp waves are still observed over a wide area of the hippocampus, spread of epileptic discharges from the basal temporal area or the temporal cortical surface should be suspected. After completion of the hippocampal transection, ECoG is further recorded over the basal and superficial temporal surface. When epileptic discharges are detected in the anterior basal area, this area can be approached through the anterior end of the opened inferior ventricle and resected without damaging the surface temporal area. The epileptic discharges in the posterior basal area and the superficial temporal surface area are generally treated by MST without compromising brain functions. With combining hippocampal transection and MST, all epileptic discharges in the temporal lobe are surgically treatable with preservation of brain functions.

Amygdala

Hippocampal Head

Hippocampal body

Figure 122b.5

Figure 122b.6

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Figure 122b.7

Surgical outcome Between January 2001 and March 2006, 35 cases of intractable temporal lobe epilepsy without hippocampal atrophy on preoperative MRI and unilaterally diagnosed focus were operated on by hippocampal transection. They consisted of 20 males and 15 females, ranging in age from 2.9 to 48 years with a mean age of 27 years. Left side hippocampal transection was performed in 22 cases and right side in 23 cases. Postoperative MRI demonstrated the access route from the superior temporal gyrus to the inferior ventricle. However, transected hippocampus did not show any deformity or transected lines when studied six months after surgery (Figure 122b.9).

Figure 122b.8

As evaluation of pre- and postoperative verbal memory, auditory verbal learning test (AVLT)14 was performed immediately (3–4 weeks) and 6 months after surgery. Seizure outcome was evaluated only in cases with more than one year follow-up. Verbal memory In 13 eligible cases undergoing left hippocampal transection, AVLT was performed for evaluation of verbal memory function. If immediate postoperative test demonstrated decline of AVLT score, the test was repeated 6 months after surgery. In all of the cases except one, the scores of AVLT did not become worse at the point of 6 months after surgery

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Figure 122b.9

(Figure 122b.10). In one case, the AVLT score worsened after surgery and did not improve even after 6 months follow-up. However, this 33-year-old male did not complain of amnestic symptoms and returned to the preoperative workplace. Seizure outcome Seizure outcome was extremely good. In 23 cases with more than 1-year follow-up, 28 cases are seizure free (Engle class IA) and four have rare seizures (Figure 122b.11). In one cases, preoperative seizures have dramatically reduced in frequency and severity, but still has several seizures per month.

Bilateral temporal lobe epilepsy If the left hippocampus can be surgically treated without postoperative neurological complications, the possibility of surgical treatment of bilateral temporal lobe epilepsy will arise. This possibility is a sea change when we remember the tragic result of H.M., who underwent resection of bilateral mesial temporal structures and suffered an almost compete loss of anterograde memory functions.15,16 However, bilateral cases have proved not as simple in distribution of epileptic foci as unilateral ones. Even when transection AVLT-score

No. 20 18 18 16 14

15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0

12 10 8 6 *

4

4 2

1 0

0 0

Figure 122b.10

of bilateral hippocampi was successfully performed in two stages, hidden epileptic foci appeared and caused new types of seizures. These complex patterns of focus distribution were particularly prominent in epilepsy caused by late-onset encephalitis. We have so far performed bilateral hippocampal transection in ten cases and followed them up for more than 1 year. Good surgical outcome was obtained only in four cases (one: free, three: rare), and the remaining six patients showed poor results. In one case with bilateral hippocampal atrophy, postoperative memory deficit was very severe (after left hippocampal transection) and has not recovered even 3 years after surgery. Based on the above experience, we now restrict application of hippocampal transection only to unilateral temporal lobe epilepsy. However, taking account of many disabled patients with bilateral temporal lobe foci, future effort is strongly demanded to solve this long-standing problem.

3-4W

6M

Class I

Figure 122b.11

Class II

Class III

Class IV

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6. 7.

8.

Engel J Jr, Van Ness P, Rasmussen T et al. Outcome with respect to epileptic seizures. In: Engel J Jr, ed. Surgical Treatment of the Epilepsies. New York: Raven Press Ltd, 1993;609–21. Bailey P, Gibbs F. The surgical treatment of psychomotor epilepsy. JAMA 1951;145:365–70. Green J, Duisberg R, McGrath W. Focal epilepsy of psychomotor type. A preliminary report of obsevations of effects of surgical therapy. J Neurosurg 1951;8:157–72. Penfield W, Baldwin M. Temporal lobe seizures and the technic of subtotal temporal lobectomy. Ann Surg 1952;136:625–34. Hermann B, Seidenberg M, Haltiner A et al. Relationship of age at onset, chronologic age, and addequacy of peroperative performance to verbal memory change after anteiror temporal lobectomy. Epilepsia 1995;36:137–45. Berenbaum S, Baxter L, Seidenberg M et al. Role of the hippocampus in sex diffeences in verbal memory: memory outcome following left anterior tempoal lobectomy. Neuropsychol 1997;11:585–91. Seidenberg M, Hermann B, Wyler A et al. Neuropsychological outcome following anterior temporal lobectomy in patients with and without the syndrome of mesial temporal lobe epilepsy. Neuropsychol 1998;12:303–16. Trenerry M, Jack CJ, Ivnik R et al. MRI hippocampal volumes and memory function before and after temporal lobectomy. Neurol 1993;43:1800–5.

9. 10. 11. 12. 13. 14. 15. 16.

Gleissner U, Helmstaedter C, Schramm J et al. Memory outcome after seletive amygdalohippocampectomy in patients with temporal lobe epilepsy. Epilepsia 2004;45:960–2. Morrell F, Whisler W, Bleck T. Multiple subpial transection: a new approach to the surgical treatment of focal epilepsy. J Neurosurg 1989;70:231–9. Duvernoy H. The Human Hippocampus. Berlin: Springer, 1998. Shimizu H., Kawai K, Sunaga S et al. Hippocampal transection for treatment of left temporal lobe epilepsy with preservation of verbal memory. J Clin Neurosci 2005;13:322–8. Zola-Morgan S, Squire L, Mishkin M. The neuroanatomy of amnesia: Amygdala-hippocampus versus temporal stem. Science 1982;218:1337–9. Rosenberg S, Ryan J, Pfitera A. Rey auditory-verbal learning test performance of patients with and without memory impairment. J Clin Neurophysiol 1984;40:785–7. Scoville W, Milner B. Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiat 1957; 20:11–20. Milner B, Corkin S, Teuber H. Further analysis of the hippocampal amnestic syndrome: 14-year follow-up study of H.M. Neuropsychologia 1968;6:215–34.

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Surgical disconnections of the epileptic zone as an alternative to lobectomy in pharmacoresistent epilepsy AL Benabid, S Chabardès, E Seigneuret, D Hoffmann, L Minotti, P Kahane, S Grand, and JF LeBas

Abstract: Temporal lobe epilepsy (TLE) is the most common form of medically intractable partial epilepsy in adults, and surgery (temporal lobectomy or amygdalo-hippocampectomy) is effective in the majority of patients. In extratemporal lobe epilepsy (mainly frontal and multi lobar epilepsy) these results are less favourable but are highly depending on the presurgical evaluation and the possibility to delineate the epileptogenic zone (EZ). However, in the majority of cases, the surgical option usually applied is the removal of the epileptic tissue We report here the method, preliminary results and safety of a new procedure for non lesional TLE and extratemporal lobe epilepsy which consists in disconnecting the EZ without removing it. Between 1998 and 2004, 62 patients suffering from temporal or extratemporal lobe epilepsy have been treated by surgical disconnection of the epileptogenic zone. 45 TLE patients (35±10 years mean, duration 24±10 years, 16 males and 29 females, handedness 12 left and 33 right) have undergone temporal disconnection (20 left, 25 right) and 17 patients underwent extratemporal disconnection (one frontal, one occipital, seven temporal lobectomy + extratemporal disconnection, and eight multilobar disconnection). Among the patients suffering from TLE, 16 patients (35%) underwent additional presurgical evaluation with depth electrodes (SEEG). while this number reached up to 100% of cases in extratemporal lobe epilepsy cases After the surgical disconnection, all patients underwent a postoperative MRI, neuropsychological testing, and repeated scalp EEG and visual field examination. Postoperative outcome was assessed using Engel’s classification. Temporal disconnection was performed under neuronavigation and consisted in disconnecting the lateral temporal neocortex, the whole hippocampus, parahippocampus and the amygdala from the rest of the brain in cases of TLE. Veins and arteries were spared in order to avoid postoperative temporal lobe ischemia and subsequent temporal lobe swelling.

Results in temporal disconnections, 38 patients out of 45 (84.4%) were seizure free (Engel’s I) at 2-years follow-up, among which 26 were class Ia (58%). Four patients were class II and three class IV. Postoperative clinical morbidity was as follows: persistent mild hemiparesia (n = 1), persistent mild facial paresia (n = 1), definitive quadranopia (n = 23), hemianopia (n = 1). When the dominant temporal lobe was disconnected, verbal memory was worsened in about 69%. In extratemporal lobe epilepsy, 75% of patients who received a multilobar disconnection and 85% of of patients who received a temporal lobectomy associated with an extratemporal disconnection were Engel’s class 1. One patient who was operated for a frontal epilepsy was Engel’s class 2. Radiological postoperative morbidity was as follows: two patients exhibited asymptomatic thalamic or pallidal limited ischemia, two patients exhibited temporal horn cystic dilatation among which one requested surgical reoperation without clinical consequences. General morbidity was represented by a single case of postoperative phlebitis. For TLE, scalp EEG performed at 6 months post-op showed temporal spikes in 27% of patients with postoperative seizures compared to 8.5% of patients seizure free. At 1-year follow-up, scalp-EEG showed temporal spikes respectively in 19 and 6% of patients. In the multilobar disconnected group, 75 % of patients were Engel’s class 1. In conclusion, this technique, in experienced hands, appears to be as effective and safe as cortectomy or lobectomy. The main advantage is that disconnection prevents brain shift and subsequent subdural collections, shortens the duration of the surgery and allows a smaller craniotomy. On the other hand, disconnections do not allow complete histological examination of the epileptogenic tissue but provide only samples. Studies in the future will have to assess the prognosis value of interictal spikes seen on postoperative EEG in order to help predicting seizure outcome during the following period. 1155

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Introduction Resective surgery such as lobectomy, or amygdalo-hippocampectomy, is the major surgical option for intractable pharmacoresistent epilepsy. The global outcome reaches nearly 90% of Engel Class I in temporal lobectomy, 1–3 except when foci are multiple, located remotely from the temporal lobe and bilateral. They however have complications, as they create a large empty volume, which can induce bleeding, brain shifts, and subdural collections (Figure 122c.1). The purpose of this work is to provide an alternative approach by disconnecting the epileptic zone, without removing the brain tissue. Advantages are simpler surgery, reduced operating time, and reduced complications (brain shift and subdural collections). The rationale of this approach was based on the following considerations: ●

●

●

●

Disconnection procedures are effective in children treated by hemispherotomy 4–7 and in cases of hypothalamic hamartomas 7–9. Removal of the cortex is not mandatory in nonlesional TLE, when there is no potentially evolutive mass lesion, or no diffuse dysplastic cortex. Disconnection might minimize the risk of brain shift, especially in large temporal lobectomy, where the large parenchymal defect favors displacement of the surrounding lobes. Disconnection can be performed with a standardized minimally invasive craniotomy, making large craniotomy not mandatory.

Material and methods Surgical procedure ● Under neuronavigation (Surgiscope, ISIS, Grenoble, France), in dorso-lateral decubitus, a circular craniotomy is

performed using a trephine (50 mm in diameter) the center of the craniotomy being positioned at the level of the superior temporal sulcus. Presurgical definition of the epileptic zone (Figure 122c.3). It is basically similar to what is done for lobectomies, as only the technical aspects vary, the indications, basic principles, area to be removed or disconnected being the same. Video-EEG alone without depth recordings is applied to patients in whom the clinical examination, the natural history of the patients’ epilepsy as well as the specific clinical, ictal and interictal electrical features of the seizures have been extensively investigated, are all concordant and point to the same epileptogenic zone (EZ). This leads to a predefinition of the area involved, from the irritative zone where the epileptic discharge is generated to the full field of its propagations, defining the epileptic zone (EZ). Following the currently admitted principles, originating from Talairach’s approach to the concepts developed by Lüders, Engel, etc, the video-EEG, associating continuous EEG recording and behavioral videotaping, provides informations on which will depend the necessity or not to be resected. Stereoelectroencephalography (SEEG), (or subdural grids in other institutions), is performed if additional informations are needed about the precise involvement of deep structures (which is more easily provided by SEEG rather than by subdural grids), or when the presurgical evaluation based on noninvasive tools are not concordant. Similarly to what has been done during video-EEG, and according to the SEEG methodology developed by Talairach and Bancaud,10 the correlation between the temporo-spatial organization of the discharge and the symptoms, allow to delineate the ictal onset zone and the epileptic zone according to the definition recently released by Nair and Luders11. In addition to the electrical and clinical analysis of the seizures, high resolution MRI is performed in all cases to detect any mass lesion, hippocampal sclerosis or dysplasia. Neuronavigation planning of the disconnection (Figure 122c.3). It is basically based on a volumetric 3D MRI performed with markers screwed to the skull and the images fed into the Neuronavigation software of the robotized microscope ISS Surgicope® Using the features of the Neuronavigation software, the first step consists in reporting on MRI the synthetic scheme of the epileptic zone, taking into account the specific anatomy of the patients, following the sulci and avoiding the vessels. One may therefore draw on each adjacent slice from the surface to the depth, the contours of the disconnection.

Figure 122c.1 Brain shift and extra cerebral fluid collection following large parenchymal resection.

Delineation of the limits of disconnection One may take the decision of additional resection of the first temporal gyrus, depending on the morphology of the insula: when the angle between the sylvian valley and the insular plane is close to 90º, it is quite often difficult to dissect the superior temporal gyrus and recline it without damaging it to access to the bottom limit of the insula. Therefore, it happens to be easier to resect by suction, or using a dissectron, the upper lip of the superior temporal gyrus. On the contrary,

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Figure 122c.2 Programming a disconnection of the right temporal lobe. a: synthetic drawing of vessels (arteries and veins), contours of the hemisphere, position of the deep recording electrodes, circular craniotomy (centre marked by the red cross), b: superimposition of the drawing of the sulci and of the ventricular system visualized by ventriculography, (yellow) c: superimposition of the ventricular system (yellow) and of the epileptogenic zone (right temporal lobe in green, tail of the hippocampus in pink), d: steps of the disconnection. Striped grey: windows of disconnection of the cortical convexity of the temporal lobe, sparing the vessels. Oblique stripes in green: subarachnoidal dissection from the sylvian valley of the mesial side of the first temporal gyrus. Vertical stripes in red: section of the white matter from the inferior boarder of the insula to the ceiling of the temporal horn, and posterior inferior disconnection by section of the white matter and cortex surrounding the tail of the hippocampus. (See Color plates.)

when this angle is around 120º or more, the sylvian valley provides a convenient approach to the ceiling of the lateral ventricle. At this stage, it is also important to recognize the particular morphology of the superior temporal gyrus, which is sometimes hidden by the middle temporal gyrus which might be overlapping the superior temporal gyrus. This is misleading, particularly when one has to start a disconnection between the gyrus T1 and T2. The placement of the center of the trephine is crucial, in order to provide a direct view in the anterior-posterior plane of disconnection, parallel to the sylvian valley as well as in the cranio-caudal plane of the posterior temporal lobe section: most often, the trephine should be centered on the superior temporal sulcus, and not more than one centimeter ahead of the plane of the posterior section of the temporal lobe (Figure 126c.2A): Surgical disconnection Typical right temporal disconnection Under general anesthesia, semi-sitting position, the head is fixed on a Mayfield clamp in lateral position. Correspondence between Neuronavigation, Surgiscope, and patient’s head (fiducials) is performed, using a pointer which is observed by the camera of the tracking system. Skin incision and

trephine are centred on the basis of the Neuronavigation program. Cruciform opening of dura is performed, its diameter aligned along the superior temporal sulcus, allowing recognition in the visible area of the elements of the brain (arteries, veins, sulci) displayed on the MRI images of the planning (Figure 122c.3A). 1. After tracing on the cortex the posterior limit of the disconnection, which often corresponds to the plane of the acqueduct of Sylvius (Figures 122c.2b and 122c.2c), the temporal lobe is sectioned along this line, using spatula, coagulation and section, down to the base, then to the tentorium and up, where one opens the lateral temporal horn. The arachnoid is cut only on the convexity, while it is not necessary to cut it on the base and on the mesial side, as this provides a security layer against the vessels of the midline and the brainstem 2. Incision of the arachnoid along the sylvian valley is performed carefully, sparing all vessels (veins and arteries), to preserve the vascularization of the temporal lobe which will be left in place and also the vascularization of the basal temporo-occipital cortex which receives branches of the mid-cerebral artery, most often the medial temporal artery (Figure 122c.2D).

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(a)

(b)

Figure 122c.3 MRI control of a temporal lobe disconnection. The different planes of imaging from the skin to the depth are presented with the MRI images on the left-hand side of each column and on the right-hand side the drawing in green of the craniotomy and in red outline the parenchymal section. Column a: from the skin incision to the convexity cortical section. Column b: parenchymal section from the subcortical planes to the disconnection of the hippocampal formation into the ventricle. (See Color plates.)

3. Using a spatula and a small smooth curette, the superior gyrus is peeled subarachnoidally, and reflected downward, almost perpendicularly, until the plane of the insula. This provides the visibility, through the arachnoid which protects them, of the insular elements, (arterial branches of the mid cerebral artery and veins, and the insula itself, until the reflection of the cortex at the bottom line of the insula), from the posterior section to the anterior part of the insula (Figure 122c.3b). One sees there that the inner surface of the superior temporal gyrus turns, along with the middle cerebral artery, around the fronto-temporal stem, which has to be carefully identified and separated from the frontal lobe (to which it is often adherent) until the pericarotid cistern, where a cotton might be inserted to mark the place, is reached. 4. Back to the posterior section of the temporal lobe, in the lateral ventricle, a cotton is inserted along the sphenoidal horn in the anterior direction, to protect the choroid plexus which is reclined upward, therefore protecting the anterior choroidal artery and its upper anatomical neighbour, the optical tract. The white matter of the insulo-temporal stem, along the inferior limit of the insula, is severed from back to anterior (one must take care to see permanently the ventricular cavity in order not to go medially and above the ventricular horn, where one

could end up in the base of the putamen), until the anterior recess of the horn, where the choroid plexus emerges, along with the anterior choroid artery from the arachnoidal veil which separates the ventricle from the Bichat fissure, where the choroidal vein goes. 5. Dissociation of this arachnoidal veil gives access to the pericarotid cistern, where the cotton previously inserted into the cistern from the sylvian dissection is seen. This makes it easy to section the fronto-temporal white matter stem which has been fully circumscribed, and which is, at this moment, the only remaining anterior connection of the temporal lobe. The amygdalo-hippocampic formation has been therefore disconnected from its anterior connections. As this formation has no mesial connections with the extratemporal brain, (the Bichat fissure is obliterated only by an arachnoidal veil which does not need to be severed), its only remaining connection is posterior at the level of the tail of the hippocampus. 6. Going back to the posterior section of the temporal lobe and into the ventricular cavity, using the spatula, the white matter of the temporo-occipital junction is severed along the hippocampal formation, until the spatula touches the arachnoid and, through it, the dura of the tentorium. This section is prolonged backward, following the volume of the hippocampus tail, which turns around the posterior

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Figure 122c.4 MRI control of an occipito-temporal disconnection. The plane of disconnection is visible from the cortical surface to the mesial face of the hemisphere. In the MRI slices 2 and 3, suction associated to spatula section has created a larger gap in the separation between the disconnected temporo-occipital part from the rest of the brain. The ablation of the disconnected part would have created a large cavity, and possibly a brain shift.

pole of the thalamus, by direct viewing into the ventricular cavity. The posterior part of the Bichat fissure is dissected by sectioning the arachnoidal veil up to the level of the white matter disconnection. At this level, the tail of the hippocampus is sectioned, carefully preserving the vascular lamina which runs in the thin intrahippocampal sulcus. Sometimes, removal of the posterior part of the hippocampus can be also performed as it can be easier and offers the possibility for histological examination to confirm hippocampal sclerosis, which is known to be of good prognosis. (Figure 122c.2D). Care must be taken not to confound the volume of the hippocampus with the volume of the anterior part of the calcarine formation, which would lead to an hemianopic deficit, less tolerated than the upper lateral homonymous quadranopia which is almost always created by the interruption of the Meyer geniculo-calcarine fibers at the level of the posterior section of the temporal lobe. When this is achieved, the temporal lobe has no more neural connections with the rest of the hemisphere: the

amygdalo-hippocampic formation has been separated from its frontobasal connections at the level of the fronto-temporal stem, and from its posterior limbic connections at the level of its tail, behind the thalamus. The temporal neocortex has been severed from the insula all along the roof of the temporal horn, form the anterior fronto temporal stem, to join the vertical posterior section which disconnects the temporal lobe from all its projections to the parieto-occipital area. Specific variations Sparing of the superior temporal gyrus can be indicated when the recording has not proven any electrical involvement of the structure. Therefore, instead of making the incision of the arachnoid along the sylvian valley, one makes it along the superior temporal gyrus, on the upper border of the second temporal gyrus. This makes easier the undercutting of the white matter at the depth of the T1-T2 sulcus (as it is practically in front of the temporal horn), which can be made without significant tissue resection. On the left side, however, usually the dominant side for language, the superior temporal gyrus has to be spared in its

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two posterior thirds. The anterior limit is marked usually by crossing of the anterior temporal artery, which is also at the level of the junction with the sylvian valley of the precentral gyrus on the MRI. Besides this temporal disconnection and its variations, disconnection can be used also, in different various areas such as the frontal lobe or the occipital lobe, where the duration of the surgery is strongly reduced, as the transhemispherical section, once the midline has been reached, is sufficient and one does not need to ablate the tissue represented by those disconnected lobes. Different examples are given in Figures 122c.3 (temporal disconnections) and 122c.4 (extratemporal disconnections). Patients’ population Patient’s selection Indications are the same as for lobectomies: limited epileptic zone, no involvement of functional (motor, sensitive, or visual) cortical areas, absence of potentially evolutive lesion (cavernomas, gangliogliomas, dysplasia? and DNEs), pharmaco resistance, no surgical contraindications. Fourty-five patients were operated for TLE (16 males, 29 females, mean age 35± 10 years, 4 children aged 3–10 years). The mean duration of epilepsy was 24 ± 10 years, 12 patients were left-handed. The TLE involved 20 left and 25 temporal lobes Pre-op MRI confirmed that the TLE was nonlesional (no mass lesion), hippocampal sclerosis was observed in 83% of the cases, and anterior temporal abnormalities in 37% of the cases Presurgical evaluation involved in all cases video-EEG, neuropsychological testing, and high-resolution MRI. PET scan was performed in 13 patients, SPECT in 17 patients, and depth recording (SEEG) in 16 cases. Postoperative follow up (mean follow up is 3 years) comprised in all cases postoperative MRI at 3 and 12 months, postoperative EEG at 3, 6, 12, and 24 months. The postoperative outcome was rated according to Engel’s classification. Seventeen patients were operated for extratemporal epilepsies (six females, 11 males, mean age 27 ± 10, two children, aged 8–16 years old). Two patients out of 17 were left-handed, and one had bilateral representation of language. One patient suffered from frontal lobe epilepsy, one from occipital epilepsy and 15 from multilobar epilepsy (either fronto-temporal or temporo-occipital). Among these patients, one had a frontal disconnection, one had occipital disconnection, eight had multilobar disconnection and seven had a temporal lobectomy associated with a frontal or parietal disconnection.

Results Seizure suppression In the 45 TLE Thirty-eight patients out of 45 (84.4%) were seizure free (Engel’s I), among which 26 were Ia (58%). Four patients were class II and 3 class IV.

Among the seven non-cured patients, one case was related to an incomplete hippocampal disconnection, as seen in the post-op MRI scan, one patient suffered from insular seizure documented by a second SEEG, three patients had late recurrences of seizure (3 years after) for unknown reasons, and two patients had a running up phenomenon related to withdrawal of AED In the 17 extratemporal epilepsies In the multilobar disconnected group, 75% of patients were Engel’s class 1. The patients operated on the occipital lobe were Engel’s class 1 and the one operated on frontal lobe was Engel’s class 2. Among the patients which were treated by a disconnection + lobectomy, 86% of them were Engel’s class 1. MRI evolution In the 45 TLE There were two temporal horn cysts (one required reintervention), two asymptomatic thalamic or pallidal small ischemia, one incomplete disconnection (posterior hippocampal disconnection), no temporal swelling, and no brain shift. In the 17 extra temporal lobe epilepsy In the unique frontal disconnection case, the cortex was atrophic at the 1-year post-op MRI and among the patients operated with multilobar disconnection, the post-op MRI showed an asymptomatic frontal ischemia located in the frontal disconnected tissue in one case and in another case, a severe controlateral ischemia of the perisylvian cortex due to a carotide dissection. EEG evolution In the 45 TLE Of post operative EEG, 70% were available at 2-years post-op. At 3 months post-op, about 75% of patients presented with interictal EEG abnormalities. In the group of patients seizure free after surgery, only one-third of patients did not have any electrical interictal abnormalities. Interestingly, 60% of patients who are not seizure free after surgery had diffuse interictal abnormalities, located outside the temporal region compared to 20% of patients who were seizure free and in whom interictal spikes could be recorded outside the temporal region. The presence of interictal electrical abnormalities outside the temporal region seems to be of bad prognosis when recorded 1 or 2 years after surgery. A patient, seizure free at 2-years follow-up after a left temporal disconnection, exhibited anterior fronto-temporal focal spikes, and electrical, asymptomatic seizures within the disconnected temporal cortex. Postoperative interictal activity was observed 2 years after surgery in a non-cured patient with left temporal epilepsy, with interictal and independent diffused spikes overlapping in the posterior temporal region (T5 –O1). In the 17 extratemporal epilepsies: all the patients exhibited interictal electrical abnormalities (mainly spikes and slow waves) usually recorded on scalp-EEG electrodes located in front of the disconnected tissue and this was seen in cured or

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Complications In the 45 TLE Clinical morbidity affected 3 patients (6%): one persistant mild controlateral hemiparesia (2%), one persistant mild controlateral facial paresia (2%), one persistant hemianopia (2%), and one phlebitis (2%). Memory deficit in the dominant lobe was observed in 7/20 patients (35%) who had a left temporal disconnection: 6/20 (30%) had a verbal memory worsening, 4/20 (20%) had a visual memory worsening, 4/20 (20%) had a working memory worsening. Lateral superior quadrantanopia was observed in 23 patients (51.1%).

What is surprisingly not observed is the existence of infraclinical spikes in the deafferented lobe, supporting again the concept of seizure suppression secondary to the isolation of the epileptogenic zone. Completeness of disconnection and absence of remnant connective pathways are logical conditions to achieve in order to obtain seizure suppression. However, a better knowledge of the precise pathways responsible for the seizure spreading could open the possibilities of partial resection (superior temporal gyrus, for instance) to facilitate disconnection, dependent on individual anatomical variations, particularly about the insula. Indeed, it might be possible, if not certain, that in lobectomies,2 as well as in total disconnections, interruption of certain pathways might not be always necessary. Functional imaging, particularly MEG, could provide data allowing such an approach.

In the 17 extra-temporal epilepsies One patient had a severe contralateral sylvian ischemia due to a spontaneous dissection of the contralateral carotid at the cervical level, which may be related to the operative position. Postoperative MRI as well as Doppler angiography did not show any parenchymal lesion and the outcome at 2 years after surgery did not present any sequelae. The other postoperative complications were as following: one transient facial paresia (frontal lobe epilepsy), two transient mild hemiparesia, one permanent quadranopia, one permanent hemianopia (temporo occipital epilepsy) and one double vision. One patient had a postoperative distal sciatic palsy due to a misposition during surgery.

What is the benefit of disconnection versus lobectomy? Postoperative MRI show that there is less bleeding in the cavity, partly because this cavity does not exist, or is much smaller. Similarly, during surgery, it is clear that the section of the parenchyma with a spatula induces little bleeding, because after the section, the application of the two walls of the section reapply on each other and provide a haemostatic effect. Disconnection needs a shorter operating time: there is no dissection of the hippocampus from the brain stem and the vascular contents of the Bichat fissure, as there is no neural connection all along it. The intrahippocampal vascular lamina does not need to be dissected as well.

non-cured patients. But usually, interictal EEG abnormality were more diffusely distributed in non-cured patients.

Discussion Disconnections are used for perisylvian hemispherectomies, and hamartomas of the third ventricle, as surgical procedures meant to minimize the duration of the surgery, and to avoid the ablation of the deafferented parenchyma, as the absence of remnant connections between the epileptogenic area with the rest of the brain is theoretically necessary and sufficient to prevent the occurrence of seizures. In these cases, as well as in the present study, this theoretical concept is verified and validates this approach. For example, our results are similar to those obtained in our group in a series of consecutive temporal lobectomy2. Moreover, this approach is justified by the low morbidity, and the reduced morphological disturbance of the brain, particularly concerning the brain shifts and subdural collections. What happens to the epileptic zone? One could have expected that the deafferented lobe could become deprived from inhibitory influences coming from the rest of the brain, therefore leading to aggravated epileptic states, or even to status epilepticus. This has not been observed, and there are no deleterious effects to be feared, related to an exacerbation of the epileptic focus and associated release of metabolic by-products. On the contrary, total disappearance of epileptic activity in the deafferented parenchyma has not been observed, discarding the hypothesis of an excitatory influence coming from the rest of the brain, which could be responsible for the sustained epileptic activity before surgery.

What are the drawbacks? The narrowness of the approach requires the usage of only a thin aspirator holding a cotton as a retractor, and a smooth spatula severing the cortex and white matter, sparing the vessels and not even cutting the arachnoid on the skull base, therefore sparing also all the vasculature contained at this level.

Conclusion Disconnection has the same efficacy compared with resective surgery. The morbidity is similar or reduced as compared with lobectomy, but a larger number of patients is required before stating a definite conclusion. Disconnecting the EZ is sufficient to cure the patient, removal of the EZ is not mandatory, as long as the cause of the epilepsy is not evolutive. This is evident for tumors, but is not demonstrated in dysplasia, as their evolutivity is unknown. Similarly, cavernomas should not be left in place by disconnections as they may evolve, but also they may bleed even if they are not epileptogenic anymore. However, one might consider that the focal removal of a cavernoma associated to a disconnection of a larger parenchymal zone might be an option to consider in some circumstances. The current work and its results, although preliminary, and together with the experience of other teams,13 open the possibility for future more minimally invasive disconnective procedures.

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REFERENCES 1. 2. 3. 4. 5. 6. 7.

Engel J Jr, Van Ness, PC., Rasmussen TB, Ojemann LM. Outcome with respect to epileptic seizures. In: Engel J Jr, Surgical Treatment of the Epilepsies. New York: Raven Press, 1993;609–21. Arruda F, Cendes F, Andermann F, et al Mesial atrophy and outcome after amygdalohippocampectomy or temporal lobe removal. Ann Neurol 1996;40(3):446–50. Clusmann H, Schramm J, Kral T, et al. Prognostic factors and outcome after different types of resection for temporal lobe epilepsy. Neurosurg 2002;97(5):1131–41. Villemure JG, Mascott CR. Peri-insular hemispherotomy: surgical principles and anatomy. Neurosurg 1995;37(5):975–81. Villemure JG, Vernet O, Delalande O. Hemispheric disconnection: callosotomy and hemispherotomy. Adv Tech Stand Neurosurg 2000; 26:25–78. Villemure JG, Meagher-Villemure K, Montes JL, Farmer JP, Broggi G., Disconnective hemispherectomy for hemispheric dysplasia. Epileptic Disord 2003;5(Suppl 2):S125–30. Delalande O, Fohlen M, Bulteau C, Jalin C. Surgery for intractable focal epilepsy in children. Rev Neurol (Paris) 2004;160 (Spec No 1): S195–202.

8. 9.

10. 11. 12. 13.

Fohlen M, Lellouch A, Delalande O. Hypothalamic hamartoma with refractory epilepsy: surgical procedures and results in 18 patients. Epileptic Disord 2003;5(4):267–73. Procaccini E, Dorfmüller G, Fohlen M, Bulteau C, Delalande O. Surgical management of hypothalamic hamartomas with epilepsy: the stereoendoscopic approach. Neurosurgery 2006;59 (4 Suppl 2):ONS336–46. Talairach J, Bancaud J. Stereotaxic approach to epilepsy. Methodology of anatomo-functional stereotaxic investigations. Progr.Neurol.Surg. 1973;5:297–354. Nair DR, Mohamed A et al. A critical review of the different conceptual hypotheses framing human focal epilepsy. Epileptic Disord 2004;6(2):77–83. Chabardes S, Kahane P, Minotti L, et al. The temporopolar cortex plays a pivotal role in temporal lobe seizures. Brain 2005;128(Pt 8):1818–31. Smith JR, VanderGriff A, Fountas K. Temporal lobotomy in the surgical management of epilepsy: technical report. Neurosurgery 2004; 54(6):1531–4;discussion 1534–6.

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Corpus callosotomy G Morrison and M Duchowny

Anatomy and physiology The corpus callosum is a prominent cerebral midline interhemispheric commissural connection said to have approximately 180 million axons in humans1 (Figure 123.1). The connections are homotopic and heterotopic2 and the effects can be excitatory or inhibitory.3 There is a differential pattern of callosal connection which may be the result of postnatal elimination of transitory callosal axons.4 The corpus callosum participates in the interhemispheric integration of perception and cognition. The fibers of the corpus callosum principally connect associative regions of the cortex and are distributed in a rostrocaudal fashion.5 Studies have tried to correlate the size of callosum with function. The splenium has been reported to correlate with intelligence, with a larger splenium being associated with higher intelligence.6 The posterior third of the callosum is reported to be larger in dyslexic men.7 This relationship between anatomy and physiology continues to unfold and requires additional study.

Regardless of their thought process, they probably did not know of Erickson’s work. Erickson did fairly note previous experiments going back to 1914, including similar work reported by Gozzano in 1936.8 Numerous investigators followed Erickson’s initial observations10,11 and it was established that the corpus callosum was primarily responsible for ensuring bilateral synchrony of spike and wave discharges, at least in the feline penicillin epilepsy model.12 Dandy may have had the first report of a corpus callosotomy but that was for access to pineal region tumors.13 More then 20 years after Van Wagenen and Herren’s report, Bogan reported on ‘cerebral commissurotomy’14,15 but the concept was not well received (utilized infrequently) until Wilson began reporting on callosotomy for seizure control in the late 1970s and early 1980s.16–19 Wilson’s first patient was a 9-year-old boy having 30 generalized seizures a day. Wilson did a complete commissurotomy (entire callosum, hippocampal and anterior commissure, and one fornix) and, remarkably, the boy became seizure free, off medications.16 Luessenhop performed callosotomies on young children20 but most early reports dealing with children were patients in the second decade.21–26

Concept and history The concept of a corpus callosotomy for a patient with medically intractable epilepsy is palliation, not cure, and is based on the diminution of interhemispheric propagation of epileptic activity. This would then prevent/reduce bilateral synchrony of cortical epileptiform activity and thus interrupt secondary seizure generalization. This may also result in a global diminution of synaptic connectivity of the cerebrum. Thus, a corpus callosotomy should be effective in treating patients with seizures that require bilateral cortical activation for their clinical expression. In 1940, Erickson reported that complete division of the corpus callosum in fourteen monkeys prevented the spread of discharges to the opposite hemisphere.8 In the same year (and in the same journal), Van Wagenen and Herren reported the first series of callosotomies for seizure control in humans.9 It is interesting that their rationale for the surgery may have been their observation that patients with tumors of the corpus callosum would have decreasing seizure frequency as the callosum was destroyed by the tumor. Additionally, the seizures seen early in these patients were generalized and, as the tumor grew, the seizures were often unilateral and without loss of consciousness. Alternatively, it may have been their observation that epileptic patients who sustained a stroke involving the corpus callosum often had improvement in their seizure disorder.

Indications There has been a wide disparity of indications for a corpus callosotomy. Very few intractable epilepsy syndromes have not been recommended for callosotomy at one time or another. In fact, this operation has applied to virtually any refractory form of seizures where there is no possibility of a focal resection. Twenty years ago corpus callosotomy was recommended primarily for patients with secondarily generalized seizures or with infantile hemiplegia. In the latter case, it was as an alternative to a hemispherectomy.27 Some patients with partial seizures (usually with rapid secondary generalization) were also treated with callosotomy as have patients with frontal lobe epilepsy or Rasmussen’s syndrome. In all cases, the seizures could not be localized or an eloquent region was involved. Callosotomy has been recommended for patients with LennoxGastaut syndrome.28,29 These seizures may be tonic, atonic, myoclonic, atypical absence, or generalized tonic-clonic in nature but it is the ‘drop attack’ seizure produced by either atonic or tonic seizures that is the most likely to respond to a callosotomy.30–33 Callosotomy has even been reported as being beneficial in the treatment of tuberous sclerosis34 and Sturge-Weber syndrome.35 More recently, most comprehensive epilepsy centers are recommending callosotomy for patients with tonic, atonic, or ‘drop attack seizures’.31,36–41 1163

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Figure 123.1

MRI of intact corpus callosum.

Patient selection Similar to candidates for other epilepsy surgery procedures, candidates for corpus callosotomy should be experiencing frequent and debilitating epileptic seizures that have been determined to be medically intractable. Their quality of life should be seriously impacted by the seizures, i.e., affected patients would potentially be held back from employment options, operating a motor vehicle, achieving in school or participating in enduring social relationships. Patients must have undergone extensive pre-surgical evaluation and have well documented seizure manifestations. For patients with multiple seizure types, the most debilitating seizure type should be the primary surgical target. Seizures that produce physical injury or life-threatening status epilepticus provide a strong rationale for intervention. When multiple seizure types exist in the same patient, it is reasonable to expect that secondary seizure types would not necessarily respond to corpus callosotomy as the primary target seizure type. The principle goal of preoperative studies is to exclude localized seizure foci amenable to excisional procedures. EEG and video-EEG monitoring studies that document ictal capture are mandatory. If seizures are localized at onset, it is then necessary to document that there is subsequent spread and secondary generalization. It is also important to document independent seizure types that arise from both cerebral hemispheres. There are no specific age-related criteria governing surgical intervention. Patients as young as 4 months20 and as old as 55 years26 have undergone the procedure. The majority of patients have been adolescent and young adults. It is advisable to consider corpus callosotomy as soon as the patient demonstrates and extablished seizure type that is not localized and would potentially benefit from callosal sectioning. Treating physicians should provide informative discussion emphasizing that the potential for complete seizure-freedom is limited, and that palliative goals are more realistic. Seizure types Seizure type is a decisive variable in the selection of epilepsy patients for corpus callosotomy. A comprehensive review of amenable seizure types has been carried out by Spencer.42 Most centers perform corpus callosotomy for intractable

generalized seizures including tonic, atonic, generalized tonicclonic and absence seizures.38 These seizures types would be expected to benefit from a procedure that would decrease bilaterally synchronous EEG abnormalities. As alternative subcortical pathways participate in bilateral EEG synchrony, complete abolition of generalized EEG activity is unlikely, but not required for improved seizure status. The benefit of corpus callosotomy has repeatedly been shown for patients with disabling drop attacks. Reutens41 reported a favorable outcome after corpus callosotomy in 64 patients, particularly for drop attacks in the setting of a unilateral focal lesion or true generalized epilepsy. Complete seizure suppression in 9/19 patients with falling attacks and an 80% reduction in 7/19 patients was noted by Rossi.43 Generalized tonic-clonic seizures were less improved. Higher rates of seizure-freedom were reported by Shimizu44 who found that 29 of 34 patients with drop attacks were seizurefree after callosotomy and four had only infrequent attacks. Only one patient did not show benefit. They additionally noted concurrent improvement in cognition and speech in 77% of their patients. Follow-up studies revealed that the cohort of children derived greater functional benefit than the adults.45 Similarly favorable results were reported by Kim.46 The variation in outcome as a function of seizure type is notable. The superior outcome of patients experiencing drop attacks suggests that the corpus callosum may be of heightened importance in cases of bilateral synchrony associated with negative motor phenomena. In contrast, positive motor manifestations of generalized epileptic discharges appear less influenced. This would suggest the existence of different mechanisms for generalization for seizures that appear bilaterally sunchronous at seizure onset.47 Etiology Corpus callosotomy has been advocated as treatment for a variety of neurological disorders associated with secondary bilateral synchrony. One of the earliest documented applications of corpus callosotomy was for patients with congenital hemiplegia.20 Callosotomy was envisioned as a less aggressive procedure than hemispherectomy. Hemispherectomy could then be performed as a back-up procedure should corpus callosotomy prove ineffective.48 Goodman27 reported ‘excellent’ results in four of five patients with congenital hemiplegia and stressed the low incidence of complications in comparison to hemispheric ablation. Should anterior callosotomy prove ineffective, complete callosal sectioning may offer additional relief. Selected patients with epilepsy due to cortical malformations have been treated with corpus callosotomy. Difficulties associated with localization of seizure origin and the extensive cortical involvement of some malformations has undoubtedly played a crucial role in candidate selection. Modest success after corpus callosotomy has been reported in three patients with subcortical laminar heterotopia.49 Ambrosetto50 reported amelioration of drop attacks in a retarded girl with the congenital bilateral perisylvian syndrome, Pallini51 noted improvement in four patients with bihemispheric cortical dysplasia, and Landy52 described improved atonic seizure status in a patient with band heterotopia. In contrast, anterior callosotomy offered no benefit to a patient with generalized seizures due to hypothalamic hamartoma.53

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Corpus callosotomy The experience with corpus callosotomy in young patients with epileptic encephalopathies has been mixed. Improvement in infantile spasms in West syndrome and cessation of drop attacks in patients with previous West syndrome was reported by Pinard.54 Seizure reduction after callosotomy was reported in an 11-month-old patient with lissencephaly presenting as West Syndrome.55 Improvement in patients with Lennox-Gastaut syndrome occurs predominantly for drop attacks.56 Corpus callosotomy has been advocated in a variety of clinical presentations where localization has been challenging, including frontal lobe seizures,57 multifocal epilepsy and Rasmussen syndrome.48 The advent of more sophisticated techniques for localization of seizure origin has largely rendered these indications obsolete.

Corpus callosum

Fornix (Corpus)

Hippocampal commissure Column of fornix Anterior commissure

Intermediate mass of thalamus

Central commissurotomy – Wilson (1977) Figure 123.2

EEG The preoperative EEG has been advocated as a tool for selecting candidates for corpus callosotomy. The degree of bilateral synchrony and the morphological similarity of generalized spike-wave discharges between hemispheres have been singled out as potential screening criteria. Matsuzaka58 reported that a more favorable surgical outcome occurred in patients with the least variation in synchrony for bursts of spike-wave discharges. Prognostically favorable ictal EEG features include generalized slow spike-wave discharges, electrodecremental patterns and low amplitude fast frequencies.59 It has also been suggested that posterior-dominant epileptiform discharges portend a poorer outcome after anterior callosotomy than anteriorly localized discharges.60 Others have been less inclined to attach significance to preoperative EEG patterns. In 36 patients undergoing anterior, posterior or two-stage callosotomy, Quattrini61 observed a reduction in bilateral synchrony in the EEG but found no correlation with reduction in seizures. Similarly, the degree of lateralization of generalized epileptiform discharges did not correlate with reduction of tonic-atonic seizures as over 80% of patients obtain seizure reduction independent of their EEG patterns.62 Blockage of bisynchronous discharges does not confer improved seizure status in children with LennoxGastaut syndrome.63 It has also been shown from the postoperative EEG that a reduction in the number of epileptiform discharges or epileptic foci is not necessary for improved seizure status.64 The persistence of bilaterally synchronous discharges in some post-callosotomy patients suggests that bilateral synchrony is also mediated via subcallosal pathways involving diencephalic or mesencepahlic structures.65

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Diagram of the anatomy of early commissurotomy.

(and still do – e.g., Yale) sectioning the anterior two-thirds to three-quarters during the first operation (Figures 123.3 and 123.4). One center (Dartmouth) staged the procedure with sectioning of the posterior half divided first.66 Regardless of which part was sectioned initially, the callosotomy was only completed if the results were unsatisfactory after the partial transaction. At the present time, the only patients suitable for a complete transaction in one operation would be the very afunctional, globally developmentally delayed individual where a postoperative disconnection problem would not clinically alter the functional level. Although most neurological surgeons favor an open approach, callosotomies have been performed with stereotactic radiofrequency67 and with radiosurgery.68 Some centers have used intraoperative EEG information to tailor the length of resection23,69,70 but most groups use it, if at all, for investigative purposes and the authors have abandoned its use. The two most popular positions are with the head lying on the side (so that gravity will help with the retraction) or brow up with the head elevated (the author’s preference). If neuronavigation is to be utilized (which can be very helpful),71 then 3-pin fixation is mandatory, otherwise it is optional. General anesthesia is similar as for other craniotomies with possible

Technique As with most surgical procedures, different techniques have been utilized by different neurological surgeons, usually with similar results. The very early procedures involved transecting the corpus callosum, the hippocampal commissure, the anterior commissure, and one fornix (Figure 123.2). The procedure evolved to a more limited sectioning of the callosum and the hippocampal commissure with rare sectioning of the anterior commissure. Centers also differed on how much of the callosum to transect at the first operation. Some (Minnesota) initially favored a total transection in one operation while most advocated

Figure 123.3 MRI of corpus callosum after an anterior twothirds sectioning.

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Figure 123.4 MRI of corpus callosum after an anterior threequarters sectioning.

precautions for air embolism taken if the head is far above the heart. Dexamethasone and prophylactic antibiotics are used without scientific evidence of their efficacy. A bi-coronal (or Soutar) incision is preferred (Figure 123.5) with the right sided limb a little longer. A bilateral craniotomy is then done at the level of the coronal suture (Figure 123.5). A callosotomy can be performed through a small craniotomy, but a larger opening gives the surgeon more flexibility in identifying the best corridor down the falx to the callosum. The venous anatomy will dictate the specific corridor as great lengths are taken to avoid sacrificing the bridging veins. Although a right-sided approach is often favored (right-handed surgeons and nondominant hemisphere), the anatomy may change the approach to the left side. This is arguable for left-handed patients but is sometimes dictated by the venous anatomy found at surgery. Theoretically this venous anatomy could be determined preoperatively (MRV) but, as of yet, this does not always show the required detail. It is important to expose the midline and the sagittal sinus so that it can be retracted (by traction sutures on the dura or with a self-retaining retractor). This is also added by opening the dura based on midline. Mannitol (0.5–1g/kg) is usually given before the interhemispheric dissection is begun. The dissection is then done with the aid of magnification (the author prefers the operating microscope) with careful separation of the midline structures. This is usually straightforward but can be confusing and there can be vessels not easily identified to one side or the other. If this occurs, it is wise to abandon this dissection and to dissect further anterior or posterior and the true anatomical nature of this vessel will usually become apparent. Although the cingulate gyrus has been confused with the corpus callosum, the adage of ‘if it’s not white, it’s not right’ is quite accurate. The white corpus callosum is visually unique. The vessels overlying the callosum are identified, separated, and preserved (Figure 123.6). Dissection is performed anteriorly and posteriorly before the actual transection to identify and secure the boundaries of sectioning. The anterior boundary is the genu and the posterior boundary is approximately two-thirds of the callosum. This is usually easily identified as the location where the callosum

Figure 123.5 Diagram of head with a skin incision and craniotomy flap outlined. A complete callosotomy can be done from the anterior incision and the craniotomy flap may be safely extended slightly behind the coronal suture. The posterior incision is used if a second operation is performed to complete the callosotomy.

begins to curve or slope inferiorly. Neuronavigational systems are a help as are measurements taken from the preoperative MRI. If a total callosotomy is to be done, the head may be moved to facilitate the posterior dissection. After the dissection, the transection begins and is carried throughout the course (Figures 123.7 and 123.8) An attempt is made to stay exactly in the midline because, even in absence of a cavum septum, there is usually a small space or midline raphe to guide the surgeon and to facilitate staying out of the ventricular system. Most neurosurgeons use combination of suction and the bipolar forceps, but various microdisectors are helpful and some surgeons have used ultrasonic aspiration and even an endoscope (in cadaveric preparations).72 An attempt is made to stay out of the ventricle but the author has not seen the difficulties described by others (e.g., hydrocephalus).16,18 However, some blood in the ventricular system can produce postoperative fever. This may be ameliorated by the use of

Figure 123.6 Operative photograph of corpus callosum exposed prior to transaction.

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Corpus callosotomy

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transected and appropriate respect is given to it. The underlying arachnoid, beneath which lie the quadrigeminal cistern and the pineal, is preserved.

Results

Figure 123.7 callosum.

Operative photograph of transected corpus

dexamethasone. Some neurosurgeons have left a titanium clip at the posterior limit of the transaction to identify the boundary by neuroimaging and, as an aid for identification if further surgery is performed. This has not been the author’s practice. Following the transaction and establishment of hemostasis, a standard closure is performed. In addition to steroids, patients are given a couple of doses of antibiotics and otherwise standard postoperative management. If a second procedure is indicated, the neurosurgeon could go back through the anterior callosotomy incision, but scarring will make the dissection difficult and most would favor a separate, posterior, incision and craniotomy (Figure 123.5). Posteriorly, the falx goes to the callosum which makes its identification, and that of midline, easier. The same principles as outlined for the anterior procedure are followed and here, instead of identifying the anterior cerebral arteries after sectioning of the genu, the vein of Galen will be visualized as the splenium is

Figure 123.8 High powered operative photograph of transected corpus callousm.

The first series of Van Wagenen and Herren included 10 patients reported in detail.9 They operated on an additional 17 patients who were not reported in detail. They reported the conversion of generalized seizures to lateralized seizures with preservation of consciousness. Nine of the originally reported ten showed significant improvement.9 It is difficult to make generalizations from subsequent reports since candidacy for callosotomy, technique, and the methods of quantifying outcome have been variable. It is difficult to compare the outcome of different published series of callosotomy patients because of variables that include: seizure type, patient’s functional ability pre- or postoperatively, extent of pre- or postoperative investigation, and the definition of a ‘good’, ‘satisfactory’, or ‘excellent’ outcome. Indeed the variation is so extreme that some report complete, or almost complete, control of atonic, tonic, or generalized tonic-clonic in the majority of patients after callosotomy,19,25,73 whereas others report a favorable response in less than 50% of operated patients.26,32 Several series have reported a significant reduction in bisynchronous discharges after callosotomy.17,19,38,74,75 One related the EEG changes to the extent of transection.65 Seven patients who underwent an anterior callosotomy showed a decrease in the quantity of epileptiform discharges.76 Postoperatively, the total number of epileptiform burst activities, mean duration, and the total number of spike discharges decreased significantly.76 There have been reports of increased partial seizure activity after callosotomy in humans25,77–82 and in subhuman primates.10,83 This worsening of seizure activity may be secondary to the loss of an inhibitory influence84,85 and Spencer has described clinical seizures as being more intense.66,84 Alternatively, postoperative partial seizures may represent a remnant of the patient’s preoperative generalized seizures.73 Satisfactory outcomes have been reported to be between 50% and 80% where ‘satisfactory’ means a seizure reduction in frequency and/or severity of 50–80%.29,66,85 Patients with atonic seizures have fared better than those with tonic seizures.19,23,33,36,38–40,43,45,80,85–88 However, dichotomy exists. Madsen reported 80% significant improvement for drop attacks of either tonic or myoclonic origin, 69% for atonic drop attacks, 70% of atypical absence seizures, and 55% of generalized tonic-clonic seizures.37 An early report from Dartmouth found excellent results in four or five patients who had a callosotomy instead of a hemispherectomy for congenital hemiplegia.27 A report from Taiwan stated an 82% significant improvement (more than 50% reduction in seizure frequency) in patients with generalized tonic-clonic seizures, 73% with atonic seizures, and complete seizure freedom in 19%.89 However, most reports continue to show better results for atonic seizures than for generalized epilepsy. A Japanese report found that ‘total callosotomy is more effective for the treatment of drop attacks than partial callosotomy and that children receive more benefit than adults after callosotomy’.45 They reported an overal 85% satisfactory outcome (90% or more seizure reduction).

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Wilson reported that 16 of 20 patients had a greater than 50% reduction in overall seizure frequency.17,19 Geoffroy had similar success in six of nine patients,22 Luessenhop in three of four,20 Amacher in four of four,21 Rayport in seven of nine,90 and Bouvier in six of six.91 Engel looked at the outcome of a large number of patients (197) from 16 centers and found that only 5% were completely seizure free, 71% improved, and 24% unimproved.92 A follow-up survey in 1991 of 563 patients found that 8% reported seizure freedom with 61% improved.93 Spencer reported a series of 22 patients, five to 39 years of age, in which complete control of seizures was seen in six of seven with tonic seizures, two of two with atonic seizures, 16 of 21 with tonic-clonic seizures, nine of 22 with complex partial seizures, and none with simple partial seizures.25 He also reported that complete callosotomy was twice as effective as partial section.25 Spencer collected data on 330 patients and reported a success rate of 71% for atonic seizures following anterior section and 74% after total section; for tonic-clonic seizures the response was 56% and 75% respectively; for tonic seizures 47% and 75% respectively; and for absence seizures 33% and 64% respectively.94 Roberts reported that for all seizures taken together, only 29% of patients undergoing anterior transaction achieved success (80% or greater reduction of seizures) but that this increased to 62% success following completion of the callosal section.95 Unfortunately, there has been much variability of reported success following callosotomy. Commonly, reports state results of 57% ‘complete suppression of the generalized seizures associated with drop attacks’ (12 of 21 patients and a ‘seizure reduction of more than 75% in 6 of the 21.46 Gates reported on 24 patients with ‘a highly statistically significant reduction of postoperative tonic or atonic seizures’.73 One report stated that a very good outcome was present in 92% of patients more than ten years of age96 and in a pediatric series where callosotomy was the predominant surgical procedure for intractable epilepsy (30% of the cases), a surgical cure for drop attacks was reported to be 91% following a total callosotomy and 67% after partial transection.97 In the latter series, the most frequent preoperative EEG abnormalities were diffuse bilaterally synchronous epileptic discharges (72%). The neuropsychological consequences of the procedures are not clear, but improvement in quality of life was reported to occur in 77% of patients (97). A small series of ten patients with bihemispheric malformations wherein a total callosotomy was performed reported cessation of drop attacks in eight (one patient subsequently relapsed).98 Overall daily functional level was also reported to improve. Completeness of resection Although Spencer initially reported that outcome depended on the completeness of the transection,25 other authors have shown no differences in seizure control between partial or complete sections.41,23,99 Spencer later reported that a complete transection of the corpus callosum should be reserved for patients who did not respond to an anterior two-thirds section82 but there is a clear benefit in proceeding to completion

in patients with persistent generalized seizures after partial section.94 An early report of 24 medically refractory seizure patients (a variety of seizure types) revealed a significant reduction in seizure frequency and severity in 75% after anterior two-thirds corpus callosum section.100 In contrast, nine of 14 patients improved after a complete callosotomy in the treatment of West syndrome, while only two of 13 improved after an anterior callosotomy.54 Prognosis The preoperative EEG has been used to predict outcome. It has been reported that the ‘preoperative quantitative EEG analyses enabled ... to predict ... the surgical outcomes in patients undergoing corpus callosotomy’.58 Another report stated that ‘the ictal EEG but not other factors is able to identify a group of patients who have a better than 90% chance for total of nearly total resolution of seizures causing sudden falls’.59 Better results may be obtained in patients with lateralized EEG abnormalities.22 Quality of life issues are more difficult to judge; while some have reported a favorable social outcome,101,102 others have pointed out that overall clinical improvement or global measures of quality of life do not always correlate with seizure reduction.103,104 However, eliminating drop attacks associated with craniofacial trauma, by corpus callosum section, is an extremely important goal, even if other seizure types persist. In an early series, Ferrell did formal neuropsychological testing on eight patients and reported improvement in six.105 Yang reported that 76% of families surveyed were satisfied with the surgical result and 72% were satisfied with the family’s quality of life.102 Positive behavioral changes, social skills, and attention spans were reported. Gillam noted similar results in that 15 of 17 families reported overall satisfaction with reported improved alertness and responsiveness.104

Complications The usual complications of a craniotomy are seen but, fortunately, infrequently. Bone flap infection may be slightly increased because this is free bone flap and not an osteoplastic flap. Venous damage can result in an infarct as can damage to one of the deep arteries. Blood in the ventricle is to be avoided, but in the author’s experience it has not been a problem and the development of hydrocephalus has not been observed. Contralateral weakness (if present) is usually transient and should be discussed pre-operatively. Long term neurological problems are rare but an exacerbation of previous lateralized deficits has been reported.106 Of concern are clinical situations particularly unique to a corpus callosotomy. There are possible acute and chronic sequelae of a callosotomy and these neuropsychological/ behavioral changes have been well described107–114 even though initial reports stated that callosotomy produced little alteration in cognition.110 An acute disconnection syndrome may occur in some patients after an anterior twothirds transection but almost always following complete transection. Affected patients are lethargic, apathetic, and mute,

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Corpus callosotomy a presentation that can be very disturbing to the family. This disconnection syndrome should also be discussed before surgery. Families should be informed that patients virtually always get better but that this recovery can take from days to weeks. The problem of mutism following a callosotomy has been recognized for twenty three years.115 Additionally, there may a hemiparesis (leg greater than arm), an apraxia and hemineglect (if testable), bilateral Babinski signs, urinary incontinence, and an increase in focal motor seizures.29,85 The chronic disconnection syndrome is often very subtle and identified only by careful neuropsychological testing. It is most often present when the splenium of the corpus callosum has been transected. Deficits in tactile transfer can exist which consist of poor naming of objects held in the nondominant hand and visual transfer problems which consist of poor naming of objects seen in the nondominant hemifield. Thus, it especially involves sensory and/or visual pathways and their connections for speech production. For example, with a posterior callosotomy an object seen only by the left visual field may be recognized but the information can not be transferred from the right hemisphere to the left dominant hemisphere for naming. In practice, this is rarely noticeable clinically because objects are viewed in both visual fields. An ‘alien hand syndrome’ has been reported wherein there is antagonistic or poorly cooperative behavior between the two hands.108 This syndrome is usually transient but can, rarely, persist. Although poorer memory and concentration have been reported,116,117 this may be more of an attentional impairment than actual memory dysfunction118 or may occur when preoperative extracallosal damage exists, particularly involving the fornix.119 Although early reports stated that patients ‘do not experience functionally significant intellectual, emotional, or social impairment’,105 deficits are possible in all patients after callosotomy and finding them may be a function of the index of suspicion. Most deficits are topographic in nature, must be carefully searched for, and are rarely clinical significant.120 In fact, neuropsychological and psychosocial assessments are not significantly altered when compared with preoperative functional levels.121 ‘Deficits due strictly to callosal section can be almost completely predicted by the patient’s preoperative behavior, cognitive deficits, and the presence of unilateral lesions resulting in interhemispheric dependence for function’.66,106 Anterior sections result in disruption of sensory or motor integration functions as would be expected.120 This is somewhat in disagreement with a report by Tassinari wherein only two of six patients undergoing an anterior callosal section demonstrated an impairment in intermanual transfer of tactile localization.122 With careful testing it is apparent that effective binocular integration across the midline requires an intact corpus callosum.123 Patients undergoing a callosotomy for seizure palliation may be different than other partial callosotomy patients, such as those who have a interhemispheric disconnection after

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traumatic brain injury where the deficits seem mild or transient.124,125 Long term problems are related to the amount of sectioning25 with deficits almost doubled for a complete callosotomy compared to an anterior two-thirds transection. Spencer reported motor difficulties in 15% vs. 8%, language impairment in 14% vs. 8%, and cognitive/behavioral impairments in 11% vs. 8%. Age may also be a factor, as the plasticity of the young provides for much better response and adaptation to any brain injury, including callosotomy.66,126 Some authors have reported that patients with low preoperative IQs are at greater risk of developing neuropsychological deficits following callosotomy,41,126 but others report no relation between IQ and surgical outcome.127,128,129 There are reports of improvement of psychomotor function, even after total callosotomy.45,97,126

Future As noted, there are many conflicting reports regarding the indications for corpus callosotomy, the extent of transection, and, most importantly, on outcome. Outcome differs markedly, in part, because of the different interpretation of ‘success’, the methods and length of follow up and the degree to which neuropsychological, neurophysiological, or neurocognitive deficits were investigated.130 While our understanding of the indications and expectations for corpus callosotomy for the treatment of intractable epilepsy continues to evolve, the last decade has seen a sharp decline in the use of corpus callosotomy for intractable epilepsy. This may be partially due to the introduction of new anticonvulsant drugs and partially because of the increased ability to identify an epileptogenic zone with improved anatomic and functional neuroimaging and metabolic studies. However, even in ‘nonlesional’ cases, more aggressive investigation (e.g., increased use of implanted electrodes with extraoperative monitoring, increased use of ictal SPECT, PET, MEG) has allowed for more focally resective surgery. New techniques might be of some benefit,114 but are highly speculative at this time. The role of vagal nerve stimulation has yet to be determined. It can be stated that a microsurgical extraventricular division of the corpus callosum can help a number of patients and that staging the procedure remains a reasonable alternative approach as a complete callosotomy is not required in all patients. Behavioral and neuropsychological sequelae of commissurotomy are well-recognized, but are rarely of long term clinical consequence. In the majority of patients the potential benefits of the procedure outweigh the risks and, finally, callosotomy is currently an underutilized procedure, especially for children with intractable atonic seizures associated with recurring falls and injuries. Corpus callosotomy should remain in the surgical armamentarium of every comprehensive epilepsy program.

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Wyllie E. Corpus callosotomy for intractable generalized epilepsy. J Pediatr 1988;113:255–72. Egli M, Mothersill I, O’Kane M, O’Kane F. The axial spasa–the predominant type of drop seizure in patients with secondary generalized epilepsy. Epilepsia 1985;26:401–15. Carmant L, Holmes GL. Commissurotomes in children. J Child Neurol 1994;9(Suppl 2):50–60. Makai GS, Holmes GL, Murro AM et al. Corpus callosotomy for the treatment of intractable epilepsy in children. J Epilepsy 1989; 2:1–7. Roberts DW. The role of callosal section in surgical treatment of epilepsies. Neurosurg Clin North Am 1993;4:293–300. Guerreiro MM, Andermann F, Andermann E et al. Surgical treatment of epilepsy in tuberous sclerosis: strategies and results in 18 patients. Neurol 1998;51:1263–9. Rappaport ZH. Corpus callosum section in the treatment of intractable seizures in the Sturge-Weber syndrome. Childs Nervous Sys 1988;4:231–2. Phillips J, Sakas DE. Anterior callosotomy for intractable epilepsy: outcome in a series of 20 patients. Br J Neurosurg 1996;10:351–6. Madsen JR, Carmant L, Holmes GL, Black PM. Corpus callosotomy in children. Neurosurg Clin N Am 1995;6:541–8. Nordgren RE, Reeves AG, Viguera AC et al. Corpus callosotomy for intractable seizures in the pediatric age group. Arch Neurol 1991; 48:364–72. Fuiks KS, Wyler AR, Hermann BP et al. Seizure outcome from anterior and complete corpus callosotomy. J Neurosurg 1991; 74:573–8. Oguni H, Olivier A, Andermann F et al. Anterior callosotomy in the treatment of medically intractable epilepsies: a study of 43 patients with a mean follow-up of 39 months. Ann Neurol 1991; 30:357–64. Reutens DC, Bye AM, Hopkins IJ et al. Corpus callosotomy for intractable epilepsy: seizure outcome and prognostic factors. Epilepsia 1993;34:904–9. Spencer SS. Corpus callosum section and other disconnection procedures for medically intractable epilepsy. Epilepsia 1988; 29(suppl 2):589–95. Rossi GF, Colicchio G, Marchese E, Pompucci A. Callosotomy for severe epilepsies with generalized seizured: outcome and prognostic factors. Acta Neurochir (Wien) 1996;138:221–7. Shimizu H, Machara T. Neuronal disconnection for the surgical treatment of pediatric epilepsy. Epilepsia 2000;41(Suppl 9): 28–30. Machara T, Shimizu H. Surgical outcome of corpus callosotomy in patients with drop attacks. Epilepsia 2001;42:67–71. Kim DS, Yang KH, Kim TG et al. The surgical effect of callosotomy in the treatment of intractable seizure. Yonsei Med J 2004; 45:233–40. Blume W. Corpus callosum section for seizure control: rationale and review of experimental and clinical data. Cleve Clin Q 1984; 51:319–32. Geoffrey G, Sauerwein H, Lassonde M, Decarie M. Inclusion and exclusion criteria for corpus callosotomy in children. J Epilepsy 1990;3:196–202. Vossler DG, Lee JK, Ko TS. Treatment of seizures in subcortical laminar heterotopia with corpus callosotomy and lamotrigine. J Child Neurol 1999;14:282–8. Ambrosetto G, Antonini L. Anterior corpus callosotomy: effects in a patient with congenital bilateral perisylvian syndrome and oromotor seizures. Ital J Neurol Sci 1995;16:311–14. Pallini R, Aglioti S, Tassinari G et al. Callosotomy for intractable epilepsy from bihemispheric cortical dysplasias. Acta Neurochir (Wien) 1995;132:79–86. Landy HJ, Curless RG, Ramsay RE et al. Corpus callosotomy for seizures associated with band heterotopia. Epilepsia 1993; 34:79–83. Pallini R, Bozzini V, Collichio G et al. Callosotomy for generalized seizures associated with hypothalamic hamartoma. Neurol Res 1993;15:139–41. Pinard JM, Delalande O, Chiron C et al. Callosotomy for epilepsy after West syndrome. Epilepsia 1999;40:1727–4. Kamida T, Muruyama T, Fujiki M et al. Total callosotomy for a case of lissencephaly presenting with West syndrome and generalized seizures. Childs Nerv Syst 2005;21:1056–60. Sakaki T, Nakase H, Morimoto T, Hoshida T, Tsunoda S. Partial corpus callosotomy beneficial for Lennox-Gastaut syndromereport of two cases. Neurol Med Chir (Tokyo) 1991;31:226–32.

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Saint-Hilaire JM, Giard N, Bouvier G, Labrecque R. Anterior callosotomy in frontal lobe epilepsy. In: Reeves AG, ed. Epilepsy and the Corpus Callosum. New York: Plenum Press, 1985:303–314. 58. Matsuzaka T, Ono K, Baba H et al. Quantitative EEG analyses and surgical outcome after corpus callosotomy. Epilepsia 1999; 40:1269–78. 59. Hanson RR, Risinger M, Maxwell R. The ictal EEG as a predictive factor for outcome following corpus callosum section in adults. Epilepsy Res 2002;49:89–97. 60. Kwan SY, Wong TT, Chang KP et al. Seizure outcomes after anterior callosotomy in patients with posterior-dominant and with anterior-dominant epileptiform discharges. Childs Nerv Syst 2001; 17:71–5. 61. Quattrini A, Papo I, Cesarano R et al. EEG patterns after callosotom,y. J Neurosurg Sci 1997;41:85–92. 62. Fiol ME, Gates JR, Mireles R, Maxwell RE, Erickson DM. Value of intraoperative EEG changes during corpus callosotomy in predicting surgical results. Epilepsia 1993;34:74–8. 63. Kwan SY, Lin JH, Wong TT, Chang KP, Yiu CH. Prognostic value of electrocorticography findings during callosotomy in children with Lennox-Gastaut syndrome. Seizure 2005;14:470–5. 64. Goldberg WE, Holmes GL, Gould J. Effects of anterior callosotomy on the electroencephalogram. J Epilepsy 1989;2:73–81. 65. Spencer SS, Spencer DD, Williamson PD, Mattson RH. Effects of corpus callosum section on secondary bilaterally synchronous interictal EEG discharges. Neurology 1985;35:1689–94. 66. Spencer DD, Spencer SS. Corpus callosotomy in the treatment of medically intractable secondarily generalized seizures of children. Cleve Clin J Med 1989;56(Suppl Pt 1):S69–78. 67. Baumgartner JE, Clifton GL, Wheless JW et al. Corpus callosotomy. Techniques in Neurosurg 1995;1:45–51. 68. Pendl G, Eder HG, Schroettner O, Leber KA. Corpus callosotomy with radiosurgery. Neurosurg 1999;45: 303–7. 69. Marino R Jr, Ragazzo PC. Selective criteria and results of selective partial callosotomy. In: Reeves AG, ed. Epilepsy and the Corpus Callosum. New York: Plenum Press, 1985:281–301. 70. Avila JO, Radvany J, Huck FR et al. Anterior callosotomy as a substitute for hemispherectomy. Acta Neurochir Suppl (Wien) 1980; 30:137–43. 71. Hodair M, Musharbash A, Otsubo H et al. Image-guided, frameless stereotactic sectioning of the corpus callosum in children with intractable epilepsy. Pediatr Neurosurg 2001;34:286–94. 72. Guerrero MH, Cohen AR. Endoscope-assisted microsurgery of the corpus callosum. Minim Invasive Neurosurg 2003;46:54–6. 73. Gates JR, Rosenfeld WE, Maxwell RE et al. Response of multiple seizure stypes to corpus callosum section. Epilepsia 1987;28:28–34. 74. Courtney W, Gates JR, Ritter F et al. Predicition of seizure outcome after corpus callosotomy in patients ten years of older. Epilepsy 1993;34(Suppl):43. 75. Huck FR, Radvany J, Avila JO et al. Anterior callosotomy in epileptics with multiform seizures and bilateral synchronous spike and wave EEG patter. Acta Neurochir Suppl (Wein) 1980;30:127–35. 76. Matsuo A, Ono T, Baba H, Ono K. Callosal role in generation of epileptiform discharges: quantitative analysis of EEGs recorded in patients undergoing corpus callosotomy. Clin Neurophysiol 2003; 114:2165–71. 77. Gates JR, dePaola L. Corpus callosum section. In: Sliovan S, Dreifuss F, Fish D et al, eds. The Treatment of Epilepsy. London. Blackwell Scientific, 1996;722–38. 78. Blume WT. Corpus callosotomy: a critical review. In: Tuxhom I, Holthausen H, Roenigk H, eds. Pediatric Epilepsy Syndromes and Their Surgical Treatment. London: John Libbey, 1997;815–29. 79. Gates JR. Candidacy for corpus callosotomy. In: Luders HO, ed. Epilepsy Surgery. New York: Raven Press, 1991;140–50. 80. Gates JR, Maxwell R, Leppik IE et al. Electroencephalographic and clinical effects of total callosotomy. In: Reeves AG, ed. Epilepsia and the Corpus Callosum. New York: Plenum Press, 1986:315–28. 81. Gates JR, Mireles R, Maxwell RE et al. Magnetic resonance imaging, electroencephalogram and selected neuropsychological testing in staged corpus callosotomy. Arch Neurol 1986;43:1188–91. 82. Spencer SS, Katz A, Ebersole J et al. Ictal EEG changes with corpus callosum section. Epilepsia 1993;34:568–73. 83. DePaola L, Gates JR, Ritter FJ et al. Persistence of generalized ictal electroencephalographic onset after total corpus callosotomy. Neurology 1996. 84. Spencer SS, Spencer DD, Glaser GH et al. More intense focal seizure types after callosal section; the role of inhibition. Ann Neurol 1984;16:686–93. 85. Spencer SS, Gates JR, Reeves AG et al. Corpus callosum section. In: Engel J Jr, ed. Surgical Treatment of the Epilepsies. New York: Raven Press, 1987:425–44.

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86. Quattrini A, Papo I, Cesarano R et al. Modifications in morphology of epileptic seizures after callosotomy. J Neurosurg Sci 1997;41:81–4. 87. Sakas DE, Phillips J. Anterior callosotomy in the management of intractable epileptic seizures: significance of the extent of resection. Acta Neurochir 1996;138:700–7. 88. Rappaport ZH, Lerman P. Corpus callosotomy in the treatment of secondary generalizing intractable epilepsy. Acta Neurochirurgica 1988;94:10–14. 89. Kwan SY, Wong TT, Chang KP, et al. Seizure outcome after corpus callosotomy: the Taiwan experience. Childs Nerv Syst 2000; 16:87–92. 90. Rayport M, Ferguson SM. Corrie WS. Outcomes and indications of corpus callosum section for intractable seizure control. Appl Neurophysiol 1983;46:47–51. 91. Bouvier G, Mercier C, St. Hilaire JM et al. Anterior callosotomy and cronic depth electrode recording in the surgical management of some intractable seizures. App Neurophysiol 1983;46:52–6. 92. Engel J Jr. Outcome with respect to epileptic seizures. In: Engel J Jr, ed. Surgical Treatment of the Epilepsies. New York: Raven Press, 1987:553–71. 93. Engel J Jr, Van Neww PC, Rasmussen TB et al. Outcome with respect to epileptic seizures. In: Engel J Jr, ed. Surgical Treatment of the Epilepsies, 2nd edn. New York: Raven Press, 1993:609–21. 94. Spencer SS, Spencer DD, Sass I et al. Anterior, total, and twostage corpus callosum section: differential and incremental seizure responses. Epilepsia 1993;34:561–7. 95. Roberts DW, Reeves AF, Nordgren RE. The role of posterior callosotomy in patients with suboptimal response to anterior callosotomy. In: Reeves AF, Roberts DW, eds. Epilepsy and the Corpus Callosum, 2nd edn. New York: Plenum Press, 1995:183–90. 96. Gates JR, Courtney W, Titter F et al. Prediction of seizure outcome after corpus callosotomy among young children. Epilepsia 1993; 34(Suppl):111. 97. Shimizu H. Our experience with pediatric epilepsy surgery focusing on corpus callosotomy and hemispherotomy. Epilepsia 2005; 46(Suppl 1):30–1. 98. Kawai K, Shimizu KK, Yagishita A et al. Clinical outcomes after corpus callosotomy in patients with bihemispheric malformations of cortical development. J Neurosurg 2004;101(Suppl):7–15. 99. Cendes F, Ragazzo PC, da Costa V et al. Corpus callosotomy in treatment of medically resistant epilepsy: preliminary results in a pediatric population. Epilepsia 1993;34:910–17. 100. Purves SJ, Wada JA, Woodhurst WB, et al. Results of anterior corpus callosum section in 24 patients with medically intractable seizures. Neurology 1988;38:1194–201. 101. Rougier A, Claverie B, Pedespan JM et al. Callosotomy for intractable epilepsy: overall outcome. J Neurosurg Sci 1997;41:51–7. 102. Yang TF, Wong TT, Kwan S et al. Quality of life and life satisfaction in families after a child has undergone corpus callosotomy. Epilepsia 1996;37:76–80. 103. Papo I, Quattrini A, Ortenzi A et al. Predictive factors of callosotomy in drug-resistant epileptic patients with a long follow-up. J Neurosurg Sci 1997;41:31–6. 104. Gilliam F, Wyllie E, Kotaal P et al. Parental assessment of functional outcome after corpus callosotomy. Epilepsia 1996;37:753–7. 105. Ferrell RB, Cluver CM, Tucker GJ. Psychosocial and cognitive function after commissurotomy for intractable seizures. J Neurosurg 1984;58:374–80. 106. Sass KJ, Spencer DD, Spencer SS et al. Corpus callosotomy for epilepsy. II. Neurologic and neuropsychological outcome. Neurology 1988;38:24–8. 107. Black PM, Holmes G, Lombroso CT. Corpus callosum section for intractable epilepsy in children. Pediatr Neurosurg 1992; 18:298–304. 108. Ferguson SM, Rayport M, Corrie WS. Neuropsychiatric observations on behavioral consequences of corpus callosum section for seizure control. In: Reeves AF, ed. Epilepsy and the Corpus Callosum. New York: Plenum Press, 1985:501–14. 109. Pilcher WH, Rusyniak WG. Complications of epilepsy surgery. Neurosurg Clin North Am 1993;4:311–25. 110. Akelaitis AF. A study of gnosis, praxis and language following section of the corpus callosum and anterior commissure. J Neurosurg 1944;1:94–102. 111. Gazzaniga MS, Risse GL, Springer SP et al. Psychologic and neurologic consequences of partial and complete cerebral commissurotomy. Neurology 1975;25:10. 112. Ledoux JE, Risse GL, Springer SP et al. Cognition and commissurotomy. Brain 1977;100:87. 113. Gazzaniga MS, Smylie CS. Dissociation of language and cognition: a psychological profile of two disconnected right hemispheres. Brain 1984;107:145–53.

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Textbook of epilepsy surgery Oepen G, Schulz-Weiling R, Zimmermann P et al. Long-term effects of partial callosal lesions: Preliminary report. Acta Neurochir 1985;77:22. Sussman NM, Gur RC, Gur RE, O’Connor MJ. Mutism as a consequence of callosotomy. J Neurosurg 1983;59:514–19. Zaidel E, Sperry RW. Memory impairment after commissurotomy in man. Brain 1974;97:263–72. Ledous JE, Risse GL, Springer SP et al. Cognition and commissurotomy. Brain 1977;100:87–104. Beniak TE, Gates JR, Risse GL. Comparison of selected neuropsychological test varfiables pre- and postoperatively on patients subjected to corpus callosotomy. Epilepsia 1985;26:534. Clark CR, Geffen GM. Corpus callosum surgery and recent memory. A review. Brain 1989;112:165–75. Caille S, Sauerwein HC, Schiavetto A et al. Sensory and motor interhemispheric integration after section of different portions of the anterior corpus callosum in nonepileptic patients. Neurosurg 2005;57:50–9. Reeves AF. Behavioral changes following corpus callosotomy. Adv Neurol 1991;55:293–300. Tassinari G, Aglioti S, Pallini R et al. Interhemispheric integration of simple visuomotor responses in patients with partial callosal defects. Behav Brain Res 1994;64:141–9. Saint Amour D, Lepore F, Lassonde M, Guillemot JP. Effective binocular integration at the midline requires the corpus callosum. Neuropsychologia 2004;42: 164–74.

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Mathias JL, Bigler ED, Jones NR et al. Neuropsychological and information processing performance and its relationship to white matter changes following moderate and severe traumatic brain injury: a preliminary study. App Neuropsychol 2004; 11:134–52. Peru A, Beltramello A, Moro V et al. Temporary and permanent signs of interhemispheric disconnection after traumatic brain injury. Neuropsychologia 2003;41:634–3. Lassonde M, Sauerwein C, Neuropsychological outcome of corpus callosotomy in children and adolescents. J Neurosurg Sci 1997;41:67–73. Mamelak AN, Barbaro NM, Walker JA, Laker KD. Corpus callosotomy: a quantitative study of the extent of resection, seizure control, and neuropsychological outcome.J Neurosurg 1993; 79:688–95. Squerwein HC, Lassonde M. Neuropsychological alterations after split-brain surgery. J Neurosurg Sci 1997;41:59–66. Woeciechowsky D, Vogel S, Meyer BU, Lehmann R. Neuropsychological and neurophysiological consequences of partial callosotomy. J Neurosurg Sci 1997;41:75–80. Wada JA. Callosal bisection and transcallosal secondary antiepileptogensis. Epilepsia 2005;46(Suppl 1):2–6. Tubbs RS, Smyth MD, Salter G et al. Eyebrow incision with supraorbital trephination for endoscopic corpus callosotomy: a feasibility study. Childs Nerv Syst 2004;20:188–91.

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Radiosurgical treatment of epilepsy I Yang and NM Barbaro

Introduction

Preclinical evidence

Radiosurgery is the precise application of focused radiation to a targeted volume area within the brain identified on magnetic resonance imaging.1 Initially conceptualized by Leksell for use in functional neurosurgery, radiosurgical treatment for neurologic disorders has progressively widened its utility and is now also an option for several neoplastic and vascular indications.2,3 Differing from standard dose-fractionated radiotherapy, radiosurgery allows the neurosurgeon to deliver precise and accurate radiation to a smaller volume without effecting large portions of normal parenchyma allowing for a powerful radiobiologic effect on the chosen targeted volume.1,4–6 Patients with epilepsy who are refractory to medical management may be referred for possible surgical management, and approximately half of them are found to be candidates for surgical resection of their seizure focus.7 Focal partial epilepsies are typically responsive to surgical treatments and are increasingly being treated using ‘structural’ means.2,8 The most common type of surgery performed is an anterior temporal lobectomy, resection of a portion of the temporal lobe.7,8 Microsurgical resection of mesial temporal lobe structures can be performed with low morbidity and even lower mortality.6 Open procedures have inherent risks including damage to the brain (either directly or indirectly by injury to important blood vessels), bleeding (which can require re-operation), blood loss (which can require transfusion), infection, and general anesthetic risks. In addition, surgical incisions can result in significant postoperative pain. Several clinical studies evaluating the morbidity of temporal lobe microsurgery report that 5–23% of epilepsy patients undergoing open surgery had a symptomatic neurologic deficit post operatively.9–13 Furthermore, open procedures require several days of care in the hospital including at least one night in an intensive care unit which contribute to the economic costs of resective surgical treatment.2 There also exists a population of patients with medically intractable epilepsy that is unsuitable for conventional resective surgery.2 These patients may have their epileptic focus in eloquent regions of the brain which could result in irreversible language, motor, or visual impairment with surgical resection.2,3 Radiosurgery is now being evaluated as an alternative treatment to open resective surgery for intractable epilepsy. Specifically, radiosurgery is under study as a treatment of epilepsy associated with vascular malformations, gelastic epilepsy associated with hypothalamic hamartomas, and medial temporal lobe epilepsy associated with mesial temporal sclerosis.1,3,4,6,14–37

Animal studies investigating focused radiosurgery in animal models of epilepsy have demonstrated the potential utility of radiosurgical treatment applied to epileptic foci to reduce seizure activity. Early animal experiments in cats indicated the potential of focused radiosurgery in a cat model of epilepsy.2,14,17 Using doses between 10 and 20 Gy (one gray, Gy, is equivalent to one joule of energy per kilogram of tissue), cats with epileptic foci treated with an implanted cobalt source had reduced seizure activity. Histologic analysis of these animals revealed ‘neuronal reafferentation’ as the proposed mechanism of seizure amelioration.14,17 Recently, Sun et al. report that focused radiosurgical treatment successfully reduced seizure activity and raised the seizure threshold in a rat epilepsy model.3 A linear accelerator was used to perform radiosurgery at doses of 10 or 40 Gy at the 90% isodose line using a 5 mm collimator. The seizure threshold to external electrical stimulation in these rats was significantly increased and the length of after-discharges was significantly decreased in the 40 Gy group. These antiepileptic effects were detectable 1 week after radiosurgery and continued for a three month follow-up period.3 Experiments from the University of Virginia were designed to evaluate the effects of radiosurgery on a chronic spontaneous limbic epilepsy model.38 In this model, hippocampal electrodes were implanted utilizing a single 90-minute period of stimulation to produce a rodent spontaneous limbic epileptic model. Ten weeks later, Gamma Knife(r) radiosurgery with doses of 10 to 40 Gy, using a 4 mm collimator, was applied. While the lowest dose group (10 Gy) showed no decrease in seizures, the 20 Gy group did exhibit a gradual and continuous reduction in seizure occurrences from 2 to 6 months after radiosurgical treatment. Lastly, the 40 Gy group displayed a dramatic reduction in seizures by the second month. Histologic analysis of radiosurgical treated targets revealed no necrosis. Furthermore, penicillin induced epileptic activity was reduced in the brain slices of those rats that were treated with 40 Gy. Synaptically driven neuronal firing was found to be intact in these brain slices, suggesting that neuronal death was not responsible for the identified seizure resistance.38 Experiments at the University of Pittsburgh were designed to determine the dose of radiosurgery that was necessary to eliminate seizures in a kainic acid rat epilepsy model.28 In this study rats underwent stereotactic injection of kainic acid into the right hippocampus to induce seizures. Ten days after the injections, the injection site was treated with Gamma Knife(r) radiosurgery using a 4 mm collimator over a range of 20–100 Gy. 1173

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The animals treated with a 20 Gy dose showed a reduction in the number of daily seizures during each week of observation after radiosurgery. Furthermore, three weeks after radiosurgery, all radiation groups – 20 Gy, 40 Gy, 60 Gy and 100 Gy showed a significant reduction in seizure activity confirmed with EEG evaluations. The authors report that histologic evaluation revealed no radiation-induced necrosis in any animals except for the 100 Gy cohort. However as the injection of kainic acid induces a loss of CA3 neurons in all animals, interpretation of histological findings may be difficult. Small areas of kainic acid necrosis were seen in 2/20 control animals and in 14/37 irradiated animals, but only in the 100 Gy radiosurgery treated group did the necrosis noted match the collimator size.28 A second study using the same kainic acid rat epilepsy model was undertaken to further evaluate the pathological and behavioral effects of ‘subnecrotic’ radiosurgery doses.39 Stereotactic hippocampal kainic acid injections were followed by single isocenter radiosurgery using a 4 mm collimated Gamma Knife(r) with radiosurgery doses of 30 or 60 Gy. A significant reduction in seizures was noted in all animals, and this effect was seen earlier in the 60 Gy cohort than in the 30 Gy group (weeks 5–9 compared to weeks 7–9). Furthermore, rats treated with radiosurgery did not demonstrate a deficit in new memory attainment tasks with water maze testing compared with kainic acid injected animals, but both groups showing impairment compared to controls without kainic injection. Two blinded, experienced observers rated the histological specimens from all animals at 13 weeks following radiosurgery. Changes typical for kainic acid injections were seen in all animals including a loss of pyramidal cells in CA3-4. In 25/46 injected animals unilateral hippocampal atrophy with cell loss extending into CA1 and CA2 was noted. Although histologic assessment is difficult to assess given the use of kainic acid, necrosis matching the target volume of radiosurgery was not observed in any of the animals.38 The authors again suggest that cessation of seizures following radiosurgery does not require concomitant loss of neurons.39 Two recent studies from the radiosurgery group in Prague report on their characterization of a ‘subnecrotic’ dose using radiosurgery in an animal model.40,41 The investigators studied doses of 25, 50, 75 or 100 Gy delivered bilaterally to rat hippocampus. Memory function tests, MRI and histological examination were performed at 1, 3, 6 and 12 months following radiosurgery. A time and dose-dependent response was noted in memory function, T2 edema and necrotic histopathology. Animals dosed with 100 Gy died by 6 months following radiation and all had necrotic lesions. All animals treated at 75 Gy displayed memory impairment at 6 and 12 months, edema on MRI, and necrotic lesions, whereas only one of the animals treated with 50 Gy were effected by edema and necrosis. Otherwise, 25 and 50 Gy irradiated animals did not show any functional or structural impairment at up to one year after radiosurgery.4 This finding of potential subnecrotic radiosurgery dose parameters prompted a second study where a 35 Gy radiosurgery dose was used and the animals were evaluated over 16 months.40 By 6 months postirradiation, T2 edema was evident on MRI and this edema peaked at 9 months. By 17 months, two of six animals had postnecrotic cavities. The four animals without frankly necrotic cavities had severe atrophy of the corpus callosum, loss of thickness of

somatosensory cortex and damage to the striatum oriens hippocampi.40 These studies clearly indicate that the full radiobiologic and histological effect of radiosurgery may only be manifested after several months following treatment. These preclinical studies report the amelioration of seizures as well as histologic neuronal changes associated with radiosurgical treatment in different animal epilepsy models. These animal studies suggest that the antiepileptic efficacy of radiosurgery is dose dependant.6,28,38,39 Most of these studies suggest that a radiosurgery dose of approximately 25 Gy is required to see therapeutic antiepileptic effect, and that the full histological and other toxicity may require several months to fully develop.2,3,28,38–44

Clinical evidence The first radiosurgical application for epilepsy surgery was utilized by Talairach in the 1950s with the implantation of radioactive yttrium in patients with MTLE without a lesion.2,3,6 Further clinical experiences with Gamma Knife(r) radiosurgery and linear accelerator (LINAC) based radiosurgery for the treatment of arteriovenous malformations and low grade tumors also noted the incidental antiepileptic effects of radiosurgery.6,18,20,23,25,26,37 Using Gamma Knife(r) and LINAC to treat arteriovenous malformations (AVMs), several groups have reported a supplementary improvement in seizure control.27,35,42 Although it is not established whether reduction of tumor size or angiographic occlusion of the vascular malformation itself may reduce seizures, these reports of clinical seizure improvement with radiosurgery provided the impetus for investigating radiosurgery as an alternative treatment for medically intractable epilepsy.

Medial temporal lobe epilepsy Medial temporal lobe epilepsy (MTLE) associated with mesial temporal sclerosis is perhaps the most well defined epilepsy syndrome responsive to surgical intervention. When temporal lobe epilepsy is due to underlying mesial temporal sclerosis (MTS), surgical cure can be expected in between 65 and 90% of patients.2,7,8,43–49 This form of adult intractable epilepsy is particularly amenable to radiosurgery because 80–90% of these cases show changes on magnetic resonance imaging.4,46 Recently, radiosurgery has been explored as an alternative to open resective surgery for MTS associated medial temporal lobe epilepsy. In the first application of Leksell Gamma Knife® for epilepsy, Regis et al. utilized radiosurgery in a small number of patients showing amelioration of seizures with minimal morbidity and mortality.31,34 A prospective, multicenter European study evaluating Gamma Knife(r) surgery for MTS showed comparable efficacy rates (65%) for seizure reduction by conventional surgery or radiosurgery after 2 years of follow up.6 Using a marginal dose of 24 Gy, Regis et al. demonstrate that radiosurgery can be used as an alternative to conventional resective surgery to treat medial temporal lobe epilepsy associated with MTS and improve quality of life with favorable rates of morbidity and mortality (Figure 124.1).6

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36 Months

27 Months

17 Months

9 Months

Radiosurgical treatment of epilepsy

Figure 124.1 Representative radiographic changes on magnetic resonance imaging (MRI) after radiosurgical treatment of mesial temporal lobe epilepsy. Radiographic effects are not observed until after 1 year correlating with delayed clinical manifestation of therapy.6

In the US, a multicenter pilot trial is currently being conducted with initial results showing that 85% of patients treated with 24 Gy (to the 50% isodose line) to the medial temporal lobe, including the amygdala, anterior hippocampus and nearby cortex followed for at least 24 months are seizurefree with minimal morbidity (Barbaro et al. unpublished). This group is planning a larger, phase 3 trial comparing open surgery with radiosurgery for patients with clinically and radiographically defined MTS. Although radiosurgery has proven effective and safe in ameliorating MTS associated seizures, the beneficial effects of radiosurgery are not displayed immediately. Most patients achieve seizure reduction at 9–12 months and complete cessation of seizures between 18–24 months after radiosurgical treatment. A transient increase in partial seizures (auras) is noted typically at approximately the same time as complex seizures decrease.6 Greater than half of treated patients may require corticosteroids to treat the radiation-induced edema associated with the initial radiosurgical effect (10–15 months posttreatment) (6 Barbaro, personal observation). One of the difficulties in applying radiosurgery broadly as an application for intractable epilepsy is the definition of the radiosurgical target. Because the MTS associated with MTLE is not well defined anatomically, the precise boundaries for radiosurgical treatment are not well known and hence is difficult to standardize amongst different treatment centers. Successful radiosurgical treatment has been shown to be target related. Recently, Regis et al. radiosurgically targeted the mesial temporal lobe structures in their series whereas Kawai et al. defined their treatment to the amygdala or hippocampus, and each series reported contrasting rates of successful amelioration of medial temporal lobe seizures with radiosurgery.6,22,31,34 Although target definition may be variable

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amongst different neurosurgeons, radiosurgery for MTS associated MTLE is an attractive option because of its low morbidity and mortality. Furthermore, conventional open temporal lobectomy can also be pursued if the initial radiosurgical treatment is ineffective and sufficient time has been permitted for the delayed radiosurgical antiepileptic effect after 3 years.6 Recent dose studies have also indicated that a lower marginal dose of 20 Gy may be less effective in reducing seizures. Cmelak et al. report unsuccessful seizure reduction with radiosurgery using a 15 Gy marginal dose.50 Kawai et al. also report two cases of radiosurgery with unsuccessful anti epileptic effect with a marginal dose of 18 Gy.22 Finally, Srikijvilaikul et al. from the Cleveland Clinic report their series of failed radiosurgical treatment for seizure control with a 20 Gy marginal dose.5 The radiobiology of radiosurgery in the setting of MTS associated MTLE is not yet completely understood. While some animal studies have suggested an anti-epileptic effect of radiation with subnecrotic doses,39 human studies indicate that a certain amount of tissue damage may be required to see a significant amelioration of seizures. The importance of this question is that radiosurgical treatment of eloquent brain regions would be possible if an effective subnecrotic dose could be found.

Histologic evaluation of radiosurgical treatment Histological examination of radiosurgically treated human mesial temporal tissue for MTLE has been limited, but some histologic analysis of radiosurgically treated tissues involving patients who underwent resection due to lack of seizure control have been reported.22,50,51 Using a subtherapeutic dose of 15 Gy, Cmelak et al. noted no radiation-induced histopathologic changes after radiosurgery.59 In another two patients treated with 18 Gy, one patient was noted to have a necrotic focus with some prominent vascular changes consisting of vessel-wall thickening, fibrinoid and hyaline degeneration. The other patient treated with this subtherapeutic dose showed no necrosis or vascular changes.22 Treated with a higher, yet subtherapeutic, dose of 20 Gy, all five patients from the Cleveland Clinic also showed necrosis, perivascular sclerosis, and macrophage infiltration upon resection and histologic evaluation.51 These observations suggest that in humans, significant histologic changes may only be observed in radiosurgical doses greater than or equal to 20 Gy. These radiobiologic and histological changes may be required for a full antiseizure effect. Thus, a dose that produces some tissue damage without producing an excessive response, likely 24 Gy, is the optimal effective dose in the radiosurgical treatment of MTLE.6,31,34

Hypothalamic hamartomas associated gelastic epilepsy Hypothalamic hamartomas are rare lesions with a prevalence of 1–2 in 100,000 commonly associated with precocious puberty, developmental cognitive delay, and gelastic epilepsy.29,54 An overwhelming majority of seizures associated with hypothalamic hamartomas are gelastic in nature and are

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medically refractory.29,52,53 These hamartomas are ectopic tissue consisting of glia, neurons and fiber bundles.24,52,53 Surgical resection of hypothalamic hamartomas has been reported to improve control of gelastic seizure activity, but due to the technical difficulties of reaching this deep lesion in a critical area, open microsurgical resection is often difficult, incomplete and associated with a high risk of complications such as motor, visual and hypothalamic deficits.24,52–55 Unger et al. report two patients treated with low-dose radiosurgery for hypothalamic hamartomas with significant seizure improvement after 36 and 54 months.36 This therapeutic delay is consistent with the radiobiological effects of radiosurgery. In a recent retrospective multicenter study, Regis et al. report ten patients treated with 18 Gy that had improvement in their seizures after radiosurgical treatment of hypothalamic hamartomas.29 In a larger series, 19 out of 30 patients were shown to have short-term improvements in 6 months of followup, but further follow-up data is still being evaluated in this series.33 This alternative treatment holds great promise as an effective alternative treatment given the surgical morbidity associated with microsurgical dissection of hypothalamic hamartomas. Further investigations with larger series, longer follow-up in a prospective manner must be conducted to establish the true safety and efficacy of this treatment option.

Cavernous malformation associated epilepsy The most frequent presentation of cavernous malformations is seizures. These congenital vascular malformations can cause hemorrhage and repetitive neurologic deficit, but more commonly manifest as repetitive seizures.30,56 The incidence of medically intractable epilepsy associated with cavernous malformations is not yet established.30 Radiosurgical treatment for cavernous malformations is controversial because clear evidence for protection from hemorrhage has yet to be established.21,24,30 Although resective, open microsurgical treatment of cavernous malformations remains the standard efficacious therapy, a recent series by Regis et al. suggest a role for radiosurgery in the treatment of seizures associated with cavernous malformations near ‘highly functional cortex’ that may preclude open resection.30 Using a mean dose of 19 Gy, 53% of 49 patients with refractory seizures became seizurefree and 20% were significantly improved at 2 years after treatment,30 demonstrating that epilepsy associated with cavernous malformations near eloquent cortex may be treated with radiosurgery to reduce seizure frequency. Given the low bleeding risk of cavernous malformations in cortical regions and common presentation with seizures,57 patients seeking an alternative to microsurgical resection with decreased morbidity may opt for radiosurgical treatment of medically intractable seizures associated with these cavernous malformations. In addition to cavernous malformations near eloquent cortex, deep seated cavernous malformations which are not amenable to open procedures may also potentially be amenable to antiepileptic therapy with radiosurgery for medically intractable seizures. Unfortunately these deep seated lesions have a higher risk of clinical bleeding and poor neurologic outcome,57 and the effect

of radiosurgery on this risk is still unclear.21,24,30 Without clear evidence of the effect of radiosurgery on bleeding risk, microsurgical resection remains the standard therapy for cavernous malformations.

Long term radiosurgical complications Although the long-term complications of radiosurgery are not yet fully characterized, it appears that these risks are minimal. There are reported cases of radiosurgery associated ‘radiationinduced’ malignancies, but these reported cases are extremely rare.6,58–61 Much longer periods of follow-up must be investigated to fully appreciate the possible long term complications, as the development of new radiation-induced neoplasms requires decades to develop. A conservative estimate suggests this rate as 3% in 30 years.

The antiepileptic radiosurgery mechanism Although radiosurgery has been shown to reduce seizures in various forms of medically intractable epilepsies, the mechanism by which this abatement occurs is not clear. It has been suggested that radiation itself has a direct antiseizure effect. This effect has been purported to operate through several mechanisms. As glial cells are more radiosensitive than neurons, Barcia-Salorio proposed low-dose radiosurgery may reduce glial scar formation allowing increased dendritic sprouting, improved cortical reorganization and fewer seizures.15 Elomaa proposed the antiepileptic effect of radiation is mediated through effects of somatostatin.62 Although the clinical results of the most recent human studies suggest the therapeutic efficacy of radiosurgery is linked to necrosis of mesial temporal structures, proof for this concept would need to come from direct observation of tissue samples in patients where radiosurgery has controlled seizures. This is unlikely to occur, as only patients with persistent seizures are likely to undergo further open resective surgery. Surrogate markers of radiation effect such as imaging changes on MRI have thus far shown mixed results. Radiationinduced edema has become evident in most patients 9–15 months following radiosurgery. These changes are usually time-limited, they are often followed by focal atrophic changes. Thus, MRI changes may not be diagnostic of true radiation necrosis. The actual mechanism by which high-dose radiation reduces neuronal hyperexcitability will not likely be found from human studies. Although preclinical evidence and the results from two early human trials suggested control of seizures might be possible with doses of radiosurgery that were lower than those typically applied to tumors,16,19 recent case reports also describe the failure of low-dose radiosurgery to control seizures.22,50,51 While failure of seizure control is easy to identify, it is a much more difficult task to determine that this is due to an insufficient radiosurgery dose. The time dependence of radiosurgical effects is also a confounding factor that has not been fully explored. A consensus among different treating radiosurgical centers for when radiosurgical treatment has

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Radiosurgical treatment of epilepsy ‘failed’ has not yet been agreed upon.32 As noted, recent, prospective results suggest that radiosurgery may have results very similar to resection where ∼30% of patients will continue to have seizures.6 The reported failures of low-dose radiosurgery are case reports and as of yet do not demonstrate a failure rate of 30%. Furthermore, radiosurgery patients who did not show adequate seizure reduction commonly had radiation doses of 20 Gy or less, and these patients showed little evidence of radiation-induced necrosis in their pathologic specimens.22,50,51 Thus, the best evidence to date from human and animal experiments suggests that there is a steep doseresponse effect for seizure reduction, that some neuronal damage is required to produce seizure abatement, and that the dose required to eliminate seizures is very close to the absolute tolerability of human brain tissue.

Conclusions Recent data suggests radiosurgery is indeed effective at reducing epileptiform activity and seizures in several forms of medically intractable epilepsy. In animals, the low doses of radiation required to be therapeutic have not been shown to cause histologic changes, disruption of normal neuronal firing patterns or significant learning deficits. When multiple

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isocenters are employed, and animals are observed over longer time periods, the patterns of changes seen on MRI closely mimic those observed in human trials and histological analysis indicates that structural lesions are created. Animal studies have not yet proven if the antiepileptic effects of radiosurgery are due to tissue damage sufficient to cause functional ablation and necrosis or if seizure activity has been eliminated in still functional parenchyma. However, the available data suggest that it is necessary to produce changes on MRI consistent with tissue damage in order to eliminate seizures in humans. Recent prospective trials suggest that radiosurgery may be an effective and safe treatment for medically intractable epilepsy associated with MTS. Prospective trials with larger numbers of patients will be required to establish radiosurgery as a standard therapy for MTLE. Further promise is shown in expanding the utility of radiosurgery for seizure control in medically intractable epilepsy associated with cavernous malformations and hypothalamic hamartomas. Radiosurgery may prove to be especially appealing in treating lesions near eloquent cortex or deep seated lesions when open microsurgical resection may not be feasible without significant morbidity. As the true long-term toxicity of radiosurgery is not known, patients treated with this modality should be carefully followed.

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Barcia-Salorio JL, Barcia JA, Hernandez G, Lopez-Gomez L. Radiosurgery of epilepsy. Long-term results. Acta Neurochir Suppl 1994;62:111–13. Barcia-Salorio JL, Vanaclocha V, Cerda M, Ciudad J, Lopez-Gomez L. Response of experimental epileptic focus to focal ionizing radiation. Appl Neurophysiol 1987;50:359–64. Eisenschenk S, Gilmore RL, Friedman WA, Henchey RA. The effect of LINAC stereotactic radiosurgery on epilepsy associated with arteriovenous malformations. Stereotact Funct Neurosurg 1998; 71:51–61. Heikkinen ER, Heikkinen MI, Sotaniemi K. Stereotactic radiotherapy instead of conventional epilepsy surgery. A case report. Acta Neurochir (Wien) 1992;119:159–60. Heikkinen ER, Konnov B, Melnikov L et al. Relief of epilepsy by radiosurgery of cerebral arteriovenous malformations. Stereotact Funct Neurosurg 1989;53:157–66. Karlsson B, Kihlstrom L, Lindquist C, Ericson K, Steiner L. Radiosurgery for cavernous malformations. J Neurosurg 1998;88:293–7. Kawai K, Suzuki I, Kurita H et al. Failure of low-dose radiosurgery to control temporal lobe epilepsy. J Neurosurg 2001;95:883–7. Kida Y, Kobayashi T, Tanaka T et al. Seizure control after radiosurgery on cerebral arteriovenous malformations. J Clin Neurosci 2000;7 (Suppl 1):6–9. Kondziolka D, Lunsford LD, Flickinger JC, Kestle JR. Reduction of hemorrhage risk after stereotactic radiosurgery for cavernous malformations. J Neurosurg 1995;83:825–31. Kurita H, Kawamoto S, Suzuki I et al. Control of epilepsy associated with cerebral arteriovenous malformations after radiosurgery. J Neurol Neurosurg Psychiatry 1998;65:648–55. Kurita H, Suzuki I, Shin M et al. Successful radiosurgical treatment of lesional epilepsy of mesial temporal origin. Minim Invasive Neurosurg 2001;44:43–6. Lunsford LD, Kondziolka D, Flickinger JC et al. Stereotactic radiosurgery for arteriovenous malformations of the brain. J Neurosurg 1991;75:512–24. Mori Y, Kondziolka D, Balzer J et al. Effects of stereotactic radiosurgery on an animal model of hippocampal epilepsy. Neurosurgery 2000;46:157–65;discussion 165–8. Regis J, Bartolomei F, de Toffol B et al. Gamma knife surgery for epilepsy related to hypothalamic hamartomas. Neurosurgery 2000; 47:1343–51;discussion 1351–2.

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Regis J, Bartolomei F, Kida Y et al. Radiosurgery for epilepsy associated with cavernous malformation: retrospective study in 49 patients. Neurosurgery 2000;47:1091–97. Regis J, Bartolomei F, Rey M et al. Gamma knife surgery for mesial temporal lobe epilepsy. Epilepsia 1999;40:1551–6. Regis J, Bartolomei F. Comment on: failure of gamma knife radiosurgery for mesial temporal lobe epilepsy: report of five cases. Neurosurgery 2004;54:1404. Regis J, Hayashi M, Eupierre LP et al. Gamma knife surgery for epilepsy related to hypothalamic hamartomas. Acta Neurochir Suppl 2004;91:33–50. Regis J, Peragui JC, Rey M et al. First selective amygdalohippocampal radiosurgery for mesial temporal lobe epilepsy. Stereotact Funct Neurosurg 1995;64 (Suppl 1):193–201. Sutcliffe JC, Forster DM, Walton L, Dias PS, Kemeny AA. Untoward clinical effects after stereotactic radiosurgery for intracranial arteriovenous malformations. Br J Neurosurg 1992;6:177–85. Unger F, Schrottner O, Haselsberger K et al. Gamma knife radiosurgery for hypothalamic hamartomas in patients with medically intractable epilepsy and precocious puberty. Report of two cases. J Neurosurg 2000;92:726–31. Whang CJ, Kwon Y. Long-term follow-up of stereotactic Gamma Knife radiosurgery in epilepsy. Stereotact Funct Neurosurg 1996;66 (Suppl 1):349–56. Chen ZF, Kamiryo T, Henson SL et al. Anticonvulsant effects of gamma surgery in a model of chronic spontaneous limbic epilepsy in rats. J Neurosurg 2001;94:270–80. Maesawa S, Kondziolka D, Dixon CE et al. Subnecrotic stereotactic radiosurgery controlling epilepsy produced by kainic acid injection in rats. J Neurosurg 2000;93:1033–40. Herynek V, Burian M, Jirak D et al.Metabolite and diffusion changes in the rat brain after Leksell Gamma Knife irradiation. Magn Reson Med 2004;52:397–402. Liscak R, Vladyka V, Novotny J Jr. et al. Leksell gamma knife lesioning of the rat hippocampus: the relationship between radiation dose and functional and structural damage. J Neurosurg 2002;97:666–73. Betti OO, Munari C, Rosler R. Stereotactic radiosurgery with the linear accelerator: treatment of arteriovenous malformations. Neurosurgery 1989;24:311–21. Bien CG, Kurthen M, Baron K et al. Long-term seizure outcome and antiepileptic drug treatment in surgically treated temporal lobe epilepsy patients: a controlled study. Epilepsia 2001; 42:1416–21. Cascino GD. Clinical correlations with hippocampal atrophy. Magn Reson Imaging 1995;13:1133–6. Cascino GD. Structural neuroimaging in partial epilepsy. Magnetic resonance imaging. Neurosurg Clin N Am 1995;6:455–64. Engel J Jr. Update on surgical treatment of the epilepsies. Summary of the Second International Palm Desert Conference on the Surgical Treatment of the Epilepsies (1992). Neurology 1993;43:1612–17.

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Engel J Jr. Finally, a randomized, controlled trial of epilepsy surgery. N Engl J Med 2001;345:365–7. Garcia PA, Laxer KD, Barbaro NM, Dillon WP. Prognostic value of qualitative magnetic resonance imaging hippocampal abnormalities in patients undergoing temporal lobectomy for medically refractory seizures. Epilepsia1994;35:520–4. Spencer SS, Berg AT, Vickrey BG et al. Initial outcomes in the Multicenter Study of Epilepsy Surgery. Neurology 2003;61:1680–5. Cmelak AJ, Abou-Khalil B, Konrad PE, Duggan D, Maciunas RJ. Low-dose stereotactic radiosurgery is inadequate for medically intractable mesial temporal lobe epilepsy: a case report. Seizure 2001;10:442–6. Srikijvilaikul T, Najm I, Foldvary-Schaefer N et al. Failure of gamma knife radiosurgery for mesial temporal lobe epilepsy: report of five cases. Neurosurgery 2004;54:1395–402; discussion 1402–4. Nguyen D, Singh S, Zaatreh M et al. Hypothalamic hamartomas: seven cases and review of the literature. Epilepsy Behav 2003;4:246–58. Berkovic SF, Arzimanoglou A, Kuzniecky R et al. Hypothalamic hamartoma and seizures: a treatable epileptic encephalopathy. Epilepsia 2003;44:969–73. Delalande O, Fohlen M. Disconnecting surgical treatment of hypothalamic hamartoma in children and adults with refractory epilepsy and proposal of a new classification. Neurol Med Chir (Tokyo) 2003;43:61–8. Fohlen M, Lellouch A, Delalande O. Hypothalamic hamartoma with refractory epilepsy: surgical procedures and results in 18 patients. Epileptic Disord 2003;5:267–73. Maraire JN, Awad IA. Intracranial cavernous malformations: lesion behavior and management strategies. Neurosurgery 1995;37:591-605. Porter PJ, Willinsky RA, Harper W, Wallace MC. Cerebral cavernous malformations: natural history and prognosis after clinical deterioration with or without hemorrhage. J Neurosurg 1997;87:190–7. Ganz JC. Gamma knife radiosurgery and its possible relationship to malignancy: a review. J Neurosurg 2002;97:644–52. Kaido T, Hoshida T, Uranishi R et al. Radiosurgery-induced brain tumor. Case report. J Neurosurg 2001;95:710–13. Shamisa A, Bance M, Nag S et al. Glioblastoma multiforme occurring in a patient treated with gamma knife surgery. Case report and review of the literature. J Neurosurg 2001;94:816–21. Yu JS, Yong WH, Wilson D, Black KL. Glioblastoma induction after radiosurgery for meningioma. Lancet 2000;356:1576–7. Elomaa E. Focal irradiation of the brain: an alternative to temporal lobe resection in intractable focal epilepsy? Med Hypotheses 1980;6:501–3.

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Vagal nerve stimulation: experimental data S Chabardès, I Najm, and HO Lüders

Introduction Vagus nerve stimulation (VNS) is a worldwide applied technique for the treatment of intractable epilepsy that cannot benefit from resective surgery. Recent clinically-controlled trials have reported a 50% seizure control rate in about 30% of patients’. However, its efficacy seems to vary among teams and the type of patients who can benefit from this technique is so far unknown, despite more than 26,000 people treated worldwide. Moreover, the mechanisms of action are still not fully understood despite increasing interest in this field. The purpose of this chapter is to give a critical overwiew of the experimental data existing in this field together with our experiments performed on rats at the Cleveland Clinic Foundation.

On the efficacy of VNS against seizures induced in animals Original reports At the end of the eighties, several teams reported the effect of repetitive VNS on seizure activities in generalized, or partial, secondary generalized models of epilepsy. It was based on preliminary observation2,3 which indicated that low-voltage vagus nerve stimulation could significantly reduce spikes from a neocortical focus produced by topical application of strychnine. First, Zabara et al. reported4,5 their experience in a chemically-induced generalized model of epilepsy using intravenous injection of strychnine in 20 dogs. They found that electrical stimulation of unilateral vagus nerve at a frequency that ranged from 30–80 Hz could abort seizures within usually less than 1 sec. This effect could last several minutes (up to 20 min) after the end of stimulation. These original very exciting results should be balanced at several levels: first, the seizure activity was not directly monitored by EEG recording, but only by EMG electrodes implanted bilaterally in both gastrocnemius muscles. Second, the authors monitored the EKG and respiration and used them as markers to asses that electrical current was properly delivered to the VN. They showed that in each case, there was a rapid but consistent bradycardia at the onset of the stimulation period together with hyperventilation. As the EEG was not monitored, one could easely argue that the powerfull cessation of ‘EMG seizure’ was in fact a nonspecific response to a severe vegetative dysfunction.

In 1990, Lockard et al.6 were the first to report the effect of VNS on a monkey model in a robust, well-designed study. They used four animals, all equipped with an epidural EEG screw and who exhibited chronic, secondary generalized, spontaneous partial motor seizure obtained after subpial injection of alumina gel in the left central cortex. Seizure activity and severity was assessed for several months with chronic video-EEG monitoring. Left VN was stimulated in two animals, and right VN was stimulated in the remaining two. Each constant-current stimulation was delivered at the onset of every spontaneous seizure and lasted for the whole seizure. This stimulation period lasted 2–6 weeks preceded and followed by at least 2 weeks of no stimulation period (baseline). Stimulation parameters were as follows: frequency from 50–250 Hz, pulse width from 0.5–0.6 ms. Two monkeys became nearly seizure free during the stimulation period, while two others were not ameliorated. According to the authors, VNS had no consistent effect on either seizure severity or EEG interictal spikes and concluded that if VNS could influence ‘the epileptogenic process’, its efficacy was ‘still in question’. At the same time, Woodbury and Woodbury7 reported the effect of VNS in the Pentylène-tétrazole (PTZ) and the 3-mercaptoproprionate (3-MP) model in rats which creates convulsive status. In an additional experiment they also used maximal electroshock seizure (MES) in wakeful rats. They showed that VNS was effective in preventing seizure, but that VNS could not terminate ongoing seizures in both PTZ and 3-MP models. They found that delay between onset of seizure, onset of stimulation, and seizure duration was significantly positively correlated. In the MES model, the authors found that VNS could not change the total duration of seizure but could prevent the tonic phase when C fibers of VN could be properly stimulated.8 The general conclusion of the authors was that VNS was effective in these three models, but the design of the study did not allow random stimulation periods. Moreover, the fact that rats which were not improved (number was not given) were all suspected not to have received the appropriate electrical stimulation properly because of technical problems is questionable as the anatomical study of VN integrity was not described in the paper. Later, McLachlan9 reported experimental data on anesthetized rats rendered epileptic by application of local penicillin (PG) in the motor cortex and ip injection of PTZ in an attempt to quantify the effectiveness of VNS on PG-induced 1179

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interictal spikes and the tonic-clonic phase of PTZ-induced seizure. The vagus nerve was stimulated using a grass system with biphasic square-wave pulses delivered at the onset of seizures. The stimulator was set at the following parameters: 0.01–1.2 mA, 20 or 50 Hz, 0.5 ms pulse duration, 1–20 s in duration. Mean spike frequency decreased significantly from 42 ± 11 to 28 ± 11 (mean reduction: 33%, p50% reduction of all seizures).36 These findings were reproduced by Hallbook et al. in children, where VNS was found to reduce IEDs, especially during REM, delta sleep, and EEG seizures. Again, there was evidence for a correlation between reduction of IEDs and effect on seizures.37

Figure 127.2 (a and b) This schema illustrates left vagus nerve afferents synapsing at several sites in the dorsal medulla, followed by projections from the pons via ascending vagosolitario-parabrachial pathways. Abbreviations: NTS – Nucleus tractus solitarius; PBN – parabrachial nucleus; PAG – periaquaeductal gray; CNA – central nucleus of the amygdale; PVN – periventricular nucleus of the hypothalamus; VPM – ventral posteromedial nucleus of the thalamus; STN – spinal trigeminal nucleus; VPL – ventral postero-lateral nucleus of the thalamus; PCG – post central gyrus; IPL – inferior parietal lobule; KFN – Kölliker-Fuse nucleus; LC – locus coeruleus; RMN – raphe magnus nucleus; PBN – parabrachial nucleus; AP – area postream; RF – reticular formation; DMN – dorsal motor nucleus of the vagus; NA – nucleus ambiguous.

synchronization of epileptiform activity, progressive increase in duration of spike-free intervals, and progressive decrease in duration and frequency of spike and wave activity with time. Patients with less frequent interictal epileptiform discharges also had a progressive decrease in the number of spikes on EEG with time, but did not show obvious synchronization or clustering of spikes. This alternating synchronization followed by more prominent desynchronization of EEG was felt to represent a potential mechanism for the action of VNS.35 Kuba et al. also reported reduction in the number of interictal epileptiform discharges (IEDs) during the period of stimulation and the interstimulation period – as compared to

Evoked potentials Animal studies showed that VNS could elicit evoked potentials in the cortex,6,8,19,38 thalamus,6,19,38 hypothalamus,7 and cerebellum.9 The effect of chronic VNS on brainstem auditory evoked potentials and somatosensory evoked potentials in humans was investigated by Naritoku et al. This study demonstrated interval increase between cervicomedullary and thalamocortical somatosensory evoked potentials in three VNS patients (as compared to baseline and to normal subjects). The authors suggested that vagus nerve stimulation alters neuronal networks outside of the brain stem vagus system, and highlighted the potential use of somatosensory evoked responses in titrating VNS therapy. However, it is difficult to draw meaningful conclusions from these series given the small number of VNS responders.39 Cerebral evoked responses following direct electrical stimulation of the vagus and esophagus were compared in eight epileptic subjects and with those recorded after esophageal stimulation in 12 healthy nonepileptic controls. Direct vagal stimulation was performed using a left cervical vagal pacemaker, which is used in the treatment of epilepsy. Esophageal stimulation was obtained with the use of an esophageal assembly incorporating two electrodes positioned 5 and 20 cm orad to the lower esophageal sphincter. Another study compared evoked responses after direct electrical stimulation of the vagus nerve with a left vagal pacemaker and of the esophagus with two electrodes placed with a manometric assembly on the esophageal mucosa in eight patients with epilepsy undergoing esophageal stimulation and in 12 healthy nonepileptic controls.40 Similar to the study by Naritoku et al. conduction velocity of the afferent response was found to be slower (7.5 m/s) in epilepsy patients as compared to healthy controls (10 m/s).40 In contrast, a third study, which investigated the effect of VNS on visual, auditory brainstem, and long latency cognitive evoked potentials, did not detect any significant changes.41 Neurotransmitters Hammond et al. reported increases in the metabolites of dopamine and serotonin – homovanillic acid and 5-hydroxyindoleacetic acid – in three out of six patients.42 In addition a decrease in aspartate was seen in five of the six patients. Changes were associated with a decrease in seizure frequency.42 Another study analyzed CSF neurotransmitters in sixteen patients before and 3 months after VNS. Decreases in the excitatory amino acid, aspartate, and increases in its inhibitory counterpart GABA were reported. Additionally, correlations between seizure reduction and increases in asparagine, phenylalanine, phosphoethanolamine, alanine and tryptophan concentrations were observed.43 Cerebral blood flow measurement by PET Garnett et al. were the first to investigate the effect of VNS on cerebral blood flow by means of H215O PET in five patients

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Vagus nerve stimulation: human studies with epilepsy. Increased blood flow was demonstrated in the left anterior thalamus and the cingulate gyrus. These results may have been confounded by the fact that two out of the five patients had seizures during the PET scan.44 As part of the manufacturer (Cyberonics) funded E04 trial, Ko et al. investigated three patients with H215O PET blood flow functional imaging. Left sided VNS resulted in activation of the right thalamus, right posterior temporal cortex, left putamen, and left inferior cerebellum.45 Henry et al. measured VNS-induced cerebral blood flow (CBF) effects after immediate and prolonged VNS in ten patients by performing H215O PET scans within one day after the onset of stimulation and by repeating the study after a period of 3 months.32,46 Most subcortical sites activated during immediate stimulation were also activated after 3 months. During both times, VNS-induced CBF increases were found in similar locations in the bilateral thalami, hypothalami, inferior cerebellar hemispheres, and right postcentral gyrus. Cortical modification of CBF was less prominent after three months (including decreased CBF in bilateral hippocampal, amygdalar, and cingulate areas and increased bilateral insular CBF).32 Interestingly seizures were found to be better controlled, when cortical blood flow decreased as a result of VNS.32 These authors postulated a relationship between seizure reduction and decreases in cortical CBF.32 SPECT and perfusion Ring et al. used (99m)Tc-HMPAO single photon emission tomography (SPECT) to investigate the effects of VNS on regional cerebral activity in seven patients, who had been receiving vagal nerve stimulation for a period of at least 6 months. VNS was found to be associated with decreased activity in left and right medial thalamus.47 Vonck et al. investigated 12 patients by means of a 99mTc SPECT with a single-day split-dose protocol before and immediately after initial stimulation and noted a decrease in left thalamic CBF after the onset of stimulation. There was no evidence to suggest a correlation between hypoperfusion and seizure reduction.48,49 Another study by the same group in a larger population of 23 patients showed evidence of deactivation in the left thalamus, right parahippocampal gyrus, and right hippocampus during initial stimulation with VNS.50 In this latter study, a correlation between, initial stimulation changes in the right amygdala and therapeutic response was reported.50 Another group confirmed the presence of decreased perfusion in the contralateral thalamus and cingulate and also reported additional areas of deactivation involving the ipsilateral brain stem, cingulate, amygdala and hippocampus.51 Functional MRI studies Functional MRI studies during VNS in five patients demonstrated the most robust activation in both thalami (left greater right) and in the insular cortices bilaterally.52 Additional activations of the ipsilateral basal ganglia, the postcentral gyri, the right posterior superior temporal gyrus, and the inferomedial occipital gyri were noted.52 Liu et al. investigated five patients with complex partial seizures using blood oxygenation level dependent functional magnetic resonance imaging (BOLD fMRI). Activation of the frontal and occipital lobes was seen in all patients. However, thalamic activation was only observed in the two patients with reduced seizure frequency.53

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Stimulation paradigms VNS parameters that can be manipulated include current intensity in milliamperes, frequency, pulse width, duration of stimulation and pattern of stimulation (stimulation paradigm). Therapeutic stimulation parameters for the E03 and E05 trials consisted of output current 0.5–3.5 mA, frequency 20–50 Hz, pulse width 500 µs, and stimulation on-time of 30–90 seconds followed by off-time of 5 minutes. The active ‘control’ group underwent ‘low-dose’ stimulation with output current 3.5 mA, frequency of 1–2 Hz, pulse width of 130 µs and stimulation on-time of 30 seconds with off-times ranging from 90–180 minutes. Frequency FDA recommended stimulation frequencies between 20 and 30 Hz. Lower frequency stimulation at 5 Hz is associated with reduced brain stimulation, as evidenced by fMRI studies comparing 5 Hz and 20 Hz stimulation protocols.54 Furthermore, low frequency stimulation may facilitate stimulation of slow conducting C-fibers and lead to increased side effects.55,56 Stimulation frequencies of 50 Hz and higher may result in irreversible vagal nerve fiber damage.55 Intensity Currently available stimulation intensities range from 0.25 mA to 3.5 mA.57 Currents between 0.8 mA and 2 mA are usually considered effective.56 Stimulation can be increased incrementally by 0.25 mA – usually every 1–2 weeks – up to 2 mA. Stimulation (with a fixed pulse width) first produces depolarization of the large myelinated fibers with subsequent involvement of smaller myelinated and lastly unmyelinated fibers as intensity increases. Threshold for stimulation of fast, myelinated A fibers is 0.02–0.2 mA, for B fibers 0.04–0.6 mA and for unmyelinated C-fibers 2 mA and above.58 The initial hypothesis that therapeutic VNS effects are related to depolarization of unmyelinated C-fibers has been disproved by Krahl et al.59 Selective destruction of C fibers with capsaicin did not influence the antiepileptic effect of VNS in a pentylenetetrazol seizure model in rats.59 Stimulation-induced side effects may increase with rising current delivery (either increased intensity or widened pulse width). Pulse width Available pulse widths include 130 µs, 250 µs and 500 µs. Usual settings include 500 and 250 µs. Increase of the pulse width leads to increased delivery of current, although this increase is not linear.56 Comparison of different pulse widths (130 µs, 250 µs, or 500 µs) in fMRI studies showed that fMRI activations were greater with pulse widths of 250 and 500 µs – compared with the shorter pulse width of 130 µs – but not significantly different from each other; fMRI deactivation was greater for pulse widths of 130 µs and 250 µs as compared to the longer pulse width of 500 µs.60 Stimulation interval Standard stimulation intervals consist of a 30 second on and a 5 minute off period. It is recommended that duty cycles do not exceed 50% of the complete stimulation paradigm in order to prevent nerve injury.55,61 Some patients may experience better seizure control with faster cycles. DeGeorgio retrospectively

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analyzed the effects of device parameter changes on seizure frequency in 154 subjects, who completed the long-term XE5 study. Comparisons were performed for the three most common off time periods of 3, 1.8, and 1.1 min. A change in off time to 1.1 min resulted in significant improvements in efficacy in a subgroup of VNS-resistant patients. A median seizure reduction from 21% before the change in off time, to 39% after the decrease in off time was observed in this subgroup of patients, who were initially felt to be VNS resistant.62 However, other investigators have not observed improved seizure control with shortened off periods.63 Stimulation paradigms These include open loop and closed loop stimulation. Open loop stimulation follows a certain stimulation pattern without consideration of seizures. Closed loop stimulation attempts to respond to the first warning symptoms of a seizure. In the preapproval studies (E03, E04, and E05) the device was programmed to deliver current to the treated group every 5 minutes for 30 seconds, regardless of seizure activity (open loop stimulation). Additionally, patients with a history of auras were encouraged to place a magnet over the VNS, when sensing that seizures were about to occur (closed loop). Adjustment of parameters After VNS implantation many centers do not start stimulation in the immediate post-operative period and for up to 5–14 days post-op. Other centers (including ours) prefer to program the device in the operating room. Initial settings usually include patterns of 30 second stimulation (on-time) every five minutes (off-time). Output current is usually increased in 0.25 mA steps. Adjustment of stimulation parameters may be indicated in patients under the age of 12 years. Koo et al. performed intraoperative investigations during implantation of VNS in 21 patients aged 4–31 years and recordings made from the rostral end of the vagus nerve. These authors demonstrated that threshold current is higher in young children as compared to adults indicating that a higher current or larger pulse width is required in children in order to achieve equivalent effects.64

Efficacy of VNS Randomized, double blind studies: E03 and E05 Two randomized placebo-controlled trials examined VNS prior to FDA approval, the E03 and the E05 trial. The first multicenter, double blind, randomized controlled trial, the E03 trial, included 114 patients over the age of 12 years with predominantly partial seizures and compared baseline seizure rates to those observed after stimulation in a ‘high’ and ‘low’ stimulation group.31,65–67 The second multicenter, double-blind, randomized controlled study (E05) included 199 patients with complex partial seizures, who were followed for a period of 3 months. Again, patients were split into two groups with ‘high’ and ‘low’ stimulation: 28% of patients in the high stimulation group experienced seizure reduction as compared to 15% in the low stimulation group.68 Inclusion criteria Patients were included in the two randomized, controlled, preapproval trials if they were between 12 and 60 years old, if

they had at least six seizures per month and if they were being treated with zero to three AEDs. In the E05 study, patients were also required to have complex-partial seizures. Stimulation paradigms As mentioned above, both of these trials compared two different VNS stimulation paradigms, ‘high’ versus ‘low’ stimulation for the treatment of partial seizures. In the E03 trial settings in the high stimulation group included an output current of 0.5–3 mA, a frequency of 20–50 Hz (control=1–2 Hz), pulse width of 500 microseconds (control=130 microseconds), on time of 30–90 seconds (control=30 seconds), and off periods of 5 minutes (control=90 minutes). In the E05 trial, settings in the high stimulation group consisted of an output current of up to 3.5 mA, a frequency of 30 Hz (control=1 Hz), pulse width of 500 microseconds (control=130 microseconds), on time of 30 seconds and off periods of 5 minutes (controls=180 minutes). Design and timeline Baseline monitoring of seizure frequency was performed over a 12–16 week interval. During this baseline, preimplantation interval, seizure frequency was recorded and AED changes were only allowed in cases of toxicity or low levels. Eligible patients, who fulfilled all baseline criteria, were subsequently implanted. Randomization to either ‘high’ or ‘low’ frequency stimulation was completed 2 weeks after implantation. During the following 2 weeks after initiation of VNS treatment, therapeutic stimulator settings were increased as high as tolerated. On the other hand, the low-stimulation group received stimulation intensities that were increased to the level of perceptible stimulation. Treatment results and seizure frequency was monitored during the following twelve weeks. Results In E03, 125 patients were initially enrolled and 114 of those were implanted. Fifty-four patients were randomized to the high stimulation group, whereas 60 patients underwent low stimulation. In E05, 199 out of 254 initially enrolled patients fulfilled the eligibility criteria and proceeded to implantation. In the E05 trial, 95 patients were randomized to the high-stimulation group and 103 to the low-stimulation group; in addition one patient was excluded due to device infection. The primary outcome parameter was change in seizure frequency during treatment as compared to baseline. Seizure frequency reduction in the E03 trial was 24.5% in the high stimulation group versus 6.1% in the low stimulation group (p12 y/o

Prospective; open-label; not controlled Prospective; open-label; not controlled

Prospective; open-label; not controlled Partial seizures; age 19–47 y/o Prospective; open-label; not controlled

Partial and generalized seizures (EO1–EO5 trials) 47 focal epilepsy; 9 idiopathic generalized epilepsy; 8 LGS Partial seizures with alteration of consciousness; >12 y/o (EO5/XE5) Children with LGS (6–20 y/o)

Partial seizures with alteration of consciousness; >12 y/o (XE5 trial) Complex partial seizures 17–44 y/o

Complex partial seizures (EO3) Complex partial seizures

114 (67) Complex partial seizures (EO3)

Design

Median seizure frequency reduction by 32% 10 fold increase in the mean number of 14-day seizure–free periods Median seizure frequency reduction was 45%

Seizure reduction by 50% in 50% of patients

Outcome parameter

164/199 (82.4%)

8/10 (80%); unchanged AEDs

67 out of 114 continued study; complete data on 50/67 (74.6%) 14/114 (lack of efficacy)

Completion rate/Drop-outs

2 years

4 years (median 56 months) 6 months

2 years

1 year

13/15 (86.6%)

17/19 (89%)

164/195 (84%)

Seizure frequency reduction 47/51 (92.1%) by 50% in 46.8% Seizure reduction by 50% 23/30(76.6%) in 61%

Median seizure reduction 45%; seizure reduction by 50% in 34% Mean seizure reduction was 20.6% Mean seizure frequency reduction 63%

Average 29 months Mean complex partial 15/25 (60%) (up to 40 months) seizure frequency reduction 42.8% 3 years Seizure reduction by 50% 440 entered long-term trial; in 43%; median seizure 93/454 at 3 years (20.5%) frequency reduction 44% Average 20 months Seizure reduction by 50% 57/64 (89%) (up to 5 years) in 45%

15 months

50 months

1 year

16-18 months

Follow-up (maximum)

3:34 PM

195

1994

George et al.66

n

3/19/08

DeGiorgio et al.77 2000

Year

Patient population (seizure types, epilepsy, or syndrome)

Long-term follow up after VNS

Author

Table 127.2

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Vagus nerve stimulation: human studies 1195

36

49

2005

2005

Majoie et al.81

Halböök et al.37

Rycklicki et al.112 2006

Alexopoulos et al.98

2006

15

2005

Huf et al.135

19

40

26

2004

Spanaki et al.82

48

prospective

Children 18 mos to 18 y/o; Prospective; open-label; 9 LGS; 27 focal epilepsy; not controlled Tuberous sclerosis (3); MCD (6); Prospective; encephalitis (2); mitochondrial disease (2); hypothalamic hamartoma (1); head trauma (1); generalized (4); unknown (34); 1–16 y/o

MCD (5); encephalitis (1); HIE (5); unknown (4); age 4–17 y/o

Head trauma (10); encephalitis (4); Prospective; open-label; febrile convulsions (1); not controlled unknown (33); 13–58 y/o at implant Partial epilepsy (24); ‘atypical Retrospective, chart review absence’ epilepsy (1); generalized epilepsy (1) Low IQ patients (50%. With a stimulation protocol slightly changed (1 Hz) 5 ×1200 pulses, Fregni and colleagues (2006) reported significant reduction in seizure frequency when stimulated focally the focal lesion. EEG pattern were also reduced. There is another study in which four subgroups were compared without a placebo condition: patients with focal epilepsies and patients with non-focal epilepsy were treated with focal stimulation and unfocal stimulation, respectively, both subgroups were subdivided in two groups with long stimulation procedure (total pulses 3000) and short stimulation (1500 pulses). There was a non-significant reduction in seizure frequency by 13.9% with a non-significant differences between long and short stimulation (−23 vs. −3%). But there was no difference at all between focal and non-focal stimulation types.

rTMS for treatment of epilepsy – where are we now? So far, only some 80 patients with epilepsy have been included in studies using rTMS as a treatment strategy. This is far below the critical number of patients needed for drawing substantial conclusions on the antiepileptic efficacy of rTMS. Most of the uncontrolled studies indicate a positive effect showing reduction in seizure frequency either during or for a short time after rTMS of up to several weeks. Mainly low-frequency rTMS with 0.3–1.0 Hz was used, mostly with stimulus intensity just below motor threshold; the number of stimuli and the period over which treatment was performed showed large variation. However, the two controlled trials existing so far failed to confirm these positive results or showed only mild and short-lived effects. In the following, with the hope of learning from disappointments in the past, we discuss some aspects that might be important for optimization of rTMS trials in the future.

Why did controlled studies fail to show a therapeutic effect of rTMS in epilepsy patients? The antiepileptic effect of rTMS does not exist? The worst and simplest possible explanation for the failures of rTMS studies would be that the assumption of an antiepileptic effect from rTMS is wrong. Although a large number of animal studies and slice studies showed that repetitive electrical stimulation is capable of modulating neuronal activity and

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Repetitive transcranial magnetic stimulation that a special type of repetitive stimulation can reduce epileptic activity, this need not hold true for magnetic stimulation ... and need not hold true in humans. Moreover, LTP and LTD are physiological phenomena demonstrated in small and circumscribed neuronal network areas, but they might only play a minor role in epileptogenesis and ‘antiepileptogenesis’. These phenomena may in humans be counterbalanced in the intact, albeit epileptic, brain if induced by rTMS at all. However, although a number of scenarios could be drawn to explain a nonexistent antiepileptic effect of rTMS, there is a large body of evidence that the effect actually exists. For the future, more studies are needed to find and explain the exact physiological mechanisms of the missing links between animal and human studies. The stimulation type was not optimal Two basically different rTMS techniques have been used in the studies described above. On the one hand, focal stimulation can be used to affect the epileptic focus, while on the other, unfocal stimulation may be chosen to reduce the cortical excitability of the neuronal network involved in the propagation of seizure activity. Taking into consideration the technical aspects discussed at the beginning of the chapter for both paradigms, we must conclude that there is no definitive answer so far to what direction and what orientation is needed to obtain optimal effects. From the majority of the treatment studies mentioned above, focal stimulation appears more advantageous, even in view of the two unsuccessful controlled studies by Theodore et al. and Tergau et al.100,102 A positive effect could have been missed due to incorrect orientation and/or incorrect direction of the focal stimulation. Another aspect may support the advantage of focal stimulation. It is known that focal stimulation at threshold intensities only activates a small area of cortex lying some 3 cm beneath the skull. It may be assumed that a mesial epileptic focus cannot be achieved effectively. This could be an explanation for the lack of better results in the study by Theodore et al., in which 10 of the 24 patients had a temporo-mesial epileptic focus. A subgroup analysis showed that neocortical epilepsies responded much better (24±22% seizure reduction) than mesial epilepsies (–11±28%). This difference, however, was not significant, probably due to the small sample size. Support for the hypothesis of superiority of focal stimulation is presented by the two placebo-controlled studies where focal stimulation showed seizure reduction110 while unfocal did not (Cantello et al.). Nevertheless a direct comparison of those two stimulation types failed to show significant effects.111 But also the unfocal stimulation concept may have some support. Brain imaging as well as neurophysiological studies showed that brain areas remote from the TMS stimulation site can be modified.103–106 However, it must be admitted that induced remote effects could lead to more contrary effects than intended, since inhibition of inhibitory neurons in the vicinity of the epileptic focus could boost epileptic activity regardless of focal or unfocal stimulation. Such a proepileptogenic effect has not been obtained so far but it may be discussed whether under certain circumstances there is a counterbalance of antagonistic effects. Specific study protocols need to be performed on suitable epilepsy syndromes to investigate further the influence of stimulation type.

1213

The stimulation parameters were not optimal In most of the studies, low-frequency stimulation between 1.0 and 0.3 Hz has been used with trains of up to 1000 stimuli per session and with several sessions over days and even weeks. While selection of the frequency is based on observation of rTMS effects on motor cortex excitability, the number and intensity of stimuli was chosen arbitrarily. No systematic studies have been performed to compare stimulation protocols that differ in these parameters. Regarding the repetition of sessions, there is evidence that a consolidation and/or magnification of long-term effects might occur when trains are repeated the next day, but further studies are needed to evaluate protocols with daily, biweekly stimulation or any other repetition rate. Optimal protocols might be different for different individuals. Moreover, it is fairly unknown whether the separation between the two obviously contradictory modifications of cortical excitability, facilitation and inhibition, is fixed at a certain stimulation frequency. Indeed, a couple of studies demonstrated a possibly large inter-individual variability with regard to susceptibility to inhibitory and excitatory rTMS.107 In addition, it is not clear whether the results with the motor cortex can be seen as generally valid for all brain regions. Nevertheless, it is well accepted in general that activation is more likely induced when higher frequencies are used and inhibition is yielded by low frequencies. This seems to be confirmed by a PET study, showing that high-frequency led to an increase of regional cerebral blood flow (rCBF) in the stimulated brain areas, whereas under low-frequency the rCBF decreased.108,109 The patient selection was not optimal The epilepsy syndrome and related factors such as focus localisation, pathology, medication, duration of disease, and seizure types may be of importance for the success of rTMS treatment. Studies so far indicate that patients with focal epilepsies due to cortical dysplasias represent and optimal patient population for rTMS. This could be explained by technical characteristics (see above) but it could also be a matter of the type of cortical lesion. To investigate this further, different types of epilepsies with circumscribed cortical pathology should be compared using identical stimulation protocols. Furthermore, the patients treated so far have been mostly drug-resistant, which means that they are a negative selection of subjects who had failed any other treatment strategy. To discover the true potential of rTMS, patients who are not drug resistant should also be studied. Finally, the number of patients was much too small to demonstrate significant effects. The expected effects could have been overestimated The impression derived from initial studies is that rTMS induces long-term effects outlasting the stimulation by days and weeks. There is, however, no evidence that any other intervention – not pharmacological treatment nor stimulation procedure – can induce therapeutic after-effects of such duration. So, why should rTMS be an exception? Moreover, physiological studies on the motor cortex showed after-effects of much shorter duration. For most of the other types of brain stimulation, even for the vagus nerve stimulator (see Chapter 127),

8

7

Open trials Tergau et al.91

Fregni et al.92

Kinoshita et al.93

Case reports Menkes et al.95 1

9cm-round

Over dysplasia 9 cm-round

Over Figure-ofcerebellar eight hemisphere

Over focus

Figure-ofeight

9 cm-round

Monophasic

Monophasic

?

?

Monophasic

Pulse

95%

90%

90%

100%

100%

0.5

5 Hz

0.9 Hz

0.5

0.33

Frequency (Hz)

810

600

1000

3.33 min

100

2 x 10 sec 100

15 min

20 min

25 min

Duration

Number of pulses per session

8

20

10

1

5

Number of sessions

8100

600

5000

Total num. of stimuli

Four weeks 800

Four weeks 2000

5 days

1 day

5 days

Treatment period

70% reduction in seizure frequency; 77% reduction of spikes

38.6% reduction in seizure frequency, four week post rTMS, significant 46.4% and 42.1% significant reduction in epileptic discharges at 15 and 30 days post rTMS57.3% and 52.1% significant reduction in seizure frequency at 15 and 30 days post rTMS Overall seizure reduction by 19.1% over two weeks post rTMS, with 35.9% reduction of complex-partial seizures and 7.4 reduction of simple-partial seizures. No significant effect 54.1% seizure reduction over four weeks during rTMS but no effect after rTMS

Effect

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Over dysplasia

Over vertex

Coil

Intensity (% of motor threshold)

3/19/08

Brighina et al.94 6

9

Authors

Stimulation site

Survey on rTMS studies in epilepsy patients

1214

Num.of pat.

Table 129.1

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Over dysplasia Figure-of-eight?

Over focus sham

Misawa et al.98 1

Controlled trials Theodore 24 et al.100 ?

120%

90%

128%

1.0

0.5

20

1.0

0.5

900

100

15 min

3.33 min

900

100

15 x 2 sec 600

15 min

3.33 min

14

1

1

1

8

1 week

Once

Once

Once

12600

100

600

900

Four weeks 800

Continued

Over 2 weeks post rTMS: 16% (active), 1% (placebo) seizure reduction; not significant Over 8 weeks post rTMS: 4.5% (active), –0.4% (placebo) seizure reduction; not significant

Reduction by 31–42% in two patients with single focal dysplasia during as well as after rTMSNo seizure reduction in two patients with multiple foci Number of myoclonic jerks was was reduced to 33%, jerk-related spikes were reduced in amplitude; number of jerk-related spikes did not change Reduction of hyperperfusion in of epileptogenic focus in the two patients with epilepsia partialis continua; In one patient seizure stopped for 24 h, one patient showed only minimal improvement Epilepsia partialis continua in hand and arm was abolished over 2 months after single rTMS trial. Results were reproduced in the same patient

3:36 PM

Monophasic

90%

90%

3/19/08

Figure-ofeight?

Over Figure-ofepileptogenic eight region

Graff2 Guerrero et al.99

Biphasic

Over Figure-ofperirolandic eight area

1

Monophasic

Rossi et al.97

Figure-ofeight

Over dysplasia

Daniele et al.96 4

9781841845760-Ch129 Page 1215

Repetitive transcranial magnetic stimulation 1215

17

21

Authors

Tergau et al.102

Fregni et al. 2006

Cantello et al. 2007

43

Round

Round

Unfocal

Vertex

Figure-ofeight

Fokal over lesion

Figure-ofeight

9 cm-round

Coil

Bipghasic

? ? ? ?

?

monophasic

Pulse

100%

100% 100% 100% 100%

100%

100%

Intensity (% of motor threshold)

Hz Hz Hz Hz

0.3 Hz

0.5 0.5 0.5 0.5

1 Hz

0.33 1.0 0.66 sham

Frequency (Hz)

55.5 min

5 min 10 min 5 min 10 min

20 min

50 min 16.6 min 25 min

Duration

1000

300 600 300 600

1200

1000

Number of pulses per session

5

5 5 5 5

5

5

Number of sessions

5

5 5 5 5

5 days

5 days

Treatment period

5000

1500 3000 1500 3000

6000

5000 5000 5000

Total num. of stimuli

Approx. 40% seizure reduction during stimulation for 0.33Hz condition, no seizure reduction for any other type or time period; no significant difference to placebo Significant reduction of seizure frequency over two months and significant reduction of epileptiform EEG discharges over 2 weeks Non-significant reduction in seizure frequency compared to baseline (−13.9%); long stimulation showed unsignificantly more reduction( −23%) compared to short (-3%); focal was not different from unfocal Significant reduction in spike frequency Non-significant reduction −15%) in verum group (placebo −9%); non-significant reduction in spike frequency (−50% in 12/38 patients)

Effect

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Over lesion (cortical malformation)

Over vertex

Stimulation site

3/19/08

Joo et al. 2007 35

Num.of pat.

Survey on rTMS studies in epilepsy patients—cont’d

1216

Table 129.1

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Page 1217

Repetitive transcranial magnetic stimulation a higher repetition rate is described as effective. Long-term studies are needed in which rTMS treatment is performed over weeks and months, like other treatment strategies.

Conclusion Repetitive TMS is a promising tool to modulate cortical excitability. Under certain circumstances rTMS seems to have

1217

antiepileptic properties strong enough to reduce epileptic activity in humans. rTMS at present is certainly not a procedure that could replace pharmacological or surgical treatment if applicable. Nevertheless, rTMS is safe, is a noninvasive technique and can be administered easily. Thus rTMS in the future may broaden the spectrum of therapeutic alternatives in epilepsy treatment. To achieve this goal, optimized protocols need to be developed, patient selection has to be improved and therapeutic effects should be confirmed in large controlled trials.

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Hufnagel A, Elger CE, Durwen HF et al. Activation of the epileptic focus by transcranial magnetic stimulation of the human brain. Ann Neurol 1990;27:49–60. Schuler P, Claus D, Stefan H. Hyperventilation and transcranial magnetic stimulation: two methods of activation of epileptiform EEG activity in comparison. J Clin Neurophysiol 1993;10:111–5. Dhuna A, Gates J, Pascual-Leone A. Transcranial magnetic stimulation in patients with epilepsy. Neurology 1991;41:1067–71. Jennum P, Winkel H, Fuglsang-Frederiksen A et al. EEG changes following repetitive transcranial magnetic stimulation in patients with temporal lobe epilepsy. Epilepsy Res 1994;18:167–73. Schulze-Bonhage A, Scheufler K, Zentner J et al. Safety of single and repetitive focal transcranial magnetic stimuli as assessed by intracranial EEG recordings in patients with partial epilepsy. J Neurol 1999;246:914–9. Hufnagel A, Elger CE, Klingmuller D et al. Activation of epileptic foci by transcranial magnetic stimulation: effects on secretion of prolactin and luteinizing hormone. J Neurol 1990;237:242–6. Chen R, Gerloff C, Classen J et al. Safety of different inter-train intervals for repetitive transcranial magnetic stimulation and recommendations for safe ranges of stimulation parameters. Electroencephalogr Clin Neurophysiol 1997;105:415–21. Wassermann EM, Grafman J, Berry C et al. Use and safety of a new repetitive transcranial magnetic stimulator. Electroencephalogr Clin Neurophysiol 1996;101:412–7. Jahanshahi M, Ridding MC, Limousin P et al. Rapid rate transcranial magnetic stimulation – a safety study. Electroencephalogr Clin Neurophysiol 1997;105:422–9. Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5–7, 1996. Electroencephalogr Clin Neurophysiol 1998;108:1–16. Bridgers SL. The safety of transcranial magnetic stimulation reconsidered: evidence regarding cognitive and other cerebral effects. Electroencephalogr Clin Neurophysiol Suppl 1991;43:170–9. Little JT, Kimbrell TA, Wassermann EM et al. Cognitive effects of 1- and 20-hertz repetitive transcranial magnetic stimulation in depression: preliminary report. Neuropsychiatry Neuropsychol Behav Neurol 2000;13:119–24. Koren D, Shefer O, Chistyakov A et al. Neuropsychological effects of prefrontal slow rTMS in normal volunteers: a double-blind shamcontrolled study. J Clin Exp Neuropsychol 2001;23:424–30. Speer AM, Repella JD, Figueras S et al. Lack of adverse cognitive effects of 1 Hz and 20 Hz repetitive transcranial magnetic stimulation at 100% of motor threshold over left prefrontal cortex in depression. J Ect 2001;17:259–63. Anand S, Hotson J. Transcranial magnetic stimulation: neurophysiological applications and safety. Brain Cogn 2002;50:366–86. Gates JR, Dhuna A, Pascual-Leone A. Lack of pathologic changes in human temporal lobes after transcranial magnetic stimulation. Epilepsia 1992;33:504–8. Roth BJ, Pascual-Leone A, Cohen LG et al. The heating of metal electrodes during rapid-rate magnetic stimulation: a possible safety hazard. Electroencephalogr Clin Neurophysiol 1992; 85:116–23. Wassermann EM. Side effects of repetitive transcranial magnetic stimulation. Depress Anxiety 2000;12:124–9. Steinhoff BJ, Stodieck SR, Zivcec Z et al. Transcranial magnetic stimulation (TMS) of the brain in patients with mesiotemporal epileptic foci. Clin Electroencephalogr 1993;24:1–5. Wedegaertner F, Garvey M, Cohen LG et al. Low frequency repetitive transcranial magnetic stimulation can reduce action myoclonus (Abstract). Neurology 1997;48:A119. Tergau F, Naumann U, Paulus W et al. Low-frequency repetitive transcranial magnetic stimulation improves intractable epilepsy. Lancet 1999;353:2209. Fregni F, Thome-Souza S, Bermpohl F et al. Antiepileptic effects of repetitive transcranial magnetic stimulation in patients with cortical malformations: an EEG and clinical study. Stereotact Funct Neurosurg 2005;83:57–62. Kinoshita M, Ikeda A, Begum T et al. Low-frequency repetitive transcranial magnetic stimulation for seizure suppression in patients with extratemporal lobe epilepsy – a pilot study. Seizure 2005;14:387–92. Brighina F, Daniele O, Piazza A et al. Hemispheric cerebellar rTMS to treat drug-resistant epilepsy: case reports. Neurosci Lett 2006;397:229–33. Menkes DL, Gruenthal M. Slow-frequency repetitive transcranial magnetic stimulation in a patient with focal cortical dysplasia. Epilepsia 2000;41:240–2.

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Daniele O, Brighina F, Piazza A et al. Low-frequency transcranial magnetic stimulation in patients with cortical dysplasia – a preliminary study. J Neurol 2003;250:761–2. Rossi S, Ulivelli M, Bartalini S et al. Reduction of cortical myoclonus-related epileptic activity following slow-frequency rTMS. Neuroreport 2004;15:293–6. Misawa S, Kuwabara S, Shibuya K et al. Low-frequency transcranial magnetic stimulation for epilepsia partialis continua due to cortical dysplasia. J Neurol Sci 2005;234:37–9. Graff-Guerrero A, Gonzales-Olvera J, Ruiz-Garcia M et al. rTMS reduces focal brain hyperperfusion in two patients with EPC. Acta Neurol Scand 2004;109:290–6. Theodore WH, Hunter K, Chen R et al. Transcranial magnetic stimulation for the treatment of seizures: a controlled study. Neurology 2002;59:560–2. Tergau F, Neumann D, Rosenow F et al. Can epilepsies be improved by repetitive transcranial magnetic stimulation? – interim analysis of a controlled study. Clin Neurophysiol (Suppl) 2003;56:400–405. Tergau F, Neumann D, Rosenow F et al. Can epilepsies be improved by repetitive transcranial magnetic stimulation? – interim analysis of a controlled study. Suppl Clin Neurophysiol 2003;56:400–5. Paus T, Jech R, Thompson CJ et al. Transcranial magnetic stimulation during positron emission tomography: a new method for studying connectivity of the human cerebral cortex. J Neurosci 1997;17:3178–84. Munchau A, Bloem BR, Irlbacher K et al. Functional connectivity of human premotor and motor cortex explored with repetitive transcranial magnetic stimulation. J Neurosci 2002; 22:554–61.

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Gerschlager W, Siebner HR, Rothwell JC. Decreased corticospinal excitability after subthreshold 1 Hz rTMS over lateral premotor cortex. Neurology 2001;57:449–55. Seyal M, Shatzel AJ, Richardson SP. Crossed inhibition of sensory cortex by 0.3 Hz transcranial magnetic stimulation of motor cortex. J Clin Neurophysiol 2005;22:418–21. Maeda F, Keenan JP, Tormos JM et al. Interindividual variability of the modulatory effects of repetitive transcranial magnetic stimulation on cortical excitability. Exp Brain Res 2000;133:425–30. Post RM, Kimbrell TA, McCann UD et al. Repetitive transcranial magnetic stimulation as a neuropsychiatric tool: present status and future potential. J Ect 1999;15:39–59. Speer AM, Kimbrell TA, Wassermann EM et al. Opposite effects of high and low frequency rTMS on regional brain activity in depressed patients. Biol Psychiatry 2000;48:1133–41. Fregni F, Otachi PT, Do Valle A, Boggio PS, Thut G, Rigonatti SP, Pascual-Leone A, Valente KD. A randomized clinical trial of repetitive transcranial magnetic stimulation in patients with refractory epilepsy. Ann Neurol. 2006;60(4):447–55. Joo EY, Han SJ, Chung SH, Cho JW, Seo DW, Hong SB. Antiepileptic effects of low-frequency repetitive transcranial magnetic stimulation by different stimulation durations and locations. Clin Neurophysiol. 2007;118(3):702–8. Epub 2007 Jan 16. Cantello R, Rossi S, Varrasi C, Ulivelli M, Civardi C, Bartalini S, Vatti G, Cincotta M, Borgheresi A, Zaccara G, Quartarone A, Crupi D, Laganà A, Inghilleri M, Giallonardo AT, Berardelli A, Pacifici L, Ferreri F, Tombini M, Gilio F, Quarato P, Conte A, Manganotti P, Bongiovanni LG, Monaco F, Ferrante D, Rossini PM. Slow repetitive TMS for drug-resistant epilepsy: clinical and EEG findings of a placebo-controlled trial. Epilepsia. 2007;48(2):366–74.

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SECTION 17 Surgical outcome

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Mesial temporal lobectomy: post-surgical seizure frequency L Jehi

Introduction Temporal lobe epilepsy (TLE) is the most common type of partial epilepsy in adults.1 Seizures arise from the mesial temporal structures (amygdale, hippocampus, and perhaps parahippocampal gyrus) in >90% of patients with TLE.2 Hippocampal sclerosis (HS) represents the pathological substrate in 44–65% of mesial TLE,3–6 with mesial TLE related to HS (MTLE-HS) recently proposed as an isolated syndromic diagnostic entity.7 Surgical removal of the mesial structures, either in isolation via a selective amygdalohippocampectomy (SAH) or in addition to varying segments of the temporal neocortex via an anterior temporal lobectomy (ATL), was shown to be of invaluable benefit for the large patient population with pharmacoresistant TLE.8–10 Seizure freedom after ATL correlates with reduced mortality9,11–17 and a better quality of life, as reflected by improved psychosocial measures and employment rates.12,18–20 Mere reduction in seizure frequency is not enough to improve most of those measures.12 It is therefore essential to optimize our understanding of the various factors impacting postoperative seizure freedom. Since Bengzon published the first article on outcome in 1968,21 thousands of studies have addressed the degree and stability of postsurgical seizure freedom while attempting to identify useful prognostic factors. This chapter will review the available outcome measures, discuss the pitfalls of outcome studies, provide an overview of the published success rates, suggest proposed prognostic factors, and finally elaborate on special issues pertaining to postoperative seizure freedom.

Available outcome measures Definitions of ‘seizure-free’ vary. Two major classification systems are currently available to assess postoperative seizure freedom. Traditionally, most studies have used Engel’s classification (Table 130.1), reporting favorable seizure outcomes as being either ‘excellent’ reflecting freedom from disabling seizures (Engel Class I), or ‘good’ with the additional inclusion of patients having rare seizures (Class I and II). Disadvantages of this system include the following: (a) certain outcome criteria, such as ‘worthwhile improvement’, are very ambiguous, leading to variation in interpretation among different centers; (b) comparison to AED drug trials is virtually impossible as those typically use ‘≥50% seizure reduction’ as their outcome measure; (c) the ‘seizure free’ category (Class I) is not restricted

to patients who are truly completely seizure free after surgery (Class IA); it also includes those with persistent auras, simple partial seizures, and generalized convulsions upon AED withdrawal (Classes IB–D). Since studies do not usually report outcome using Engel’s classification subcategories, the independent evaluation of truly seizure free patients is not always possible. To address the above issues, the International League Against Epilepsy (ILAE) recently issued a commission report proposing a new outcome classification scheme (Table 130.2). Completely seizure-free patients are classified separately; seizures are quantitated in each category and compared to a well-defined baseline frequency, and results can be easily compared to AED drug trials. To date, only one study23 compared both systems in its outcome assessment, and found similar results at the last available follow-up. Some centers reported their outcomes using internally validated scoring systems.23–25 Others chose a pre-specified period of seizure freedom – usually 12–24 months – as reflecting a favorable outcome.26–29 This wide variation in outcome measures is only one of many pitfalls complicating the interpretation and comparison of the results among different outcome studies.

Pitfalls of outcome studies First, the evaluated patient cohorts are heterogeneous with differing demographic characteristics, epilepsy duration, and pathological substrates. Some studies included patients with temporal and others with extratemporal epilepsy in the same outcome analysis.30–33 This is problematic as certain prognostic variables may have completely different implications in different populations: febrile seizures for example may represent a good prognostic indicator for TLE patients34–38 while conferring a grim outcome after surgery in frontal lobe epilepsy.39 Outcome evaluations in ‘non-pure’ cohorts may then produce misleading conclusions. Second, few studies were done in the era of high resolution MRI, and even less accounted for evolving pathological classifications of entities like hippocampal sclerosis and cortical dysplasia. Many ‘non-lesional’ patients from earlier cohorts may actually have subtle MRI lesions on current imaging. Third, significant issues exist in the statistical methods used. We know now that cross-sectional studies40–43 depict outcome at a snapshot in time, usually at 12 or 24 postoperative months, missing late recurrences and not adjusting for the 1223

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Engel’s classification of postoperative outcome

Class I: Free of disabling seizuresa A: Completely seizure free since surgery B: Nondisabling simple partial seizures only since surgery C: Some disabling seizures after surgery, but free of disabling seizures for at least 2 years D: Generalized convulsions with AED discontinuation only Class II: Rare disabling seizures (‘almost seizure free’) A: Initially free of disabling seizures but has rare seizures now B: Rare disabling seizures since surgery C: More than rare disabling seizures since surgery, but rare seizures for the last 2 years D: Nocturnal seizures only Class III: Worthwhile improvementb A: Worthwhile seizure reduction B: Prolonged seizure-free intervals amounting to greater than half the followed-up period, but not 75% reduction in seizure frequency

Engel IA Engel Ia,b,d

Complete seizure freedom to last follow-up or for ≥2 yrs at time of outcome assessment’ Engel I Seizure freedom ±auras (completely seizure free or since 5 yrs postop) Engel IA Engel IB-D Engel IA

Engel I 2 year remission from seizures ±auras.

ILAE 1

Engel I Engel I Engel I (All) Engel I (MTS) Engel I Engel I ILAE 1 All

Outcome measure used

76% 44%

62%

55%

77%

71%

46%

71%

66% 67% 78%

2 yr

64%a

54%

48%

74%

52%

58%

75% 69%

64%

41% 37% 47% 43%

at at at at

65%

Mesial temporal lobectomy: post-surgical seizure frequency Continued

85% 92% (of those 62% seizure free except auras)

10 yrs, 15 yrs. 10 yrs, 15 yrs.

66% at 10 yrs

50% at 30 yrs

Neocortical 50%

MTS 68%

70%

63%

66%

Date of last follow-up

59% 53% at 10 yr 55% at 10 yr

>5 yr 72% 71% 85% 91% 56%

5 yr

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4.6 (1- n/a) 4.6 (2–7.3)

Surgery

80 ATL 81 SAH 100 (69 with MTS) ATL, TL or SAH

N

Percentage of favorable outcome at

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6.1 (2–17) 4.2 (1–n/a) 5.5 (1–14.1)

6.7 (2–11) 4.5 (2–11) 4.4 (n/a–n/a)

Years of follow-up: Study period mean (range)

Surgical outcome in major studies evaluating pure cohorts of patients with HS

Sindou et al.89

Paglioli et al.53

Author

Table 130.3

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1225

Yoon et al.47†

5.4 (3 months– 10.5 y) 7.2 (1–24)

1988–1999

1975–1999

1975–1995

1996–2000

1962–1984

n/a

1984–1995

1989–1995

n/a

1990–1996

1988–1991

Jutila et al.58

Wieser et al.75

Hennessy et al.28

Wiebe et al.9

Foldvary et al.45

Kilpatrick et al.42

Salanova et al.15**

Assaf et al.114

Hermann et al.159

Schuh et al.106

Radhakrishnan43 3.6 (2–5.7)

n/a (1–n/a)

0.5–0.7

n/a (2–n/a)

3.2 (1.7–5)

14 (2.1–33.6)

1

5.2 (n/a)

5.9 (n/a)

Kilpatrick et al.104†† 1993–2002

8.4 (3.1–20)

1972–1992

Author

175

102

30

75

145

56

79

80

116

369 (with MTLE, 151 with HS)

140

80

175

N

71% 56%

64%

51%

1 yr

Seizure freedom ± auras 66%

12 consecutive months of absolute seizure freedom ± auras Freedom from 58% seizures impairing awareness Seizure free 63%

Engel I ILAE Class 1a

‘Continuously seizure-free’ Engel I All MTS ILAE 1

Outcome measure used

Seizure free or auras only ATL (± superior Seizure free without temporal gyrus auras or simple resection) partial seizures ATL Engel Ia Engel Ib-d ATL Seizure free or nondisabling seizures at last follow-up

ATL

ATL

ATL

ATL (in all except one with SAH) ATL

ATL

SAH

ATL or SAH

n/a

n/a

Surgery

63%

53%

70% 50%

58%

2 yr

60%

52%

67%

65% 38%

50%

5 yr

55% at 10 yrs

55% 15% 77%

55–60%

69%

45% at 65% Engel I 35% 10 yrs ILAE 1a 86%

75% 76% 58%

Date of last follow-up

50% at 9 yrs 62% 66.9% 34% at 57.1% 10 yrs

>5 yr

Percentage of favorable outcome at

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Years of follow-up: Study period mean (range)

Surgical outcome in major studies evaluating pure cohorts of patients with HS

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1980–1990 1987–1993 1986–1990

n/a n/a 1989–1992 1988–1992 1987–1990 1980–1986

Silander et al.168 Zentner et al.169 Sperling et al.12

Arruda et al.105 Mihara et al.170 Holloway et al.171 Loring et al.172 Liu et al.173 Chung et al.139 74 132 28 55 35 59

62 178 89

50 108 100

ATL or SAH ATL or SAH ATL ATL ATL ATL

ATL ATL or SAH ATL

ATL ATL ATL

Engel I and II Engel I Engel I ‘Seizure free’ ‘Seizure free’ Seizure free8auras during the second postoperative year

Engel I Engel I Seizure free for ≥2 years ‘Seizure free’ Engel I Engel I

80%

b

53.2% 70% (55% ILAE1)

28.5%* 62%

72% 70% 75%

62%

78% 69% 58%

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Assessed at 63 months. Familial MTLE. c Bold prospective studies. d Italic: all TLE (not distinguishing MTLE from neocortical). e * Those were SF since discharge. An additional 34.2% became SF ‘after early attacks’... so maybe included patients with immediate postop sz. f ** Included in cohort published in 2005. g† includes extratemporal (temporal only 140). h†† includes Kilpatrick 1999.

2.8 (1–n/a) 5.7 (2–11.9) n/a (1–n/a) n/a (1–n/a) 1.1 (0.2–3) n/a (2–n/a)

n/a (2-n/a) 3 (1–6) 5

n/a (1–n/a) n/a (1–n/a) 5.5 (1–16)

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a

1989–1996 1992–1994 1978–1992

Chung et al.167 Lancman et al.98 Blume et al.29

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lobe epilepsy (MTLE) cases, and clear outcome measures and description of the statistical design. When cohorts from the same center were evaluated twice, we only show the most recent evaluation. In general, outcomes are favorable. One randomized controlled trial9 showed that only two patients need to be treated surgically for one patient to become free of disabling seizures. This is superior to most interventions in neurology. Several meta-analyses using retrospective studies,31,32,55,56 and few prospective studies12,52–54 showed comparable results with about two-thirds of the patients becoming seizurefree postoperatively, compared to 5–8% with medical therapy. Similar outcomes were shown in cohorts of pure HS.18,27,28,40–42,44,54,57 Favorable outcomes of more than 50% are still seen more than 10 years after ATL reflecting a sustained benefit.13–15,45,47,51,57,58 Outcomes are usually stable. If a patient is seizure free at 1 year postoperatively, the likelihood of remaining seizure free is 87–90% at 2 years, 74–82% at 5 years, and 67–71% at 10 years.13–15,43,45,47,59–61 If a patient was seizure free for 2 years postoperatively, chances of seizure freedom increase up to 95% at 5 years, 82% at 10 years, and 68% at 15 years.14,23,45,60,62,63 So, seizure-freedom for 2 years might be a better predictor of long-term outcome, although both the 1-year and the 2-year states correlate fairly well with future outcome.

Timing of seizure recurrence: early versus late relapse Most recurrences happen early during the postoperative course with more than half of first recurrences occurring within 6 months,12,45,64 62–86% within the first year,15,45,51,58,65 and up to >95% within 2–5 postoperative years.12,15,45,51,65 An initial phase of steep seizure recurrence is followed by a relapse rate of 2–5% per year for 5 years with subsequent more stable seizure freedom.14,45,47–51 Recent data suggest that prognostic factors affecting those two phases of recurrence are distinct,27,47,51,66 possibly reflecting different mechanisms for early versus late relapses. Multiple factors have been implicated in early recurrences, mostly attributed to incomplete resection of the epileptogenic zone. However, the factor most consistently associated with late relapses (beyond 2–5 years) is lack of abnormal pathology,47,51 suggesting possibly an underlying diffuse functional abnormality at the molecular or cellular level.51 An underlying ‘age-dependent etiology’ of surgical failures was proposed in a recent prospective multicenter study where delay to remission predicted later relapse in medial TLE patients.52 Long epilepsy duration,27 increasing age at surgery,52,61 preoperative bilateral interictal spiking( 5 sec) and postoperative ipsilateral spiking66 were also implicated. Many of the above risk factors are actually seen with long-standing HS. Knowing that HS is likely a progressive disease as suggested by animal studies,67 increase in the incidence of bilateral spiking with time,68 the progression to temporal lobe atrophy in chronic epilepsy,69 and the proven bilaterality in most cases on MRI70 and pathology 3,4 might make this entity an ideal ‘age-dependent etiology’ where both genetic 41,71,72 and environmental factors

lead to surgical refractoriness after years leading to medical refractoriness.27

‘Running-down’ phenomenon The counterpart of late seizure relapses also exists. The ‘running-down’ phenomenon, defined as the late remission of postsurgical seizures,73 occurs in 3.2–20% of TLE surgery cases.22,23,44,66,73,74 The frequency of seizures during the running-down interval may be up to several per month,35 but a seizure-free state is usually achieved within two years.35,60,62 The most accepted explanation for this phenomenon is a dekindling effect, an opposite process to secondary epileptogenesis, where the induced synaptic dysfunction gradually declines in the surrounding epileptogenic cortex after pacemaker resection, and eventually ‘runs itself down’.35,73,74 Patients in this group are more likely to have a history of febrile seizures,35 normal neurological examination,35 unilateral interictal EEG preoperatively,23,35 etiologies other than head trauma or encephalitis,35 and a smaller and more anterior epileptiform preresection EcoG,35 i.e., findings consistent with a more localized anterior epileptogenic focus when compared to those who continue with refractory seizures. Furthermore, this phenomenon occurs more in SAH patients compared to ATL (12% vs 20%)35,73,75 with seizure freedom being achieved earlier in ATL compared to SAH (2 yrs vs 2.6 yrs). This supports the notion that patients patients who experience the ‘running-down phenomenon’ have foci of ‘intermediate epileptogenicity’ between restricted epileptogenic zones in those who immediately go into remission, and larger, often more posterior epileptogenic zones of refractory cases who never remit.35

Possible predictors of recurrence Clinical variables Age at onset of epilepsy Patients with an earlier age at onset of epilepsy (usually 50 years old), although chances of achieving seizure freedom are not as high as in younger patients (3/6 SF in Cascino et al.,91 6/20 in Mclachlan et al.,92 16/30 in Sirven et al.93) versus 75% in younger individuals.93 Older patients however were not more likely to have neuropsychological deficits from surgery and enjoyed the same benefits as young patients with regard to driving.93 Therefore, older age by itself should not be a deterrent from surgery. Absence of secondarily generalized tonic-clonic seizures (SGTCS) Only 57% of MTLE-HS patients with SGTCS achieved a 1year remission compared to 80% remission rate in those who had only partial seizures in one study.28 Patients who had no GTCs were 2.2 times more likely to be seizure free 5 years after surgery in another study.44 This effect may be most significant when GTCs are frequent (>2/year) and occurring within 3 years of surgery.14 It correlates with early (by 2 years) but not later recurrences.27,51 Although many studies of mixed TLE subgroups identified a prognostic role to GTCs,33,51,58,82 one recent prospective multicenter trial found that their significance is restricted to outcome of MTLE patients.52 No correlation to outcome was found in smaller or cross-sectional studies.42,46,83,94 SGTCS are not typical of MTLE-HS.7,87 Their occurrence correlates with more extensive hippocampal sclerosis95 and with multifocal irritative areas.96 MTLE patients who had SGTCS prior to PET examination have an extended hypometabolism compared to those who have no SGTCS.97 All those findings suggest that SGTCS may affect outcome

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through reflecting a diffuse epileptogenic zone or secondary epileptogenesis. Preoperative seizure frequency While multiple studies found no correlation between seizure frequency and outcome,23,33,42,44,52,79,82,83,98 frequent seizures (>20/month) were associated with lower rates of seizure freedom: 50, 44, and 28%, and 17% vs 72, 67, 56%, and 50% SF estimates at 6 mo, 1 yr, 5 yr, and 10 yrs in one study45 and 80, 74, 67% vs 89, 84, and 79% SF at 6 mo, 1 yr, and 2 yr in another study.51 History of febrile seizures Data regarding the prognostic significance of febrile seizures are again contradictory. Multiple studies found no effect.27,28,42,43,52,58,99 Some suggested that any proposed beneficial effects of febrile seizures found in many studies34–38,52,100 simply reflects their association with HS.43 The differing view argues that complex febrile convulsions, in contrast to simple febrile convulsions, correlate with a more restricted epileptogenic zone and constitute the main favorable prognostic indicator15,27,52 and that failure to distinguish between the two types of febrile convulsions in analyzing outcome would miss this interaction. In fact, Janszky found in 2003 that complex febrile convulsions predicted a 91% SF rate at 2 years in MTLE (versus 64% if absent).36 Re-evaluating the same cohort of patients 2 years later but without differentiating between simple and complex febrile convulsions, this effect could not be re-confirmed.27 Preoperative auras No correlation between occurrence of auras and outcome was proven.15,35,44,51,83 Imaging variables Magnetic resonance imaging Multiple studies24,43,48,52,83,101–105 and a recent meta-anlaysis56 concur that a unilateral MRI abnormality is one of the strongest predictors of a good surgical outcome. Patients with MRI evidence of HS had a 54% chance of seizure freedom at 10 years after ATL compared to 18% if MRIs were normal in a recent longitudinal study.14 However, the presence of ANY unilateral temporal MRI lesion also confers a good prognosis.14,43,46,58,89,101,104,106,107 Recent data suggests similar outcomes regardless of the nature of the MRI lesion, although more research is needed to clarify this point.14,54 Concordance of imaging with ictal and interictal EEG improves outcome,56 up to 94% at last follow-up in certain studies.43 In fact, concordance of interictal EEG and MRI represented the test combination of closest association with outcome in MTLE.108,109 The traditional view that a normal MRI is an automatic correlate to surgical failure43,48,110 has recently been challenged by several studies showing seizure freedom rates of 41–48% as far as 8 years after ATL.40,51,111–113 The pathologic substrate of this category of patients remains open to debate. Some findings suggest that successfully treated patients with normal MRIs actually represent undetected HS. This is supported by better seizure freedom rates of 78%111–100%112 when presurgical evaluation is consistent with a mesial temporal focus: a history of febrile seizures,

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anterior interictal discharges and a unilateral regular theta temporal ictal rhythm predicted better outcomes in 17 patients with normal MRI.111 Those findings have all been correlated with HS on pathology.114,115 In one study, all patients with a good outcome and normal MRI had pathologically confirmed HS.105 Conversely, another study concluded that most cases of normal appearing hippocampi on high-resolution MRI have neocortical TLE since they had less febrile seizures, more delta rhythms at ictal onset and more extensive lateral neocortical changes on PET with surgical outcomes still comparable to those of MRI obvious HS113 It should be emphasized that surgery was successful in nonlesional patients only when performed in context of concordant EEG and PET data.51,113 ‘Normal’ MRIs correlating with bad outcomes in older studies using lower quality imaging may have included patients with extratemporal or contralateral pathology, findings that would currently exclude viable surgical options.51,113 Focal epileptogenic zones may arise from tissue with microscopic or cellular dysfunction that is too subtle to be visible on MRI, but may still be amenable to surgical treatment.51 A normal MRI should not therefore preclude a presurgical evaluation because an ATL performed with concordant presurgical data may still offer major benefits in refractory patients where with other treatment modalities such as AEDs and VNS, the chances of seizure freedom for more than 1 year are still less than 5%.116,117 Bilateral MRI lesions, including grossly bilateral HS, reflect multiple potentially epileptogenic foci and correlate with a worse surgical outcome: 58% seizure free at 2 years compared to 78% when compared to unilateral lesions or even normal MRI.51,101,103,118 Subtle hippocampal asymmetries in studies using volumetrics were less predictive of outcome.70,119 Nuclear imaging Unilateral temporal hypometabolism on FDG-PET predicts a good surgical outcome in patients with MTLE.107,120–123 This effect is independent of pathological findings and is observed regardless of whether MRI is normal or not. In a recent review of the literature,120 Casse found that 86% of patients with unilateral temporal hypometabolism ipsilateral to the side of surgery had a good outcome as defined by more than 90% reduction in seizure frequency or Engel Class I or II. This number was slightly reduced to 82% if the MRI was normal. Chances of successful outcome, similarly defined, dropped to 62% when PET was normal and to 50% when it showed bitemporal hypometabolism.120 With extratemporal hypopmetabolism, chances of seizure freedom are even worse: complete seizure freedom at last follow-up (mean 6.1 years) was seen in 45% of patients with extratemporal cortical hypometabolism confined to the ipsilateral cerebral hemisphere, and only 22% with contralateral cortical hypometabolism.124 Abundant data supports the usefulness of ictal SPECT in localizing the epileptogenic zone in TLE125–130 with 70–100% of ictal being correctly localising and only 0–7% incorrectly localizing.130 Clear correlations with postoperative outcome, however, need further clarification. Atypical perfusion patterns on ictal SPECT correlated with lack of pathology in the surgical specimen and with a poorer surgical outcome (33% SF after 2 years of follow-up) when compared to typical (60% SF after 2 years), typical with posterior extension (69%) and even bilateral temporal hyperperfusion pattern (67%).131 Multiple other studies have also suggested that a

correct localization of the epileptogenic focus by ictal SPECT correlates with a favorable seizure outcome.132–136 This conclusion was not confirmed though when a multivariate analysis was performed evaluating the predictive value of multiple noninvasive modalities: Son et al. found that while MRI, EEG, and PET had comparable predictive values for Engel Class I, SPECT had less predictive value.137 Results for interictal SPECT suggest that it is relatively poor at localising the seizure focus.130 Further research is needed to clarify the role of SPECT in TLE. Electrophysiological variables Noninvasive EEG Focal interictal EEG predicts a favorable outcome when lateralized to the side of surgery,35,43,57,138,139 or when highly localized to the resected temporal lobe.28,30,35,57,66,94 Patients whose interictal EEGs showed ≥90% predominance on the operatedon side had an 80% chance of complete seizure freedom after a mean 5.5 years of follow-up versus 54% in those with lesser degrees of lateralization in a recent prospective study.57 In general, interictal evidence of a diffuse irritative zone predict a worse outcome: postoperative seizure freedom is worse when interictal spiking was posterior temporal,35,114 extratemporal,28,43 or bitemporal35,43,66,94 in multiple studies. Posterior temporal and extratemporal spiking in patients with pathologically confirmed HS may reflect diffuse epileptogenicity, or ‘dual pathology’ with associated neocortical epileptogenic zones thereby explaining the associated worse prognosis.28,35,43 However, prognostic implications of bilateral interictal spiking on surface EEG deserve more careful consideration, as they do not automatically preclude postoperative seizure freedom. One study found that if ≥90% of surface interictal bitemporal spikes arise from one temporal lobe, excellent outcome is possible (92% seizure-free in the second postoperative year vs 50% if 5 APOSs after hemispherectomy had a more prolonged and complicated hospital course and worse postsurgery seizure control, more AED use and higher reoperation rate than patients without or up to 5 APOSs. Thus the number of APOSs was found to be a valuable predictor of postsurgery seizure control and a useful parameter to counsel patients or families about prognosis after hemispherectomy. In the same study the seizure types observed were described as focal tonicclonic, unilateral tonic head and eye movements, staring and eye rolling, mouth twitching, myoclonic shoulder twitching, and tonic extension of both extremities. In addition, extensive spasms and a frightened look were also described. In general, the APOSs compared to the pre-surgical seizure type in over 78% of the patients examined. The clear predictive value of the number of APOSs (>5) for post hemispherectomy seizure control may be related to the fact that the younger patients undergoing CH have multiple seizures every day before surgery compared to adult temporal lobe patients who usually only have a few seizures per week. In addition, APOSs tended to occur more in patients with lower pre-surgical Vineland DQ scores. The authors recommend that video-EEG telemetry after hemispherectomy should document whether patients

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have a habitual seizure versus a non-seizure event, whether the seizure was typical of the pre-surgical events and whether abnormal EEG findings were noted over the non-resected brain or hemisphere that might support the concept of induced secondary epileptogenesis.14 These findings were duplicated in a more recent study in which APOSs were analysed in extratemporal resections and hemispherectomy patients.15 Only 13% of the hemispherectomy patients had APOSs compared to 37% of the extratemporal resective cases and similar to the previous study the presence of APOSs was highly predictive for long-term seizure control which was only seen in 15% of children with APOSs compared to 63% of those without APOSs.15

Post CH seizures – newer studies analyzing the influence of pathology and surgical technique Postoperative seizures were reported in a recent study of 30 patients operated over a time span from 1987 to 2003 in which the effect of surgical technique and pathology on seizure frequency and general morbidity were analyzed.16 Of 21 patients who could be followed-up for one year 17 remain seizure free or had a 90% seizure reduction and the four patients who continued to have seizures had a recurrence within the first few days after surgery. Two of these patients were reported to have an incomplete disconnection of the corpus callosum, the etiologies were Rasmussen’s encephalitis and malformation of cortical development. In the total series only two patients did not improve significantly after surgery.16 The authors discuss the relevance of pathology and surgical technique as main factors for postoperative seizure control based on their study and further series in the literature.17–20 The authors found incomplete disconnections in 18.5% of their cases which is the same incidence reported previously from the UCLA series.21 In another series using modified periinsular hemispherotomy 9% incomplete disconnection was reported,22 while Mittal reported no incomplete disconnections in their series of transsylvian keyhole functional hemispherectomy.20 In a large series reported from Johns Hopkins18 five out of 111 patients who underwent hemidecortication had repeat surgery for persistent seizures as residual tissue could be identified on MRI. In the Bethel series of 105 hemispherectomies 9 patients (9%) had reoperations for incomplete disconnections, however the rate of incomplete disconnections is higher as only children that had poor postoperative seizure control had a second surgery.11 Incomplete disconnections may occur with all techniques and relate to the pathology and specific anatomical features of malformed hemispheres so that thick cortical mantles and large distorted hemispheres require good surgical technique and experience of the neurosurgeon to achieve complete disconnection so that the expertize of the neurosurgeon is very important for outcome.13 The authors concluded that hemispherectomies are procedures where pathology and surgical technique interact narrowly to determine post-surgical prognosis and morbidity. The UCLA series spanning surgeries from 1986 to 1995 reports excellent seizure control and motor function in 50 patients with more than 1 year follow-up of 90% of

seizure reduction.21 Late postoperative seizure breakthrough required reoperation and further disconnection in five of 27 functional hemispherectomy patients and three of 27 anatomical hemispherectomy patients. In more detail 74% (37) were completely or nearly seizure free with no more than occasional seizures after one year, seven additional patients (14%) showed a greater than 90% reduction in seizure frequency and 10% had a moderate reduction, while one patient showed no improvement. Therefore 88% of the patients had extremely favourable results with greater that 90% seizure reduction. The study presents no MRI data. The authors also discuss technique issues and based on their results and experience they recommend anatomical hemispherectomy in patients with a small lateral ventricle on the affected side because this small window of access increases the difficulties in the disconnection portion of the functional technique. They also state that the presence of large cysts or very marked atrophy is an argument for an anatomic procedure as there is much less disconnection through brain tissue. An anatomic hemispherectomy is also favoured in patients with dysplastic syndromes in which the tissue may become hemorrhagic. They counterbalance the increased risk of hydrocephalus in their argumentation and recommend that functional hemispherectomy should be favoured in patients with a large lateral ventricle present on the affected side, because this facilitates an access for disconnection. By this argument children with middle cerebral artery infarcts are good candidates for the hemispherotomy procedure and particularly where adhesions and scar tissue may obstruct access to the large cerebral arteries which is necessary when performing an anatomic resection. From their experience and data analyses these authors conclude that anatomical functional and modified anatomical hemispherectomy provides an excellent seizure control in young hemiplegic children with intractable epilepsy. They do suggest that the choice and type of hemispherectomy should be individualised with safety and efficacy with regard to seizure control being the primary factors to be considered. In a follow-up study from the same centre 2-year postsurgery seizure control is reported for a larger series of 115 patients as follows: 78.6% were seizure free at 6 months (n = 112), 76.3% at one year (n = 97), 70% at 2 years (n = 88), and 58% at 5 years (n = 50). There is a decline in seizure-free patients between 2–5 years postsurgery, which is quite similar to that reported in other cases of extratemporal pediatric epilepsy surgery. The authors note that fewer HME patients were seizure free in follow-up compared to other pathology categories but the differences were not statistically significant, age at surgery and duration of seizure did not correlate with seizure control. The authors comment that the HME cases were surgically the most challenging and of the pathology groups undergoing surgery had the lowest post surgery seizure control which however was higher (58.3%) than in previously reported studies (37%).23 In a parallel study from the same centre a comparison of three techniques by pathologic substrates was evaluated in the same group of patients and the factors stratified in the way they affected seizure control: heir conclusion was that the pathologic substrate is less influential with regard to posthemispherectomy seizure control than other factors such as follow-up length, duration of seizure at surgery, completeness of disconnection of cortex and subcortical structures in patients with cortical dysplasia and Rasmussen’s encephalitis.24

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Hemispherectomy: post-surgical seizure frequency

Long-term seizure control post-hemispherectomy Seventeen patients treated with hemispherectomy from 1950 to 1971 with a seizure-free or near seizure-free outcome in half of 16 patients (94%) who were followed up long-term up to 38 years were reported by Davies.25 Similarly, the long-term follow-up26 of eight patients showed excellent seizure control, improved neuropsychologic functioning, but a relatively high rate of early postoperative hydrocephalus and CT scan was found valuable to diagnose late complications. The authors emphasize the marked reduction in seizure frequency and improved behaviour, however, with little change in intellect or postoperative hemiplegia. Seizure-free rates between 50–65% have been reported in studies with 5 or more years follow-up after hemispherectomy, compared with 67 to 88% in reports with shorter follow-up periods.25 Late recurrences of seizures between 2–5 years are known to occur in pediatric patients after extratemporal resections, however the reasons for late

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seizure recurrence are not well studied but the phenomenon needs to be considered when comparing seizure control in different clinical series – follow-up duration is an important factor that needs to be considered. The authors, in addition, discuss the effect of including the basal ganglia and thalamus in the resection/disconnection for posthemispherectomy seizure control, especially in patients with cortical dysplasia and Rasmussen’s encephalitis. Studies clearly show that in patients where the basal ganglia and thalamus are preserved the seizure-free rates are lower, reported between 31–67%.27–29 In studies where deeper structures were removed or disconnected the seizure-free rates are higher, 67–87%.22,24,30,31 Recently the favourable long-term seizure outcome results and low complication rate of 83 children who had vertical parasagittal hemispherotomy were reported by Delalande.32 Similarly the first adult series of 9 patients with follow-ups of up to 30 years was reported with 83% remaining seizure free in the long term and no mortality reported over this period.33

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Vining EP, Freeman JM, Pillas DJ et al. Why would you remove half a brain? The outcome of 58 children after hemispherectomy – the John’s Hopkins experience: 1968 to 1996. Pediatrics 1997;100:163–71. Krynauw RA. Infantile hemiplegia treated by removing one cerebral hemisphere. J Neurol Neurosurg Psych 1950;13:243–67. Ignelzi RJ, Bucy PC. Cerebral hemidecortication in the treatment of infantile cerebral hemiatrophy. J Neur Mental Dis 1968;147:14–30. Wilson PJE. Cerebral hemispherectomy for infantile hemiplegia: a report of 50 cases. Brain 1970;93:147–80. Carmichael EA. The current status of hemispherectomy for infantile hemiplegia. Clin Proc Childrens Hospital of the District of Columbia 1966; 22:285–93. Falconer MA, Wilson PJE. Complications related to delayed hemorrhage after hemispherectomy. J Neurosurg 1969;30:413–26. Villemure JG. Hemispherectomy techniques: a critical review. In: Tuxhorn I, Holthausen H, Boenigk HE, eds. Pediatric Epilepsy Syndromes and their Surgical Treatment London: John Libbey, 1997:729–38. Delalande O, Pinard JM, Basdevant C et al. Hemispherotomy: a new procedure for central disconnection. Epilepsia 1992;33(3):99–100. Villemure JG, Roy TD. Peri-insular hemispherectomy in pediatric epilepsy. Childs Nerv Syst 2006;22:967–81. Schramm J, Behrens E, Entzian W. Hemispherical deafferentation: an alternative to functional hemispherectomy. Neurosurgery 1995;36:509–15. Holthausen H, May TW, Adams CTB et al. Seizures post hemispherectomy. In: Tuxhorn I, Holthausen H, Boenigk HE, eds. Pediatric Epilepsy Syndromes and their Surgical Treatment London: John Libbey, 1997:749–773. Gonzales-Martinez JA, Gupta A, Kotagal P et al. Hemispherectomy for catastrophic epilepsy in infants. Epilepsia 2005;46(9):1518–25. Villemure JG, Daniel RT. Peri-insular hemispherotomy in paediatric epilepsy. Childs Nerv Syst. 2006;8:967–81. Koh S, Nguyen S, Asarnow RF et al. Five or more acute postoperative seizures predict hospital course and long-term seizure control after hemispherectomy. Epilepsia 2004;45:527–33. Mani J, Gupta A, Mascha E et al. Postoperative seizures after extratemporal resections and hemispherectomy in pediatric epilepsy. Neurology 2006;66:1038–43. De Almeida AN, Marino R Jr, Marie SK et al. Factors of morbidity in hemispehrectomies: Surgical technique pathology. Brain Dev 2006;28(4):215–22. Kossoff EH, Buck C, Freeman JM. Outcomes of 32 hemispherectomies for Sturge-Weber syndrome worldwide. Neurology 2002;59:1735–38.

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Kossoff EH, Vining EP, Dillas DJ et al. Hemispherectomy for intractable unihemispheric epilepsy etiology vs outcome. Neurology 2003;61:887–90. Sugimoto T, Otsubo H, Hwang PA et al. Outcome of epilepsy surgery in the first three years of life. Epilepsia 1999;40:560–5. Mittal S, Farmer JP, Rosenblatt B et al. Intractable epilepsy after a functional hemispherectomy: important lessons from an unusual case. J Neurosurg 2001;94:510–14. Peacock WJ, Wehby-Grant MC, Shields WD et al. Hemispherectomy for intractable seizures in children: a report of 58 cases. Childs Nerv Syst 1996;12:376–84. Shimizu H, Maehara T. Modification of peri-insular hemispherotomy and surgical results. Neurosurgery 2000;47:367–73. Jonas R, Nguyen S, Hu B et al. Cerebral hemispherectomy. Neurology 2004;62:1712–21. Cook SW, Nguyen ST, Hu B et al. Cerebral hemispherectomy in pediatric patents with epilepsy: comparison of three techniques by pathological substrate in 115 patients. J Neurosurg 2004;100(2):125–41. Davies KG, Maxwell RE, French LA. Hemispherectomy for intractable seizures: long-term results in 17 patients followed for up to 38 years. J Neurosurg 1993;78:733–40. Verity CM, Strauss EH, Moyes PD et al. Long-term follow-up after cerebral hemispherectomy: Neurophysiologic, radiologic, and psychological findings. Neurology 1982;32:629–39. Carreno M, Wyllie E, Bingaman W et al. Seizure outcome after functional hemispherectomy for malformations of cortical development. Neurology 2001;57:331–3. Devlin AM, Cross JH, Harkness W et al. Clinical outcomes of hemispherectomy for epilepsy in childhood and adolescence. Brain 2003;126:556–66. Schramm J. Hemispherectomy techniques. Neurosurg Clin N Am 2002;13:113–34. Delalande O, Fohlen M, Jalin C et al. From hemispherectomy to hemispherotomy. In: Lüders HO, Comair YG eds. Epilepsy Surgery 2nd edition. Philadelphia: Lippincott Williams & Wilkins, 2001:741–746 Di Rocco C, Iannelli A. Hemimegalencephaly and intractable epilepsy: complications of hemispherectomy and their correlations with the surgical technique: a report on 15 cases. Ped Neurosurg 2000;33:198–207. Delalande O, Bulteau C, Dellatolas G et al. Vertical parasagittal hemispherectomy: surgical procedures and clinical long-term outcomes in a population of 83 children. Neurosurgery 2007;60 (2 Suppl 1):19–32. McClelland S, Maxwell RE. Hemispherectomy for intractable epilepsy in adults: The first reported series. Ann Neurol 2007 (in press).

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133a

Psychiatric outcome of epilepsy surgery AM Kanner and AJ Balabanov

Introduction Patients with medically intractable epilepsy are at risk for mood, anxiety, psychotic, and attention deficit disorders (ADHD) (see also Chapter 94). For example, lifetime prevalence rates of depressive disorders range between 30–50%, those of anxiety disorders between 10 and 30% and those of ADHD between 20 and 30%.1–4 It is not surprising that prevalence rates of these psychiatric disorders are relatively high in patients being considered for epilepsy surgery. In a review of the literature Koch-Stoecker found prevalencerates ranging from 43 to 80% among seven case series.5 In the case series from the Bethel Epilepsy Center, 43% of patients met criteria for a psychiatric syndrome according to the criteria described in the Diagnostic and Statistical Manual of Mental Disorder, Third Edition, Revised, while an additional 29% met criteria for a psychiatric syndrome and a personality disorder. Recognition of post-surgical psychiatric complications of epilepsy surgery goes back to more than 50 years. For example, in 1957, Hill et al. described post-surgical depressive episodes occurring independently of seizure outcome and remitted within 18 months.6 For a long time, most of the data were obtained in case series at The Guy Maudsley Hospital in London, United Kingdom;6,7 nonetheless, in the last 15 years there has been a marked increase in the number of published studies. Psychiatric issues related to epilepsy surgery are complex and can be grouped into four main questions: (1) What are the prevalence rates and clinical manifestations of post-surgical psychiatric complications and what is their relation to postsurgical seizure outcome? (2) To what degree do pre-surgical psychiatric comorbidities contribute to post-surgical psychiatric complications? (3) What is the impact of pre-surgical psychiatric comorbidities on post-surgical seizure outcome and psychosocial adjustment? (4) What is the impact of epilepsy surgery on the course of pre-surgical psychiatric comorbidities? The purpose of this chapter is to address these four questions.

Post-surgical psychiatric complications Post-surgical psychiatric complications can be the expression of (i) a de novo psychiatric disorder, (ii) a recurrence of psychiatric disorder that had been in remission for a period of time prior to surgery, (iii) an exacerbation in severity of a psychiatric 1254

disorder that was present in a subclinical form or that was mild enough in severity that had gone unrecognized by patient, family and clinician or that was identified because of a more careful evaluation of the patient. The most frequent post-surgical psychiatric complications include; (i) depressive and anxiety disorders, (ii) psychotic disorder, (iii) psychogenic nonepileptic events (PNEE) and other types of somatoform disorders. A study completed at the Rush Epilepsy Center will serve to illustrate the various forms in which post-surgical psychiatric complications present.8 The study included 99 consecutive patients, 59 men and 40 women that had undergone an antero-temporal lobectomy and had a minimal post-surgical follow-up period of 2 years (median follow-up duration: 7 years; range, 2–13 years). Their mean age was 31±10.7 years (range, 8–59 years) and the mean duration of their seizure disorder was 19.9±8.8 years (range, 4–40 years). A post-surgical psychiatric complication was rated as; (i) a de novo episode/disorder, (ii) an exacerbation in severity, or (iii) a recurrence of a pre-surgical disorder. Any of these complications were rated as persistent if they had failed to remit despite several treatment strategies that included pharmacologic trials and psychotherapy. Psychiatric disorders that were present before and after surgery and did not change in their severity after surgery were rated as unchanged, while those that remitted after surgery were rated improved. Among the 99 patients, 62 had temporal lobe epilepsy (TLE) secondary to mesial temporal sclerosis (MTS), 18 had lesional TLE and 19 idiopathic TLE, documented with volumetric measurements of mesial structures. Fifty-five patients (55.6%) had a lifetime psychiatric history before surgery, 46 of whom had a mood disorder which consisted of depression alone in 22 patients, and mixed depression and anxiety disorders in 24 while three had in addition ADHD. Among these 46 patients, 26 had experienced a major depressive disorder, 14 a dysthymic disorder and six bipolar illness. Nine patients had other psychiatric disorders that included ADHD or pure anxiety disorder. Among the 99 patients, 44 (44.5%) met our criteria for post-surgical psychiatric complications: nine patients (11%) with de novo depressive/anxiety disorders and four patients (4%) with de novo psychotic episodes. Thirty one patients experienced an exacerbation in severity of presurgical depressive/anxiety disorders; these complications occurred during the first 12 months after surgery in all patients. In addition, seven of these 31 patients developed de novo PNEE. At the last contact, the post-surgical psychiatric

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Psychiatric outcome of epilepsy surgery complication of 14 patients (13.5%) had failed to remit despite multiple pharmacologic trials; two of these patients had developed a de novo post-surgical depressive disorder. Univariate analyses identified persistent seizures, pre-surgical psychiatric history and a left temporal seizure focus as predictors of post-surgical psychiatric complications. Multivariate regression models, however, identified a pre-surgical history of depression and a left sided seizure focus as predictors of post-surgical psychiatric complications, but not post-surgical seizure outcome. Interestingly enough, having failed to obtain gainful employment after surgery was not a predictor of post-surgical psychiatric complications (see below).

Post-surgical depressive and anxiety disorders The prevalence rates of post-surgical depressive disorders vary widely among the different studies ranging from 5% up to 63%, with a mean of 26%. In a study of 274 patients, Bruton et al. found a 20-fold increase in the prevalence rate of depression after surgery9 varying in severity from mild dysphoric to major depressive episodes associated with suicidal attempts. More often than not, these post-surgical complications are an expression of a recurrence or exacerbation of pre-surgical comorbid disorders. Furthermore, de novo psychiatric disorders are less frequent and are also likely to occur in the first six months after surgery. Here are some examples. Wrench et al. published a study of 62 patients who underwent epilepsy surgery; 43 had an ATL and 19 an extratemporal lobectomy ETL.10 Both groups had comparable pre-surgical histories of depression and anxiety (33% and 23% respectively for ATL and 53% and 18% respectively for ETL). At 1 month after surgery, symptoms of anxiety and/or depression were reported by 66% of ATL patients and 19% of ETL. At 3 months, 54% of ATL and 33% of TL patients were still symptomatic with 30% of ATL and 17% of ETL patients still experiencing a depressive episode. Furthermore, at the 3-month evaluation 13% of ATL patients had developed a de novo depression and 15% a de novo anxiety disorder, while 18% had developed other type of de novo psychiatric disorders. In contrast, only 17% of ETL patients had developed de novo anxiety, but not depression or other psychopathology. At 3 months follow-up, there was no significant association between post-surgical psychopathology and seizure outcome. Glosser et al. published a study of 44 patients who underwent an ATL; in the first month after surgery, 12 patients (31%) developed de novo depression and/or anxiety disorders or recurrence of a disorder that had been in remission during the six months preceding the surgical procedure.11 By 6 months, they were still symptomatic but significantly improved and by 1 year, all but two patients had become free of symptoms. In a study of 49 patients who underwent an ATL and were followed for a period of almost 11 years, Altshuler found that five (10%) developed de novo depressive episodes, four within the first post-surgical year.12 Similar findings were reported by Ring et al. in a study of 60 consecutive patients who underwent an ATL and had a psychiatric evaluation prior to surgery, at six weeks and three months after surgery.13 At 6 weeks, 45% of all patients were

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experiencing emotional lability that reflected a de novo psychiatric complication in half of the patients. By 3 months, the emotional lability and symptoms of anxiety had remitted or improved significantly but not so the depressive states. Blumer et al., reported a much higher prevalence rates of de novo psychiatric complications in a study of 50 consecutive patients, 44 of who underwent an ATL and six a frontal lobe resection;14 14 patients (32%) developed de novo psychiatric disorders presenting as an interictal dysphoric disorder in six patients, depressive episodes in two and a psychotic disorder in six, while only three patients (7%) experienced an exacerbation of a pre-surgical interictal dysphoric disorder. In all but two patients the psychiatric complications occurred within 2 months after surgery. All psychiatric complications remitted with psychotropic treatment. Blumer et al. associated the development of post-surgical psychiatric complications with persistent seizures. The role played by the side of surgery on the risk of developing post-surgical depressive disorders has been also investigated. Quigg et al studied the relation between the laterality of the seizure focus and the risk of depression before surgery and 1 year post-surgically among 107 patients, 90 of who underwent an ATL and 17 an ETL.15 Higher pre-surgical depressive comorbidity and right-sided surgery were significant predictors of more severe postoperative depressive symptoms. Worse preoperative depressive traits predicted worse postoperative scores on scales measuring symptoms of depression. Although the side of surgery did not predict worse post-surgical symptoms of depression, there was a trend for patients with right-sided foci. Findings for the ATL subgroup (n = 90) were similar to those of the overall sample. These authors concluded that patients undergoing epilepsy surgery in the right hemispheric, especially those with high presurgical depression-related morbidity, may be particularly susceptible to clinical depression. These data differ with the findings of our study in which left-sided focus was a predictor for post-surgical depressive episodes.8 Pre-surgical ictal fear or panic has been also associated with post-surgical psychiatric complications. For example, Kohler et al. studied the association of ictal fear with mood and anxiety disorders before and 1 year after ATL.16 They compared 22 patients with ictal fear with two matched groups of patients with other type of auras and no auras at all. Presurgical and post-surgical evaluations at one to two months and one year after ATL were carried out to identify mood and anxiety disorders and the use of psychotropic medication. The majority of patients in the three groups experienced mood and anxiety disorders before surgery with comparable frequencies. Mood and anxiety disorders declined in the two control groups, but not in the ictal fear group after surgery. Postoperative mood and anxiety disorders were more common in patients with persistent seizures and in those in the ictal fear group who were seizure free. Furthermore, a majority of patients with ictal fear required the use of psychotropic medication after surgery. In addition, Kanemoto et al. have identified an association between pre-surgical postictal psychotic episodes (PIPE) and post-surgical mood disorders in a study of 52 patients who underwent an ATL. Post-surgical mood disorders presented as manic and depressive episodes during the first two post-surgical years.17

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Post-surgical psychosis The prevalence rates of post-surgical psychotic complications have been estimated to range between 1% and 10% among patients undergoing ATL. Unfortunately, the data of postsurgical psychotic studies are significantly less robust than those of post-surgical mood and anxiety disorders and consist more often than not of small case series or anecdotal reports. Several case series have include a mixture of patients with pre-surgical and de novo post-surgical psychotic disorders. De novo post-surgical psychotic episodes may present as schizophreniform-like disorders, manic episodes and postictal psychotic episodes. In the study carried out at Rush Epilepsy Center cited above, Kanner et al. identified a de novo psychotic episode in four patients within the first 6 months after surgery consisting of a manic episode in two and a paranoid episode in the other two patients.8 Symptoms remitted in two patients with pharmacotherapy without the need of hospitalization while the other two had to be hospitalized in a psychiatric unit. In one patient, symptoms remitted after the first admission, while the second patient had to be hospitalized twice. Two of these patients had lesional epilepsy caused by dysembrioplastic neuroepithelioma (DNET) in one and a ganglioglioma in the second. Shaw et al. identified 11 patients who developed de novo post-surgical schizophreniform psychosis among 320 consecutive patients (3.2%) who underwent an ATL.18 Psychotic symptomatology became apparent within the first year in all patients. These 11 patients were compared to a control group of 33 patients. Psychotic patients were more likely to have bilateral epileptiform activity, a smaller amygdala in the nonoperated side and pathologies other than MTS. Stevens identified a de novo psychotic disorder in two patients within the first 12 months after surgery among a group of 14 patients who had undergone an ATL and who were followed for a period of 20–30 years.19 Both patients were seizure-free. In a study of 57 consecutive patients who underwent an ATL, Leinonen et al., identified five (8.8%) who developed postoperative psychotic episodes.20 Two (3.5%) patients had experienced PIPE before surgery which they continued to have post-surgically. Among the other three patients, two (3.5%) experienced a definite and one (1.8%) a probable de novo schizophreniform psychotic disorder. Among 74 patients who underwent an ATL, Jensen and Larsen identified nine who developed a de novo psychotic disorder.21 Six of the latter nine patients began experiencing psychotic symptoms after they became seizurefree. Some investigators, have associated the risk of post-surgical psychotic episodes with a right temporal seizure focus. For example, Mace et al.22 reported seven consecutive patients who developed a de novo psychotic disorder following an ATL, six in the right: one developed a delusional depression and four a schizophrenic-like psychosis, while one patient was diagnosed with Capgras’ syndrome. Nonetheless, the relation between side of seizure focus and the risk of developing post-surgical psychosis cannot be established on the bases of these small case series. As in the study by Kanner et al.8 other authors have associated the presence of gangliogliomas or dysembrioplastic neuroepitheliomas with the development of de novo post-surgical psychotic disorders. Andermann et al. reported six patients who experienced a de novo psychotic disorder in six patients

from four centers.23 The psychotic disorders consisted of schizophreniform-like episodes with paranoid and depressive symptomatology. These investigators estimated a risk of 2.5% for the development of de novo psychosis (1 of 39) in patients with this type of lesions that undergo an ATL. Such association remains to be established in larger studies, however. As stated above, post-surgical manic episodes can be psychiatric complications of ATL. For example, Carran et al. reported 16 patients who developed a de novo manic episode following an ATL.24 These patients were identified from a case series of 415 consecutive patients (i.e., 3.8% of patients) who had undergone an ATL at the Comprehensive Epilepsy Center of Jefferson University Medical Center. These patients were compared to a control group of asymptomatic patients matched for age and gender and a second group of 30 patients who experienced a post-surgical depression. The manic episode occurred within the first year after the ATL and was shortlived in all but one patient. Compared to the two control groups, patients with post-surgical mania were more likely to display bilateral electrographic abnormalities, to have a right temporal seizure focus, though this difference did not reach significance when compared to the depressed group. Both post-surgical symptomatic patients were more likely to have experienced GTC seizures before surgery and to fail to achieve seizure freedom post-surgically. Postictal psychotic episodes can also occur de novo after ATL. Christodoulou et al.25 reported three cases (1%) among 282 consecutive patients who had undergone an ATL. All three patients had seizures predominantly from the contralateral (nonsurgical) site or had bilateral independent seizures, while none of the patients who failed surgery but continued to have seizures from the site of the surgery developed de novo PIPE. This supports the conclusion that patients with PIPE (chronic or de novo) have bilateral independent temporal lobe dysfunction.26 Manchanda et al. identified four patients (1.3%) who developed a de novo PIPE among a group of 298 consecutive patients who had undergone an ATL.27 All four patients had a right sided resection and had no preoperative psychiatric history. It has been established in several studies that patients with PIPE are at significantly greater risk of having bilateral independent ictal foci.26,28–30 In a study completed at the Rush Epilepsy Center, the occurrence of PIPE predicted the presence of bilateral independent ictal foci with an 89% probability.26 By the same token, patients with recurrent PIPE are at significant risk of developing interictal psychosis. To minimize this risk, clinicians must carefully weigh the possibility of offering ‘palliative’ surgery to patients with PIPE and bilateral ictal foci, particularly those with MTS, provided that most seizures originate from the side of the MTS and the neuropsychological data are concordant with the intended surgical target.

Post-surgical psychogenic nonepileptic events Ferguson and Rayport were the first authors that described the occurrence of post-surgical de novo PNEE in1965.31 The development of these events has been attributed to the ‘stress’ associated with a ‘seizure-free’ life in patients with chronic epilepsy that are not ‘emotionally, physically or economically ready’ to face their own or their families increased expectations.

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Psychiatric outcome of epilepsy surgery While this ‘hypothesis’ makes intuitive sense, the available data does not seem to support it. Here is some of the evidence. The prevalence rates of post-surgically PNEE are relatively low, ranging between 1.8–10% among the different case series. For example, in the study carriedout at the Rush Epilepsy Center cited above, 7% of the patients developed de novo PNEE8 (Kanner et al., submitted). A pre-surgical (lifetime) psychiatric history was associated with the development of post-surgical PNEE but was not found to be a predictive variable in univariate analyses. Interestingly enough, PNEE were not reported in seizure-free patients; in fact, persistent seizures were significantly associated with the development of de novo PNEE. Furthermore, failure to obtain gainful employment was not associated with the development of PNEE. Ney et al. reported the occurrence of post-surgical PNEE among 96 patients who underwent epilepsy surgery over a period of 11 years.32 Five patients (5.2%) developed de novo post-surgical PNEE. Low full-scale IQ, preoperative psychiatric comorbidity and major surgical complications were identified as risk factors. Glosser et al. identified 22 patients with post-surgical PNEE corresponding to a prevalence rate just below 10%.33 Most of these patients were women with primary right-hemisphere seizure foci and onset of their epileptic seizures after adolescence. In this study, preoperative psychiatric diagnoses were not related to increased risk of PNEE. Reuber et al. identified 13 patients with both epileptic and PNEE and investigated their post-surgical outcome:34 11 of the 13 patients had significant clinical improvement post-surgically. However, in two out of 13 patients the severity of the PNEE (including pseudo-status epilepticus) increased postoperatively despite a significant improvement of their epileptic seizures. Both patients had a pre-surgical psychiatric history. V-EEG monitoring is required in order to make the diagnosis. Once diagnosed, the PNEE are usually self limited, however psychiatric help with cognitive therapy and counseling might also be needed.

Post-surgical somatoform disorder This type of psychiatric complication is either rare or underrecognized. To-date there has been one case series of ten patients who developed somatoform disorder (other than PNEE) after ATL.35 Seven of the ten patients developed an undifferentiated somatoform disorder, one had pain and body dysmorphia, another had pain disorder, and another had body dysmorphia alone. Somatoform disorder was significantly more common among patients who underwent a right ATL (n = 9).

Treatment of post-surgical psychiatric complications Depression and anxiety disorders The treatment of post-surgical depression includes the use of pharmacotherapy, psychotherapy, particularly cognitive behavior therapy or a combination of both treatment modalities can be considered. In patients with de novo depressive disorders, it is of the essence to rule out any prior history of manic or hypomanic disorder or a family history of bipolar illness before starting an antidepressant drug, as these agents

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may worsen the course of a bipolar disorder if given without concomitant mood stabilizing agents.36 The use of antidepressant drugs of the selective serotonin reuptake inhibitor (SSRI) family are the agents of choice in the management of depressive and anxiety episodes in patients with epilepsy.37 The use of SSRIs in the treatment of anxiety disorders includes panic, generalized anxiety and obsessive compulsive disorders.37 Some of the depressive disorders can be very severe and may not respond to pharmacotherapy. In such cases, the use of electroshock therapy (ECT) can be considered. Krahn et al. reported one such case of a 25-year-old woman who developed a psychotic depression one year after undergoing a left ATL.38 ECT resulted in symptom remission without any impact on the seizure disorder. Psychotic disorders These require the use of antipsychotic drugs; this class of drugs can lower the seizure threshold and thus, should be started at low doses, titrated up slowly and kept at as low a dose as possible. Among the older antipsychotic drugs, haloperidol remains the safest with respect to the risk of seizure occurrence.39 Among the newer antipsychotic drugs (also known as atypical antipsychotic agents) all have a lower risk of causing seizures with the exception of clozapine.40 Quietapine is a drug favored by many clinicians as being the safest; although, no controlled data is available. Of note, quietapine has been one of the antipsychotic drugs not to have been found to cause slowing of the electrographic recordings’ background activity.

Impact of epilepsy surgery on pre-surgical psychiatric disorders Anxiety and depressive disorders following ATL and ETR Epilepsy surgery appears to decrease the prevalence of psychiatric comorbidities at follow-up evaluations. In the study carried out at the Rush Epilepsy Center, a lifetime psychiatric history prior to surgery had been identified in 55 patients of whom 51 were symptomatic at the time of the psychiatric evaluation.8 At the last contact, 14 continued to be symptomatic despite multiple treatment strategies and an additional 14 patients were symptomfree on psychotropic medication. Thus, epilepsy surgery resulted in total remission off psychotropic medication in 45% of patients. Among the 44 patients reported by Glosser et al., six (15%) were symptomatic before surgery and became asymptomatic post-surgically.11 Twenty-one patients were unchanged in their psychiatric status: eight who were symptomatic and 13 who were asymptomatic before surgery. While the overall prevalence of psychiatric disorders had not changed 6 months after surgery, the symptom severity measured with the Brief Psychiatric Rating Scale had improved significantly. In the study reported by Altshuler et al., 17 of 49 patients (35%) had a lifetime history of at least one major depressive episode.12 Eight of these patients never experienced another major depressive episode post-surgically. In this study, like in our study, the only predictor for post-surgical depressive disorder was a pre-surgical history of depression. Devinsky et al. reported the results of a study of 360 patients from seven epilepsy centers in the USA

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who underwent epilepsy surgery; 89% had an ATL.41 Psychiatric syndromes were identified at baseline and two years after surgery with the structured interview Composite International Diagnostic Interview (CIDI). Pre-surgically, 75 patients (22%) met criteria for a diagnosis of depression, 59 (18%) of anxiety disorders and 12 (4%) of other psychiatric disorders including bipolar illness and schizophrenia. At the two-year post-surgical evaluation, only 26 patients (9%) met diagnostic criteria for depression and 20 (10%) for anxiety, while three patients (1%) met criteria for other psychiatric diagnoses. Thus epilepsy surgery had resulted in symptom remission in more than 50% of patients. In this study, the presence of an anxiety or depressive disorder postsurgically was not associated with seizure outcome. Psychotic disorders The decision to consider epilepsy surgery in patients with refractory epilepsy and comorbid psychotic disorders has been the source of much controversy. Indeed, some epilepsy centers consider the existence of a psychotic disorder as a contraindication for epilepsy surgery while others do not, as long as the patient can cooperate during the pre-surgical evaluation and has a clear understanding of the therapeutic expectations and risks of the surgical procedure. The impact of ATL on the post-surgical course of the psychotic disorder has varied from unchanged (in a majority of cases) to improved psychotic status and/or level of functioning.42–47 Yet, several reports have suggested that, in the long term, psychiatric symptoms such as irritability and aggressive behavior can improve following ATL. For example, in a study of 74 patients who underwent an ATL, Jensen and Larsen identified 11 with a psychotic disorder pre-surgically.21 The surgical procedure had no impact on the psychotic disorders that were present pre-surgically. In a study of 52 patients, Kanemoto et al. reported recurrence of psychosis in more than two-thirds of the patients with preoperative history of interictal psychosis. Some of the patients (7/12) remained in acute psychosis for a long time.44 In a series of five patients with a chronic psychotic disorder who underwent an ATL, Reutens et al.45 reported an excellent seizure outcome in all patients. The surgical procedure did not modify the psychotic disorder post-surgically, but the absence of seizures facilitated their level of functioning. Marchetti et al. reported six patients with pre-surgical interictal psychosis who underwent an ATL.46 Five of the six patients achieved a seizure-free outcome and there was no worsening of their psychotic disorder, with relative improvement in the mental conditions of five patients. These same authors reported an additional case of a 45-year-old female patient with a 30-year history of epilepsy and recurrent postictal psychotic episodes since the age of 35 which evolved to a chronic refractory interictal psychosis.47 Following a right ATL she became seizurefree with remission of the psychotic disorder. All of these case series exemplify that patients with interictal psychosis can successfully complete a pre-surgical evaluation.

Epileptic encephalopathies The term of ‘epileptic encephalopathies’ is used to refer to psychiatric and cognitive disturbances whose onset can be

traced back to that of the seizure disorders and which can be expected to improve and at times totally remit with the abolition of the epileptic activity. In some epileptic encephalopathies, clinical seizures are rare or not identified but EEG recordings display abundant epileptiform activity. One example of this type of encephalopathy is the acquired epileptic aphasia of childhood (also known as Landau-Kleffner syndrome (LKS), in which severe language and psychiatric disturbances are the major expression of the epileptic disorder and cure of the seizure disorder often is followed by their partial to full recovery48 (see also Chapter 43). Hypothalamic hamartomas with gelastic epilepsy (HHGE) is another example of an epileptic encephalopathy but which is associated with a pharmacoresistant seizure disorder. It presents characteristically with severe psychiatric and cognitive disturbances associated with the onset of a variety of epileptic seizures but particularly gelastic seizures, and also including complex partial, secondarily generalized tonic-clonic seizures, and at times atonic or tonic seizures.49 Epilepsy surgery has become one of the treatment modalities of these two epileptic encephalopathies and the severe psychiatric and cognitive disturbances appear to remit or improve significantly with the successful cessation of epileptic activity. Unfortunately, the pre and post-surgical psychiatric disturbances have not been evaluated in a systematic manner in either of these two disorders and in most patient series the reports of improvement have been based on parents’ reports and not on structured interviews or diagnostic instruments. Thus, the absence of such data precludes a totally objective assessment of the impact of surgical treatment on the pre-surgical psychiatric manifestations and post-surgical changes of these disorders but some data are available and worth reviewing. Landau–Kleffner syndrome The surgical technique employed in LKS has consisted primarily of multiple subpial transection (MST) of the epileptogenic area, which typically involves intra and perisylvian cortex.50 Kanner et al. reviewed the post-surgical outcome of 22 children with LKS who underwent epilepsy surgery at the Rush Epilepsy Center between the years 1990–2003 (for more details see Chapter 43).51 Among the 22 children, 14 were boys and eight girls who were 6.95±1.95 years old at the time of surgery. The mean age of onset of LKS was 4.3±1.4 and the mean duration of the disease before surgery was 2.5±1.3 years; 21 had nonfunctional language for a period of at least 18 months; one child had functional language but had been experiencing frequent and recurrent language regressions that failed to be prevented with pharmacotherapy that included multiple AEDs trials and steroids. Behavioral problems were reported in 19 children; clinical seizures were also identified in 19 patients. In 14 patients (63.6%) only MST of intra and/or perisylvian cortex was performed. In seven (32%) a combination of MST and resection of temporal lobe structures was carried out, while one child underwent a resection of the planum temporale in the right hemisphere of a right-handed boy. Among the 19 children with clinical seizures before surgery, 15 (79%) became seizure free, two had rare seizures, one had >90%, and one had >90% seizure frequency reduction. The presence of epileptiform activity (but not a CSWS pattern) in the last EEG was not associated with a worse post-surgical

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Psychiatric outcome of epilepsy surgery language recovery. On the other hand, recurrence of language disturbances occurred in three patients who had a recurrence of a CSWS pattern after surgery. Post-surgical neuropsychological and speech evaluations were carried out after a mean period of 34.1±19.9 (7–75 months). The mean baseline score of the language test used for evaluation of expressive vocabulary, the Expressive One Word Picture Vocabulary Test-Revised (EOWPVT-R, expressed as age equivalent in months old) was 12.8±9.0 months, while the mean baseline score of the Peabody Picture Vocabulary TestRevised (PPVT-R) which is used for evaluation of receptive language was 14.6±12.9 months. At the last formal speech evaluation, the mean EOWPVT and PPVT scores displayed significant increments to 144±72.9 months and 144±73.8 months, respectively with mean gains of 124±60.1 months and 129±59.2 months respectively. In addition, there was a significant correlation between the duration of post-surgical follow-up and the gains made on the PPVT (r = 0.56, p = 0.02) and a statistical trend for the EOWPVT (r = 0.4, p = 0.09). At that time, 20 of the 22 patients were still receiving speech therapy. Following a mean post-surgical follow-up period of 48.3±30.2 months, 16 children (72%) had regained functional language as defined by the ability to use complex sentences and understand what was being said to them. Despite these significant gains, only nine of these children (41%) were in a regular class without a need of assistance or further speech therapy. Finally, behavioral improvement was reported in 17 of the 22 patients (77%) by the parents, though there was no significant association between recovery of functional language and reported behavioral improvement. Encephalopathy due to HHGE Three surgical techniques have been advocated for the treatment of HHGE, including resection of the hypothalamic hamartoma, radiation with gamma knife and disconnection or destruction of the hamartoma with stereotactic radiofrequency.49,52–54 The behavioral and cognitive changes reported in these patients are quite variable. In most patients, behavioral difficulties are characterized by aggressive behavior, uninhibited tendencies, and clinical pictures indistinguishable from attention deficit with hyperactivity, and irritability. Up to 30% of patients may have autistic features. In those patients who appear to have normal cognition, insidious changes often

Table 133a.1

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develop before puberty.49 In most patients, gelastic events often are the only seizure manifestation during the first 5–10 years of life. However, most patients develop other seizure types before puberty. The frequency of the gelastic seizures may be as high as 100 attacks per day. The frequency of other seizures is variable, but often they occur weekly. Of note, some patients who have frequent gelastic seizures do not deteriorate, whereas others with other types of epileptic seizures have worse outcome. The association between seizures and behavioral changes is not clear as the number of seizures in this syndrome often is difficult to estimate. However, depth EEG recordings from the hamartoma often demonstrate almost continuous discharges with or without secondary spread. It is possible that this almost continuous epileptic activity causes considerable cortical and subcortical dysfunction. For parents, the behavioral and cognitive problems often become more important than the seizures. At least 11 case series of patients with HHGE treated with one of the three techniques cited above and totaling more than 120 patients have been published in the literature in the last 10 years. There is a consensus among the various investigators that successful lesioning or removal of the hamartoma leads to major improvements in cognitive performance and behavior. Most astonishing is the rapid cognitive and behavioral changes observed in these patients. Of the 11 case series published, data from seven are included in Table 133a.1 and presents cognitive and behavioral information on cognitive and behavioral changes post-surgically.55–61 Five of the series consisted of resection of the HH and one of stereotactic surgery with gamma knife and one with interstitial radiation. Improvement of cognitive and psychiatric disturbances was observed in a majority of patients.

Impact of pre- and post-surgical psychiatric illness on post-surgical seizure outcome Most of the studies that have investigated the relationship between post-surgical psychiatric disturbances and seizure outcome have found a significant association between persistent post-surgical seizures and post-surgical depressive disorders. Furthermore, Vickery et al. have also demonstrated an

Surgical case series with data on post-surgical cognitive and psychiatric changes Pre-surgical disturbances

Authors

N

Cognitive disturbances

Psychiatric disturbances

Improvement post-surgically Cognitive disturbances

Psychiatric disturbances

Seizures

Rosenfeld (2003) Fohlen (2003) Palmini (2002) Bonhage (2003)

5 18 13 8

5 18 13 8

5 18 13 8

5 17 13 5

5 17 13 5

5 17 13 5

Freeman (2003) Striano (2005) Regis (2005)

12 6 25

12 6 25

12 ? 0

12 3 9

11 ? 9

11 3 18

Surgical procedure Resection Resection Resection Interstitial Radiation Resection Resection Gamma knife

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association between persistent seizures, including persistence of only auras and poor quality of life post-surgical.62,63 Indeed, compared to patients who are completely seizurefree including free of auras had significantly higher scores on the Quality of Life in Epilepsy Inventory-89 (QOLIE-89) than those with only auras. The negative impact of persistent auras on the quality of life may be mediated by the need to be kept on AEDs or even the use of higher doses of AEDs to assuage the concern of recurrent seizures. Nonetheless, these data are counterintuitive since patients with auras but no disabling seizures can function normally in all areas. In fact, in a study by Kanner et al., a pre-surgical lifetime psychiatric history of depression was the strongest predictor of persistent auras (in the absence of disabling seizures) on the one hand, and of post-surgical psychiatric complications, particularly depression on the other64 and (Kanner et al., submitted). Thus, these data raise the question of whether the worse QOLIE-89 scores in patients with persistent auras are driven by a concurrent mood disorder and not (only) by the auras. A few studies have suggested that a pre-surgical psychiatric history is associated with a worse post-surgical seizure outcome. For example, in a study of 121 patients who underwent an ATL, Anhoury et al. reported a worse post-surgical seizure outcome for patients with a lifetime psychiatric history compared with those without.65 Koch-Stoker investigated the postsurgical seizure outcome among 100 consecutive patients who underwent an ATL; 78 had a pre-surgical lifetime psychiatric history. Among patients without comorbid psychiatric history, 89% were seizure free after surgery while this occurred in only 43% of patients with pre-surgical psychiatric history (unpublished data). In the study cited above, Kanner et al.64 used a logistic regression model to identify predictors of postsurgical seizure outcome in the 99 consecutive patients who had undergone an ATL. Covariates included: (i) cause of TLE (MTS, lesional TLE and idiopathic TLE); (ii) history of secondarily generalized tonic-clonic seizures (never, only at the onset of the seizure disorder, 1–2/year, >2year); (iii) duration of seizure disorder; (iv) lifetime history of depression (may have included major depressive disorder, dysthymia). As already mentioned above, a lifetime history of depression was the sole predictor of persistent auras in the absence of disabling seizures. In addition, the cause of the temporal lobe epilepsy and a lifetime history of depression were both significant predictors of failure to achieve freedom from disabling seizures. When the outcome variable was no disabling seizures in the last 2 years, the cause of TLE was the strongest predictor, while a lifetime history of depression yielded a statistical trend. These data raise another question – ‘Is it possible that a psychiatric history, particularly depression is an ‘indicator’ of a more severe form of epilepsy?’

Psychosocial outcome Family dynamics Epilepsy surgery is expected to have a positive significant impact on the patient’s life. With the achievement of seizure freedom, patients can become more independent, not only as it pertains to their ability to drive but in other areas of their life. Paradoxically, in some cases seizure freedom can have a negative impact on family dynamics. Indeed, some family

members become accustomed to the patients’ limitations and dependency on others and have difficulties allowing the patient to become more independent and see their role in life (unconsciously) as that of a ‘caretaker’ without which they cannot ‘function’. Unfortunately, these dysfunctional family dynamics are not rare in families of patients with a chronic illness like epilepsy and invariable are bound to lead to conflict when patients try to become more independent. In fact, divorce is not an uncommon ‘complication’ of successful epilepsy surgery. Thus, all couples and families need to be evaluated for the eventual risk of this type of family problems. Gainful employment Obtaining gainful employment or getting a better job are some of the obvious goals of a successful surgical treatment. Unfortunately, such is not always the case. A review of the literature reveals that the main factors associated with postsurgical employment are: reduction of seizures or seizure freedom, pre-surgical cognitive ability, psychiatric comorbidity, pre-surgical employment and improvement of neuropsychological function.66 In a study of 88 adult patients who underwent an ATL at the Rush Epilepsy Center, the predictors of post-surgical gainful employment included: working before surgery, achieving a seizure-free state, a negative lifetime history of depression and being a woman.67 Lendt et al. found that a young age at the time of the surgery and improvement of the general neuropsychological functioning and especially attention are associated with employment after the surgery.68 In another study, Reeves et al. found that being a student or working full time within a year before the surgery, driving after the surgery and obtaining further education after the surgery were associated with full time work postoperatively.69 Clearly, these data are indicative of the need to carry out vocational evaluations before surgery among unemployed patients.

Disclosure of post-surgical psychiatric complications As shown above, epilepsy surgery is associated with postsurgical psychiatric complications which should be openly discussed with patients and family members with as much detail as the other surgical risks. Indeed, patients should be advised of the risk of post-surgical depressive and anxiety episodes occurring within the first 12 months, with a higher symptom incidence in the first 3–6 months and a tendency to remit by 12 to 24 months. This is especially true when the patient has a previous history of mood disorder and the symptoms are actually an expression of a recurrence or exacerbation of pre-surgical depressive and/or anxiety disorders, while de novo mood/anxiety disorders are significantly less frequent. In patients undergoing ATL de novo depressive and anxiety disorders can be expected in 10–15% and a risk of 10–15% of persistent mood and anxiety disorders should be disclosed. Patients undergoing extratemporal resections have a lower risk of developing post-surgical psychiatric complications compared to patients undergoing an ATL, though the data available on post-surgical complications after ETL are rather sparse and more studies are needed to establish the

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Psychiatric outcome of epilepsy surgery actual risk. With respect to the potential risk of post-surgical psychotic complications, patients and family members should be advised that while de novo post-surgical psychotic complications have been estimated to range between 1–10% following an ATL, the actual frequency remains to be established.

Concluding remarks The data reviewed in this chapter clearly indicates that patients undergoing epilepsy surgery are at risk of developing psychiatric complications during the first post-surgical 12 months.

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While in a majority of patients, symptom remission is expected, 10–15% of patients may continue experiencing psychiatric symptoms that may fail to respond to multiple treatments. On the other hand, epilepsy surgery is expected to improve the course of psychiatric disorders, particularly anxiety and depressive disorders in more than 50% of patients. This is another advantage of epilepsy surgery which is rarely discussed with patients and families, in part because of a failure to include a psychiatric evaluation in most pre-surgical evaluations. Finally, the suggestion that pre-surgical psychiatric disorders may be predictive of post-surgical seizure outcome requires further research as it may help identify common pathogenic mechanisms between psychiatric and epileptic disorders.

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Kanner AM. Depression in epilepsy: prevalence, clinical semiology, pathogenic mechanisms and treatment. Biol Psychiatry 2003;54:388–98. Kessler RC, McGonagle KA, Zhao S et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: results from the national comorbidity study. Arch Gen Psychiatr 1994;51:8–19. Toone BK, Garralda ME, Ron MA. The psychoses of epilepsy and the functional psychoses: a clinical and phenomenological comparison. Br J Psychiatry 1982;141:256–61. McDermott S, Mani S, Krishnaswami S. A population-based analysis of specific behavior problems associated with childhood seizures. J Epilepsy 1995;8:110–18. Koch-Stoecker S. Psychiatric effects of surgery for temporal lobe epilepsy. In: Trimble M Schmitz B, eds. The Neuropsychiatry of Epilepsy. Cambridge: Cambridge University Press, 2002:266–82. Hill D, Pond DA, Mitchell W, Falconer MA. Personality changes following temporal lobectomy for epilepsy. J Ment Sci, 1957;103:18–27. Taylor DC. Mental state and temporal lobe epilepsy. A correlative account of 100 patients treated surgically. Epilepsia 1972;13(6):727–65. Kanner AM, Tilwalli S, Byrne R. Psychiatric and neurologic predictors of post-surgical psychiatric complications following a temporal lobectomy. Neurology, 2005;64:(Suppl):1 A–358. Bruton CJ. The neuropathology of temporal lobe epilepsy. In: Maudsley Monographs 31. Oxford;Oxford University Press, 1988. Wrench J, Wilson SJ, Bladin PF. Mood disturbance before and after seizure surgery: A comparison of temporal and extratemporal resections. Epilepsia, 2004;45:534–43. Glosser G, Zwill AS, Glosser DS et al. Psychiatric aspects of temporal lobe epilepsy before and after anterior temporal lobectomy. J Neurol Neurosurg Psychiatry 2000;68:53–8. Altshuler L, Rausch R, DeIrahim S, Kay J, Crandall P. Temporal lobe epilepsy, temporal lobectomy and major depression. J Neuropsychiatry Clin Neurosci, 1999;11(4):436–43. Ring HA, Moriarty J, Trimble MR. A prospective study of the early postsurgical psychiatric associations of epilepsy surgery. J Neurol Neurosurg Psychiatry 1998;64(5):601–4. Blumer D, Wakhlu S, Davies K et al. Psychiatric outcome of temporal lobectomy for epilepsy: incidence and treatment of psychiatric complications. Epilepsia 1998;39:478–86. Quigg M, Broshek DK, Heidal-Schultz S et al. Depression in intractable partial epilepsy varies by laterality of focus and surgery. Epilepsia 2003;44(3):419–24. Kohler CG, Carran MA, Bilker W et al. Association of fear auras with mood and anxiety disorders after temporal lobectomy. Epilepsia 2001;42(5):674–81. Kanemoto K, Kim Y, Miyamoto T, Kawasaki J. Presurgical postictal and acute interictal psychoses are differentially associated with postoperative mood and psychotic disorders. J Neuropsychiatry Clin Neurosci 2001;13(2):243–7. Shaw P, Mellers J, Henderson M et al. Schizophrenia-like psychosis arising de novo following a temporal lobectomy: timing and risk factors. J Neurol Neurosurg Psychiatry 2004;75:1003–8. Stevens JR. Psychiatric consequences of temporal lobectomy for intractable seizures: a 20–30-year follow-up of 14 cases. Psychol Med 1990;20(3):529–45.

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Leinonen E, Tuunainen A, Lepola U. Postoperative psychoses in epileptic patients after temporal lobectomy. Acta Neurol Scand 1994;90(6):394–9. Jensen I, Larsen JK. Mental aspects of temporal lobe epilepsy. Follow-up of 74 patients after resection of a temporal lobe. J Neurol Neurosurg Psychiatry 1979;42:256–65. Mace CJ, Trimble MR: Psychosis following temporal lobe surgery: a report of six cases. J Neurol Neurosurg Psychiatry 1991;54(7): 639–44. Andermann LF, Savard G, Meencke HJ et al. Psychosis after resection of ganglioglioma or DNET: evidence for an association. Epilepsia 1999;40(1):83–7. Carran MA, Kohler CG, O’Connor MJ, Bilker WB, Sperling MR. Mania following temporal lobectomy. Neurology 2003;61:770–4. Christodoulou C, Koutroumanidid M, Hennessy MJ et al. Postictal psychosis after temporal lobectomy. Neurology 2002;59(9): 1432–5. Kanner AM, Soto A. Ictal recordings in postictal psychosis and postictal depression. Neurology 1998;50:4(Suppl 4):A397. Manchanda R, Miller H, McLachlan RS. Post-ictal psychosis after right temporal lobectomy. J Neurol Neurosurg Psychiatry 1993;56(3): 277–9. Devinsky O, Abrahmson H, Alper K et al. Postictal psychosis: a case control study of 20 patients and 150 controls. Epilepsy Res 1995;20:247–53. Umbricht D, Degreef G, Barr WB et al. Postictal and chronic psychosis in patients with temporal lobe epilepsy. Am J Psychiatry 1995;152:224–31. Kanemoto? Kawasaki J, Kawai I. Postictal psychosis: a comparison with acute interictal and chronic psychoses. Epilepsia 1996;37 (Suppl 6);551–6. Ferguson SM, Rayport M. The adjustment to living without epilepsy. J Nerv Ment Dis. 1965;140:26–37. Ney GC, Barr WB, Napolitano C et al. New-onset psychogenic seizures after surgery for epilepsy. Arch Neurol, 1998;55(5): 726–30. Glosser G, Roberts D, Glosser DS. Nonepileptic seizures after resective epilepsy surgery. Epilepsia, 1999;40(12):1750–4. Reuber M, Kurthen M, Fernandez G et al. Epilepsy surgery in patients with additional psychogenic seizures. Arch Neurol 2002;59(1):82–6. Naga AA, Devinski O, Barr WB. Somatoform disorders after temporal lobectomy. Cogn Behav Neuro 2004;17(2):57–61. Hirschfield RMA, Bowden CL, Gitlin MJ et al. Practice guideline for the treatment of patients with bipolar disorder. Am J Psychiatry 2002;159(Suppl 4):1–15. Tollefson GD, Rosenbaum JF. Selective serotonin reuptake inhibitors. In: Schatzberg AF, Nemeroff CB, eds. Textbook of Psychopharmacology, 2 edn. Washington, DC: American Psychiatric Association Press, 1998:219–37. Krahn LE, Rummans TA, Peterson GC, Cascino GD, Sharbrough FW. Electroconvulsive therapy for depression after temporal lobectomy for epilepsy. Convuls Ther 1993;9(3):217–19. Whitworth AB, Fleischhacker WW. Adverse effects of antipsychotic drugs. Int Clin Psychopharmacol 1995;9(Suppl 5):21–7. Pacia SV, Devinsky O. Clozapine-related seizures: experience with 5,629 patients. Neurology 1994;44(12):2247–9.

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Devinsky O, Barr WB, Vickrey BG et al. Changes in depression and anxiety after resective surgery for epilepsy. Neurology 2005;65(11):1744–942. Walker AE, Blumer D. Behavioral effects of temporal lobectomy for temporal lobe epilepsy. In: Blumer D, ed. Psychiatric Aspects of Epilepsy. Washington, DC: American Psychiatric Press, 1984: 295–323. Trimble MR. Behaviour changes following temporal lobectomy, with special reference to psychosis. J Neurol Neurosurg Psychiatry 1992;55:89–91. Kanemoto K, Kim Y, Miyamoto T, Kawasaki J. Presurgical postictal and acute interictal psychoses are differentially associated with postoperative mood and psychotic disorders. J Neuropsychiatry Clin Neurosci 2001;13(2):243–7. Reutens DC, Savard G, Andermann F, Dubeau F, Olivier A. Results of surgical treatment in temporal lobe epilepsy with chronic psychosis. Brain 1997;120:1929–36. Marchetti RL, Fiore LA, Valente KD et al. Surgical treatment of temporal lobe epilepsy with interictal psychosis: results of six cases. Epilepsy Behav 2003;4(2):146–52. Marchetti RL, Tavares AG, Gronich G, Fiore LA, Ferraz RB. Complete remission of epileptic psychosis after temporal lobectomy: case report. Arq Neuropsiquiatr 2001;59(3-B):802–5. Landau WM, Kleffner F. Syndrome of acquired aphasia with convulsive disorder in children. Neurology 1957;7: 523–30. Kuzniecky R, Guthrie B, Mountz J et al. Intrinsic epileptogenesis of hypothalamic hamartoma and gelastic epilepsy. Ann Neurol 1997;44:60–67. Morrell F, Whisler WW, Smith MC et al. Landau-Kleffner syndrome: treatment with subpial intracortical transection. Brain 1995;118:1529–46. Kanner AM, Byrne R, Van Slyke P et al. Functional language recovery following a surgical treatment of Landau-Kleffner Syndrome. Neurology 2005;64:(Suppl 1):A-359. Valdueza J, Cristante l, Dammann O et al. Hypothalamic hamartomas. Special reference to gelastic epilepsy and surgery. Neurosurgery 1994;34:949–58. Kanner AM, Kuzniecky R. Psychiatric and cognitive phenomena as an expression of epileptic encephalopathies. In: Ettinger AB, Kanner AM, eds. Psychiatric Issues in Epilepsy, 2 edn. Baltimore: Williams and Wilkins, 2006: Chap 20. In press. Breningstall G. Gelastic seizures, precocious puberty and hypothalamic hamartomas. Neurology 1983;35:1180–83. Regis J, Hayashi M, Eupierre LP et al. Gama knife surgery for epilepsy related to hypothalamic hamartomas. Acta Neurochir Suppl 2004;91:33–50.

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Rosenfeld JV, Harvey AS, Wrennall J, Zacharin M, Berkovic SF. Transcallosal resection of hypothalamic hamartomas, with control of seizures, in children with gelastic epilepsy. Neurosurgery 2001;48(1):108–18. Fohlen M, Lellouch A, Delanlande O. Hypothalamic hamartoma with refractory epilepsy: surgical procedures and results in 18 patients. Epileptic Disord 2003;5(4):267–73. Palmini A, Paesschen WV, Dupont P, Van Laere K, Van Driel G. Status gelasticus after temporal lobectomy: ictal FDG-PET findings and the question of dural pathology involving hypothalamic hamartomas. Epilepsia 2005;46(8):1313–16. Schulze-Bonhage A, Homberg V, Trippel M et al. Interstitial radiosurgery in the treatment of gelastic epilepsy due to hypothalamic hamartomas. Neurology 2004;62:644–7. Freeman JL, Harvey AS, Rosenfeld JV, Wrennall JA. Generalized epilepsy in hypothalamic hamartoma. Neurology 2003;60:762–7. Striano S, Striano P, Sarappa C, Boccella P. The clinical spectrum and natural history of gelastic epilepsy-hypothalamic hamartoma syndrome. Seizure. 2005;14(4):232–9. Vickrey BG, Hays RD, Engel J Jr et al. Outcome assessment for epilepsy surgery: the impact of measuring health-related quality of life. Ann Neurol 1995;37(2):158–66. Vickrey BG, Hays RD, Rausch R et al. Outcomes in 248 patients who had diagnostic evaluations for epilepsy surgery. Lancet 1995;346(8988):1445–9. Kanner AM, Tilwalli S, Smith MC et al. A presurgical history of depression is associated with a worse postsurgical seizure outcome following a temporal lobectomy. Neurology, 2004;62:(Suppl 5): A389. Anhouri S, Brown RJ, Krishnamoorthy ES, Trimble MR. Psychiatric outcome following temporal lobectomy: a predictive study. Epilepsia, 2000;41:1608–15. Kanner AM and Balabanov AJ. Neurorehabilitation in epilepsy. In: Textbook of Neural Repair and Rehabilitation. Selzer ME, Cohen L, Gage FH, eds. Cambridge: University Press, 2006: Volume 2, 542–59. Kanner AM, Frey M, Byrne R. Predictors of postsurgical gainful employment following an anterotemporal lobectomy. Presented at the Annual Meeting of the American Academy of Neurology, San Diego, CA, May, 2006. Lendth M, Helmstaedter C, Elger CE. Pre- and postoperative socioeconomic development of 151 patients with focal epilepsies. Epilepsia 1997;38:1330–7. Reeves AL, So EL, Evans RW et al. Factors associated with work outcome after anterior temporal lobectomy for intractable epilepsy. Epilepsia 1997;38(6):689–95.

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Sudden unexpected death in epileptic patients after epilepsy surgery D Schmidt and P Ryvlin

Introduction People with epilepsy have a reduced life expectancy.1 Mortality has been consistently shown to be 2–3 times higher in people with epilepsy than in the general population (for a review see Tellez-Zentano and Wiebe, 2005)2 and even higher in populations with more severe epilepsy or associated disorders.3–5 This increased mortality is attributable to both the underlying disease and to epilepsy itself, and, in rare cases, to fatal side effects of medical or surgical treatment. Common causes of death include pneumonia and other medical illnesses, suicide, seizure-related death and sudden unexpected death (SUDEP). The latter two causes account for between one–fourth and two-thirds of all deaths,6 making SUDEP the most common cause of death in patients with epilepsy.7 Reducing mortality is an important aim of epilepsy management.8 Given that epilepsy surgery is the only intervention to render large proportions of patients with drug resistant epilepsy seizurefree with or without antiepileptic drugs,9 it is of interest to examine the potential of epilepsy surgery to reduce seizure-related mortality. In this chapter, we focus on the question if epilepsy surgery is able to reduce the incidence of SUDEP in refractory epilepsy.

Definition of SUDEP To establish the presence of SUDEP, an expert panel in 1997 10 suggested all of the following criteria: (a) a diagnosis of epilepsy; (b) death occurring unexpectedly while in a reasonable state of health; (c) death occurring suddenly; (d) death occurring during normal activities and benign circumstances; (e) not finding an obvious medical cause of death during postmortem examination; (f) death not resulting from trauma, asphyxia due to aspiration or intractable status epilepticus. SUDEP is considered ‘definite’ when all criteria are met, and ‘probable’ when there are no postmortem data. Other definitions of SUDEP exist.11,12 Some authors use Nashef and Brown’s definition of SUDEP,11 i.e., ‘sudden, unexpected, nontraumatic and drowning death in an individual with epilepsy with or without evidence for a seizure and excluding documented status epilepticus, where postmortem examination does not reveal a cause of death’. All definitions share the prob-

lem of accurate classification due to insufficient information about the circumstances surrounding death, and to the infrequent practice of postmortem examinations.

SUDEP in surgical candidates and operated patients A review of 19 studies looking at overall mortality in epilepsy determined that the proportion of SUDEP among all causes of death in surgical candidates or operated patients ranged from 40–77%.2 The annual incidence of SUDEP was highest in studies of patients who had epilepsy surgery or were surgical candidates (2.2:1000–10:1000) or were undergoing vagus nerve stimulation therapy (4:1000), with a median of 3.6:1000 patient-years.2 Accordingly, in a review pooling data from all drug-resistant epilepsy series providing detailed numbers of SUDEP and patient-years of follow-up, we found a total of 154 SUDEP among 41, 439 person-years, resulting in a mean annual SUDEP incidence of 3.7/1000.13 A high number of AEDs, high frequency of seizures, and long duration of epilepsy were found to be more commonly found in high-risk than in low risk populations.2 In addition, uncontrolled tonicclonic seizures have been associated with a higher risk of seizure-related death and SUDEP.6,14 The role of seizures in the pathophysiology of SUDEP is therefore briefly discussed in the next paragraph.

Seizures and SUDEP Although a detailed account of the pathophysiology of SUDEP is beyond the scope of this chapter, a large body of evidence suggests that SUDEP, although unexpected, is not fully unexplained any more.15 SUDEP is seizure related in the majority of witnessed cases.14,16–19 Two major mechanisms have been implicated, one is obstructive or central apnea and neurogenic pulmonary edema.11,18,20–24 The other is ictal cardiac dysfunction, either through ictal asystole, or ictal cardiac ischemia.25–29 The cardiac hypothesis of SUDEP has been strenghtened by the detection of potentially fatal asystole in three out of 20 patients with drug-resistant partial epilepsy when examined by implantable loop EKG.31 Furthermore an

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incidence of 0.4 % of ictal asystole has been documented in 1244 video-EEG recordings.31 Thus, it is not unreasonable to expect that improving seizure control or disease changes associated with better seizure control after epilepsy surgery might reduce mortality. In the following paragraph, we briefly review the evidence that the incidence of SUDEP is actually reduced after surgery for epilepsy.

Does epilepsy surgery lower the incidence of SUDEP? The impact of resective epilepsy surgery on mortality has been evaluated in several series comparing pre- and postoperative mortality rates (Table 133b.1). Three of these series have concentrated on temporal lobe surgery and demonstrated that the postoperative mortality rate was normal in seizure free patients, whereas it was significantly higher, and comparable to that observed in drug resistant epilepsy cohorts, in patients with poor seizure outcome after surgery.6,32–33 The authors implied that had surgery not been performed, the patients would have continued to suffer excess mortality, dying at rates similar to patients whose seizures persisted.6,32–33 This result suggests that successful surgery is associated with dramatic reduction of the risk of epilepsy-related death. However, the authors cautioned that they cannot exclude the possibility that the different responses of their patients to surgery could indicate underlying biological differences that are related to mortality rates.6,32–33 In fact, other series could not confirm the above findings, and reported comparable death rates in patients with and without postoperative seizure control.34,33 In addition, a number of confounding factors need to be considered when examining the relationship between seizure

Table 133b.1

control and mortality after epilepsy surgery. If, for example, mortality is reduced after surgery only in those with complete seizure control, or epilepsy surgery increases mortality in those who remain uncontrolled or the minority with worse control after surgery, the net group effect of surgery on mortality may be small. Furthermore, if the subgroup that responds to surgery had no increased seizure-related mortality to begin with, surgery may have had no effect on mortality even when improving seizure control. Also, theoretically, all-cause mortality may be related to the underlying cause of the epilepsy, and surgery might not be able to completely remove the cause and thus be not able to lower mortality. Finally, reports of survival after epilepsy surgery have been heterogeneous in sample selection, observation periods, analytic methods, choice of comparison groups, and based on small numbers of deaths.6,34–37 Also, patients were not stratified according to their pre-surgical risk factors for SUDEP or seizure-related death. Another attempt to study the impact of resective epilepsy surgery on mortality, is to compare cohorts of surgically and medically treated patients. Seven studies have addressed this issue, using various methodologies, and again providing controversial results (Table 133b.2). Only two of the seven series reported a significantly lower death rate in operated patients as compared with those medically treated.35,39 However, the result by Vickrey and co-workers could be partly explained by preoperative differences between the two populations, including the type of epilepsy (mainly nonlocalized in the medical group and temporal in the operated patients) and the baseline seizure frequency which was significantly higher in the non operated patients.35 Furthermore, the other five series failed to demonstrate a difference in mortality between operated and nonoperated patients.37,32,38–42 In the next paragraph we examine the evidence that surgery was in fact responsible for the lower mortality rate reported in some studies.

Impact of resective surgery on mortality: seizure-free versus not seizure-free patients

Study population (no. of patients)

SMR: seizure-free patients

SMR: not seizure-free patients

Authors

196 total, 106 TLE

228 at 2 years: 5 died, SMR=3.8 (3 SUDEP); 69 at 2 years, SMR = 6; no difference

255 at 2 years: 6 died, SMR=4.3 (3 SUDEP) 100 at 2 years, SMR = 7.8

393 TLE

199, no death; significantly lower

215 TLE

148 patients, follow-up: 1–15 years: 3 died, SMR = 1.7 (CI: 0.35–5.0), 1 SUDEP, 1 cancer, 1 suicide; significantly lower 11/13 who died were not seizure free (4 SUDEP (definite and probable), 7 seizure-related) 313 with Engel outcome score I, death and SUDEP rate per person-year: 1/535, 0

194, 11 died, SMR = 4.7 (9 epilepsy related) 67 patients follow-up: 1-15 years: 8 died, SMR = 7.4 CI: 3.1–14.5); 5 Seizure/ SUDEP, 3 accident/ suicide 3/13 who died were seizure free (2 SUDEP, 1 killed by vehicle, seizure-related) 85 patients with Engel outcome score II–IV, death and SUDEP rate per person-year: 1/81.3, 1/97.6

Nilsson et al. (2003) (ns) Stavem and Guldvog (2005) (ns) Sperling et al. (1999) (p = 0.05) Salanova et al. (2002) (no Overlap of CI, significant difference) Hennessey et al. (1999) (difference)

596 total, 355 TLE

299 surgical patients 398 surgical patients

Sinha et al. (2005), (p = 0.36)

Abbreviations. SMR = standard mortality ratio per 1000 patient years, SUDEP = sudden unexplained death I epilepsy, TLE = temporal lobe epilepsy.

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Sudden unexpected death in epileptic patients after epilepsy surgery Table 133b.2

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Impact of surgery on mortality: operated versus nonoperated patients

Study population (no. of patients)

SMR: operated patients

SMR: nonoperated patients

Authors

202 surgical vs. 46 nonsurgical patients

14 died (7%) at 6 yr. follow-up

9 died (20%) at average follow-up of 6 yr.

196 total, 106 TLE

69 at 2 years, SMR = 6

100 at 2 years, SMR = 7.8

Vickrey et al. 1995 (p 1 yr

103

–

79

–

125

71

SF-36 HAD MMPI WPSI ESI-55

> 2 yrs mean 4 yrs 2m 1 yr > 1 yr

Improvement: seizure-free aura-free > aura-free > continuing seizures Improvement in 6/11 scales at 24 m, better than at 6 or 12 m. Improved when seizure free or 90% reduction. Decline in others Improvement when seizure free v 10 seizures a year or no surgery Correlation with seizure outcome Seizure free: improved 7/8 scales Improved only when seizure free

Selai 200011

25

15

Mean 1 yr

Markand 200017

53

37

QOLAS ESI-55 EQ-5D QOLIE-89

Wiebe 200114 Spencer 200315 Lowe 200431

40

40

QLIE-89

1 yr

231

–

QOLIE-89 BAI, BDI

> 2 yrs

Improvement apparent at 3 mo’s Correlation with seizure outcome

50

–

QOLIE-89

>2 yrs

Improvement when seizure free

Kellet 199730 Malmgren 199746 Wheelock 199821 Gilliam 19991

For abbreviations of QOL instruments, see pages 5,6

1, 2 yrs

Improved 8/11 scales Correlation with mood, employment, driving, AED use but not seizure status Improved 2/3 ESI-55 composite scores and QOLAS when seizure free or >75% seizure reduction Improved 10/17 scales Greater improvement at 2 yrs v 1 yr Seizure free aura free best outcome Surgery group improved more than medical group

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Psychosocial outcome and quality of life outcome All studies have shown an improvement in usually more than one quality of life domains. Some have shown an improvement as early as 3 months,14,15 while two reports noted that improvement was greater at 24 months than at earlier time points.16,17 Half of the studies employed a ‘control’ or comparison group of patients who did not have surgery: either because they did not have a localizable epileptogenic zone amenable for surgery, or because candidates declined surgery or were still awaiting surgery. All except one study1 that specifically looked at the relationship between postoperative seizure control and QOL outcomes revealed a correlation between postoperative seizure status and QOL measurements: namely that a seizure-free status, or very few seizures, were correlated with higher QOL scores. The most detailed analysis of postoperative seizure outcome status with QOL measurements was that by Vickery based on UCLA data.22 It showed significantly higher QOL scores in patients who were completely free of seizures and auras (Engel Class Ia), as compared to those who had residual auras, who in term were separable in QOL measures from those with 2–12 seizures a year, and from those with >12 seizures a year. The latter had the lowest scores. Of interest, the study found no difference in QOL measure amongst seizure-free patients whether they remained on antiepileptic medications or not. That seizure-free and aura-free patients had the most pronounced improvement in QOL was confirmed by another study.17 There have been gratifyingly few indicators pointing to deterioration in psychosocial functioning after surgery, but it could be that this has not been looked into carefully. In order to answer this and other questions an ideal study would comprise both a surgery and medical treatment arm, with sequential QOL measures over time, starting at baseline

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before intervention. The one study that satisfied this design did not have the details to address this issue.14 Anecdotal clinical experience suggests that deterioration in psychosocial function does unfortunately occur in a minority of patients, usually in those who have failed to obtain satisfactory seizure control sometimes with compounding neurological or cognitive deficits. Partial support comes from the Bonn series that found socioeconomic deterioration when it occurs to be related to insufficient seizure control.3 Markand17 found the only significant decline in QOL scores from baseline in patients with persisting seizures (not including auras) and that was in the social support domain of the QOLIE-89.

Summary There is now a wealth of data that can be called on when counseling patients going through surgical evaluation and treatment. In addition to and in consequence of an improvement in seizure control, patients can rightfully anticipate an improvement in the potential to participate in the full range of life activities, which can extend to work and driving. As would seem to be obvious, seizure-free patients would no longer be exposed to the risk of sudden death as compared to those with continuing seizures. How long it takes for the positive benefits of epilepsy surgery to become apparent remains a subject of enquiry. Although some studies showed an improvement as early as 3 months after surgery, gains in life functions and employment will likely take much longer. Despite the consensus for positive change after successful surgery, we need to be mindful that there are others who can be unsettled or challenged by changes that come about after surgery.

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Robinson L, Saykin A. Psychological and psychosocial outcomes of anterior temporal lobectomy. In: Bennett T, ed. Neuropsychology of Epilepsy. New York: Plenum Press, 1992:661–7. Guldvog B, Loyning Y, Hauglie-Hansen E, Flood S, Bjonaes H. Surgical versus medical treatment for epilepsy. II. Outcome related to social areas. Epilepsia 1991;32:477–86. Wiebe S, Blume W, Girvin JP et al. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med 2001;345:311–18. Spencer SS, Berg AT, Vickrey BG et al. Initial outcomes in the multicenter study of epilepsy surgery. Neurology 2003;61:1680–5. McLachlan RS, Rose KJ, Derry PA et al. Health-related quality of life and seizure control in temporal lobe epilepsy. Ann Neurol 1997;41:482–9. Markand OM, Salanova V, Whelihan E, Emsley CL. Health-related Quality of life outcome in medically refractory epilepsy treated with anterior temporal lobectomy. Epilepsia 2000;41:749–59. Bladin PF. Psychosocial difficulties and outcome after temporal lobectomy. Epilepsia 1992;33:898–907. Wilson SJ, Bladin PF, Saling MM, McIntosh AM, Lawrence JA. The longitudinal course of adjustment after seizure surgery. Seizure 2001;10:165–72. Rausch R, Crandall PH. Psychological status related to surgical control of temporal lobe seizures. Epilepsia 1982;23:191–202. Wheelock I, Peterson C, Buchtel HA. Presurgery expectations, postsurgery satisfaction, and psychosocial adjustment after epilepsy surgery. Epilepsia 1998;39:487–94. Vickrey BG, Hays RD, Engel J Jr et al. Outcome assessment for epilepsy surgery: The impact of measuring health-related quality of life. Ann Neurol 1995;37:158–66.

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Perrine K, Hermann BP, Meador KJ et al. The relationship of neuropsychological functioning to quality of life in epilepsy. Arch Neurol 1995;52:997–1003. Derry PA, Rose KJ, McLachlan. Moderators of the effect of preoperative emotional adjustment on postoperative depression after surgery for temporal lobe epilepsy. Epilepsia 2000;41:177–85. Jones JE, Berven NL, Ramirez L, Woodard A, Herman BP. Long-term psychosocial outcomes of anterior temporal lobectomy. Epilepsia 2002;43:896–903. Augustine EA, Novelly RA, Mattson RH et al. Occupational adjustment following neurosurgical treatment of epilepsy. Ann Neurol 1984;15:69–72. Vickrey BG, Hays RD, Rausch R et al. Outcomes in 248 patients who had diagnostic evaluations for epilepsy surgery. Lancet 1995;346:1445–9. Sperling MR, Saykin AJ, Roberts FD, French JA, O’Connor MJ. Occupational outcome after temporal lobectomy for refractory epilepsy. Neurology 1995;45:970–7. Reeves Al, So EL, Cascino GD et al. Factors associated with work outcome after anterior temporal lobectomy for intractable epilepsy. Epilepsia 1997;38:689–95. Kellett MW, Smith DF, Baker GA, Chadwick DW. Quality of life after epilepsy surgery. J Neurol Neurosurg Psychiatry 1997;63:52–8. Lowe AJ, David E, Kilpatrick CJ et al. Epilepsy surgery for pathologically proven hippocampal sclerosis provides long-term seizure control and improved quality of life. Epilepsia 2004;45:237–42. Fraser RT, Gumnit RJ, Thorbecke R, Dobkin BH. Psychosocial rehabilitation, a pre- and postoperative perspective. In: Engel J Jr, ed. Surgical Treatment of the Epilepsies, 2nd edition. New York: Raven Press, 1993:669–77. Strauss E, Westerveld M. Neuropsychological and psychosocial outcome in children. In: Lüders HO, Comair YG, eds. Epilepsy Surgery, 2nd edition. New York: Lippincott Williams & Wilkins 2001:855–863. Van Empelen R, Jennekens-Schinkel A, van Rijen PC, Helders PJM, van Nieuwenhuizen O. Health-related quality of life and

35. 36. 37. 38. 39. 40.

41. 42. 43. 44. 45. 46.

self-perceived competence of children assessed before and up to two years after epilepsy surgery. Epilepsia 2005;46:258–71. Sabaz M, Lawson JA, Cairns DR et al. The impact of epilepsy surgery on quality of life in children. Neurology 2006;66:557–561. Meyer FC, Marsh R, Laws ER, Sharbrough FW. Temporal lobectomy in children with epilepsy. J Neurosurg 1986;64:371–6. Eliashiv SD, Dewar S, Wainwright I, Engel J Jr, Fried I. Long-term follow-up after temporal lobe resection for lesions associated with chronic seizures. Neurology 1997;48:1383–8. Devinsky O, Barr WB, Vickrey BG et al. Changes in depression and anxiety after resective surgery for epilepsy. Neurology 2005; 65:1744–9. Koch-Stoecker S. Psychiatric Outcome. In: Lüders HO, Comair YG, eds. Epilepsy Surgery, 2nd edition. New York: Lippincott Williams & Wilkins 2001;837–844. Guldvog B, Loyning Y, Hauglie-Hanssen E, Flood S, Bjornaes H. Surgical versus medical treatment for Epilepsy. I. Outcome related to survival, seizures, and neurologic deficit. Epilepsia 1991; 32:375–88. Nashef L, Fish DR, Sander JWAS, Shorvon SD. Incidence of sudden unexplained death in an adult outpatient cohort with epilepsy at a tertiary referral center. J Neurol Neurosurg Psych 1995;58:462–4. Vickrey BG. Mortality in a consecutive cohort of 248 adolescents an adults who underwent diagnostic evaluation for epilepsy surgery. Epilepsia 1997;38(Suppl. 11):S67–9. Sperling MR, Feldman H, Kinman J, Liporace JD, O’Connor MJ. Seizure control and mortality in epilepsy. Ann Neurol 1999; 46:45–50. Sperling MR, Harris A, Nei M, Liporace JD, O’Connor MJ. Mortality after epilepsy surgery. Epilepsia 2005;46 (Suppl. 11): 49–53. Dodrill CB. Commentary: psychological evaluation. In: Engel J Jr, Ed. Surgical Treatment of the Epilepsies. New York: Raven Press, 1987:197–201. Malmgren K, Sullivan M, Ekstedt G, Kullberg G, Kumlien E. Health-related quality of life after epilepsy surgery: A Swedish multicenter study. Epilepsia 1997;38:830–8.

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Neuropsychological outcome WB Barr

Introduction It is known that up to 60–80% of those patients undergoing surgical treatment for partial epilepsy with a well-defined seizure focus will become seizure free following surgery.1 However, it is also acknowledged that 25–40% of these individuals will also experience a postoperative decline in memory, language, or some other aspect of cognitive functioning. This chapter will review an evolving literature demonstrating how results from presurgical neuropsychological testing, combined with demographic variables and other neurodiagnostic findings, are useful for predicting which patients are at greatest risk for developing a postoperative drop in neuropsychological functioning. The current review will, in a manner that is consistent with the available literature, emphasize findings from studies of adults undergoing temporal lobe resection. Neuropsychological testing, as a methodology, has provided valuable information regarding the effects of epilepsy surgery. This type of testing has proven critical to the operation of any epilepsy center. Findings from the original Maudsley series, published over 50 years ago, demonstrated postoperative memory changes in a subset of patients undergoing temporal lobectomy.2,3 More details regarding the nature of these memory changes have described in an elegant series of studies performed by Brenda Milner and her colleagues at the Montreal Neurological Institute.4,5 These studies brought attention to the fact that not all patients experience the same cognitive outcome from surgery and that a number of surgical variables, such as side and extent of the surgical resection, can be used to predict what types of deficits might be observed afterwards. Studies from the 1970s and 1980s demonstrated that the degree of postsurgical deficit often related to surgical outcome, as defined by a reduction in seizure frequency.6 An interesting finding provided by Novelly and colleagues at Yale University, indicated that postsurgical deficits associated with functions of the surgical hemisphere were, in some cases, accompanied by concurrent improvement in functions in the opposite hemisphere.7 The fact is that most types of epilepsy surgery involve resection of brain areas considered important for normal memory processing. Emphasis has thus been placed on predicting memory outcome, with results indicating that a considerable number of patients may experience a decline in some aspect of language or cognitive functioning following standard procedures for anterior temporal lobectomy (ATL). Development of global amnestic syndromes was reported in

some early series8,9, but the occurrence of such devastating impairments in memory is now estimated to appear in less than 1% of cases after utilizing a number of methods to prevent its occurrence.10 Predicting other types of neuropsychological deficits is generally based on brain topography and what is known about the functional neuroanatomy of the brain. Changes in executive functions and behavior are generally predicted when surgery is performed on the frontal lobes. Deficits in other functions, such as perception and higherorder sensory functions are seen in some cases involving surgery of more posterior brain regions. Postoperative deficits in language and related functions are a natural concern when one is performing surgery on traditional ‘language zones’ of the dominant hemisphere. Many surgical centers make great efforts to ascertain the site and nature of cortical language representation using procedures such as the intracarotid amobarbital procedure (IAP) or intracranial language mapping either intraoperatively or through stimulation of subdural grids. Many are now also using newer techniques such as functional magnetic resonance imaging (fMRI) and magnetoencephalograpy (MEG) for evaluating hemispheric representation of language. The prediction of postoperative memory decline has received the most attention and has been guided by two basic theoretical approaches, with both based on findings from neuropsychological research. One is based on Milner’s11 initial observation that material-specific memory deficits in verbal and nonverbal memory will be observed following surgery on the left (dominant) and right (nondominant) temporal lobes respectively. The second is based on a model developed by Chelune,12 predicting that the degree of postoperative memory deficit, as well as seizure outcome itself, will be determined by the ‘functional adequacy’ of the tissue to be resected. An analysis of material-specific memory findings, as predicted by Milner’s model, is included in nearly every neuropsychological study of postoperative outcome. The conclusion drawn from recent reviews of the literature is that there is strong empirical support for the link between surgery on the left temporal lobe and postoperative deficits in verbal memory.13 However, there is substantially less support for the proposed relationship between nonverbal memory impairment and surgery on the right temporal lobe.13,14 Effects sizes from a recent meta-analytic study of verbal and nonverbal memory scores from Wechsler Memory Scale are depicted in Figure 135.1. The findings from a variety of sources thus demonstrate that patients undergoing surgical resection of the language dominant hemisphere are at the greatest level of 1277

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1 Presurg Postsurg

0.8

Memory decline

0.6 0.4

Table 135.1 Factors important for predicting outcome from epilepsy surgery (from Elger, Helmstaedter, and Kurthen)22 1.

The ‘functional adequacy’ of the tissue to be resected, as determined by EEG, neuroimaging, and neuropsychological testing.

2.

The degree of ‘mental reserve’, as reflected by patient’s age, educational attainment, and level of presurgical intellectual functioning.

3.

The degree of postoperative seizure control, particularly the frequency of generalized tonic-clonic seizures.

0.2 0 −0.2 −0.4

Memory improvement

LMI

LMII

VRI

VRII

Figure 135.1 Effect sizes from 33 studies assessing verbal and nonverbal memory performances before and after temporal lobectomy (Adapted from Lee, Yip, and Jones-Gotman).13

risk for undergoing an identifiable decline in postoperative memory functioning. For years, it was unclear whether prediction on postoperative cognitive outcome should be based on observation of the functioning of the side that was to be resected or the side that would remain following surgery. Initial studies using the IAP focused on information on functioning from the side contralateral to surgery to predict whether a patient was at risk for developing a postsurgical amnestic syndrome. However, results from subsequent studies using neuropsychological testing in conjunction with information from the IAP, neuroimaging, and histological analyses, has indicated that the functions of the side to be resected is an important factor to consider in predicting a patient’s postoperative level of functioning. According to Chelune’s functional adequacy model, the degree of postoperative memory decline can be predicted by examining the integrity of the proposed surgical zone, as defined by integration of a number of predictive variables.12 Initial evidence for the functional adequacy model was based on findings that significant decrements on memory testing following temporal lobe resection were observed in those patients with higher levels of performance on presurgical testing.15,16 Results of subsequent research17 demonstrated that patients with the highest levels of memory performance, in particular, showed greater decline in memory performance in the 6 months following surgery. Less significant decline in functioning was observed in patients with lower levels of presurgical memory functioning. The authors argued that these findings were not simply the result of a statistical ‘regression to the mean’, but rather a tendency for the most functional patients at baseline to be more vulnerable to experiencing postoperative memory loss. The functional adequacy has now been supported by findings from a number of other neuropsychological studies.18–21 The theory has also received support from a number of neuroimaging and IAP-Wada studies, which will be reviewed below. It is now generally accepted that this model, combined with other factors, is effective in predicting a patient’s neuropsychological outcome from surgery.22 A brief listing of these factors is provided in Table 135.1. The following sections will review further characteristics of neuropsychological functioning following epilepsy surgery as well as other factors that can be used to predict outcome.

Profile of change in postoperative neuropsychological functions Clinicians and patients are interested in knowing which cognitive functions are at risk for decline following surgery. The following section provides a review of what is known about changes in various aspects of neuropsychological functions following surgery: General intelligence One of the earliest findings from neuropsychological studies is that epilepsy surgery results in very little change in overall intellectual functioning.23 Some studies have found an IQ increases in some patients following surgery, particularly in those that become seizure free. However, from a psychometric standpoint, changes in 6–8 IQ points are required to constitute a significant change, and changes of that magnitude are rarely observed after surgery. The view that patients with lower levels of intelligence do not benefit from surgery has been dispelled by research findings showing similar levels of seizure reduction in both low and high IQ groups.23,24 Patients with higher levels of preoperative intellectual functioning and memory performance do tend to experience a greater degree of net decline following surgery, although they also continue to exhibit a higher level of postoperative functioning than do patients with lower levels of presurgical functioning.25 This finding has been considered supportive of the model of ‘cognitive reserve’ that has gained acceptance in the research fields of dementia and traumatic brain injury.26,27 Memory Memory decline is a primary concern when considering neuropsychological outcome from epilepsy surgery. A number of studies have shown that memory change is commonly reported in patients following surgical resection of the temporal lobe and such change exerts a significant impact on a patient’s perception of quality of life.28 Studies using neuropsychological testing have demonstrated that if a patient undergoes a decline in functioning after surgery, it is most likely to occur in the realm of verbal memory.13,17 Similar to what has been observed in IQ studies, the findings generally show that patients with higher levels of memory performance before surgery will undergo a greater degree of decline afterward.23

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Neuropsychological outcome There has been some evidence of improvement in some memory skills following surgery, particularly for those functions associated with the hemisphere contralateral to the surgery.7 Decrements in postoperative memory functioning have been observed using a range of verbal memory tasks. Several studies have shown that the paragraph-recall (Logical Memory) subtest from the Wechsler Memory Scales (WMS) provides one of the most sensitive measures of postoperative memory change.13,29,30 Other studies have demonstrated that measures of acquisition and delayed recall from measures, such as the California Verbal Learning Test, Rey Auditory Verbal Learning Test, and Selective Reminding Test, are also sensitive to identifying postoperative changes in memory performance.17,31,32 Additional success has been obtained from testing the ability to learn and retain word pairs, as provided in Paired Associate subtest from the WMS.16,28,33,34 Using findings based on the study of Patient H.M. as a prototype, it was initially thought that memory disturbance resulting from unilateral temporal lobectomy was characterized primarily in terms of ‘rapid forgetting’ or as a deficit in memory ‘consolidation’.33,34 However, findings from contemporary studies using more refined assessment techniques have determined that the decline in verbal memory following left anterior temporal resection is more multifaceted, as it is also characterized by prominent impairments in encoding and retrieval stages of memory processing.35 Others have described a specific effect on relational memory.36 Deficits in memory processing are also known to occur in patients undergoing frontal lobe resection, although the pattern of disturbance is qualitatively different as these patients are more prone to having difficulties with selection or retrieval processes and more prone to making intrusion or perseverative errors than patients undergoing temporal lobe resection.37,38 As mentioned above, there has been much less support for the presence of visual memory impairment resulting from surgery performed on the nondominant hemisphere. It has been thought that a number of factors contribute to the lack of findings of a decline in nonverbal memory functioning following right ATL, including limited theoretical knowledge of the right temporal lobe’s role in memory processing as well as the sensitivity of most commonly used measures for assessing visual memory.39,41 Little success has resulted from using traditional measures of figural memory, such as the WMS designs or Rey’s complex figure, to identify memory changes in patients undergoing surgical resection of the nondominant hemisphere.13,14,42 However, findings from recent studies have indicated that the latest version of the Wechsler Memory Scale (WMS-III) may be more sensitive than other commonly used measures to identifying material specific memory impairment following unilateral ATL,43 although it does not appear sensitive to identifying lateralized deficits in patients prior to surgery.44 This study demonstrated that a combination of findings from the Verbal Paired Associates, Faces, and Family Pictures subtests can be used to discriminate right and left ATL patients with 81.3% accuracy.43 Mixed findings have been obtained from studies using figural learning paradigms, analogous to verbal list-learning tasks, where designs ranging in complexity are reproduced after viewing them over repeated trials.14,45–48

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Some success in identifying material-specific decline in nonverbal memory functions has been demonstrated using specialized test methods. Based on findings from the primate literature, it has been hypothesized that memory dysfunction following resection of the nondominant temporal lobe will reflect a disturbance of the ventral processing stream, which has related to processing object, as opposed to spatial, information.39 Given the proximity to the fusiform face area,49 processing and retaining facial information would be expected to be particularly affected. In fact, studies using facial recognition paradigms have shown the emergence of subtle deficits in facial perception following right temporal lobe resection.50 Difficulties with remembering unfamiliar faces, both before and after right temporal lobe resection, have been reported in numerous studies.14,39,51–53 It has been shown that the primary impairment is related more to memory than to perceptual processing of the faces.54 One study has demonstrated the specificity of this deficit, as demonstrated by a decline in facial, but not spatial, memory following right temporal lobe resection.55 However, in spite of these observations, a number of studies have demonstrated spatial memory deficits using a variety of innovative paradigms.56–58 While most attention is placed on postsurgical evaluation of possible deficits in new learning, a number of studies have demonstrated difficulties with recalling remote knowledge following anterior temporal lobe resection. Several studies have shown deficits in recognizing and naming familiar faces, such as those of celebrities such as politicians, actors, musicians, and athletes.59–62 A recent study has shown that patients undergoing left ATL may develop difficulties with naming famous individuals depicted in pictures, while those undergoing right ATL appear to have a more basic difficulty with the perceptual aspects of identifying those depicted in the photograph.60 Recent interest has also turned to the examining changes in processing and retaining emotional stimuli in patients undergoing temporal lobe resection.63 Studies have shown that patients undergoing right ATL may develop a specific reduction in their startle response or in their ability to perform in a fear conditioning paradigm.64,65 These observations have carried into memory paradigms, where is has been demonstrated that patients undergoing resection of the amygdala exhibit a specific reduction in the ability to learn and retain emotionally charged information.66–70 Language Prevention of postoperative language impairment is a concern, particularly when surgery involves the language-dominant hemisphere. Surgery performed on the dominant temporal lobe is most commonly associated with postoperative naming deficits, as typically measured by tests of confrontation naming and verbal fluency. While impairments on other language tasks, such as sentence repetition or auditory comprehension may be encountered, they are seen far less often. A decline in naming performance is thought to occur in approximately 30–40% of patients undergoing surgery on the language dominant hemisphere.71,72 Naming decline is not limited to those undergoing extensive resection of the lateral cortex as a relationship between naming impairment and excision of the hippocampus has been demonstrated.73

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Surgical studies have placed far less emphasis on assessment of naming deficits than on changes in verbal memory functions. Demographic predictors of naming decline appear to be similar to those used for evaluating the risk of memory loss. A specific risk to postoperative naming abilities has been found for those patients undergoing left hemisphere surgery with a later age of onset or an absence of early risk factors for seizures and negative findings on neuroimaging.73,74 Assessing changes in naming performance following surgery is typically performed through use of a picture recognition paradigm, such as the Boston Naming Test. However, results from recent studies have indicated that naming changes might be identified more accurately using auditory naming tasks as opposed to visual naming paradigms.75–77 Results of studies attempting to characterize the type of postoperative naming impairment have been somewhat conflicting. One study found that left ATL is associated with a category specific impairment in naming nonliving as opposed to living things, whereas another study showed the opposite findings. 78,79 Other studies have found that retrieval of object names is affected more than verb naming and words learned at a later age are more likely to be affected those acquired early in life following left temporal lobe surgery.80,81 Studies on postoperative language change have also shown decreases in verbal fluency following both left and right unilateral temporal lobectomy.82 Fluency, as defined in these studies, is assessed through paradigms requiring a generation of word lists beginning with either a specific letter of the alphabet or coming from a predefined semantic category, such as animal names. A decrease in verbal fluency is observed in some patients following surgery to the dominant frontal lobe.83 Improvement in verbal fluency has been observed in some patients following frontal lobe resection, particularly in cases obtaining good postoperative seizure control.81,84 Other neuropsychological functions Studies using standard neuropsychological measures of motor and sensory functions have found very little change in patients undergoing resection of the temporal lobe. Findings from one study found presurgical baseline impairment in somatosensory functions, with some apparent improvement observed in a subset of patients following surgery.85 Changes in olfactory functions have been observed after anterior temporal lobectomy, with no consistent association with the side of the resection.86 Patients undergoing right temporal lobe excision exhibit less accurate recognition of emotion and less change in response to emotional stimuli than do left temporal lobe patients.66,87 There are no consistent findings demonstrating deficits in visual perceptual or spatial functions associated with right anterior temporal lobe resection.88,89 Specific impairment in facial recognition has been observed in one study, although the size of the overall effect was mild.50 Patients undergoing right temporal lobe surgery have been found to have greater difficulty integrating spatial information while walking a linear path.90 Development of spatial neglect is rarely seen following temporal lobe resection. However, it has been observed following surgery to the parietal cortices of the right

hemisphere.91 Other studies have demonstrated changes in auditory perception, most notably directional pitch and spatial location, following surgical resection of the right temporal lobe.92–94 Greater attention has been placed on assessment of executive functions before and after surgery. In general, patients undergoing frontal lobe resection generally exhibit decline on measures of executive functions.37 Those with resection of premotor or SMA regions exhibit specific decreases in response maintenance and inhibition, while those with surgery on the left hemisphere also exhibit some decline on language tasks.23,83 Studies using newer measures of frontal lobe functioning from the Delis-Kaplan Executive Functioning System have demonstrated particular deficits in set-shifting, nonverbal fluency, and response inhibition in frontal lobe surgical patients.95–97 A decline in spatial working memory has also been reported in patients undergoing frontal lobe surgery.98 A number of studies have found impairment in executive functions in patients with temporal lobe epilepsy, contrary to predictions based on early studies finding a double dissociation between frontal and temporal lobe resection groups.99 Deficits in performance on the Wisconsin Card Sorting Test, a traditional measure of ‘frontal lobe functions’ has been observed in patients with temporal lobe dysfunction presurgically, with some of these patients exhibiting a normalization in performance following anterior temporal lobe resection.100,101 It has been hypothesized that the postsurgical improvement is related to a removal of nociferous cortex affecting remote frontal lobe functions.102 A recent observation if improvement in verbal fluency performance following temporal lobe resection is interpreted supports that hypothesis.84

Predictors of neuropsychological decline It is clear that a number of factors are required to accurately predict postoperative changes in cognitive functioning. The level of evidence has now reached a point where one can use information from neuropsychological tests, obtained presurgically, combined with other surgical and neurodiagnostic values, to predict which patients are at risk for neuropsychological decline.22 A listing of some of the most commonly known factors for predicting decline are listed in Table 135.2. More details regarding demographic, surgical, and neurodiagnostic predictors of cognitive decline are provided below.

Table 135.2 Predictors of poor cognitive outcome from surgery on the language-dominant hemisphere (from Elger, Helmstaedter, and Kurthen)22 1. 2. 3. 4. 5.

Persistent seizures. Intact memory performance preoperatively. Extent of surgical resection. Notable collateral brain damage after surgery. Low reserve capacity.

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Neuropsychological outcome Demographic variables Developmental factors, including age at the time of surgery and the stage of development at the time of seizure onset, are important factors for predicting postoperative cognitive decline. Most of what is known about postoperative outcome is based on studies of individuals ranging in age from 20 to 45 years, which is the group most likely to undergo surgical intervention. The risk of cognitive decline following surgery appears to be lower in children below the age of 16 years than in adults.103 At the other end of the age spectrum, older individuals appear to experience greater memory loss, consistent with a profile of accelerated aging.25 Continuing decline in memory performance may be seen in some individuals ten years or more following surgery.28 The postoperative deficit in verbal memory in patients rendered seizure free is similar to what is observed over time in nonsurgical patients that are continuing to experience seizures.25 Age of onset of epilepsy is thought to interact with both functional and structural indices in a manner consistent with predictions of the functional adequacy model.12,104 Those with a younger age of onset will have experienced pathology at an earlier stage of development and will have experienced seizures for a longer period of time. This will lead to a greater state of neurological compromise accompanied by more severe and widespread cognitive impairment. However, this would also cause a redistribution of function to other brain areas, which would lead to a less severe deficit following surgery. In contrast, individuals who develop epilepsy later in life are not as compromised from a neurological standpoint and do not exhibit the same degree of cognitive dysfunction preoperatively. In these individuals, surgery would involve removal of more functional brain tissue, leading to development of a greater level of deficit postoperatively. Support for these findings with age was present in some early studies, but at least one recent study has failed to find a link between severe hippocampal pathology, memory decline, and early onset of seizures.104 Another general finding is that, with increasing age, cognitive deficits become more specific and less reversible with surgery. It has been suggested that the pattern of findings involving age of onset are more consistent for cognitive functions associated with neocortical zones than for those associated with the mesial temporal lobe.23 For example, findings have suggested that more severe naming deficits are observed in older patients. Other studies examining demographic factors have suggested that women, in general, exhibit less severe cognitive decline following surgery than men.105 Surgical variables A relationship between postoperative memory decline and continued seizures has been observed inconsistently across studies.28 However, the general finding is that postoperative improvement in memory is seen most frequently in patients with greater than 75% seizure reduction.7,16,106 The type of surgical procedure has not borne out as a consistent influence on postoperative memory functioning in temporal lobectomy patients. A number of studies have found that a more selective resection of the anterior temporal lobe leads to less severe postoperative deficit than a standard anterior

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temporal lobe resection.48,106–109 However, one study has shown that there is no difference in outcome between various surgical approaches.48 Another multicenter study demonstrated no influence of tailored temporal lobe resections for preventing naming changes in surgical cases involving the language dominant hemisphere.110 Surgical removal of the superior temporal gyrus during left temporal lobe surgery has been found to have no specific influence on postoperative naming performance.111 Much less is known about the neuropsychological outcome of other types of epilepsy surgery. One study found that patients undergoing frontal lobe resection are prone to developing deficits in executive functions after surgery, whereas patients undergoing temporal lobe resection experience relative improvement in these functions.37 Mild changes in performance IQ, as measured by the WAIS-R, has been reported following surgery to the posterior cortices, irrespective of side.112 Preliminary data have indicated that a reduced risk of postoperative neuropsychological decline is not associated when gamma knife surgery is used as a treatment for temporal lobe epilepsy.113 In cases of callosotomy, one must be prepared for the possible emergence of the well-described ‘split-brain’ syndrome, particularly features of the alien hand syndrome. However, it has been shown that language is more likely to undergo a decline following callosotomy than any other function.23 The occurrence of severe language impairment, in the form of postoperative mutism, is known to occur in some patients with atypical patterns of hemispheric language dominance.114 It is thus critical to ascertain a candidate’s pattern of language dominance through the IAP or fMRI prior to surgery. Improvement in social functions has been observed as a positive finding in some cases following callosotomy, with the greatest level of improvement observed in patients that were younger at the time of surgery.115 Hemispherectomy has been demonstrated to be an effective treatment for patients with hemimegalencephaly or with Rasumussen or Sturge-Weber syndromes. It is generally assumed that in surgeries involving the left hemisphere, language has moved to the right side, making postoperative language changes unlikely. Research findings have shown that this is most often the case, but some children do continue to be prone to language changes following surgery.116 Improvements in IQ and attention following hemispherectomy have been reported in some series.23 Neurodiagnostic variables Many studies have demonstrated that a multidisciplinary model, using a combination of neurodiagnostic, demographic, and performance-based factors, is most effective for predicting neuropsychological outcome from epilepsy surgery.19,117,118 Results from neuropathological studies have consistently demonstrated that memory outcome is impacted significantly by the preoperative presence of hippocampal sclerosis (HS) on the side to be resected.71,119,120 Individuals with severe unilateral HS tend to exhibit lower levels of preoperative memory functioning and are likely to exhibit less decline in memory performance following surgery.121

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Neuroimaging findings The functional adequacy model has been supported by results of studies using MRI measures of hippocampal pathology.122,123 The findings show that removal of a nonatrophic left hippocampus is generally associated with the greatest degree of memory decline, although it is also possible to observe memory loss in some patients with the most severe presurgical levels of HS.35 It is now known that surgery performed on individuals with bilateral hippocampal pathology does not necessarily cause global amnesia. However, greater rates of memory decline are seen in those patients with bilateral hippocampal atrophy who undergo surgery on the dominant left temporal lobe.35 These and other findings indicate that the functional integrity of the left temporal lobe plays a critical role in predicting memory outcome, independent of the presence of structural pathology.124,125 Functional adequacy has been predicted through results of magnetic resonance spectroscopy (MRS).126,127 Functional MRI (fMRI) has been shown to be useful for predicting postoperative naming.128 Studies using functional imaging methods have indicated that both FDG-PET and fMRI can be helpful in predicting postoperative memory impairment.129,130 In the case of FDG-PET, a lack of left side hypometabolism predicted the onset of memory loss in patients undergoing left ATL.131 Intracarotid amobarbital procedure (IAP) IAP memory scores, combined with MRI measures of hippocampal volume, have been shown together to be related to the degree of memory change following temporal lobectomy.132 However, it has been suggested that these variables are used most optimally for prediction of verbal as opposed to nonverbal memory changes.133 A recent study has demonstrated a significant negative correlation between IAP scores ipsilateral to the surgical resection and postoperative memory change, consistent with predictions based on the functional adequacy model.134 There has been some suggestion that, in cases with right hemisphere language dominance, verbal memory functions might also shift to the right hemisphere, resulting in the observation of less severe memory decline after surgery. Language mapping While an emphasis has been placed on language mapping prior to dominant hemisphere surgery,135 results from studies using both grid and intraoperative brain mapping procedures have been variable. Some studies have shown that standard ATL without stimulation mapping is safe for long-term language functions.136 One multicenter study found that the rate of postoperative naming decline was not influenced by the availability of mapping data.110 Removal of basal temporal zones found to be patent for language functioning on mapping have not been associated with consistent decrements in postoperative language abilities.137 However, others have recently found that identification of mapping sites critical for auditory descriptive naming is important for predicting both auditory and visual naming outcome.138 A more distributed region of language functions has been described in patients with decreased intelligence and lower levels of educational attainment.139 Results from mapping studies using magnetoencephalograpy (MEG), have suggested a reorganization of

hemispheric language representation following dominant hemisphere resection.140

Recent methodological advances One of the criticisms of neuropsychological research is that it has typically focused on results of group analyses, making it difficult to translate the results into manner that can be useful in counseling patients. There has also been a view that focusing on analysis of group differences following surgery may mask many of the differences between patients undergoing left and right temporal lobe resection. There has been a recent trend moving from group methods of analysis towards predicting the risk of postoperative change in individual patients. To optimize the prediction of individual risk, investigators have been using statistical methods, such as the reliable change index (RCI) and standardized regression-based (SRB) methods to control for the reliability of the instruments, practice effects, and regression to the mean. These measures are readily obtained through studies of test-retest changes observed in non-surgical patients.30,141–144 Experience shows that RCI’s are the most easy to use in a clinical setting, with a level of expected change observed on retesting translated into 95% confidence intervals. Modifications to the original RCI formula are made, correcting for practice effects.144 Values for some of the most commonly used neuropsychological tests are provided in Tables 135.3 and 135.4. Clinicians are encouraged to use these values to determine whether significant changes in neuropsychological test scores are observed in individual patients following surgery. Results from postsurgical studies using RCI and SRB methodology are summarized in Table 135.5. When patients are considering surgery, they can now be informed, on the basis of results from these studies, that the risk for postoperative decline in verbal memory ranges from 28–49% in patients undergoing left temporal lobe surgery while the risk for decline patients undergoing right temporal lobe surgery ranges from 7–33%, depending on the memory measure that is used to assess outcome.72 Other studies have revealed greater degrees of risk in patients undergoing left anterior temporal lobe resection with minimal evidence of hippocampal sclerosis on MRI.104 Another study found that bilateral hippocampal atrophy, in the presence of left temporal lobe seizures, increases the risk of memory decline following left temporal lobectomy.35 Bilateral hippocampal atrophy did not provide a risk to patients undergoing right temporal lobectomy. One study has shown that patients with MTS and normal preoperative memory performance are still at risk for developing memory changes following surgery.124 Using indices from the CVLT, 17% exhibited a drop on acquisition scores, while 65% experienced a decline in verbal retrieval. This point was made again in a case report where intact preoperative memory performance in the presence of numerous signs of hippocampal sclerosis resulted in a significant postoperative decline in memory.125 The results from the studies using methodology for assessing change have thus provided evidence that results from presurgical testing provide a critical predictor of

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Neuropsychological outcome Table 135.3 logical tests

Reliable change index (RCI) values for the WAIS-III, WMS-III, and other neuropsycho-

Neuropsychological test

Adjusted 90% RCI*

Wechsler Adult Intelligence Scale – III (WAIS-III) •Full Scale IQ •Verbal IQ •Performance IQ •Verbal Conceptual Index (VCI) •Perceptual Organization Index (POI)

≤ –6, ≥ +8 ≤ –8, ≥ +8 ≤ –7, ≥ +13 ≤ –7, ≥ +9 ≤ –8, ≥ +14

Wechsler Memory Scale – III (WMS-III) •Auditory Immediate Memory Index •Auditory Delayed Memory Index •Visual Immediate Memory Index •Visual Delayed Memory Index

≤ –14, ≤ –19, ≤ –15, ≤ –13,

Tests of Executive Functions •Wisconsin Card Sorting Test Total Errors (Raw Score) Perseverative Errors (Raw Score) •Trailmaking Test Part A (Time in seconds) Part B (Time in seconds) Language and Visuospatial Functions •Boston Naming Test (Raw Score) •Controlled Oral Word Association Test (Raw Score) •Benton Facial Recognition Test (Raw Score) •Judgment of Line Orientation Test (Raw Score)

≥ ≥ ≥ ≥

Reference 29

29

+16 +15 +21 +23

141

≤ –40, ≥ +22 ≤ –22, ≥ +16

140

≤ –14, ≥ +10 ≤ –37, ≥ +44 ≤ –5, ≥ +5 ≤ –12, ≥ +14 ≤ –6, ≥ +6 ≤ –3, ≥ +7

141 141 140 140

*Corrected for practice.143

Table 135.4 memory

Reliable change index (RCI) values for commonly used tests of verbal and nonverbal

Test Verbal Memory Tests •California Verbal Learning Test Total Learning (5 Trials, Raw Score) Long Delayed Free Recall (Raw Score) Discriminability (Raw Score) •Rey Auditory Verbal Learning Test Total Recall (5 Trials, Raw Score) Delayed Recall (Raw Score) •WMS-III Verbal Paired-Associate Subtest Verbal Paired-Associates I (Scaled Score) Verbal Paired-Associates II (Scaled Score) •WMS-III Logical Memory Subtest Logical Memory I (Scaled Score) Logical Memory II (Scaled Score) Nonverbal Memory Tests •Rey Complex Figure Test Delayed Recall (Raw Score) •Recognition Memory Test Faces (Raw Score) •WMS-III Faces Subtest Faces I (Scaled Score) Faces II (Scaled Score) •WMS-III Family Pictures Subtest Family Pictures I (Scaled Score) Family Pictures II (Scaled Score) *Corrected for practice.143

Adjusted 90% RCI*

≤ –11, ≥ +15 ≤ –3, ≥ +7 ≤ –17, ≥ +23 ≤ –15, ≥ +5 ≤ –7, ≥ +5 ≤ –3, ≥ +3 ≤ –4, ≥ +4 ≤ –3, ≥ +3 ≤ –4, ≥ +4 ≤ –11, ≥ +12 ≤ –5, ≥ +9 ≤ –3, ≥ +5 ≤ –3, ≥ +5 ≤ –3, ≥ +3 ≤ –4, ≥ +4

Reference 140

141 29 29

142 141 29 29

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Textbook of epilepsy surgery Table 135.5 Rates of memory decline in dominant and nondominant temporal lobectomy patients using RCI and SRB methodology Test measure/study

Dominant ATL

Wechsler Memory Scale – Logical Memory II A. Martin et al. 198871 •Improved •Unchanged •Declined B. Stroup et al., 200219 •Improved •Unchanged •Declined California Verbal Learning Test Delayed Recall A. Stroup et al., 200219 •Improved •Unchanged •Declined Total Learning–Five Trials B. Martin et al. 198871 •Improved •Unchanged •Declined

Nondominant ATL

9% 42% 49%

9% 58% 33%

3% 60% 37%

7% 82% 11%

0% 54% 46%

0% 89% 11%

2% 71% 28%

2% 91% 7% Left ATL Patients

Mild HS California Verbal Learning Test Total Learning – Five Trials C. Martin et al. 2002103 •Improved •Unchanged •Declined

neuropsychological outcome independent of information obtained from neuroimaging.

Conclusion A number of important advances have been made over the past 50 years in assessing neuropsychological outcome from epilepsy surgery. Most attention is place on the prevention of declines in naming and verbal memory, which are most likely to be seen in a sizeable minority of patients following surgical procedures conducted on the language-dominant

20% 20% 60%

Mod HS

0% 78% 22%

Sev HS

0% 77% 23%

hemisphere. Current practices involve a model utilizing presurgical neuropsychological testing, along with information obtained from neuroimaging and the IAP, to assess a given patient’s risk for postoperative decline. Patients with evidence of intact cognitive functions on the site to be resected are considered at greatest risk for postoperative memory decline, independent from structural imaging findings. Studies using newer statistical approaches to evaluating neuropsychological change are providing clinicians with information that makes it easier to counsel individual patients on the risk of developing postsurgical changes in memory and language.

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Temporal lobe epilepsy surgery: surgical complications D Sasaki-Adams and EJ Hadar

Introduction No professional man gets greater pleasure from the record of his successes than a surgeon. How delightful when the uninformed refer to them as miracles! And how inaccurate! But no one regrets his failures more ...1 Surgical complications are perhaps the most humbling of all mistakes. The role of this chapter is to delineate the most frequent complications encountered in surgery for temporal lobe epilepsy. In addressing the potential pitfalls of this surgical procedure, perhaps one can hope to determine means to avoid them. During the last century, a considerable amount of general knowledge has been gained in surgical evaluation for temporal lobe epilepsy. The implications and outcomes have been fine tuned over the past 50 years at many epilepsy centers to make temporal lobe resection for medically intractable disease the most common surgical procedure for epilepsy worldwide.2–11 The benefits of this surgery have revolutionized the prospect of epilepsy being a potentially curable disease. Surgical resection for medically refractory seizures has demonstrated very promising results with respect to seizure control. A multitude of studies have estimated a 60–70% rate of seizure freedom and up to an 85% rate of significant reduction in seizure frequency.3,4,11 A prospective randomized controlled trial found 64% of patients who underwent surgical resection were seizure free compared to only 8% in the medical group on optimal medical therapy.11 They concluded that surgery was superior to prolonged medical therapy. However, one must remember in counseling patients for surgical intervention, that complications do occur and can be life altering. The temporal lobe performs a myriad of functions including integration of such higher level functions as language, musical appreciation, emotion, and memory. Its location bordering the frontal, parietal, occipital lobes makes it ideal for acting to coordinate and process multivariate information. Likewise, its mesial structures, including the hippocampus, are deeply involved in episodic memory processing. Additionally, one must remember that the temporal lobe borders the vascular supply of essential relay stations including the thalamus, internal capsule, and basal ganglia. Interference of these pathways, either by temporal lobe pathology or surgical intervention, can result in significant loss of function. The optic tract and visual pathways traverse the temporal lobe making a visual field deficit a possible outcome to disturbance of this area. Lastly, several cranial nerves approximate the mesial portion of the temporal lobe as is evidenced by the typical sign of a third nerve palsy with uncal herniation. 1288

The temporal lobe acts to coordinate sensory information and synthesize it as it relates to higher level cognitive function. For example, in recalling a memory, one can often remember the specific situation in fine detail. With such an integral processing station, it is no surprise that surgery in this region can be associated with a multitude of complications. Temporal lobe epilepsy, in its natural progression, is often associated with many of the neuropsychological complications described here. Patients with longstanding temporal lobe epilepsy often will demonstrate a cognitive decline with difficulties in language, memory, and psychosocial functioning. The chapter will begin by discussing the intricate anatomy of the temporal lobe and providing a brief overview of the various surgical approaches. An understanding of the resection bed’s proximity to a multitude of essential anatomical pathways and structures will assist in explaining some of the various complications that are commonly encountered. We will then embark on a brief overview of the most commonly described surgical complications associated with general craniotomy. The remaining portion of the chapter will focus on the various neurological complications that have been documented. The neurological sequelae will be subdivided into motor, sensory, visual field, and cranial nerve deficits. We will then discuss neuropsychological complications including language, memory, and general cognitive disturbances. Lastly, we will address various psychiatric complications which have been observed following temporal lobe surgery for epilepsy.

Anatomy The anatomy of the temporal lobe, including the mesial structures, is quite complex and requires a three dimensional understanding of its relationship to the rest of the brain before embarking on surgical intervention.12 It is separated from the frontal lobe superiorly by the Sylvian fissure. One can follow the Sylvian fissure medially until it ends at the circular sulcus. This structure separates the insula from the temporal stem which comprises the white matter outflow tracts of the temporal lobe. Inferior and medial to the temporal stem lies the temporal horn of the lateral ventricle. The mesial structures of the temporal lobe reside along the medial aspect of the ventricle. The complex anatomy of the mesial temporal structures and their proximity to the brain stem and other critical vascular and neuronal structures makes surgery in this region challenging. The mesial structures start at the parahippocampal gyrus and extend medially curling upwards contiguous with

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Temporal lobe epilepsy surgery: surgical complications the hippocampus. The hippocampal sulcus separates the parahippocampal gyrus from the hippocampus proper. The ambient cistern lies between the mesial temporal lobe and the brain stem. The posterior cerebral artery, posterior communicating artery, basal vein of Rosenthal, and the third nerve pass through this cistern. The hippocampus and the limbic lobe are C-shaped structures which extend posteriorly and follow the course of the lateral ventricle and corpus callosum. The hippocampus comprises the medial wall of the temporal horn of the lateral ventricle. The fornix, which is the outflow tract of the hippocampus, extends posteriorly and follows the course of the ventricular system to the mammillary bodies. The choroidal fissure delineates the hippocampus and fornix from the diencephalon, optic tract, and basal ganglia medially. The amgydala is contiguous with the basal ganglia and lies just anterior to the head of the hippocampus. Please see Wen and Rhoton’s section describing surgical anatomy for more detail.13

Approaches In the context of temporal lobe surgery for epilepsy, most surgical strategies are aimed at resection of the hippocampus and associated mesial structures. Hippocampal exposure is usually accomplished via the ventricular system and access to the ventricle has been described through multiple approaches.8,14–19 Each approach necessitates some type of tissue disruption and each has its described advantages and disadvantages. These are described in detail elsewhere in this book.

Surgical complications Surgical complications in this chapter include those complications associated with general craniotomy for all indications. Many centers quote different complication rates with respect to postoperative hematoma, infarct, retraction injury, wound complications, and infection as have been observed in their individual institutions.2,3,9–11,20 These types of complications vary with the experience of the center, the resources of the institution, and the degree to which these are reported and recorded. Generally, infection is felt to be the highest surgical risk estimated in 1–5% of cases with the risk increasing with prolonged intracranial monitoring.2,20 In a study evaluating risk of craniotomy and postoperative infection and role of antibiotic prophylaxis in 4578 craniotomies, it was found that the overall rate of infection was 6.6%.20 Several studies have been done to correlate increased risk of infection with chronic invasive subdural grid and subdural electrode monitoring.21,22 In a review and prospective analysis of 38 patients who underwent craniotomy for electrode implantation, clinical infection was observed in 7.9% of patients, with a 13.2% positive culture rate indicating that laboratory results do not always correlate with clinical outcome.22 In a retrospective analysis of 198 monitoring sessions in 187 patients, the overall rate of infection was found to be 12.1%.21 These studies suggest that the risk of infection increases significantly with preresection craniotomy for intracranial monitoring. Hematoma and infarct are seen far less often; in less than 3 % of cases.2,9,21 Upon review of the 449 therapeutic procedures performed in

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Sweden between 1990 and 1995, infection was observed in 5.1%, hematoma in 0.4%, deep venous thrombosis in 0.4%, hydrocephalus in 0.7%, and CSF leak in 0.7%.9 In a retrospective analysis of a series of 429 consecutive patients operated on during 6.5 years in the University of Bonn epilepsy program, a total of 33 surgical complications were encountered, 7.5% stemming from temporal lobe resections.2 Of those described, deep vein thrombosis and pulmonary embolism were observed in 2% of patients. Postoperative meningitis was observed in 1%, with postoperative wound infection seen in 2.8%. A retrospective analysis of 215 patients who underwent temporal lobectomy for medically intractable epilepsy found no surgical mortality, but 1.3% of the patients harbored an infection of the bone flap.10 In summary, when considering the general risks associated with craniotomy in this region, one must appreciate the individual experience of the home institutions where these operations are performed as well as the unique nature of these procedures. The risk of infection is often higher than that for a routine craniotomy as many of these patients undergo placement of subdural grids for prolonged intracranial monitoring prior to the definitive surgical resection. In routine craniotomy without subdural grid monitoring, the risk can be estimated for most centers as between 1 and 3%. This risk increases with preresection monitoring to 8–12%. The risk of serious complications such as hematoma and infarct appear to occur on the order of 1–2%, but may vary according to the home institution’s individual experience. Preoperative medical evaluation and perioperative monitoring are essential in reducing risk for developing such complications as deep venous thrombosis, pulmonary embolism, and perioperative myocardial infarction and should be utilized routinely. Additionally, perioperative antibiotic prophylaxis should be considered in an effort to reduce infection risk as well as strict adherence to a wound care regimen.

Neurological complications Motor deficits Hemiparesis of the contralateral side following surgery for temporal lobe epilepsy has been well described in the literature. In the manuscript, “Manipulation Hemiplegia”, Penfield, Lende, and Rasmussen eloquently describe this complication and propose various theories for its etiology.23 All operations carried out in the temporal regions by Penfield between 1948 and 1955 were retrospectively reviewed to include 161 in total with 8 incidents of hemiparesis accounting for 5%. Additionally, complete homonymous hemianopsia was also produced in all cases. Hemihypesthesias were also present. The hemiplegia improved to some extent in all cases. It was hypothesized that this triad of symptoms was attributable to injury of the internal capsule and associated structures where the corticospinal tracts, optic radiations, and thalamic radiations could be affected. It was proposed that this injury was likely vascular. It was further felt to be the result of injury to the anterior perforating arteries. It has since been attributed to injury to the anterior choroidal artery which supplies the optic tract, ventral thalamus, part of the striatum, and part of the posterior limb of the internal capsule.

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Since Penfield’s intial observations, numerous other institutions have documented postoperative motor deficits following temporal lobe surgery for medically intractable epilepsy. In 1975, Jensen reported his results from a survey covering 2,282 published temporal lobe resections around the world performed from 1928–1973 with respect to seizure control outcome and complications.24 They found persistent hemiparesis in 2.4% and transient hemiparesis in 4.2% of temporal lobe resections respectively. In a retrospective analysis reviewing complications in 654 procedures recorded in the Swedish National Epilepsy Surgery Register between 1990 and 1995, hemiparesis was observed in 2.2%.9 Of the 247 temporal lobe resections, one patient was observed to have hemiparesis after a temporal lobe resection excluding the hippocampus and four occurred after temporal lobe resection including the mesial structures. This was felt to support the theory that hemiparesis occurred as a result of injury of the anterior choroidal artery. In Behrens’ report, hemiparesis was the most frequent neurological complication being observed in 1.8% of the temporal lobe resection group.2 Upon review, it was found that in two cases, manipulation of the anterior choroidal artery led to infarction of the internal capsule as documented on postoperative computed tomography scans. In a cohort of 215 patients, two patients suffered from a postoperative hemiparesis.10 A regression analysis was performed in an attempt to identify potential risk factors for this potential complication. These two patients were greater than the mean age of 34 suggesting the possibility of advanced age as a risk factor for developing this complication. In review of the above studies, hemiplegia and associated deficits following injury to the anterior choroidal artery and perforant vessels appears to occur on the average of 2%. Long-term studies have not been conducted to determine the percentage of patients with this complication who develop improvement. Subjectively, upon gross review of the literature, it would appear, that in a majority of cases of this type of complication, the hemiplegia is transient and tends to improve over several months to a year. Whether advanced age could be a risk factor for the development of this complication remains unclear. Visual field deficits Surgery for temporal lobe epilepsy afforded a new outlet for studying the route of optic radiations through the middle cranial fossa. Prior to temporal lobe resections for epilepsy, anatomical studies of visual field defects were limited to surgery for neoplastic resection as illustrated in Cushing’s series, or by Meyer’s studies of secondary degeneration following vascular or traumatic lesions.25,26 Soon after the initial descriptions of temporal lobe resections for epilepsy were published, several case series examining the effect of the surgery on visual fields were presented. In the initial reports, it became evident that a majority of patients demonstrated a partial homonymous contralateral visual field defect limited to the upper quadrant. This was felt to be a reflection of the degree of the surgical resection and likely attributable to injury to Meyer’s loop; the lateral most portion of temporal optic radiations. Penfield in 1954 stated, that if the excision was limited to less than 6 cm of the temporal lobe, no visual field defect was observed and resection of greater than

6 cm was associated with a partial visual field defect and greater than 8 cm was associated with a complete homonymous hemianopsia.8 In contrast, Falconer’s experience in 40 patients did not demonstrate a clear association with the degree of visual field defect with respect to the extent of the temporal lobe dissection.5,27 In 1958, two case series were published from Montreal Neurological Institute and Guy’s de Maudsley Neurosurgical Institute in London.28,29 In the former, 41 patients who underwent temporal lobe resection in an effort to elucidate the architecture of the optic radiations in the temporal lobe were examined pre- and postoperatively with perimetry visual field testing.27,28 They found that there was no increased risk to central vision, visual acuity, or blind-spot margins. They found visual field defects in 82% of the patients. All were found to be quadrantic in nature. Ten were found to be congruous and 23 were incongruous with the defect closer approaching the fixation point in the eye on the side of the surgery. Additionally, they noted a slanting inferior margin of some of the defects expanding to a homonymous hemianopsia rather than a pure quandrantanopsia. They then embarked on a review of the existing literature describing the optic radiations of the temporal lobe. They concluded that the visual defects encountered were due to the effects of surgical ablation and not edema of the temporal portion of the visual radiation, as the deficits persisted 4 and 9 months postoperatively. Falconer and Wilson from London studied the visual field changes in 50 consecutive patients treated by anterior temporal lobectomy.27 They found the chances of developing an upper quadrantic defect was on the order of 5 to 1. They determined that there was no significant difference in the range of the extent of the hemianopsia with regard to the extent of the dissection between 4.5 and 8 cm from the temporal pole extending posteriorly. All of their results demonstrated a congruous visual field defect, in contrast to the results reported by Van Buren and Baldwin. Ten years following these two illustrative manuscripts, Marino and Rasmussen performed a more detailed review examining 50 patients operated upon for temporal lobe epilepsy at the Montreal Neurological Institute between 1962 and 1967.30 Preoperative perimetry and tangent screen tests were normal in all patients in this series. It was found that 58% of the patient exhibited partial or complete quadrantic defects. The smallest defect being a small triangular sector near the vertical meridian with the most severe being a complete homonymous hemianopsia. It was found that in 34% in whom no field defects were noted, temporal lobe removals extended between 4 and 8 cm. They found a poor correlation between the extent of the defects and the extent of temporal lobe resection. This lended support to the idea of the presence of considerable variability in the formation of the optic radiations between patients. They reported the visual field defects were congruous in 79% of patients. More recently, several large reviews have been undertaken to study the various complications associated with the procedure. In the review of the Swedish National Epilepsy Surgery Register of 449 procedures performed between September 1990 to 1995, two patients were found to have experienced hemianopsia.9 In Jensen’s review of 868 cases, visual field deficits reported ranged from 2.9–93% with an average of 50.9%.24 After the two extremes reported were eliminated, it was found that visual field defects occurred at a frequency of

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Temporal lobe epilepsy surgery: surgical complications 46% with the majority being partial hemianopsias and only 4% were complete homonymous hemianopsias. In a study of 215 patients, only one patient demonstrated a hemianopsia equaling 0.4%.10 In Wiebe’s prospective randomized trial quadrantic visual field defects occurred in 55% of patients in the surgical group.11 However, these were asymptomatic and were only evident on detailed visual field testing. A recent study was carried out at the National Hospital in London to evaluate the extent of visual field defects and to discuss its implication in passing the British driving examination.31 Of patients who had undergone temporal lobe surgery,24 underwent postoperative evaluation with both Goldmann and Humphrey perimeter testing. It was noted that a field deficit was found in 54% of patients using the Goldmann test and 46% using the Humphrey analysis. In 25% of these patients, the defect was large enough to fail the vision criteria set forth by the British driving regulations, prompting the role of preoperative discussion of this side-effect prior to surgical resection. The majority of these studies thus far have attributed the visual field defects to an injury to the optic radiations which traverse the temporal lobe. The superior quadrantanopsia appears to be associated with a primary injury to Meyer’s loop, whereas a complete homonymous hemianopsia has been attributed to removal of a greater extent of the temporal lobe as well as disruption of the optic radiations as they course medially and inferiorly. It would make sense that there would be a variance in the incidence of visual field deficits with respect to differing surgical approaches. A study comparing the standard anterior temporal lobectomy (ATL) approach with selective amygdalohippocampectomy (SAH) with respect to visual field deficits was carried out by Egan et al.32 Twenty-nine patients were enrolled, with 14 undergoing SAH and 15 ATL. The patients were tested using Goldman perimetry 1 month postoperatively. Approximately 75% were found to have a superior quandrantanopsia. There was no statistical difference between the two approaches. It was postulated that the visual field defect occured during ATL when the temporal tip is removed. In SAH, it was explained that visual field defects occurred as the suction device and retractors are driven through the optic radiations en route to resection of the medial temporal lobe. In conclusion, visual field defects following surgery for temporal lobe epilepsy range from minor triangular defects to complete homonymous hemianopsias. In the majority of cases, the patients demonstrated a superior quadrantanopsia and were unaware of their deficit as it was diagnosed only with detailed visual field testing. The range of patients to exhibit visual field defects ranges from 46% to 82% in earlier studies. A quote of a 50% chance of possibly incurring a visual field defect is reasonable when counseling patients for this procedure. The extent of the visual defect does not appear to clearly correlate with the degree of dissection or approach of the surgery. The optic radiations, which make up the most lateral aspect of Meyer’s loop appear to be most susceptible to injury. However, in the majority of cases, the patients who were found to have a superior quadrantanopsia on detailed testing were unaware of their deficit. In those few cases of patients who suffer a more extensive hemianopsia, it may be related to the amount of resection or individual variance on the course of the optic radiations as they encompass the temporal lobe and appears to with a frequency of 4–12%.

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Cranial nerve deficits The cranial nerves most often implicated in potential complications following surgery for temporal lobe epilepsy are the oculomotor CN III and the trochlear CN IV nerves. The oculomotor nerve passes through the ambient cistern bordering the medial aspect of the temporal lobe en route to the cavernous sinus. The trochlear nerve innervates the superior oblique muscle of the orbit. It exits the brain stem dorsally and decussates in the superior medullary velum. It then courses lateral to the cerebral peduncles and passes between the posterior cerebral and superior cerebellar arteries just lateral to CN III as it runs medial to the temporal lobe before entering the cavernous sinus. Several studies have demonstrated cranial nerve palsies following temporal lobe surgery. Rydenhag et al. documented two trochlear nerve and two oculomotor nerve palsies following mesial temporal lobe resections upon their review of 247 temporal lobe resections.9 Third nerve palsy was seen transiently in four of 279 cases reviewed by Behren’s et al.2 In Salanova’s study of 215 patients, seven manifested transient cranial nerve palsies with nerves III or IV following temporal lobectomy.10 This accounted for 3.2% of their series and was observed to have resolved in several weeks. Jacobsen et al. reviewed 22 cases of patients who underwent anterior temporal lobectomy for treatment of epilepsy at the Marshfield clinic between 1987 through 1993 and found three cases of transient postoperative diplopia.33 Detailed neurological examination was performed which demonstrated ipsilateral trochlear nerve palsies. Postoperative imaging did not demonstrate any evidence of infarction. It was felt that this complication was likely secondary to traction. The trochlear nerve is the thinnest cranial nerve residing in the lateral wall of the cavernous sinus and may be vulnerable to mechanical distortions of the lateral wall which may occur during temporal lobe resection. The authors felt that trochlear nerve palsies may be underdiagnosed due to their difficulty in diagnosis and that the prevalence may be higher than initially supposed. Thus, after review of the literature, it would appear that the risk for developing a cranial nerve palsy of either the oculomotor or trochlear nerve is on the order of 1.5–3%. Additionally, this deficit appears to be transient in the majority of cases which would correlate with a possible retraction injury as opposed to direct injury to the nerve or vascular compromise. Language deficits The role of language in the temporal lobe can be appreciated by observing certain seizure semiologies. Often persons are completely aphasic during a seizure or exhibit abnormal language with perseveration and paraphasic errors. The posterior superior portion of the temporal lobe has been mapped as Wernicke’s area; with lesioning of that area associated with a receptive aphasia. The inferior frontal gyrus overlying the superior temporal lobe is implicated in Broca’s area, the lesioning of which is associated with an expressive aphasia. The two are believed to be connected via the arcuate fasciculus where lesions have been characterized as producing a conductive aphasia. Numerous studies have demonstrated language difficulty following surgery of the temporal lobe. Many centers report a transient aphasia characterized by

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dysnomia following temporal lobectomy for epilepsy.34–38 However, the more long-term impact on temporal lobe resection on language function has been less clearly elucidated. The role of this section will provide a broad overview of the temporal lobe’s function in language and to outline the most common complications encountered following surgery in this area. In the initial surgeries for temporal lobe epilespy, intraoperative language mapping was employed routinely as well as an attempt to avoid the superior temporal gyrus secondary to the risk of injury to Wernicke’s area. In recent years, the role for language mapping has been debated. Hermann conducted a prospective analysis of 29 patients who underwent partial resection of the anterior temporal lobe utilizing intraoperative mapping.35 No significant loss in either dominant or nondominant-sided resections with respect to language function was observed. Anecdotally, improved seizure control was observed in patients from this study who were unable to tolerate intraoperative mapping for various reasons. As a result, Hermann carried out a follow-up study with 64 consecutive patients who underwent anterior temporal lobe resection without intraoperative language mapping.36 The patients were administered the multilingual aphasia test preoperatively and 6 months postoperatively. A median of 4.25 cm of lateral dominant temporal cortex or 4.5 cm of nondominant temporal cortex was removed including resection of the superior temporal gyrus. No measurable compromise was appreciated when comparing preoperative and postoperative scores. In fact, dominant temporal lobectomy patients were seen to have gained in language comprehension function postoperatively. The surgical approach has been implicated as a means for protecting language function. It has been argued that sparing the superior temporal gyrus results in less postoperative dysnomia. It has also been implied that preoperative or intraoperative language mapping results in less difficulty with language post operatively. In a large multicenter study, four surgical approaches were examined with respect to visual confrontation naming following Wada proven language dominant left temporal lobectomy for epilepsy.39 A total of 217 patients underwent surgery either via tailored resection with intraoperative mapping, tailored resection with extraoperative mapping, standard resection with sparing of the superior temporal gyrus, and standard resections including excision of the superior temporal gyrus. They found that in all surgical groups there was significant decline in visual confrontation naming as assessed by the Boston Naming Test by an average of 8%. They saw no significant change between naming outcomes as a function of surgical approach. Contrastly, Ojemann conducted a study of 117 patients undergoing Wada proven left language dominant hemispheric resections for various reasons where language mapping was undertaken.40 It was found that essential areas for language were often organized in a 1–2 cm mosaic pattern of discrete areas of language function. Mosaics essential for language were usually located in the frontal cortex or in the temporoparietal cortex. These findings were often highly localized and reproducible within a given patient but were not found uniformly in a group analysis. These findings imply a great degree of variability within localization of essential naming and language function to suggest a role for language mapping. Since its inception the role for intraoperative mapping and

partitioning of the superior temporal gyrus has been debated. Currently, temporal lobe epilepsy surgery has expanded so that many centers no longer perform tailored resection according to language mapping nor do they routinely spare the superior temporal gyrus. Dysnomia appears to be the most common deficit encountered in language function following surgery for temporal lobe epilepsy. Hermann published a study to evaluate the presence of dysnomia following dominant anterior temporal lobectomy.41 Patients with Wada proven left hemisphere speech dominance with intractable nonlesional epilepsy and fullscale IQ > 69, underwent anterior temporal lobectomy without functional mapping at the University of Tennessee, and were evaluated with respect to language. These patients were administered a standard aphasia battery preoperatively and 6 months postoperatively. The primary area of interest was a visual naming subtest. The extent of lateral dominant resection averaged 4.3 cm from the temporal tip. No significant difference in the mean preoperative to postoperative score was seen for the right temporal lobectomy group. Left temporal lobectomy patients experienced a 23–27% decline from their preoperative performance. A study by Martin et al. showed in a total of 101 Wada proven left language dominant patients who underwent anterior temporal lobectomy for medically intractable epilepsy showed that nearly 50% of the left-sided resected patients experienced clinically meaningful declines with respect to the Boston Naming Test.42 This contrasted with right-sided resected patients who showed no significant decline on the Boston Naming Test. Following, these and other studies which demonstrated a clear decline in postoperative naming ability after resection of the Wada proven language dominant temporal lobe, many studies have been aimed at predicting risk factors for developing this difficulty. Stafiniak et al. evaluated 45 patients who underwent anterior temporal lobecomy for medically refractory epilepsy.38 All patients received comprehensive neuropsychological evaluations preoperatively and 3 weeks after surgery. After left dominant lobectomy 60% of patients with no early risk factors such as early neurologic insult via infection or trauma, or febrile seizure demonstrated a > 25% decline in naming. However, none of the patients without early risk factors experienced a postoperative decline in naming. None of the patients who underwent right-sided surgery experienced a naming decline postoperatively. This study would suggest that perhaps patients with a neurological insult early in life are able to collateralize language ability to some extent allowing for decreased risk for dysnomia postoperatively. Bell studied 26 patients with Wada proven left-sided language dominance who underwent left anterior temporal lobectomy with respect to naming performance.43 The age of onset of epilepsy was the only predictor of postoperative dysfunction. Patients who developed epilepsy at an earlier age were more likely to exhibit less difficulty with naming postoperatively. Patients who had felt that they had learned the particular word in question at a later age were more likely to have difficulty naming it in the time prescribed during the Boston Naming Test on their postoperative evaluation. In a multicenter trial to compare surgical approach with language difficulty postoperatively, one risk factor which was identified was the age at onset of epilepsy. Patients who developed seizure onset at a later age demonstrated increased difficulty in naming.44

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Temporal lobe epilepsy surgery: surgical complications The above studies demonstrate a postoperative decline in naming ability following dominant temporal lobe resection. However, the stability of this deficit over time has been less clearly observed. Stafaniak et al. evaluated 41 patients with respect to dysnomia following surgery for temporal lobe epilepsy and found that four of the six patients who experienced an average decline of 61% in naming ability pre- to postoperatively improved to a mean decline of 18% at 1 year follow-up.38 This finding suggests that this naming deficit often shows significant improvement over time. In a prospective study by Davies et al., 95 consecutive patients undergoing standard anterior temporal lobectomy for intractable complex seizures were studied with respect to language functioning.34 Patients underwent a neuropsychological evaluation to assess naming of objects preoperatively and 1 year postoperatively. Comparison of the preoperative scores showed a significantly lower score for the left-side dominant group for several of the language measures. At the 1 year follow-up, left-sided lobectomy patients demonstrated a significant improvement in verbal fluency and performance IQ. Right-sided temporal lobectomy patients also showed a significant improvement with respect to verbal fluency and performance IQ. In these resections, the superior temporal gyrus was resected without evidence for detriment to language function. In fact, this study seemed to support that the surgical resection allowed for improvement in language fluency and performance IQ. This may be a result of improved seizure control, or perhaps, the idea of relieving abnormal circuitry to allow normal circuitry to develop and progress. Functional magnetic resonance imaging has prompted a new cadre of non-invasive means to study language organization. In one study designed to evaluate reading skills in patients who underwent left-sided language dominant temporal lobectomy for medically intractable epilepsy compared patients to age matched controls.45 Those patients who demonstrated higher level reading skills postoperatively were more likely to recruit right hemispheric activity, specifically the in the right inferior frontal gyrus, right hippocampus, and right inferior temporal gyrus. The introduction of magnetoencephalograms has also added to the abundant studies underway to determine language localization. In a recent study by Pataria et al., 12 patients were examined using MEG who underwent left temporal lobectomy.46 They found that patients who exhibited bihemispheric recruitment preoperatively for language tasks were more likely to show increased right hemispheric activity postoperatively. The temporal lobe’s function in language has long been recognized as is evidenced by Wernicke’s and Brodman’s mapping studies. Temporal lobe epilepsy is often associated with semiology whereby the patients demonstrate language difficulty during seizures. The implications of temporal lobe resection on language ability have been somewhat surprising. Initially, it was felt that resections should be undertaken with intraoperative mapping and careful preservation of the superior temporal gyrus. Numerous studies have demonstrated no significant difference between outcomes in language function when intraoperative mapping is not utilized or the superior temporal gyrus is resected. However, there may exist individual variance between patients to support utilization of intraoperative mapping per Ojemann’s argument which must be considered when counseling patients of surgical risk of language difficulty. Additionally, though many studies have demonstrated a

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significant problem with dysnomia following surgery, it would appear that this is often a transient deficit which resolves in the first 12 months postoperatively. It was also found that patients with Wada proven language dominance on the side of the resection were more likely to suffer language difficulty postoperatively than those who underwent non-language dominant resections. Additional risk factors for language difficulty aside from dominant hemisphere resections included later age of epilepsy onset. New imaging analyses have shown that possibly patients who recruit the opposite hemisphere are better able to compensate for language difficulty postoperatively. Taken together, these data may lend support to the idea that patients who develop epilepsy at a younger age and who may exhibit a higher degree of plasticity, are at an advantage as they may be able to develop bihemispheric projections to support language function. This would argue proposal of surgical intervention in the younger population with medically intractable epilepsy. In conclusion, patients considering surgery for temporal lobe epilepsy need to understand the risk of language difficulty postoperatively. This risk appears to be increased in patients undergoing resection in the Wada proven dominant hemisphere, later age of onset of epilepsy, and absence of childhood neurological insult such as infection, trauma, or febrile seizures. Additionally, it would appear that, in a majority of patients, perioperative language difficulty is a transient phenomenon which demonstrates significant improvement 1 year following surgery. Memory deficits Since the inception of temporal lobe epilepsy surgery, a correlation has been observed between resection of the mesial structures and memory. Unfortunately, much of the knowledge that has been gained in this regard has been at the expense of surgical complications. Penfield and Scoville described several case reports of patients who underwent either unilateral hippocampal resection for temporal lobe epilepsy or bilateral resection for psychiatric illness, and developed severe anterograde amnesia.47,48 In all of these patients, there was evidence of difficulty in acquiring new memories to the extent that these patients were no longer able to carry out their activities of daily living. In those patients who underwent unilateral resection, it was found postoperatively that the opposite hippocampus exhibited a destructive lesion. After careful analysis of these patients, it was concluded that bilateral hippocampal dysfunction was correlated with this severe form of amnesia. The Wada test was introduced in Japan by Juhn Wada in 1949 and initiated into Western medical literature in 1960.49 The test involves injection of sodium amytal into each carotid artery to induce a temporal loss of function in the injected hemisphere. Lanugage is then assessed by monitoring the EEG-slowing and associated hemiparesis. Memory is assessed 10 minutes following injection and following return of EEG behavior to baseline. This test was initially utilized in 20 patients being evaluated for epilepsy surgery in Japan in an effort to determine language hemisphere dominance. However, after it was determined that memory likely also demonstrated some degree of lateralization, Branch and Milner published a retrospective analysis of 50 patients being evaluated for surgical resection at the Montreal Neurological Institute.50 They hypothesized that no memory defect should

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be seen after unilateral amytal injection unless there was a poorly functioning hippocampal formation on the contralateral side. They found memory disturbance in 13% of patients. This study led to the idea of utilizing the Wada test as a means of assessing the ability of the contralateral hemisphere to support memory independently when planning for resection of ipsilateral mesial temporal structures. The Wada test is employed on a routine basis in most epilepsy centers in an effort to prevent devastating memory loss following hippocampal resection. Rausch describes outcome data for 214 patients at UCLA who underwent anterior temporal lobectomy.51 All patients underwent Wada testing prior to procedure and demonstrated 67% of correct responses when sodium amytal was injected on the side ipsilateral to the resection. No significant postoperative memory decline was demonstrated after resection. Jones-Gotman evaluated the results of patients who failed Wada memory tests compared to those who had passed (found to support memory in the contralateral hemisphere) and who had undergone temporal lobectomy.52 Seventy-two patients were included in the sample; 11 who had failed the preoperative Wada test contralateral to the planned resection. Substantial postoperative losses with respect to long-term memory deficits 1 year after surgery were observed in those patients. In conclusion, the Wada test aids in determining whether or not memory can be adequately supported by the hemisphere contralateral to the planned resection. The hippocampal formation appears to correlate with episodic memory functioning used in day-to-day living as opposed to semantic memory which refers to knowledge of a more encyclopedic variety. Patients with temporal lobe epilepsy have been found to have progressive memory decline with respect to normal controls.53,54 Likewise after surgical resection, further decline has been reported. Despite a great deal of progress, the pathways of memory formation, consolidation, and retrieval have not been completely elucidated and appear to demonstrate considerable variability between subjects. Regardless, numerous studies implicate the neocortex of the temporal lobe in short-term or working memory functioning. Contrastly, the hippocampus has been implicated in memory consolidation.53–55 Hermann et al. report on a series 57 patients with full scale IQ > 69, medically resistant temporal lobe epilepsy, with Wada proven left hemisphere dominance.55 All subjects were given the California Verbal Learning Test preoperatively and 6 months postoperatively. This test provides information on overall recall ability, rate of learning, and indices of forgetting in addition to characterizing between different types of memory consolidation. This test involves oral presentation of a ‘shopping’ list of 16 items followed by five immediate recall trials. They found that patients who underwent a right-sided resection showed greater recall of words from the middle of the list, were able to utilize semantic clustering and demonstrated an overall greater ability to recall verbal material after a short delay. The patients undergoing left-sided temporal resection showed a lower proportion of words recalled from the middle of the list and exhibited more errors in free recall. The left-sided resected patients were more inefficient in their memory strategy. Given a list of 30 or more words, they were less able to remember words towards the top of the list and appeared to try to remember them by serial connection rather than semantic clustering. This means that they would attempt to recall the words by

remembering the order in which they were presented rather than making associations to connect the various words together. This study lends support to the theory that the language dominant hemisphere hippocampus is important in allowing the person to cement memories into functional quanta. Multiple studies including volumetric as well as histologic analyses have been done to demonstrate the role of the hippocampus in verbal memory functioning. A study by Trenarry et al. compared preoperative MRI-based hippocampal volumes with pre- and postoperative performance on an assortment of memory tests in 80 patients who underwent temporal lobectomy for medically intractable epilepsy.56 The average hippocampal volume was noted to be smaller on the side ipsilateral to the resection which correlates with the numerous patients exhibiting mesial temporal sclerosis as a pathologic entity. They found that greater atrophy of the left hippocampal formation when compared to the right was associated with improved verbal and visual memory following a left temporal lobectomy. Contrastly, resection of a non-atrophic normal sized hippocampus resulted in verbal and visual memory decline. This data lends support to the idea that the hippocampus may be involved in both verbal and visual memory consolidation. Previous studies have shown that hippoampal cell loss in the CA1 region is observed reliably in patients with hippocampal sclerosis. Rausch and Babb evaluated 25 patients who underwent temporal lobe surgery for medically intractable epilepsy and found that the degree of hippocampal neuron loss was significantly related to memory function.57 Preoperatively, patients with left temporal lobe seizures with severe neuron loss, defined as greater than 80% cell loss when compared to controls, performed worse than those with less than 80% cell loss. Postoperatively both sets of patients with left-sided resections decreased their performance on word pair tasks and delayed recall. Numerous studies have been done to demonstrate postoperative memory decline following surgery for temporal lobe epilepsy. Chelune et al. conducted a prospective analysis of 42 patients with medically intractable epilepsy who underwent temporal lobectomy with Wada proven left-sided language dominance.58 The patients were tested 3 months prior to their surgeries and at 6 months postoperatively. They found a significant decline in verbal memory tasks with those patients scoring the highest preoperatively demonstrating the most significant decline. A decrease in 1.5 standard deviations was evident in the verbal memory score. Rausch et al. compared 44 patients who underwent temporal lobectomy with eight patients who were found not to be surgical candidates.54 All participants underwent cognitive testing preoperatively, 1 year postoperatively, and at least 9 years later. All patients had language dominance in the left hemisphere confirmed by Wada testing. Ninety Percent of patients were found to exhibit hippocampal sclerosis on pathologic analysis. They found that the group of patients who underwent left temporal lobectomy demonstrated decreased performance in verbal memory scores when compared with preoperative scores. Patients who underwent right temporal lobectomy showed increases in verbal memory scores. Long-term follow-up demonstrated progression in decline in verbal memory for both patients undergoing right- and left-sided resections as well as those patients who did not undergo surgery. These results support that left-sided temporal lobectomy for left-sided language

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Temporal lobe epilepsy surgery: surgical complications dominant patients is associated with a decline in verbal memory functioning postoperatively. However, the study implies that patients with temporal lobe epilepsy may exhibit a more rapid decline in memory functioning than would be expected in the general population. Helmstaedter et al. enrolled a total of 144 patients who underwent temporal lobectomy.53 Participants were matched with respect to sex, age, seizure frequency, and IQ. Patients who failed the Wada test or who showed right hemisphere language dominance were not included. They found that left-sided temporal lobe epilepsy patients did significantly worse on preoperative performance measures of short and long delayed recall than patients with epilepsy localized to the right temporal lobe. Short and long delayed recall were impaired in only 34–40% of patients with right temporal lobe epilepsy compared to 70–80% of patients with left temporal lobe epilepsy. Postoperatively, no significant change was appreciated in any measure of verbal memory in right temporal lobe resections. Left temporal lobe resections by contrast showed marked negative effects on learning, recognition, and recall. The deficits observed were most pronounced in tests of memory acquisition and recognition. The lateral neocortex has been implicated more in naming and short-term working memory tasks. The mesial temporal lobe and hippocampus specifically has been associated with long-term memory consolidation and retrieval. A study by Helmstaedter et al. sought to confirm this representation by comparing the type of memory deficits suffered by persons undergoing lateral versus mesial resections for epilepsy surgery.54 They examined 47 patients with medically intractable temporal lobe epilepsy localized to the left hemisphere who underwent standard anterior temporal lobectomy, cortical lesionectomy, and selective amygdalohippocampectomy. Memory was assessed preoperatively and 3 and 12 months postoperatively using a variant of the Rey Auditory Verbal Learning Test. This test was designed to assess different aspects of declarative memory including working memory by means of immediate recall as well as long-term aspects such as consolidation and retrieval by asking for free recall following distraction, delayed recall, and recognition. The results were compared to 175 matched controls with no history of a central nervous system disease. A significant decrease in delayed free recall and an increase in recognition errors in patients who underwent anterior temporal lobectomy and selective amygdalohippocampectomy when compared to the cortical lesionectomy group. They also found a significant effect in patients who underwent temporal lobectomy with respect to selective amygdalohippocampectomy with a further deterioration in total immediate recall. A repeat analysis 12 months postoperatively was consistent with 3-month data to suggest stability of the outcome over time. These data support the hypothesis that the mesial temporal structures are correlated with long-term memory retrieval and consolidation while the lateral temporal lobe is more implicated in working memory. This study implies that perhaps anterior temporal lobectomy results in a deficit in both working memory and long-term memory whereas selective amygdalohippocampectomy may offer some preservation of working memory. However, a study of 140 patients who underwent selective amygdalohippocampectomy demonstrated a significant decline in all aspects of verbal learning and memory.60 The results were standardized according to normative data of

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200 healthy controls. Patients underwent a neuropsychological examination of verbal and visual memory functions preoperatively and 3 months postoperatively. Left-sided resected patients scored 2–3 standard deviations below the mean postoperatively. These deteriorations involved verbal memory learning, delayed free recall, and recognition. The authors found no recovery of postoperative verbal memory declines as clinically meaningful losses were evident in 33–50% of patients at the 1 year follow-up.61 Tailored resection for temporal lobectomy has been proposed in patients to preserve both language and memory function. A study by Ojemann and Dodrill demonstrated memory centers localized in the lateral neocortex of the temporal lobe.62 In a study of 14 adults who underwent left temporal lobectomy with intraoperative mapping, the Weshler Verbal Memory Scale was employed to study memory function pre- and postoperatively. The score decreased an average of 22% at 1 month and 11% at 1 year. In the mapping studies, they found the presence of temporo-parietal zones of memory sites which largely bordered naming sites. They then correlated the presence of these sites with the proximity to the resection bed. They found that the presence of these sites within the resection zone was present in five of six patients who demonstrated a significant memory decline postoperatively indicative of an 80% predictive ability. Numerous studies have been done in an attempt to elucidate which patients may be at greater risk for postoperative memory decline. One study found that later age at onset of epilepsy and older chronologic age were risk factors for memory deficits.63 Two hundred three patients were assessed using the California Verbal learning Test preoperatively and 6 months postoperatively following anterior temporal lobe resection. In this study, higher postoperative scores correlated with higher preoperative scores, younger chronologic age, higher full-scale IQ, female sex, and right-sided resection. To explain the variance in higher preoperative scores being associated with higher postoperative scores, they suggest that, when all other preoperative variables are held constant, a person with higher intelligence is better able to compensate. In a multiple regression analysis performed on 144 patients who underwent anterior temporal lobectomy several factors were felt to be predictors of postoperative deterioration.53 High presurgical performance level, older age, longer duration of epilepsy, extensive en bloc resection, preexisting deficits in memory performance and preoperative secondarily generalized seizures were all associated with a decline in memory function postoperatively. The effect with respect to age appeared to correlate well with an age of 30 years at the time of surgery. Only 17% of patients aged > 30 demonstrated stable or improved memory performance postoperatively. A further analysis to evaluate the role of regression based outcome methodology was employed on a cohort of 101 patients found a significant performance decline in 25–50% of patients with left-sided resections.42 However, they noted a significant range of memory outcome within groups to support the great deal of variability found in numerous other studies. In a study by Hermann et al., 60% of patients with left anterior temporal lobectomy experienced postoperative decrease in verbal memory but 38% showed improvement illustrating the great deal of individual variance between patients with respect to functional outcomes.

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In summary, the role of the temporal lobe in memory function is both complex and critical. The Wada test is an important tool which has been developed to determine the ability for the contralateral hemisphere to adequately support memory following temporal lobe and hippocampal resection. However, even when one is careful to offer surgery only to those patients who have favorable Wada test results, memory deficits remain a significant complication observed following this surgery. In patients with left-sided language dominance, the risk of memory dysfunction postoperatively appears to be greater than those who undergo right-sided resection. The presence of preoperative memory deficit in setting of mesial temporal sclerosis may mitigate the risk of a decline in verbal memory postoperatively. The deficits that are observed following temporal lobectomy are characterized by difficulty with working memory and memory consolidation. Resection of the lateral neocortex appears to result in a deficit of working memory whereas resection of the mesial structures results in difficulty with memory consolidation. These deficits often require the patient to adopt different strategies for memory consolidation such as outward documentation to assist them in their day-today living. Postoperative neuropsychological testing, in addition to studying the types and degree of memory difficulty observed following temporal lobe resection, provides a tool for the patient and patient’s family to identify particular weaknesses which then may be addressed. Older age at epilepsy onset, older chronologic age, higher preoperative functioning, and left-sided resections appear to be risk factors for memory deficits postoperatively. Taken together, these data illustrate particular trends which may correlate to predictive analysis of postoperative memory decline but that for each individual there exists a great deal of variance. Cognitive deficits Cognitive difficulty has been noted in patients with temporal lobe epilepsy when compared to controls. Progression of the disease is associated with progressive cognitive impairment prompting a role for medical or surgical control of seizures. The question of whether the extent of the neocortical resection correlated to the degree of cognitive impairment was addressed by Lutz et al. comparing 80 randomized patients who either underwent transylvian approach or transcortical approach for mesial resection.64 All patients received comprehensive neuropsychological testing of verbal, non-verbal memory, attention, and executive functions before and 6 and 12 months following surgery. It was found that 75% of patients became seizure free with no appreciable difference observed with regard to surgical approach. Repeated multivariate analysis of variance measures demonstrated no statistical difference between cognitive outcomes with the exception of phonemic fluency which was improved after transcortical but not after transsylvian approach. This improvement in verbal fluency with the transcortical approach has traditionally been attributed to seizure freedom postoperatively. However, the authors felt that the improvement with the transcortical approach may be a reflection of this function being more closely associated with frontal lobe manipulation. Verbal fluency could be regarded more as an executive function and, as such, has its seat in the frontal lobe. The frontal lobe is manipulated with retraction more with the transylvian approach than with the transcortical approach.

In a study by Wachi et. al., 26 patients who underwent anterior temporal lobectomy including excision of the hippocampus were evaluated with a battery of neuropsychological tests pre- and postoperatively.65 They found a uniform improvement in cognitive functioning following resection. A significant increase was observed in verbal IQ from 85.1 to 89.3. Performance IQ also increased from 89 to 95 1 year postoperatively. Full-scale IQ scores also were observed to increase at 1 year after surgery from 85.5 to 88.5. There was no significant difference between memory function as determined using story recall test, Benton’s visual retention test, Rey-Osterreith complex figure test, and the WMS-R between preoperative analysis and postoperative analysis. These improvements were felt to be reflective of an overall decrease in seizure frequency with 62% of the patients being seizure free. However, the study was made of a small sample size and statistically significant comparisons could not be made between left- and right-sided resection. The role of tailored resection with respect to cognitive preservation was undertaken by Leitjen et al.66 Eighty patients with pathologically proven mesial temporal lobe sclerosis underwent surgery. These patients underwent a standard neuropsychological test battery 6 months prior to and 6 months after the surgery including verbal IQ (VIQ), performance IQ (PIQ), visual naming, and a complex figure test. Sixty-one percent of the patients demonstrated neocortical spikes on the intraoperative ECoG. Interestingly, patients with left-sided resections with neocortical spikes demonstrated a slightly improved VIQ preoperatively than their counterparts without spikes. They found an improvement in PIQ in patients who underwent tailored resection, but not in any other modality. It was felt that this was in contrast to their initial hypothesis that neocortical spikes were indicative of dysfunctional tissue and that removal of such spikes would allow for a better cognitive performance outcome, especially in regard to language function thought to be harbored in the neocortex of the temporal lobe. Taken together, these studies support that improved seizure frequency results in overall improvement in visual and performance IQ following surgery for temporal lobe epilepsy. A complete resection of the mesial structures without regard to intraoperative mapping may allow for greater seizure control and thus correlate with improved outcome in cognitive functioning. Psychiatric deficits Epilepsy in itself has been associated with a higher incidence of a major depressive illness and suicide. It is estimated that the suicide rate in epilepsy patients is five times that of the general population.67,68 One study found that up to 50% of patients with epilepsy suffer from depressive syndromes.69 Patients with temporal lobe epilepsy have been found to have an even higher risk of depression.63 Temporal lobe epilepsy, in particular, has been associated with a variety of psychological disturbances both before and after resective procedures. The proximity to the limbic structures has been implicated as a possible reason for higher incidence in mood and psychiatric disturbances. The amygdala in particular has been associated with processing of fear response. In one study of 28 patients who had undergone anterior temporal lobectomy, a postoperative impairment was found in recognizing facial expressions

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Temporal lobe epilepsy surgery: surgical complications of fear, anger, sadness, and disgust.70 In a prospective randomized controlled trial of 80 patients who either underwent temporal lobectomy or received optimal medical therapy the rate of depression was fairly equally represented between both groups.11 Eighteen percent of patients were diagnosed with depression in the surgical group compared to 20% of patients in the medical groups indicating the increased prevalence of this problem in this population. Since the landmark study by Kluver and Bucy describing a state of hypersexualuality, loss of fear, hyperphagia, and generalized apathy following bilateral temporal lobectomy, various psychiatric derangements have been attributed to the temporal lobe.71 Disturbances in mood, emotional responses, and even schizophrenic-type illnesses have been localized to the temporal lobe. Blumer’s report, based on a series of 50 patients who underwent temporal lobectomy and were followed for an average of 17 years sought to examine the type of psychiatric sequelae of the surgery.68 Fifty patients experienced an exacerbation or onset of a chronic schizophrenia-like psychosis. Ten percent also demonstrated angry and aggressive behavioral outbreaks. Many patients preoperatively demonstrated hyposexuality. These patients were observed to have developed normal sexual arousal and occasional hypersexuality postoperatively. Fenwich et al. conducted a literature review and circulated a questionnaire to multiple centers around the world to study the current practice and outcomes of surgery with regard to psychiatric complications.72 In comparing three separate series, there was a rate of developing a schizophrenia-type psychosis in 15.4%, which is greatly increased from the stated 1% lifetime incidence documented for the general population. A retrospective analysis was performed by Inoue and Mihara to assess the presence of psychiatric morbidity in association with epilepsy surgery.73 Their subjects consisted of 226 patients who underwent surgical therapy between 1983 and 1997. Seventy-eight percent of the patients exhibited psychiatric disorders before and after surgery. Of those 61 patients who demonstrated psychiatric disturbances before surgery, one-third of them resolved following surgery. Nine patients were found to have transient affective disorder immediately postoperatively which resolved in 1–2 months. Eight patients developed a chronic psychiatric disorder de novo following surgery. Of these, six were found to have psychosis and two developed behavioral disorders. This study suggests that about a third of persons with psychiatric disorders prior to surgery will experience resolution of their symptoms postoperatively, while the rest will persist. It also suggests, that in a select minority of patients, a de novo psychiatric disturbance will become manifest after surgery. Shaw, interested in the association between temporal lobe surgery and postoperative schizophrenia-like psychosis, performed a retrospective analysis of a series of 320 surgical patients.74 They identified 11 patients who developed a schizophrenia-type psychotic illness postoperatively and compared them with 33 control subjects who remained free of psychosis. The psychotic illness was characterized by the presence of persecutory delusions and auditory hallucinations. They found no clear association between postoperative seizure activity and the development of psychotic symptoms. However, they did find that those patients were more likely to demonstrate pathologies other than mesial temporal sclerosis as five of the 11 had lesions such as vascular hamartoma, DNET, ganglionglioma, and abscess. Additionally, they

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found that the psychotic patients were more likely to demonstrate bilateral EEG abnormalities. Christodoulou et al. made an interesting observation in reviewing a case series of 282 consecutive patients who underwent temporal lobe resections for epilepsy.75 Fifty-six patients demonstrated persistent or recurrent seizures postoperatively. Three of these patients developed a chronic psychotic illness. Upon further study, it was found that all three of these patients demonstrated a new seizure type postoperatively arising from the side contralateral to the resection. This appears to support the theory that patients prone to psychotic breaks may have some inherent involvement of both hemispheres, perhaps brought out by resection of one side of the mesial temporal structures. Epilepsy surgery has also been associated with a higher predisposition to somatic-type disorders. A retrospective review of 325 anterior temporal lobectomies performed between 1991 and 2000 at New York University Hospital found 10 patients (3%), who developed somatoform disorder.76 These were characterized by body dysmorphia and pain disorder. Nine of the ten had undergone right resections which correlate with previous data implicating the right temporal lobe in psychotic corrolaries. It is difficult to assess objectively the psychiatric complications of temporal lobectomy for epilepsy as many of these patients demonstrated abnormal psychiatric profiles preoperatively. In general, it is felt that a majority of patients develop stronger emotional ties, family relationships, and become more functionally independent following the procedure likely secondary to its improvement in seizure control. However, for a select few, it may predispose them to developing a severe psychotic illness similar to schizophrenia. It is recommended that potential candidates for resective surgery be considered for a psychiatric assessment prior to the procedure to ensure that they are receiving optimal therapy prior to any potential surgical intervention.

Conclusion In conclusion, surgery for medically intractable temporal lobe epilepsy is associated with a broad variety of complications. When counseling prospective candidates for this procedure, one must keep in mind the intricate structure and relationship of the temporal lobe with its surroundings as well as the variety of functions intrinsic to the temporal lobe itself. The surgical complications most frequently encountered include hematoma and infection. The risks of craniotomy vary between institutions and should be quoted as such. In general, a risk of postoperative infection is on the order of 2–5%. Risk reduction is achieved by employing sterile technique and perioperative antibiotics. The risk of a clinically significant hematoma is on the order of 1–2% which may necessitate a need for a repeat craniotomy for hematoma evacuation. Wound complications such as dehiscence, superficial wound infections, and CSF leak all have been seen with routine craniotomies as well as with temporal lobe epilepsy surgery. Wounds should be monitored closely postoperatively and a strict wound care regimen should be followed. In consideration of the potential neurological complications, one must recall the more rare deficits such as injury to

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the anterior choroidal artery and resultant hemiplegia as well as the routinely observed contralateral upper quadrantanopsia seen postoperatively. Motor deficits postoperatively appear to be secondary to vascular injury. Risk factors for vascular disease such as increasing age, hypertension, hypercholesteromia may all be considered not only for risk to specific vessels but also in regard to the patient’s overall surgical risk. The risk for a potential visual field defect is on the order of 50%. The majority of patients are unaware of this deficit, but in up to 12% of patients, a more significant and disabling defect such as a complete homonymous hemianopsia may develop. Cranial nerve palsies of the third and fourth cranial nerve can occasionally be observed postoperatively. These may be quite bothersome for the patient but usually are transient in nature. The potential adverse effects on language and memory were discussed in detail. The temporal lobe harbors various regions associated with language function such as Wernicke’s area and other regions identified with intraoperative mapping studies, and resection of the language dominant temporal lobe can result in a significant dysnomia. This appears to improve with increasing postoperative period and may resolve entirely. Older age at onset of epilepsy appears to be a risk factor which may be associated with poorer postoperative language function. Many patients demonstrate improvement in language which is likely multifactorial but may be associated with overall seizure control. The possible detriment to memory function is significant and can be severe. The ability for the contralateral hippocampal formation to independently support memory should be evaluated preoperatively and surgical resection planned accordingly. The type of memory most

affected appears to be episodic memory consolidation. Patients who develop postoperative memory deficits appear to exhibit difficulty with employing strategies for recalling information attributable to the events of daily living that is not in their immediate memory banks. This type of deficit appears to be stable with time. Patients may benefit from learning various means to cope with this outcome. Lastly, the psychological sequelae of this surgery were discussed. Temporal lobe epilepsy of its own right is associated with an increased incidence in psychiatric morbidity including mood disorders, somatic disorders, as well as psychotic disturbances. The risk of introducing a new psychiatric illness is fairly rare, but there is a clear association between development of a postoperative psychotic illness similar to schizophrenia and surgery for temporal lobe epilepsy. Neuropsychological analysis should be considered prior to surgery to ensure that the patient is enrolled in optimal treatment paradigms. This chapter serves as a basic outline of the potential pitfalls associated with surgery for temporal lobe epilepsy. One must remember that in addressing the risks and benefits of this surgical procedure, each patient should be assessed as an individual. The percentages and data presented here serve only as guidelines. The neurosurgeon and neurologist involved will need to balance each patient with respect to individual risk for surgery, potential neurological complications, potential cognitive complications, as well as psychiatric complications. The surgical approach and the use of mapping need to be considered on an individual basis. In doing so, one can hope to provide the best hope for a good surgical outcome unfettered with complications.

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ment for epilepsy. In: Theodore WH, ed. Surgical Treatment of Epilepsy. New York: Elsevier Science Publications, 1992:77–85. Jones-Gotman M. Neuropsychological techniques in the identification of epileptic foci. In: Theodore WH, ed. Surgical Treatment of Epilepsy. New York: Elsevier Scientific Publications, 1992:87–94. Helmstaedter C, Elger CE. Cognitive consequences of two-thirds anterior temporal lobectomy on verbal memory in 144 patients: a three-month follow-up study. Epilepsia 1996;37:171–80. Helmstaedter C et al. Differential involvement of left temporolateral and temporomesial structures in verbal declarative learning and memory: evidence from temporal lobe epilepsy. Brain Cogn 1997;35:110–31. Hermann BP et al. Differential effects of left and right anterior temporal lobectomy on verbal learning and memory performance. Epilepsia 1992;33: 289–97. Trenerry MR et al. MRI hippocampal volumes and memory function before and after temporal lobectomy. Neurology 1993;43:1800–5. Rausch R, Babb TL. Hippocampal neuron loss and memory scores before and after temporal lobe surgery for epilepsy. Arch Neurol 1993;50:812–17. Chelune GJ et al. Prediction of cognitive change as a function of preoperative ability status among temporal lobectomy patients seen at 6-month follow-up. Neurology 1991;41:399–404. Rausch R et al. Early and late cognitive changes following temporal lobe surgery for epilepsy. Neurology 2003;60:951–9. Gleissner U et al. Memory outcome after selective amygdalohippocampectomy: a study in 140 patients with temporal lobe epilepsy. Epilepsia 2002;43:87–95. —-. Memory outcome after selective amygdalohippocampectomy in patients with temporal lobe epilepsy: one-year follow-up. Epilepsia 2004;45:960–2. Ojemann GA, Dodrill CB. Verbal memory deficits after left temporal lobectomy for epilepsy. Mechanism and intraoperative prediction. J Neurosurg 1985;62:101–7. Davies KG et al. Prediction of verbal memory loss in individuals after anterior temporal lobectomy. Epilepsia 1998;39:820–8. Lutz MT et al. Neuropsychological outcome after selective amygdalohippocampectomy with transsylvian versus transcortical approach: a randomized prospective clinical trial of surgery for temporal lobe epilepsy. Epilepsia 2004;45:809–16. Wachi M et al. Neuropsychological changes after surgical treatment for temporal lobe epilepsy. Epilepsia 2001;42 Suppl 6:4–8. Leijten FS et al. The effects on cognitive performance of tailored resection in surgery for nonlesional mesiotemporal lobe epilepsy. Epilepsia 2005;46:431–9. Blumer D et al. Psychiatric outcome of temporal lobectomy for epilepsy: incidence and treatment of psychiatric complications. Epilepsia 1998;39:478–86. Blumer D. Psychiatric aspects of intractable epilepsy. Adv Exp Med Biol 2002;497:133–47. Schmitz B. Depression and mania in patients with epilepsy. Epilepsia 2005;46 Suppl 4:45–9. Brierley B et al. Emotional memory and perception in temporal lobectomy patients with amygdala damage. J Neurol Neurosurg Psychiatry 2004;75:593–9. Kluver H, Bucy PC. Preliminary analysis of functions of the temporal lobe in monkeys. Arch Neurol Psych 1939;42:979–1000. Fenwich PB, Fenwick PB. Psychiatric assessment and temporal lobectomy. Acta Neurol Scand Suppl 1988;117:96–102. Inoue Y, Mihara T. Psychiatric disorders before and after surgery for epilepsy. Epilepsia 2001;42 Suppl 6:13–18. Shaw P et al. Schizophrenia-like psychosis arising de novo following a temporal lobectomy: timing and risk factors. J Neurol Neurosurg Psychiatry 2004;75:1003– 08. Christodoulou C et al. Postictal psychosis after temporal lobectomy. Neurology 2002;59:1432–5. Naga AA, Devinsky O, Barr WB. Somatoform disorders after temporal lobectomy. Cogn Behav Neurol 2004;17:57–61.

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Neocortical focal epilepsy surgery: surgical complications JA González-Martínez and WE Bingaman

Introduction The main goal of the pre- and intraoperative evaluation for epilepsy surgery is to identify possible candidates in whom surgical intervention will totally or partially control seizures without increasing neurological deficits or general morbidity. The neurosurgeon is dependent on this evaluation, to identify potential candidates for epilepsy surgery, for developing a safe operative strategy, and to minimize complications. For that reason, this chapter will concentrate on the topic ‘surgical complications in neocortical focal epilepsy surgery’ addressing complications from diagnostic and therapeutic procedures. In general, we can divide complications in focal neocortical epilepsy surgery based on pathophysiological mechanisms: Surgical complications ● Infection ● Hematoma ● Brain swelling ● Hydrocephalus ● Vascular compromise (arterial or venous) Injury to eloquent areas of the brain causing neurological impairment ● Hemiparesis ● Hemiplegia ● Visual field defect ● Aphasia ● Alexia ● Neuropsychological impairment (deficits in cognition, memory, language, attention, and concentration). Psychosocial impairment ● Family and interpersonal relationships ● Self esteem ● Vocational/educational Psychiatric impairment ● Depression ● Anxiety ● Psychosis 1300

In regard to surgical procedures related to neocortical focal epilepsy, we can additionally classify complications due to focal neocortical resections in: Diagnostic procedures Complications associated with subdural grid and strip electrodes, depth electrodes and stereoelectroencephalography (SEEG).

●

Therapeutic procedures – resective surgery ● Complications associated with frontal (mesial and lateral) resections ● Complications associated with temporal lobe resections ● Complications associated with parietal and occipital resections.

Procedural complications Diagnostic procedures: subdural grids/strip electrodes, depths electrodes, and SEEG complications When noninvasive studies remain nonconcordant or inconclusive regarding the localization and the extent of the seizure onset zone and/or the eloquent cortex, invasive studies using subdural grids, strips or depths electrodes may be needed.1–3 Jayakar and colleagues proposed the following relative indications for the evaluation with invasive monitoring: normal structural imaging, extratemporal location, divergent noninvasive data, encroachment on eloquent cortex, tuberous sclerosis, and cortical dysplasia.3 Rosenow and Lüders4 recommended the use of invasive monitoring only in patients with focal epilepsy (single focus) in whom there is a clear hypothesis regarding the location of the epileptogenic zone (derived from noninvasive studies). The intracranial placement of subdural grid electrodes via craniotomy has received increasing acceptance over the past decade. Invasive electroencephalogram (EEG) monitoring by subdural grid electrodes facilitates prolonged electrographic assessment as well as extraoperative functional brain mapping. Also, it is particular important in pediatric cases in which awake surgery and intraoperative functional mapping is often difficult. The principal complications of grid electrode implantation include infection and subdural hematoma formation

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Figure 137.1 Intraoperative aspect of large subdural hematoma located underneath the subdural grid.

(Figure 137.1), which may be associated with neurological deficits, elevations of intracranial pressure, and even death.5–7 Other complications may include brain swelling and arterial or venous infarctions (Figure 137.2). In a recent series, of the two hundred twenty-eight cases from nine centers, the reported complications included infection, hemorrhage with transient deficit, increased preexisting hemiparesis, aseptic necrosis of the bone flap, and transient elevations in intracranial pressure.8 In an individual series from the Cleveland Clinic, an initial infection rate of 22% declined to 7% when subcutaneous tunneling of electrode cables was instituted.9 More recently, routine use of perioperative antibiotics and water-tight dural closure with sutures at cable exit sites has been advocated in our group.10 Since these modifications were introduced, the infection rate has declined markedly.

Figure 137.2 Complication of subdural grid placement: Venous infarction located in the left frontal lobe region after subdural grid placement. Postoperative CT after subdural grid removal and bone decompression.

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In the absence of a multicenter, prospective complications survey, anecdotal reports of subdural hematoma formation, increased intracranial pressure (ICP), and death following grid placement have been documented in the literature.11 Some centers recommend routine, perioperative decadron and mannitol administration over the 2–3 days after surgery, dural grafting, or leaving out the bone flap during the period of monitoring as responses to the threat of increased intracranial pressure. Circumferential dural incision, linning of the outer grid surface with hemostatic agents, and tapering of valproic acid are also recommended to reduce hematoma formation.12 There is no data with respect to the relative value of any of these practices in preventing individual complications. Regarding subdural strip implantation, the epilepsy surgery literature suggests that subdural strip electrode insertion may be safer than depth electrode placement.7,13–15 No examples of significant hemorrhagic complications associated with prolonged neurological deficit or death have been reported so far. Localized infections occur at a slightly lower frequency when compared with depth recordings and usually respond to antibiotic therapy alone. In a recent series of three hundred fifty patients, two cases of meningitis, one brain abscess associated with hemiparesis, and three superficial wound infections were reported.16 In two additional reports studying 122 patients, no hemorrhagic, neurologic, or infectious complications occurred following strip electrode placement.17,18 Different techniques of invasive monitoring exist and each has its advantages and disadvantages. Chronically implanted subdural electrodes allow recording from large superficial cortical areas, but they provide limited coverage of deeper structures, such as the hippocampus, the interhemispheric region or cortex within sulci. Intracerebral electrodes have the advantage of excellent sampling from mesial structures and from deep cortical areas, with the disadvantage of providing information from a limited volume of tissue. Combined use of subdural and intracerebral electrodes also has been advocated. In a recent publication, Cossu et al.19 presented a retrospective study of a large series of patients (211 patients) who underwent stereoelectroencephalography (SEEG) evaluation. SEEG provided additional guidance towards epileptic focus resection in 183 patients (87%), resulting in a seizure-free outcome in 44% of the cases, and an overall significant improvement in 82%. Major complications occurred in less than 1% of the patients, with an overall hemorrhagic event risk of 4.2%. Other complications included one brain abscess, not resulting in permanent deficit, one episode of focal cortical edema, and one retained broken electrode. The authors concluded that SEEG is a useful and relatively safe tool in the presurgical evaluation of focal epilepsy.19 As highlighted by others, important issues relating to depth electrode placement and associated complications include: (1) the relative safety of lateral, parasagittal, and tangential methods of insertion, (2) the relative safety of flexible versus rigid electrodes, (3) the role of computer-assisted work-stations in the improvement of stereotactic accuracy and the reduction of vessel injury, and (4) the effect upon infectious complications of length of monitoring, antibiotic prophylaxis, tunneling of electrode leads, and methods of electrode removal.19

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Resective surgery complications: temporal neocortical focal resections In general, there are at least four different surgical approaches to treat mesial temporal lobe epilepsy. These approaches include: (a) en bloc temporal resection or standard temporal lobectomy, (b) awake temporal lobectomy with tailored resection, (c) amygdalohippocampectomy, and (d) radical hippocampectomy. Each technique represents a different approach to the identification and resection of the epileptogenic zone. Because this chapter is focused on complications in neocortical epilepsy surgery, complications related to mesial temporal lobe resections will not be discussed. In an extensive review of the literature performed by Pilcher and Ojemann regarding complications of anterior temporal lobectomy, mortality occurred in less than 1%, mainly caused by hemorrhage, infarction, pulmonary complications and sudden death. Other complications included hemiparesis (transient or permanent) in 2–4%, minimal visual field defects in more than 50%, and severe field defects (hemianopsia) in 2–4%. Infections (meningitis, abscess), epidural hematoma, and III nerve palsy (transient) occurred in less than 2%. Neurobehavioral complications included transitory anomia (less than 1 week) in 20% of the patients, persistent dysphasia in 1–3%, and transitory psychosis/depression in 2–20%.12 Penfield reported a 2.5% hemiplegia in an early Montreal Neurological Institute (MNI) series. He attributed this complication to excessive manipulation of branches of the middle cerebral artery (MCA) during the trans-sylvian resection of insular cortex.20 Alternative explanations included direct capsular injury with insular resection as well as compromise of the lenticulostriate vessels and the anterior choroidal artery. Visual field deficits occur following temporal lobe resections in approximately 50% of operated patients. These deficits are often incongruous or worse in the ipsilateral eye, due to the anterolateral location of ipsilateral fibers overlying the anterior portion of the temporal horn (Meyer’s loop). Severe visual field deficits considered disabling by patients are less frequent and were reported in 8% in our previous series.9 Rasmussen et al. suggested that by limiting the extent of the superolateral ventricular opening to 1 cm, quadrantic deficits could be avoided entirely.21–23 Other studies also suggested that the magnitude of the visual field deficit was entirely related to the extension of the ventricular opening, mainly in the ventricular roof in the temporal horn. Alternatively, direct surgical injury to the optic tract, lateral geniculate nucleus, or optic radiation in the posterior temporal lobe white matter can also cause visual field deficits. Postoperative anomia or dysphasia is not uncommon following dominant temporal lobectomy. These aphasias are largely resolved after 1 week. Transitory dysphasias are reported in up to 30% of operated patients in the setting of awake surgery with intraoperative language mapping. Removal of the anterior temporal or inferior-basal language sites may explain this phenomenon.12 Other explanations include resection of cortex within 1–2 cm from essential language areas, brain retraction, and disruption of white matter pathways connecting language areas.

According to Crandall and colleagues, persistent language disorders were found in three of 53 patients undergoing temporal lobe resection.24 In another series, five of 25 patients were aphasic at the time of discharge (Katz et al. 1989).25 In the MNI series, using intraoperative language mapping, two of 250 patients were reported to have long-lasting aphasia after surgery.21–23 In both cases, aggressive resection near essential speech areas was performed. In the Seattle series, removal of brain within 1–2 cm of essential sites established by intraoperative mapping was associated with mild language deficits.26–28 The ‘tailored operation’ is designed to use language mapping techniques to identify and protect neocortical language sites. In a comparison of ‘standard’ versus tailored temporal lobectomies performed by a single surgeon, a slight increase in postoperative dysnomia was identified 6 months after surgery following a ‘standard’ operation.29

Therapeutic procedures: extratemporal neocortical focal resections The extratemporal epilepsies considered for resective therapy are less frequent, more variable in their presentation, and are associated with a less favorable seizure outcome postoperatively than is the temporal lobe epilepsies. Additionally, the epileptogenic zone is more likely to involve eloquent cortex and intraoperative or extraoperative brain mapping is often necessary. All of these factors have a direct impact upon the complications of extratemporal neocortical focal resections, especially the functional consequences of adequate removal of the epileptogenic zone in eloquent cortex. In a systematic fashion, we can divide extratemporal focal resections into frontal, central, parietal and occipital resections.

Frontal resections The frontal lobe encompasses one-third of the cerebral cortex volume, yet, despite its large size, the frequency of surgically treated frontal lobe epilepsy is small as compared to temporal lobe epilepsy. This varies between 18%30,31 and 5.5% in larger series. This may be due to the inherent complexity, variable presentation, presence of eloquent cortex, and difficulty with EEG localization often seen with frontal lobe epilepsies. The manifestations of frontal lobe epilepsy can be divided into three major subgroups:32–34 Supplementary motor seizures, complex partial seizures and focal motor seizures. The localization of an ictal onset area is difficult in frontal lobe epilepsy and is facilitated when a lesion is present on imaging.30 Anatomically, Broca’s area is located in the inferior frontal gyrus at pars triangularis and pars opercularis of the dominant frontal lobe, and this region is generally avoided when dominant frontal resections are performed under general anesthesia. The cortical representation of essential language sites may be quite variable and brain mapping techniques are often utilized to tailor frontal resections and avoid language complications. These investigations may identify zones of language cortex quite separate from Broca’s area within middle,

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Neocortical focal epilepsy surgery: surgical complications superior, and even parasagittal frontal cortex in the region of the supplementary motor area. Transitory aphasic syndromes are often caused when resections are carried within 1–1.5 cm of these essential language areas.26,27 Long lasting expressive aphasia can follow resection or operative injury (vascular compromise) to language sites in the posterior inferior frontal gyrus. Any resection involving frontal cortex, but especially parasagittal cortex (superior frontal gyrus), may cause compromise of draining frontal veins with associated postoperative edema and potentially venous infarction leading to postoperative language and motor deficits. The supplementary motor area (SMA), defined by Penfield and Welch35 is located in the mesial superior frontal cortex of the lower extremity, superior to the cingulate gyrus. Functional studies have shown that this area is activated during initiation of movement and vocalization. Stimulation of this area leads to a fencing posture with bilateral motor movement. The SMA is extensively and somatotopically connected to the corpus callosum, resulting in fast spread of the ictal discharges to the contralateral side, making lateralization of the ictal onset zone difficult.36 Resection of the supplementary motor area may produce a supplementary motor cortex syndrome characterized by mutism (dominant SMA cortex), and contralateral neglect with a hemiparesis characterized by diminished spontaneous movement which gradually resolves over several weeks.37,38 On long term follow-up, gross motor deficits are rare. The orbito-frontal area is limited laterally by the orbitofrontal sulcus, medially by the olfactory sulcus, anteriorly and superiorly by the frontomarginal sulcus, and posteriorly by the anterior perforated area. The orbito-frontal cortex is extensively connected with the anterior and mesial temporal lobe, cingulum, and opercular area and thus frequently misdiagnosed as anterior temporal seizures.39 Adequate sampling of these structures using invasive electrodes is recommended. On the nondominant side, extensive resection of the orbitofrontal cortex can be performed without deficit. The intersection of the optic nerve and the olfactory nerve and the anterior face of the M1 segment of the middle cerebral artery are used as the posterior anatomical landmarks of the resection. On the dominant side, mapping of Broca’s area should be performed. The cognitive effects of extensive frontal resections are clinically insignificant with minimal consequences in daily life activities.40 Furthermore, provided that a careful subpial technique is employed with preservation of the vascular supply to motor cortex, frontal excisions may be safely carried up to the pial bank of the precentral gyrus. Care must be taken, however, not to undermine the motor cortex if the resection is extended into the white matter.

Central resections (perirolandic) Central type epilepsy or seizures arising from the primary motor and sensory area are relatively infrequently encountered in surgical series. In patients with preserved motor function, these epilepsies present considerable challenges. A more aggressive approach to the perirolandic epilepsies is gaining acceptance with improved surgical techniques such as

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extraoperative functional mapping of central cortex, intra-operative mapping by direct cortical stimulation, and microsurgical technique. Resection of the face motor cortex The partial resection of the nondominant face motor cortex may be safely performed, resulting in a transitory contralateral facial asymmetry. Complete removal may be associated with perioral weakness and dysarthria in some patients. The superior resection margin should extend no higher than 2–3 mm below the lowest elicited thumb response. In the dominant hemisphere, some surgeons report postoperative dysarthrias and dysphasias following face motor cortex excision. Nevertheless, Rasmussen et al. reported that complete removal of dominant face motor and sensory cortex may be safely performed provided that manipulation of underlying white matter or ascending vascular supply is avoided.21–23 It is our experience that essential motor language sites may be found just anterior to motor tongue cortex in the inferior or even middle frontal gyrus. Certainly, mapping of these areas is mandatory to avoid a postoperative deficit after dominant frontal lobe resections involving the lower perirolandic cortex. Resection of the hand/leg motor cortex The resection of the primary hand motor cortex produces a permanent deficit of fine motor control and should be avoided if useful hand function is present preoperatively. Resection of the primary leg motor cortex will elicit an immediate flaccid leg paralysis followed by gradual partial recovery of ambulatory capacity over months.21–23 Proximal limb function is likely to recover however distal ankle and foot permanent weakness are often present, requiring use of orthoses for safe ambulation. Resection of the sensory cortex The resections of leg or face sensory cortex cause permanent but clinically insignificant deficit of proprioception in the leg or two-point discrimination in the lower face.41 In contrast, resection of hand sensory cortex is followed by important functional impairment, with the majority of patients showing deficits of pressure sensitivity, two-point discrimination, point localization, position sense, and tactual object recognition, which makes functional use of the involved hand difficult.41

Parietal resections Seizures originating in the parietal lobe account for up to 6% of reported series but very few articles reporting complications in parietal resections are available in the literature. A large proportion of patients exhibit an aura, most commonly somatosensory.33 Pain, vertiginous sensation, aphasia, or disturbance of body image is suggestive of parietal origin. The ictal manifestations are varied and reflect the quick spread to the frontal lobe in superior parietal epilepsies and to the temporal lobe in inferior parietal cases.42 Interictal and ictal scalp EEG recordings were not reliable markers for parietal lobe epilepsy. In two recent series, surgery resulted in

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satisfactory seizure control. Salanova et al. reported the MNI experience of 79 patients with nontumoral parietal lobe epilepsy. Of these, 45.5% were seizure free, 19% had rare seizures, and 21.5% had worthwhile improvement. Persistent dysphasia was noted in two patients, a Gerstmann’s syndrome in one, and contralateral weakness in three cases. Large parietal resections may be undertaken posterior to the central cortex in the nondominant hemisphere without causing a sensorimotor deficit and with a rate of hemiparesis of approximately 0.5%.21–23 A non-dominant parietal syndrome may follow these resections in some individuals. In the dominant hemisphere, language mapping must be used to avoid postoperative language deficits. When resections are extended into the parietal operculum, contralateral lower quadrantic or, hemianopic visual field deficits (rare) may occur as resections are performed beyond the depths of the sulci into the white matter.8,21–23

calcarine cortex and optic radiations must be spared as much as possible if the occurrence of an hemianopsia is to be avoided. The use of intraoperative visual evoked potential (VEP), intraoperative direct stimulation, and radiological techniques to map the geniculocalcarine projections (diffusion tensor imaging or DTI) are still under investigation. If adequate data from invasive monitoring is available to suggest that the superior calcarine gyrus may be spared, an inferior calcarine gyrus resection with or without an aggressive resection of mesial temporal lobe structures will result only in a superior quadrantic deficit associated with minimal disability. Excision to within 2 cm of Wernicke’s area in the domimant hemisphere may elicit persistent dyslexia.21–23 Therefore, exposure at craniotomy should be adequate to provide access to the postcentral gyrus and parieto-temporal language areas, which will serve as the anterior limits of resection.

Occipital resections

Conclusions

Occipital lobe seizures are rare, representing just 1% of epilepsy surgery patients in the MNI series.33 Early clinical manifestations of elementary visual hallucinations, ictal amaurosis, eye movement sensations, and blinking are highly suggestive of an occipital origin.42 In infra-calcarine cases, quick spread to the temporal lobe can produce symptomatology typical of mesial temporal lobe epilepsy. An imaging abnormality is found in a large proportion of cases.42 In patients with hemianopsia, resective surgery carries minimal risk. On the dominant hemisphere, the speech related cortex should be identified and spared. The management of patients with intact vision is challenging. When a circumscribed lesion is found, lesionectomy can yield satisfactory results. In nonlesional cases, the ictal onset area should be precisely localized using invasive electrodes.43 These are used in addition to mapping of the calcarine cortex and speech related cortex. With this strategy, visual deficts can be minimized. Resections of the dominant basal temporal lobe should be carefully planned as this can yield an alexia without agraphia deficit.1,2 Contralateral homonymous hemianopsia often follow resections in this area, despite careful extraoperative mapping of cortical function. If vision is intact preoperatively,

A valid appreciation of the complications of epilepsy surgery is fundamental to balance the risks and benefits of diagnostic and therapeutic procedures. Unfortunately, the medical literature available on this topic does not reflect contemporary surgical practice. Available data is derived from the surgical experience of a few highly experienced surgeons working in well-established comprehensive epilepsy centers and used patient selection criteria and operative approaches which have since been modified or radically changed. Although a prospective trial to study the risks of invasive monitoring and other surgery related complications is not feasible, more literature on contemporary outcomes and complications using modern day surgical techniques is necessary. As the number and complexity of patients referred for epilepsy surgery continue to increase, surgeons are obligated to accurately report complications occurring from surgical treatment. As this chapter has outlined, complications are quite variable depending largely on the region of the brain operated. Armed with this knowledge, the surgeon and patient can truly make informed decisions regarding the risks and rewards of cortical resections to treat medically intractable epilepsy.

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Spencer SS. Depth versus subdural electrode studies for unlocalized epilepsy. J Epilepsy 1989;2:123–7. Spencer S, Spencer D, Williamson P, Mattson R. Combined depth and subdural electrode investigation in uncontrolled epilepsy. Neurol 1990;40:74–9. Sperling M, O’Connor M. Comparison of depth and subdural electrodes in recording temporal lobe seizures. Neurology 1989; 39:1497–504. Wyler AR, Walker G, Somes G. The morbidity of long-term seizure monitoring using subdural grid electrodes. J Neurosurg 1991; 74:734–7. Boon P, Williamson P. Pre-surgical evaluation of patients with partial epilepsy. Indications and evaluation techniques for resective surgery. Clin Neurol Neurosurg 1989;91:3–11. Rosenbaum TJ, Laxer KD. Subdural electrode recordings for seizure focus localization. J Epilepsy 1989;2:129–35. Cossu M, Cardinale F, Castana L et al. Stereoclechoencephalo graphy in presurgical evaluation of focal epilepsy: a rectrospective analysis of 215 procedures. Silfvenius H, Gloor P, Rasmussen T. Evaluation of insular ablationin surgical treatment of temporal lobe epilepsy. Epilepsia 1964; 5:307–20. Rasmussen T. Surgery for epilepsy arising in regions other than the temporal and frontal lobes. In: Advances in Neurology, Neurosurgical Management of the Epilepsies, vol 8. New York: Raven Press, 1975:207–26. Rasmussen T. Surgery of frontal lobe epilepsy. In: Purpura DP, Penry JK, Walter RD, eds. Advances in Neurology, vol 8. New York: Raven Press, 1975:197–205. Rasmussen T. Surgical treatment of patients with complex partial seizures. In: Penry JK, Daly DD, eds. Advances in Neurology, vol 8. New York: Raven Press, 1975;197–205. Crandall PH. Postoperative management and criteria for evaluation. In: Purpura DP, Penry JK, Walter RD, eds. Advances in Neurology. New York: Raven Press, 1975;265–79. Katz A, Awad I, Kong A, Chelung G et al. Extent of resection in temporal lobectomy for epilepsy: II. Memory changes and neurological complications. Epilepsia 1989;30:763–71. Ojemann G. Surgical therapy for medically intractable epilepsy. J Neurosurg 1987:66:489–99. Ojemann GA, Dodrill CB. Intraoperative techniques for reducing language and memory deficits with left temporal lobectomy. In: Advances in Epileptology, vol 16. New York: Raven Press, 1987; 327–30. Ojemann GA, Ojemann J, Lettich E, Berger M. Cortical language localization in left, dominant hemisphere. J Neurosurg 1989;71:316–26.

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Hermann BP, Wyler AR. Comparative results of temporal lobectomy under local or general anesthesia: language outcome. J Epilepsy 1988;1:127–34. Laskowitz DT, Sperling MR, French JA, O’Connor MJ. The syndrome of frontal lobe epilepsy. Neurology 1995;45:780–7. Olivier A, Awad IA. Extratemporal resections. In Engel J Jr, ed. Surgical Treatment of the Epilepsies. 2nd edn. New York: Raven Press, 1993;489–500. Salanova V, Andermann F, Rasmussen et al. Tumoral parietal lobe epilepsy. Clinical manifestation and outcome in 34 patients treated between 1934 and 1988. Brain 1995;118:1289–304. Salanova V, Andermann F, Olivier A et al. Occipital lobe epilepsy: electroclinical manifestations, electrocorticography, cortical stimulation and outcome in 42 patients treated between 1930 and 1991. Brain 1992;115:1655–80. Salanova F, Morris HH, Van Ness P et al. Frontal lobe seizures, electroclinical syndromes. Epilepsia 1995;36:1–24. Penfield W, Welch K. The supplementary motor area of the cerebral cortex; a clinical and experimental study. AMA Arch Neurol Psychiatry 1951;66:289–317. Tuxhorn I, Van Ness PC, Lüders HO. Supplementary motor area seizures: EEG patterns with interhemispheric subdural plate electrodes. Neurology 1992;42(Suppl 3):158. Olivier A. Surgical strategies for patients with supplementary sensorimotor area epilepsy. The Montreal Experience. Adv Neurol 1996;70:429–43. Rostomily R, Berger M, Ojemann G et al. Postoperative deficits and functional recovery following removal of tumors involving the dominant hemisphere supplementary motor area. J Neurosurg 1991;62–8. Tharp BR. Orbital frontal seizures. An unique electroencephalographic and clinical syndrome. Epilepsia 1972;13:627–42. Milner B. Visually-guided maze learning in man: effects of bilateral hippocampal, bilateral frontal and unilateral cerebral lesions. Neuropsychologia 1965;3:317–38. Corkin S, Milner B, Rasmussen T. Somatosensory thresholds: contrasting effects of postcentral gyrus and posterior parietal lobe excisions. Arch Neurol 1970;23:41–58. Williamson PD, Boon PA, Thadani VM et al. Parietal lobe epilepsy: diagnostic considerations and results of surgery. Ann Neurol 1992; 31:193–201. Comair Y, Choi HY, Van Ness P. Neocortical resections. In: Engel J Jr, ed. Epilepsy: A Comphehensive Textbook. Philadelphia: Lippincott-Raven Publishers, 1997.

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SECTION 18 Post-surgical management

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Early post-surgical management of patients with epilepsy I Melamed and AA Cohen-Gadol

Introduction Post-operative management of patients who have undergone epilepsy surgery should be tailored based on the needs of each individual patient but is similar to those who have undergone other types of major craniotomies. There are certain common factors that should be considered in the early post-operative management of patients who undergo epilepsy surgery. These include prevention and control of post-operative seizures, infection, cerebral swelling, and new expanding mass lesions such as a hematoma. Thorough communication with the patient and family is especially important to decrease their anxiety and make them comfortable about the need for additional interventions and the prognosis. The patients undergoing surgery for intractable epilepsy also form a unique subset of patients with very specific needs that should be addressed in the immediate post-operative period. One of the specific needs of major importance pertains to prevention and control of post-operative seizures. Therefore, the major portion of this chapter is dedicated to management of early post-operative seizures for patients who undergo epilepsy surgery. We will also briefly discuss the relevant post-operative psychosocial issues among this patient group.

Management of post-operative infection and hematoma With recent advances in epileptogenic focus localization and microsurgical techniques, epilepsy surgery has become relatively safe. In the report for temporal lobe and localized neocortical resection for epilepsy, Engel and his associates summarized a total of 556 patients from seven institutions in whom the morbidity and mortality of resective procedures were addressed.1 In this group, there were two deaths (0.4%). These were not a direct result of surgery but occurred within 1 month of surgery. Two subdural hematomas were reported but those did not lead to a permanent morbidity. There were 34 patients with new neurological deficits (6%). These included 17 mild aphasias, five 3rd or 4th cranial nerve palsies, ten visual field deficits, greater than a quadrant, and 12 instances of hemiparesis. Sixteen (3%) of these 34 patients had deficits that were transient, resolving within 3 months, while 18 (3%) had permanent deficits. There were 26 (5%) instances of infection, nine (35%) of which were wound infections.

The use of prophylactic antibiotics to prevent infection is routine and an intravenous antibiotic of choice (usually Kefzol) is continued for 24 hours after surgery. The use of gluococorticosteroids to prevent and control cerebral swelling is less routine and is tailored according to the preference of the surgeon. It is interesting to note that one of the first studies to note the use of steroids in reducing post-operative cerebral edema was conducted among patients who had undergone temporal lobe resective epilepsy surgery.2 Most patients would benefit from gastric ulcer prophylaxis (especially if they are taking steroids), as well as deep vein thrombosis prophylaxis. Patients who undergo an intracranial monitoring study using subdural grids, strips or depth electrodes may be at increased risk of infection. Intravenous antibiotics are most commonly continued during the course of their study until the electrodes are removed and resective surgery is conducted (antibiotics are usually continued for an additional 24 hours after the last surgery). For patients who harbor intracranial electrodes, signs of infection including persistent fever, cerebrospinal fluid drainage from the wound, and decreased level of consciousness require work-up to rule out CSF infection. If the suspicion for infection is high, removal of electrodes urgently is indicated. Expanding hematomas may form around or underneath subdural grids or strips causing mass effect and an altered neurological status. Is this case, a head computed tomography (CT) imaging may assist with the diagnosis; however, the artifact caused by the electrodes on this form of study may interfere with an adequate visualization of the hematoma. If mass effect and distortion of ventricles/midline structures is noted and is responsible for the neurological decline, emergent evacuation of hematoma is indicated. If the patient has signs of CSF space infection more than a week post-operative ly, a head CT with contrast to rule out cerebritis (early cerebral abscess) or subdural empyema is reasonable. In addition, a lumbar puncture will exclude post-operative meningitis. An acutely decreased level of consciousness will certainly make the performance of the work-up more emergent.

Management of acute post-operative seizures Acute post-operative seizures (APOS) (those occurring within 7–10 days of surgery) occur in 20–28% of patients who undergo epilepsy surgery.3–5 Up to 12.6% of patients who undergo a 1309

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craniotomy may suffer from an APOS despite not having any seizures before surgery.6 The APOS are defined as ‘early’ if the seizures were present in the first 24 post-operative hours or ‘late’ if the seizures occurred between post-operative days 2–7. Others have called acute post-operative seizures as ‘neighborhood’ seizures within one month post-surgery (Commission on Neurosurgery of the International League against Epilepsy, 2001).7 Possible etiologies for APOS include: subtherapeutic drug levels, fevers, metabolic disturbances such as acidosis or hyponatremia and/or residual unresected epileptogenic focus.5 Such seizures can also signify the presence of a postoperative complication such as hemorrhage or infection. The seizure itself should be treated and a search for reversible etiologies such as those listed above should be initiated. In the absence of any underlying acute structural and metabolic post-operative etiologies that is remediable, acute post-operative habitual seizures (same seizure semiology as the pre-operative period) can be distressing psychologically to the patient, family and surgeon and therefore an understanding of their prognostic influence on long-term seizure control is of great importance. Several studies have shown that patients with seizures within the first week after surgery have a greater likelihood of suffering from recurrent seizures.4,8–10 However, others state that APOSs have no significant bearing on the overall outcome from seizure surgery.11,12 Malla and co-workers,4 in their paper on acute post-operative seizures following anterior temporal lobectomy, suggested that only patients who had APOS similar to their pre-operative habitual seizures were less likely to have an excellent outcome than patients without APOS. In this study, 160 consecutive patients who underwent an anterior temporal lobectomy and amygadalohippocampectomy at the Mayo Clinic (Rochester, MN) for nonlesional temporal lobe epilepsy were included. The patients were divided into groups based on the type of seizure they experienced, presence of risk factors, and whether the seizure occurred early (within 24 hours) or later (day 2–7) in the post-operative course. Thirty-two patients developed APOS. Five of these patients had identifiable risk factors for APOS such as subtherapeutic drug levels or infection. During the last follow up visit 20/32 (62.5%) patients had excellent results (they were seizure free or had experienced one seizure after the discontinuation of medication), while 96/128 (75%) of the patients without APOS had excellent results. Seven of the patients with early APOS had habitual seizures. Of those seven, only one (14.3%) had excellent outcome at the last follow-up. Interestingly there were no statistically significant differences in outcome between early and late APOS, or between patients with and patients without precipitating factors identified for their APOS. Therefore recurrent habitual seizures during the acute post-operative period may indicate that the epileptogenic focus has not been adequately resected. Such information may be used for patient counseling. On the other hand, patients suffering from APOS which are not the same as their habitual pre-operative seizures should therefore be reassured of a good long-term chance of seizure freedom. In the pediatric population,5 another study of patients 18 years or younger who underwent epilepsy surgery documented a 63–78% lower chance of seizure freedom among

patients who suffered from APOS as opposed to those who did not. In this study, a multivariate analysis showed that APOS was an independent predictor of a less-favorable outcome. Nevertheless, 51% of the patients with APOS were seizure free at the last follow-up. In this study, subtherapeutic drug levels were not a significant risk factor for the occurrence of APOS, however; fever was a ‘key post-operative risk factor’, defined as two consecutive readings (taken every 4 hours apart) if >38 degrees. A history of febrile seizures was not associated with an increased chance of APOS. In another study of pediatric patients at UCLA who underwent hemispherectomy, Mathern3 found that the incidence of five or more acute post-operative seizures predicted longer seizure duration before surgery, longer hospital course, later oral food intake, more frequent lumbar punctures, worse overall seizure control at 0.5 and one year after surgery, more antiepileptic drug use at 2 and 5 years after surgery, and higher reoperation rate. The authors in this study did not find any difference between the patients with 0 and 1–5 APOS. The timing of the APOS did not predict outcome. The cause of recurrent post-operative seizures in these patients may have been the capability of the opposite intact hemisphere to generate seizures that were not appreciated before surgery. The relationship of APOS and long-term seizure outcome may also be dependent upon the epilepsy syndrome and resection location. The incidence of APOS may be slightly higher among adult extratemporal resections (average 42%; range 26–46%) as compared with pediatric and adult temporal lobe epilepsy patients (average 30%, range 17–49%.) For the patients who have undergone extratemporal resections, the importance of APOS in predicting long-term seizure freedom is less clear. A study reported that APOS among patients who have undergone frontal lobe resection has no prognostic significance 13 while others have found less favorable seizure outcome among patients who have undergone extratemporal resection and have suffered from APOS.5,8 Lüders8 found that seizure recurrence was significantly higher when seizures occurred during the first week after surgery. Although seizure recurrence increased progressively with longer follow-ups, the 6-month post-operative seizure outcome was an excellent predictor of long-term outcome. Lüders therefore recommended that, seizure frequency should be reported at fixed follow-up periods, e.g., at 6 months and 1, 2, 5, and 10 years. This reporting strategy will allow comparison of outcomes between different studies.9 Others have suggested that early APOS (within 24 hours of surgery) may be less important in long-term prognostication of seizure outcome. This is the time when the effect of anesthesia and surgical manipulation on cerebral physiology is greatest, increasing the risk of a seizure.14 In general, the occurrence of APOS should be interpreted cautiously and individually for each patient. Although the presence of seizures post-operatively may signify a lower chance of longterm seizure freedom, one must remember that a significant majority of these patients do become seizure free. Several limitations are present in the majority of the studies which have studied the importance of APOS. Video-EEG monitoring is not routinely performed subsequent to surgery.

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Early post-surgical management of patients with epilepsy The care takers who report the ictal behavior may not be qualified for such purpose. Often, the family member may observe an APOS and may not be able to adequately identify the postoperative seizure semiology.

Post-operative management of antiepileptic drugs The effects of anesthesia, stress of surgery as well as missing doses of medications have been known to cause varying changes in the blood levels of antiepileptic drugs (AEDs) in patients who have recently undergone epilepsy surgery. This phenomenon exposes the post-operative patient to an increased risk of a seizure. The seizure may cause uncontrollable spikes in blood pressure, causing intracerebral hemorrhage in the resection bed during the early post-operative period as well as prevent rapid patient’s post-operative recovery and mobilization. Therefore, prevention of post-operative seizures is of special importance. Effstorm, Friel and their associates have demonstrated a reduction in drug levels following surgery among the patients on stable doses of medications.15,16 Friel et al. followed drug levels of 12 patients treated with phenytoin, carbamazepine and valproate. In the six patients on phenytoin and the six on carbamazepine, there was a significant reduction in serum levels at 48 hours post-operatively compared to those immediately pre-operatively.16 However, in the five patients treated with valproate there was no significant change. In another study, the toxic levels of carbamazepine observed after surgery for subdural grid placement may suggest that the metabolism of carbamazepine can actually become slower following surgery.17 It is thus recommended that the levels of AED medications be followed closely during the first 48 hrs after surgery to avoid sub- and/or supratherapeutic drug levels which in turn can lead to post-operative seizures or toxic reactions, respectively. AEDs should not be tapered during the immediate postoperative period despite a lack of seizures. The time-line for tapering or discontinuing AEDs after successful surgery is not clear. The patients who undergo epilepsy surgery typically require fewer AEDs than those who did not have surgery.18 Schiller et al.19 retrospectively studied 210 patients after temporal and extratemporal resections for epilepsy at the Mayo Clinic (Rochester, MN). In this group of patients, the medications were tapered sequentially with a varied taper typically lasting 6–25 months. The medications were altered in 180 of the 210 patients. AEDs were tapered and discontinued in 84 (40%) and reduced in 96 (46%). Discontinuation of the AED treatment was associated with recurrent seizures in 22 of the 84 patients. Reinstitution of the AED treatment resulted in seizure control in 20 of the 22 patients. The remaining two patients developed medically refractory epilepsy despite AED therapy. Thirteen of 96 (14%) who reduced the number or dose of AED medications had recurrent seizures. In trying to define the patients who would be at an increased risk of seizure recurrence after medication adjustment, these authors investigated numerous factors. Patients with a normal pre-operative MRI

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study showed a tendency for higher seizure recurrence. Nevertheless, this difference did not reach statistical significance. No difference was observed in seizure relapse between patients with and without epileptic spikes in the post-operative EEG studies. Furthermore, reviewing the length of medical therapy after surgery, the authors could not find any correlation between the duration of seizure-free post-operative AED treatment and seizure recurrence after AED withdrawal. Thus, this study could not find a way to predict who would have recurrent seizures after AED adjustments. It would seem wise to wait at least 6 months in order to allow the patient to recover from surgery and assure successful surgical outcome before discussing tapering medications.

Post-operative psychosocial issues Epilepsy has had a long historical association with psychiatric and behavioral disturbances. It has been estimated that about 20% of temporal lobe epilepsy patients have depression. Wrench et al. studied the effects of seizure surgery on mood disturbances.20 This study included 43 patients who underwent temporal resections, and 17 patients who underwent extratemporal resections. Prior to surgery, each patient was seen by a psychiatrist, while after surgery each patient was screened by the treating clinical neuropsychologist and referred for psychiatric assessment where indicated. Before surgery 57% of the patients had previous psychiatric history to include depression, anxiety, postictal psychosis, personality disorder, anorexia nervosa, dysthymia, substance dependence, and delusional disorder. At discharge from the hospital, 32% of the patients were experiencing psychiatric difficulties. At one month, reports of psychiatric difficulties increased to 52% among patients who underwent temporal resections, significantly greater than extratemporal patients. No association was found between the outcome of the surgery and general psychopathology, depression or anxiety. Other studies have also documented that temporal lobectomy patients have a tendency to develop symptoms of mood disturbance within six weeks of their post-operative period.21,22 The patients who are at a higher risk for such disturbances might benefit from preand post-operative counseling.

Conclusions Acute or early post-operative seizures can be emotionally devastating to the patients and their families due to the possible negative impact of these acute seizures on long-term seizure outcome following epilepsy surgery. The precise impact of acute post-operative seizures on the long-term outcome of epilepsy surgery has remained controversial. The available studies have predicted a negative or no impact on final outcome of surgery in patients who suffer from acute post-operative seizures compared to those who remain seizure free early in the post-operative period. The appropriate post-operative care can help in the management of these patients and assist them on their way to recovery from this epilepsy disorder.

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REFERENCES 1.

2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Engel J Jr, Wiebe S, French J et al. Practice parameter: temporal lobe and localized neocortical resections for epilepsy: report of the Quality Standards Subcommittee of the American Academy of Neurology, in association with the American Epilepsy Society and the American Association of Neurological Surgeons. Neurology 2003;60:538–47. Rasmussen, Gulati D. Cortisone on the treatment of postoperative cerebral edema. J Neurosurg 1962;19:535–44. Koh S, Nguyen S, Asarnow RF et al. Five or more acute postoperative seizures predict hospital course and long-term seizure control after hemispherectomy. Epilepsia 2004;45:527–33. Malla BR, OBrien TJ, Cascino GD et al. Acute postoperative seizures following anterior temporal lobectomy for intractable partial epilepsy. J Neurosurg 1998;89:177–82. Park K, Buchhalter J, McClelland R, Raffel C. Frequency and significance of acute postoperative seizures following epilepsy surgery in children and adolescents. Epilepsia 2002;43:874–81. Matthew E, Sherwin A, Welner S, Odusote K, Stratford J. Seizures following intracranial surgery: Incidence in the first postoperative period. Can J Neurol Sci 1980;7:5–90. McIntosh AM, Kalnins RM, Mitchell LA et al. Temporal lobectomy: long-term seizure outcome, late recurrence and risks for seizure recurrence. Brain 2004;127:2018–30. Lüders HO, Murphy D, Dinner D. Prognostic value of epileptic seizures occurring in the first week after surgery of epilepsy. Epilepsia 1988;29:679. Lüders HO, Murphy D, Awad IA et al. Quantitative analysis of seizure frequency 1 week and 6, 12, and 24 months after surgery of epilepsy. Epilepsia 1994;35:1174–8. Wingkun EC, Awad IA, Lüders HO, Awad CA. Natural history of recurrent seizures after resective surgery for epilepsy. Epilepsia 1991;32:851–6. Engel J Jr, Van Ness P, Rasmussen T, Ojemann L. Outcome with respect to epileptic seizures. Surgical Treatment of the Epilepsies. New York: Raven Press, 1993:609–621.

12. 13. 14. 15. 16. 17. 18. 19. 20. 21.

22.

Falconer M, Serafetinides E. A follow-up study of surgery in temporal lobe epilepsy. J Neurol Neurosurg Psychiatry 1963;26: 154–63. Tigaran S, Cascino GD, McClelland RL, So EL, Richard Marsh W. Acute postoperative seizures after frontal lobe cortical resection for intractable partial epilepsy. Epilepsia 2003;44:831–5. Garcia PA, Barbaro NM, Laxer KD. The prognostic value of postoperative seizures following epilepsy surgery. Neurology 1991;41:1511–12. Effstrom J. Plasma protein binding of phenytoin after cholecystectomy and neurosurgical operation. Acta Neurol Scand 1977;55: 455–64. Friel P, Clark H, Ojemann G. Decreased serum anticonvulsants levels after epilepsy surgery. Epilepsia 1987;28:588. Hahn J, Lüders HO. Placement of subdural grid electrodes at the Cleveland Clinic. Surgical Treatment of the Epilepsies. New York: Raven Press, 1987:621–7. Vickrey B, Hays R, Rausch R. Outcomes in 248 patients who had diagnostic evaluations for epilepsy surgery. Lancet 1995;346: 1445–9. Schiller Y, Cascino GD, So EL, Marsh WR. Discontinuation of antiepileptic drugs after successful epilepsy surgery. Neurology 2000;54:346–9. Wrench J, Wilson S, Bladin P. Mood disturbance before and after seizure surgery: a comparison of temporal and extratermporal resections. Epilepsia 2004;45:534–43. Blumer D, Wakhlu S, Davies K, Hermann B. Psychiatric outcome of temporal lobectomy for epilepsy: incidence and treatment of psychiatric complications. Epilepsia 1998;39: 478–86. Vickrey B, Hays R, Rausch R. Quality of life of epilepsy surgery patients as compared with outpatients with hypertension, diabetes, heart disease and/or depressive symptoms. Epilepsia 1994;35: 597–607.

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Post-surgical pharmacotherapy: discontinuation of anticonvulsants AS Tanner and D Schmidt

Introduction Resective surgery for epilepsy is currently offered to a wide variety of patients with different kinds of focal medically refractory epilepsy in centers around the world. Specifically, temporal lobectomy is now well established as effective in patients with intractable temporal lobe epilepsy.1 The body of literature on resective epilepsy surgery, heavily concentrated on temporal resections on adult patients, has shown a wide range of seizure-freedom rates for all procedures, (33–90%)2 with the highest rates after anterior temporal lobectomy for medial temporal lobe epilepsy.1 While several series reported in the literature have included small numbers of patients and have used different follow up periods, methodologies and study designs2 most of them agree on the long-term benefit of temporal lobectomy for the treatment of refractory epilepsy. Reported figures show rates of seizure freedom that range between 53–80% during the first year postoperatively, 53–58% at year two, and 52–55% at year five.2 For patients that have undergone neocortical resections this figure is shown to be somewhat lower than for temporal resections, and around 50% at two years.3 For children, studies report that around 70% of pediatric patients with temporal lobe epilepsy4 and 54–82% of patients with pathologies such as Rasmussen’s encephalitis, hemiplegia, or SturgeWeber are seizure free after surgery5. Many patients (anywhere between 10% and 60%), however, relapse after epilepsy surgery and evidence shows that most of these relapses occur early after surgery (within the first two years)6,7 although later recurrences have been reported.7,8 Some of the factors cited as predictors for relapse include longer preoperative illness, normal pathology8 and the presence of secondarily generalized seizures before surgery.7 A factor that has only recently been explored is the role that antiepileptic drugs (AEDs) play after epilepsy surgery especially in relationship to the risk of relapse.9 This is an extremely important and relevant variable not only because of obvious importance when counseling patients and planning therapeutic decisions after surgery, but because of the expectation from patients that freedom from drugs follows surgery.10 The literature on these topics is unfortunately not as abundant as in other areas of epilepsy surgery. Reasons for this may include the inherent difficulties in assessing outcomes after discontinuation AEDs, in designing adequate clinical trials that address this particular issue and the lack of universal guidelines. We will review the relevant literature in this chapter.

Discontinuation of AEDs: relevant literature Most of the literature in AED discontinuation after resective surgery again relates to temporal lobe epilepsy.1,2,6,7,11–16 Few papers address this issue on neocortical, extratemporal and all types of resections in children.3–5,17–24 Schiller and his colleagues21 reported in 2000 a series of 210 patients that underwent either a taper or discontinuation of AEDs after epilepsy surgery. The majority of these patients were adults, and most of them underwent temporal lobe resections. After 1 year of seizure freedom (including patients with isolated auras), patients were divided into a group that reduced but not withdrew AEDs, and a group that tapered and discontinued AEDs; they were compared to a ‘control group’ of patients that were seizure free after surgery and did not alter their medication regimen. Their retrospective study revealed seizure recurrence in 14% and 36% of patients by the end of 2 and 5 years respectively after complete AED withdrawal, and recurrence of 9% and 14% of patients who partially reduced AED treatment by the end of 2 and 5 years. (Table 139.1) There were no statistical differences on the clinical features between the groups that partially discontinued AEDs with the control group. Reinstitution of AEDs resulted in seizure control in 91% of patient who relapse after complete AED withdrawal. Among the variables that they studied abnormal preoperative MRI carried a higher tendency for seizure recurrence. They did find that seizure recurrence was unrelated to the duration of the seizure-free post-operative AED treatment. In a recent publication, Kim13 and his colleagues reported on a series of patients that underwent AED discontinuation. They included patients of all ages and a majority undergoing temporal lobectomy for hippocampal sclerosis. Altogether, 33% of patients who attempted AED tapering experienced seizure relapse in the course of discontinuation. The seizure recurrence rate was not different in patients that had become seizure free immediately after surgery than on those who became seizure free sometime after surgery. The majority of patients (70%) regained seizure freedom after reinstitution of AEDs. Schmidt et al.22 analyzed six retrospective series of patients undergoing planned AED discontinuation under medical supervision. Their review showed an average relapse rate of 34% for all surgeries, most often temporal lobe resections with recurrence rates increasing with the length of follow-up. 1313

Temporal lobectomy: 100%

N = 88 Age mean: 27.3; range: 11– 41 49 f; 39 m N = 376 Age mean: 32 ±11 166 f; 210 m N = 129 Age median: 36 years N = 97 Age mean: 11 Range: 3 months –18 years

Kim et al.13

Lachhwani et al.18

Berg et al.25

Temporal lobe resections: 100% (selective amygdalohippocampectomies) Temporal lobe: neocortical and medial temporal Temporal and extra-temporal resections

Temporal lobe resections: 89.5% Extratemporal resection: 10.5%

N = 210 Age mean: 31.9; range: 9 – 55. 107 f; 103 m

Schiller et al.21

Wieser et al.15

Procedures included

Number of patients age/ gender

Study (Reference number)

Retrospective

Prospective

Retrospective

Retrospective

Retrospective

Design

Median: 37 Range: 1–134 months

Mean: 77.4 months range: 36 –144 Median: 7.5 ± 05.7 Range: 1–25 Not stated

Mean: 5.1 ± 0.3 range: 3– 8 Years

Follow-up

57/68 (84%)

88/129 (68%)

92/111 (82.9%)

57/84 (67%) after complete discontinuation; 83/96 (86%) after partially reducing AEDs 37/66 (56%)

Proportion of surgical patients seizure free after discontinuation of AEDs

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Table 139.1

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Post-surgical pharmacotherapy: discontinuation of anticonvulsants Interestingly, among all patients analyzed, only 48% of seizure-free adult patients discontinued AEDs, whereas 71% of seizure-free children did so. Their findings suggested that there was no benefit in waiting to attempt AED tapering (1 year in children and 2 in adults), and that the occurrence of rare seizures or auras did not preclude successful AED discontinuation. In accordance with other studies and observations, more then 90% of adult patients with seizure recurrence regained seizure control after reinstitution of AEDs. This study failed to find a strong association between relapse after AED withdrawal and factors such as age of onset of epilepsy, duration of epilepsy and preoperative MRI findings. Wieser and Häne15,16 reported retrospectively on patients that had undergone amygdalohippocampectomy. In their study the overall risk of relapse associated with AED tapering and withdrawal was 17%; they concluded that in this population monotherapy was an adequate option, and therefore AED reduction to monotherapy could be advisable as early as 1 year postoperatively with discontinuation at year two. In a recent report, Berg and her colleagues from the Multicenter Study of Epilepsy Surgery25 analyzed the impact of reducing AEDs in subjects who attained a 1-year seizure remission after surgery. The authors found that 41 of 129 patients (32%) relapsed after reducing AEDs. No difference was found between reducing from two to one AED or from one to no AEDs. Delayed remission after surgery was significantly associated with an increase rate of relapse, while continued auras were marginally associated with relapse. Of note, in the series of patients reported by Berg, 45% of patients (73 of 162) in the nonreduction arm also recurred. Overall, 39% of all patients who attained seizure freedom for one year recurred (114 of 301). The literature addressing AED discontinuation after epilepsy surgery in children is scarce. As indicated earlier, anywhere between 50% and 80% of pediatric patients become seizure-free after surgery for temporal lobe epilepsy, seizures associated with infantile hemiplegia or seizures accompanying tumors.4,5 The report by Lachhwani18 (included in the analysis by Schmidt cited earlier) showed that 16% of patients that underwent AED discontinuation had seizure recurrences. No significant differences were found based on etiology. The majority of these patients regained seizure control after the AEDs were reinstituted. One related question that patients and physicians have is the long-term seizure prognosis following epilepsy surgery in patients off AEDs.

Long-term surgical seizure outcome off AEDs: relevant literature Although surgery is often seen as a curative treatment for patients with drug-resistant temporal lobe epilepsy, little information is available regarding how many cases are seizure free for at least five years without taking AEDs. This question was reviewed by Schmidt et al.26 The review included 13 retrospective and five prospective clinical observations published since 1980 provided data on long-term seizure control off AEDs in a total of 1658 patients (Table 139.2). No randomized studies were found. Following temporal lobe surgery, approximately one in four adult patients and approximately one in three chil-

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dren or adolescents were shown to be seizurefree for 5 years without AEDs (25%, mean of eight studies in adults, 95% CI: 21–30%, and 31%, mean of three studies in children, 95% CI: 20–41%). The rate of seizure control off AEDs seemed to be stable after 2 years of follow-up. However, as 55% of patients free of disabling seizures preferred not to discontinue their medication completely as late as 5 years after surgery, it is impossible to know if more patients could have been seizure free, if all had discontinued their medication. No features predictive of surgical cure were detected except for better outcome in children versus adults with hippocampal sclerosis and in patients with typical versus atypical Ammonshorn’s sclerosis or tumor in one small study each. In conclusion, the available evidence on seizure outcome off AEDs after temporal lobe surgery is based on nonrandomized studies and, in part, data were collected retrospectively.11,15,19,26–41 In a single–center study of long-term seizure outcome off AEDs following temporal lobe surgery, which appeared after completion of the above review, Kelley and Theodore42 reported a similar result. In their analysis one in three patients were seizure free of AEDs when reexamined 10–30 years after surgery.

Discussion The importance of the quality, quantity and length of AED treatment in patients that have undergone epilepsy surgery goes beyond the pure consideration of seizure freedom versus seizure recurrence: AEDs influence quality of life because of side effects, interactions with other drugs, issues related to contraception, pregnancy, lactation, menopause, bone health as well as financial issues.43–46 Therefore, understanding their role after epilepsy surgery is vital when treating and counseling these patients for more than one reason. The current relevant literature suggests that a significant minority of patients (about a third of adults, perhaps a lower percentage in children) will have seizure recurrence upon AED discontinuation after resective surgery for epilepsy. In addition, based on long-term studies, one in three patients can expect to be free of seizures without taking AEDs anymore. Because the goal of many patients considered for epilepsy surgery is to be free of medications, this literature becomes an important tool for discussing this issue after surgery. Fortunately, the literature shows that the vast majority of these patients will regain seizure control once AEDs are restarted, with only a small minority of up to 10% going on to have intractable or recurrent seizures. Many important issues, however, remain unanswered. Most of the relevant papers addressing AED discontinuation have included in their analysis both patients undergoing temporal and extratemporal resections, and in some cases children and adults alike. This ‘lumping’ of cases does not allow us to make specific determinations for these different groups, and it can, as a matter of fact, confound the results. Are patients with nonlesional MRIs and neocortical resections at higher risk of recurrence than are patients with lesional cortical epilepsies? Are patients with classical mesial temporal epilepsy at a different risk? If we control for other variables, do all groups have the same risk? Future research has to address this issue in different cohorts of patients. Another point that ought to be considered is whether or not there was bias in

Velasco et al.39 York et al.41

Oxbury et al.36

Wieser et al.15 Williamson et al.40

N = 50 Age: children group median 14 (8 –15), adult group: 22 (16 – 36) Gender: n/a N = 22 Age mean: 32, range: 15 – 48 11f; 11m N = 145 Age mean:27.9, range: 7 – 57 82f, 63m

N = 51 Age mean: 31.9 27f; 24m N = 22 Age mean: 21 11f; 11m N = 184 Age median: 31; range:7 – 86 years 100f; 84m N = 89 Age mean: 31.9, range 10 – 60 years 44f; 45m N = 376 Age mean: 32 165f; 211m N = 67 Age and gender n/a

McLachlan et al.34 Mizrahi et al.35 So et al.37

Sperling et al.38

N N N N N N N

Derry et al.28 Elwes et al.29 Gilliam et al.30 Li et al.32 King et al.31 Maher et al.33 Mathern et al.19

Anterior temporal lobectomy Anterior temporal lobectomy

Temporal lobe resections

Amygdalohippocampectomy Temporal lobe resections

Anterior temporal lobectomy

Anterior temporal lobectomy Temporal lobe resections: anterior temporal lobectomy and amygdalohippocampectomy Temporal lobectomy Anterior temporal lobectomy Anterior temporal lobectomy Anterior temporal lobectomy Anterior temporal lobectomy Temporal lobe resections Hemispherectomy; lobar and multilobar resections, temporal lobe resections Anterior temporal lobectomy Anterior temporal lobectomy Anterior temporal lobectomy

N = 44 Age median: 12.7, range: 2.5 –15.8 N = 148 Age mean: 31.5; range 8.8 – 63

Adams et al.27 Bien et al.11

= 30 18f; 12m = 101 Age median: 23; range 3 – 53 48f; 54m = 196 Age mean:33. 110f; 86m = 23 Age mean: 29.7 = 23 Age mean: 31.5 = 93 Age mean: 32 48f; 45m = 198 (TLE =31) 87f; 111m

Procedures included

Number of patients age/gender

Prospective Retrospective

Retrospective

Retrospective Retrospective

Prospective

Prospective Retrospective Retrospective

Prospective Retrospective Cross-sectional Prospective Retrospective Retrospective Retrospective

Retrospective Prospective

Design

2 years 1 year

5 years 5.7 years (mean) Range 2 – 14 years 5 years

3.4 years (median) Range: 1.1 – 5.7 5 years

2 years

1 year 2 years 2 years

8.5 years 61 months n/a

4.8 years (mean)

Follow up

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Study (Reference number)

Long-term surgical seizure outcome off antiepileptic drugs: relevant literature

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Table 139.2

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Post-surgical pharmacotherapy: discontinuation of anticonvulsants selecting the patients that have undergone AED tapering or withdrawal. Were the ‘high-risk’ patients excluded? Are the risks of recurrence actually higher? Only prospective, carefully designed trials will answer this question as well as issues such as the identification of other predictors of seizure recurrence and of patients ‘pre-determined’ to recur after surgery regardless of AEDs. One further consideration is whether different techniques of tapering have confounded the results. Does reduction carry a different risk than discontinuation? A constant among most studies is the lack of unified way to taper and discontinue: the majority will cite that tapering and discontinuing

1317

was done at the direction of the treating neurologist. What is the best way to taper? Does this influence recurrence? Again adequately designed trial may answer this. Although some investigators have suggested timelines for tapering, an issue that remains inconclusive is how long AEDs should be kept after surgery. In conclusion, we now know that a subset of patients initially seizure free after surgery will relapse after AED taper and/or discontinuation, and that upon reinstitution most of them will regain control of their seizures again. However, numerous other issues are yet to be elucidated and future research should focus on addressing this vital information.


6. 7.

8. 9. 10. 11.

12. 13. 14. 15. 16.

17. 18

Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med 2001;345(5):311–18. McIntosh AM, Wilson SJ, Berkovic SF. Seizure outcome after temporal lobectomy: current research practice and findings. Epilepsia 2001;42(10):1288–1307. Spencer SS, Berg AT, Vickrey BG et al. Predicting long-term seizure outcome after resective epilepsy surgery: the multicenter study. Neurology 2005;65(6):912–18. Keene DL, Higgins MJ, Ventureyra EC. Outcome and life prospects after surgical management of medically intractable epilepsy in patients under 18 years of age. Childs Nerv Syst 1997;13(10): 530–5. Holtausen H, May TW, Adams CTB. Seizures post-hemispherectomy. In: Tuxhorn I, Holthausen H, Boenigk H, eds. Paediatric Epilepsy Syndromes and their Surgical Treatment. London: John Libbey, 1997:749–73. Foldvary N, Nashold B, Mascha E et al. Seizure outcome after temporal lobectomy for temporal lobe epilepsy: a Kaplan-Meier survival analysis. Neurology 2000;54(3):630–4. McIntosh AM, Kalnins RM, Mitchell LA, Fabinyi GC, Briellmann RS, Berkovic SF. Temporal lobectomy: long-term seizure outcome, late recurrence and risks for seizure recurrence. Brain 2004;127 (Pt 9):2018–30. Yoon HH, Kwon HL, Mattson RH, Spencer DD, Spencer SS. Longterm seizure outcome in patients initially seizure-free after resective epilepsy surgery. Neurology 2003;61(4):445–50. Berg AT. Stopping antiepileptic drugs after successful surgery: what do we know? And what do we still need to learn? Epilepsia 2004;45(2):101–2. Taylor DC, McMackin D, Staunton H, Delanty N, Phillips J. Patients’ aims for epilepsy surgery: desires beyond seizure freedom. Epilepsia 2001;42(5):629–33. Bien CG, Kurthen M, Baron K et al. Long-term seizure outcome and antiepileptic drug treatment in surgically treated temporal lobe epilepsy patients: a controlled study. Epilepsia 2001;42(11): 1416–21. Griffin CT, Abastillas ME, Armon C et al. Early antiepileptic drug reduction following anterior temporal lobectomy for medically intractable complex partial epilepsy. Seizure 2004;13(6):434–7. Kim YD, Heo K, Park SC et al. Antiepileptic drug withdrawal after successful surgery for intractable temporal lobe epilepsy. Epilepsia 2005;46(2):25–7. Radhakrishnan K, So EL, Silbert PI et al. Prognostic implications of seizure recurrence in the first year after anterior temporal lobectomy. Epilepsia 2003;44(1):77–80. Wieser HG, Hane A. Antiepileptic drug treatment before and after selective amygdalohippocampectomy. Epilepsy Res 2003;55(3): 211–23. Wieser HG, Hane A. Antiepileptic drug treatment in seizure-free mesial temporal lobe epilepsy patients with hippocampal sclerosis following selective amygdalohippocampectomy. Seizure 2004;13 (8):534–6. Berg AT, Vickrey BG, Langfitt JT et al. The multicenter study of epilepsy surgery: recruitment and selection for surgery. Epilepsia 2003;44(11):1425–33. Lachhwani D, Wyllie E, Loddenkemper T et al. Discontinuation of antiepileptic medications following epilepsy surgery in childhood and adolescence. Neurology 2003;60(Suppl 1):A259.

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Mathern GW, Giza CC, Yudovin S et al. Postoperative seizure control and antiepileptic drug use in pediatric epilepsy surgery patients: the UCLA experience, 1986–1997. Epilepsia 1999; 40(12):1740–9. McLachlan RS, Maher J. Management of antiepileptic drugs following epilepsy surgery: a review. Can J Neurol Sci 2000; 27 (Suppl 1):S106–10. Schiller Y, Cascino GD, So EL, Marsh WR. Discontinuation of antiepileptic drugs after successful epilepsy surgery. Neurology 2000;54(2):346–9. Schmidt D, Baumgartner C, Loscher W. Seizure recurrence after planned discontinuation of antiepileptic drugs in seizure-free patients after epilepsy surgery: a review of current clinical experience. Epilepsia 2004;45(2):179–86. Spencer SS, Berg AT, Vickrey BG et al. Initial outcomes in the Multicenter Study of Epilepsy Surgery. Neurology 2003;61(12): 1680–5. Tonini C, Beghi E, Berg AT et al. Predictors of epilepsy surgery outcome: a meta-analysis. Epilepsy Res 2004;62(1):75–87. Berg AT, Vickrey BG, Langfitt JT et al. Reduction of AEDs in postsurgical patients who attain remission. Epilepsia 2006;47 (1):64–71. Schmidt D, Baumgartner C, Loscher W. The chance of cure following surgery for drug-resistant temporal lobe epilepsy. What do we know and do we need to revise our expectations? Epilepsy Res 2004;60(2–3):187–201. Adams C.B.T, Beardsworth ED, Oxburt SM et al. Temporal lobectomy in 44 children: outcome and neuropsychological follow up. J Epilepsy 1990;Suppl:157–8. Derry PA, McLachlan RS, Cervinka M. Surgical versus medical treatment management of epilepsy:an eight-year prospective outcome analysis of seizure frequency and quality of life. Epilepsia 2001;42(Suppl 5):190–1. Elwes RD, Dunn G, Binnie CD, Polkey CE. Outcome following resective surgery for temporal lobe epilepsy: a prospective follow up study of 102 consecutive cases. J Neurol Neurosurg Psychiatry 1991;54(11):949–52. Gilliam F, Kuzniecky R, Meador K et al. Patient-oriented outcome assessment after temporal lobectomy for refractory epilepsy. Neurology 1999;53(4):687–94. King DW, Flanigin HF, Gallagher BB et al. Temporal lobectomy for partial complex seizures: evaluation, results, and 1-year follow-up. Neurology 1986;36(3):334–9. Li H. Comprehensive therapy in intractable temporal lobe epilepsies – a comparison of surgically treated and non-surgically treated cases. J Tokio Med Univ 2002;60(6):469–82. Maher J, McLachlan RS. Antiepileptic drug treatment following temporal lobectomy. Neurology 1998;51(1):305–7. McLachlan RS, Rose KJ, Derry PA et al. Health-related quality of life and seizure control in temporal lobe epilepsy. Ann Neurol 1997;41(4):482–9. Mizrahi EM, Kellaway P, Grossman RG et al. Anterior temporal lobectomy and medically refractory temporal lobe epilepsy of childhood. Epilepsia 1990;31(3):302–12. Oxbury JM, Adams CBT, Fenwick PBC, Oxbury SM. Surgery in childhood gives the best chance to ‘cure’ drug-resistant temporal lobe epilepsydue to severe hippocampal sclerosis. Epilepsia 1996; 37(Supplement 5):209.

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So EL, Radhakrishnan K, Silbert PL et al. Assessing changes over time in temporal lobectomy: outcome by scoring seizure frequency. Epilepsy Res 1997;27(2):119–25. Sperling MR, O’Connor MJ, Saykin AJ, Plummer C. Temporal lobectomy for refractory epilepsy. JAMA 1996;276(6):470–5. Velasco AL, Boleaga B, Brito F et al. Absolute and relative predictor values of some non-invasive and invasive studies for the outcome of anterior temporal lobectomy. Arch Med Res 2000;31 (1):62–74. Williamson PD, French JA, Thadani VM et al. Characteristics of medial temporal lobe epilepsy: II. Interictal and ictal scalp electroencephalography, neuropsychological testing, neuroimaging, surgical results, and pathology. Ann Neurol 1993;34(6):781–7.

41.

42. 43. 44. 45. 46.

York MK, Rettig GM, Grossman RG et al. Seizure control and cognitive outcome after temporal lobectomy: a comparison of classic Ammon’s horn sclerosis, atypical mesial temporal sclerosis, and tumoral pathologies. Epilepsia 2003;44(3):387–98. Kelley K, Theodore WH. Prognosis 30 years after temporal lobectomy. Neurology 2005;64(11):1974–6. Bazil CW. Comprehensive care of the epilepsy patient – control, comorbidity, and cost. Epilepsia 2004;45(Suppl 6):3–12. Foldvary N. Treatment issues for women with epilepsy. Neurol Clin 2001;19(2):409–25. Harden CL. Menopause and bone density issues for women with epilepsy. Neurology 2003;61(6 Suppl 2):S16–22. Harden CL. Sex, drugs, and epilepsy. Epilepsy Curr 2004;4 (5):200–1.

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Post-surgical rehabilitation R Thorbecke and B Hötger

Why rehabilitation in the context of epilepsy surgery? For the majority of patients undergoing epilepsy surgery this intervention effects a dramatic change in the course of their illness, i.e., they reach ultimate freedom of seizures. It seems that patients anticipate this and generate expectations respectively aims going beyond the aim of mere seizure relief – e.g., they plan to get a driving license or to begin a new professional career, etc.1,2 From the early times of epilepsy surgery in the 1950s until today (also on the professional side) the goal of epilepsy surgery has not only been to stop seizures but in consequence to improve the patient’s wellbeing, functioning and their social situation especially with respect to employment and independent life.3,4 However, from the first reports on social outcome until today it is obvious that not all patients gain from the procedure as might be expected from the excellent prognosis after surgical intervention. There may be barriers to the attainment of the preoperatively defined goals – e.g., neuropsychological deficits5,6 or psychiatric disturbances already existing before surgery, or a low potential to discard a sick role with low expectations held over many years.7–9 There might also be barriers in the patient’s environment not perceiving the new possibilities for growth and for taking over more demanding roles.10 Rehabilitation in the context of epilepsy surgery means supporting the patient to attain their goals when they decide to have surgical treatment. This may be psychological support for adaptation to a new situation with new and more expectations than during the years before surgery. It may also include social work, counselling to improve one’s employment situation. It must however be kept in mind that the expectations connected to the surgery might be unrealistic in relation to the patient’s capabilities or formulated not concrete enough to work at their realization.1 Here rehabilitation means to shape expectations into a more realistic form with the patient – in the best already before surgery. Plan of this chapter In the first part the patient’s aims tied to surgical interventions are depicted. In the second part the knowledge on outcome of surgical interventions in relation to these aims is reported, discussing at the same time relevant prognostic factors. In respect to rehabilitation, it is important to understand that postoperative seizure status is not the only, and not always the most, important prognostic factor for social outcome. Rather we have to account for the patient’s cognitive and

behavioral resources to adopt new roles. The Bethel Epilepsy surgery programme has existed for more than 15 years now and, from the beginning, there was a focus on social outcome, its determinants, and how to optimize it. Therefore a section with the Bethel experiences from 1990 – 2004 will be included. In the third part, finally, practical advices for rehabilitation interventions in epilepsy surgery patients stemming from the literature and from the experiences in the Bethel epilepsy surgery program will be reported.

Aims / expectations of patients associated with epilepsy surgery Several studies have preoperatively investigated expectations with respect to the postoperative psychosocial situation. Baxendale et al. asked patients to rate themselves with a selfconcept scale, first in a general way and second under the presupposition that the proposed surgery would be successful in eliminating their seizures. It appeared that the patients were expecting to be happier, more in control, and more hopeful, independent and interested in life.11 Thorbecke, in a similar way asked for expected changes in several social domains. The greatest expectations were present for elimination of seizures followed by improved mobility, employment opportunities, sports, leisure time activities, and more social contacts, and the hope to find a partner. In fact the perception of difficulties in any social domain correlated consistently and highly with the strength of the expectation of change after surgery.12 Wheelock et al. asked patients and significant others for expected life changes following epilepsy surgery. Having more friends, being less dependent on others, others worrying less about the patient, improved marital/family relationships, ability to drive, ability to work, and ability to do more things independently were mentioned most often.13,14 Taylor et al. asked 69 patients who already had decided to get surgery, and who were able to depict their postoperative aims with respect to their cognitive and psychiatric status. The mean number of statements was three (range 1–5). Improved work situation, driving, independence, socializing, relief from taking medication/relief of side effects were the five most often-mentioned aims. Surprisingly there was little expressed interest in improving cognitive functioning.2 An interesting question addressed in these studies is what type of expectations have the best chances to be fulfilled. From Wheelock’s study comes the finding that those patients whose expectations were fulfilled, postoperatively were more satisfied, and this was associated with better psychosocial functioning.13,14 Wilson et al. asked the patients preoperatively about their expectations in respect to surgery and postoperatively to rate 1319

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the success. ‘The successful subgroup primarily reported expectations that led to a practical or clearly identifiable result, such as seizure ablation, driving, employment and the initiation of new activities’. In contrast, the unsuccessful subgroup reported less practical expectations (difference for expectations to become employed < 0.05) but more expectations of psychosocial nature and the expectation that the operation would generally enhance their QOL.1 In Wheelock’s and Thorbecke’s studies it was the opportunity to do these practical things now which was delineated as postoperative changes. In all three studies1,12–14 no differences with age or gender are reported and in all three studies persons who had not become completely seizure free reported less changes. Wheelock et al., and in a similar way Wilson et al., showed that the expectations of those whose seizures were not completely eliminated but improved were only slightly or moderately fulfilled. It is evident that these findings should have practical consequences for preand postoperative counselling especially for a better adaptation of those improved but not completely seizure free. An interesting comment in this context comes from Wheelock et al. when they compare preoperative evaluation of risks with the behaviour in a game of chance: ‘… on hearing from their physicians that they have a 70 – 75% chance of becoming seizure free, patients may automatically place themselves in the positive outcome category rather than acknowledge that they may be among the patients who continue to experience seizures.’ 14

Factors determining social prognosis Outcome might be very different for different social domains, and different outcomes might be affected by different factors, e.g., seizures having stopped might influence the capability to drive or the possibilities to do certain types of sports in a very direct way, whereas living independently or starting a new career might be much more determined by age, cognitive abilities, and social skills than by mere seizure status. Overview from the literature Employment The majority of studies in the early years of epilepsy surgery between 1960 and 1980 showed dramatic improvements in employment rates after epilepsy surgery.3,15,16 Up to the eighties such effects were less obvious17,18 or there were no effects at all.19–21 In the US multicenter study of epilepsy surgery in a cohort of 396 patients followed for at least 2 years after surgery, there was only a not significant increase of employment from 45–52%.22 A somewhat different picture evolves in studies using a control group. A Norwegian study demonstrated that persons who are employed at the time of surgery stay longer in the work force than controls,10 and in a study from the U.S. the rate of persons in full time employment was significantly higher in the surgery group compared with a medical management group.23 Nevertheless in the surgery group there remained 31% without full-time employment. In the early studies it seemed clear that improved seizure status was predictive for improved employment situation.2,16 However, in the more recent studies there is not such a clear picture and it seems that additional factors must be accounted for. In a study by Jones et al., the employment rate of those

having become seizure free was higher than for persons who were not seizure free, the difference, however, did not reach significance.23 Lendt and colleagues found four factors relevant for postoperative employment – preoperative employment, low age at surgery, improvement in general neuropsychological functioning especially attention, and good seizure outcome.18 Reeves et al. observed that being a student or working full time within a year before surgery, driving after surgery, and obtaining further education after surgery were associated with full-time work postoperatively.20 These results are not as favourable as expected in view of a patient group in which about 70% of the patients have become seizure free at the time of follow-up. So it is not surprising that the need of rehabilitation efforts, especially in the vocational domain, is underlined in the more recent studies. ‘Vocational rehabilitation efforts should be enhanced and should include those who were working prior to surgery but unemployed at follow-up.’ 27 To make progress in this direction, however, would need a careful analysis of barriers to gainful employment in the patient such as already preoperatively existing cognitive deficits and psychiatric disturbances as well as barriers in the environment, e.g., when the patient’s enlarged work abilities after surgery are not perceived.10 Independent living To live more independently is one aim expressed by patients in all studies addressing aims/expectations (see above). Also, professionals are interested in the effects of epilepsy surgery on independent living for economical reasons. There is, however, a dearth of data allowing some conclusion in this direction. In older studies highly significant gains with respect to independent living were reported.24 There were, however, no control groups. A study from Norway showed a strong decrease in the need to be looked after in the surgically-treated patients at the end of the mean follow-up interval of 17 years. In the control group however the same course could be observed although seizure frequency at follow up was significantly higher.10 Thus the decrease in supervision reflected rather a general attitude change towards independent living of persons with disabilities or the subjects simply growing older than true changes resulting from surgery. There are also difficulties in finding a definition of independent living which is independent from cultural norms.25–27 In the controlled study of Jones et al. independent living was defined as not requiring assistance in any of three activities of daily living (e.g., organizing and taking medications, keeping appointments, and showering) and as living alone, with a roommate(s), or with significant other(s) (not living with parents or living in an assistedliving arrangement). The proportions living independently were, for the surgery group pre 53%, post 85%, for the control group pre 39%, post 48% (p < 0.001). Possible prognostic factors were not evaluated.23 The Bethel experiences are reported below. For rehabilitation purposes some general findings on independent living in PWE might be helpful (delineated in Thorbecke’s review 2001):26,27 epilepsy might only be of importance if there are frequent and severe (grand mal) seizures. Decisive factors seem to be additional disabilities, e.g., physical limitations like hemiparesis and cognitive deficits.

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Driving Reeves et al. reported that in their series 79% of 112 patients were driving postsurgically which is in good accord with 80% having an excellent seizure outcome. In this study driving after surgery was one important predictor for full-time work at follow-up.20 In the study of Jones et al. 67% of the patients were driving 5 years after surgery in contrast to only 22% of the controls (p < 0.001), freedom of seizures being a significant predictor.23 Although to overcome driving restrictions is one of the most important aims of patients deciding to undergo surgery, there may be complications which prevent them postoperatively from driving. In a study on effects of visual field defects and epilepsy control seven out of 13 patients were seizure free and also seven out of 13 had visual fields that would allow them to drive. However only five met both criteria, significantly altering the percentage of patients who were actually eligible to drive.28 The authors concluded that the probability of driving should be discussed at length prior to any temporal lobe surgery (see also).29 At least in countries were a formal examination is necessary to get a driving license it might be that already preoperative or postoperative cognitive deficits may hinder the patient to pass it successfully. This should be discussed with patients at risk prior to surgery.

Bladin, in his study on psychosocial difficulties after TLR, observed 4 years after surgery a level of 6% divorce which was unremarkable against a general divorce rate of 1:3.19 Carran et al. reported the proportion of married patients pre- and postoperatively not to differ significantly from each other – 37% versus 43%. However 33 of 190 patients had changed marital status postoperatively with 21 who became married, and 12 who became divorced.33 Although the divorce rate seems to be low the divorces reported might be related to surgery, e g., if the patient preoperatively had sustained the relationship only because of the dependency in consequence of the seizures and, after having become seizure free, escapes.19

Family relationships, social contacts and significant others There is only little information on this domain. Mihara et al. asked patients and families to rate satisfaction with different social domains pre- and postoperatively independently from each other and then computed change scores. The assessments of patients and their families concurred well. About 2/3 of the patients and somewhat less of the family members rated emotional wellbeing and leisure time activities as improved 2 years after surgery. There were, however, much lower changes in respect to social contacts, family relations and in respect to financial status.30,31 Bladin et al., when doing a rating together with patients and families found nonfamilial relationships improved nearly at the same degree as Mihara et al. Changes in family relationships were reported however much lesser, the majority of the 107 interviewed saying that relations remained unchanged.19 In both studies changes were influenced by seizure outcome. In both studies, however, it was not clear if the quality of preoperatively already-existing relationships had improved or new postoperative contacts had been initiated. Anyway, from both studies it can be inferred that 10 – 15% of the patients also postoperatively had major difficulties in nonfamily relationships, respectively social contacts. Langfitt et al. in an extensive study in which the family interactions of 43 patients 2 – 3 years after surgery were videotaped, looked for family predictors of social adjustment i.e., functioning in the areas of work/school, social/leisure time, and family relationships. Predominant affect in the family and, to a lesser degree, seizure outcome explained 50% of the variance in social adjustment. The correlations were especially high for the group of patients who had not become seizure free. The authors underline the importance of family support for this patient group, which has much more difficulties, to rely on a social network outside their family.32

These authors contend that these problems could be prevented by formulating clear and realistic expectations preoperatively. There are other factors apart from seizure status decisive for postoperative quality of life. Personality traits like neuroticism,40,41 learned helplessness, a measure closely related to depression,35,36 and learned resourcefulness which refers to a personality style that not only buffers negative effects of stress, but which also prompts the initiation of corrective personal change strategies such as the use of thoughts to control emotion, application of problem solving strategies, and delaying immediate gratification influence HROL independently from seizure outcome.42 Depression is the strongest predictor for HRQOL explaining up to 45% of HRQL independently from seizure status.43 Depressive syndromes (dysthymic disorders, major depression) may be found up to half of the patients preoperatively, and de novo mood disorders in about 10% postoperatively, the latter mostly being of transient nature 44 (see Chapter 95). From this it becomes obvious that apart from seizure outcome a close psychiatric follow-up in the first 2 years postoperatively may be decisive for the outcome as judged by the patient in quality of life terms. Finally there is the small group of patients with no improvement at all. This group may deteriorate in HRQOL in comparison to the baseline preoperatively.4 A surprising finding is that the overwhelming majority of patients who did not become seizure free say that they would have surgery again in a comparable situation 23 i.e., they are not at odds with the unsuccessful therapeutic trial. Nevertheless this is the group needing the most intensive medical, psychiatric/psychotherapeutic, and social-work support postoperatively.

Psychological wellbeing It is now well established that TLR improves HRQL.34 However this hold only for those patients who have become completely seizure free. In patients who still have auras (Engel class IB) no improvements could be observed35–38 although there was substantial seizure reduction. However such a Failure is a judgement based on preoperative expectations. To reduce the seizure frequency by half, or to eliminate one of two seizure types could be seen as favourable outcomes if they had been agreed-upon goals prior to surgery.39

Difficulties to adapt to a situation without seizures (burden of normality) Bladin and Wilson in recent years repeatedly reported on difficulties associated with the cessation of seizures after surgery,

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e.g., inability to cope with a new situation imposing less social constraints but at the same time making new demands – inappropriate, self-indulgent behavior in consequence of this, or being at odds with ones fate because surgery came too late.9 Such phenomena have loas been observed and gave the starting point for rehabilitation in epilepsy surgery.7,15,45 Wilson et al. observed these phenomena with an increasing frequency in up to 30% of the patients until 2 years postoperatively.46 From the features described it is, however, not clear for what proportion of the patients they are of clinical relevance. Wheelock also reported such difficulties in seizure free patients but the frequency was low. She conceded however that her sample (n = 32) might have been too small to give an adequate estimation.13,14 A further difficulty is that from the newer reports of Wilson et al. it is not clear who is especially prone for the described difficulties in adaptation. In the older reports 45 it seemed that patients with preoperative personality disorders and/or extremely unrealistic expectations were especially susceptible to such reactions. In our experience, patients with few resources for adaptation i.e., a dearth of social skills and cognitive impairments preoperatively especially with an IQ in the range of a learning disability preferably develop these maladaptive reactions. Experiences from the Bethel epilepsy surgery programme In the preceding section it was shown that there is a lack of studies dealing with the social situation of epilepsy patients after surgery. Especially pre- and postoperative changes in the patients’ objective social situation have not often been analyzed. We did a follow-up on social outcome in our program twice – for patients getting ATL between 1991 and 1996 26,27 and between 1998 and 2004.47 Here we report some results of the second follow-up. Patients and methods This study was undertaken in 115 patients with temporal lobe epilepsy who were treated in the epilepsy surgery program Bethel between 1998 and 2004. The patients’ demographic features are presented in Table 140.1. All patients were interviewed by a social worker pre- and postoperatively and were asked to fill out the PESOS-Questionnaire

Table 140.2

Table 140.1

Bethel program – basic data

Sex m/f Right temporal lobe epilepsy/ left temporal lobe epilepsy Age mean years (SD); range Duration of epilepsy mean years (SD); range Surgery: right TLE/left TLE/ lesionectomy Seizure outcome: Engel class I/II/III/IV

53/62 68/47 35.04 (10.6); 15–60 21.97 (12.0); 1– 53 62 /46/7 79/17/11/8

Patients who suffered from a progredient tumor were excluded from the study.

before surgery and two years after that. The PESOS-Questionnaire (PESOS = Performance, Sociodemographic aspects, Subjective evaluation/estimation) is a tool which was developed in the Epilepsy Center Bethel to assess the impact of epilepsy, the epilepsy related quality of life and the psychosocial problems of epilepsy patients.48 Additionally patients rated their quality of life on a seven point Lickert-Scale 6 months after surgery. Neuropsychological testing was conducted pre- and 6 months postsurgically. The standard test battery consisted of tests which are indicators for verbal and nonverbal memory, attention, ability to explore, spatial constructive abilities, short-term and working memory, cognitive flexibility and intelligence. Sixty-five patients were included in a specific rehabilitation programme focusing on work related integration. The focus on rehabilitation in Bethel has existed from the beginning, but a special rehabilitation unit was not installed before 1997.

Results Changes in specific social domains To be able to analyze postoperative changes in the abovedefined categories we dichotomized patients’ answers. There was a significant improvement of the patients’ objective social situation in most domains (Table 140.2). In comparison to the results observed in our first follow up26,27 the results were even more promising.

Differences prepost for the whole group

Social domain Accidents Not driving Not leaving without accompanying person No sports Unemployment Disability pension Unsatisfactory employment situation Living with parents Social contacts < 1/week No partner ( ): Results Thorbecke (2001).

Pre 22.3% 91.0% 10.6% 51.5% 19.8% 13.9% 49.5% 27.0% 33.3% 34.9%

p

Post (31%) (96%) (23%) (65%) (19%) (15%) (64%) (39%) (29%) (48%)

2.7% 59.3% 2.7% 34.8% 8.9% 14.9% 15.7% 15.7% 24.1% 28.1%

(8%) (70%) (7%) (58%) 15% (23%) (34%) (26%) (32%) (46%)

< 0.001 < 0.001 0.006 0.001 0.013 n.s. < 0.001 0.002 n.s. < 0.001

(< 0.001) (< 0.001) (0.0002) (n.s.) (n.s.) (n.s.) (0.0008) (0.0002) (n.s.) (n.s.)

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Post-surgical rehabilitation After describing differences prepost a stepwise logistic regression analysis was done including neuropsychological, social, and clinical variables as predictors for the postoperative score in the analyzed domain. We also included the patients’ presurgical score in every domain as a predictor. Employment Surgery did not cause a significant change in the amount of people who were in disability pension. In fact only one more person received a disability pension after surgery. The pre-postsurgical comparison however shows that there was a significant decrease in the unemployment rate after surgery. While about 20% of all patients were out of work before surgery less than half of them (9%) were unemployed afterwards (p = 0.013). Furthermore the perceived employment situation improved a lot: while 49.5% called their working situation unsatisfactory presurgically only 15.7% felt the same 6 months after surgery (p < 0.001). To gain a better objective judgement of the patients’ employment situation social workers grouped it into four categories: as good as before (employed before and after surgery), as bad as before (out of work before and after surgery), improved (unemployed presurgically, employed postsurgically) and deteriorated (employed before surgery, out of work postsurgically). Housewives were excluded from these categories. About half of the patients (52.3%) were employed before and after surgery (as good as before), in 5.4% of the cases the negative employment situation had not changed (as bad as before), 22.5% had been out of work before surgery but were employed afterwards (improved) of all patients 19.8% had to cope with a more negative employment situation, e.g., they had been employed before surgery but were out of work or in pension after it. Work-related problems which epilepsy patients have to deal with decrease after surgery. The PESOS-Questionnaire contains a scale concerning different aspects of problems at work (days on sick leave, slow working speed, memory and attention problems, staying a whole work day, seizures at work). Before surgery 59.1% of the patients said to have such problems, postsurgically comprised only 24.6% (p = 0.002) In the logistic regression analysis (Cox and Snells-R 2 = 0.405; Nagelkerkes-R 2 = 0.723) the preoperative status was proved as a significant predictor, e.g., patients who received disability pension before surgery were more likely to be still in pension afterwards (p < 0.001). An additional predictor was the age at first seizure, a greater proportion of patients with epilepsy onset later than 20 years receiving early disability pension (p = 0.023). The postsurgical employment status and also the subjective perception of the work situation can be best predicted by the presurgical work situation (p = 0.010, Cox and Snells-R2 = 0.103; Nagelkerkes-R2 = 0.168). Mobility The majority of patients (more than 85%) were independent before and after surgery (i.e., patients left their home without an accompanying person). After surgery even more people were able to leave home without company (p = 0.006). In the logistic regression analysis only the presurgical situation was

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a significant predictor (p < 0.001, Cox and Snells-R2 = 0.155; Nagelkerkes-R2 = 0.292). Sports In contrast to Thorbecke’s results a significant increase in the percentage of people doing sports regularly (48.5% preoperative vs. 65.2% postoperative) could be observed. The analysis for predictors (Cox and Snells-R2 = 0.145; Nagelkerkes-R2 = 0.204) showed an effect of the seizure outcome (p = 0.042) and the preoperative frequency of doing sports (p = 0.004). Persons who had already been active in sports before surgery and who were seizurefree postsurgically did sports more often. Independent living The pre-postsurgical comparison showed that postsurgically fewer patients lived with their parents (27% vs. 15.7%, p = 0.002). After surgery more patients called their living situation satisfying: presurgically 15.3% were not satisfied with their living situation, postsurgically only 8.1% thought their living situation was not satisfying. Significant factors for predicting (Cox and Snells-R2 = 0.346; Nagelkerkes-R2 = 0.593) the postoperative living situation were the patient’s age (p = 0.004), the presurgical living situation (p < 0.001), and the neuropsychological parameter ‘nonverbal memory’ (p = 0.013). Patients who lived independently were significantly older (F(40)=2.19; p = 0.002) than patients still living with their parents. Additionally patients who lived at home presurgically were at a greater risk to still live with parents after surgery (F(1) = 63.97; p < 0.001). People with a poor nonverbal memory performance were more likely to live with their parents. Social contacts No significant change in the frequency of social contacts could be observed after surgery. Respectively 76.7 and 85.9% of the patients had social contacts outside the family pre- and postoperatively at least once per week. In contrast there was a significant change in the number of friendships (p =0.004).While preoperatively 29.4% of all patients reported to have very few or no friends, postoperatively only 15.9% made this statement. There was also a positive change in the subjective evaluation of social contacts. Postsurgically significantly more patients called the quality and number of friendships satisfying (p < 0.001). Only 11.6% were not satisfied with their social life after surgery while presurgically 19.5% were not pleased with their social contacts. Two factors were suitable to predict the postsurgical situation with respect to social contacts: the presurgical frequency of social contacts (p = 0.024) and the extent of epilepsy-related fear (p = 0.046). Patients who had had more social contacts before surgery and who had a lower level of epilepsy-related fear were more likely to have a high frequency of social contacts (Cox and Snells-R2 = 0.095; Nagelkerkes-R2 = 0.143). Partnership In contrast to the results from 2001 there was a significant increase in the percentage of people having a partner

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∗∗ ∗∗ ∗∗ ∗∗ ∗∗

∗

∗∗ ∗

ut

se i of

(p < 0.001). While presurgically 34.9% of our patients had no partner, only 28.1% had no partner after surgery. In addition to that, less people reported epilepsy-related problems in their relationship (35.3% postsurgically vs. 13.8% presurgically). However, the presurgical status was the only predictor (Cox and Snells-R2 = 0.238; NagelkerkesR2 = 0.352).

∗∗ ∗∗

∗∗ ∗∗ ∗∗

pre post

be wit fin ep s hd di ta e een raw ng nce to a fr te as l b ien rm le y ds o s s w s in the ith te rs th llig ep e e ep nt ile an ps pr ilep no y a oh sy ya s a ibi nc h tio e an ns a d th bou ica p in gs t dr go ugs se wro lfes ng te em

∗

to

co

m

ac c

Difficulty in copying with epilep (0=no,100=very strong)

Subjective social situation The patients’ subjective situation was assessed with four scales: impairment due to epilepsy, emotional adaptation to epilepsy, stigmatization and epilepsy-related fear. The pre-postoperative comparison of these scales is presented in Figures 140.1 to 140.3. Figure 140.1 shows the comparison for the subjective impairment due to epilepsy. A significant reduction of impairment could be observed in every single item of this scale. Thus patients’ felt, less restricted in domains such as going out without company, using public transport, etc. Additionally the change in the scale sum score became highly significant (p < 0.001). Figure 140.2 shows the results of the pre-postsurgical comparison of two scales: the underlined items belong to the scale ‘stigmatization’, the other items are part of the scale

∗∗

Figure 140.2

∗∗ ∗∗ ∗∗

∗∗

∗∗ ∗∗

∗

∗∗

pre post

zu re s

pu

ith o

in g

tw

us

ou in g go

Figure 140.1 Differences pre-post in subjective impairment due to epilepsy.

70 60 50 40 30 20 10 0

∗∗

Differences prepost in coping with the epilepsy.

se

∗∗ ∗∗

pre post

∗∗

of

∗∗

80 70 60 50 40 30 20 10 0

w he iz ur n es go in in fro of g o nt re ut of fus ot al he r o o of f b f s to d s se of ein eiz ie iz ur to of bra g t ure es c be in ea s in au ing da sed th se d ma e a et g w n ec e r a of ong cc ted m si ide is tu nt ad a ve tion nt ur e

∗∗

co m pa b l liv ic dr ny i in t r an ving g in s m dep hob por ee e b t tin nd ies e re g fr ntly fin la ien a tio d fin nc ns s an ial h ps g cia pos fa ip y c e l p s i mi ho ne os bil ly lo ral sib itie gi w il s ca e iti l w llb es el ein lb g ei ng

80 70 60 50 40 30 20 10 0

Amount of anxiety (0=no,100=very strong)


Strengh of impairment (0=no,100=very strong)

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Figure 140.3

Differences pre-post in epilepsy related fear.

‘emotional adaptation to epilepsy’. While all pre-postsurgical comparisons became significant (p < 0.001) with respect to the latter scale only one significant change could be observed when looking at the stigmatization scale: Patients felt more accepted after the surgery (p < 0.001). Figure 140.3 shows that the patients did not suffer from epilepsy-related fear as strongly as they did presurgically. Nevertheless the fear of being teased remained. To conclude, in general quality of life indicators improved significantly. There was however little change in perceived stigmatization.

Conclusions The results from our second follow up are in good agreement with our former results 26,27 as well as with results reported by others (see the second section). The patients’ objective and subjective social situation in most domains improves after epilepsy surgery. No significant change, however, can be observed in felt stigmatization. In comparison with our former results, especially the outcome on work related variables is more positive than before. While no difference in the postoperative employment situation could be found in 2001, there is a significant improvement in the second cohort. This improvement could be due to the establishment of a special rehabilitation unit in our centre in 1997 (for a description of the rehabilitation unit see below. Nevertheless, there are persisting restrictions. First of all, no significant improvement can be observed in the frequency of social contacts. Possibly this result is coherent with the finding that patients still feel stigmatized after surgery. Thus patients with a high degree of felt stigma could be lacking the self-certainty to take the first steps to build up new relationships. Changes in social behaviors perhaps may need more time to have measurable effects. The same holds true for changes in the work situation. While a significant decrease in the unemployment rate can be observed in the second follow-up, the percentage of people who receive a disability pension remains stable. All in all the studies presented in the previous section and also our own results show that there is a need for rehabilitative

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Post-surgical rehabilitation interventions because even surgically-treated patients with a good seizure outcome suffer from social difficulties. The Bethel experience gives hints that rehabilitative care is indeed important and can positively influence patients’ social situation after surgery.

Rehabilitation interventions Pre and postoperative rehabilitation Preoperative rehabilitation As we have demonstrated in the second section, the evaluation of outcome by the patient and also individual motivation to work for postoperative improvements of the psychosocial situation depends strongly on preoperative expectations/aims set in connection with the surgical intervention. Therefore rehabilitation should always begin preoperatively with working out realistic expectations together with the patient and family. This seems essential in view of the high proportion of patients with psychiatric and neuropsychological deficits already existing preoperatively. In both follow-up studies from Bethel, about 60 % of the patients had personality disorders (Koch-Stoecker 2001,44 unpublished data 2005). Preoperative neuropsychological deficits were reported repeatedly by Helmstaedter.5,6 In our experience, expectations with respect to social outcome should not be discussed with the patient immediately before surgery because at this time the patient is involved in evaluation of the medical risks informed by the neurosurgeon. An ideal time is after the patient management meeting (see Chapter 104 this volume) because then medical, neuropsychological, psychiatric, and psychosocial work-up is finished so seizure prognosis, and the patient’s rehabilitation potential can be assessed. Working out expectations should not only be done by the neurologist, and the patient, but also other team members (neuropsychologist, social worker) should be consulted if their knowledge is relevant. Wilson et al.,1 suggest the following questions to tap expectations: 1. What is the main reason you have sought surgical intervention? 2. Do you see the operation as a chance to change your life? 3. Have you made any postoperative plans? 4. Do you plan engaging in any new activities/hobbies postoperatively? In our center we discuss expectations with two open-ended questions. 1. What changes in your life do you expect postoperatively if you do not become seizure free, your seizure status however improve strongly? 2. What changes in your life do you expect postoperatively if you become completely seizure free? In our experience the first question makes it easily possible to single out those patients who assess the surgery a failure if there is not complete seizure relief. Furthermore answers to both questions are a very good starting point for working on concrete expectations.2 Taylor et al. learned from their interviews that people vary greatly in their capacity to formulate

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an answer when posed a question such as ‘How shall you know 2 years from now, that you are better?’ and propose an individualized approach without preformulated questions.2 Anyway, it is important to document the expectations/aims because there might be phases later in which the patient may feel overburdened by new expectations and then it might be helpful to remind him of his own plans from the preoperative workup. The topics to be addressed when discussing expectations would be: 1. Inform the patient and relatives regarding expected seizure outcome. Also when the patient’s chances to become seizure free are very high it should be made clear that there is a possibility, even if small, that seizures may persist after surgery. 2. Discussion of the patient’s and his family’s individual expectations/aims in relation to surgery. Relying on neuropsychological assessment and the patient’s history, e.g. patient’s employment career, realistic expectations must be discussed. When the patient, and his family’s expectations are unrealistic, e.g., a patient with a learning disability who believes that he can successfully accomplish a high-level professional training postoperatively, first steps of vocational rehabilitation should be done already before surgery. Otherwise the difficulties will be masked after unsuccessful operation (‘because I have not become completely seizure free it does not work’) or he will be frustrated although successfully operated because his expectations are not fulfilled. Postoperative rehabilitation Horowitz et al.8 delineated a rehabilitation model with five phases in which the patient detaches himself from his chronic disease. The first phase is described as a moratorium during which the old roles are continued or unrealistic expectations arise. It is followed by reappraisal, a phase during which new behaviors are tried out or new restrictions arise directed by the fear to provoke seizures. The next phase is called great expectations, Excessive expectations may lead to the perception of failure in the patient; the persons in his environment on the other side may react with removal of support or with a rigidification of the role structure. It is the authors’ contention that in this phase psychotherapeutic support and support by a social worker is crucial. In the next two phases named turbulent period with the self and gradual adaptation the authors describe two different endpoints of rehabilitation, one in which the role of the chronically ill person is reinstalled and made permanent; this happens when the construction of a new identity does not succeed and may be accompanied by severe psychiatric reactions; the other in which the person gradually gains more autonomy, and needs less support by his family. Although this model was designed from experience with only 17 patients in the sixties it also seems to give a frame for understanding the postoperative psychosocial development today. In our experience the first three phases–moratorium, reappraisal, and trying going in new directions–are passed in the first 6–12 months post-surgery, and only in rare cases it takes longer, and it seems that the situation 24 months postoperatively can be taken as the ‘outcome of surgery’.

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Wilson et al., when describing different ways of postoperative adaptation as ‘outcome trajectories’ noted early anxiety as a marker for a poor psychosocial outcome and no vocational changes in the first 12 months as indicators for a poor employment outcome 24 months post-operatively.49 Situations which require special rehabilitation efforts We feel that a team composed of the neurologist, psychiatrist, neuropsychologist, and social worker, who have met the patient already preoperatively, is essential for successful rehabilitation. Situation immediately after surgery If the patient is seizure free, and there are no neurological complications or noticeable neuropsychological deficits, and emotional adaptation seems adequate, the most important thing is to advise the patient when to return to the workplace or when to takeup duties as a homemaker. It is the experience of other centres (Wilson trajectories) and also our own that premature return to work may be followed by complications such as a long sick leave, etc. We inform our patients preoperatively that it may take 3 months until they are able to return to work, and then make an individualized plan postoperatively. It seems that age at surgery is the most important factor for the time needed for postoperative recovery. If possible it may be very helpful to re-enter work stepwise i.e., to start with less hours than normal and then gradually increase the number of work-hours per day. There are, however, patients who have relapsed immediately after surgery or who have a high risk to do so. Furthermore there are patients who have a high level of anxiety or other psychiatric complications, or who are at risk to deteriorate psychiatrically (see Chapters 144 and 150), patients who had neuropsychological deficits already preoperatively, or whose performance has deteriorated postoperatively, and patients who had preoperatively social or employment difficulties or who are at risk to deteriorate. In our centre in 1997 a short-term inpatient rehabilitation program lasting about three weeks was installed for this group. Medical treatment, psychiatric support, psychotherapeutic counselling, neuropsychological training to learn compensatory strategies for word–finding difficulties, visual field or memory deficits, occupational therapy, sports and recreational therapy, intensive counselling, and a structured patient education program especially designed for postoperative patients are offered.50 Continuing psychosocial difficulties several months after surgery We feel, that at about 6 months after surgery it is possible to assess whether a patient is not progressing according to expectations. This includes patients who have become seizure free and have no psychotic disturbances, but in whom one of the following complicating factors can be indicated: persisting mood disturbances, psychosomatic complaints (see Chapter 144), neuropsychological deficits which may or may not have been present preoperatively, occurrence of role conflicts in the family, work situation having become more difficult because the improved seizure situation is not accounted for by colleagues, and patients who apparently do not use their improved mobility and their new possibilities for leisure-time activities.

We offer an intensive team counselling these patients during a 3-day intake 6 months after surgery. We also offered a weekend workshop for couples in which one partner had had surgery twice. Patients and partners complained about different problems, and conflicts were mostly reported by the partners. Psychoeducational methods including role-play were employed. From this resulted the experience that solutions for conflicts could be found, although this might be difficult. All couples said at the end that they would try out the new ways of communication they had learned to solve conflicts.51 There are also patients who have not yet returned to their work-place 6 months after surgery, who continue to be unemployed, or who have not become seizure free and now plan to apply for early disability pension. Furthermore there are patients whose early disability pension now finishes, and who need support for work reintegration. If we cannot solve these difficulties during the 3-day intake, we try to get funds for a second intake in our short-term rehabilitation unit. During the intake immediately after surgery the patients get medical treatment, psychiatric support, psychotherapeutic counselling, and neuropsychological training, which are extended to occupational assessment and real work-experience in companies downtown where professions similar to those the patient intends to return to are found. There are also intensive contacts to employers and to the agencies responsible for labour mediation and vocational rehabilitation. In our series with 115 patients with TLR (see section above) we had nine second intakes 6 months after surgery. Five had a successful rehabilitation outcome: two young adults received afterdischarge vocational training, one adult received vocational retraining, two patients were able to return to their workplace, one of them not being seizure free and having severe neuropsychological deficits. The four patients with a negative rehabilitation outcome all had not become seizure free, additionally one had a severe psychiatric complication, and two had deteriorated in their neuropsychological abilities. For one patient the reasons were not clear. Patients with late relapses There is a significant risk for late relapses. In a recent study about half of these patients remitted, the others continued to have seizures although in low frequency.52 Unfortunately there is little research on the social prognosis of this group. From clinical experience we know that there are patients who become resigned, giving comments like ‘now I am again an epileptic and must bear the consequences’. Apart from a thorough medical assessment those patients need social-work support and sometimes also psychiatric counselling to prevent their situation from destabilizing.

Conclusions By going through the literature and by presenting results from our own program we tried to show that a need for rehabilitation interventions before and after epilepsy surgery is consistently described. This review also identifies a number of predictors for social outcome that allow the planning of targeted pre- and postoperative rehabilitation interventions. Depending on the special outcome domain the predictors vary. The results from our program as well as from other studies show

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Post-surgical rehabilitation that the majority of the patients postsurgically remain in the same situation as before. However, this is not only true for the well adapted but also for those in an unsatisfactory situation. From our experience it is the small number of patients who are able to improve postoperatively, and the also small group which deteriorates postoperatively which must be the target group for rehabilitation interventions. If there is a thorough preoperative work-up and a close follow-up during the first 6 months postoperatively these patients can be identified and addressed for rehabilitation interventions. These interventions should rely on the prognostic factors known from literature (third section) and on the practical experiences reported in the fourth section.

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Timing would be one important aspect. From the literature it seems that a great deal of rehabilitation counselling has to be done preoperatively to shape the expectations of the patient and relatives and to develop the individual’s potential for rehabilitation. In the postoperative course we delineated three occasions for considering rehabilitation support: 1. Immediately after surgery if there is a high risk for psychosocial complications or complications have already occurred. 2. About 6 months after surgery when there are hints that the patient did not profit as much as would have been possible. 3. When the patient relapses after some time without seizures.

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Wilson S, Salas I et al. Patient expectations of temporal lobe surgery. Epilepsia 1998;39(2):167–74. Taylor DC, McMackin D et al. Patients’ aims for epilepsy surgery: desires beyond seizure freedom. Epilepsia 2001;42(5):629–33. Green JR. Temporal lobectomy, with special reference to selection of epileptic patients. J Neurosurg 1967;26:584–93. McLachlan RS, Rose KJ et al. Health-related quality of life and seizure control in temporal lobe epilepsy. Annals of Neurology 1997;41(4):482–8. Helmstaedter C, Kurthen M et al. Chronic epilepsy and cognition: a longitudinal study in temporal lobe epilepsy. Annals of Neurology 2003;54(4):425–32. Helmstaedter C. Neuropsychological aspects of epilepsy surgery. Epilepsy Behav 2004;5(Suppl. 1):45–55. Ferguson SM, Rayport M. The adjustment to living without epilepsy. J Nerv Ment Dis 1965;140(1):26–37. Horowitz MJ, Cohen FM et al. Psychomotor epilepsy: rehabilitation after surgical treatment. J Nerv Ment Dis 1970;150(4): 273–90. Wilson S, Bladin P et al. Paradoxical results in the cure of chronic illness: the ‘burden of normality’ as exemplified following seizure surgery. Epilepsy Behav 2004;5:13–21. Guldvog B, Loyning Y et al. Surgical versus medical treatment for epilepsy. II. Outcome related to social areas. Epilepsia 1991; 32:477–86. Baxendale SA, Thompson PJ. If I didn’t have epilepsy ... patient expectations of epilepsy surgery. Journal of Epilepsy 1996; 9(4):274–81. Thorbecke R. Social outcome after temporal lobe surgery in adolescents compared to adults. In: Tuxhorn I, Holthausen H, Boenigk HE, eds. Pediatric Epilepsy Syndromes and Their Surgical Treatment. London: John Libbey, 1997:326–33. Wheelock I. Expectations and life changes associated with surgery for intractable epilepsy. J Epilepsy 1998;11(1):48–57. Wheelock I, Peterson C et al. Presurgery expectations, postsurgery satifaction, and psychosocial adjustment after epilepsy surgery. Epilepsia 1998;39(5):487–94. Taylor DC, Murray AF. Clinical, socio-economic, and psychological changes after temporal lobectomy for epilepsy. Br J Psychiatry 1968; 114:1247–61. Crandall PH. Postoperative management and criteria for evaluation In: Purpura DP, Penry JK, Walter D, eds. Advances in Neurology. New York: Raven Press, 1975:8 265–79. Sperling MR, Saykin AJ et al. Occupational outcome after temporal lobectomy for refractory epilepsy. Neurology 1995;45:970–7. Lendt M, Helmstaedter C et al. Pre- and postoperative socioeconomic development of 151 patients with focal epilepsies. Epilepsia 1997;38(12):1330–7. Bladin PF. Psychosocial difficulties and outcome after temporal lobectomy. Epilepsia 1992;33:898–907. Reeves AL, So EL et al. Factors associated with work outcome after anterior temporal lobectomy for intractable epilepsy. Epilepsia 1997;38(6):689–95. Helmstaedter C, Andersen B et al. Der Beitrag der chirurgischen Epilepsietherapie zur sozialen Wiedereingliederung und Lebensqualität: Prospektive Studie an 108 Patienten mit pharmakoresistenter Epilepsie. Neurolog Rehab 2001;7(9):281–97.

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Chin P, Berg A et al. Employment following resective epilepsy surgery (abstract). Epilepsia 2005;46(Suppl / 8):255. Jones JE Berven NL et al. Long-term psychosocial outcomes of anterior temporal lobectomy. Epilepsia 2002;43(8):896–903. Jensen I. Temporal lobe epilepsy–social conditions and rehabilitation after surgery. Acta Neurol Scand 1976;54:22–44. Dodrill CB, Chelune GJ et al. Classification of surgical outcome with respect to quality of life. In: Lüders HO, Comair YG, eds. Epilepsy Surgery. Philadelphia. Lippincott Williams & Wilkins, 2001:991–1002. Thorbecke R. Outcome of comprehensive care in relation to employment and independent living. In: Pfäfflin M, Fraser Rt. Thorbecke R, Specht Wolf P, eds. Comprehensive Care for People with Epilepsy. London: John Libbey & Company, 2001:307–18. Thorbecke R. Postsurgical Rehabilitation. In Lüders HO, Comair. YG, eds Epilepsy Surgery. Philadelphia: Lippincott Williams & Wilkins 2001:891–900. Ray A, Pathak-Ray V et al. Driving after epilepsy surgery: effects of visual field defects and epilepsy control. Br J Neurosurg 2002; 16(5):456–60. Mani H, Plant GT. Epilepsy surgery, visual fields, and driving: a study of the visual field criteria for driving in patients after temporal lobe epilepsy surgery with a comparison of Goldmann and Esterman perimetry. J Neurol Neurosurg Psychiatry 2000;68:80–2. Mihara T, Inoue Y et al. Recommendation of early surgery from the viewpoint of daily quality of life. Epilepsia 1996;37(Suppl 3): 33–6. Mihara T, Inoue Y et al. Improvement of quality of life following resective surgery for temporal lobe epilepsy: results of patients and family assessment. Th J J Psychiatry Neurol 1994;48(2):221–9. Langfitt J, Wood BL et al. Family interactions as targets for intervention to improve social adjustment after epilepsy surgery. Epilepsia 1999;40(6):735– 44. Carran MA et al. Marital status after epilepsy surgery. Epilepsia 1999;40(12):1755 –60. Wiebe S, Blume WT et al. A randomized, controlled trial of surgery for temporal-lobe epilepsy. New Eng J Med 2001;345(5): 311–18. Hermann BP, Wyler AR. Depression, locus of control, and the effects of epilepsy surgery. Epilepsia 1989;30(3):332–8. Hermann, BP, Wyler AR et al. Short-term psychological outcome of anterior temporal lobectomy. J Neurosurg 1989;71:327–34. Vickrey BG, Hays RD et al. A health-related quality of life instrument for patients evaluated for epilepsy surgery. Med Care, 1992; 30(4):299–319. Markand ON, Salanova V, Wheliham E et al. Health related quality of life outcome in medically refractory epilpsy treated with anterior temporal lobectomy. Epilepsia 2000;41(7):749–59. Derry P, Wiebe S. Psychological adjustment to success and to failure following epilepsy surgery. Can J Neurol Sci 2000; 27(Suppl 1):116–20. Rose KJ, Derry PA et al. Neuroticism in temporal lobe epilepsy: assessment and implications for pre- and postoperative psychosocial adjustment and health-related quality of life. Epilepsia 1996; 37(5):484–91. Rose KJ, Derry PA et al. Determinants of health-related quality of life after temporal lobe epilepsy surgery. Qual Life Res 1996;5:395–402.

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Chovaz C, McLachlan R Derry PA et al. Psychosocial function following temporal lobectomy: influence of seizure control and learned helplessbess. Seizure 1994;3:(3)171–6. Loring DW, Meador KJ et al. Determinants of quality of life in epilepsy. Epilepsy Behav 2004;5:976–80. Koch-Stoecker S. Psychiatric effects of surgery for temporal lobe epilepsy. In: Trimble M, Schmitz B, eds. The Neuropsychiatry of Epilepsy. Cambridge: Cambridge University Press, 2002:266–82. Horowitz MJ. Psychosocial Function in Epilepsy. Springfield: Charles C. Thomas, 1970. Wilson S, Bladin P et al. The longitudinal course of adjustment after seizure surgery. Seizure 2001;10:165–72. May T, Pfäfflin M. Evaluating comprehensive care: Description of the PESOS and its psychometric properties. In: Pfäfflin M, Fraser RT, Thorbecke R, Specht U, Wolf P, eds. Comprehensive Care for People with Epilepsy. London: John Libbey & Company, 2001:319–40.

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Loer B. Medizinische, soziale und neuropsychologische Prädiktoren des sozialen Outcomes nach epilepsiechirurgsichen Eingriffen. Bielefeld, Diplomarbeit: 2005. Wilson S, Bladin P et al. Characterizing psychosocial outcome trajectories following seizure surgery. Epilepsy Behav 2005; 6:570–80. Specht U, Thorbecke R. Short term inpatient rehabilitation unit. In: Pfäfflin M. Fraser RT. Thorbecke R, Specht U, Wolf P, eds. Comprehensive Care for People with Epilepsy. London: John Libbey & Company, 2001;213–20. Niemann H, Koch-Stoecker S et al. Rollenveränderungen und Konflikte zwischen operierten Epilepsiepatienten und ihren Partnern: Erfahrungen eines Workshops. In: Stefan H, Canger R, Spie G, eds Epilepsie 93. Berlin: Deutsche Sektion der Internationalen Liga gegen Epilepsie, 1994;181–6. Sperling MR, Nei M et al. Prognosis after late relapse following epilepsy surgery. Epilepsia 2005;46(Suppl 8):245–6.

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SECTION 19 Neuropathology and research related to epilepsy surgery

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Neuropathology of mesial temporal sclerosis I Blümcke

Introduction Mesial temporal sclerosis (MTS) is the major finding in patients with temporal lobe epilepsies (TLE) and histopathologically characterized by segmental neuronal cell loss and gliosis within the hippocampal formation (syn. hippocampal sclerosis, Ammon’s horn sclerosis). The majority of hippocampal specimens also reveal alterations within the dentate gyrus, i.e., granule cell dispersion. In addition, variable cell loss can be detected within adjacent cortical regions, including the subiculum, entorhinal cortex, and amygdala. Cortical dyslamination and increased numbers of ectopic white matter neurons within the ipsilateral temporal lobe may also occur in MTS. Neuropathological evaluation of surgical specimens is, therefore, an important diagnostic tool to characterize the morphological substrate of the epileptogenic region. In most patients, clinical histories point to an early onset, such as precipitating events before the age of 4 years, and recent molecular studies targeted developmental pathomechanisms of hippocampal architecture to play a role in the formation of MTS, i.e., loss of Reelin and granule cell dispersion. In contrast, surgical treatment is usually carried out at an end stage of the disease and make any sequential relationship of mesial temporal pathology in TLE patients difficult to obtain. In order to better address underlying etiologies in the heterogeneous group of TLE patients and to stratify post-surgical outcome, a novel clinico-pathological classification system is proposed, which point to early preceding events, respectively the developmental state at which such an event compromises mesial temporal lobe maturation, as a reliable predictor for severe hippocampal pathology.

Clinico-pathological findings in MTS Histopathological studies in patients with pharmacoresistant TLE have identified mesial temporal sclerosis (MTS, syn., Ammon’s horn sclerosis, hippocampal sclerosis) as major pathological finding1,2 MTS can be detected in approximately 65% of patients with MTLE1 and 24.8% of a consecutive cohort of 3319 epilepsy patients undergoing surgical resection for various etiologies in Germany (Table 141.1). Although the pathogenesis of MTS remains to be identified, clinical histories follow a characteristic schedule in most patients. In our series of 824 patients obtained from major German epilepsy centers, including the Universities of Berlin, Bonn,

Erlangen, and Freiburg as well as the Bielefeld-Bethel clinics, three periods were identified. Approximately 50% of patients presented with an initial precipitating injury before the age of 4 years.1 In this cohort, complex febrile seizures are the most frequently noted findings. Birth trauma, head injury or meningitis were other early childhood lesions observed in TLE patients. The mean age at onset of spontaneous complex partial seizures is 11.1 years (Table 141.1). As a matter of fact, structural, molecular or functional analysis cannot be obtained during this early and clinically silent period. The diagnosis of MTS can be verified in surgical specimens mainly after a long period of frustrane antiepileptic medication. The mean age at the time of surgery is about 34 years with a medium history of epileptic seizures of almost 23 years (Table 141.1). As in most other series reported so far, both genders were equally affected and a familial history of TLE was very rare indicating that hereditary genetic factors do not play a major role in MTS associated TLE. Histopathologically, MTS is characterized by segmental pyramidal cell loss in CA1 (Sommer’s sector), CA3 and CA4 (endfolium), whereas CA2 pyramidal and dentate gyrus granule cells are most seizure resistant (Figure 141.1). Notwithstanding, several interneuronal cell populations were also affected, i.e., neuropeptide Y- and somatostatin-immunoreactive interneurons and/or mossy cells in the CA4 sector.3,4 Neuronal cell loss is invariably associated with reactive astrogliosis, which results in stiffening of the tissue and established the traditional term of Ammon’s horn sclerosis.5 An intriguing question relates to the mechanisms of selective neuronal vulnerabilities between these morphologically similar neuronal cell populations. Notwithstanding, this topic is matter of ongoing studies and will not be further discussed in this chapter. Major pathomechanisms include, besides many others, abnormal neuronal circuitries (aberrant mossy fiber sprouting)6 and molecular rearrangement/plasticity of ion channel and neurotransmitter receptor expression.7

Clinico-pathological classification of MTS Clinical studies assume mesial temporal lobe epilepsies as a heterogenic entity with different etiologies and clinical histories.8–10 Hence, neuropathological investigations described different patterns of neuronal cell loss within hippocampal subfields and adjacent temporal lobe structures.4,11,12 1331

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Table 141.1

Clinico-pathological findings in MTLE patients Hemisphere Number

MTS DUAL with LEAT with Malformation with scars with vasc. Lesion with inflammation NOS No MTS

LEAT Malformation No lesion Scars Vascular lesion Inflammation

Age OP

Gender 343 L/356 R

407 M/418 F

Onset

Duration

11.1

22.9

824

34.0

127 53 31 17 13 9 4

21.7 26.0 13.7 28.2 20.2 16.2 16.0

30 15 15 4 6 2 2

L/73 R L/33 R L/15 R L/12 R L/6 R L/5 R L/2 R

80 34 20 10 9 6 1

M/47 F M/19 F M/11 F M/7 F M/4 F M/3 F M/3 F

8.7 11.2 3.2 13.4 5.7 10.9 1.3

13.5 15.6 10.7 15.9 14.6 5.3 14.8

76 62 41 24 12 9

25.5 13.7 25.8 23.4 30.9 21.1

30 23 13 8 4 6

L/27 R L/30 R L/21 R L/9 R L/5 R L/3 R

38 34 21 15 9 7

M/38 F M/28 F M/20 F M/9 F M/3 F M/2 F

12.5 5.4 12.9 7.4 16.7 14.6

13.1 9.5 14.2 16.4 12.5 6.4

Evaluation of 1175 patients with mesial temporal lobe epilepsies and surgical resection including the hippocampal formation. All data were obtained from the German Neuropathological Data Base for Epilepsy Surgery. Histopathological evaluation and clinical histories are as following: MTS: mesial temporal sclerosis; DUAL: dual pathologies; LEAT: long-term epilepsy associated tumors; Vasc.: vascular; NOS: not otherwise specified; Age OP = age of patients at surgery (in years); Hemisphere: L (left), R (right); Gender: F = female, M = male; Onset = age at onset of spontaneous seizure activity (in years); Duration = duration of seizure disorder before surgical treatment (in years).

An intriguing issue is, therefore, to identify determining factors on hippocampal pathology patterns. A reliable neuropathological classification system will also be most helpful to separate distinct pathological subgroups and to better predict post-surgical outcome. A first systematic attempt was published in 1992 by Wyler11, referring to percentages of neuronal cell loss within identified hippocampal subfields CA1-CA4 (Table 141.2). The Wyler-Score is well established in the neuropathological work-up of MTS and threshold values are defined either by 10% (Wyler score 1 = mild MTS) or 50% of neuronal loss. Classification includes five grades (W0 = normal, W1 = mild, W2 = moderate, W3 = classical hippocampal sclerosis and W4 = severe hippocampal sclerosis). End folium sclerosis is subsumed into W2. In previous investigations, certain difficulties evolved using the Wyler-Score to identify mild hippocampal sclerosis on the basis of 10% neuronal cell loss within CA1 and CA3/CA4. Our own analysis even identified 10% neuronal loss within the first standard deviation of age-matched control individuals. An extension and revision of the Wyler-Score was then published by Proper et al.13 including mossy fiber sprouting. Mossy fiber sprouting as well as reactive gliosis are frequently associated with long-term mesial temporal lobe epilepsy, and were confirmed in a variety of different animal models.12,14–19 However, any histopathological classification system should be deliberately based on general histopathology techniques and staining protocols applicable in any pathology laboratory worldwide, without further time and cost-intensive or capricious neuroanatomical techniques, i.e., Timm staining for aberrant mossy fiber sprouting.9 We propose, therefore, a novel clinico-pathological classification system for hippocampal cell loss in patients suffering from mesial temporal lobe epilepsies (MTLE). Five distinct patterns were recognized (Table 141.2) and associate with specific clinical histories and/or post-surgical outcome.20

No MTS Despite electrophysiological evidence for mesial temporal lobe generation of seizures, a cohort of approximately 19% of MTLE cases do not show microscopical features of neuronal cell loss (Table 141.1; Blümcke et al., 2007)20 and cell density measurements were not significantly different from age matched autopsy controls (±10% difference in neuronal cell densities are explicable only by the standard deviation obtained from human control values !). We designated this group as no mesial temporal sclerosis (no MTS; Table 141.2). This observation has been frequently reported in neuropathological surveys of similar MTS series.1,2 The epileptogenic pathomechanisms of hippocampal seizure generation remains to be further determined, and we suggest a mechanism similar to the kindling animal model. Indeed, focal lesions adjacent to the hippocampus can be frequently identified in this cohort of TLE patients (Table 141.1). MTS type 1a and 1b (classical and severe hippocampal sclerosis) With 70% of MTS cases, the largest group present with a classical or severe pattern of segmental neuronal cell loss affecting CA1 and CA4. Due to considerable similarities of neuronal cell loss patterns and clinical histories, we designated these two groups as MTS type 1a (20%) and 1b (50%). In our hands, the degree of CA3 and CA2 pyramidal cell loss is likely to differentiate between MTS type 1a (with moderate CA2 cell loss) and MTS type 1b (with severe CA2 cell loss). This distinction is reasonably similar to that described by Wyler et al.11 Correlation with clinical data pointed to an early age of preceding events (< 3 years) as important predictor of this classical and severe hippocampal pathology pattern.

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type 1b (> 83% seizure freedom), whereas only half of patients with atypical MTS patterns (type 2 and type 3) became seizure free (Table 141.3). Notwithstanding, TLE patients without hippocampal neuronal loss have also a proven benefit from epilepsy surgery. An intriguing challenge for any neuropathological classification system of CNS diseases is the relationship between cellular/molecular lesion patterns and clinical parameters as well as its predictive value for post-surgical outcome. The age of the first preceding event such as birth trauma, febrile seizures, head trauma, encephalitis or first seizure in the absence of a preceding event was significantly different in the neuropathology groups. Early events occurring in pre-school age under age of 7 years came along with severe neuronal loss in hippocampal subfield CA1. Moreover, earlier events under the age of 3 years presented with more widespread hippocampal damage comprising all hippocampal sectors as well as the dentate gyrus. Occurrence of an event or epilepsy onset (in the absence of an event) during early adolescence did affect only the hilar region and spared also other hippocampal subfields to a greater extent. Events occurring even at later adolescence were associated with a rather normal appearing hippocampal formation. Many reports emphasize the association between initial preceding events and development of MTS. The frequent association with febrile seizures in early childhood supports this hypothesis. Seizures during early childhood are associated with aberrant mossy fibre axon connections without evidence of seizure-induced cell death.27 Moreover, prolonged seizure discharges stimulate dentate granule cell neurogenesis as a potential repair mechanism, leading to aberrant connections.14 Such alterations may affect normal brain development and further promote epileptogenesis, whereas seizure activity during later adolescence may strengthen recurrent excitation and induce excitotoxic cell damage, i.e., MTS.19

(b) Figure 141.1 Neuropathological findings in mesial temporal sclerosis (MTS). Neuropathological hallmarks of MTS represent segmental pyramidal cell loss affecting the CA1 and CA4 sectors (b). In contrast, CA2 pyramidal and dentate gyrus (DG) granule cells are most seizure resistant. a: Histograph of a human hippocampus obtained from autopsy. SUB: Subiculum. Pigment-Darrow Red Staining. Scale bars = 1 mm in a and 0.5 mm in b. Note the significant atrophy of the MTS specimen in b. (See Color plates.)

Atypical MTS type 2 (CA1-sclerosis) and type 3 (endfolium sclerosis) We identified two atypical variants characterized either by severe neuronal loss restricted to sector CA1 (MTS type 2; 6%) or to the hilar region (MTS type 3, 4%). In MTS type 2, preceding events were documented at a later age (mean six years), whereas in MTS type 3 and normal appearing hippocampus (no MTS) the first event appeared beyond the age of 13 and 16 years, respectively. The novel MTS classification system allows some prediction of post-surgical outcome (Table 141.3). In our large cohort of TLE patients, the overall six months outcome revealed a rate of 78% seizure freedom, which is in the well-recognized range of earlier reports.8,10,22–26 The best outcome was achieved, however, in patients presenting with MTS type 1a and MTS

Granule cell dispersion The population of dentate gyrus granule cells is pathologically affected in the vast majority of patients with MTS (Figure 141.2). Lesional patterns in this anatomical distinct compartment range from granule cell dispersion, which occur in almost 50% of patients1 to severe cell loss in MTS type 1a and 1b (Table 141.2). Neuropathological criteria for granule cell alterations have not been firmly established.9 We consider any increase in granule cell lamination above 10 layers with smaller perikarya and larger intercellular gaps as pathologic and compatible with GCD. Ectopic cluster and bilamination within the molecular layer can also be identified, although to a smaller extent. Since granule cell pathology is not internationally standardized by a classification system, clinicopathological studies yielded complementary results. Granule cell dispersion may be associated with early seizure onset or status epilepticus at an initial stage of the disease.28,29 On the other hand, Mathern et al. failed to establish a correlation between dentate granule cell densities and onset of seizures.30 A positive correlation was found between the presence of granule cell dispersion and the severity of hippocampal neuronal loss.2,16,31 This finding suggests that the processes of granule cell dispersion and MTS are closely linked. Furthermore, the occasional observation of granule cell dispersion in the absence of

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Table 141.2

Histopathological classification systems for MTS

Reference (Blümcke et al., 2007) no MTS MTS type 1a MTS type 1b MTS type 2 MTS type 3 (Wyler et al., 1992b) Wyler Score 0 Wyler Score 1 Wyler Score 2 Wyler Score 3 Wyler Score 4

Pattern

CA1

CA2

CA3

CA4

DG

normal classic severe atypical atypical

no loss 80% 85% 80% 20%

no loss 30% 49% 20% 25%

no loss 30% 70% 20% 30%

no loss 40% 85% 25% 45%

no loss 55% 60% 20% 35%

normal mild moderate classic severe

no loss 10% 10 –50% > 50% > 50%

no loss – – 50%

no loss 10% 10 – 50% >50% >50%

no loss 10% 10 – 50% > 50% > 50%

– – – – involved

Comparison between two MTS classification systems proposed by Wyler et al.11 and by Blümcke and et al.20 Neuronal cell loss is expressed as percentage from control values within hippocampal subfields (CA1–CA4) and dentate gyrus (DG). Semi quantitative analysis should be applied to determine the extent of pyramidal cell loss. Values represent mean percentages of persisting neurons. It is important to note, that standard deviations need to be applied for scoring individual numbers (data not shown). A software analysis system will be available upon request from the author to automatically calculate the new MTS score.

hippocampal cell loss but with widespread cortical malformations would also point towards a malformative origin.32

Dual pathologies In a proportion of patients with MTS, depth electrode recordings and intraoperative electrocorticography characterize more widespread areas of epileptiform activity involving both mesial and lateral temporal lobe regions.33–35 From neuroimaging and neuropathological studies it is well established that MTS can occur in combination with a second temporal lobe epileptogenic pathology such as cortical dyslamination (i.e., Focal Cortical Dysplasia type I), ectopic white matter neurons or low-grade glio-neuronal tumors.1,33,36–41 There are also occasional reports of distinct hippocampal malformations occurring with MTS42 and structural hippocampal abnormalities on MRI which appear to preceed MTS.43,44 In the German Neuropathological Data Base for Epilepsy Surgery, dual

Table141.3 Correlation between pathology patterns and post-surgical outcome

no MTS MTS type MTS type MTS type MTS type Total

1a 1b 2 3

Engel 1

Engel 2

Engel 3

Engel 4

n n n n n

71.0 85.7 83.3 50.0∗ 42.9∗

12.9 10.7 8.9 20.0 14.3

9.7 3.6 7.8 20.0 28.6

6.5 – – 10.0 14.3

n

77.7

10.8

9.0

2.4

Outcome according to Engel’s classification was determined with a minimum period of six months after epilepsy surgery. A total of 166 patients were included in this analysis (Blümcke et al., 2007).20 ∗ Note the better outcome in MTS type 1a and 1b, whereas only 50% of patients with atypical MTS type 2 and 43% with atypical MTS type 3 became seizure free ( p = 0.051).

pathologies were identified in approx. 10% of cases (Table 141.1). There is some evidence for less severe hippocampal neuronal loss when a ‘dual pathology’ is present (i.e., MTS type 3). In these cases, ‘kindling’ of the hippocampus by the adjacent temporal lobe lesion may play a role. There is some evidence to support the notion that progressive hippocampal atrophy occurs with longer duration of seizures.45–47 It has been shown, however, that surgical removal of both lesions results in the best post operative seizure outcome for dual pathologies40 indicating that each component contributes to the genesis of seizures. The coincidence of dual temporal lobe pathologies also raises the important question of a common predisposing malformative process for both lesions. Furthermore, in a larger proportion of TLE cases, less well defined, subtle microscopic malformations may be identified. Such alterations lend further evidence for underlying temporal lobe dysgenesis which renders it more vulnerable to seizures, neuronal injury and ultimately MTS.48,49 A major difficulty, however, reflect the poor interrater concordance for the neuropathological classification of dual pathology in MTS patients. We propose, that the term ‘dual pathology’ is restricted to a combination of MTS and those lesions, which are likely to represent a distinct pathogenic etiology, i.e., MTS and LEAT, MTS and vascular lesions, MTS and glial scars/trauma. White matter neuronal ectopy and cortical dyslamination of the temporal lobe may not inevitably fit to this assumption and need, therefore, careful attention. The same holds true for the frequent association between LEAT and cortical dysplasias, which may not arise from different pathogenic mechanisms.

A pathogenetic model for MTS – associated TLE Molecular-neuropathological studies of surgical specimens obtained from patients with chronic TLE have focused on different pathogenetic mechanisms, such as (i) structural (axonal/dendritic) and molecular reorganization patterns

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A

1335

B

ML

GC

100 μm

PML

C

D

Figure 141.2 The spectrum of granule cell pathology in MTS. Different patterns of granule cell pathologies can be observed in surgical MTS specimens. A: Normal, densely packed granule cell layer of the dentate gyrus (ML – molecular layer; GC – granule cell layer; PML – pleomorphic cell layer). B: A cluster of ectopic granule cell displaced into the molecular layer is depicted. C: A frequent finding comprises granule cell dispersion with a broader thickness of GC and increased gaps between individual neurons. D: In a few patients the granule cell layer present as bilayered structure. Compared to controls, borders to adjacent layers are always less distinguishable in GC pathologies. Scale bar in B = 100 µm (applies also to A, C, and D).

(neurotransmitter receptors, extracellular matrix), (ii) selective neuronal vulnerability (CA1 pyramidal cell loss), (iii) activity dependent changes in neuronal function/synaptic plasticity (voltage dependent ion channels), (iv) gliosis (spatial ion buffering capacity/glutmate receptor expression/gap junctions) as well as (v) epilepsy-associated neurogenesis. A comprehensive model encompassing the chronic disease history in individual patients has, however, been difficult to obtain. Considering the major clinical milestones and molecular-pathological and pathophysiological changes that can be observed at the end stage of the disease (when neurosurgically resected hippocampal specimens are available) the following pathogenic model of MTS associated TLE will be discussed. We conclude that MTS is an early disorder compromizing normal development of mesial temporal lobe organization with the dentate gyrus as the primarily target.1 Whether a somatic genetic component plays a role, i.e. affecting neurodevelopmental signaling pathways such as the reelin cascade, can not be excluded yet. However, increased neurogenesis and/or persistence of Cajal-Retzius cells in TLE patients with MTS point towards a prolonged and abnormal maturation period50,51 and may be regarded as predisposition/susceptibility factor to seizures and neuronal cell loss. This hypothesis is supported by the notion that long-term epilepsies per se do not inevitably damage the hippocampus (repetitively shown in cohorts of TLE patients with poorly controlled seizures).2

During a latency period, which usually extends into the ‘teenager period’, a number of structural and molecular reorganization mechanisms can be assumed. This model is difficult to address in human surgical tissue specimens obtained from an end stage of the disease. However, there is ample evidence from animal models of limbic epilepsy indicating a number of activity dependent reorganization events preceding the onset of spontaneous seizure activity. In particular, neurotransmitter receptor complexes dramatically change their molecular composition in a region-specific manner. Such modulatory changes can functionally reduce seizure threshold levels in the dentate gyrus.52–54 Following onset of spontaneous seizure activity within the hippocampal formation and mesial temporal lobe structures during adolescence, secondary changes associated with excitotoxic cell damage may lead to the full-blown pattern of MTS.1 This model does not rule out that segmental neuronal cell loss can occur already during an earlier period. We do, however, propose that limbic seizure activity on its own cannot induce MTS without preceding anatomical and functional alterations in the hippocampus/dentate gyrus network. This assumption is supported by our studies in lesion-associated TLE, in which patients suffer from low-grade tumors, malformations or vascular lesions (Table 141.1). In these patients, the hippocampus does not unequivocally reveal neuropathological changes (Table 141.2) although seizure semiologies and clinical histories can be very similar to MTS-associated TLE patients.1

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Our new MTS classification systems fits very well into this model, since most patients with classic or severe MTS (type 1a/1b) suffer from early precipitating injuries. In contrast, atypical patterns with cell loss restricted either to CA1 (MTS type 2) or to the hilus (MTS type 3) associate with later seizure onset.20 Further studies will be warranted to extend and confirm MTS classification systems and to better stratify the heterogeneous group of TLE patients.

Acknowledgments The Neuropathological Reference Center for Epilespy Surgery is a consortium of distinguished colleagues from the following German epilepsy centers: (Berlin) H.J. Meencke,

M. Merschhemke, N.T. Lehmann. (Bielefeld) A. Ebner, H.W. Pannek, F. Woermann, V. Hans. (Bonn) C. Elger, C. Bien, C. Helmstaedter, J. Schramm, H. Clusmann, H. Urbach, A. Becker, M. Majores. (Erlangen) H. Stenfan, B. Kasper, E. Pauli, M. Buchfolder, A. Dorfler, T. Engelhorn, I. Blumcke, M. Hildebrandt. (Freiburg/Kehl-Kork) B. Steinhoff, A. Schulze-Bonhang, S. Fauser, J. Zentner. (Greifswald) S. Vogelgesang. (Marburg) F. Rosenow, S. Knake. (Munich) P.A. Winkler, S. Noachtar. (Stuttgart) P. Winkler. (Ulm) H. Lerche. (Vogtareuth) H. Holthausen, T. Pieper Financial support was granted from the European Community (‘EpiCure’ consortium), German Research Council (DFG B 421/1+2) and Bavarian Hochschulverbund ‘ForNeuroCell’.


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Fuerst D, Shah J, Kupsky WJ et al. Volumetric MRI, pathological, and neuropsychological progression in hippocampal sclerosis. Neurology 2001;57:184–8. Thom M, Holton JL, D’Arrigo C et al. Microdysgenesis with abnormal cortical myelinated fibres in temporal lobe epilepsy: a histopathological study with calbindin D-28-K immunohistochemistry. Neuropathol Appl Neurobiol 2000;26:251–7. Thom M, Sisodiya S, Harkness W, Scaravilli F. Microdysgenesis in temporal lobe epilepsy. A quantitative and immunohistochemical study of white matter neurones. Brain 2001;124:2299–309. Blumcke I, Beck H, Suter B et al. An increase of hippocampal calretinin-immunoreactive neurons correlates with early febrile seizures in temporal lobe epilepsy. Acta Neuropathol 1999; 97:31–9. Blumcke I, Schewe JC, Normann S et al. Increase of nestinimmunoreactive neural precursor cells in the dentate gyrus of pediatric patients with early-onset temporal lobe epilepsy. Hippocampus 2001;11:311–21. Brooks-Kayal AR, Shumate MD, Jin H, Rikhter TY, Coulter DA. Selective changes in single cell GABA(A) receptor subunit expression and function in temporal lobe epilepsy. Nat Med 1998; 4:1166–72. Shumate MD, Lin DD, Gibbs JWR, Holloway KL, Coulter DA. GABA(A) receptor function in epileptic human dentate granule cells: comparison to epileptic and control rat. Epilepsy Res 1998;32:114–28. Becker AJ, Chen J, Zien A et al. Correlated stage- and subfieldassociated hippocampal gene expression patterns in experimental and human temporal lobe epilepsy. Eur J Neurosci 2003; 18:2792–802.

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Pathology of neocortical epilepsy M Thom and S Sisodiya

Introduction A range of focal developmental brain disorders and other cortical abnormalities are now recognized to be highly associated with intractable seizures. Diverse and subtle structural lesions can be identified by neuroimaging and further localized with regions of abnormal activity on EEG and functional imaging and in many cases they may be amenable to surgical resection. One goal of neuropathological examination and study of the tissue removed, above providing a tissue diagnosis, is to investigate more precisely the relationship between the abnormal neuronal and glial cell types identified, and their connections between the lesional and perilesional cortex. This can be correlated with preoperative studies and will continue to improve our knowledge of the cellular basis for seizure onset, which may lead to more directed surgical resections and further improve postoperative quality of life.

Neuropathology methods Tissues from surgical resections carried out for the treatment of neocortical epilepsy are in general rapidly transported to the neuropathology laboratory fresh from theater in order to allow optimal tissue sampling. Where electrophysiological studies are being carried out on single cells or tissue slices, immediate immersion of the identified cortical region for study into cold, oxygenated, artificial CSF is necessary, from which thick (200–300 µm) vibratome sections are rapidly cut. Neuronal electrophysiological properties, can then be investigated and correlated with cell morphology and local connectivity.1 Intraoperative marking of electrically abnormal areas identified by subdural grids also allows study of particular histopathological features in the seizure-onset zones in comparison to functionally more normal regions.2 For structural abnormalities seen on MRI, reliable co-registration and mapping of the pathological changes in the resected specimen also requires careful tissue handling. Following removal, resected brain tissues naturally undergo distortion as well as significant volume changes when subjected to standard tissue fixation, processing and tissue sectioning methods. However, careful orientation and precise slicing of the specimen (Figure 142.1) with reformatting of volumetric MRI images may allow reasonable registration between the specimen and in vivo images.3 Such methods will become particularly important when investigating more subtle pathological features, for example those in mild dysplasias. 1338

Tissue sampling protocols for neocortical resections in epilepsy will vary between laboratories and with the type of tissue resection carried out. For example the availability of adjacent perilesional or more electrically and structurally ‘normal’ cortex depends on the underlying condition, operative approach, localization of lesion and functional eloquence of that cortical region. For many epilepsy pathologies, eg., low-grade tumors, complete resection may be more desirable rather than biopsy for the best post-operative outcome and for other lesions (e.g., cavernomas), additional resection of marginal tissue may be beneficial. Ideally, samples for freezing, routine formalin fixation and for electron microscopy should be taken from both the abnormal regions as well as ‘more normal’ regions. Such archiving of tissues is important both for future diagnosis and molecular research. In most neuropathology laboratories, standard histological stains for the routine diagnosis of neocortical lesions in epilepsy include cresyl violet (Nissl stain) with luxol fast blue to demonstrate abnormalities of the cortical laminar and myeloarchitecture and the presence of abnormal cell types. Immunohistochemistry panels are selected appropriate to the suspected pathology but neuronal markers such as NeuN, phosphorylated and nonphosphorylated neurofilament proteins, glial markers as GFAP and markers of interneuronal groups are more widely used as routine cellular markers in epilepsy neuropathology.

Neocortical neuropathologies in epilepsy Common neocortical pathologies encountered in some reported epilepsy series, (not including the more frequent temporal lobectomy series reports), are listed in Table 142.1. The most common pathologies include cortical malformations (also discussed in Chapter 148), vascular malformations (Chapter 149), low grade tumors (Chapter 150), inflammatory lesions, in addition to cortical scarring and gliosis. Focal neocortical malformations The neuropathology of generalized malforma-tions due to abnormal cortical development are covered in Chapter 148. The main types of focal malformations encountered in epilepsy surgery are divided into three main groups: focal cortical dysplasis, mild dysplasias (mild MCD), and hamartomatous lesions.

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Figure 142.1 Simple metal cradles (7 × 5 cm) can be designed for the handling and slicing of cortical resection specimens in epilepsy to allow even slicing of blocks to correlate with preoperative MRI. In addition, particular regions of the specimen (as shown) can be linked intraoperatively for further localisation of abnormalities.

Focal cortical dysplasia Focal cortical dysplasia (FCD) describes a type of malformation of cortical development where the abnormality is largely restricted to a region of the cortical plate and characterized by distinctive cyto-architectural changes. These lesions are easily recognized in histological sections but in the past the terminology used has lacked consistency between centers.

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Recent reappraisal of the nomenclature4 has resulted in a widely adopted classification system of these lesions in most epilepsy centres which will facilitate their further study. In this system FCD is divided into two types, type I and II, based on the presence of specific neuropathological features as outlined in Table 142.2. Type II FCD, for example is characterized by the presence of abnormal cell types including dysmorphic neurones and balloon cells. Macroscopic abnormalities may be present in surgical resections from FCD cases. There may be apparent thickening of the cortical gray matter, blurring of the gray-white border and the tissue may appear firmer. The overall lesion size varies and can be up to several centimetres broad, involving both sulci and gryri. On histological examination, abnormalities of cortical laminar architecture (also called ‘dyslamination’) are common to all types of FCD with loss of distinction between cortical layers, more easily visualised with Nissl stain or NeuN immunohistochemistry (Figure 142.2). Cortical layer I may often remain relatively cell-free and better defined than other laminae in the region of dysplasia, but may be broader or narrower than normal. The junction between the deep cortical layers and white matter is also typically ill-defined. A lack of radial alignment of neurones compared to normal cortex may also be present in FCD type II. However in FCD I, particularly in childhood epilepsy, an exaggeration of columnar neuronal arrangement has been reported.5,6 Care should obviously be taken with the interpretation of any perceived cytoarchitectural abnormality in relation to normal regional variations.

I II III IV V VI

(a)

(b)

(d)

(e)

(c)

Figure 142.2 FCD type II highlighting changes in the cortical cytoarchitecture as seen with NeuN immunostaining. (a) Normal cortex with distinction between cortical laminae and in (b) in FCD although layer I remains well defined, clear distinction between deeper cortical layers is lost and in (c) a pediatric FCD case, dysplastic neurnones predominate in upper and lower cortical laminae and layer I appears broader than normal. (d) A dysplastic neurone in FCD in H&E preparation and (e) a balloon cell.

68

327 (10 years)

133 (17 years)

1.6%

128 (8 years) 80 (20 years)

–

–

-

3%

6%

108

6. 2%

8.5%

1%

26%

14%

37.6% 3% 44.4% (neuronal heterotopia in white matter) 4.5% hamartoma 18% 4%

6% 2.5% hamartoma

12.5%

22%

Vascular malformations

51%

53%

35% – (1.4% DNT 11% GG)

20%

5%

33% (a dual – pathology – HS in isolation not included in this series) – 18%

14%

5.5%

Hippocampal sclerosis

28% 31% (dual (18% pathology DNT in 5.5%) 8.8% GG)

20.9% (4.5% DNT 5% GG)

75% (65% DNT 7.5% GG)

10%

8.5%

Low-grade tumours

5%

RE=1.5% No pathology identified= 17% RE=1.2% No pathology identified = 15.6%

9.8%

2.4%

0.5%

Rasmussen’s encephalitis/ others

T = temporal, F = Frontal, M = Multilobar, DNT = dysembryoplastic neuroepithelial tumour, GG = ganglioglioma, HS = hippocampal sclerosis, EFS = end folium sclerosis, RE = Rasmussen’s encephalitis, ‘en-bloc temporal lobe resection’ includes hippocampus and amygdala. 1. Eriksson S, Malmgren K, Rydenhag B et al. Surgical treatment of epilepsy–clinical, radiological and histopathological findings in 139 children and adults. Acta Neurol Scand 1999; 99(1):8–15. 2. Hennessy MJ, Elwes RD, Honavar M et al. Predictors of outcome and pathological considerations in the surgical treatment of intractable epilepsy associated with temporal lobe lesions. J Neurol Neurosurg Psychiatry 2001; 70(4):450–58. 3. Frater JL, Prayson RA, Morris IH, Bingaman WE. Surgical pathologic findings of extratemporal-based intractable epilepsy: a study of 133 consecutive resections. Arch Pathol Lab Med 2000; 124(4):545–9. 4. Pasquier B, Peoc HM, Fabre-Bocquentin B et al. Surgical pathology of drug-resistant partial epilepsy. A 10-year-experience with a series of 327 consecutive resections. Epileptic Disord 2002; 4(2):99–119. 5. Schramm J, Kral T, Kurthen M, Blumcke I. Surgery to treat focal frontal lobe epilepsy in adults. Neurosurgery 2002; 51(3):644–54; discussion 654–5.

Bonn, Germany 20025

Lesionectomy (11.6%) Corticectomy (49.5%) Combined (38.8%) 81.6% included temporal lobe Focal frontal Adult lobe resections

Grenoble, France 20024

Mean age 21years; range 3 months – 57 years Mean age 24.5 years (range 2.5 to 61.2 years).

Extratemporal neocortical resections

Cleveland, Ohio 20003

Children (0–18 years) Adults (18yrs+) 50% less than 20 years

Major MCD

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T (25%), F (21%), M (21%) T (75%), F (15%) En bloc temporal lobe resection (excluding HS alone)

Age of patients

Old scars/ gliotic/ atrophic lesions

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Goteborg, Sweden 19991

Series (Ref)

Types of resection

Focal dysplasias: FCD Mild MCD Hamartomas

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Number of cases (time period)

Table 142.1 Range of common neuropathological diagnosis in some larger reported epilepsy surgical series which included extratemporal resections (results shown in %)

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Table 142.2 Pathological features of FCD subtypes as outlined in the system by Palmini et al. (2004) Useful immunohistochemistry panel to aid lesion characterization

Type

Subtype

Pathology features

MRI

FCD type I

IA

Architectural cortical abnormalities ± features of mild MCD Architectural abnormalities and giant (hypertrophic) or immature neurones Architectural abnormalities with dysmorphic neurones but no balloon cells

Structural imaging – not usually identified

NeuN – to demonstrate cortical architecture

Structural imaging – not always identified

Hypertrophic neurones Neurofilament proteins; Phosphorylated and nonphosphorylated heavy and light chain (enhanced expression), NeuN Dysmorphic neurones Neurofilaments NeuN Developmental proteins; Doublecortin, PSA-NCAM, Nestin, MAP1B Balloon cells Variable expression: GFAP, vimentin, neurofilaments, synpatophysin, CD34, CD133, nestin, doublecortin, MAP1B

IB

FCD type II

IIA

IIB

Architectural abnormalities with dysmorphic neurones and balloon cells

(May be normal) Increased cortical thickness Blurring of the gray-white junction Above plus Increased signal on T2 or FLAIR (extending toward ventricle in some cases)

MCD = Malformation of cortical development.

Abnormalities of the cortical myelo-architecture may also be striking features in FCD, with the presence of excessive and abnormally-orientated cortical myelinated fiber bundles. Myelin rarefaction of the immediate subcortical white matter is also a common finding. The identification of abnormal cortical neurones and glial cells in FCD define the subtypes (Table 142.2). Dysmorphic neurones have an abnormal orientation, dendritic branching pattern and cytoskeletal structure (Figures 142.2 and 142.3). In Cresyl violet stained sections, the Nissl substance of these neurones appears abnormally clumped and eccentric thickening of nuclear membranes is seen. Such neurones may be present in any cortical lamina or may predominate in pyramidal cell layers III and V and are occasionally seen as single cells within apparently normal cortex away from the main lesion, or in clusters trailing into the underlying white matter. The abnormal orientation of these neurones ranges from slight rotation to complete inversion.1 The dendrites show increased tortuosity but decreased spine density. Balloon cells have large round cell bodies with eccentric nuclei and pale pink, glassy cytoplasm on H&E. Multinucleate or giant cell forms are frequent. Cells with mixed balloon cell/ dysmorphic neuronal appearances may also be identified as indeterminate or transitional cell forms. Balloon cells lack axons and dendritic spines and tend to be located in deeper cortical layers, spilling into the white matter, but can be present throughout the cortex, including layer I (Figures 142.2 and 142.3). Giant or hypertrophic pyramidal neurones differ from dysplastic neurones in that they retain an overall pyramidal morphology and orientation but may present in any, or throughout all, cortical layers. These cells have abnormally tortuous but shorter dendrites, with increased branching. Their cross-sectional area is significantly larger than normal pyramidal cells.1 Immature

neurones are less frequently identified in FCD lesions. These are round or oval cells (diameter 10–12 µm) with a thin rim of cytoplasm and rudimentary dendrites and they may aggregate in clusters. Although these abnormal cell types are readily recognizable in routine sections, immunohistochemistry may aid their further characterization and classification (Table 142.2 and Figure 142.3). Neurofilament gene expression has been shown to be augmented in FCD neurones7 and immunopositivity may highlight abnormal morphology, alignment and laminar position (Figure 142.3). Dysmorphic neurones are also highlighted with silver stains, such as Bielchowsky (Figure 142.3) although tau-positive Alzheimer disease-like tangles are only rarely present in these neurones and usually in older patients. In addition, in many abnormal cell types in FCD there is aberrant expression of developmentally-regulated proteins (Table 142.2). Strong cytoplasmic immunopositivity of abnormal neurones in FCD may be seen for nestin8 whilst balloon cells show variable expression of nestin, vimentin, GFAP, neurofilaments, and MAP1B, an immature MAP isoform.9 More recent studies have also shown membranous expression of stem cell markers CD34 and CD133 in balloon cell populations located predominantly in the white matter.10,11 Co-expression of both neuronal and glial markers by abnormal cell types is also another common finding,9,12 confirming aberrant glial-neuronal differentiation. These findings reflect the likely mal-developmental origins of FCD. How these abnormal cell types may be involved in the generation of seizure activity is under study. Single cell recordings from dysplastic neurons have demonstrated abnormal intrinsic membrane properties and ion channel functions.1 Using current clamp techniques in in vitro slice preparations however, no spontaneous epileptiform depolarisations

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(e)

(a)

(b)

(c)

(d)

Figure 142.3 Cell types in FCD type IIB. (a) Hyertrophic pyramidal neurones in layer III show strong immunolabelling with nonphosphorylated neurofilament antibodies (SMI32) and in (b) labelling of dysmorphic neurones and numerous processes in the cortex is shown with phosphorylated neurofilament epitope (SMI31). Dysmorphic and hypertrophic neurones in FCD II can also be highlighted with silver stain methods (c). Membranous expression of CD34 on balloon cells in the white matter is a common finding in FCD IIB (d). Proliferative potential of balloon cell populations in FCD type IIB is demonstrated by double labelling for cell cycle marker Mcm2 (nuclear stain, green) and nestin (red) (e). (See Color plates.)

in cytomegalic neurons were noted, suggesting they are unlikely to operate as ‘pacemaker’ neurons.13 Balloon cells do not display spontaneous synaptic current or action potentials1 and lack synaptic contacts14 suggesting they are relatively inert bystanders. Direct electrocorticographic recordings also support that the centre of the FCD lesion containing balloon cells are less epileptogenic than other regions.2 In these patients the epileptogenic regions mainly reside in the surrounding regions that are dysplastic but relatively devoid of balloon cells. The dysmorphic neurons in FCD show increased expression for glutamate receptor subunits, including NMDA receptors.15 These are heteromeric receptors assembled from NR1, NR2A-D and NR3 subunits and the composition confers specific physiological properties, for example sensitivity to Mg2+ blockade. Normal cortical neurons mainly express NR1 and NR2A NMDA receptors. Studies of NMDA receptor subunit expression in large dysmorphic neurons show increased NR1 and NR2 immunolabelling, indicative of a greater number of receptors per cell, although overall receptor density may not be increased.14 Reports also suggest varying alterations in subunit composition and assembly of NMDA receptors in these cell types in FCD, considered likely to influence their electrophysiological output16–18 as well as synaptogenesis and

possibly neuronal migration during development. AMPA receptor mRNA is also increased in dysplastic neurons.16,19 A potential role for the differential expression of NR2B in dysplastic neurons was validated in recent in vitro electrophysiological studies in freshly resected human slices; Ifenpordil, a specific inhibitor of the NR2B subunit of the NMDA receptor almost completely suppressed epileptiform discharges in FCD types I and 2A but had no effect on control tissue.18 In further support of a local excitatory-inhibitory imbalance in FCD lesions there is evidence for a reduction of number of local inhibitory interneurons and terminals in FCD type II lesions using labelling for GAD, parvalbumin and calbindin.20,21 GABAA receptor subunit (β1, β2, α1, α2) mRNAs are decreased in abnormal neurons of FCD19 as well as in TSC lesions17 and a reduction in GABA transporter 1 (GAT1) has also been shown in FCD.20 This potential deficit in inhibitory input may have a role in intrinsic bursting of excitatory neurons. However, other studies propose preserved GABAergic activity in the region of dysplasia13 and hypertrophic, inhibitory synaptic terminals are often seen to surround dysplastic neurons in ultrastructural studies.14,20,22 Indeed, recordings from in vitro slice preparations of FCD have implicated a role for GABAergic synchronisation of ictal discharges.23

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Pathology of neocortical epilepsy The pathogenesis of FCD is unknown. It is widely considered to represent the result of arrested neuronal migration, abnormal differentiation, progenitor cell proliferation or programmed loss of neurones during cortical development possibly following some localised insult. Abnormal numbers of cortical neurones have been shown in FCD lesions24,25 with preservation of the proliferative potential of balloon cells (Figure 142.3). FCD is not familial and there is no animal model that exactly resembles the human counterpart. It is plausible that FCD results from a somatic mutation in precursor or progenitor cell populations during development. Single cell analysis has shown that the cells within FCD are not clonally derived but probably arise from mixed populations of progenitor cells.26 As the histological features of FCD IIB are similar to neocortical tubers of the tuberous sclerosis complex (TSC) (see Chapter 156) several research programs have sought to identify a common genetic link. Sequence alterations (polymorphisms) in the TSC1 locus and loss of heterozygosity have been identified in FCD type IIB27 but not in FCD IIA samples28 potentially implicating TSC genes in balloon-cell containing FCD lesions as distinct from other FCD types. The TSC gene products interact with several intracellular signalling pathways, including Rap1 (binding with ezrin which effects cell adhesion, migration, polarity and cell cycle progression), dysregulation of the insulin signalling mTor/p70SK-S6 pathway (influences cell size and proliferation) and the wnt1/β-Catenin pathway (implicated in cell survival, cell shape and differentiation, polarity and migration). Molecular studies utilising single cell capture, however, have also disclosed differences between balloon cells and giant cells in FCD and tubers suggesting that the pathological mechanisms in operation are not identical in these lesions.29–32 Furthermore histological and molecular similarities also exist between FCD and more extensive malformation causing hemimegalencephaly (HME). HME is often sporadic and associated with epilepsy, but occasional linked with syndromes such as linear sebaceous neavus syndrome, proteous syndrome and rarely TSC. Like FCD, activation of the wnt-1/β-catenin pathway has been shown in HME.29 The reelin and cdk5 signalling pathways have also been implicated in the pathogenesis of FCD, as mice deficient in these proteins display marked cortical laminar abnormalities. Finally there is also an alternative hypothesis, although with relatively less evidence to support it, that FCD is a localised lesion that occurs as a result of cortical structural re-organisation and plasticity following a prior cerebral-cortical insult, for example early cerebral trauma.33–35 Mild MCD (malformation of cortical development) in neocortical epilepsy Mild MCD in epilepsy encompass the more subtle end of the spectrum of focal cortical malformations. These lesions were previously labelled microdysgenesis or architectural dysplasias. Microdysgenesis (or microscopic dysplasia) has been used to cover a wide variety of microscopic minor cyto-architectural cortical abnormalities, including poor distinction between laminar boundaries, an excess of cortical neuronal clusters, an excess of layer I and white-matter neurones and prominent perivascular oligodendroglia-like cell aggregates among others.36–38 Mild MCD is a term used more discriminately and in the updated Palmini classification, they are divided into two categories: type I with ectopic neurones placed in or adjacent

1343

to layer I and type II with microscopic neuronal heterotopia outside layer I (Figure 142.4). Cortical laminar abnormalities are now included under FCD type IA. Excess single or ‘ectopic’ neurones in layer I in mild MCD type I may have varied origins including residual preplate cells from earlier developmental stages (for example, reelin-secreting Cajal-Retzius cells),39 other early neurones of the marginal zone, abnormally persistent subgranular cell layer neurones, radial migrating GABAergic neurones from the ganglionic eminence or heterotopic cortical plate neurones. In some cases, layer I hypercellularity is readily apparent on qualitative inspection of resected tissues, with occasional formation of nodular aggregates. Quantitative evaluation to distinguish Mild MCD type I from normal cortex may prove of practical value but is time consuming.21,24,25,39,40 As yet there is no established immunohistochemical panel that can distinguish ‘ectopic’ from normal layer I neuronal populations and therefore in many cases the diagnosis based on routine stains may be difficult. Similarly with Mild MCD type II, which includes ectopic single white matter neurones, there are practical diagnostic issues in the separation of pathological ‘ectopia’ from normal interstitial neurones of the white matter, particularly in the temporal lobe where such cells are more numerous. Possible origins of white matter neurones in mild MCD type II include an excess of residual subplate cells or ‘true’ heterotopic cortical plate cells. White-matter neurones have mixed morphologies and include pyramidal and small inhibitory interneurones. Several quantitative studies have been carried out, mainly in temporal lobe epilepsy, and confirm higher white matter neuronal densities compared to controls but diagnostic criteria differ between these studies regarding the types of neurones included and the method of quantitative analysis.38,40–42 Furthermore, in epilepsy, processes such as atrophy and gliosis affect tissue volume and may falsely exaggerate cell number. Consequently there is less consensus agreement on the diagnosis of mild MCD compared to histologically more easily-recognized forms of FCD. The frequency of mild MCD, in both temporal lobe and neocortical epilepsy is uncertain, with reports suggesting figures of between 16.7–43% in surgical series.37,43,44 Furthermore as both type I and II mild MCD are typically not visible using current neuroimaging techniques, neuropathology remains the only method of detection. The pathogenesis of mild MCD is unknown. There are some animal models, such as the Ihara rat, which show microdysgenetic features reminiscent of the human trait. As to an underlying genetic basis for Mild MCD, a recent study demonstrated TSC1 genomic sequence polymorphisms in surgical epilepsy specimens showing single white matter neuronal heterotopia and lesions of FCD type I.28 In contrast to FCD type II, there is as yet little evidence confirming a direct link between mild MCD and cortical epileptogenesis. An excess of layer I neurones with cell hypertrophy was particularly associated with infantile spasms in one study.24 However, mild MCD-like pathologies have also associated with other behavioral and cognitive conditions without seizures.4 Dysplasias adjacent to low grade tumors in epilepsy Focal dysplasia has also been reported in the context of epileptogenic low-grade glioneuronal tumours, such as DNT and

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(b)

(a)

(c)

(d)

Figure 142.4 Mild MCD. (a) Subtle changes in cortical cytoarchitecture described in Mild MCD include and excess of ectopic neurones in layer I as seen in this Nissl stained section showing a cluster of small neurones (long arrow) and a single large ectopic neurone (short arrow). (b) An excess of single mature neurones in the white matter is one feature of Mild MCD type II, as shown here with NeuN staining. The cortex adjacent to epileptogenic glio-neuronal tumours may show dysplastic features including hamartia like aggregates of immature neurones (c) and an excess of small cells and immature neurones in layer I as highlighted with CD34 staining (d). (See Color plates.)

ganglioglioma, possibly indicating a common biological origin. The type of cortical dysplasia reported varies but is usually cortical/dyslamination (corresponding to FCD type IA). Layer I hypercellularity or a ‘subpial cellular band’ (mild MCD type I) is also commonly reported45–47 (Figure 142.4). Clusters of immature neuronal cells mixed with mature neurones and glial cells forming aggregates around 0.2–1 mm across are also common findings in the cortex adjacent to these tumours. These are often referred to as hamartias or ‘microdysgenetic nodules’.48 They may represent tumour precursor lesions and can escape detection on routine H&E but are highlighted with immunolabelling for nestin or the stem cell marker CD34, particularly when in the temporal lobe.49,50 More severe types of cortical dysplasia, such as balloon cell types of FCD, are rarely reported in association with DNT or ganglioglioma.47 The diagnosis of additional cortical dysplasia must be distinguished from disturbance to the cortical architecture resulting from local tumour infiltration. The presence of of cortical dysplasia in the vicinity of glioneuronal tumors raises the possibility of a common biological origin and furthermore the question of the source of the intrinsic epileptogenicity,

which is important for surgical management. Intracerebral EEG recordings in ganglioglioma suggest that ictogenesis resides in the itself.50 The exact mechanisms resulting in hyperexcitability remain to be determined; the prominent mature and immature neuronal component of these tumours is one obvious explanation and expression of several glutamate receptors subtypes on both the neuronal and glial component have been shown51 and may contribute to proepileptogenic circuits integrating with the adjacent cortex. Hamartomata in neocortical epilepsy Hamartomata occurring in epilepsy are a relatively poorlydefined pathological group compared to cortical dysplasias and tumors, being less well represented in epilepsy surgical series. Glio-neuronal hamartomata have been described in various cortical locations, particularly temporal and frontal lobes. They are composed of circumscribed masses of mature, but haphazardly arranged, cell types.52 The imaging characteristics are variable53,54 but their lack of growth and mitotic activity help to distinguish these lesions from low grade tumors.52 Following resection recurrence is unusual. The hypothalamic hamartoma is a distinct lesion that has a strong association

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Pathology of neocortical epilepsy with intrinsic subcortical epileptogenesis, particularly manifesting with gelastic seizures and may be associated with the development of secondary cortical epileptogenesis55 and is further discussed in Chapter 43. Unlike the tuberous sclerosis complex, hamartomas or malformative cortical lesions are relatively rarely reported in neurofibromatosis type 1 (NF1) a syndrome in which epilepsy occurs in up to 6% of patients. Neurofibromatosis type 2 (NF2) can be associated with multiple cortical glial micro-hamartomata that are often incidental findings at post mortem, in addition to meningioangiomatosis. Meningioangiomatosis (MA) is a presumed hamartomatous developmental lesion, as distinct from meningeal tumours. It is associated with epilepsy, more commonly in sporadic MA (over 80% of patients) than for MA associated with the NF2 complex.56 MA more commonly occurs in the frontal or temporal lobes forming a superficial or plaque-like hemispheric mass. Histologically it is composed of an intracortical and leptomeningeal collection of small blood vessels and perivascular spindle cells. The intervening cortical parenchyma can appear disorganized and gliotic and neurofibrillary tangles may be present. The more common sporadic form of MA is typically solitary and EEG suggests the epileptogenicity is confined to the adjacent cortex. Indeed, seizures may persist in over half of patients following surgical treatment.57 It is unexplained as to why patients with MA in NF2 typically do not manifest with seizures.56 Rasmussen’s encephalitis Rasmussen’s syndrome or encephalitis is a rare, progressive unilateral neurological disorder, typically presenting in childhood with intractable focal seizures (see Chapter 44). Cortical inflammation, neuronal loss and gliosis of one hemisphere are the typical pathological findings in surgical resection specimens, including hemispherectomies. The inflammation is often patchy even in a localized region of the brain. It appears to proceed through various stages of activation representing the presumed immunological destruction of the cortical parenchyma. The early stages are marked by infiltrates of T lymphocytes, microgliosis and astrocytosis (Figure 142.5). In end stages, there is marked neuronal loss, and pan-laminar

1345

cortical cavitation.58 There is a correlation with the pathological stage and the duration of the illness, although within a single specimen regions at non-contiguous stages may be in close proximity. In addition the pathology may be more severe in patients with younger age of onset, suggesting brain maturity may modulate the inflammatory response.59 The aetiopathogenesis of Rasmussen’s encephalitis remains unknown; T-lymphocyte cytotoxicity is currently favored over viral infection. Nonspecific cortical scarring The neuropathology of old traumatic scars and cerebral injuries are discussed in Chapter 156. In some neocortical resection specimens subtle degrees of cortical scarring are present and do not appear to be directly attributable to cerebral trauma or perilesional changes and more likely represent tissue changes as a result of seizures themselves. Recurrent generalized seizures or episodes of status epilepticus can result in laminar cortical neuronal loss (Figure147.6) typically involving pyramidal neurones with a corresponding laminar gliosis. Gliosis may also be marked in the subpial region and in the white matter, where perivascular atrophy, vascular degenerative changes and deposits of corpora amylacea are not infrequent findings. The cause of these ‘nonspecific’ degenerative changes is unknown. Recent studies, however, highlight the importance of not dismissing glial cell proliferations in epilepsy as a mere structural scarring reaction as these cells have important physiological properties. Glutamate released from glial cells can activate neuronal NMDA receptors with the capacity for epileptiform discharges60 and through establishing local pathological networks, could be a mechanism for synchronising local neuronal activity.61 Glutamate receptors are also expressed on astrocytes62 which may also form an extensive syncytium via gap-junctional coupling. Astrocytes have roles in neurotransmitter transport and regulation of levels in the extracellular space. Therefore, proliferation of these glial cells in regions of scarring may potentially play a functional role in neocortical epilepsies and seizure spread.63

Molecular and genetic research in epilepsy neuropathology

Figure 142.5 Active stage of Rasmussen’s encephalitis with infiltrates of lymphocytes in the cortex and early cortical neuronal loss, cavitation, and gliosis.

Access to well-preserved human brain tissue with a detailed history of insults, seizures, and drug exposure, through surgical programs for the treatment of drug-resistant epilepsy, is one of the great advantages researchers in epilepsy have compared to those working in other neurological diseases. Mostly such material consists of varying amounts of tissue, usually including hippocampus, from the temporal lobe, but focal or lobar extratemporal or even hemispherectomy material is sometimes also available. Studies have been undertaken on fresh and fixed tissues, at macroscopic, microscopic, immunohistochemical, electron microscopic, molecular and genomic and functional levels, mainly in hippocampal sclerosis, but also to lesser extents in tumors, brain malformations (including vascular malformations), traumatic brain injury and other pathologies. The range of research is enormous, and

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(a)

(b)

(c)

(d)

(e) Figure 142.6 Nonspecific cortical changes in patients with epilepsy include regions of superficial cortical and subpial gliosis as seen on GFAP stain (a), areas of cortical gliosis (b). Neuronal loss may be identified in superficial cortical layers (d) compared to normal cortex (c). Marked accumulation of corpora amylacea may be present in the white matter and around small vessels (e) as well as the cortex. (See Color plates.)

only general principles and illustrative brief examples can be given. The interested reader is referred to detailed texts and reviews.63 Investigation has revealed a gamut of changes in the two most common surgically-resected pathologies, hippocampal sclerosis (HS) and focal cortical dysplasia (FCD), ranging from changes in entire cell populations, loss of specific immunophenotypic subtypes, alterations in cell morphologies, distributions and processes, disruptions to cellular architecture, genomic expression,31 protein signatures, processing and function:16 most of this work has been immunohistochemical,

but electron microscopic and functional studies have also contributed. Genomic investigations are only beginning to be undertaken, and are well illustrated by work from Peter Crino’s group. Thus, for example, the possible clonality of origin of cells in FCD has been considered; more recent data raise the possibility of somatic mutation underlying FCD29 and hemimegalencephaly, with extensive changes in entire cellular pathways such as the mTOR cascade.30 The use of single-cell laser capture microdissection and single cell mRNA amplification and analysis will become more widely applied, and

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Pathology of neocortical epilepsy integrated with examination of variation in germline DNA, to produce comprehensive pictures of pathophysiology using neuropathological material. There remain problems. Completely normal comparable brain tissue is very difficult to obtain; most studies that include control tissue use adjacent histologically-normal tissue, but this has its detractors. Almost universally, only a single time point can be examined from one individual, in

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comparison to animal models: cause and effect, and disease progression, can only be inferred or separated with additional information. There are threats to the availability of tissue from issues of consent, misuse, and legislation, but there is also recognition that these tissues are invaluable for advancing understanding. Undoubtedly, there is still much to be learnt from modern neuropathological analyses of epilepsy brain material.

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Emery JA, Roper SN, Rojiani AM. White matter neuronal heterotopia in temporal lobe epilepsy: a morphometric and immunohistochemical study. J Neuropathol Exp Neurol 1997;56(12):1276–82. Bothwell S, Meredith GE, Phillips J et al. Neuronal hypertrophy in the neocortex of patients with temporal lobe epilepsy. J Neurosci 2001;21(13):4789–800. Kalnins RM, McIntosh A, Saling MM et al. Subtle microscopic abnormalities in hippocampal sclerosis do not predict clinical features of temporal lobe epilepsy. Epilepsia 2004;45(8):940–97. Tassi L, Colombo N, Garbelli R et al. Focal cortical dysplasia: neuropathological subtypes, EEG, neuroimaging and surgical outcome. Brain 2002;125(Pt 8):1719–32. Daumas-Duport C. Dysembryoplastic neuroepithelial tumours. Brain Pathol 1993;3(3):283–95. Daumas-Duport C, Varlet P, Bacha S et al. Dysembryoplastic neuroepithelial tumors: nonspecific histological forms – a study of 40 cases. J Neurooncol 1999;41(3):267–80. Honavar M, Janota I, Polkey CE. Histological heterogeneity of dysembryoplastic neuroepithelial tumour: identification and differential diagnosis in a series of 74 cases. Histopathology 1999;34(4):342–56. Blumcke I, Lobach M, Wolf HK, Wiestler OD. Evidence for developmental precursor lesions in epilepsy-associated glioneuronal tumors. Microsc Res Tech 1999;46(1):53–8. Blumcke I, Giencke K, Wardelmann E et al. The CD34 epitope is expressed in neoplastic and malformative lesions associated with chronic, focal epilepsies. Acta Neuropathol (Berl) 1999;97(5):481–90. Blumcke I, Wiestler OD. Gangliogliomas: an intriguing tumor entity associated with focal epilepsies. J Neuropathol Exp Neurol 2002;61(7):575–84. Aronica E, Yankaya B, Jansen GH et al. Ionotropic and metabotropic glutamate receptor protein expression in glioneuronal tumours from patients with intractable epilepsy. Neuropathol Appl Neurobiol 2001;27(3):223–37.

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Volk EE, Prayson RA. Hamartomas in the setting of chronic epilepsy: a clinicopathologic study of 13 cases. Hum Pathol 1997;28(2):227–32. Diehl B, Prayson R, Najm I, Ruggieri P. Hamartomas and epilepsy: clinical and imaging characteristics. Seizure 2003;12(5):307–11. Gomez-Anson B, Thom M, Moran N, Stevens J, Scaravilli F. Imaging and radiological-pathological correlation in histologically proven cases of focal cortical dysplasia and other glial and neuronoglial malformative lesions in adults. Neuroradiology 2000;42(3):157–67. Kerrigan JF, Ng YT, Chung S, Rekate HL. The hypothalamic hamartoma: a model of subcortical epileptogenesis and encephalopathy. Semin Pediatr Neurol 2005;12(2):119–31. Perry A, Kurtkaya-Yapicier O, Scheithauer BW et al. Insights into meningioangiomatosis with and without meningioma: a clinicopathologic and genetic series of 24 cases with review of the literature. Brain Pathol 2005;15(1):55–65. Wiebe S, Munoz DG, Smith S, Lee DH. Meningioangiomatosis. A comprehensive analysis of clinical and laboratory features. Brain 1999;122 (Pt 4):709–26. Bien CG, Granata T, Antozzi C et al. Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement. Brain 2005;128(Pt 3):454–71. Pardo CA, Vining EP, Guo L et al. The pathology of Rasmussen syndrome: stages of cortical involvement and neuropathological studies in 45 hemispherectomies. Epilepsia 2004;45(5):516–26. Rogawski MA. Astrocytes get in the act in epilepsy. Nat Med 2005;11(9):919–20. Tian GF, Azmi H, Takano T et al. An astrocytic basis of epilepsy. Nat Med 2005;11(9):973–81. Seifert G, Huttmann K, Schramm J, Steinhauser C. Enhanced relative expression of glutamate receptor 1 flip AMPA receptor subunits in hippocampal astrocytes of epilepsy patients with Ammon’s horn sclerosis. J Neurosci 2004;24(8):1996–2003. de Lanerolle NC, Lee TS. New facets of the neuropathology and molecular profile of human temporal lobe epilepsy. Epilepsy Behav 2005;7(2):190–203.

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Pathology of malformations of cortical development R Spreafico and AJ Becker

Cortical development At the end of the 18th century Camillo Golgi described glial fibers ‘radiating’ from the central canal towards the periphery of the spinal cord suggesting that ‘... the key for the solution of many questions is enclosed in the embryogenesis of the nervous central organs’.1 Santiago Ramón y Cajal, aware of the works of Golgi, published his first report on the developing cerebral cortex in 1889 stating that cell division occurred preferentially in the ‘vicinity of the epithelium’, that neuroblasts migrated beneath the outer part of the developing cortex and that radial glia served as scaffold structure for embryonic development.2 A particular hallmark regarding mechanisms of cortical development is represented by Rakic’s work3 who clarified the intercellular neuron-glia relationship demonstrating that ‘late-generated cells find their way to the cortex by assuming a bipolar shape and moving outward in direct and constant apposition to radial glial processes that span almost the entire width of the telencephalic wall’. More recent findings provided evidence for distinct nonradial migration routes of certain cell cohorts that migrate parallel to the pial surface. Further novel data indicate that radial cells are capable, by asymmetric division, to give origin to neurons and glial cells, thereby pointing towards the neurogenic potential of radial glial cells.4–8 Cell proliferation, migration, differentiation, maturation, as well as programmed cell death represent the fundamental events involved in the developmental shaping of the cerebral cortex. At the beginning of cortical development, a homogeneous population of undifferentiated cells is present, organized as a pseudostratified columnar epithelium, and called the ventricular zone (VZ). From these undifferentiated cellular population, the neocortex is generated through successive and partially irreversible steps and the final laminated cortex of mammals, including humans, is generated through the formation of transient structures. After the appearance of the VZ, a new area, called the marginal zone (MZ), is formed just below the pial surface. This area is supposed to be the first functionally active zone of the developing cortex. It constitutes the site of initial synapses formation with brainstem-derived afferents. The MZ also promotes the maturation of early generated neurons in the subpial region, presumably triggering the subsequent migratory events.9 Thus, the appearance of the MZ marks the initial

event of cortical neurogenesis and precedes the formation of all the other cortical layers. The superficial lamina containing the first differentiated neuronal elements is termed primordial plexiform layer (PPL). Subsequently, after a mitotic cycle, the neuroblasts from the VZ migrate upward and by arrival of the first migratory neurons the PPL is split into two regions. The most dorsal one, close to the pial surface, becomes the prospective layer I; the second one, named the subplate (SP), lies below the newly arrived cohort of neurons forming the cortical plate (CP). The SP is considered the area recipient of fibers incoming from subcortical structures, which establish synapses with the neurons of SP, and represents the waiting compartment for these afferents during CP development. SP neurons are destined to die later on through a process of programmed cell death, and the fibers will then be released to reach their appropriate and final cortical target. During further developmental stages, the thickness of the CP progressively increases due to the arrival of subsequent waves of migrating neuroblasts. This process follows an inside-out sequence, i.e., the early generated and migrated neurons will form the deep layers of the future neocortex, displaced downward by the neurons generated later and forming the most superficial layers.9,10 By these mechanisms, layers II through VI are formed. As mentioned above, two main trajectories, a radial and a tangential route, have been identified for neuronal migration. The process of radial migration implies that newly generated neuroblasts from the proliferative zone migrate to the CP climbing along radially oriented fibers that extend from the ventricle to the pial surface.6–8,10 Radially migrating neurons give rise primarily to pyramidal neurons (i.e., projection neurons), which are excitatory and utilize glutamate as main neurotransmitter. Nonradially migrating neurons are generated in the ganglionic eminence, the primordium of the future basal ganglia, located in the ventral forebrain. The cells generated in the ganglionic eminence follow a long tangential migratory route to reach the CP and constitute the majority of non pyramidal neurons (i.e., cortical interneurons), which are GABAergic.4–6 These two migratory mechanisms have been extensively studied in animal models; although in principle they are present also in humans, recent data suggest that the population of GABAergic neurons reaching the cortex through tangential migration is only 20–30% of the total inhibitory population resident in the adult neocortex. 1349

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Thus, during cortical development, a spatially and ordered sequence of migratory events is accomplished to construct the cerebral cortex. Although the intimate processes leading to the mature cortical structure are not yet completely understood it is evident that both intrinsic (genetic) and environmental mechanisms are involved in corticogenesis and that disturbances of these processes can result in a wide range of alterations, from severe brain malformations to local disruption of cortical structure. Malformations of cortical development (MCD), recognized as pathologically since the end of the 19th century, constitute a heterogeneous group of focal or diffuse anatomical derangement with pathological features more largely depending on the timing of the defect within the developmental process than on its cause. The advent of high-resolution imaging techniques, particularly magnetic resonance imaging (MRI), made it possible to diagnose MCD in vivo and, several types of partial epilepsies previously defined as cryptogenetic are now recognized as secondary to cortical lesions. As a consequence correlations between imaging and electroclinical data have increased the number of patient that appear as candidates for surgical treatment. Neuronal migration disorders (NMDs) are generally considered a subgroup of MCD, and their definition may imply that disruption of migration is the only mechanism on which the malformation is based. However, not all the so-called NMDs have been shown to be due directly to impaired neuronal migration, and other mechanisms are therefore involved. The cortical malformations previously grouped under the general term of NMDs are currently diversified to reflect the improved knowledge of the pathological substrate, the possible aetiological factors and the relationship between altered structural features of the malformation and type of epilepsy.11–15

Lissencephaly Abnormalities related to cortical development may either affect proliferation and lead to abnormally sized and shaped neuronal and glial cells or be associated with aberrant neuronal migration, which results in abnormal neuronal positioning and compromized cortical architecture.12 Migration of virtually all cortical neurons is severely affected in lissencephaly. This alteration goes along with an abnormally smooth cerebral surface.16 Classic lissencephaly shows a prevalence of 11.7 per million births.17 However, the prevalence of milder forms of the disorder remains undetermined. Initially thought to be an extremely rare disorder going along with severe epilepsy, retardation and early death, MRI reveals individual patients to survive until adulthood. In normal brain development, the even, agyric cerebral surface, which is present until the 11th week of gestation, is replaced by gyral architectures developing from the area of the sylvian fissure during the following weeks. Gyration is physiologically terminated around the 32nd fetal week. The determination stage for pathological manifestation of a lissencephalic compromised brain development is between fetal weeks 11–13.18 Transitional forms between lissencephaly/agyria and

pachygyria occur. In pachygyria, the cortical architecture appears more advanced compared to agyria. Different genetic causes underly lissencephalic brain abnormalities, which can lead to substantial alterations with respect to the distribution of the pathological alterations as well as the aberrant cortical architecture. Linkage studies have particularly pointed towards alterations in two genes, i.e., doublecortin (DCX) on the X chromosome19 and LIS1 on chromosome 17.20–22 Mutations in DCX cause lissencephaly (XLIS) in hemizygous male individuals and subcortical band heterotopia (SBH) in heterozygous females.23,24 DCX is a microtubule-associated phosphoprotein maintaining cytoskeletal plasticity during axonal outgrowth, neuronal maturation and cell migration.25 Impaired DCX function in vitro results in interruption of microtubuli. Thereby, the cellular shape and cytoskeletal function as well as cell migration are compromised in vivo.19,26,27 The combination of high resolution MRI and genetics has recently shown that women with nonsydromical mental retardation, epilepsy and normal MRI may have DCX mutations. Women were identified due to male relatives with subcortical band heterotopia or lissencephaly. Therefore, DCX may be regarded as candidate gene for women with cryptogenic epilepsy and retardation in the absence of male relatives or a known relevant family history.28 Heterozygous deletions of the chromosomal region 17p13. containing LIS1 underlie extensive phenotypical alterations, summarized as Miller-Dieker syndrome, which comprises severe lissencephaly, craniofacial defects, substantial EEG abnormalities. The syndrome generally is associated with a reduced lifespan. Intragenic deletions or mutations of LIS1 cause isolated lissencephaly. LIS1 codes a subunit of the acetylhydroxylase and is expressed by Cajal-Retzius cells.29,30 Other genes located on chromosome 17p are likely to be involved in the phenotype of the Miller-Dieker syndrome. A recent study has identified at least one gene in this region that influences neuronal migration, YWHAE, which encodes a protein termed 14-3-3ε.31 It has been pointed out, that the pachy- or a-gyral alterations associated with LIS1 are pronounced in the posterior occipital area, whereas the structural abnormalities in XLIS are more pronounced in the anterior occipital brain.23 LIS1 is expressed and may have a structural role in the adult human brain. It is differentially activated by seizure activity in animal models.30 DCX is regarded to be expressed in the human brain only during development. For both genes, an immediate link between the mutational event and a causative, phenotypic effect has not been shown and does not appear very likely. Epileptic seizures may more probably occur due to complex functional changes resulting from disruption of the normal development of the cortex and white matter and an aberrant neuronal network architecture. Another form of lissencephaly with an autosomal-recessive transmission mode is caused by deletions in the reelin (RELN) gene.32 In the affected individuals, moderately severe pachygyria is associated with extensive cerebellar hypoplasia. In addition to seizures, severe hypotonia and developmental delay constitute clinical hallmarks of the syndrome. Type-II-lissencephaly is represented by alterations described as ‘pachygyric micropolygyria’.33 The cerebral surface appears agyric but not smooth. Histologically, abundant and confluent microgyri are present. In the cerebellum multiple cortical

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Pathology of malformations of cortical development heterotopias are present. Type-II-lissencephaly is frequently associated with oculocerebellomuscular anomalies including the Walker-Warburg-syndrome.34 or the Fukuyama-type congenital muscular dystrophy.35,36 Pathological hallmarks of the lissencephalic brain are absence (agyric) or decreased presence (pachygyric) of convolutions. In pachygyria, the gyri appear flat and smoth. The border between gray and white matter appears unsharp and the cortical organization is severly compromised. With respect to histopathological alterations, two types of lissencephaly are distinguished (Figure 143.1)37: type-I reveals a thick, only rarely differentiated cortex under a smooth, rather agyric cerebral surface. White matter appears rather thin. The cortical area is composed by four layers: ● ●

A marginal (molecular) layer An outer neuronal layer

●

●

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A cell-depleted layer with tangentially orientated myelinated fibres An inner neuronal layer.

This architecture is typically present in the Miller-Dieker syndrome. The neurons that are compromised in migration may form an additional cortical layer in the white matter, which may result in a double cortex. The type-II lissencephalic phenotype relates to pachygyric alterations, reduced gyration of the cerebral surface and increased width of gyri. The claustrum in most cases is absent. Additional alterations occur in the medulla-cerebellum area, where impaired neural migration in the cerebellar cortex as well as heterotopias of the nucleus olivaris may be present.18 At the conversion zone of the pachygyric to the normal cortical architecture, the outer neural layer shows a transition to the normal cortex. In contrast, the inner neural layer does not show

(a)

(b)

(c)

(d)

Figure 143.1 Neuropathological findings in lissencephaly. In lissencephaly, the gyri can be flat and smooth, an appearance termed pachygyria (white arrow), or absent, i.e., agyric (black arrow) (a, kindly provided by Volkmar Hans, MD, Bielefeld-Bethel, Germany). On the macroscopic section, a compromised cortical architecture becomes manifest in the agyric areas of the brain (b, kindly provided by Volkmar Hans, MD, Bielefeld-Bethel, Germany). On histological sections, the aberrant architecture of the lissencephalic cortex becomes visible, i.e., lack of cortical organization (gray asterisk) as well as pathological four-layer structure (black asterisk) (c, hematoxilin and eosin, ×100). The characteristic four-layer structure in lissencephaly can differentiated according to a marginal (molecular) layer (I), a outer neuronal layer (II), a cell-depleted layer with tangentially orientated myelinated fibres (III) and an inner neuronal layer (IV) (d, hematoxilin and eosin, ×400).

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continuity to the normal cortex. This histological finding may help to differentiate pachygyric alterations from polymicrogyria.

Polymicrogyria The presence of an excess number of abnormally small gyri that lead to an irregular cortical surface is described by the term polymicrogyria. The outermost cortical layer, i.e., molecular layer, commonly fuses, which results in the appearance of a rather smooth cortical surface. At least two general histological types are observed, the four-layered and the unlayered type. Clearly, a variety of intermediate neuropathological phenotypes exist. Polymicrogyria may be identified on MRI by excessive cortical gyration in the absence of significant cortical volume and an irregular border between gray and white matter.15 An important aspect of polymicrogyria is the regional distribution. The malformation may occur unilaterally as well as bilaterally. The manifestation of polymicrogyria at variable brain regions refers to a variety of specific subsyndromes.38–40 A subsyndrome with distinct clinico-pathological findings and familial recurrence is bilateral perisylvian polymicrogyria, in which the individuals suffer from parallel pseudobulbar palsy, spastic quadraparesis, learning disability and epilepsy.39,41 There is substantial variation with respect to the extent of polymicrogyria with a wide range of clinical manifestations, from severe encephalopathy with intractable epilepsy to only selective impairment of cognitive function.42 Various patterns of inheritance have been described for the different subtypes of polymicrogyria.41 No individual genes have been linked to any of the bilateral forms with isolated polymicrogyria, although a mutation in MECP2 was observed in a male patient with bilateral perisylvian disorder and severe neonatal encephalopathy.43 Further, various linkages to

(a)

distinct chromosomal regions have been reported.44,45 A recent hybrid genetic-MRI approach led to the identification of the homeobox gene PAX6 as a factor, in which mutations can result in unilateral polymicrogyria.46 As observed frequently for other types of cortical malformations, polymicrogyria may be part of multiple congenital anomaly syndromes.15 The mechanisms of epileptogenesis related to polymicrogyria are not entirely understood. An experimental model has been used, where a single or few microgyri are generated by a freezing insult. Recent data indicate a widespread region of functional impairment, which extends the visual-ized abnormality in the model.47,48 Also in patients with polymicrogyria, surrounding cortex appears be involved in epileptogenesis. Therefore, surgical resection of an area of polymicrogyria alone is rarely likely to substantially attenuate or abolish recurrent epileptic seizures.49,50 Polymicrogyria is, however, not inevitably associated with epilepsy, and it may present as developmental delay or congenital hemiparesis. In contrast to agyria or pachygyria, gyri are formed in polymicrogyria. However, gyri are atypically organized and lack the physiological laminar cytoarchitectural structure. Polymicrogyria is frequently observed in the vicinity of encephaloclastic lesions such as schizencephaly.51,52 Exogenic causes of polymicrogyria comprise infections including cytomegaly, toxoplasmosis, rubeola as well as impaired haemodynamic with predelection to the perfusion area of the middle cerebral artery. Histologically, polymicrogyric lesions show a variety of alterations. On the one side of the spectrum (type 1), unlayered polymicrogyria can be observed (Figure 143.2). The molecular layer is continuous and does not follow the convolution profiles. The neurons have a radial distribution and do not show a laminar organization.53 Microscopically, polymicrogyria (type 2) shows a laminar structure composed of four layers:

(b)

Figure 143.2 Neuropathological findings in polymicrogyria. Histopathologically, polymicrogyria comprises a spectrum of alterations. The molecular layer commonly fuses. Polymicrogyria (type 2) shows a laminary structure composed of four laminae, i.e., molecular layer, outer neuronal layer, nerve fiber layer, inner neuronal layer (a, NeuN, ×100). In polymicrogyria (type 1), the molecular layer is continuous and does not follow the convolution profiles. The neurons have a radial distribution and do not show a laminary organization (b, hematoxilin and eosin, ×400).

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Pathology of malformations of cortical development ● ● ● ●

Molecular layer Outer neuronal layer Nerve fiber layer Inner neuronal layer

Apparently, the third layer (nerve fiber) is a result of cellular necrosis and subsequent myelinisation. Occasionally, in the neuronal cell layers granular as well as pyramidal neurons can be observed resembling residuals of the normal six-layer cortical architecture. These two histopathological subtypes do not necessarily have a distinct origin, as both may coexist in contigiuous cortical regions.54,55 A main differential diagnosis of polymicrogyria and lissencephaly is given by ulegyria.56,57 Ulegyria has a prominent scar character with substantial fiber gliosis. Polymicrogyria and lissencephaly lack this extensive astrogliosis. In contrast to ulegyria, there is a dense network of tangentially orientated myelinated fibres in the subpial outer areas of the molecular layer in polymicrogyria.

Schizencephaly Porencephaly or schizencephaly constitute cystic cortical lesions, which result in open connections between the lateral ventricles and the subarachnoidal space. Schizencephaly is currently grouped with polymicrogyria among the malformations of cortical development (MCD; group IIIA 1,2).15 Schizencephaly represents a lesion presenting with a transcortical cleft, open or closed (with unapposed or apposed cortical lips, respectively), lined by cortex. Schizencephaly may be further related to regional absence of proliferating neurons and glia or to abnormal cortical organization. Local failure of induction of neuronal migration or focal ischemic necrosis with destruction of the radial glial fibers during early gestation has been hypothesized.55 Recent studies have pointed to molecular alterations in schizencephaly, suggesting germ line mutations in the EMX2 homeobox gene in approximately 70% of the cases.58–60 With respect to the areas affected, there is a predelection for the central region as well as areas perfused by the middle cerebral artery. Hypoxic damage manifests during fetal development until the end of cortical maturation. There is combination of schizencephaly with polymicrogyria53 (type 1) as well as co-occurrence of schizencephly with radial orientation of the gyri in the vicinity to the cortical defect (type 2).54,61,62 Frequently, schizencephaly occurs bilaterally. However, substantial pathological alterations including the morphological manifestation in form of a porus, is often present only unilaterally. In such cases, abnormal gyration may be observed on the side contralateral to the porus. In some cases the inner glioependymal surface may extend to the external cortical surface, which can appear as a membranous, pale cover. Clefts may be associated with a range of other malformations of, for example, the septum, optic nerve, callosum or hippocampus.63 Surgical therapy of refractory epilepsy due to schizencephaly has been reported, but is rarely considered in the most number of cases.49 In congenital porencephaly, there is a parallel amygdalahippocampus-atrophy in a high number of cases. With respect to the differential diagnosis of schizencephaly, cystic necroses that are due to inappropriate perfusion at peri- and postnatal stages have to be differentiated. Frequently, these cystic lesions

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do not exhibit a communication between the inner and outer liquor spaces.

Hemimegalencephaly Hemimegalencephaly (HME) is a rare, complex brain malformation characterized by enlargement of one hemisphere. In the past it has been included into one of the three major forms of megalencephaly64,65 and considered as a consequence of aberrant neuronal migration. Although its etiology remains unknown recent molecular genetic studies, imaging and neuropathological data have provided insights in the pathogenesis of this malformation which is actually considered either an early, genetically programmed developmental disorder related to cellular lineage and establishment of symmetry66 or a primary disorder of proliferation.67 Barkovich et al.15 include HME among the non-neoplastic malformations due to abnormal neuronal and glial proliferation; two major subgroups are identified: the isolated forms and those associated with neurocutaneous disorders. Sarnat and Flores-Sarnat68 differentiate, on the basis of morphological and molecular genetic criteria, three main subgroups partially overlapping the Barkovich classification:15 isolated HME, syndromic HME (associated with other diseases mainly neurocutaneous syndromes) and total HME characterized by associated enlargement of the ipsilateral half of the brain stem and cerebellum. Being a rare congenital malformation, despite many cases or small series reports, reviews of large cohort of patients is rare in English literature. Tinkle et al.69 in a retrospective study of 15 patients of identified HME reported 53% of nonsyndromic cases and 47% associated with known or suspected syndrome. In a nationwide survey of 44 patients Sasaki et al.70 reported that 36% of the patients had underlying disorders. In their cohort the right hemisphere was mainly affected (66%) with male predominance and no familial cases. Neurological symptoms are similar in the syndromic and isolated forms66,70 and characterized by epilepsy, contralateral hemiparesis and psychomotor retardation. Severe epilepsy, often refractory to medical treatment and thus suitable for surgical treatment, is occurring in the vast majority of patients.71 Imaging studies are fundamentals for the in vivo study of HME although no substantial differences are present between isolated and syndromic forms. In addition to the evident asymmetry of hemispheres, unilateral thick cortex with broad, flat gyri associated with pachygyria or micropoligyria are evident in the affected hemisphere. Schizencephaly, asymmetry of corpus callosum, heterotopia in white matter can also be observed. White matter abnormalities with loss of gray-white matter differentiation are also present.66,70,72,73 Few autoptic cases are reported and the majority of neuropathological studies derive from specimens obtained from multilobar resections or hemispherectomies (Figure 143.3) performed for epilepsy treatment.73–77 The neuropathological features, like clinical, EEG and MRI aspects, do not allow a differentiation between syndromic and isolated cases and strictly overlaps the gross anatomical abnormalities depicted by imaging studies. Gross specimen inspection shows areas with sulci and gyri of variable configuration (Figure 143.3); thickened gray matter as well as white matter larger than normal volume with blurring of gray-white matter are constantly found.

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Figure 143.3 Hemimegalencephaly as appears before surgical hemispherotomy; note the broad and irregular gyri. (kindly provided by Prof. G. Broggi).

The lateral ventricle of the enlarged hemisphere is frequently straightened and corpus callosum is frequently asymmetric and thin. At histopathological level a wide spectrum of morphological alterations with combination of different aspects of malformations of cortical development (pachygyria, polymicrogyria and cortical dysplasia with heterotopic neurons in the white matter) can be observed. Dysplastic cortical areas are characterized by cortical dyslamination with columnar arrangement. Large and small neurons are mixed randomly with many disoriented cells. Neuronal cytomegaly with enlarged axons is usually observed so that morphometric analysis demonstrates a significant increase, over controls, in neuronal profile area.75 The co-occurrence of balloon cells associated with giant dysmorphic neurons are similar to the histopathological findings observed in Taylor’s type focal cortical dysplasia (Type IIB in the classification by Palmini et al.).12 Astrocyte proliferation, demonstrated by GFAP immunostaining, is present in both gray and white matter. In some cases dysmielinization is also present in the white matter as suggested by MRI findings. Some ultrastructural data are available but no vascular abnormalities, metabolic storage material or mitochondrial alteration have been observed.75,77 Some neurons in HME are expressing markers of cellular immaturity such nestin, MAP1B and vimentin suggesting a defect of cell differentiation or proliferation. Thus its is likely that this developmental malformation may results from somatic gene mutation affecting progenitor cells in one hemisphere during brain development. Recently Crino and coworkers have addressed the molecular pathogenesis of HME.78,79 by assaying, in eight patients, the expression of 200 cell signalling, growth, angiogenic and transcriptional factor genes with targeted cDNA arrays. The authors found altered expression of 31 mRNAs from four gene families that may lead to aberrant cell growth and hemispheric enlargement in HME.

Heterotopia The term heterotopia comprises malformations of cortical development characterized by the presence of apparently

normal neurons in abnormal position and in general in the subcortical hemispheric white matter. Three main categories are recognized: individual misplaced neurons in the white matter (neuronal heterotopia), nodules of gray matter within the white matter (nodular heterotopia) and band heterotopia (double cortex). In the original classification by Jacob80 neuronal heterotopia was not considered and only subependymal nodular and band (laminar) forms were included. In the recent classification by Barkovich et al.15 conditions of abundant neurons in the white matter are considered as being due to abnormal neuronal migration. However, classification issues of neuronal heterotopia are still matter of intense debate and authors indicate that the presence of exceeding neurons in the white matter (frequently associated with different forms of MCD) can be ascertained only after accurate morphometric analysis of surgical specimens.81,82 In this chapter we will focused on the neuropathological aspects of nodular and band heterotopia. Periventricular nodular heterotopia (PNH) The incidence of PNH in the general population and in patients with epilepsy is unknown. In a large cohort of 132 epileptic patients with different forms of cortical dysgenesis at the Montreal Neurological Institute, 15% had PNH while Raymond et al.13 reported that 20% of the cases with MCD presented PNH. At the C. Munari Epilepsy Surgery Centre approximately 7% of the patients operated on for intractable epilepsy presented PNH. Only a few autoptic cases are reported however, recent high-resolution imaging techniques allow a precise definition of the macroscopic morphology and extent of nodular heterotopia. Surgical specimens were rare since it was generally considered that epileptic patients with PNH did not respond to surgical treatment; however recent reports suggest that in patients with unilateral heterotopia, surgery can be highly beneficial when epileptogenic zone is carefully identified by refined electroclinical presurgical assessments including invasive recordings.83,84 The increasing data from genetic studies and MRI (Figure 143.4a) as well as the availability of surgical specimens are determining a continuous refinement of the sub classification system for PNH. Barkovich et al.15 subdivided the PNH into subependymal and subcortical groups. Tassi et al.83 on the basis of their surgical and neuropathological experience proposed a three subgroups: unilateral, bilateral symmetric and bilateral asymmetric. Battaglia et al.85 further refined the classification recognizing two main groups: the bilateral and unilateral. Three subgroups have been distinguished in the bilateral form and two in the unilateral. In familial bilateral PNH an X-linked dominant inheritage has been established also characterized by a high incidence of spontaneous miscarriage in male foetuses; linkage analysis mapped this disorder to Xq28. Sporadic cases of bilateral PNH both in female and male have also been described. Nodular heterotopia may also been observed in other conditions for with multiple causative genes and environmental aetiologies are suggested.86 As noted before, neuropathological studies on tissue from epileptic patients with nodular heterotopia are rare and an autoptic study of a patient with genetically proven FLN1 mutation has been recently published.87 In all cases the nodules consist of masses of neurons, without laminar organization, with well defined boundaries, surrounded by white matter

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(a)

(c)

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(d)

Figure 143.4 Periventricular nodular heterotopia. a. MRI showing large asymmetrical nodular heterotopia. b. Luxol Fast Blue stained section from specimen obtained after surgical resection. Note the large number of irregular nodules one of which (boxed area) can be observed at higher magnification in c. and showing aggregates of neurons with different size and morphology surrounded by white matter fibres. Some fibers penetrate within the nodule (d).

fibres some of which infiltrate the nodules (Figures 143.4b–d). Within the nodules aggregate of small pyramidal neurons, with some immature features and with haphazardly oriented dendrites, appear intermingled with neurons positive for calcium binding proteins suggesting the presence of different subpopulations of GABAergic interneurons.83,87,88 Taken together these data suggest that the final structure of nodules seems to be independent from their etiology and unrelated to whether the heterotopia is unilateral or bilateral, subependymal or subcortical.

With regard to the neocortex overlying the nodular heterotopia, although MRI frequently suggests polymicrogyria, recent neuropathological data reported abnormal gyration but without histological abnormalities consistent with the typical four-layered or unlayered polymicrogyria.83 In most, although not in all, of the reported neuropathological studies various degrees of cortical dysplasia are described with reduced expression of calcium binding proteins suggesting an impairment of GABAergic system. In other cases a normally layered cortex can be found although cortical disruption can

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be noted in areas where nodules impinge on the cortex. In cases when nodular heterotopia involve the temporal lobe hippocampal sclerosis can also be present.13,89 Band heterotopia This malformation is classified by Barkovich et al.15 among those due to abnormal neuronal migration and included in the subgroup called lissencephalies/subcortical band heterotopia spectrum. However from the neuropathological aspect laminar heterotopia, also defined as band heterotopia or double cortex, is frequently included within the broad group of ‘heterotopia’. The genetic aspects of this malformation has been reviewed in the ‘lissencephalies’ paragraph. Being a diffuse cortical malformation, frequently genetically determined, only few neuropathological reports are available mainly on sporadic autoptic cases.65 Although laminar heterotopia can be associated to intractable epilepsy, focal surgical resections have been reported to yield inadequate results.90 However case reports on surgically treated patients with satisfactory postsurgical outcome have been published.91,92 Despite the reduced number of neuropathological specimens an increasing number of evidences and careful anatomical descriptions are available thanks to the high resolution imaging also providing genotype/phenotype correlations of this malformation.50,51,93 The gross anatomical aspect observed on both MRI and neuropathological specimens is characterized by a continuous bilateral, roughly symmetrical, band of gray matter located between the cortical mantle and the ventricles. The thickness of the band varies among patients and seems to be correlated with the degree of associated mental retardation. The outer cortex may be normal although a slight reduction in number of gyri and pachygyria can be observed. The histological aspect of the cortex is generally normal with a regular six layers (Figures 143.5a and b) and normal distribution of neuronal elements with no cytological alterations.91,94 Beneath the outer cortex a zone of white matter of variable thickness is present containing abundant heterotopic neurons frequently arranged in columns (Figure 143.5b). The heterotopic band consists of unlayered small and medium sized rounded or pyramidal neurons (Figure 143.5b). Although macroscopical (as also observed at MRI) the heterotopic band appears as a continuous aggregate of neurons. At microscopic level it appears discontinuous and interrupted

(a)

(b)

Figure 143.5 Laminar (band) heterotopia. Low power photomicrographs showing two adjacent sections from specimen obtained after surgical resection. a. Nisll stained section showing a regularly layered outer cortex and the heterotopic unlayered bend. In the white matter between the two cortices aggregates of heterotopic neurons arranged in columns are evident b. with NeuN immunostaining. (modified by Mai et al. Neurology 2003;60:1834–8).

by radially oriented fibers. Within the white matter and in the heterotopic band the pyramidal neurons appear haphazardly oriented and nonpyramidal neurons express different calcium binding proteins suggesting the presence of different subpopulations of GABAergic interneurons.


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Pathology of neurocutaneous abnormalities, vascular abnormalities: post-infectious and post-traumatic pathologies associated with epilepsy I Blümcke and M Hildebrandt

Introduction With recent advances in high-resolution brain imaging, focal lesions became increasingly detectable in patients suffering from chronic, intractable epilepsies. Tailored resection strategies emerged as a beneficial therapeutic option in many of these patients. Increasing access to lesional brain tissue allows systematic neuropathological investigation as well as molecularbiological and genetic studies. This comprehensive approach will further improve our understanding of specific pathomechanisms as well as enhanced seizure susceptibility of focal lesions. In this chapter, the spectrum of neoplasms and malformations associated with neurocutaneous syndromes as well as epilepsy-associated vascular, post-infectious or posttraumatic lesions will be discussed. Genetically determined neurocutaneous syndromes are particularly challenging. Often, multiple lesions are identified, i.e., cortical tubera, subependymal nodules, or subependymal giant cell astrocytomas in patients suffering from tuberous sclerosis complex (TSC). Sturge-Weber syndrome, another phakomatosis frequently associated with focal epilepsies, manifest with proliferation of leptomeningeal veins (meningoangiomatosis) of the subarachnoidal space and/or superficial neocortex. Progress in molecular-genetic analysis highlighted compromized developmental signaling pathways as underlying pathogenic mechanism whereas enhanced seizure susceptibility appears to result from axonal and molecular reorganization of adjacent brain tissue. Besides genetically determined pathology, posttraumatic and post-infectious lesions are other frequent findings in focal epilepsies. Astroglial cell populations transform into scarring tissue and altered molecular expression patterns, i.e., glutamate transporter versus receptors or other molecules associated with ion homeostasis may contribute to the generation of spontaneous seizure activity. In addition, axonal reorganization in brain tissue adjacent to a specific lesion as well as immunogenic mechanisms tackling affected neurons appear to play a major role. During postnatal development, progressive cortical dysplasia in the vicinity of affected brain regions also contribute to enhanced epileptogenesis. Vascular malformations will also be covered in this chapter.

Cavernomas, arterio-venous malformations as well as rare hamartomatous lesions with a prominent vascular component can be histologically identified as underlying morphological substrate, whereas molecular pathomechanisms and enhanced epileptogenicity remain to be determined.

Neurocutaneous syndromes Two distinct neurocutaneous syndromes typically associate with severe seizures, i.e., tuberous sclerosis complex (TSC) and Sturge-Weber syndrome (SWS). TSC manifests clinically with a triad of seizures, mental retardation, and facial angiofibroma (adenoma sebaceum).1 However, presence of hamartomatous lesions in the brain, i.e., multiple cortical tubera, periventricular nodules, and subependymal giant cell astrocytomas (SEGA) or other organs, e.g., periungual angiofibromas, retinal tumors, angiolipomas in the kidneys or rhabdomyoma in the heart as well as dermal depigmentation (‘white spots’ as identified during Wood-light inspection) are hallmarks of the clinical diagnosis.2 Sturge-Weber syndrome usually presents with facial ‘port wine haemangioma’ (flame naevus) associated with the ophthalmic division of the trigeminal nerve, ipsilateral leptangiomatosis and glaucoma. Typical clinical manifestations are intractable seizures, stroke-like episodes, headaches, cognitive impairment, hemiparesis, and homonymus hemianopsia. Often mental retardation occurs. Other frequent findings include glaucoma, which affects nearly half of these patients. Brain manifestation usually shows unilateral venous angiomas, preferential within the occipital and parietal lobes. However, all lobes could be affected, occasionally both hemispheres are involved. Macroscopic and microscopic findings in tuberous sclerosis complex (TSC) Brain manifestations of TSC include cortical tubera, presenting as round hyperdense lesions in cortical gyri.3 They occur 1359

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multifocal, are firm to palpation and extend into the white matter. The most characteristic feature of cortical tubera is the presence of giant cells (Figure 144.1). They are five to ten times larger than cortical pyramidal cells, present with an opaque cytoplasm and are often multinucleated. Distinct features

of neuronal and/or astrocytic differentiation can only rarely be identified.4 However, some giant cells express immunohistochemically either neuronal or glial antigens, occasionally coexpression occurs. More importantly, expression of immature markers can be observed in the majority of surgical

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Figure 144.1 A cortical tuber (indexed by asterisk in a) was identified in this epilepsy patient suffering from tuberous sclerosis (serial sections in a = HE, c = Vimentin and e = Neurofilament; 12.5×, scale bar = 1000 µm). Higher magnification in b (HE), d (Vimentin) and F (Neurofilament) demonstrated a biphasic composition with dysplastic neurons (arrows in b and f) and opaque giant cells (arrowhead in b; scale bar = 50 µm) immunoreactive for vimentin (d).

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Pathology of neurocutaneous, vascular abnormalities: post-infectious and post-traumatic pathologies specimens, including vimentin, nestin or the stem cell epitope CD34, which is compatible with an arrested differentiation of compromized progenitor cells.4,5 Although the surrounding non-affected neocortex demonstrates usually with a normal cytoarchitecture, calcifications, either within or adjacent to the lesion, are frequently encountered in TSC patients. Other typical features occurring in TSC are periventricular nodules, well-circumscribed masses containing giant cells as described above and subependymal giant cell astrocytomas (SEGA; Figure 144.2). The latter occur in 6–16% of patients with TSC and can occur at various localizations. SEGA is a benign, slowly growing tumor typically arising in the wall of the lateral ventricles corresponding to WHO Grade I. Histopathologically SEGA presents as a well circumscribed, often calcified tumor, mainly composed of large, plump cells resembling astrocytes. Perivascular pseudopalisading (Figure 144.2B) and clustering of tumor cells are common features. Cellular pleomorphism and occasional mitosis are common and do not indicate a malignant behavior. Anaplastic tumor progression has never been reported in TSC patients, although exophytic growth may reach extensive

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masses associated with severe clinical symptoms.6 Recent microarray analysis identified similar expression profiles between cortical tubers, SEGA and conditional Tsc1 knockout mice, indicating pathogenic origin from related defects in progenitor cell differentiation during brain development.7 Molecular-genetic findings and enhanced epileptogenesis TSC is a autosomal dominant inherited genetic disorder with a prevalence of approx. 9/100 000.8 Despite its high penetrance considerable phenotypic variability can be observed, even within affected family members. The mechanisms remain, however, to be specified. Sixty percent of patients suffer from spontaneous de novo mutations. Two genetic loci are characterized. TSC1 is mapped on 9.q34, includes 23 exons, and encodes for the protein hamartin, which is strongly expressed in brain, heart, and kidney.9 The transcript contains 8.6 kb. Hamartin consists of 1164 amino acids and has a molecular weight of 130 kDa. It inhibits tumor formation possibly by regulating cellular adhesion through ezrin-radixin-moiesin family proteins and the small GTP-binding protein Rho.10

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Figure 144.2 Subependymal giant cell astrocytoma (SEGA) in a patient with tuberous sclerosis. Tumor cells formed perivascular pseudopalisading (arrows, HE, scale bar = 1000 µm). Microcalcification can be frequently encountered (arrow in b, HE). Higher magnification characterize pleomorphic and multinucleated eosinophilic tumor cells (c and d, scale bar = 20 µm), frequently expressing vimentin (e) or neuronal marker proteins (arrowheads in f Microtubule associated protein MAP2).

(Continued)

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(e)

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Figure 144.2—cont’d

The immunohistochemical pattern overlaps with tuberin, the gene product of TSC2, which is mapped to chromosomal region 16p13.3 and includes 41 exons.11 The transcript contains 5.5 kb. Alternative splice variations are common. Tuberin contains 1807 amino acids with a molecular weight of 180 kDa. It bears significant homology with the catalytic domain of the GTPase-activating protein Rap1-GAP, a member of the ras family. It regulates cell cycle by inhibiting the G1/S transition and promoting entry to the G0 phase.12 A two-hit model is assumed for the clinical manifestation of TSC. Inactivating germline mutations of TSC1 or TSC2 is followed by a later somatic mutation in hamartomatous cells, explaining the clinical variability in an autosomal dominant inheritance. Loss of second TSC1- or TSC2-allels, i.e., loss of heterozygosity (LOH) leads to a homozygote negative state. LOH of TSC1 or TSC2 also occurs in sporadic tumors, e.g., carcinomas of mamma or bladder. Therefore both genes are likely to represent tumor suppressor genes. The recent finding that the TSC1/TSC2 complex is involved in the insulin growth factor receptor signaling pathway13 is compatible with variable histomorphological phenotypes including defects in proliferation (SEGA), differentiation (occurrence of giant cells) and migration (missing lamination and heterotopic immature cells in the white matter). The Eker rat with hereditary kidney cancer presents with germline mutations of the TSC2 homologue and functions as an animal model of human TSC. In Eker rat brains, lesions occur as cortical tubers, subcortical hamartomas, subependymal hamartomas, and anaplastic gangliogliomas.14 Even though anaplastic gangliogliomas are not part of human TSC, the animal model demonstrates the similarity of glioneuronal lesions suggesting a comparable origin. Furthermore, TSC in humans shares histopathological features of glioneuronal tumors, especially gangliogliomas and dysembryoplastic neuroepithelial tumors (DNT) and tuberous form of focal cortical dysplasia (FCD) type IIb providing the hypothesis of a common origin.15 The epileptogenicity of TSC associated brain lesions have been addressed in various clinical and molecular studies. Cortical localization, disrupted lamination, cytoarchitectural disturbances and possible altered synaptic connectivity of dysplastic neurons may account for intrinsic

epileptogenicity of tubers, whereas giant cells are likely to be physiologically inert (Cepeda et al., 2003).16 Sturge-Weber syndrome (SWS; macroscopic and microscopic findings) Imaging and gross examination reveals widespread, usually unilateral leptomeningeal angiomatosis, cortical calcifications in a ‘railroad track’ pattern and less frequently atrophy of the underlying neocortex (Figure 144.3). White matter abnormalities are common and may be linked to chronic ischemia and reactive gliosis. Angiography demonstrates an overall lack of superficial cortical veins, non-filling of the dural sinuses and tortuous course of veins towards the vein of Galen.17 Functional brain imaging has demonstrated decreased glucose metabolism and hypoperfusion of the affected neocortex.18 Focal epilepsies are frequent clinical symptoms observed in almost 80% of SWS patients.19 Microscopically, leptomeningeal angioma in SWS presents with large tortuous and abnormal venous structures in thickened leptomeninges (Figure 144.3). The underlying brain tissue may be atrophic and displays neuronal loss, reactive astrogliosis, and microcalcifications. Laminar cortical necrosis may occur, suggesting ischemic damage secondary to venous stasis in leptomeninges and cerebral vessels. The underlying cortical vessels are increased in number, typically thin-walled and narrowed by hyalinization and subendothelial proliferation. Repeated stroke-like episodes and thrombosis may result in disease progression and neurological deterioration. Molecular findings and enhanced epileptogenesis in Sturge-Weber syndrome SWS occurs sporadically with a frequency of approximately 1/50 000. Inheritance is so far not established. Non-Mendelian genetic hypotheses, including chromosomal instability have been suggested. Spontaneous somatic mutations in a common progenitor cell line of dermal, neuronal and ocular tissue in the first trimester of development may lead to genetic mosaicism of the affected areas.20 A case report about one of two monozygotic twins presenting with SWS supports this hypothesis.21

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Figure 144.3 Leptomeningeal angiomatosis in a Sturge-Weber patient presenting with focal seizures (a HE, b Elastica van Gieson; 12.5×, scale bar in a = 1000 µm, applies also to b and d). The underlying neocortex demonstrates cortical atrophy with microcalcifications (arrows in c; HE 40×, scale bar = 200 µm) and reactive astrogliosis (d; GFAP).

Another possibility refers to a two-hit model combining hereditary and spontaneous factors. Excessive vascular proliferation of the angioma diverts blood flow from parenchyma and creates an anoxic environment in the surrounding brain, leading to cellular damage. As a result, the underlying cortex becomes atrophied, calcified, and eventually dysfunctional,22 leading to seizures. The endothelial basal lamina contains an extracellular matrix composed of glycoproteins and proteoglycans including laminin, fibronectin, and tenascin. Fibronectin has been identified as a key regulator in angiogenesis and vasculogenesis and plays a crucial role in brain tissue response to ischemia and maybe to seizures.23 Increased fibronectin gene expression levels were indeed observed in fibroblasts obtained from port-wine hemangiomas compared to normal skin samples. Moreover, there was a trend towards increased fibronectin protein expression in SWS brain samples compared to postmortem controls. Therefore, fibronectin is supposed to be a likely candidate for SWS. Furthermore, analysis of families with hereditary port-wine stain identified RAS1 mutation on chromosome 5q.24 The RAS1 gene product is p120-RasGAP, a negative regulator of the Ras-mitogen-activated protein kinase signaling pathway.

It may also be a candidate for involvement in vascular abnormalities of SWS.

Vascular malformations associated with focal epilepsies Vascular malformations are classified with regard to caliber and configuration of the blood vessels, their continuity with the normal cerebral vasculature and the amount of intervening brain parenchyma. They are assumed to represent congenital lesions as a result of disturbed mesodermal differentiation between the third and eighth week of gestation. Vascular malformations may be part of a distinct syndrome but also occur in combination. Cavernomas Cavernous hemangiomas (cavernomas) occur within the brain parenchyma or the leptomeninges. MRI usually reveals a well circumscribed superficial lesion with surrounding hemosiderine deposit. The lumen is occasionally occluded; therefore they

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did not fill on angiography. Histologically, they are composed of closely apposed dilated vascular channels without intervening brain parenchyma (Figure 144.4). Elastica van Gieson (EvG) staining discovers thin blood vessel walls, containing endothelium and a collageneous adventitia. Calcification or even ossification can be microscopically detected. A peripheral rim of hemosiderin-storing macrophages may be identified in the surrounding tissue. Molecular findings and enhanced epileptogenesis associated with cerebral cavernous malformations (CCM) The prevalence of cavernomas is 0.02 up to 0.5%. Approximately 4–6% of pharmacoresistant epilepsies are caused by cerebral cavernous malformations (Table 144.1). There is no evidence that space occupying mass effect leads to epileptogesis. Rather repeated microhemorrhages and hemosiderin deposits in the surrounding cortical tissue may cause hyperexcitability by iron ions, providing free radicals and lipid peroxides. Furthermore, reactive glial proliferation may be epileptogenic. In some cases, dual pathology with Ammon’s horn sclerosis occurs.25

Cerebral cavernous malformations (CCM) can occur in a sporadic form as well as a familial form. Familial CCM are inherited in the autosomal dominant mode, and three genes have been localized to chromosome 7q11.2-21 (CCM1), 7p15-13 (CCM2) and 3q25.2-27 (CCM3).26 KRIT1 (Krev interaction trapped 1) is likely to represent the disease causing gene in CCM1.27 Approximately 40% of families with cerebral cavernous malformations carry KRIT1-mutations. KRIT1 encodes a protein with a four ankyrin repeat domain at the N-terminus and C-terminal domain for interaction with Krev-1 (Rap1a, ras-related protein 1A). Most KRIT1 mutations are loss of function mutations leading to increased interaction between ICAP1α and β1 integrin, which influences integrin β1-dependent cell adhesion, migration and angiogenesis. Mutation of CCM2 gene occurs in 20% of patients with familial CCM. It contains a phosphotyrosine-binding domain (PTB), but its function is unknown.28,29 Approximately 40% of CCM families are linked to the CCM3 locus, so-called PDCD10 (programmed cell death 10). Its role in vascular morphogenesis remains to be investigated.30

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Figure 144.4 A cavernoma showing thin-walled vessels without intervening brain parenchyma is depicted in a (HE, scale bar = 200 µm, applies also to b, d). b: Elastica van Gieson staining (EvG) of a serial section to a; c: EvG staining at higher magnification fail to show regular lamination of vessel walls; scale bar = 100 µm. d: Hemosiderin storing macrophages are recognized using Berliner-blue reaction.

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Table 144.1 Summary of 2386 epilepsy associated focal lesions (German neuropathological data base for epilepsy surgery) DIAGNOSIS

NUMBER

AGE

DURATION

MTS

AHS DUAL

902 137

33,9 22,8

22,8 12,6

TUMORS

GG DNT ASTRO OLIGO PXA SEGA

423 129 112 36 22 14

25 26,9 32,4 36,6 30,7 19,3

13,6 12,9 13,1 11,1 17 14

MALFORMATIONS

FCD Type II HETEROTOPIA FCD Type I HAMARTOMA PMG HEMI

160 50 37 30 24 7

17,3 29,2 12,4 23,7 6,4 1,7

13,1 17,6 8,6 16,9 2,9 1,7

VASCULAR

CAVERNOMA

161

36,8

13

TRAUMA

SCAR/PORUS

98

25,9

15,8

ENCEPHALITIS

VARIOUS RASMUSSEN

29 15

24,9 11,6

10,3 3,4

NUMBER of patients included in the neuropathological database; AGE at operation (years); DURATION of epilepsy (years); MTS: mesial temporal lobe sclerosis; AHS: Ammon’s horn sclerosis; DUAL: dual pathology presenting with AHS and another distinct histomorphological lesion (i.e., tumor, vascular lesion); GG: ganglioglioma (WHO grade I–III); DNT: dysembryoplastic neuroepithelial tumor (WHO grade I); ASTRO: astrocytoma (WHO grade I–III); OLIGO: oligodendroglioma or mixed glioma (WHO grade II–III); PXA: pleomorphic xanthoastrocytoma (WHO grade II); SEGA: subependymal giant cell astrocytoma (WHO grade I); FCD: focal cortical dysplasia (Type I or Type II according to Palmini et al., 2004); HETEROTOPIA: ectopic neurons in white matter (single or neuropil islands) or nodular heterotopias; HAMARTOMA: glio-neuronal hamartomas or hamartias; PMG: Polymicrogyria; HEMI: Hemimegalencephaly; ENCEPHALITIS, VARIOUS: summary of lesions associated with bacterial, viral or parasitic infections.

Arterio-venous malformation (AVM) AVMs may occur in all parts of the CNS but most commonly in the territory of the middle cerebral artery. AVMs range in size from grossly invisible to those which involve a large part of the entire hemisphere. They may enlarge over time by recruitment of contiguous blood vessels. MRI shows vascular lesions with abnormal vessels and surrounding hemosiderine deposits. Angiography reveals arteriovenous shunting. Histological examination discovers vessels of irregular size, shape, and degree of muscularization. Besides venous appearing vessels with thin amuscular walls, arteries with intact media and lamina elastica could be observed (Figure 144.5). Arterio-venous shunts with disruption of arterial vessel wall architecture are visible using Elasticavan-Gieson staining. Interposed brain parenchyma is usually gliotic and frequently contains hemosiderin storing macrophages after recurrent bleedings. Remnants of preoperative embolisation may be incorporated into vessels. Molecular findings and enhanced epileptogenesis associated with arteriovenous malformation (AVM) AVMs arise congenital during embryogenesis and account for 70% of all cerebral vascular malformations in children. Immature developing veins and arteries contact with each other before development of capillaries. Lack of development of a capillary bed leads arterio-venous shunts and consecutive

dilatation of the receptive venous system. AVM become symptomatic at any age but most commonly present in the second to forth decade with recurrent subarachnoidal bleeding. Seizures may be related to brain ischemia caused by ‘stealing’ of blood from surrounding brain parenchyma into the malformation.31,32 As well as in cavernomas iron deposits after bleeding or reactive gliosis could also cause seizures. AVMs seem to be sporadic lesions, and familial intracranial AVMs are rare.33 However, recent studies identified possible candidate genes related to angiogenesis. Microarray analysis revealed increased mRNA of vascular endothelial growth factor A (VEGF A) and its protein product as well as increased expression of integrin αvβ3 protein, leading to a possible role of integrins in AVMs.34 An earlier study demonstrated a markedly decreased Tie-2 and also VEGF-R2 expression in AVM vessels, which may contribute to the pathogenesis of AVMs. Some arteriovenous malformations (AVMs) are associated with hereditary hemorrhagic telangiectasia type 1. Endoglin, the gene mutated in this disorder, is expressed at reduced levels on blood vessels of these patients. Endoglin is a component of the transforming growth factor-beta receptor complex critical for vascular development and homeostasis. Even though it seems not to be involved in the generation of AVMs, the presence of endoglin on fibroblasts in the perivascular stroma suggests an active role for this protein in vascular remodeling in response to increased blood flow and shear stress.35

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Figure 144.5 a: Arterio-venous malformation with vessels of irregular size (HE, scale bar = 1 mm, refers also to b). b: Occurrence of preoperative embolisation (EvG). c: Arterio-venous shunt vessel (EvG, scale bar = 500 µm, refers also to d). d: Hemosiderin saving macrophages, Berliner-blue reaction.

Capillary teleangiectasia Capillary teleangiectasias are often an incidental finding during brain autopsy and cannot be detected by imaging unless the lesions are confluent or hemorrhagic. They are composed of dilated blood vessels separated by relatively normal brain parenchyma, which often shows reactive astrogliosis (Figure 144.6). Molecular findings and enhanced epileptogenesis associated with capillary teleangiectasia Capillary teleangiectasia have a high prevalence and are usually asymptomatic. Beeding is rare. If capillary teleangiectasias occur in distinct brain regions, e.g., within the hippocampus, or in association with other vascular malformations, seizures may occur. However, hereditary hemorrhagic teleangiectasias (HHT), an autosomal dominant vascular malformation of skin, mucosa and viscera can also manifest in brain vessels. Three gene loci are known: HHT1 on chromosome 9q34.1, HHT2 on chromosome 12q11-14 and HHT3 on chromosome 5q31.5-32.26 HHT1 is caused by mutations in endoglin which encodes a TGFβ binding protein expressed predominantly in

endothelial cells and lays an important role in vascular remodeling and the maintenance of vessel wall integrity.36 HHT2 results from mutations in the ALK1 gene which encodes a type1 serine-threonine kinase receptor in endothelial cells. Alk1 binds to TGFβ1 and activin-A, and signal through phosphorylation of SMAD1 and SMAD5.37 A third genetic locus, HHT3 was recently identified in a family without linkage to endoglin, ALK1 or SMAD4 on chromosome 5. However, the specific gene of HHT3 has not been identified yet.38 There exists also an association with juvenile polyposis (JP), caused by mutations in the MADH4 gene on chromosome 18q21.1 which encodes SMAD4. SMAD4 is an integral downstream effector on the TGFβ signal transduction pathway.

Inflammatory lesions Bacterial infections The risk to develop epilepsy after cerebral infection is likely to dependent on the type of infection rather than on age. No obvious increase in risk to develop epilepsy is seen after

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Figure 144.6 a: Ectatic vessels within the hippocampal hilus are identified in this epilepsy patient, the arrows indicate the dentate gyrus, frozen section (HE, scale bar = 500 µm). b: Ectatic vessels in the same specimen following paraffin embedding (HE, scale bar = 200 µm), c: Elastica van Gieson (EVG). d: Gliotic intervening brain parenchyma (GFAP), scale bar =100 µm, refers also to c).

aseptic meningitis. However, likelihood is fivefold increased in patients with bacterial meningitis. The highest risk comes along with viral encephalitis, especially if viral encephalitis is associated with early seizures. Brain abscess Brain abscesses may occur per continuitatem from neighboring foci in the paranasal sinus, middle ear or mastoid sinus or via hematogenous dissemination in the context of sepsis. The latter is advantaged by congenital heart disease with septal defect. Most common organisms are Staphylococcus aureus, hemolytic streptococci, Streptococcus viridans, and various aerobic gram negative rods. MRI usually reveals a round lesion presenting with a thin capsule and a circumscribed contrast enhancing ring. Due to collagen the abscess capsule is characteristically dark on T2weighted MRI scans. A broad perilesional edema reflects the suppurative nature of the lesion. Histologically early stages present with granulocyte infiltrates, necrotic blood vessels, extravasated erythrocytes, and numerous bacteria. Subsequently microvascular proliferates and fibroblast migration from the

blood vessel walls occurs as a response to hemorrhage and local infarction. With advanced abscess formation a firm fibrous, partly collagenous capsule encloses a saccular mass filled with purulent material surrounded by lipid-laden macrophages and aggregates of inflammatory cells (neutrophilic granulocytes). Meningoencephalitis The agent of bacterial meningitis varies with age. In newborns, Escherichia coli and group B streptococcus are the most frequent causes of bacterial meningitis. In children up to 12 years Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitides are most common. The latter two are also frequent in adults, whereas older age comes along with a higher incidence of Haemophilus influenzae.32 Acute bacterial meningitis proceeds in two phases. The inital phase is characterized by bacterial proliferation from the primary respiratory focus, leading to bacteraemia. It is assumed that release of toxic molecules by bacterial lysis leads to disruption of the blood brain barrier. CSF has only a slight possibility to counteract infection. Meningeal inflammation is caused

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by bacterial cell-wall components, activation of alternative complement pathway, and induction of inflammatory cytokines such as IL-1, IL-6, IL-8, and TNFα. Brain edema is a complication caused by disturbed blood-brain barrier, inflammatory mediators, and vascular changes. Edema and cerebral hypoxemia may lead to tissue damage and consecutive seizures. Moreover, neutrophilic granulocytes and bacterial products may exert a direct cytopathic effect on neurons or glia.39 In the early stages of purulent meningitis, neuroimaging often fails to identify the inflammatory foci. In later stages, contrast enhancing of meninges may occur. However, radiology is useful to detect complications such as edema, hemorrhages, or intracerebral abscesses. Histologically, acute phase is characterized by sparse exudation with numerous bacteria and margination of polymorphs in the leptomeningeal arterioles. If the patient survives for more than 2 days, migration of leucocytes leads to development of pus. At this stage cellular exudat composed of polymorphonuclear neutrophilic granulocytes is visible in the subarachnoidal space. Wisps of fibrin and bacteria occur intra- and extracellularly. Underlying cortex is not infiltrated, but it shows edema and beginning ischemic neuronal damage. Parasitic infections Within parasitic infections of the brain, neurocysticercosis is the most commonly associated with epilepsy. The cerebral lesion is caused by larvae of the pork tapeworm Taenia solium. Under physiological conditions, humans harboring the intestinal tapeworm are the definitive hosts, whereas pigs infected by eggs from the human stool are the intermediate hosts. The pig contains disseminated larvae. Ingestion of larvae due to inadequately cooked pork infects the human gastrointestinal tract to form mature worms. In contrast, in cysticercosis eggs are ingested by humans, and larvae infect primarily skeletal muscle and the brain. Here the organisms grow within the parenchyma, usually confined to the gray matter or within meninges. Solid or multiple lesions may occur. MRI shows solid, often calcified cystic lesions with a contrast enhancing rim and an internal point of enhancement that represents the scolex. After en bloc resection the organism presents with a surrounded rim of gliotic indurated parenchyma. Microscopically, cysts are composed of an outer eosinophilic lamina and a marginal cell layer containing scant nuclei. Internal parts contain loose connective tissue. The organism is armed with suckers and intimidating hooklets. The surrounding brain shows acute and chronic inflammation. Necrosis with peripheral palisading of monocytes may be seen, but giant cells are not common. Degeneration of the cysts leads to calcification and fibrosis of the lesion, often resulting into chronic seizures. CNS infections with Taenia echinococcus or Schistosomas rarely cause epilepsy. Protozoa producing cerebral lesions may come along with seizures, namely Toxoplasma gondii and Plasmodium falciparum. In malaria, seizures are major clinical findings.32 Viral infections and immunological findings associated with enhanced epileptogenesis Rasmussen’s encephalitis Rasmussen encephalitis (RE) was first described in 1958 in three patients with focal seizures due to chronic and focally

localized encephalitis.40 RE occurs sporadic, since there is no evidence for a genetic component.41 A viral etiology was already suggested by Rasmussen due to immune reaction in the brain with lymphocyte infiltration and microglial nodules. The similarities of RE and Russian spring summer meningoencephalitis, caused by flavi virus support this hypothesis.42 However, a viral agent has not been identified so far. Recent data suggest an immune basis to the pathogenesis of RE, including humoral factors, i.e., autoantibodies as well as cytotoxic T cells.41 There exist two different hypotheses how autoantibodies lead to brain tissue destruction and seizure activity. First GluR3 autoantibodies have been identified, mediating a cytotoxic activation of the glutamate receptor.42 Other investigators found signs of induced complement activation by GluR3 autoantibodies, primarily affecting glial cells.43 However, GluR3 autoantibodies are not present in all RE patients. Moreover, GluR3 autoantibodies were found in other forms of epilepsy and may result rather from neuronal cell degeneration. In RE the majority of inflammatory round cells are T lymphocytes.44 Immunohistochemical studies provide evidence for Granzyme B (GrB) mediated cytotoxic T lymphocyte attack against neurons.41 RE usually occurs unilateral in a progressive way. It is assumed, that seizures disturb the bloodbrain barrier (BBB) allowing autoantibodies which in contrast to activated T cells cannot cross an intact BBB to reach the brain tissue. The interplay between immunopathology and seizures seems to provide progressive course of RE. However, the precise nature and sequence of the pathogenetically relevant processes is not clear. At disease onset, RE becomes manifest with unilateral enlargement of inner and outer CSF compartments which are accompanied by an increased cortical or subcortical T2 or FLAIR signal. Transient focal swelling may occur. Subsequently, a spread of signal changes and atrophy arises within the affected hemisphere.45 Usually the uppermost amount of tissue loss happens during the first 12 months after onset of the acute disease state.46 The histopathological changes in RE are those of a chronic inflammatory process with subsequent neuronal loss and gliosis. Pathological changes have been classified in four stages.47 The active phase is characterized by numerous microglial nodules with facultative neuronophagia, perivascular cuffing, and reactive gliosis (Figure 144.7). During the active and remote state, these changes are accompanied by necrosis and cavitation of the cortex. Within the remote state neuronal loss and gliosis becomes prominent whereas microglial nodules occur to a lesser extent. At least inflammatory changes run short leading to a residual state with outstanding neuronal cell loss and gliosis. Inflammatory changes are confirmed by immunohistochemistry, indicating activated T lymphocytes with CD3 (Figure 144.7) and macrophages by CD68. Gliosis can be demonstrated by antibodies against glial fibrillary acidic protein (GFAP). Limbic encephalitis Patients suffering from tumors can develop an encephalopathy due to limbic encephalitis. Most common neoplasms associated with limbic encephalitis are small cell carcinomas of the lung, ovarian and breast cancers, seminomas, or Morbus Hodgkin.32 However, limbic encephalitis is not necessarily associated with tumors. Recently, cases with spontaneously occuring non-paraneoplastic limbic encephalitis (NPLE) have

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Figure 144.7 Rasmussen encephalitis presenting with cortical edema and atrophy (a). HE staining, scale bar = 500 µm). Cortical gliosis is visualized by GFAP immunohistochemistry (b). Scale bar = 1000 µm. Additional hallmarks of RE include perivascular T lymphocytes (arrows in c) and d (CD3), microglial nodules (arrow in e) and neuronophagia (arrow in f, CD68).

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been described.48 Both entities come along with similar MRI and histological findings. The course of the disease is characterised by subacute development. MRI shows increased T2 signal in variable areas, mainly confined to limbic structures. It may occur unilateral or bilateral. Different stages may be present in the same image: Acute lesions with cortical swelling and increased signal besides recovering lesions with decreased signal intensity. There is no evidence for local tumor growth or viral infection. Histopathologically, NPLE is characterised by parenchymal and perivascular lymphocytic infiltration and microglial activation, partly in the forms of microglial nodules. Separation from Rasmussen’s encephalitis (RE) is not always easy. However, whereas Rasmussen’s encephalitis usually occurs within early childhood, NPLE starts rather in adulthood. Moreover, RE is usually restricted to one hemisphere and leads to progressive atrophy, while NPLE may affect both hemispheres with the capability to recover. Herpes simplex encephalitis (HSE) Among viral encephalitides herpes simplex is the most common cause of chronic epilepsy. In virus encephalitis, most infectious agents reach the brain by the blood stream, while herpes simplex virus reaches the brain by traversing peripheral nerve axons. HSE is the most common form of severe endemic encephalitis. Initial seizures occur in 60% of patients. Despite antiviral treatment mortality is still high. Most survivors present with severe neurological deficits and therapy refractory epilepsy.49 Polymerase chain reaction amplification of viral DNA in the cerebrospinal fluid confirms the diagnosis. Almost all cases are caused by HSV-1 virus. Infection with HSV-2 virus is rare. The disease principally occurs at any age with a highest incidence in adolescence and in an immunesuppressive state. Radiologically, HSE presents as a unilateral or often bilateral temporal, insular and frontal lobe process with widespread increased T2 signal. Contrast enhancement is possible.50 By macroscopic inspection, the acute lesion consists of an expanding mass of necrotic, often hemorrhagic parenchyma. Microscopic findings include large necrotic areas with macrophage infiltration. Inflammation is characterized by lymphocyte perivascular cuffing and focal aggregates of microglial nodules. Appearance of viral intranuclear inclusion bodies, so-called Cowdry A inclusions within neurons or glia confirms the diagnosis. They typically appear as round or irregular, eosinophilic, intranuclear masses surrounded by a chromatine-free zone. Additional findings are homogenous red-wine nuclei. Subacute sclerosing panencephalitis (SSPE) SSPE is a rare but severe complication occurring in 1–22/ 100 000 patients after measles infection. It manifests months up to 10 years after primary infection. Pathogenetically, SSPE is caused by a genome mutation of intracellularly persisting measles virus (MV), causing viral nucleocapsides to accumulate in the brain cells. MV is not present in cerebrospinal fluid (CFS), therefore a negative PCR for measles in CSF does not exclude SSPE. Oligoclonal bands in the CSF and MV-specific IgG support the diagnosis. Rare SSPE manifestation after measles infection and occurrence of SSPE in siblings leads to a predisposing immune defect.51 However, a specific predisposing immune defect is not known. Recent studies lead to a

decreased cytotoxic T1 helper cell immune response or a defect in virus-specific production of interferonγ.52,53 Pathognomic EEG features are so-called Radermecker complexes, indicating fundamentally disrupted brain function. MRI findings are unspecific. Depending on the stage of the disease localized and diffuse T2 hyperintensities may occur, indicating inflammatory and gliotic lesions followed by regional or global brain atrophy in later stages. Histological investigation reveals common findings in viral encephalitis with perivascular inflammatory cells, necrosis and nuclear inclusion bodies. The latter are large eosinophilic haloed intranuclear masses occurring within ganglion cells. Subtle intracytoplasmatic inclusions may also occur. Immunohistochemistry identifies measles virus antigen. Ultrastructurally nucleocapsids of SSPE are occasionally seen in neuronal processes.

Head injuries Pathological findings Head injuries can be separated in perforating and nonperforating lesions. The former are characterized by impressive skull fractures and bare the risk of severe complications by invasion of bone fragments, contamination with debris and pathogen organisms. The pathology of non-perforating head injury includes two types, focal and diffuse lesions. Contusions and lacerations are the hallmarks of focal lesions differing in intact or torn pia mater. The latter condition is more likely to be found in fronto-temporal localization as well as in superficial gyri. Head trauma usually results a wedge-shaped defect with hemorrhage and edema, complicated by subdural hematoma due to laceration. At later stages, a V-shaped scar develops at apical gyri which carry yellow-to-brown hemosiderin pigment deposition (to be histologically verified using Berliner-blue reaction). The defect zone is surrounded by gliotic tissue and occasionally focal white matter demyelination. As in hemorrhagic infarction macrophage invasion and microvascular proliferates are common findings. Contusions are frequently accompanied by contre-coup lesions opposite to the initial trauma. The most precarious complication after head trauma is intracranial hemorrhage. Hematoma and contusion lead to brain swelling which results in secondary brain damage. Imaging and macroscopic investigation reveal flattening of the gyri and, in severe cases, shift of the midline structures towards herniation. Diffuse lesions include ischemic brain damage predominantly involving the hippocampus, brain swelling secondary to vasogenic edema, diffuse vascular injury appearing as multiple petechiae, particularly evident in the white matter of the fronto-temporal lobes and diffuse axonal injury.32 Hippocampal damage frequently occurs bilaterally and predominantly affects the hippocampal subfield CA1, whereas CA4, CA3, and CA2 are involved during disease progression. Molecular findings and enhanced epileptogenesis associated with head injuries Head injuries responsible for post-traumatic epilepsy can be divided into penetrating brain trauma with focal damage and

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Pathology of neurocutaneous, vascular abnormalities: post-infectious and post-traumatic pathologies closed brain trauma due to a generalized insult. Incidence of post-traumatic epilepsy was found to be 7%–39% in patients with undamaged dura, whereas in patients with lacerated dura incidence rose from 20% to 57%. Post-traumatic epilepsy is predicted by the age of affected patients, with a higher incidence in children under 5 years, severity of the injury, localization, especially parietal lesions, duration of post-traumatic amnesia, and presence of intracranial hematoma.32 Blood-brain barrier dysfunction, vasogenic oedema, anoxic-ischemic neuronal damage, axonal sprouting, altered excitatory synapses, and synaptic disassembly are assumed to play a pivotal role in post-traumatic epileptogenesis.54 Earlier studies found evidence for the hypothesis that post-traumatic epilepsy may result from blood extraversion and subsequent iron-mediated peroxidation of brain cell membranes.55 However, recent findings point to a major impact of BBB disruption. As shown in animal studies, cortical exposure of low levels of serum albumin led to extravasion of serum proteins into the extracellular space and early activation of astrocytes followed by a lasting neuronal hypersynchronization.56 Albumin may also play a role in microglial activation which is implicated in the neurotoxicity of neurodegenerative diseases.57 Furthermore, intracerebral bleeding followed by activation of the coagulation cascade triggers brain edema. In addition, thrombin produces brain injury via direct brain cell toxicity.58 There is further evidence that proinflammatory and anti-inflammatory molecules are synthesized during epileptic activity in glial cells. Various cytokines have been shown to affect neuronal excitability, leading to the hypothesis that they may play a role in altering synaptic transmission in epileptic conditions. Numerous studies indicate a central role of IL-1β for the exacerbation of brain damage after ischemic, traumatic

1371

or excitotoxic insults, suggesting that it may also contribute to neuronal cell injury associated with seizures.59 Besides reactive astrogliosis there seems to be evidence for disturbed astrocyte function following head trauma. The extracellular homeostasis of glutamate in the brain is maintained by the efficient uptake into astroglial cells. High extracellular glutamate levels seen during seizures probably result from an increased synaptic release and a deranged glutamate uptake. A prior study demonstrated decreased cortical levels of astrocytic glutamate transport protein GLT-1 in a rat model of post-traumatic epilepsy.60

Acknowledgments The Neuropathological Reference Center for Epilepsy Surgery is a consortium of distinguished colleagues from the following German epilepsy centers: (Berlin) H.J. Meencke, M. Merschhemke, N.T. Lehmann. (Bielefeld) A. Ebner, H.W. Pannek, F. Woermann, V. Hans. (Bonn) C. Elger, C. Bien, C. Helmstaedter, J. Schramm, H. Clusmann, H. Urbach, A. Becker, M. Majores. (Erlangen) H. Stefan, B. Kasper, E. Pauli, M. Buchfelder, A. Dorfler, T. Engelhorn, I. Blumcke, M. Hildebrandt. (Freiburg/Kehl-Kork) B. Steinhoff, A. Schulze-Bonhage, S. Fauser, J. Zentner. (Greifswald) S. Vogelgesang. (Marburg) F. Rosenow, S. Knake. (Munich) P.A. Winkler, S. Noachtar. (Stuttgart) P. Winkler. (Ulm) H. Lerche. (Vogtareuth) H. Holthausen, and T. Pieper. Financial support was granted from the European Community (‘EpiCure’ consortium), German Research Council (DFG Bl 421/1-2) and Bavarian Hochschulverbund ‘ForNeuroCell’.


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Whitney KD, McNamara JO. GluR3 autoantibodies destroy neural cells in a complement-dependent manner modulated by complement regulatory proteins. J Neurosci 2000;20:7307–16. Farrell MA, Droogan O, Secor DL et al. Chronic encephalitis associated with epilepsy: immunohistochemical and ultrastructural studies. Acta Neuropathol (Berl) 1995;89:313–21. Chiapparini L, Granata T, Farina L et al. Diagnostic imaging in 13 cases of Rasmussen’s encephalitis: can early MRI suggest the diagnosis? Neuroradiology 2003;45:171–83. Bien CG, Widman G, Urbach H et al. The natural history of Rasmussen’s encephalitis. Brain 2002;125:1751–9. Robitaille Y. Neuropathologic aspects of chronic encephalitis. In: Andermann F, ed. Chronic Encephalitis and Epilepsy. Rasmussens’s Syndrome. Boston: Butterworth-Heinemann, 1991:79–110. Bien CG, Schulze-Bonhage A, Deckert M et al. Limbic encephalitis not associated with neoplasm as a cause of temporal lobe epilepsy. Neurology 2000;55:1823–8. Davis LE, Shih JJ. CNS infections and epilepsy. In: Kotagal P, ed. The Epilepsies. San Diego, London, Boston, New York, Sydney, Tokyo, Toronto: Academic Press, 1999:265–82. Burger PC, Scheithauer BW, Vogel FS. The Brain: Infammatory disoprders. In: Burger PC, Scheithauer BW, Vogel FS, eds. Surgical pathology of the nervous system and its coverings, 4th edn. New York: Churchill Livingstone, 2002;113–59. Vieker S, Schmitt JJ, Behrens C, Weissbrich B, Hartmann H. Subacute sclerosing panencephalitis in two brothers. Neuropediatrics 2003;34:326–9. Gascon GG. Subacute sclerosing panencephalitis. Semin Pediatr Neurol 1996;3:260–9. Hara T, Yamashita S, Aiba H et al. Measles virus-specific T helper 1/T helper 2-cytokine production in subacute sclerosing panencephalitis. J Neurovirol 2000;6:121–6. Castejon OJ, Castejon HV, Zavala M, Sanchez ME, Diaz M. A light and electron microscopic study of oedematous human cerebral cortex in two patients with post-traumatic seizures. Brain Inj 2002;16:331–46. Willmore LJ, Sypert GW, Munson JB. Recurrent seizures induced by cortical iron injection: a model of posttraumatic epilepsy. Ann Neurol 1978;4:329–36. Seiffert E, Dreier JP, Ivens S et al. Lasting blood-brain barrier disruption induces epileptic focus in the rat somatosensory cortex. J Neurosci 2004;24:7829–36. Hooper C, Taylor DL, Pocock JM. Pure albumin is a potent trigger of calcium signalling and proliferation in microglia but not macrophages or astrocytes. J Neurochem 2005;92: 1363–76. Lee KR, Drury I, Vitarbo E, Hoff JT. Seizures induced by intracerebral injection of thrombin: a model of intracerebral hemorrhage. J Neurosurg 1997;87:73–8. Vezzani A, Moneta D, Richichi C, Perego C, De Simoni MG. Functional role of proinflammatory and anti-inflammatory cytokines in seizures. Adv Exp Med Biol 2004;548:123–33. Samuelsson C, Kumlien E, Flink R, Lindholm D, Ronne-Engstrom E. Decreased cortical levels of astrocytic glutamate transport protein GLT-1 in a rat model of posttraumatic epilepsy. Neurosci Lett 2000;289:185–8. Palmini A, Najm I, Avanzini G, Babb T, Guerrini R, FoldvarySchaefer N, Jackson G, Luders HO, Prayson R, Spreafico R, Vinters HV. Terminology and classification of the cortical dysplasias. Neurology 2004;62:S2–8.

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Pathology of epileptogenic neoplasms RA Prayson

Summary This chapter focuses on the pathology of tumors associated with chronic epilepsy. Topics that will be discussed include: ●

●

●

The prevalence of various tumor types as reported in the literature. Issues and pitfalls that may complicate the diagnosis of tumors in this clinical setting. Details regarding specific tumor types including ganglioglioma, dysembryoplastic neuroepithelial tumor, astrocytomas and oligodendrogliomas.

Introduction Neoplasms have been long recognized as a cause of medically intractable epilepsy. Several series in the literature have reviewed large numbers of patients which have undergone surgical excision of lesions for chronic epilepsy. The frequency of various pathologies are a bit different if one examines temporal lobe epilepsy versus extratemporal lobe epilepsy. Table 145.1 summarizes the pathologic findings in four large series of temporal lobe resections, all of which had greater than 200 cases evaluated. The prevalence of tumors in this setting ranged from 12.6–56.3%.1–4 In the temporal lobe epilepsy literature, summarized in Table 145.2, the prevalence of tumors is generally less; malformations of cortical development (cortical dysplasia) account for a significantly higher percentage of identified lesions.5,6 In a subset of tumors arising in this setting, the tumor represents part of a dual

Table 145.1

pathology, where another lesion is pathologically identified which may itself be epileptogenic.7–11 Most commonly, this second pathology is a form of cortical dysplasia. Several of the tumors which will be later discussed in this chapter are well known to be associated with cortical dysplasia. Tumors that are associated with chronic, medically intractable epilepsy, tend to present earlier in life, frequently in childhood, and are generally low-grade lesions. Table 145.3 summarizes the prevalence of tumors in various reported series arising in the setting of medically intractable, chronic epilepsy.12–17 In most series, either low grade glioneuronal tumors, such as gangliogliomas or dysembryoplastic neuroepithelial tumors, or low-grade gliomas, most commonly diffuse or fibrillary type astrocytomas, are the most commonly encountered tumors. There are obviously a number of differences between results observed in various surgical series and there are several explanations for why these differences exist. The most recent version of the World Health Organization (WHO) Classification of Tumours of the Nervous System includes definitions of many of the lesions that will be subsequently discussed in this chapter.18 Despite this, there are unavoidable differences between pathologists with regard to interpretation of these definitions. For example, exactly how much atypia one needs to see in a lesion to determine that it represents a low grade astrocytoma as opposed to gliosis or hamartomatous lesion can be difficult to decide, and to some degree be in the eye of the beholder. Other lesions, such as the dysembryoplastic neuroepithelial tumor, although fairly strictly defined by the WHO, has been variously interpreted by different pathologists. In contast, the WHO definition of oligoastrocytoma

Pathologic findings in temporal lobe epilepsy

Pathology Tumors Cortical dysplasia Vascular malformation Hippocampal sclerosis Normal Other pathology

Wolf et al. (1993)4 N=216

Plate et al. (1993)3 N=224

Bruton (1988)2 N=249

Mathieson (1975)1 N=301

34.7% 18.1% 6.0%

56.3% 6.3% 8.9%

Not specified Not specified 1.6%

12.6% 1.3% 2.3%

71.8% of cases that were available Not specified 6.5%

21.9%

42.9%

20.6%

1.8% 4.9%

16.2% 8.4%

26.2% 25.2%

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Table 145.2 Pathologic findings in extratemporal lobe epilepsy

Pathology

Wolf et al. (1993)5 √ N=63

Tumor Cortical dyslasia/ malformative lesion Infarct/ischemic lesion No pathology Vascular malformations

Frater et al. (2000)6 N=133*

19.0% 33.3%

27.8% 37.6%

25.4%

18.0%

14.3% 3.2%

17.2% 2.3%

*Some cases with dual pathology.

(mixed glioma) is somewhat more vague; precise guidelines as to what percent of a minor component needs to be present in a given lesion in order to make the diagnosis has not been agreed upon. Although most pathologists would agree that tumors with geographically distinct areas of oligodendroglioma and astrocytoma qualify as a mixed glioma, lesions in which the two patterns are intermixed are more problematic, and subsequently, the reproducibility of diagnosis is less than optimal. Some series reported in the literature have not separated out or enumerated various subtypes of astrocytoma e.g., pilocytic astrocytoma, from the larger diffuse fibrillary astrocytoma group. There are also differences in terms of how one defines medically intractable or chronic epilepsy that has allowed for the inclusion of certain high grade tumors such as glioblastoma multiforme in some series. However, it is hard to conceive of a glioblastoma multiforme, which has such a poor prognosis, being a cause of ‘chronic epilepsy’, unless it is the end point of a malignant progression or degeneration from a prior low-grade astrocytoma that has been around for a long period of time. Tissue sampling is an important consideration in rendering an accurate diagnosis in many of these cases. Gangliogliomas, for example, are tumors marked by an atypical ganglion cell

Table 145.3

component and a glioma component. Both components of the tumor are generally not evenly distributed throughout the entire neoplasm. In fact, in some gangliogliomas, the ganglion cell component may be present in only a small part of the tumor; obviously, if this region of the tumor is not sampled, a correct diagnosis will not be made. The classic dysembryoplastic neuroepithelial tumor is a multinodular, cortical based microcystic tumor. Small biopsies make it quite difficult or impossible to recognize the architectural pattern which is a salient and useful diagnostic feature of this tumor. In such cases, the differential diagnosis expands to include other lowgrade tumors which can have a microcystic appearance and are comprised primarily of cells with rounded nuclei (such as microcystic oligodendroglioma and protoplasmic astrocytoma). Pilocytic astrocytomas classically have a biphasic appearance, which may not be readily apparent if a limited tissue sampling is obtained. Rosenthal fibers and granular bodies, which are useful diagnostic clues to a diagnosis of pilocytic astrocytoma, are not present in all cases, and their absence may also cause diagnostic confusion. To further complicate matters, occasional pilocytic astrocytomas can contain areas with small rounded cells marked by pericellular clearing, mimicking an oligodendroglioma. More recently, many have come to recognize that there are certain lesions that are not easily classifiable. Over the last several years, there has also been a slowly growing literature describing lesions that seem to have mixed features of more than one tumor type. The rest of this chapter will address specific details on the pathology of some of the more commonly encountered tumors associated with chronic epilepsy.

Ganglioglioma Gangliogliomas are tumors which are defined as well differentiated, slow growing, neuroepithelial neoplasms comprised of an atypical ganglion cell component in combination with a glioma component.19–24 The majority of gangliogliomas are designated as grade I or II tumors in the WHO classification.18

Tumor types encountered in medically intractable epilepsy

Tumor type

Zentner et al. (1997)12 N=146

Pasquier et al. (1996)13 N=63

Morris et al. (1996)14 N=124

Britton et al. (1994)15 N=51

Wolf et al. (1993)16 N=87

Bourgeois et al. (1999)17 N=98 11 Not specified 21* 24 15 23

Ganglioglioma Pilocytic astrocytoma

65 21

17 0

49 2

4 6

4 17

Fibrillary astrocytoma Oligodendroglioma Oligoastrocytoma Dysembryoplastic neuroepithelial tumor Pleomorphic xanthoastrocytoma Other

15 14 10 19

3 1 0 30

29 10 6 15

12 15 6 4

10 10 2 6

1

4

1

1

1

0

1

8

12

3

0

4

*Designated as ‘astrocytoma’ without any further specification.

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Pathology of epileptogenic neoplasms Rare anaplastic gangliogliomas (grade III tumors) are recognized as well.19,25–27 Gangliogliomas may present at any age, but are most commonly encountered in the first two decades of life. They arise anywhere throughout the neuroaxis, but are most commonly observed in the temporal lobe. Grossly, the tumor may be solid or cystic and is generally not marked by mass effect. Calcification may be present. Necrosis and hemorrhage are unusual findings, the former being observed more commonly in anaplastic forms. Microscopically, gangliogliomas are marked by an atypical ganglion cell or neuronal cell component (Figure 145.1). This component is not necessarily distributed evenly throughout the neoplasm, and therefore, sampling is sometimes required to discover it. A neuronal cell component may be marked by increased numbers of abnormally distributed or clustered ganglion cells. Many times, there are morphologic alterations to these cells including binucleation, abnormal distribution of Nissl substance, and rarely the presence of neurofibrillary tangles. Binucleate neuronal forms may be observed in up to 60% of these tumors. Immunohistochemical staining with markers of neuronal differentiation, such as synaptophysin, may be helpful in highlighting this component of the tumor. The typical neuronal cell component is often intermixed with a gliomatous component. The glioma component most commonly resembles a low-grade astrocytoma (Figure 145.2). The degree of cellularity may be focally prominent. Mild vascular proliferative changes may also be evident. Prominent mitotic activity and necrosis are generally not features of lower grade tumors and are used to differentiate the rare anaplastic variant. Occasionally, the glioma component may show features resembling a pilocytic astrocytoma or oligodendroglioma. Focal extension to involve the leptomeninges may be evident (Figure 145.3) Perivascular chronic inflammation, consisting primarily of lymphocytes, is not commonly encountered. Eosinophilic granular bodies and microcalcifications may also be focally present (Figure 145.4). Microcystic degenerative changes are also a feature of a subset of these tumors. Care should be taken not to overinterpret synaptophysin positive staining in normal resident neurons as the ganglion cell component of a tumor.28

Figure 145.1 A ganglioglioma marked by predominantly ganglionic cells and blood vessels with mild perivascular chronic inflammation.

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Figure 145.2 A ganglioglioma with intermixed large ganglionic cells and smaller glial cells.

Studies which have examined cell proliferation markers in these tumors found low rates of proliferation in the majority of neoplasms.19,20 The two largest series to date that have examined this issue have observed Ki-67 or MIB-1 labeling indices of approximately 1%.19,20 The rare anaplastic variant shows high rates of cell proliferation. Information regarding genetics on these tumors is limited. These tumors demonstrate multiple chromosomal abnormalities.29 P53 expression by immunohistochemistry has not been observed; however, increased immunoexpression in a subset of tumors with antiapoptotic proteins bcl-2 and bcl-XL have been reported.20,30 Fairly recent work has noted a splice-typeassociated polymorphism in the tuberous sclerosis 2 gene that may predispose one to the development of sporadic ganglioglioma.31. Polymorphisms have also been noted in the tuberous sclerosis 1 gene.32 Gangliogliomas generally have an excellent prognosis and are quite amenable to surgical resection. There is little role for the use of adjuvant radiation therapy or chemotherapy in the routine management of these tumors. Such adjuvant therapies may be utilized in the management of the rare anaplastic variant.

Figure 145.3 Extension of a ganglioglioma to involve the leptomeninges (right).

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Figure 145.4

Foci of dystrophic calcification in a ganglioglioma.

The origin of ganglioglioma is still not known. As previously discussed, there may be a genetic component to the development of a subset of these tumors. A number of studies have also established an association of ganglioglioma with malformations of cortical development (cortical dysplasia).19,20,33,34 The coincidence of cortical dysplasia with ganglioglioma appears to be more than just chance. Similar to cortical dysplasia, gangliogliomas may have a maldevelopmental basis to their origin. Some forms of cortical dysplasia are morphologically quite similar to ganglioglioma and distinction of one from the other may be difficult without the proper clinical or radiographic context.

Dysembryoplastic neuroepithelial tumor Dysembryoplastic neuroepithelial tumors were first recognized as a distinct pathologic entity in 1988 by DaumasDuport et al.35 Prior to this time, many of these lesions were likely diagnosed as oligodendroglioma or perhaps even ganglioglioma. Subsequent literature on the entity has established it as a distinct lesion, which is commonly encountered in the setting of chronic epilepsy.36–41 These tumors are generally thought of as glioneuronal neoplasms, marked by a multinodular architectural pattern and predominant cortical location. They are regarded by the WHO as grade I. Similar to gangliogliomas, they may arise at any age; however, they show a predominance in the pediatric population. Origin of these tumors in a variety of locations throughout the central nervous system have been reported, although the majority of them arise in the temporal or frontal lobes. Grossly and on imaging studies, they are predominantly intracortical in location and multinodular (Figure 145.5). Peritumoral edema is usually absent. Foci of microcystic change are frequently present. The involved surface cortex may show a bubble-like or blustered appearance, secondary to this microcystic change. Microscopically, the tumor is marked by a proliferation of cells with generally rounded nuclei, scant cytoplasm, and frequent pericellular clearing, very similar to oligodendroglial

Figure 145.5 Low magnification appearance of a portion of a dysembryoplastic neuroepithelial tumor depicting the superficial, cortical basal location of the tumor.

cells (Figures 145.6 and 145.7). These cells are often arranged against a microcystic background. Floating in the cystic pools are benign, normal appearing neuronal cells. Small numbers of astrocytic cells are interspersed among the other cells present. The tumor demonstrates minimal cytologic atypia. A chickenwire or arcuate capillary vascular pattern is often prominently noted. Mitotic activity is frequently absent. Necrosis and vascular proliferative changes are not seen. Occasional tumors may demonstrate evidence of focal calcification. By immunohistochemistry and ultrastructural studies, a subpopulation of the oligodendroglial-like cells may also demonstrate evidence of neuronal differentiation, but the majority of cells do not.40,42 Similar to ganglioglioma, an association of the dysembryoplastic neuroepithelial tumor with adjacent malformations of cortical development has also been described.34–39,43 It has been suggested that these tumors might arise from subpial granular cells layer, their specific derivation has not been universally

Figure 145.6 Typical microcystic appearance of a dysembryoplastic neuroepithelial tumor. Most of the tumor’s cells resemble rounded oligodendroglial cells with an occasonal normal appearing neuron.

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Pathology of epileptogenic neoplasms

Figure 145.7 A more solid region of a dysembryoplastic neuroepithelial tumor showing both oligodendroglial-like cells and neuronal cells.

agreed upon. Again, the coexistence of this lesion with cortical dysplasia suggests a malformative basis for the tumor. Studies which have examined cell proliferation markers in these tumors have demonstrated low labeling indices, typically on the order of 1% or less.38,39,43,44 Because of the morphologic resemblance to neurocytomas and oligodendrogliomas, a few studies have explored genetic markers that are more commonly associated with these tumor types. Allelic loss on chromosomes 1p and 19q have not been observed in dysembryoplastic neuroepithelial tumors, in contrast to oligodendrogliomas, where approximately 60% of tumors demonstrate these allelic losses.45,46 Similar to gangliogliomas, dysembryoplastic neuroepithelial tumors are amenable to surgical resection and are potentially curable with a gross total resection. There is currently no role for adjuvant chemotherapy or radiation therapy in the management of these tumors. Rarely, cases of supposed malignant transformation or progression of these tumors to highgrade lesions have been reported; however, careful examination of these cases often shows atypical features making the diagnosis suspect. If one maintains strict criteria for the diagnosis, these tumors almost invariably have a benign clinical course. Because the diagnosis requires assessment of architectural pattern, small biopsies may be inadequate and inappropriate for purposes of definitive diagnosis. The strong resemblance of this tumor to a low-grade microcystic oligodendroglioma or protoplasmic astrocytoma may cause differential diagnostic problems in the setting of a limited biopsy, where the location of the tumor, multinodularity of the lesion, or adjacent cortical dysplasia may not be appreciated.

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these tumors. The clinical course of higher-grade lesions (glioblastoma multiforme) often culminates in the death of the patient within a relatively short period of time. Therefore, these patients typically do not present with a medically intractable epilepsy. The World Health Organization stratifies the fibrillary astrocytomas into three grades. The low-grade lesions are generally designated as grade II neoplasms and are the lesion of primary interest in the chronic epilepsy venue. Higher-grade tumors are designated as anaplastic astrocytoma (grade III) and glioblastoma multiforme (grade IV). Typically, the low-grade astrocytomas arise in the white matter and have an infiltrative growth pattern. As tumor cells infiltrate into the overlying cortex, they frequently obscure the gray-white interface. Microcystic or grossly cystic areas may be evident. Microcalcifications may be observed in approximately 15% of tumors. Histologically, low-grade fibrillary astrocytomas are marked by increased cellularity due to a proliferation of atypical appearing astrocytes (Figure 145.8). The atypia is marked by nuclear enlargement, nuclear hyperchromasia associated with a coarse chromatin pattern, and nuclear irregularity or pleomorphism. Rarely, mitotic figures may be observed; they are more readily discernible in the higher-grade tumors. Vascular proliferative changes and necrosis, which are features more commonly associated with glioblastoma multiforme, are absent in low-grade tumors. Occasional tumors may show a prominent gemistocytic component. These gemistocytic cells are characterized by prominent eosinophilic cytoplasm and a laterally displaced, slightly enlarged nucleus with small nucleolus.47,48 Tumors with a significant gemistocytic component tend to behave in a more aggressive fashion. Rates of cell proliferation utilizing cell proliferation markers are generally low in the grade II fibrillary astrocytomas.49–51 In general, the mean labeling index of the low grade fibrillary astrocytoma group is a bit higher than the gangliogliomas and dysembryoplastic neuroepithelial tumors. Tumor cells are generally (GFAP) positive. As previously mentioned, distinction of this lesion from ganglioglioma may sometimes be dependent on the extent of sampling of the

Diffuse or fibrillary astrocytomas Diffuse or fibrillary astrocytomas comprise the most common primary neoplasms of the central nervous system.18 They arise anywhere in the neuroaxis and have peak incidence in young adults between the ages of 30–40 years; although, they may arise at any age. Seizures are a fairly common presentation for

Figure 145.8 A low-grade fibrillary astrocytoma marked by atypical astrocytic cells with enlarged nuclei and irregular nuclear contours.

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lesion in that the gliomatous component of ganglioglioma may resemble a diffuse or fibrillary type astrocytoma. In contrast to most gangliogliomas and dysembryoplastic neuroepithelial tumors, fibrillary astrocytomas are well known to evolve over time into higher-grade lesions. This underscores the importance of distinguishing this entity from ganglioglioma. There is some recent suggestion in the literature that among the grade II fibrillary astrocytomas, a subgroup of these tumors arising in patients with long term epilepsy may have a more benign clinical course with a lower rate of occurrence and higher percentage of survival at 10 years.50 Although differences were observed in this study based on clinical parameters, the morphologic distinction of this subset of tumors from other fibrillary astrocytomas is not possible. In contrast to gangliogliomas and dysembryoplastic neuroepithelial tumors, it appears that a significant subset of low-grade fibrillary astrocytomas demonstrate p53 mutations or alterations.18 Treatment is generally determined by a variety of parameters including grade of tumor at time of presentation, location, age, and time course of the neoplasm. Low-grade lesions may be amenable to surgical excision and followed by observation. Adjuvant therapies are often reserved for tumors which demonstrate progression or are higher-grade lesions.

Protoplasmic astrocytoma The protoplasmic astrocytoma is a rare low-grade astrocytic neoplasm (WHO grade II) that also has been linked to chronic epilepsy.18 Many of these tumors arise in the first few decades of life and present with a long history of epilepsy. Temporal and frontal lobes are the most common sites of origin.52 Many of these tumors appear to be cortical based. Microscopically, these tumors are marked by a proliferation of astrocytic cells with round or slightly oval nuclear contours and scant amount of cytoplasm (Figure 145.9). Cells are arranged against a microcystic background. Prominent mitotic activity, vascular proliferative changes, and necrosis are not seen. Eosinophilic granular bodies or

Figure 145.9 A protoplasmic astrocytoma composed of astrocytic cells with generally rounded nuclei arranged against a cystic or loose background.

Rosenthal fibers, features that are fairly typical of pilocytic astrocytoma, are not observed in these tumors. In contrast to dysembryoplastic neuroepithelial tumors, which protoplasmic astrocytomas may also resemble, the protoplasmic astrocytoma lacks adjacent cortical dysplasia and usually presents as a unifocal mass. The rate of cell proliferation in these tumors is rather low, with a mean MIB1 labeling index in one series of 0.7.53 P53 immunoreactivity is present in a minority of tumors.53 In contrast to oligodendrogliomas, 1p chromosomal deletions are not observed in these tumors.54 Clinically, most of these tumors behave like low-grade lesions. Their superficial location may make them somewhat more amenable to surgical excision.

Pilocytic astrocytoma Pilocytic astrocytomas are the most common of the astrocytoma variant tumors. These neoplasms most commonly arise in the cerebellum, region adjacent to the third ventricle, brainstem, and optic nerve/chiasm. A subset of these tumors may present in the clinical setting of medically intractable epilepsy. Recognized by the World Health Organization as a grade I lesion, these tumors have a much better prognosis than the fibrillary type astrocytomas, and are important to distinguish from these tumors for that reason.18 The majority of pilocytic astrocytomas arise in the pediatric age group. Grossly, the classic pilocytic astrocytoma is a cystic tumor that has a mural nodule or nodules. Radiographically, these nodules enhance because of the increased vascularity of these neoplasms. Microscopically, the classic pilocytic astrocytomas are biphasic neoplasms (Figure 145.10). Areas of the tumor consist of a dense fibrillary background and spindled cells. Often in these more compact areas, brightly eosinophilic Rosenthal fibers may be evident (Figure 145.11). These dense fibrillary areas are frequently juxtaposed to other regions of the tumor which may have a looser, more microcystic appearance. Often in these more microcystic areas, eosinophilic granular bodies may be evident. Foci of perivascular chronic inflammation

Figure 145.10 Compact fibrillary and loose patterns characterize the biphasic appearing pilocytic astrocytoma.

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Figure 145.11 Numerous eosinophilic Rosenthal fibers in a compact area of a pilocytic astrocytoma.

Figure 145.12 A markedly cellular pleomorphic xanthoastrocytoma with perivascular chronic inflammation.

consisting primarily of lymphocytes are frequently present. Vascular sclerotic changes may also be evident. Nuclear pleomorphism may prominent. Misinterpretation of the vascular proliferative changes and pleomorphism as representing features of a fibrillary type astrocytoma may result in an erroneous diagnosis of anaplastic astrocytoma or glioblastoma multiforme. Prominent mitotic activity and necrosis are generally not viewed as features of the pilocytic astrocytoma. Being astrocytic in derivation, these tumors demonstrate GFAP immunoreactivity. Distinction of these tumors from ganglioglioma must be considered, given that the gliomatous component of the ganglioglioma may on occasion resemble a pilocytic astrocytoma. Rates of cell proliferation are generally low in keeping with the low grade of these neoplasms.55–58 Many of the genetic alterations that have been previously attributed to diffuse or fibrillary type astrocytomas are generally not observed in pilocytic astrocytomas. The literature seems divided over the frequency of p53 mutations in these tumors.59–61 The vast majority of these tumors behave in a benign fashion and are amenable to surgical excision. Only rare cases of malignant degeneration or progression have been documented.62 There is generally no role for adjuvant therapy in the treatment of most pilocytic astrocytomas.

xanthomatous changes in the cytoplasm of astrocytic cells may evident (Figure 145.13). Multinucleated, giant astrocytes may also be present. On casual inspection, these tumors resemble high-grade fibrillary astrocytoma in terms of cellularity and pleomorphism. Vascular proliferative changes, which may be quite prominent in these tumors and account for the enhancement seen radiographically, may cause further confusion with high grade fibrillary astrocytoma. In contrast to high grade fibrillary astrocytomas, however, pleomorphic xanthoastrocytomas generally lack significant mitotic activity or evidence of necrosis. Eosinophilic granular bodies are frequently present as are perivascular collars of lymphocytes. In contrast to the usual fibrillary type astrocytoma, pleomorphic xanthoastrocytoma shows increased reticulin deposition between individual cells and small groups of tumor cells. In the usual fibrillary astrocytoma, reticulin deposition is confined to blood vessels and vascular proliferative changes. Rare examples of more aggressive pleomorphic xanthoastrocytomas, so-called anaplastic pleomorphic xanthoastrocytoma

Pleomorphic xanthoastrocytoma Pleomorphic xanthoastrocytomas are low-grade tumors (WHO grade II) that account for less than 1% of all astrocytic neoplasms.18,63–65 The majority of patients are in the pediatric age group. Tumors are typically located in the temporal or parietal lobes. On imaging studies, these tumors often have a cystic component with enhancing mural nodule or nodules. Focal areas of dystrophic mineralization may be evident. They are usually superficial and often attached to the meninges. Leptomeningeal spread of tumor may occasionally be observed. The neoplasm is marked by prominent hypercellularity, comprised of cells which demonstrate considerable nuclear pleomorphism (Figure 145.12). In some cases, vacuolated or

Figure 145.13 Scattered pleomorphic tumor cells and occasional vacuolated or lipidized appearing tumor cells in a pleomorphic xanthoastrocytoma.

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(WHO grade III), have been recognized and are marked by increased mitotic activity and/or necrosis.66–68 GFAP immunoreactivity in these tumors is evidence for their astrocytic differentiation. Of interest in pleomorphic xanthoastrocytomas is that a small subpopulation of cells demonstrate evidence of neuronal differentiation by immunostaining, suggesting that perhaps these tumors may be glioneuronal in nature rather than purely astrocytic.69 Furthermore, the presence of associated cortical dysplasia in a subset of these tumors and existence of cases of ganglioglioma/pleomorphic xanthoastrocytoma mixed tumors raise further questions with regard to the exact nature of this neoplasm.70–72 In one series in which 29 tumors were evaluated with MIB1 antibody, a mean labeling index of 1.9 ± –3.1% was observed.65 As a group, pleomorphic xanthoastrocytomas generally do well with surgical excision. As previously indicated, a subset of tumors have demonstrated more aggressive behavior and may require additional adjuvant therapy

Oligodendrogliomas and mixed gliomas (oligoastrocytomas) Oligodendrogliomas comprise between 5–18% of intracranial gliomas.18 Similar to astrocytomas, the majority of cases arise in adults, with the peak incidence in the 5th and 6th decades of life. They are relatively uncommon in the pediatric population. Many pediatric lesions, which were historically diagnosed as oligodendrogliomas, have turned out to be dysembryoplastic neuroepithelial tumors. Several large series that have been published on these tumors show that oligodendrogliomas arise in the white matter, with frontal lobe being the most common location, and often present with a long preoperative history of neurologic signs and symptoms.73–78 Like their fibrillary astrocytoma counterparts, these tumors frequently are infiltrative and cause obscuring of the gray matter/white matter interface. The majority of tumors demonstrate calcification. Cystic degenerative changes and evidence of hemorrhage may be seen. Microscopically, these tumors are marked by a proliferation of cells with rounded nuclei and scant cytoplasm (Figure 145.14). An artefact of delayed formalin fixation results in the classic ‘fried egg’ or perinuclear halo that may be seen morphologically. A delicate capillary vascular pattern is evident in these tumors. Microcalcifications are also fairly frequent findings (in up to 80% of tumors). Occasional tumors may be marked by a population of cells with increased eosinophilic cytoplasm, so-called mini gemistocytes; there is no prognostic significance attached to these cytologic changes. The WHO recognizes two grades of oligodendroglioma (grades II and III).18 Grade III or anaplastic oligodendrogliomas are marked by increased cellularity and nuclear pleomorphism, readily identifiable mitotic activity, vascular proliferative changes, and/or necrosis. To date, there are no reliable immunohistochemical markers for the identification of oligodendroglial cells. Studies looking at cell proliferation indices in these tumors have shown correlation of grade with labeling indices. Of particular note is the presence of deletions on chromosome 1p and

Figure 145.14 A low grade oligodendroglioma characterized by a proliferation of rounded cells with pericellular clearing or halos (fried egg appearance) and focal calcification.

19q in the majority of these tumors.78–82 Interestingly, these deletions have been associated with better prognosis and chemoresponsiveness in the anaplastic oligodendroglioma group.78–82 This has prompted some institutions to routinely screen their oligodendrogliomas for these molecular markers. In addition, the markers may also be useful in selected situations from a diagnostic standpoint. A limited biopsy of a microcystic tumor in the temporal lobe consisting of rounded cells with interspersed neurons raises a differential diagnosis of infiltrating oligodendroglioma involving gray matter versus dysembryoplastic neuroepithelial tumor. Evidence of deletions on chromosomes 1p and 19q in this setting would favor oligodendroglioma.46 In a tumor that does not demonstrate deletions on these chromosomes, the differentiation between the two entities may still be uncertain. In contrast to diffuse fibrillary astrocytomas, oligodendrogliomas are often (although not invariably) chemoresponsive. As previously noted, chemoresponsiveness appears to be associated with certain chromosomal deletions. High-grade tumors may also be treated with adjuvant radiation therapy. There clearly are a subset of low-grade gliomas that appear to demonstrate mixed features of oligodendroglioma and fibrillary astrocytoma. In some cases, these two patterns of cell types are intermixed, and in other instances, there appears to be geographically distinct areas of each tumor type. The designations of mixed glioma or oligoastrocytoma have been used in reference to this subset of gliomas.83–85 A universally agreed upon precise definition as to what constitutes a mixed glioma has not been well defined in the literature. Arbitrary cutoff points between 20–35% of a minor component have been variously used. Due to the lack of uniformity with regard to definition and diagnosis of this entity, it has been difficult to come to an understanding of the significance or the characteristics of this group of tumors. Similar to oligodendrogliomas, the World Health Organization stratifies these lesions into low grade (grade II) and high grade anaplastic (grade III) lesions.18 There is some data to suggest that a subset of mixed gliomas demonstrates deletions on chromosomes 1p and 19q, and this subset may be more amenable to chemotherapy.80

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Composite lesions A number of cases reports and small series have been published describing tumors which demonstrate features of more than one tumor type, i.e., composite tumors. Cases of composite pleomorphic xanthoastrocytoma and ganglioglioma70,71,86,87 as well as reports of tumors demonstrating areas of dysembryoplastic neuroepithelial tumor and ganglioglioma,88–90 have been reported. Coexistence of these lesions raises interesting questions regarding the pathogenesis of these entities and possible malformative nature of this group of tumors. Interestingly, these are also tumors that have been described arising in association with cortical dysplasia.

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elements, but in contrast to gangliogliomas, they lack appreciable cytologic atypia (Figure 145.15). Occasional granular bodies and microcalcifications may be present. Adjacent cortical dysplasia may also be noted. Cell proliferation markers show negligible evidence of cell proliferation. Because of the benignity of these lesions and their circumscribed nature, they are amenable to surgical excision and have a good postoperative outcome.

Meningioangiomatosis

Hamartomatous lesions may rarely account for chronic epilepsy. Hamartomas in this context are defined as tumoral lesions composed of disorganized, but mature cellular elements.91 These lesions may consist of admixtures of both glioneuronal

Meningioangiomatosis is a rare benign lesion that probably has a maldevelopmental basis to its origin that may arise as a mass lesion in the setting of chronic epilepsy.92–95 This lesion has been variously associated with a neurofibromatosis. The entity is marked by a benign proliferation of blood vessels collared by meningothelial cells which extends into the cortex and white matter (Figure 145.16). The intervening neural parenchyma shows gliosis and may show dystrophic mineralization. Gross total resection of the lesion appears to be curative.

Figure 145.15 Glioneuronal hamartoma characterized by a disordered admixture of relatively benign appearing glial and neuronal cells.

Figure 145.16 Meningoangiomatosis marked by a prolifertion of blood vessels collared by benign meningothelial cells.

Hamartoma

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Hirose T, Scheithauer BW, Lopez MBS et al. Dysembryoplastic neuroepithelial tumor (DNT): an immunohistochemical and ultrastructural study. J Neuropathol Exp Neurol 1994;53:184–5. Nolan MA, Sakuta R, Chuang N et al. Dysembryoplastic neuroepithelial tumors in childhood. Long-term outcome and prognostic features. Neurology 2004;62:2270–6. Leung SY, Gwi E, Ng HK et al. Dysembryoplastic neuroepithelial tumor. A tumor with small neuronal cells resembling oligodendroglioma. Am J Surg Pathol 1994;18:604–14. Daumas-Duport C. Dysembryoplastic neuroepithelial tumours. Brain Pathol 1993;3:283–95. Tatke M, Suri VS, Malhotra V et al. Dysembryoplastic neuroepithelial tumors: Report of 10 cases from a center where epilepsy surgery is not done. Pathol Res Pract 2001;197:769–74. Fujisawa H, Marukawa K, Hasegawa M et al. Genetic differences between neurocytoma and dysembryoplastic neuroepithelial tumor and oligodendroglial tumors. J Neurosurg 2002;97:1350–5. Prayson RA, Castilla EA, Hartke M et al. Chromosome 1p allelic loss by fluorescence in situ hybridization (FISH) not observed in dysembryoplastic neuroepithelial tumors. Am J Clin Pathol 2002;118:512–17. Krouwer HGJ, Davis RL, Silver P et al. Gemistocytic astrocytomas: a reappraisal. J Neurosurg 1991;74:399–406. Watanak K, Tachibana O, Yonekawa Y et al. Role of gemistrocytes in astrocytoma progression. Lab Invest 1997;76:277–84. Sallinen PK, Haapasalo HK, Visakorpi T et al. Prognostication of astrocytoma patient survival by Ki-67 (MIB-1), PCNA, and S-phase fraction using archival paraffin-embedded samples. J Pathol 1994;174:275–82. Schramm J, Luyken C, Urbach H et al. Evidence for a clinically distinct new subtype of grade II astrocytomas in patients with longterm epilepsy. Neurosurgery 2004;55:340–8. Wakimoto H, Aoyagi M, Nakayama T et al. Prognostic significance of Ki-67 labeling indices obtained using MIB-1 monoclonal antibody in patients with supratentorial astrocytomas. Cancer 1996; 77:373–80. Prayson RA, Estes ML. Protoplasmic astrocytoma. A clinicopathologic study of 16 tumors. Am J Clin Pathol 1995;10:705–9. Prayson RA, Estes ML. MIB-1 and p53 immunoreactivity in protoplasmic astrocytomas. Pathol Int 1996;46:862–6. Prayson RA. Cyclooxygenase-2, Bcl-2 and chromosome 1p analysis in protoplasmic astrocytomas. Hum Pathol 2004;35:317–21. Ito S, Hoshino T, Shibuya M et al. Proliferation characteristics of juvenile pilocytic astrocytomas determined by bromodeoxyuridine labeling. Neurosurgery 1992;31:413–19. Kordek R, Biernat W, Alwasiak J et al. Proliferating cell nuclear antigen (PCNA and Ki-67) immunopositivity in human astrocytic tumors. Acta Neurochir (Wien) 1996;138:509–13. Machen SK, Prayson RA, Cyclin D1 and MIB-1 immunohistochemistry in pilocytic astrocytomas: A study of 48 cases. Hum Pathol 1998;29:1511–16. Giannini C, Scheithauer BW, Burger PC et al. Cellular proliferation in pilocytic and diffuse astrocytomas. J Neuropathol Exp Neurol 1999;58:46–53. Litofsky NS, Hinton D, Raffel C. The lack of a role for p53 in astrocytomas in pediatric patients. Neurosurgery 1994;34:967–73. Von Deimling A, Louis DN, Meron AG et al. Deletions on the long arm of chromosome 17 in pilocytic astrocytoma. Acta Neuropathol 1993;86:81–5. Hayes VM, Dirven CMF, Dam A et al. High frequency of TP53 mutations in juvenile pilocytic astrocytomas indicates role of TP53 in the development of these tumors. Brain Pathol 1999;9:463–7. Tomlinson FH, Scheithauer BW, Hayostek CJ et al. The significance of atypia and histologic malignancy in pilocytic astrocytoma of the cerebelum: a clinicopathologic and flow cytometric study. J Clin Neurol 1994;9:301–10. Kepes JJ, Rubinstein LJ, Eng LF. Pleomorphic xanthoastrocytoma: A distinctive meningocerebral glioma of young subjects with relatively favorable prognosis. A study of 12 cases. Cancer 1979;44:1839–52. Kepes JJ. Pleomorphic xanthoastrocytoma: the birth of a diagnosis and a concept. Brain Pathol 1993;3:269–74. Giannini C, Scheithauer BW, Burger PC et al. Pleomorphic xanthoastrocytoma. What do we really know about it? Cancer 1999; 85:2033–45. Macaulay RJB, Jay V, Hoffman HJ et al. Increased mitotic activity as a negative prognostic indicator in pleomorphic xanthoastrocytoma. J Neurosurg 1993;79:761–8. Bayindis C, Balak N, Karasu A et al. Anaplastic pleomorphic xanthoastrocytoma. Childs Nerv Syst 1997;13:50–6.

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Prayson RA, Morris HH III Anaplastic pleomorphic xanthoastrocytoma. Arch Pathol Lab Med 1998;122:1082–6. Powell SZ, Yachnis AT, Rorke LB et al. Divergent differentiation in pleomorphic xanthoastrocytoma: evidence for a neuronal element and possible relationship to ganglion cell tumors. Am J Surg Pathol 1996;20:80–5. Furuta A, Takahashi H, Ikuta F et al. Temporal lobe tumor demonstrating ganglioglioma and pleomorphic xanthoastrocytoma components. J Neurosurg 1992;77:143–7. Perry A, Giannini C, Scheithauer BW et al. Composite pleomorphic xanthoastrocytoma and ganglioglioma: Report of four cases and review of the literature. Am J Surg Pathol 1997; 21:763–71. Lach B, Duggal N, DaSilva VF et al. Association of pleomorphic xanthoastrocytoma with cortical dysplasia and neuronal tumors: a report of three cases. Cancer 1996;78:2551–63. Burger PC, Rawlings CE, Cox EB et al. Clinicopathologic correlations in the oligodendroglioma. Cancer 1987;59:1345–52. Giannini C, Scheithauer BW, Weaver AL et al. Oligodendrogliomas: Reproducibility and prognostic value of histologic diagnosis and grading. J Neuropathol Exp Neurol 2001;60:248–62. Daumas-Duport C, Varlet P, Tucker ML et al. Oligodendrogliomas. Part I. Patterns of growth, histological diagnosis, clinical and imaging correlations: a study of 153 cases. J Neuro-Onc 1997;34:37–59. Dehghani F, Schachenmayr W, Laun Al et al. Prognostic implication of histoathological, immunohistochemical and clinical features of oligodendrogliomas: a study of 89 cases. Acta Neuropathol 1998;95:493–504. Celli P, Nofrone I, Palma L et al. Cerebral oligodendroglioma: prognostic factors and life history. Neurosurgery 1994;35:1018–35. Hartmann C, Mueller W, von Demling A. Pathology and molecular genetics of oligodendroglial tumors. J Mol Med 2004;82:638–55. Cairncross JG, Ueki K, Zlatescu MC et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplatic oligodendrogliomas. J Natl Cancer Inst 1998; 90:1473–9. Smith JS, Perry A, Borell TJ et al. Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastroctyomas. J Clin Oncol 2000; 18:636–45. Ino Y, Zlatescu MC, Sasaki H et al. Long survival and therapeutic responses in patients with histologically disparate high-grade

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gliomas demonstrating chromosome 1p loss. J Neurosurg 2000; 92:983–90. Kelly TW, Tubbs RR, Prayson RA. Molecular techniques for the clinical evaluation of gliomas. Diagn Mol Pathol 2005;14:1–8. Hart MN, Petito C, Earle KM. Mixed gliomas. Cancer 1974; 33:134–40. Shaw EG, Scheithauer BW, O’Fallon JR et al. Mixed oligoastrocytomas: a survival and prognostic factor analysis. Neurosurgery 1994;34:577–82. Beckmann MJ, Prayson RA. A clinicopathologic study of 30 cases of oligoastrocytoma including p53 immunohistochemistry. Pathology 1997;29:159–64. Evans AJ, Fayaz I, Cusimano MD et al. Combined pleomorphic xanthoastrocytoma-ganglioglioma of the cerebellum. Arch Pathol Lab Med 2000;124:1707–9. Vajtai I, Varga Z, Aguzzi A. Pleomorphic xanthoastrocytoma with gangliogliomatous component. Pathol Res Pract 1997;193:617–21. Prayson RA. Composite ganglioglioma and dysembryoplastic neuroepithelial tumor. Arch Pathol Lab Med 1999;123:247–50. Hirose T, Scheithauer BW. Mixed dysembryoplastic neuroepithelial tumor and ganglioglioma. Acta Neuropathol 1998;95:649–54. Shimbo Y, Takahashi H, Hayano M et al. Temporal lobe lesion demonstrating features of dysembryoplastic neuroepithelial tumor and ganglioglioma: a transitional form? Clin Neuropathol 1997;16:65–68. Volk EE, Prayson RA. Hamartomas in the setting of chronic epilepsy: a clinicopathologic study of 13 cases. Hum Pathol 1997;28:227–32. Halper J, Scheithauer BW, Okasaki H et al. Meningo-angiomatosis: a report of six cases with special reference to the occurrence of neurofibrillary tangles. J Neuropathol Exp Neurol 1986;45:426–46. Prayson RA. Meningioangiomatosis: a clinicopathologic study including MIB-1 immunoreactivity. Arch Pathol Lab Med 1995;119:1061–4. Sakaki S, Nakagawa K, Nakamura K et al. Meningioangiomatosis not associated with von Recklinghausen’s disease. Neurosurgery 1987;20:797–801. Perry A, Kurtkaya-Yapicier O, Scheithauer BW et al. Insights into meningoangiomatosis with and without meningioma: a clinicopathologic and genetic series of 24 cases with review of the literature. Brain Pathol 2005; 15:55–65.

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In vitro neurophysiological studies GL Möddel and IM Najm

Introduction For the past 50 years researchers have developed powerful methods in order to study the mechanisms which are involved in the generation of epileptic activity in neuronal tissues. In general, experiments can be performed using either living laboratory animals (‘in vivo’), or tissue preparations (e.g., brain slices or separated single neurons) derived from such subjects (‘in vitro’). In vivo experiments enable the researcher to study epileptic phenomena in an intact brain with all its neuronal structures and white matter connections preserved. Accordingly, those experiments constitute a rather valid model mimicking the processes that generate seizures in an epilepsy patient. However, many questions arising in regard to the basic mechanisms of epileptogenesis require more reduced, simplified models that enable the researcher to control for as many experimental parameters as possible and to manipulate others.

in exact, graded concentrations and without interference by the blood–brain barrier, transsection of defined axonal connections, or electrical stimulation of gray or white matter structures. Extracellular recording electrodes (‘field potential electrodes’) can be used to assess spontaneous or electrically induced synchronized discharges of the surrounding neuronal population (‘epileptiform field potentials’, EFP) or the extracellular correlate of synchronized action potential generation (‘population spike’). Positioned within the dendritic layers of the neocortex or hippocampus, the extracellular correlate of excitatory or inhibitory synaptic potentials (eEPSPs, eIPSPs) can be recorded. Sharp electrodes which penetrate neuronal membranes are used to record membrane potential fluctuations of individual neurons as well as to inject positive or negative current pulses into neurons. These intracellular recordings can be maintained for many hours, and the effects of changes in the perfusion medium can be assessed. Parameters of interest are, for example, ●

In vitro neurophysiological methods in experimental epilepsy research – an overview The ‘brain slice in vitro’ preparation constitutes such a powerful experimental model. In short, axial sections of the hippocampus or neocortex of about 400–500 µm thickness are prepared from the brains of experimental animals (i.e., mostly, rats, mice, or guinea pigs). Additionally, human brain tissue samples resected from epilepsy patients for the treatment of intractable epilepsy have been studied using the in vitro slice model since resective surgery became a widely accepted treatment for intractable focal epilepsy in the late 1970s.1–4 Brain slices contain a limited, relatively simple, virtually two-dimensional neuronal network that is anatomically and physiologically well-described.5 Following preparation, brain slices are incubated and stored in artificial cerebrospinal fluid (ACSF, i.e., saline mimicking the ional and glucose concetrations of CSF).6 For electrophysiological recordings, individual brain slices are placed in a recording chamber and constantly superfused with oxygenated ACSF. Flow velocity, temperature, and pH are monitored and held constant throughout the experiment (Figure 146.1). This setup allows experimental manipulations such as changing the ionic composition of the extracellular medium, application of convulsant or anticonvulsant substances 1384

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the resting membrane potential, input resistance (i.e., change of membrane potential in relation to amplitude of injected current), EPSPs and IPSPs (spontaneous, electrically induced, pharmacologically induced), spontaneous and electrically induced firing pattern (i.e., regular action potential firing with slow adaptation, fast adaptation, or intrinsically bursting firing mode; see Figure 146.2).

The patch-clamp technique7 allows single-cell recordings using low-resistance electrodes in conjuction with special software to keep either the membrane potential or the current across a membrane patch constant over time (i.e., ‘voltageclamp’ or ‘current-clamp’) while measuring the respective other parameter. By using suitable ion channel agonists and antagonists, the voltage-clamp technique can be employed to ‘filter out’ individual channel species and thus assess, for example, the time course of fast sodium currents or slow calcium currents directly. Besides, patch-clamp electrodes in situ can be used to inject neurons with dyes, so that individual recorded neurons can later be identified in histologically or immunocytochemically stained sections. Ion-selective electrodes are sensitive to concentration changes of defined ion species in the extracellular medium, so that localized activity-dependent changes in extracellular ion concentrations (e.g., potassium or chloride) can be assessed. Comb-like arrays of up to eight or ten extracellular electrodes provide field potential profiles, e.g., across neocortical layers. Recently, optical imaging techniques

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Experimental setup used for in vitro neurophysiological experiments. a, Mechanical setup; b, electrical setup.

have been developed which employ voltage-sensitive dyes and two-dimensional diode arrays instead of electrodes in order to assess the spread of neuronal activity across a brain slice and along pathways with high time and space resolution.8 When recording from a brain slice bathed in normal ACSF, spontaneous synchronized network activity is only rarely

present. This is the case, for example, in cortical samples derived from surgically excised seizure foci of patients with medically intractable epilepsy,9 or in slices prepared from animals with exprerimentally induced epileptogenic lesion or a genetic epileptic predisposition. In most cases, however, additional manipulations are necessary to induce epileptiform activity in brain slices. These ‘in vitro seizure models’ include: ●

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(c) Figure 146.2 Typical neuronal discharge patterns, elicited by intracellular injection of positive current pulses (400 nA, 200 msec). a: Fast adaptation. b: Regular spiking with slow adaptation. c: Intrinsically bursting neuron. (guinea pig, hippocampus, CA3 pyramidal cells).

Electrical stimulation of afferent or efferent axonal pathways Application of substances which block GABAergic inhibition, such as penicillin,10–12 bicucullin or picrotoxin.13,14 Application of agents which block repolarizing voltagegated potassium channels, such as 4-aminopyridine or barium.15 Changes of the ionic composition of the bathing medium, such as – lowering of [Cl-]o, [Ca2+]o, [Mg2+]o, or [K+]o – elevating [K+]o.

Among these models, the lowering of [Mg2+]o (‘low-magnesium model’ or ‘zero-magnesium model’) has been proven to be especially useful because it reliably induces robust periodic spontaneous network bursts in both hippocampal and neocortical slices without requiring external stimulation. These ‘epileptiform field potentials’ (EFP) of 10–200 ms duration resemble interictal spikes in the EEG and were therefore termed ‘interical bursts’. The epileptogenic effect of low [Mg2+]o is mainly mediated by increasing sodium and calcium influx through N-methyl-D-aspartate (NMDA)-receptor associated ion channels.16–21 At normal resting membrane potential of around –60 mV, magnesium ions block the NMDA-receptor channel pore, so that the channel remains inactive despite binding of the agonist glutamate to the receptor. Depolarization of the postsynaptic membrane (e.g., by concomitant activation via AMPA receptors) reduces the electrochemical gradient and causes magnesium ions to exit the channel pore, thereby removing the block. (Figure 146.3) Calcium ions entering the neuron cause further depolarization and serve as second messengers, inducing processes that are the basis for activity-dependent neuronal plasticity, such as induction of long-term potentiation (LTP),22,23 or changes in

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Textbook of epilepsy surgery Ca

low-[Mg2+]o include: direct membrane depolarization, as the ‘screening’ of negative phospholipid surface charges by the divalent cations magnesium and calcium is impaired,28 and reduced presynaptic adenosin-receptor mediated inhibition.29

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Simultaneous extracellular and intracellular recordings in the hippocampus demonstrated that synchronized epileptiform field potentials are correlated intracellularly by bursts of action potentials riding on a slow depolarizing wave-like potential fluctuation see Figure 146.4a).21,30 Similar bursts had first been recorded by Spencer and Kandel31 from the CA3-region of the hippocampus in cats in vivo. Plateau-like epileptiform bursts beginning with a steep initial depolarization are also termed ‘parosysmal depolarizing shifts’ (PDS).32,33 Alongside epileptiform bursts resembling interictal spikes, prolonged seizure-like discharges have been described in brain slices in vitro.4,6,9,15,34–36 Intracellular reocordings show a steep initial depolarization with occasional superimposed action potentials, followed by a plateau and prolonged, slow repolarization with multiple superimposed after discharges (Figure 146.4b).

2+

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(c) Figure 146.3 Gating of the NMDA receptor associated channel by extracellular magnesium ions. a: At normal resting membrane potential (–60 mV), the NMDA receptor channel pore is blocked by a magnesium ion, preventing cation influx into the postsynaptic neuron despite NMDA binding. b: Depolarization of the postsynaptic membrane releases the magnesium block. NMDA binding consecutively leads to sodium and calcium influx. c: When extracelluar magnesium concentration is markedly reduced, NMDA receptor activation leads to cation influx into the postsynaptic neuron without previous depolarization of the postsynaptic neuron. (0 Mg2+: virtually magnesium-free extracellular solution; RMP: resting membrane potential; EC: extracellular; IC: intracellular).

gene expression patterns. When [Mg2+]o is reduced by using nominally magnesium-free ACSF, NMDA-receptor associated ion channels can be activated at resting membrane potential without requiring prior depolarization, resulting in increased glutamatergic excitation. Secondarily, increased intracellular calcium, via calcium-calmodulin dependent enzymes, induces dephosphorylation of GABA-A receptors24 which impairs GABA-ergic inhibition by reducing the receptor affinity for GABA.25–27 NMDA-receptor independent effects of

‘Interictal-like’ epileptiform bursts and epileptiform field potentials (EFP) The majority of hippocampal pyramidal cells respond to supra-threshold depolarizing stimulation (i.e., injection of square current pulses via intracellular electrodes) with trains of action potentials showing slow or fast frequency adaptation. A subpopulation, however, generates intrinsic bursts of action potentials riding on a slow wave-like depolarizing envelope (‘intrinsically bursting neurons’, Figure 146.2). Intrinsic bursters serve as putative amplifying elements within neuronal networks and are thought to initiate synchronous activity in the hippocampus.31,37,38 Dichter and Spencer39 and Ayala et al.40 have postulated that the process of synchronization is mainly facilitated by recurrent excitatory synaptic connections. Using computer simulations of hippocampal networks, Traub and Wong41–43 and Traub and Dingledine44 developed the following model scenario for the generation and spread of synchronous burst activity in the CA3 region of the hippocampus: postsynaptic membranes generate occasional ‘spontaneous excitatory postsynaptic potentials’ (EPSPs), e.g., by ‘random’ transmitter release from presynaptic terminals. If two or more of these spontaneous EPSPs occur virtually simultanously in an ‘intrinsically bursting’ neuron, the cell will generate an epileptiform burst. Given that (a) the excitatory interconnectivity is strong enough and (b) recurrent and lateral inhibition are weak enough to evoke consecutive epileptiform bursts in more than one neighboring neuron, a chain reaction will result: as soon as the number of simultaneously bursting neurons within the population exceeds a critical value, the number of firing cells will first rise explosively and then suddenly drop as the majority of neurons will almost simultaneously be hyperpolarized by recurrent inhibitory interneurons. The electrical correlates of this event as recorded by extracellular electrodes will be an ‘epileptiform

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Figure 146.4 Spontaneous interictal and ictal-like epileptiform discharges recorded in vitro. Simultaneous extracellular field potential (FP) and intracellular membrane potential (MP) recordings, guinea pig, hippocampus, CA 3 region, pyramidal cell layer. Epileptiform activity was induced by reduction of the extracellular magnesium concentration (0 Mg2+).

field potential’ (EFP) in vitro, or an epileptiform spike or sharp wave in vivo. According to this model, the propensity of a neuronal network to generate EFPs is directly dependent on the proportion of intrinsic bursters within the neuron population, the degree of excitatory connectivity, and on active inhibition. Seizure-like discharges Alongside epileptiform bursts resembling interictal spikes, prolonged seizure-like discharges have been described in brain slices in vitro. Intracellular reocordings show a steep initial depolarization with occasional superimposed action potentials, followed by a plateau and prolonged, slow repolarization with multiple superimposed after discharges (Figure 146.4b). Extracellularly, an initial negative spike is followed by a sustained negative potential shift and multiple afterdischarges towards the end of the event. The occurrence of seizure-like discharges suggests that the mechanisms involved in epileptiform burst repolarization are impaired. This includes increased excitatory neurotransmission, reduced inhibition, or impaired intrinsic membrane repolarizing mechanisms: ●

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low [Cl−]o which reduces GABA-A-mediated chloride currents6,34 penicillin and bicuculline that block GABA-A-ergic inhibition35 4-aminopyridine which blocks repolarizing K+ channels15 low [Mg2+]o which leads to increased NMDA-receptor activation,4,9 low [K+]o (unknown mechanism, probably increased AMPA/kainate receptor activation36

As the transition of epileptiform bursts into prolonged seizure-like discharges serves as a model for interictal to ictal transition in vivo, the involved mechanisms are of special clinical relevance.

Mechanisms of epileptogenesis revealed by in vitro neurophysiological studies The following processes have been postulated to underly the generation of synchronized network dicharges: ●

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Intrinsic burst activity. Membrane excitability is regulated by – ‘active membrane properties’ such as voltage-gated ion channels or ligand-gated ion channels, and – ‘passive membrane properties’ such as the resting membrane potential, membrane resistance and capacitance, neuron geometry, leak channels, etc. Excitatory coupling between neurons, which can hypothetically be mediated by – excitatory synaptic connections, – electrical coupling via gap junctions, – direct electrical (‘ephaptic’) interactions between neighbouring neurons, and – changes in the concentrations of extracellular K+ concentration. Reduced or impaired inhibition. Membrane properties, excitatory neurotransmission, and inhibition are further regulated by – Extra- and intracellular ion concentrations, – Neuromodulators, and – Second-messenger mechanisms.

Mechanisms regulating neuronal membrane excitability Active membrane properties: voltage gated channels, ion-gated channels The wave-like depolarization underlying an epileptiform burst has been shown to be caused by a slow cation influx. For hippocampal CA3 pyramidal cells and dentate gyrus granule

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cells, slow voltage-activated sodium and calcium currents have been identified.45–48 In CA1-neurons, a persistent sodium current (INa,p) is of major relevance.49,50 Superimposed somatic action potentials are generated by an interplay between fast voltage-activated sodium currents and subsequent ‘delayed rectifying’ potassium efflux. Pyramidal cell dendrites generate slow calcium-dependent action potentials (‘calcium spikes’) which may coincide with somatic sodium spikes, producing the after-depolarization (ADP) that is often seen following action potentials recorded from the cell soma. The epileptiform burst ends with a repolarization, followed by an afterhyperpolarization (AHP) of up to 2 seconds duration. The initial burst repolarization is mainly facilitated by slow voltage-activated potassium channels and GABA-A-receptor mediated recurrent inhibition leading to chloride influx.51 The same GABA-A-induced chloride influx contributes to the early phase of the AHP. The late phase of the AHP, which also determines the duration of the AHP, is generated by two potassium-dependent mechanisms: GABA-B mediated inhibition and slow Ca2+-acitvated potassium currents.14,52–54 Chamberlin and Dingledine55 found that the duration of the AHP correlates positively with the inverval between two subsequent epileptiform bursts (‘inter-burst interval’) and negatively with the repeptition rate of EFP. Therefore, burst repetition rate in the hippocampus is regulated by GABA-B mediated inhibition and by the extracellular potassium concentration. These data on burst generation mechanisms have facilitated research investigating the efficacy of voltage-gated ion channel blockers as anticonvulsant drugs. Blockade of slow voltage-activated calcium channels by application of the organic calcium antagonist verapamil exerts strong suppressant effect on bicuculline-induced and low-Mg2+-induced epileptiform burst dicharges in the hippcampus and in the neocortex.56–58 Similar results have demonstrated the efficacy of flunarizine in vitro. Severe cardiac side-effects in vivo have so far precluded these drugs from clinical use as anticonvulsants. Inhibitors of voltage-gated sodium channels, such as lidocaine, are widely used clinically as local anesthetics and antiarrhythmic drugs. However, their anticonvulsant properties are also well described (e.g., Schurr et al. 1986).59 Lidocaine has been proposed as a drug of third choice for the treatment of refractory status epilepticus. Moreover, blockade of sodium channels is thought to be the major mechanisms of action of the anticonvulsant drug phenytoin. Passive membrane properties The excitability of neurons is crucially dependent on intrinsic properties of neuronal membranes. The resting membrane potential (RMP), described mathematically by the Goldman equation,60 is determined by concentration gradients of ions in the extra- and intracellular compartments and by the membrane permeabilities of the respective ions. At resting conditions, the membrane permeability for potassium ions by far exceeds the permeability for all other ions, so that the RMP is basically a function of the relation between intracellular and extracellular potassium concentration. Potassium permeability is mainly dependent on potassium leak channels (IK,leak), whereas ion concentration gradients are maintained by active transport through ATP-dependent pumps (e.g., Na-K-ATPase). Although, to the authors’ knowledge, no experimental data exists so far that links changes of IK,leak to epileptogenesis, the

block of this current can result in sustained changes in RMP and thereby change the probability of action potential generation. Inhibition of the Na-K-ATPase by the cardiac glycoside dihydroouabaine (DHO) has been shown to induce synchronized burst discharges in the CA1 area of rat hippocampus.61 Hypoxia-induced epileptiform discharges62 are, at least in part, mediated by ATP depletion and resulting impairment of ion pumps. Neuronal geometry is another, commonly underestimated determinant of excitability: The capacitance of neuronal membranes, i.e., the amount of electrical charge (e.g., number of ions) necessary to produce a given change in membrane potential, is a function of membrane surface area. The length constant of dendritic processes determines the probability of distal dendritic input to depolarize the soma and is the greater the larger the diameter of the dendrite. Cepeda et al.63 have shown that these passive membrane properties are altered in dysmorphic neurons in cortical dysplastic lesions resected from pediatric epilepsy patients. Dysplastic neurons are characterized by thickened dendritic shafts and a loss or enlargement of dendritic spines.64 Dendritic spines control excitability by compartmentalization of postsynaptic calcium influx, by enlarging total membrane area, and by attenuating electrotonic propagation of EPSPs: The spine neck accounts for approximately one half of the electric resistance between a given synapse and the cell soma. Hence, loss of spines in cortical dysplasia may be one factor responsible for hyperexcitability. Mechanisms regulating network connectivity Excitatory synaptic neurotransmission Induction of epileptiform activity in hippopcampal slices by disinhibition (bicuculline, penicillin) or reduction of extracellular magnesium concentration gives rise to paroxysmal depolarization shifts (PDS), which behave like giant synaptic potentials: Their amplitude is dependent on the membrane potential, with hyperpolarization increasing and depolarization decreasing PDS amplitude.36,65 Therefore, excitatory synaptic transmission plays an important role in synchronization of neuronal networks, at least during ‘interictal’ conditions. Excitatory neurotransmission in the mammalian brain mainly depends on the amino acid transmitter glutamate. Two classes of ionotropic glutamate receptors have been described: (1) those that respond to alpha-amino-3-hydroxyl-5-methyl4-isoxazole propionic acid (AMPA) or kainic acid, and (2) those that respond to N-methyl-D-aspartate (NMDA). AMPA/kainate receptors AMPA/kainate receptors are tetramers or pentamers of subunits (termed GluR1-GluR7, KA-1, and KA-2) derived from three gene families and constitute the major vehicles for fast excitatory synaptic transmission. Their activation gives rise to excitatory post-synaptic potentials (EPSPs) which are mainly mediated by sodium influx and characterized by a short latency, rapid rise time, and short duration of several milliseconds. A subgroup of AMPA/kainate receptors that lack the GluR2 subunit are also permeable to Ca2+ ions.66,67 In most in vitro preparations, interictal epileptiform burst discharges are dependent on AMPA/Kainate receptor activation: Sponaneous,9 electrically induced,68 and low-Mg2+-induced69 epileptiform burst discharges in human neocortical neurons are completely abolished by the AMPA/Kainate-receptor

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In vitro neurophysiological studies specific antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). In contrast, blocking AMPA receptors with 1(aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466) in rat neocortex only gradually reduces low-Mg2+ and 4-aminopyridine (4-AP) induced epileptiform discharges, while still abolishing spontaneous discharges induced by bicuculline.70 This might reflect species differences between rodent and human neocortex. The horizontal propagagion of epileptiform discharges in normal rat somatosensory cortex71 as well as in an animal model of focal cortical dysplasia induced by cortical freeze lesions72 is dependent on AMPA-repeptor activation. In the hippocampus (CA1) of rats, the ampltitude of epileptiform discharges is reduced by application of CNQX, but block of both AMPA/kainate and NMDA receptors is necessary to completely abolish spontaneous bursts in the bicuculline model.73 Excessive hippocampal activation by repetitive seizures has been shown to increase the number of functional AMPA receptors at Schaffer collateral synapses, indicating their potential role in activity-dependent plasticity and kindlinginduced epileptogenesis.74 In rat hippocampal slices made chronically epileptic by perinatal hypoxia, the expression of GluR2 subunits is markedly reduced, resulting in increased calcium influx through AMPA receptors.75 Hence, intracellular calcium is likely to play an important role in the development of chronic epileptogenesis. NMDA-receptors Numerous studies, using different in vitro seizure models, demonstrate the blocking effect of NMDA receptor antagonists on epileptiform activity, implying that NMDA receptors play a pivotal role in the generation of synchronized discharges. Avoli and Olivier4 showed that the the nonspecific NMDA receptor antagonist D-2-amino-5-phosphonovalerate (APV) blocks electrically-induced epileptiform bursts in human neocortical slices resected from epilepsy patients. In rodent hippocampus, the durations of bicuculline- or pentylenetetrazol-induced epileptiform depolarizations is reduced by APV.76 Several features make NMDA receptors particularly interesting for the pathophysiology of epilepsy: (a) the NMDA receptor is activated in a voltage-dependent manner, i.e., depolarization of the membrane is necessary for relieving the block by Mg2+ of the ion channel pore; (b) the NMDA receptor interacts with numerous intracellular scaffolding, anchoring and signalling molecules associated with the postsynaptic density, such as the tyrosine kinase Fyn or neuronal nitric oxide synthase (nNOS);77–79 (c) Ca2+-permeability of NMDA receptor associated channel by one to two orders of magnitude larger than Ca2+-permeability of AMPA/kainate receptors, depending on the subunit composition of receptors.66,67,80–83 Intracellular calcium acts as a second messenger with short-term (e.g., activation of protein kinases and nNOS) and long-term (alteration of the gene expression pattern) effects, thus NMDA receptors constitute an important substrate for synaptic plasticity;84–86 (d) NMDA receptors display slow kinetics with an inactivation time constant one to two orders of magnitude longer than that of AMPA receptor channels. NMDA receptors are likely to play an important role in the generation of seizure-like discharges. Upon activation, NMDA receptors generate prolonged excitatory postsynaptic currents (EPSCs). These prolonged NMDA-receptor mediated

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depolarizations are normally masked by recurrent inhibition via GABAergig interneurons. Luhmann and Prince87 showed that minimal disinhibition by application of low doses of bicuculline in adult rat neocortex can ‘unmask’ the NMDA receptor mediated depolarizations and give rise to synchronized afterdischarges which are senstitive to APV. In juvenile rat neocortex, the same investigators demonstrated long-lasting oscillatory NMDA-dependent field potential responses upon layer VI electrical stimulation without experimental disinhibition, indicating an imbalance between NMDA-mediated excitation and GABA-mediated inhibition in immature cortex. Additionnally, excessive NMDA receptor activation is known to reduce GABA efficacy by Ca2+-mediated dephosphorylation of the GABAA receptor.24,87,88 Repetitive tetanic electrical stimulation of hippocampal stratum radiatum induces increased NMDA-receptor activity. Hence, changes in NMDA and, consecutively, GABA receptor efficacy are probably the molecular basis for kindling-induced hyperexcitability.87 Three families of NMDA receptor subunits have been identified, termed NR1, NR2, and NR3. The NR 1 subunit is a singlegene product with eight different mRNA splice variants.89 The four different NR2 subunits (termed NR2A-D) and two NR3 subunits (NR3A-B) are encoded by separate genes. Native NMDA receptors are heterotetramers or pentamers90,91,92 consisting of multiple NR1 subunits and at least one NR2 subunit. NR2 subunits alone cannot form functional receptors, but have to co-assemble with NR1. Heteromeric NR1-NR2A NMDA receptors dominate in the mature neocortex. In contrast, NR1-NR2B receptors are physiologically expressed during fetal and early postnatal development and display higher peak ionic currents and a six times slower inactivation time constant,93–95 resulting in an increased Ca2+ influx upon activation. Several reports have demonstrated the association of increased NR2B expression with human epilepsy.69,96–98 Crino et al.96 reported increased NR2B and NR2C, along with decreased NR2A mRNA levels in dysplastic compared with pyramidal neocortical neurons in surgical specimen from epilepsy patients with focal cortical dysplasia. Ying et al.97 and Najm et al.98 have demonstrated differential NR2B expression in areas of cortical dysplasia resected from patients with intractable epilepsy and correlated the density of immunocytochemical staining for NR2B with in situ epileptic activity assessed by subdural grid recordings. Epileptiform field potentials recorded from NR2B-overxpressing dysplastic human neocortex are differentially blocked by the NR2Bspecific NMDA receptor antagonist ifenprodil.69 Electrical synapses: gap junctions and the influence of pH Gap junctions are connections between neighbouring neurons made up by large transmembranous proteins that extend through the membranes of both cells, forming ion permeable pores that result in direct electrical coupling of neurons. At least in some brain regions, the conducting properties of gap juctions can additionally be altered by neurotransmitters or modulators. Traditionally, gap junctions have been thought to be of minor importance for neurotransmission in the mammalian brain. However, Somjen et al.99 found that action potentials in dentate gyrus granule cells and CA3 pyramidal cells of the rat hippocampus are highly synchronized without detectable preceding synaptic potential, indicating that direct

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electric interactions exist between these neurons. Some recent publications suggest that gap junctions might be involved in the pathophysiology of epilepsy. Naus et al.100 and Elisevich et al.101 found that mRNA and protein levels of the heart-type gap junction protein connexin 43 are increased in temporal lobe neocortex and hippocampus, respectively, of patients with intractable seizures. The patency of gap junctions is regulated by intracellular pH, with intracellular acidosis reducing, and intracellular alkalinization increasing their ion permeability. Additionally, gap junctions are blocked by heptanol, octanol, or carbenoxolone. Intracellular acidification or addition of octanol, heptanol, or carbenoxolone has been shown to reduce epileptiform activity in rat hippocampus,102–105 whereas alkaline perfusion with ammonium chloride induced spontaneous ictal-like epileptiform discharges in piriform cortex,106 suggesting that gap junctions indeed play a role in epileptic synchronization. Köhling et al.107 demonstrated that hippocampal gap junctions are involved in the transition from interictal to ictal-like activity in the low-Mg2+ model. Gap junction blockers reversibly block low-Mg2+induced ictal-like activity without abolishing interictal bursts. Intrinsic membrane properties and chemical synaptic transmission are not altered by gap junction blockers.107 As spontaneous and evoked epileptiform discharges in hippocampal slice cultures chronically exposed to bicuculline are correlated with an increased expression of connexin 43 and connexin 32,108 activity dependent gap junction protein upregulation may be involved in the epileptogenic process. Finally, besides neuronal electrical coupling, gap junctions connecting glial cells may play a role in hypersynchronously active cortex. Lee et al.109 found increased gap junctional coupling between astrocytes in human epileptic cortex specimen, compared to extrafocal cortex. As glial cells are involved in clearing and buffering extracellular potassium following intense neuronal activity, syncytial coupling of glia may facilitate the spread of ‘potassium waves’ that lead to increased neuronal synchronization.110 Ephaptic interactions and the role of extracellular osmolarity Ephaptic interactions refer to interaction between neighboring neurons caused by direct electrical field effects. Neuronal activation induces extracellular electrical potential and ion concentration gradients. These result in extracellular currents which direcly influence surrounding cells. The degree of ephaptic electrical interactions between neurons is dependent on the spacial proximity of the cells and is therefore increased when the extracellular space shrinks. Ephaptic interactions are involved in synchronizing neuronal networks and can also influence firing patterns of single neurons.111 Ephaptic coupling is increased by conditions that induce cell swelling, such as intense neuronal activity, or hypoosmolar extracellular medium: high-[K+]o-induced seizure-like events in the hippocampal CA1-subfield increase the electrical resistance of the tissue by 10–20%, indicating a reduction of extracellular volume.112 Hypoosmotic bath solutions increase synchronized burst firing in hippocampal slices. Conversely, media made hyperosmotic by addition of agents that remain restriced to the extracellular space (such as mannitol, sucrose, or dextran) abolish high-[K+]o-induced seizure-like events in the hippocampal CA1-region and reduce the duration of interictal

bursts in CA3, while simultaneously decreasing the electrical resistance of the tissue.112 The epileptogenic effect of hypoosmolarity (e.g., hyponatremia-induced seizures) and the depressant effect of extracellular hyperosmolarity on neuronal excitability (e.g., hyperosmolar coma diabeticum) are in line with common clinical observations. The role of extracellular potassium in network synchronization Increased extracellular potassium concentration. There is good evidence for the crucial involvement of synaptic transmission in interictal burst discharges. However, seizure-like events in vitro are seen under experimental conditions that preclude neuronal communication via chemical synapses, suggesting that interictal spikes and focal seizures are triggered by different mechanisms. Blockers of synaptic transmission abolish high[K+]o-induced interictal-like bursts in hippocampal slices, but do not inhibit the initiation of seizure-like events in the CA1subfield.113 Lowering of extracellular calcium concentration ([Ca2+]o) to values less than 0.2 mM blocks synaptic transmission, because calcium influx into the presynaptic terminal is the triggering stimulus for the release of synaptic vesicles. Despite this block, low-[Ca2+]o induces spontaneous seizurelike events in CA1, suggesting that mechanisms other than synaptic transmission are sufficient to synchronize a neuronal network.114 Yaari et al.115 showed that washout of [Ca2+]o, as well as transient hypoxia, are accompanied by a rise in extracellular potassium concentration ([K+]o) that precedes the onset of seizure-like events. Lian et al.,116 using the same model, demonstrated that this nonsynaptic synchronization between CA3 and CA1 region, mediated by a slowly diffusing ‘wave’ of increased extracellular potassium, persists even when the axonal connections between CA3 and CA1 subfields are physically transected. Insertion of a thin water-impermeable film into the transsection site abolished synchronization. In another study, Voskuyl et al.117 demonstrated that one type of 4-aminopyridine-induced spontaneous discharges in hippocampal slices slowly propagates from CA3 to CA1 and cannot be suppressed by blockade of synaptic transmission. Even transsection of the Schaffer axon collaterals that connnect CA3 and CA1 pyramidal neurons, does not block propagation of these discharges as long as stratum moleculare is preserved.117 These data indicate that potassium homeostatis is likely to play a crucial role in seizure initiation. The amplitude of a potassium current with given membrane potential and membrane conductance is dependent on the potassium equilibrium potential (‘Nernst potential’), which is determined by the relation between extracellular ([K+]o) and intracellular potassium concentration ([K+]i). The electrochemical gradient for repolarizing potassium currents is increased by low [K+]o and decreased by high [K+]o. Accordingly, changes of [K+]o effectively change both the excitability of single cells and the behaviour of neuronal networks. There is extensive evidence that elevated [K+]o induces epileptiform activity118–120 and increases the repetition rate of EFP.121,122 Jensen et al.123 found an increased proportion of intrinsically bursting neurons in the hippocampal CA1-region with elevated [K+]o. Besides reducing the amplitude of repolarizing potassium currents, elevated [K+]o leads to direct neuron depolarization.124 Korn et al.118 showed that increased [K+]o is accompanied by increased intracellular

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In vitro neurophysiological studies chloride concentration ([Cl−]i), probably by activation of a K-Cl co-transporter, with consecutive reduction in the amplitude of inhibitory GABA-A mediated chloride currents. Extracellular potassium ions released from the intracellular compartment during neuronal activity are normally cleared by neuronal and glial K+ reuptake. Excessive elevation of [K+]o leads to osmotic glial swelling119,120 with reduction of the extracellular volume and increased ephaptic interactions between neighbouring neurons (see above). These findings have major implications for the pathophysiology of epileptic seizures: during excessive neuronal activity, [Ca2+]o decreases to values incompatible with synaptic transmission.110 Maintenance of long-lasting epilepitc acitvity as it occurs, for example, during status epilepticus, is therefore very unlikely to be dependent on synaptic mechanisms. As extracellular potassium concentration increases to values above 10 mM during seizures, impaired potassium homeostasis may be one of the key mechanisms leading to prolonged ictal discharges. Reduced extracellular potassium concentration Elevation of [K+]o during neuronal activity is normally followed by a transient reduction of [K+]o below the physiological baseline (‘K+ undershoot’,121,122 possibly by excessive Na+-K+-ATPase activation. The effect of reduced [K+]o on epilptiform activity is not yet well characterized, but several studies report an epileptogenic effect of low extracellular potassium.36,123 The epileptogenic effect of low [K+]o may be related to increased GABA-B mediated potassium outward currents leading to recruitment of low-threshold calcium channels which are inactivated at normal resting potential. Inhibition Gamma-amino butyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain. Two major types of GABA receptors play a role in the neocortex and hippocampus, termed GABA-A and GABA-B receptors. (GABA-C receptors are encountered in the retina and are not further discussed here). GABA-A mediated inhibition The cortical glutamatergic principal neurons innervate GABA-ergic interneurons, which in turn inhibit the original pyramidal cell (‘recurrent inhibition’), and surrounding excitatory neurons (‘lateral inhibition’), thus restricting neuronal activity temporally and spacially. GABA binding to postsynaptic GABA-A receptors opens chloride (Cl–) selective ion channels. As the chloride equilibrium potential (‘Nernst potential’) at baseline conditions is negative to the resting membrane potential (RMP), chloride ions will enter the cell and cause a hyperpolarizing, inhibitory postsynaptic potential (IPSP). In rodent hippocampus, as well as in human and rodent neocortex, application of substances that block GABA-A-ergic inhibition, such as bicuculline or penicillin, leads to synchronized epileptiform bursts driven by large and long-lasting inhibitory synaptic conductances.10–13,35,124–126 In the neocortex, these bursts are initiated within small, spatially discrete subpopulations of cells127 and then spread to the disinhibited surrounding cortex. The role of lateral inhibition in confining neuronal activity to a limited portion of cortex has been demonstrated by Chagnac-Amitai and Connors:128 using horizontal arrays of extracellular electrodes, they showed that neuronal activity

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evoked by focal electrical stimulation remained restriced to a narrow strip of cortex at control conditions, whereas disinhibition by application of graded concentrations of bicuculline first increases the spatial spread of acitvity and finally gives rise to synchronized evoked epileptiform activity. Interestingly, epileptiform activity occurred at bicuculline concentrations that were still insufficient to completely abolish IPSPs. This finding suggests that minimal disinhibition can already induce epileptiform activity. Although these findings derived from in vitro models are dependent on pharmacological manipulations, they are of major relevance for the initiation and spread of epileptic acitivity under clinical conditions: Strowbridge et al.129 showed that inhibitory synaptic potentials are reduced in the vicinity of cortical lesions resected from patients for treatment of intractable epilepsy, indicating that loss of inhibition is involved in the pathophysiology of epileptogenic foci. It remains unclear, however, whether disinhibition constitutes an underlying cause for epileptiform activity, or merely one step in a pathophysiological sequence that finally leads to seizures: repetitive GABA-A-receptor activation during longlasting neuronal firing is associated with chloride influx into neurons. As extracellular chloride concentration is reduced, the chloride equilibrium potential (‘Nernst potential’) is shifted to more positive values, with IPSPs decreasing in amplitude. As soon as the chloride equilibrium potential becomes more positive than the resting membrane potential, GABA-activated chloride currents become excitatory, leading to a breakdown of GABA-A-receptor mediated inhibition. Impaired recurrent inhibition interferes with the termination of burst discharges, facilitating ictal transition, whereas impaired lateral inhibition allows spread of seizure activity. The epileptogenic effect of reduced extracellular chloride concentration ([Cl–]o) has been demonstrated by Chamberlin and Dingledine:130 reduction of [Cl–]o from the physiological 136 mM to 53 mM induced spontaneous interical bursts in hippocampal slices, which was associated with a +10 mV positive shift in the chloride reversal potential. Recent experiments using intraoperative microdialysis in epileptogenic foci of patients undergoing epilepsy surgery have indeed demonstrated extracellular chloride concentrations which are incompatible with intact inhibition (Speckmann, unpublished observations). GABA-A mediated inhibition is also related to the anticonvulsant action of benzodiazepines. Benzodiazepine binding to its binding site on the extracellular domain of GABA-A receptors facilitates GABA-ergic inhibition by increasing chloride influx. Long-term exposure to benzodiazepines, however, induces secondary changes in the efficacy of the GABAergic system that have epileptogenic effects. Davies et al.,131 for example, showed that long-term incubation of rat hippocampal slices with clonazepam induces spontaneous epileptiform bursts, which are associated with a reduced duration of the post-spike-train afterhyperpolarization. This is the putative basis for benzodiazepine withdrawal seizures. GABA-B mediated inhibition GABA-B receptors are located pre- and postsynaptically and induce G-protein mediated opening of potassium channels.132,133 The hyperpolarization caused by GABA-B receptor activation has a slower onset and longer duration than the ‘fast’ GABA-A inhibition. GABA-B mediated IPSPs therefore contribute to the late phase of the afterhyperpolarization (AHP)

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following epileptiform bursts and determine its duration. Presynaptic GABA-B receptors inhibit synaptic neurotransmitter release. Data about the involvement of GABA-B receptors in epileptogenesis are ambiguous: Asprodini et al.134 report that in vivo kindling of rats reduces the sensitivity of presynaptic GABA-B receptors as assessed by the EC50 of the GABA-B receptor agonist baclofen needed to depress EPSPs, suggesting a protective role of GABA-B receptors against excessive excitatory activity. On the other hand, presynaptic GABA-B receptors can enhance epileptiform activity by reducing synaptic GABA release by interneurons.135 Sutor et al.136 report a concentration-dependent differential effect of GABA-B receptor antagonists on bicuculline-induced epileptiform activity in rat neocortex, with low concentrations enhancing, but higher concentrations suppressing stimulus-evoked epileptiform discharges. GABA-B receptor activation by baclofen has been shown to induce a long-lasting potentiation of evoked population spikes and spontaneous epilepitform discharges.137 Low-Mg2+ and 4-aminopyridine induced interictal-like epileptiform activity in the hippocampus is reversibly transformed to ictal activity by application of baclofen.138,39 These findings suggest that interictal discharges may be to some degree protective against ictal transition. Reducing the repetition rate of interictal discharges by enhancing the GABA-Bmediated late phase of the burst afterhyperpolarization might be a mechanism involved in seizure generation, possibly by synchronizing large cell populations and/or by recruiting cation conductances that are otherwise incativated at resting membrane potential, such as the hyperpolarization-activated inward current (Ih) or low-threshold Ca2+ channels.140 A similar interaction between GABA mediated inhibition and slow conductances activated by hyperpolarization has been proposed as the underlying mechanism for the generation of generalized spike-wave seizures through thalamocortical loops.141

Neuromodulators and second messenger mechanisms Metabotropic glutamate receptors Metabotropic glutamate receptors (mGLU) are second-messenger coupled receptors that have diverse effect on neuronal excitability and are likely to be involved in neuronal plasticity. Some evidence suggests a role of mGLU receptors in epileptogenesis.142,143 Pasti et al.144 have demonstrated that mGLU receptors mediate glutamate release from astrocytes, which might play a role in seizure propagation. However, several studies have shown that some mGLU subtypes have anticonvulsant effects as well. For example, mGLU types I and II reduce the ampltidute of AMPA- and NMDA-receptor mediated EPSPs by a presynaptic mechanism.145,146 This may be a means of regulating excitatory transmission during massive excitation. The relevance of these various data for human epilepsy is still unknown and requires further investigation. Adenosine receptors Adenosine is an endogenous neuromodulator that is released following excessive metabolic activity and exerts inhibitory effects on neurons. As extracellular adenosine concentration

rises markedly during seizures, its depressant effects on excitability and extitatory transmission may be involved in seizure termination. Adenosine and other purinoreceptor agonists suppress epileptiform activity in the CA3 region of the hippocampus by a presynaptic mechanism.147 Blockers of the adenosine receptor, such as caffeine and other methylxanthines, have well-known stimulating effects on cortical activity. In the guinea pig hippocampus in vitro, caffeine induces epileptiform discarges.148 Moreover, blocking effects on adenosine receptors have been shown to be involved in the epileptogenic effect of reduced extracellular magnesium concentration.29 Acetylcholine (ACh) receptors Muscarinic ACh receptors Slow excitatory postsynaptic potentials (EPSPs) have been identified in rat neocortical slices which are antagonized by muscarinic acetylcholine receptor antagonists and enhanced by cholinesterase inhibitor,149 suggesting a role of muscarinic acetylcholine receptors in regulating excitability. In cat visual cortex, acetylcholine induces depolarization by reducing the conductance of potassium channels.150 Application of muscarinergic substances such as pilocarpin causes severe seizures in rodents. Nicotinic ACh receptors Activation of the nicotinic ACh receptor–ion channel complex by ACh leads to fast unspecific ion influx through a nonselective cation channel. The pharmacological properties of nicotinic ACh receptors are dependent on their subunit composition which is differentially distributed throughout the brain. The role for the pathophysiology of epilepsy is still unclear from a mechanistic standpoint. Genetic studies, however, revealed that a missense mutation in one nicotinic ACh receptor subunit is associated with nocturnal frontal lobe epilepsy in an Australian family.151 Noradrenergic receptors Noradrenaline (norepinephrine) (NA) exhibits differential modulatory effects on epileptiform activity. Via alpha-1 receptors, NA blocks low-Mg2+-induced epileptiform activity in the entorhinal cortex.152 In rodent dentate gyrus and neocortex, in contrast, NA exerts proconvulsant effects mediated by beta receptors.149,152 Beta receptor activation induces prolongation of low-Mg2+-induced ictal discharges, probably by activation of a slow synaptic cation current. Dopamine receptors Co-application of dopamine (DA) and NMDA enhances NMDA-induced membrane depolarization and action potential firing. Co-application of DA and glutamate, however, decreases fast synaptic potentials mediated by non-NMDA glutamate receptors.153 From a neurocognitive perspective, this might represent the underlying mechanism of dopamine as regulator of the ‘signal-to-noise ratio’ in the neocortex. The proconvulsant properties of dopamine antagonists, such as neuroleptic drugs, may be related to enhancement of AMPA/kainate receptor mediated lateral spread of epileptiform activity.

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In vitro neurophysiological studies Neuropeptide Y Neuropeptide Y (NPY) and two neuropeptide Y agonists ((P)YY(3-36) and 1-4-(6-aminohexanoic acid)-25-36([ahx(5-24)])-NPY) inhibit low-Mg2+- and picrotoxininduced interictal epileptiform discharges in rat hippocampal slices in vitro by inhibiting glutamatergic synaptic transmission, suggesting a protective role of NPY against epileptogenic hyperactivity.154 Nitric oxide Nitric oxide (NO) is synthetized by nitric oxide synthase (NOS) from L-arginine.155 The neuronal form of NOS (nNOS) is linked to the postsynaptic density protein complex156 and is activated by increase of intracellular free Ca2+, mediated by Ca2+-calmodulin, which enters the cell through NMDA-receptor channels and voltage-gated Ca2+channels.157–160 NO affects neuronal excitability via a multitude of actions that are mediated by guanylate cyclase activation161–163 and S-nitrosylation of target proteins.164,165 Most effects of NO are excitatory: As a ‘retrograde transmitter’, NO increases presynaptic glutamate release after crossing the synaptic cleft by diffusion.157,167 Besides, it facilitates voltagegated Na+ channels,168 and decreases GABAA repeptor mediated

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currents.169 On the other hand, NO also exerts some depressant actions on excitability: it dampens excitatory post-synaptic potentials (EPSPs) by decreasing AMPA-receptor170,171 and NMDA-receptor172–174 mediated currents, thus providing a ‘negative feedback’ following synaptic activation. It may also decrease membrane excitability by inducing tonic activation of K+ channels.175 Other neuromodulatory effects on epielptiform activity Activation of mu opioid receptors in the ventral, but not in the dorsal hippocampus induces triggered and spontaneous epileptiform bursting.176 Pregnanolone, a metabolite of progesterone, depresses the amplitude of population spikes in the CA1 region of the hippocampus, probably by enhancing GABA-A receptor function.177 This might have implications in regard to catamenial epilepsy. Ethanol reversibly suppresses the duration of NMDA-receptor mediated synaptic responses, implying that it exerts anticonvulsant properties when acutely applied.178 Long-term exposure to ethanol, in contrast, leads to up-regulation of NMDA-receptor NR2B subunits, thereby increasing the potency of NMDA receptors.179 This may be the mechanism underlying epilepsy induced by chronic alcohol intake.

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Chamberlin NL, Dingledine R. GABAergic inhibition and the induction of spontaneous epileptiform activity by low chloride and high potassium in the hippocampal slice. Brain Res 1988;445(1):12–18. Davies MF, Sasaki SE, Carlen PL. Benzodiazepine-induced epileptiform activity in vitro. Brain Res 1987;437(2):239–44. Dutar P and Nicoll RA. A physiological role for GABAB receptors in the central nervous system. Nature 1988;332:156–8. Thalmann RH. Evidence that guanosine triphosphate (GTP)-binding proteins control a synaptic response in brain effect of pertussis toxin and GTPflS on the late inhibitory post-synaptic potential of hippocampal CA3 neurons. J Neurosci 1988;8:4589–602. Asprodini EK, Rainnie DG, Shinnick-Gallagher P. Epileptogenesis reduces the sensitivity of presynaptic gamma-aminobutyric acidB receptors on glutamatergic afferents in the amygdala. J Pharmacol Exp Ther 1992;262(3):1011–21. Haas KZ, Sperber EF, Moshe SL, Stanton PK. Kainic acid-induced seizures enhance dentate gyrus inhibition by downregulation of GABA(B) receptors. J Neurosci 1996;16(13):4250–60. Sutor B, Luhmann HJ. Involvement of GABA(B) receptors in convulsant-induced epileptiform activity in rat neocortex in vitro. Eur J Neurosci 1998;10(11):3417–27. Burgard EC, Sarvey JM. Long-lasting potentiation and epileptiform activity produced by GABAB repector activation in the dentate gyrus of rat hippocampal slice. J Neurosci 1991;11(5): 1198–209. Swartzwelder HS, Lewis DV, Anderson WW, Wilson WA. Seizure-like events in brain slices: suppression by interictal activity. Brain Res 1987;410(2):362–6. Avoli M, Benini R, de Guzman P, Omar A. GABA(B) receptor activation and limbic network ictogenesis. Neuropharmacol 2004;46(1):43–51. Foehring RC, Waters RS. Contributions of low-threshold calcium current and anomalous rectifier (Ih) to slow depolarizations underlying burst firing in human neocortical neurons in vitro. Neurosci Lett 1991;124(1):17–21. Wallenstein GV. The role of thalamic IGABAB in generating spike-wave discharges during petit mal seizures. Neuroreport 1994;5(11):1409–12. Merlin LR, Taylor GW, Wong RKS. Role of metabotropic glutamate receptor subtypes in the patterning of epileptiform activities in vitro. J Neurophysiol 1995;74:896–900. Taylor GW, Merlin LR, Wong RKS. Synchronized oscillations in hippocampal CA3 neurons induced by metabotropic glutamate receptor activation. J Neurosci 1995;15:8039–52. Pasti L, Pozzan T, Carmignoto G. Long-lasting changes of calcium oscillations in astrocytes: a new form of glutamate-mediated plasticity. J Biol Chem 1995;270:15203–10. Sheardown MJ. Metabotropic glutamate receptor agonists reduce epileptiform activity in the rat cortex. Neuroreport 1992; 3(10):916–18. Iserhot C, Gebhardt C, Schmitz D, Heinemann U. Glutamate transporters and metabotropic receptors regulate excitatory neurotransmission in the medial entorhinal cortex of the rat. Brain Res 2004;1027(1–2):151–60. Ault B, Wang CM: Adenosine inhibits epileptiform activity arising in hippocampal area CA3. Br J Pharmacol 1986;87(4):695–703. Moraidis I, Bingmann D, Lehmenkuhler A, Speckmann EJ. Caffeineinduced epileptic discharges in CA3 neurons of hippocampal slices of the guinea pig. Neurosci Lett 1991;129(1):51–4. Benardo LS: Acetylcholine and norepinephrine mediate slow synaptic potentials in normal and epileptic neocortex. Neurosci Lett 1991;126(2):137–40. Krnjévic K, Pumain R, Renaud L. The mechanism of excitation by acteylcholine in the cerebral cortex. J Physiol 1971;215 (1):247–68. Steinlein OK, Mulley JC, Propping P et al. A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 1995;11(2):201–3. Stanton PK. Noradrenergic modulation of epileptiform bursting and synaptic plasticity in the dentate gyrus. Epilepsy Res Suppl 1992;7:135–50. Cepeda C, Radisavljevic Z, Peacock W, Levine MS, Buchwald NA. Differential modulation by dopamine of responses evoked by excitatory amino acids in human cortex. Synapse 1992;11(4):330–41.

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Klapstein GJ, Colmers WF. Neuropeptide Y suppresses epileptiform activity in rat hippocampus in vitro. J Neurophysiol 1997;78(3):1651–61. Bredt DS, Snyder SH. Isolation of nitric oxide synthase, a calmodulin-requiring enzyme. Proc Natl Acad Sci USA 1990;87:682–5. Brenman JE, Bredt DS: Synaptic signaling by nitric oxide. Curr Opin Neurobiol 1997;7:374–8. Garthwaite J. Glutamate, nitric oxide and cell–cell signalling in the nervous system. Trends Neurosci 1991;14:60–7. Garthwaite J, Boulton CL. Nitric oxide signaling in the central nervous system. Ann Rev Physiol 1995;57:683–706. Iadecola I. Bright and dark sides of nitric oxide in ischemic brain injury. Trends Neurosci 1997;20:132–9. Contestabile A. Roles of NMDA receptor activity and nitric oxide production in brain development. Brain Res Rev 2000;32:476–509. Stasheff SF, Bragdon AC, Wilson WA. Induction of epileptiform activity in hippocampal slices by trains of electrical stimuli. Brain Res 1985;344(2):296–302. Arnold WP, Mittal CK, Katsuki S, Murad F: Nitric oxide activates guanylate cyclase and increases guanosine 3’:5’-cyclic monophosphate levels in various tissue preparations. Proc Natl Acad Sci USA 1977;74(8):3203–7. Katsuki S, Arnold W, Mittal C, Murad F. Stimulation of guanylate cyclase by sodium nitroprusside, nitroglycerin, and nitric oxide in various tissue preparations and comparison to the effects of sodium azide and hydroxylamine. Cyclic Nucleotide Res 1977;3(1):23–35. Miki N, Kawabe Y, Kuriyama K. Activation of cerebral guanylate cyclase by nitric oxide. Biochem Biophys Res Commun 1977;75(4):851–6. Stamler JS, Simon DI, Osborne JA et al. S-nitrosylation of proteins by nitric oxide: Synthesis and characterization of biologically active compounds. Proc Natl Acad Sci USA 1992;89:444–8. Jaffrey SR, Erdjument-Bromage H, Ferris CD, Tempst P, Snyder SH. Protein- S-nitrosylation: a physiological signal for neuronal nitric oxide. Nat Cell Biol 2001;3:193–7. O’Dell TJ, Hawkins RD, Kandel ER, Arancio O. Test of the roles of two diffusible substances in long-term potentiation: evidence for nitric oxide as a possible early retrograde messenger. Proc Natl Acad Sci USA 1991;88:11285–9. Kawai F, Miyachi E. Modulation by cGMP of the voltage-gated currents in newt olfactory receptor cells. Neurosci Res 2001;39:327–37. Leidenheimer NJ. Effect of PKG activation on recombinant GABAA receptors. Mol Brain Res 1996;42:131–4. MacMahon DG, Ponomareva LV. Nitric oxide and cGMP modulate retinal glutamate receptors. J Neurophysiol 1996;76: 2307–15. Lei S, Jackson MF, Jia Z et al. Cyclic GMP-dependent feedback inhibition of AMPA receptors is independent of PKG. Nat Neurosci 2000;3(6):559–65. Lei SZ, Pan ZH, Aggarwal SK et al. Effect of nitric oxide production on the redox modulatory site of the NMDA receptor-channel complex. Neuron 1992;8(6):1087–99. Lipton SA, Choi YB, Pan ZH et al. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 1993;363:626–32. Manzoni O, Prezeau L, Marin P et al. Nitric oxide-induced blockade of NMDA receptors. Neuron 1992;8:653–62. Klyachko VA, Ahern GP, Jackson MB. cGMP-mediated facilitation in nerve terminals by enhancement of the spike after-hyperpolarization. Neuron 2001;31:1015–25. Lee PH, Xie CW, Lewis DV et al. Wilson WA, Mitchell CL, Hong JS: Opioid-induced epileptiform bursting in hippocampal slices: higher susceptibility in ventral than dorsal hippocampus. J Pharmacol Exp Ther 1990;253(2):545–51. Landgren SO. Pregnanolone (3-alpha-hydroxy-5 alpha-pregnane20-one), a progesterone metabolite, facilitates inhibition of synaptic transmission in the Schaffer collateral pathway of the guinea pig hippocampus in vitro. Epilepsy Res 1991;10(2–3): 156–65. Gean PW. Ethanol inhibits epileptiform activity and NMDA receptor-mediated synaptic transmission in rat amygdaloid slices. Brain Res Bull 1992;28(3):417–21. Kalluri HS, Mehta AK, Ticku MK. Up-regulation of NMDA receptor subunits in rat brain following chronic ethanol treatment. Brain Res Mol Brain Res 1998;58(1–2):221–4. Walz W. Role of glial cells in the regulation of the brain ion microenvironment. Prog Neurobiol 1989;33:309–33. Stasheff SF, Bragdon AC, Wilson WA. Induction of epileptiform activity in hippocampal slices by trains of electrical stimuli. Brain Res 1985;344(2):296–302.

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In vitro cytochemical studies in epilepsy JA González-Martínez, CQ Tilelli, and IM Najm

Introduction Initially, data about the histology of epileptic tissue started with histochemical descriptions in tissue processed by relatively simple techniques such as cresyl-violet, Nissl, hematoxylin-eosin and Golgi stainings.1–3 The current epileptic tissue research includes not only these studies, but also singlecell injection of markers that fill all the projections of the cell,4,5 immunohistochemistry of many proteins6–8 and in situ hybridization that shows expression of mRNA.9,10 Those techniques provide not only morphological data, but also elucidate cell morphology, type, functionality, chemistry and role in the epileptic brain.11 In this chapter, we will review the general findings in cytochemical studies in epilepsy research and their contribution in the understanding of pathophysiological mechanisms of epileptogenicity.

In vitro cytochemical studies in temporal lobe epilepsy More than a century after the first histological description of sclerotic hippocampus associated with temporal lobe epilepsy (TLE),3 much has been added to the description of the tissue, but the mechanisms by which hippocampal sclerosis (HS) occurs and its specific role in seizure initiation and propagation is still uncertain. Hippocampal sclerosis Hippocampal sclerosis (HS) is characterized by extensive loss of pyramidal neurons from areas 1, 3, and 4 of the Ammon’s horn (CA1, CA3, and CA4, respectively), as well as neurons in granular, polymorphic and molecular layers of dentate gyrus (DG).3,12 Granular cells of DG suffer dispersion and marked plasticity, which includes primarily a simplification of its dendritic arbor, loss of dendritic spines and nodulation of dendrites.2,13,14 Cytochemical studies showed the loss of dentate gyrus (DG) interneurons, supposedly GABAergic, with plasticity of the remaining ones.15–17 In addition, synaptic terminals coming from granular cells of DG and probably also from the supramammilary tract sprout their connections through the inner third of DG molecular layer.18 Hippocampal-related areas such as amygdala and temporal lobe cortices can also have cell loss in different magnitudes, and although this is frequently found in association with HS,

it can also be independent.19 Indeed, amygdala damage may contribute to seizure propagation, as this structure receives monosynaptic inputs from large areas (frontal and temporal cortices), and spreads the signals to its outputs by activating dense intradivisional connections (extrapyramidal system, cortex and hippocampal formation).18 Hystological studies revealed that the volume of amygdala reduces as a function of lifetime seizure number, and also argue that the presence of fear in seizures may be an indication of amygdala participation.18 Hippocampal sclerosis and mossy fiber sprouting One of the most striking findings from cytochemical studies in HS tissue is the mossy fiber sprouting (MFS), which was first described in animal models of epilepsy and later confirmed in human specimens by in vitro cytochemical studies.7,20 This intense reorganization of excitatory connections in the hippocampal circuitry can be easily visualized by TIMM’s staining, a cytochemical technique that enhances zinc-containing synaptic terminals,21 which are supposedly linked to excitatory neurotransmission. The dentate gyrus (DG) of sclerotic hippocampus presents a zinc-positive region in the inner third of molecular layer, which is completely absent in the normal hippocampus.20 Hippocampal neuroanatomy is very well characterized, and the MFS findings with HS attracted so much attention to hippocampus as a probable seizure-causative structure in epilepsy that for decades the study of other related structures was put aside. Interestingly, the first theories that considered MFS in HS and its relation to seizure initiation and propagation claimed that loss of inhibitory interneurons and/or the recurrent excitatory pathway in the DG would contribute to the hyperexcitation of the hippocampus.22,23 Later, evidence both in animal models and human studies showed that the DG, in spite of hyperexcitation, presented a tonic hyperinhibition, and that the collapse of such inhibition would be responsible for seizure initiation.19 Much work remains to further illustrate how such circuitry alterations contribute to seizures in epileptic patients. There is evidence suggesting that modifications occurring in HS are an acute process, and seizures do not contribute to damage of remaining neurons.24,25 Mathern et al.24 based this assumption on results from children’s HS compared to autopsy cases, where they confirmed hippocampal sclerosis and found no evidence of increased dead neurons (using TUNEL staining, a technique that marks neuronal apoptosis). Additionally, some studies utilizing immunocytochemistry to PSA-NCAM and GAP-43 (developmental related molecules) suggested that 1397

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sprouting is an ongoing event in sclerotic hippocampus from TLE patients, as both molecules are increased in the molecular layer of the DG in this tissue.26,27 Neurotransmitters and receptors Characterization of neurotransmitters and receptors in the epileptic area can indicate the relation between excitation and inhibition in the tissue. The differential expression of many excitatory receptors is already described in HS.9 Ying et al. found NMDA-R1 receptor (NR1) upregulated in both granular cells and molecular layer of DG in sclerotic hippocampus as compared to nonsclerotic hippocampus of epileptic patients with TLE.28 In contrast, Mathern et al. did not find NR1 protein expression increased in HS, but its mRNA. In addition, they also found that other subunits of glutamate receptors of AMPA and NMDA families were increased, both mRNA and proteins (GluR1-3 and NR2b).9 They discuss the fact that other works found decreased expression in the same proteins/mRNAs, and point to the possibility that these differences can be a result of presence or absence of correction of the quantification per neuron in HS, as there are much less neurons in sclerotic hippocampus that survive and are able to express proteins as compared to a normal, nonsclerotic hippocampus. Different receptor compositions can result in different patterns of channel activation and inactivation, what could directly impact on neurotransmitter-mediated neuronal response. Indeed, heteromeric combinations of NMDA receptors (NR1 plus NR2B) result in higher and slower decay currents when compared to a channel composed exclusively by NR1.29,30 There is a 100% increase in AMPA receptors binding and a 50% decrease in NMDA receptors binding in DG of human HS.31 This could indicate a differential expression of receptors or a different affinity of the receptors to its binding molecules. In contrast, studies in a rat model of TLE show a reduction of AMPA binding in hippocampus.31 In a study of MTLE granular cells of DG, glutamate currents were found prolonged and this phenomenon would be related to NMDA receptors activation.5 They suggest that the dendritic alterations usually seem in DG granular cells may have a role in this excitatory facilitation, based on the fact that cells growing in a medium containing bicuculline develop epileptic tissue-like characteristics.5 According to in vitro cytochemical studies, inhibitory neurons can be extensively affected and modified in epileptic tissue. Parvalbumin (PV)-positive cells are reduced in MTLE patients, compared to autopsy hippocampi.15 The surviving cells in HS receive the majority of inputs probably excitatory (asymmetric synapses as seen by electron microscopy) and send inhibitory (symmetric synapses) connections to pyramidal neurons of the Hippocampus.15 In addition to PV-positive, the number of calbindin (CB)-positive neurons is also reduced in HS.16 These interneurons are dispersed in the DG granular layer and this dispersion is accompanied by proliferation of PV- and CB-positive terminals, as well as in GABA transporter 1-positive terminals, mainly in hippocampi presenting stronger sclerosis.16 Additionally, there are chandelier terminals in the granular cells layer of DG, which are absent or less complex in nonsclerotic hippocampi. Chandelier terminals are synaptic buttons complexes localized in the axon of

pyramidal cells, proximal to cell body, and have strong inhibitory action.17 The same increased complexity of synaptic terminals is found in PV-positive basket formations around surviving neurons at the border between CA1 and subicullum areas.16 Interestingly, cytochemical studies revealed that microregions of the DG maintained cellular density but lacked inhibitory terminals, maybe resulting in hyperexcitatory microregions. Additionally, there are evidence that GABAB receptor histology in non-sclerotic hippocampi closely matches hippocampal cytoarchitecture, but it is down regulated in HS.32 Maglóczky et al. also report loss of CB-positive neurons in TLE, but additionally describe that the remaining cells have larger soma, acquire somatic spines and present invaginated nuclei (indicative of been metabolically very active). On the other hand, those cells are extensively surrounded by glia, what can bock the formation of synapses.33 In the same work, they report that calretinin (CR)-positive neurons are also lost, and the remaining ones also present nucleus invagination and are surrounded by glial processes.33 CR-positive terminals distribution is expanded in the DG, and the authors suggested that these terminals are probably coming from the supramammillary tract, indicating a second source of excess excitation of DG cells in addition to de MFS.33 Maybe even more interestingly then the compensatory sprouting described above, substance P receptor (SPR)-positive neurons change their position, migrating from inside the hilus of DG to the molecular layer.33 These neurons also present a deeply invaginated nucleus and a cell body partially covered by glial processes.33 Substance P containing neurons in MTLE have also been described by de Lanerolle et al. (2003),34 with concomitant sprouting of substance P-containing fibers to the DG.

In vitro studies in neocortical epilepsy and malformations of cortical development Malformations of cortical development (MCD) are one of the main causes of epilepsy in humans.35–37 They include many pathologies, among them polymicrogyria, paquigyria, hemimegalencephaly, tuberous sclerosis, and focal cortical dysplasia (FCD).38,39 In this review, we will focus our discussion in in vitro cytochemical findings in human FCD. FCD are characterized by a disruption of the normal lamination of the cortex that can vary in intensity, ranging from a light disruption of lamination with normal-appearing neurons to a strong loss of lamination, usually accompanied by the appearance of dysmorphic and misoriented neurons, neuronal clustering, giant neurons and balloon cells (BC).1,40,41 In addition, heterotopic neurons and gliosis are observed in the white matter,1,40,41 sometimes concomitant with a lack of myelin in that region.42 Giant neurons in FCD apparently have a normal content of cytoplasmatic organelles43 and, as normal pyramidal cells, receive numerous symmetric synapses in cell body and proximal dendrites.43 There is evidence for morphological alteration of both excitatory and inhibitory neurons in FCD.6,44,45 FCD may be a consequence of erroneous migration of stem cells, or their maturation, programmed cell death that also

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In vitro cytochemical studies in epilepsy occurs in ontogenesis, or maybe even a combination of various factors.46–48 Based on morphological studies using antibodies against NeuN, a specific marker for neurons, Andres et al.40 suggested that some characteristics of the dysplastic cortex resemble prenatal cortex of primates and humans and propose that FCD would be a defect occurred in late phases of development. This data is partially in agreement with Mischel et al.49 who proposed a classification of the MCD with a grading system, based on the probable time-frame when the abnormality of development takes place, suggesting that mild FCD (or FCD type I) would be in late development and FCD with BCs would be severe (or FCD type IIb), happening in early developmental phases.36 The study of protein expression in FCD is very useful in order to help to highlight dysmorphisms in the disrupted cortex.6 Using immunocytochemical studies (with primary antibodies for MAP2, neurofilaments, GFAP, PV, CB, and CR), Spreafico et al.48 suggested that the lesion observed in MRI does not correspond exactly to the area of dysplasia, but is included in it. Additionally, an abnormally increased expression of neurofilaments can be observed in the areas where FCD is more evident on MRI. MAP1B is increased in dysmorphic neurons from FCD, and it is abundant in immature brain, declining with maturation in the normal brain, thus indicating that morphological remodeling may be an ongoing process in FCD.6,50 Other proteins that are usually expressed during brain development and are downregulated in mature neurons such as vimentin, nestin, and SMI311 (marker for nonphosphorilated filaments), are expressed in BCs from FCD, tuberous sclerosis and hemimegalencephaly.6,47 mRNA of vimentin, nestin, neurofilament, peripherin, and α-internexin are also suggestive of neuron immaturity and are detected in a subset of neurons in FCD tissue.37 In malformations of cortical development, the histological appearance and the location of balloon cells suggest that they are developmentally immature. By using silver impregnation technique, Derosa et al.51 had shown the presence of nucleolar organizer regions that were believed to be involved in cell proliferation. Additionally, transcription of genes for nestin and vimentin were enhanced in the balloon cells.37 Over the past several years, much more attention has been focused on nestin, a marker for neuronal progenitor cells.52–55 Recently, human hematopoietic stem cell antigen AC133, also called CD133, was shown to be expressed in both hematopoietic and neuropoietic cells.56 CD133 positive cells are capable of neurosphere initiation, self renewal, and multilineage differentiation at the single cell level.56 Therefore, CD133 has been used to identify neural stem cells in the human brain.56–58 Balloon cells were found to be immunoreactive to CD133, nestin, Bcl-2, Tuj1, vimentin, and GFAP. Confocal double labeling analyses also showed that balloon cells were dual immunopositive for CD133/nestin; CD133/GFAP; CD133/Bcl-2, and nestin/GFAP (Figure 147.1). The expression of CD133 protein in BCs may suggest that these cells fail to mature fully and therefore continue to express embryonic genes. Subsequently, these immature cells may lack some of the cellular machinery for migration. This may explain at least in part the localization of the BC in the white matter and gray/white matter junction. Using organotypic slice preparation, our group identified the presence of BrdU uptake in neocortex of patients with

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epileptic cortical dysplasia, suggesting increase cell proliferation in epileptic cortical dysplastic samples. It is unknown if the increment in BrdU uptake observed in the epileptic samples corresponded to neurogenesis (Figure 147.2). We also found the presence of Tuj1 expressing cells (a marker for immature neurons) in the subventicular zone of dysplastic epileptic patients (Figure 147.3a). The immature neurons were organized in chains, suggesting the presence of migration. Additionally, in the same tissue samples, BrdU positive cells double-labeled with nestin were presented, suggesting stem cell proliferation and probably differentiation (Figure 147.3b). There is an extensive modification of neurotransmitters receptors in FCD.28,59 For example, NR2A/B and NR1-1a, 1b, 2a, and 2b are over-expressed in FCD tissue, more specifically in dysplastic neurons.60 Other glutamate receptor subunits are distributed equally in both FCD and normal cortex, such as NR1-3a, 3b, and 4a.28 This abnormal expression of glutamate receptors in FCD may be part of the mechanism of epileptogenesis in this tissue. In microdissected cells of FCD tissue, where RT-PCR was used in order to identify mRNA differential expression, there is a reduction in glutamate receptors subunits Glu R1 and NMDA-R2A, and GABA receptor subunits GABA α1, α2, β1, and β2.59 Increased expression was described for Glu R4, NR2B, and NR2C glutamate subunit receptors.59 In vitro cytochemical studies also indicated differential expression and interaction between glutamate receptor subunits and related proteins. Ying et al.61,62 found an increased expression and co-assembly of NR1, NR2B, and PSD-95 in epileptic versus nonepileptic cortical samples from patients with cortical dysplasia and epilepsy who underwent resective surgery. Interestingly, in another set of experiments using ICC, the same group found no change in NR1 quantity in epileptic cortex from FCD, but increased expression of NR2A/B in dysplastic area.44,63 These results suggested that these alterations and apparent differential interaction between NR1 and NR2A/B may be an important mechanism of epileptogenesis in FCD.61 Electrophysiology of FCD tissue showed that normal appearing neurons have characteristics of neurons from control cortex, but dysmorphic neurons have lower capacitance, increased resistance and decreased time constant.64 On the other hand, giant neurons are more excitable, as they present increased capacitance, decreased resistance and longer time constant,4,8 and need prolonged time to recovery from desensitization to NMDA.8 Cepeda et al.8 found that BCs are not excitable at all, and suggested that their presence could lead to modification of the structure of surrounding cortex, thus collaborating to the net excitability of the tissue. Advanced molecular techniques such as proteomics and cDNA arrays are becoming important tools in the investigation of FCD and other types of epilepsy. Nonetheless, although some first works in this area have been successful in finding variation in various molecules in FCD as compared to normal cortex, they are not able to discuss in details their findings, probably because of the quantity of molecules with altered expression as well as the fact that many of those molecules have their role in nervous system poorly understood or apparently not related to mechanisms that could lead to epileptogenicity. Kim et al.65 found seven genes that had modified regulation in FCD compared to normal cortex, three of them up-regulated and 4 down-regulated, showing that those

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(a)

(b)

(c)

(d)

Figure 147.1 Colocalization of antibodies against CD133 with antibodies to intermediate filament proteins (nestin and GFAP) in balloon cells by confocal microscopy. Co-expression of CD133 with either nestin or GFAP was clearly detected in the balloon cells (a and d). The presence of singly-labeled CD133, nestin, or GFAP were also observed. Co-expression CD133 and Bcl-2 in a subset of balloon cells is shown in c. A population of balloon cells is shown to be immunoreative to both nestin (red) and GFAP (green) (b). Double staining for CD133 and MAP2 failed to reveal any co-locolization of these proteins in the balloon cells. (See Color plates.)

molecules may have a potential role in cascades that are related to epileptogenesis, as they participate in neurogenesis, apoptosis and migration-regulation processes. Another study using proteomics showed nine molecules differentially regulated in dysplasic temporal lobe neocortex.66 Among them, the authors selected two to be discussed, the mitochondrial type Mn-superoxide dismutase, that takes place in antioxidant processes, and the glycerol phosphate dehydrogenase,

which is a multifunctional protein involved in triglycerides metabolism.66 The comparison between FCD with other types of MCD may give hints of the underlying mechanisms of epileptogenicity in those pathologies. For example, hamartin- and tuberin-expressing genes TSC1 and TSC2, respectively, are found altered in tuberous sclerosis pathology.67 These proteins are part of a tumor-suppression mechanism, related to cell

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(a)

(b)

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Figure 147.2 Difference in BrdU-labelling in normal versus epileptic dysplastic neocortex and adjacent white matter. a, Cresylviolet (CV) staining from lateral temporal cortex showing normal cytoarchitetonic columnar organization. b, CV staining from dysplastic lateral temporal lobe showing loss of columnar organization and the presence of cytomegalic cells. c, Similar sample depicted in a showing NeuN expression, demonstrating the normal columnar organization of neocortical neurons. d, Similar sample depicted in b showing NeuN expression, demonstrating the loss of the columnar organization and the presence of cytomegalic neurons (arrow). e, Adjacent white matter (intermediate zone [IZ]) related to the cortical samples depicted in a and c showing the absence of BrdU staining. f, IZ related to the cortical samples depicted in b and d, demonstrating intense BrdU staining. (See Color plates.)

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(a)

(b)

Figure 147.3 ICC for Tuj1 in the SVZ from epileptic dysplastic sample. Bar: 40 µm. (3b) Double-labeled immunoflorescence (Nestin-red, BrdU-green) in the SVZ from epileptic dysplastic sample. (See Color plates.)

growth and proliferation regulation.68,69 Both TSC1 and TSC2 genes role were investigated in FCD, and indicate that FCD with BCs is characterized by a high incidence of TSC1, but not TSC2.68,69 Interestingly, TSC2 is more frequently found altered in familial tuberous sclerosis pathology, while TSC1 alterations are found related to sporadic incidence.69 When comparing immunocytochemistry in FCD type IIb, hemimegalencephaly and tuberous sclerosis tissue, Fauser et al. described similarities in CD34 (neural development marker), GFAP (glia marker), and neurofilament (neural marker) expressions in all groups.70 Based on similarities between TS and FCD, Mackay et al.71 suggested genetic counseling to patients presenting FCD with balloon cells. Crino et al.6 suggested that extensive histological similarities can be found when comparing hemimegalencephay and FCD, with disorganized cortical lamination and presence of white matter heterotopias and BCs, the main difference been the area committed in the pathology. Glia in epilepsy Studies that analyzed the role of glial cells in epileptic tissue point to an important role of those cells in seizure initiation and maintenance.72–74 Gliosis is frequently found in epileptic tissue.2,11,73 There is evidence that glia in epileptic tissue is not able to maintain K+ and Ca++ homeostasis.72,75,76 In MTLE tissue, glial cells from DG hilus have a reduction in the number of K+ channels, what could contribute for the decreased K+ conductance in specific regions in the epileptic brain.76–78 Glial cells from FCD may also have their electrophysiological characteristics modified, suggesting inability to

maintain ionic balance in epileptic tissue, thus maybe contributing to its hyperexcitability.76 Potassium homeostasis may be important in neurons excitability, as its increased concentration in the extracellular medium may result in cell depolarization.72–74 There is an upregulation of Na+ channels inHS astrocytes, possibly leading to an enhancement of intracellular sodium, and consequently increasing glial intracellular calcium. Increased intracellular calcium would promote the release of transmitters, cytokines and growth factor in the epileptic tissue.72

Conclusions The availability of resected focal epileptic tissue from patients with medically intractable focal epilepsy and the development and characterization of animal models for various types of epilepsies have provided a better understanding of some of the cellular and electrophysiologic mechanisms of epileptogenesis. At the single-cell or local circuitry level, in vitro models of hyperexcitability or synchronization have provided additional insights about the various mechanisms of epileptogenicity. Synaptic and nonsynaptic mechanisms have been proposed as having critical role in seizure generation and spread. Using in vitro cytochemical studies, changes in excitatory and inhibitory receptors, imbalance between excitation and inhibition and the evidence for plasticity and neurogenesis are being investigated, constituting important mechanisms involved in the generation and maintenance of intrinsic epileptogenicity.

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Tamaki S et al. Engraftment of sorted/expanded human central nervous system stem cell from fetal brain. J Neurosci Res 2002; 69:976–86. Schwartz PH et al. Isolation and characterization of neural progenitor cells from post-mortem human cortex. J Neurosci Res 2003; 74:838–51. Crino PB, Duhaime AC, Baltuch G et al. Differential expression of glutamate and GABA-A receptor subunit mRNA in cortical dysplasia. Neurology 2001;56:906–13. Ying Z, Najm IM. Mechanisms of epileptogenicity in focal malformatins caused by abnormal cortical development. Neurosurg Clin N Am 2002;13(1):27–33. Ying Z, Babb TL, Mikuni N et al. Selective coexpression of NMDAR2A/B and NMDAR1 subunit proteins in dysplastic neurons of human epileptic cortex. Exp Neurol 1999;159:409–18. Ying Z, Bingaman W, Najm IM. Increased numbers of coassembled PSD-95 to NMDA-receptor subunits NR2B and NR1 in human epileptic cortical dysplasia. Epilepsia 2004;45:314–21. Babb TL, Ying Z, Mikuni N et al. Brain plasticity and cellular mechanisms of epileptogenesis in human and experimental cortical dysplasia. Epilepsia 2000;41(Suppl 6):S76–81. Cotter D, Honavar M, Lovestone S et al. Disturbance of Notch-1 and Wnt signalling proteins in neuroglial balloon cells and abnormal large neurons in focal cortical dysplasia in human cortex. Acta Neuropathol (Berl) 1999;98:465–72. Kim SK, Wang KC, Hong SJ, et al. Gene expression profile analyses of cortical dysplasia by cDNA arrays. Epilepsy Research 2003;56(2–3):175–83. Eun SY, Hong YH, Kim EH et al. Glutamate receptor-mediated regulation of c-fos expression in cultured microglia. Biochem Biophys Res Commun 2004;325(1):320–7.

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Crino PB, Henske EP. New developments in the neurobiology of the tuberous sclerosis complex. Neurol 1999;53:1384–90. Fassunke et al. 2004 Becker AJ, Urbach H, Scheffler B et al. Focal cortical dysplasia of Taylor’s balloon cell type: mutational analysis of the TSC1 gene indicates a pathogenic relationship to tuberous sclerosis. Ann Neurol 2002;52:29–37. Fauser S, Becker A, Schulze-Bonhage A et al. CD34-immunoreactive balloon cells in cortical malformations. Acta Neuropathol (Berl) 2004;108:272–8. Mackay MT, Becker LE, Chuang SH et al. Malformations of cortical development with balloon cells: clinical and radiologic correlates. Neurology 2003;60:580–7. Steinhauser C, Seifert G. Glial membrane channels and receptors in epilepsy: impact for generation and spread of seizure activity. Eur J Pharmacol 2002;447:227–37. Dudek FE, Yasumura T, Rash JE. ‘Non-synaptic’ mechanisms in seizures and epileptogenesis. Cell Biol Int 1998;22:793–805. D’Ambrosio R. The role of glial membrane ion channels in seizures and epileptogenesis. Pharmacol Ther 2004;103:95–108. Grisar et al. 1986. Bordey A, Spencer DD. Distinct electrophysiological alterations in dentate gyrus versus CA1 glial cells from epileptic humans with temporal lobe sclerosis. Epilepsy Res 2004; 59:107–22. Hinterkeuser S, Schroder W, Hager G et al. Astrocytes in the hippocampus of patients with temporal lobe epilepsy display changes in potassium conductances. Eur J Neurosci 2000; 12:2087–96.

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Animal models of epilepsy with special reference to models relevant for transitional research S Chabardès, I Najm, and HO Lüders

Animals models of epilepsy have been used extensively for the study of mechanisms underlying the epilepsies in general, but also to test new antiepileptic drugs and clarify their mode of action. To face the diversity of epilepsies encountered in human pathology, a large variety of animal epilepsy models have been developed and characterised at a behavioral, electrical, histopathological, and sometimes genetic level. Development of neurosurgical strategies will require also the development of relevant animal models mimicking intractable epilepsies in humans. Epilepsy models in animals are frequently severe, leading to the death of the animal. This is not what is usually seen in humans. New treatment strategies such as electrical brain stimulation (DBS, VNS, cortical stimulation) or local drug delivery, require chronic models to assess the efficacy of the procedures. Besides, excessive severity of seizures may obscure potential efficacy of these therapies. This chapter will review the main characteristics of animal models of epilepsy and the possible usefulness of these models to evaluate clinical problems. In this review, we have classified the animal models in a clinical way trying to mimic as much as possible the clinical situations usually encountered in humans.

Focal or regional seizures Focal epilepsy is the most common type of human intractable epilepsy. The most frequent involves the temporal lobe but can also involve extratemporal cortex. Limbic seizures Acute In rats, limbic status is easily produced by a single intraperitoneal (ip) injection of KA (10 mg/kg). Hippocampal seizures usually occur 5–10 minutes after KA injection and last 50–100 sec. These seizures eventually spread to the neocortex within minutes and sometimes generalise (See Figure 148.1–2). The status usually last 8–12 h. Clinical behaviour is generally well stereotyped with arrest phases, wiping nose, head nodding, and motor manifestation. Histopathological findings show neuronal loss in the amygdala, the hippocampus (mainly CA1, subiculum, and CA1), the entorhinal, and piriform cortex, and also widespread cortical lesions.1,2 This model is very easy

to use, reproducible, with limited interindividual variability, and the seizures tend to be pharmacoresistant. The disadvantage of this model is that usually even the first injection produces inner cell bodies damage created by the KA itself. These structural lesions together with the severity of the seizures do not allow chronic experiments and introduce some bias in case-control studies. Chronic Chronic models of limbic seizures can be produced by local injection of small amounts of drugs like KA in the hippocampus and the amygdala, or by single/repetitive (kindling) stimulation of these structures. Small doses of KA (0.8–2.0 µg) injected in the hippocampus or the amygdala create limbic status1,3 followed by intermittent limbic seizure 2–4 weeks later. Electrical and clinical manifestations of these seizures have been classified by Racine et al.4–6 into five reproducible steps which allow comparison of the severity of seizure from one situation to another. Repetitive electrical stimulation of the hippocampus or the amygdala (kindling) in cats has been described by Alonso-De Florida and Delgado in 19587 and has since been applied in most species used in experimental conditions. In rats, this technique has been described in details.8–13 Briefly, the amygdala or the ventral hippocampus is stimulated through bipolar electrodes using trains of 400 µA in intensity, 50 Hz in frequency, and 2–5 sec in duration, for a period of 90 min. The first seizure appears after 8–38 days in 70% of the stimulated rats.12 Recently, Nissinen et al.14 have proposed a new kindling paradigm that shortens the stimulation period and produces a temporal seizure that closely mimics temporal lobe epilepsy (TLE) encountered in human pathology. The parameters used are as following: 60 hz bipolar pulse, pulse width 1 ms, 400 µA applied in trains of 100 ms every 0.5 ms for 20–30 min. Using these parameters, 85% of rats developed limbic seizures 6–85 days after the stimulation. Histopathologically, observation indicated neuronal loss in the hippocampus, the amygdala, and surrounding cortex with mossy fiber sprouting in the dentate gyrus. Interestingly, these rats eventually developed memory impairment as assessed in the Morris water-maze. This model is very useful in preclinical studies as it is well characterized, standardized, easy to produce in the lab, and lesions appear to be the result of the seizures and not the result of KA damage. 1405

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Figure 148.1 Example of seizures recorded in rats after ip injection of kainic acid. aLH, aRH: left, right hippocampus electrode; RF,LF: right, left frontal electrode. Status involves both hippocampi while bilateral seizures are also recorded at the frontal neocortical level and occur chronically every 10 to 20 seconds.

Neocortical / motor seizures Focal neocortical seizures are difficult to produce in rats or mice but can be produced more easily in bigger mammals such as cats or monkeys. In rats, partial seizures tend to involve extensive areas of the brain rather than strictly focal areas. Acute After discharge model Acute focal seizures (see Figure 148.3, personal observations) can be obtained using electrical bipolar stimulation of the

surface of the cortex.15 In this model recently revisited by Shigeto et al.16 at the CCF, focal seizure lasting 5–30 sec can be elicited by electrical stimulation. In this model, seizures are obtained using a bipolar, biphasic square pulse of current with pulse width set at 1 ms, frequency at 50 Hz, duration at 5 sec, and intensity varying from 0.5–2 mA. This model, could be relevant for testing the epileptogenicity threshold. However, the electrical stimulation creates an artefact electrical noise which can hide the beginning of seizures.

Figure 148.2 Example of seizures recorded in rats after intraperitoneal injection of kainic acid. aLH, aRH: left, right hippocampus electrode; RF,LF: right, left frontal electrode. Referential montage. Seizures start in the hippocampus bilaterally. Seizure activity secondary spreads to the frontal neocortex.

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Figure 148.3 After discharges elicited by bipolar stimulation of the neocortex in rats. The seizure is mainly observed in the stimulating electrodes (D1 and D2) and on recording electrodes (RP1 and RP2) located at the vicinity of vicinity of the stimulating contacts (D1 and D2).

Focal chemical agents: penicillin model Topical application of GABA antagonists agents can produce acute focal or regional spikes. This includes penicillin (PG),17–24 bicuculline25–28 and 4-aminopyridine (4AP).29,30 Topical use of other agents such as KA (glutamatergic agonist) can also produce focal spikes.31,32 However, seizures produced by topical applications of convulsivant agents (unpublished data) are more difficult to standardize and are less reproducible, leading to frequent rapid generalisation. GABA withdrawal has also been used to elicit focal seizure which starts immediately after having injected GABA in the cortex. In our experience,33 intra cortical injection of small amounts of Penicillin G produces very focal, long lasting, reproducible seizures. For preclinical studies, we developed an acute model of focal neocortical status epilepticus, using intracortical injection of PG in the motor cortex of rats. This model of motor seizure mimics seizures that are usually seen in patients suffering from epilepsia partialis continua. Briefly, the right motor cortex was implanted with an intracortical injection-recording cannula, and epidural screws were used for EEG recordings. PG was injected through the cannula using a Hamilton syringe at a dose of 1125–2250 IU per min for 5 min. All the rats developed focal epileptic status (see Figure 148.4 a,b,c,d) in the ipsilateral frontal cortex that lasted up to 36 hours and was always associated with contralateral forelimb clonic movements. Secondary generalisation was very rare and only occurred once when a higher amount of PG was used. In this model, EEG and behavioral patterns are both reproducible in their occurrence and predictable in their evolution. An in-house program for offline analysis was developed in order to automatically detect and characterize the number and amplitude of all spikes (Figures 148.5a and 148.5b). Histopathological examination of the focus revealed no lesions. This model has the advantage to be simple to produce; it is reproducible, well standardized and can be quantified because of the properties of spikes which are well identified. PG injections can be repeated several times in a single animal without any damage.

Chronic/semi chronic Metal deposits at the surface of the cortex Different metals introduced in the cortex produce neocortical, focal or regional seizures. One of the most convenient models for transitional research is probably the one obtained after local insertion of cobalt. This model originally developed in the 1970th34–37 has been recently revisited by Chan et al.38 It consists in inserting a small piece of cobalt wire in the cortex and, approximately 10 days later, focal seizures can be recorded in electrodes surrounding the placement of the cobalt (see Figure 148.6a; 148.6b, personal observations). Seizures are usually stereotyped, focal or regional. The number of seizures increases progressively for 2 or 3 weeks and then stops. Iron, zinc, and aluminum were also used to create focal neocortical seizures.39–43 In big mammals like rabbits, cats, dogs, and monkeys, the alumina cream model of focal neocortical seizures has been described extensively.44–51 Focal neocortical seizures are produced by subpial injection of 0.2–0.4 ml of alumina. Two to four months later, focal seizures can usually be recorded, and these can continue for several years. This model has the advantage of producing neocortical seizures that mimic those usually seen in humans for whom the seizures persist for several years. On the other hand, the seizure focus requires several weeks or months to be established and the severity of the focus tends to vary between animals. dysplasic related seizures Models of epilepsy related to cortical dysplasia are of major importance since cortical dysplasia is a frequent cause of intractable epilepsy affecting children and adolescents. Unfortunately, models of epilepsy produced by cortical dysplasia are very rare.52,53 Cortical malformations can be obtained by utero insults produced by X irradiation or by exposure to methyl-azoxymethanol (MAM) which is a DNA alkylating agent. To be effective, the exposure must occur between embryonic days 14–17. These methods create a neuronal migration disorder. Experiments conducted at CCF recently showed that low (100 cGy) or mild irradiation (145 cGy), were more effective to create seizures

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(b) Figure 148.4 a. EEG pattern of a focal neocortical seizure occurring 3 to 8 minutes after penicillin injection in the right motor cortex in rat. For a duration of 1 to 3 min, irregular low amplitude spikes (200–800 V) are restricted to the right frontal electrode (RF1) located at the side of the PG injection. b. EEG pattern of a focal neocortical seizure occurring 4 to 11 min after penicillin injection in the right motor cortex in rats. Bursts of rhythmic focal spiking (800 to 1200 µV in amplitude, 2 to 4 Hz in frequency), are recorded for a duration of 3 to 20 min. These focal spikes are mainly recorded from the right frontal (RF1, RF2) and at times from the right parietal (RP) electrodes. They are always associated with contralateral forelimb clonic movements.

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Figure 148.4 c. EEG pattern of a focal neocortical seizure occurring 7 to 31 min after penicillin injection in the right motor cortex in rats. It consists of continuous rhythmic focal (frontal electrodes) or lateralized (ipsilateral parietal area) high amplitude spikes or polyspikes (1200 to 3000 µV in amplitude, 0.5 to 2 hz in frequency) that last between 2 and 8 hours. Each spike is associated with contralateral forelimb and or facial clonic movement. d. EEG pattern of generalised seizure occurring after penicillin injection in the right motor cortex in rats. This is a late seizure evolution pattern consisting of generalized spiking intermixed with low amplitude fast spiking (10–20 Hz). This pattern occurred only once in one rat and apparently is produced by injecting a higher dose of PNG relatively fast.

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(b) Figure 148.5 a.Time course (± SD) of spikes after one single injection of penicillin in the right motor cortex in rats (n=7). Each point represents the mean number of spikes ± SD occurring during 1 mn. Spikes started within 5 min of PG injection, increased rapidly to reach a aximum of 88 spikes/min at an average of 11 min after PG injection. Then, the spike numbers decreased progressively for 2–5 hour. b. Time course of spike amplitudes following a single injection of penicillin in the right motor cortex in rat (n=7). Each point represents the mean amplitude of spikes (± SD) occurring in one minute. Threshold of spikes detection was set at 500 ∝V. The amplitude increased dramatically within the first 20 min after penicillin injection and reached a plateau that lasted for several hours. A maximum amplitude of 1934 µV (± 327.1 ) was achieved 223 min after the penicillin injection.

compared to high dose (175 cGy) of irradiation.54,55 The EEG characteristics of these models have also been recently described by the same group.56 Freeze lesions have also been used to induce focal cortical malformations. They usually create microgyri with hyper excitable cortical tissue because of an excess of excitatory glutamatergic neurons projecting to the affected gyrus.57–61

Generalized seizures Absence-like seizures Acute models Various chemical agents have been used to create absence-like seizures. Penicillin injected intraperitoneally in cats and Gamma OH injected intraveinously in monkeys are examples of such models. Snead et al.62 described that in monkeys

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(b) Figure 148.6 (a) Example of interictal spikes recorded on the electrode ‘C3’ located at the vicinity of the site of the cobalt insertion at the surface of the neocortex. (b) Example of focal seizure recorded 15 to 20 days after the insertion of a small piece of Cobalt at the surface of the motor cortex in a rat. Usually, these seizures can be recorded 2 to 4 weeks after the cobalt insertion at the surface of the cortex and then stopped spontaneously after several weeks.

treated with IV injections of Gamma Hydroxybutirate (200–400 mg/Kg), continuous and hypersynchronous spikeand-wave discharges (SWD) at a frequency of 1–3 Hz occurred 5 min after the injection. Usually, during SWD, the monkeys stared and were immobile, with the eyes closed and without any response stimuli.65 After injection of ethosuximide (150 mg/Kg), SWD stopped. Snead et al. concluded that this was a good model of ‘petit mal absence’. Intraperitoneal injection of pentylenetetrazol (PTZ)64,65 in rats also induces acute ‘petit mal absence’. Chronic/genetic The Genetic Absence Epileptic Rats of Strasbourg (GAERS) and the WAG/Rij strain of rats mimic absence seizures. GAERS are a strain of Wistar rats in which all animals show spike and wave discharges (SWD) in the cortical electroencephalogram. The seizures occur very often (One up to three

per minute) and usually last approximately 20 minutes. They are characterized by generalized spike-and-wave discharges (SWD), and are associated with behavioral arrest. They share many features with human absence epilepsy and generalized epilepsy in human, and the seizure can be suppressed by all antiabsence drugs. These discharges are facilitated by reduction of noradrenergic and dopaminergic neurotransmitters, and increments of Gabaergic transmitters. They are suppressed by ethosuximide and other antiabsence drugs, but are exacerbated by phenytoin and other anticonvulsant drugs. Progress in the understanding of the role of basal ganglia in the control of seizures has strongly benefited from the use of this genetic model of generalized non-convulsive seizures.66,67 Studies in this model suggest that the cortex, the reticular nucleus, and the ventrobasal relay nuclei of the thalamus play a predominant role in the development of SWD. However, recent evidence68 seems to indicate a seizure

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initiation site within the perioral region of the primary somatosensory cortex (S1po) in the Wag/Rij stain of rats, as another well characterised genetic model of absence seizures.69–72 The tottering mouse also, exhibits features of generalized epilepsy (generalized spike-waves on EEG and absence-like clinical seizures). ‘EL mice’ are the only genetic animal models that express seizure-associated damage to the hippocampus, a region of the brain commonly damaged by epilepsy in humans. In the past 5 years, the genetic mutations responsible for epilepsy in several different mouse models were identified. Unlike GAERS, the tottering and the stargazer mice have a known genetic mechanism. The stargazer mutation (21), which occurred in a newly discovered calcium channel gamma subunit, interferes with proper functioning of calcium channels, allowing overexcitation of neurons that leads to seizures. A second form of seizure, known as ‘slow-wave epilepsy’ because of its characteristic pattern of electrical recordings from the brain, is caused by a mutation that inactivates the sodium–hydrogen transporter. Tonic-clonic seizures Acute The Maximal electroshock model (MES) has been extensively used in particular in pharmacological studies to screen AED. Stimulation parameters used are usually as follows: 150 mA,

60 Hz for 0.2 sec delivered via corneal electrodes. Seizures are ‘Maximal’ when animals show tonic hind-limb extension and flexion followed by clonus.42 Chronic /genetic The genetically epilepsy-prone rats GEPRs have three types of convulsive epilepsy: generalized tonic-clonic seizures, partial seizures, and partial seizures with secondary generalized tonic-clonic seizures. GEPRs have a predisposition to soundinduced seizure assessed by an audiogenic response score (ARS), (0: no response to 9: severe seizure). GEPR rats exhibit a characteristic convulsive response to each ARS. (GEPR 3s: moderate seizures exhibiting clonic convulsions. GEPR 9s: complete tonic extensions). Anticonvulsant treatment can lower the ARS score. GEPRs respond to broad spectrum drugs, and also to those useful in generalized tonic-clonic seizures and partial seizures, but not to baclofen and chlorpromazine. Conclusions The existence of many models of epilepsy reflect the vast spectrum of epilepsies that clinicians have to face daily. However, on the other hand, it also reflects the fact that these models have a lot of limitations and unfortunately do not fitful all the clinical, electrical and genetic characteristics of human epilepsies. One must be cognizant of these limitations especially when new preclinical therapeutic strategies are tested in these models.

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layers in the perilesional motor cortex. Arch Neurol 1980 37(5): 287–90. Lamarche M, Menini C et al. Experimental models of frontal lobe epilepsy. Adv Neurol 1992;57:159–79. Hashimoto H, Sakaki T et al. The effect of lesionectomy and the perilesional GABAergic neuronal changes in alumina creaminduced focal motor epilepsy in cats. Neurol Res 1998;20(3): 253–8. Chevassus-au-Louis N, Baraban SC et al. Cortical malformations and epilepsy: new insights from animal models. Epilepsia 1999;40(7):811–21. Schwartzkroin PA, Roper SN et al. Cortical dysplasia and epilepsy: animal models. Adv Exp Med Biol 2004;548:145–74. Kellinghaus C, Kunieda T et al. Severity of histopathologic abnormalities and in vivo epileptogenicity in the in utero radiation model of rats is dose dependent. Epilepsia 2004;45(6):583–91. Kellinghaus C, Moddel G et al. Dissociation between in vitro and in vivo epileptogenicity in a rat model of cortical dysplasia. Epileptic Disord 2007;9(1):11–9. Kondo S, Najm I et al. Electroencephalographic characterization of an adult rat model of radiation-induced cortical dysplasia. Epilepsia 2001;42(10):1221–7. Luhmann HJ, Karpuk N et al. Characterization of neuronal migration disorders in neocortical structures. II. Intracellular in vitro recordings. J Neurophysiol 1998;80(1):92–102. Luhmann HJ, Raabe K et al. Characterization of neuronal migration disorders in neocortical structures: extracellular in vitro recordings. Eur J Neurosci 1998;10(10):3085–94. Jacobs KM, Hwang BJ et al. Focal epileptogenesis in a rat model of polymicrogyria. J Neurophysiol 1999;81(1):159–73. Kraemer M, Roth-Haerer et al. Metabolic and electrophysiological alterations in an animal model of neocortical neuronal migration disorder. Neuroreport 2001;12(9):2001–6. Schmidt S, Bruehl C et al. Impairment of functional inhibition in the contralateral cortex following perinatally acquired malformations in rats. Exp Neurol 2006;201(1):270–4. Snead OC III Gamma hydroxybutyrate in the monkey. I. Electroencephalographic, behavioral, and pharmacokinetic studies. Neurology 1978;28(7):636–42. Gao DM, Benabid AL Involvment of GABAa receptor in the experimental absence seizures in monkeys. Chin J Neurosci 1996; 3(3): 97–103. Snead OC III, Depaulis A et al. Absence epilepsy: advances in experimental animal models. Adv Neurol 1999;79:253–78. Wong M, Wozniak DF et al. An animal model of generalized nonconvulsive status epilepticus: immediate characteristics and long-term effects. Exp Neurol 2003;183(1):87–99. Danober L, Deransart C et al. Pathophysiological mechanisms of genetic absence epilepsy in the rat. Prog Neurobiol 1998;55(1): 27–57. Depaulis A, Moshe SL The basal ganglia and the epilepsies: translating experimental concepts to new therapies. Epileptic Disord 2002;4 Suppl 3:S7–8. Meeren HK, Pijn JP et al. Cortical focus drives widespread corticothalamic networks during spontaneous absence seizures in rats. J Neurosci 2002;22(4):1480–95. van Luijtelaar EL, Coenen AM Two types of electrocortical paroxysms in an inbred strain of rats. Neurosci Lett 1986;70(3):393–7. Coenen AM, Van Luijtelaar. The WAG/Rij rat model for absence epilepsy: age and sex factors. Epilepsy Res 1987;1(5):297–301. Coenen AM, Drinkenburg WH et al. Genetic models of absence epilepsy, with emphasis on the WAG/Rij strain of rats. Epilepsy Res 1992;12(2):75–86. Coenen AM, Van Luijtelaar. Genetic animal models for absence epilepsy: a review of the WAG/Rij strain of rats. Behav Genet 2003;33(6):635–55.

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SECTION 20 Surgical failures: reoperation

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Surgical failures: pre-surgical evaluation CT Skidmore and MR Sperling

Introduction Epilepsy surgery has been shown to be a reasonably safe and effective therapy for medically refractory localization-related epilepsy. The success of surgery at 1 year ranges from approximately 50–80% depending on the location of the surgery and the underlying pathology.1–3 However, long-term follow-up reports demonstrate that a substantial proportion of patients, approximately 50%, relapse within 5–10 years of temporal lobectomy.3–4 Relapse rates are even higher for extratemporal epilepsy, with 70% of patients experiencing a relapse within 5 years of frontal lobe surgery.1 Therefore, recurrent seizures are a common problem after epilepsy surgery.1,3,5,6 It is common practice to consider performing a second operation in selected patients to see if seizures can be stopped, thereby obtaining maximum surgical benefit. This practice is supported by literature reports demonstrating that 48–81% of reoperated patients achieve seizure control or have rare seizures.5–12 This chapter will focus on the repeat pre-surgical evaluation which needs to be performed prior to subsequent operations. Before addressing the evaluation process, we should first review which patients are suitable candidates to consider for reoperation. In brief, if the goal of surgery was to abolish seizures, then any patient with persistent seizures after surgery might be a candidate for reoperation. However, deciding to offer additional surgery is not always straightforward. Some patients who relapse after surgery later enter remission, experiencing the ‘running down’ phenomenon.13 This observation leads many physicians to adopt a conservative posture, and wait at least a few months, perhaps more, before considering further surgery. Some patients recur after surgery but their seizures are quite rare, so the value of surgery may be uncertain. Lastly, should a physician try additional medications prior to considering reoperation? Whether new medication trials offer a realistic hope of alleviating seizures after unsuccessful epilepsy surgery is uncertain. It seems reasonable to try at least one new medication before proceeding to additional surgery, given the relative risks. Nonetheless, the decision to embark upon the path towards reoperation is a difficult one. Ultimately, the patient must decide for himself whether he is satisfied with the surgical result, and if not, reoperation should be considered. In our experience, patients who have had as few as two seizures in the year after surgery have asked

for additional surgery, since their goal of seizure freedom was not attained, and the secondary benefits of operating a motor vehicle and increased independence were not achieved. Others with more frequent seizures, or seizures that produced injury, have also been interested in reoperation, since the reasons to have surgery the first time remain. Others have elected not to have surgery, because of doubts as to efficacy, or because of satisfaction with the reduction in seizure frequency or severity that might have occurred.

Review of data from the first operation The first question to be answered is why the initial surgery failed. Possible reasons for surgical failure include inappropriate interpretation of the initial pre-surgical data, incomplete resection of an epileptogenic zone, or the presence of a de novo epileptogenic zone. Unfortunately, there is no single test or method to identify this region precisely prior to epilepsy surgery. One can only know the approximate location of the epileptogenic zone after surgery – if seizures persist, then it was not completely removed. Determining its boundaries relies on the accurate interpretation and application of the pre-operative testing. The surgical plan was employed to address the most logical hypothesis as to the location of the epileptogenic zone based upon this testing. In order to determine why the first surgery failed, a detailed analysis of the initial pre-surgical data and hypothesis needs to be repeated (Table 149.1). If it was known at the time of surgery that complete resection was not possible, then surgical failure might not be a surprise. This should be easy to accomplish when the patient was operated in the same institution, but there are sometimes challenges in obtaining complete records from other institutions. This barrier is quickly being eliminated by the ability to share electronic records, which allows for the independent reinterpretation of the initial data. Reviewing the initial data and post-operative MRI allows a physician to determine if the initial hypothesis was correct and if the appropriate resection was performed. If it is determined that the localization was incorrect, then alternative hypotheses with regard to location of the epileptogenic zone might be generated to help guide a repeat surgical evaluation. One must reassess all aspects of the evaluation, to determine the concordance of the data and the accuracy of the interpretation. 1417

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Analysis of evaluation prior to first operation

Initial surgery

Questions to consider

Ictal behavior

Was the history correct? Was there more then one type of seizure? Were all types of seizures captured with video-EEG? Was the interictal focus focal or not? In what state did the spikes occur? Was the ictal EEG interpreted correctly? Was the electrode placement adequate? Did the EEG onset precede behavioral onset? How rapidly did the seizure spread to additional regions or to the contralateral hemisphere? Were spread patterns consistent and logical? Was the localization concordant with the other information? Is there a predominant focus? Was it concordant with the resection? Were the proper sequences performed? Was the image interpreted correctly? Was a lesion identified? Was there a single lesion or multiple? Was focal hypometabolism identified? Was an ictal hyperperfusion identified with SPECT? Was the hypothesis correct? How concordant was the pre-operative data? Was there evidence for multifocal disease? Was the localization clearcut? Was the surgical plan appropriate? Was the intended resection accomplished? Was the desired extent of resection limited by functional or anatomic barriers?

Scalp EEG Intracranial EEG

MEG MRI

Functional imaging Data synthesis/Surgical plan

Surgery

History and semiology The first step to be performed is to review the epilepsy history and pre-operative seizure semiology. Does the history suggest a particular epilepsy syndrome? Is it consistent with the syndrome that was diagnosed? Is the patient’s or family’s description of the seizure consistent with the diagnosis? Did the patient have more then one seizure type, and were all types of seizures captured during the video-EEG monitoring session? The assessment of the history provides critical information that aids in identifying the location of the epileptogenic zone. Neurophysiology The pre-surgical scalp and intracranial EEG evaluations must be reviewed. If both evaluations were performed they should be reviewed independently to determine if the data are concordant. The EEG evaluation helps determine the irritative and ictal onset zones. Several questions must be addressed. First, were the EEGs correctly interpreted? What was the location of the interictal spikes, and was their more than one location? In what states did they occur? When examining the ictal EEG, were seizures localized and how many ictal patterns were seen? What was the relationship between the timing of the ictal onset, and clinical onset? Was the onset and spread pattern of the seizure consistent with the ultimate localization? If intracranial EEG was performed, did ictal onset precede the clinical onset? Also, if an invasive evaluation was performed, was cortical sampling adequate? Invasive EEG is highly susceptible to sampling error and occasionally too much weight is placed upon the value of intracranial recordings. Therefore, was the intracranial EEG consistent with the rest of the data,

or did it contradict the other findings? Lastly, if magnetoencephalography (MEG) was performed, was it correctly interpreted, and where were the interictal spikes located? Video The video enables direct observation of the seizure and testing of the patient during seizures. Was the behavior suggestive of a particular type of seizure? Was the behavioral localization reliably seen with several seizures, and was more than one ictal behavior observed? Most importantly, was the behavioral localization consistent with the site of surgery? Imaging Perhaps the most important step in the re-evaluation is the review of the pre-operative and post-operative imaging studies, particularly the MRI. The presence of a structural lesion which colocalizes with the other data is perhaps the best prognostic sign for successful surgical treatment. The pre-operative MRI should be re-evaluated to determine if it was correctly interpreted. Was any structural lesions present, if so, how many, and were they within the proposed resection margins? If the extent of resection was limited by the relationship between the presumed epileptogenic zone and eloquent cortex, reassessment of the surgical extent can be performed, and perhaps sub-pial transection considered. Other imaging data, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT), must also be reviewed, to ascertain whether they were correctly interpreted and whether relevant imaging abnormalities were included within the resection line.

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Surgical failures: pre-surgical evaluation Synthesis Since the goal of reassessment is to review all of the available data, one must then determine whether a reasonable hypothesis was generated, and if the appropriate surgery was performed. This assessment requires intellectual honesty and rigor, and a willingness to take a fresh look at the data. After review of the data, one must consider alternative hypotheses, and these will help guide the repeat pre-surgical evaluation. The physician or treatment team may reinterpret the findings of the initial evaluation, perhaps formulating a different hypothesis regarding localization of the epileptogenic zone, or may draw the same conclusions as before. In either circumstance, a rigorous examination of the pre-operative data must be done before embarking on new investigations.

Re-evaluation The second pre-surgical evaluation has exactly the same goals and objectives of the first, to define the boundaries of an epileptogenic structural lesion. The presence of a structural lesion must be determined, and the limits of the epileptogenic zone established. One must reassess and define the symptomatogenic zone (region producing symptoms), irritative zone (region of EEG or MEG interictal spikes), ictal onset zone (region of EEG ictal onset), and functional deficit zone (regions of abnormal function defined by examination, PET, SPECT and other testing methods) and the extent of an epileptogenic lesion (defined by MRI), though this task is made more complex by the presence of a skull defect and the prior cortical resection. The methods utilized in the repeat evaluation are the same as before the first operation, including performance of a detailed history, neurological examination, scalp video-EEG monitoring, MRI, and a neuropsychological evaluation at a minimum (Table 149.2). Additional tests which may be employed include PET scan

Table 149.2

with fluorodeoxyglucose (FDG), interictal and ictal SPECT scans, magnetoencephalography (MEG), and functional MRI (fMRI). A full discussion of these technologies is beyond the scope of this chapter and is reviewed elsewhere in this text. History and semiology The first order of business is to assess the neurological history, with particular attention to seizures and the psychiatric state of the patient. Have seizures changed in character compared with the pre-operative seizures? Does the patient experience the same aura, and exhibit the same behaviors during seizures? Do family members note a change in the behavior, either during or after a seizure? Is there more than one type of aura? These factors are all important to assess the effects of surgery and determine whence seizures might originate. A change in aura symptoms or behavior might suggest a modification to the pre-existing epileptogenic zone, the development of a new epileptogenic zone, or it might suggest a different ictal propagation pattern. Careful review of the signs and symptoms might lead one to favor one of these possibilities over the others. Do seizures have different implications with regard to risk of injury and ability to function compared with the pre-operative state? Have new psychiatric problems emerged, such as depression, anxiety, or psychosis? These first require treatment, and might affect patient ability to make an informed decision about additional surgery. Changes in the neurological or neuropsychological examination may suggest the existence of new lesions, and offer clues as to the location of these lesions. On the other hand, new deficits in neuropsychological functioning have impact regarding the risks of additional surgery. For example, development of even modest language problems after a first operation may lead a physician to counsel against extending the prior resection, whereas lack of post-operative deficit would not deter further surgery.

Re-evaluation after failed surgery

Repeat surgical evaluation

Questions to consider

Ictal behavior

Has the seizure semiology changed? Is there more then one type of seizure? Were all types of seizures captured with video-EEG? Is the interictal focus focal or not? Is the ictal EEG localizing? Are there multiple ictal onsets? Is there a predominant focus? Does it support the other data? Is the electrode placement adequate? Does the EEG onset precede behavioral onset? What is the relationship between the prior resection and the ictal onset? Is the localization concordant with the other information? Were the proper sequences performed? Was the initial surgery complete? Is there evidence of a new lesion or surgical complication? Was an ictal hyperperfusion identified with SPECT? How concordant is the data? Is there evidence for multifocal disease? Is the localization clearcut? Is a safe surgical procedure technically feasible?

Scalp EEG MEG Intracranial EEG

MRI Functional imaging Data synthesis/Surgical plan

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Neurophysiology Next, video-EEG monitoring is usually done. The diagnosis of epileptic seizures should be confirmed, since some have found de novo psychogenic seizures after epilepsy surgery.14 The seizure description should be confirmed by analyzing ictal behavior with video monitoring. Behavioral analysis may yield valuable clues as to location of the remaining epileptogenic tissue. The interictal and ictal EEG need to be assessed and compared with the pre-operative data. This analysis may help reveal the location of the diseased cortex, defining the relationship between the prior surgery and the current ictal onset zones, and assessing whether new areas may be involved in seizure generation. Hennessy et al. presented data on 282 consecutive temporal lobe resections with a failure rate of 18%. On analysis of 44 surgical failures, 70% of the post-operative seizures were noted from the ipsilateral hemisphere in patients with mesial temporal sclerosis and in 64% of patients with non-specific pathology.15 In the remaining patients, findings suggested either a contralateral focus or were inconclusive. However, EEG analysis is influenced by several factors. First, skull defects have been created which alter the potential field of both interictal and ictal EEG discharges. Second, changes in cerebral anatomy occur as a consequence of surgery. These may alter the field distribution of EEG potentials, so that the source of the discharges might be incorrectly identified. Lastly, removal of a portion of a lobe of the brain often results both in different propagation patterns of seizures and loss in amplitude of the ictal discharge in the region of prior surgery. These can lead to false lateralization or localization of ictal discharges. However, the location of the interictal spike often provides a clue as to whether the seizure localization is genuine, for it is uncommon for seizures to arise from the hemisphere contralateral to a prominent unilateral interictal spike focus. MEG may serve a useful role when evaluating patients for reoperation.16,17 MEG can identify interictal spikes, providing further definition to the irritative zone and the source localization is not altered by skull defects. Since MEG detects dipoles that are tangential to the EEG, spikes that are invisible to EEG are readily detected with MEG. Also, MEG can be used to identify sensory and language cortex; knowledge of these regions are helpful when planning surgery. Imaging Imaging studies play an important role in the evaluation process. The post-operative MRI scan must be reviewed to determine if the initial surgical plan was carried out successfully (i.e., the entire lesion and perilesional tissue was removed), and to determine if a surgical complication such as an infarct or hemorrhage occurred, or if a previously unidentified epileptogenic lesion was missed. To our knowledge, there is no extant literature defining the expected findings at the resection margin after epilepsy surgery. Therefore, in the absence of new lesions, it is difficult to know whether a small gliotic lesion adjacent to the prior resection constitutes a new epileptogenic lesion, or is benign post-operative gliosis. This might only be defined with electrophysiological techniques at a later time. Functional MRI (fMRI) may at times aid in presurgical investigation. It may be used to identify eloquent cortex, thereby guiding the surgeon and perhaps reducing operative morbidity. While fMRI has been used to study

interictal spikes, this use is still investigational and not suited for clinical use.18 PET-FDG scans are generally not useful after epilepsy surgery, since the resection produces a metabolic defect in the region of resection, and distant areas of diaschisis appear as well. Synthesis and completion of evaluation Once the non-invasive evaluation is complete, the data can be synthesized (Figure 149.1). The principles that apply at the time of initial evaluation are still valid when contemplating reoperation. Successful surgery usually relies upon multiple lines of evidence converging on a single location. Hence, one hopes to find that the preponderance of data indicates a single location. Reoperation can be considered provided one can generate a clear hypothesis as to why the first surgery failed and determine where the epileptogenic zone now lies. Often, the non-invasive data does not provide information that is sufficiently precise. In these cases, it is advisable to record seizures with intracranial EEG before performing additional resection. This enables confirmation of the location of proposed area to be excised, and permits mapping of cortical function, so that critical areas can be spared. Both interictal and ictal data are obtained with intracranial video-EEG monitoring; these can help define the boundaries of the resection. However, using intracranial EEG does not guarantee success, since it is but one tool, subject to many limitations and biases. What strategy should be employed when using intracranial electrodes? Electrodes should be placed in any area that is reasonably suspected to be the source of seizures. A sufficient number of electrodes should be used to accurately define the cortex in which seizures originate and the initial spread patterns. One cannot know where seizures begin unless they can be shown to start focally in one area. Thus, it is mandatory that some electrode contacts not show ictal onset but instead show later ictal spread, and that the observed spread pattern logically derives from known anatomic connections. If there is a suspicion that seizures arise from more than one region of the brain, electrodes should be placed in both regions (Figure 149.2). This aids the physician in establishing whether a single epileptogenic zone exists, or if there are multiple areas that trigger seizures. If surgery is contemplated near eloquent cortex, then electrodes should be placed over relevant areas, so that vital functions can be mapped and the boundaries of resection defined.

Factors affecting outcome Many of the initial reports6,11 identified the presence of residual epileptogenic tissue as a favorable prognostic factor with regards to reoperative success. However many of these patients were operated before the widespread availability of MRI and advanced intraoperative navigation. Siegel et al.12 assessed seizure outcome in 64 patients who underwent at least one additional surgery and found duration of epilepsy less then 5 years and focal interictal epileptiform activity as positive predictors. Holmes et al.9 reported that data concordant with the prior resection imparted a good prognosis, while no patient with a CNS infection was rendered seizure free. The location of surgery, whether temporal or extratemporal, did not influence outcome after a second procedure. Salanova et al.10 reported

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Surgical failures: pre-surgical evaluation

Figure 149.1

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Flow chart demonstrating the typical decision algorithm when considering additional epilepsy surgery.

residual interictal epileptiform activity in the postresection electrocorticogram as a poor prognostic sign in patients with frontal lobe epilepsy. González-Martínez et al.5 reported no relation between outcome and history of febrile seizures, CNS infections, seizure semiology, duration of epilepsy, or response to the first surgery. However, patients with tumors or dual pathology at the time of reoperation had a significantly better outcome compared with patients who had cortical dysplasia or mesial temporal sclerosis. Possible reasons for this include the inability to successfully image the entire extent of the cortical dysplasia and the possibility of the development of a contralateral mirror focus in the presumed normal temporal lobe. In an analysis of data from our center, we evaluated 30 patients who underwent reoperation in an attempt to determine if the response to the first surgery could predict the response to the second operation.19 We found no relationship between response to the first surgery and the outcome of the second surgery. We also found no difference in outcome between temporal versus extratemporal resections or extension of a prior resection compared to resection within a different region.

Illustrative cases Case 1 A 29-year-old right-handed woman developed complex partial seizures after the birth of her third child. The seizures were

described as beginning with an ineffable feeling for several seconds followed by a loss of consciousness. She then had a look of terror on her face, afterward becoming unresponsive with late right-sided clonic activity. She had 4–5 seizures per month despite appropriate medical therapy. Four years after onset of her epilepsy, she had a left anterior temporal lobectomy based on a scalp evaluation. Seizures stopped, and her antiepileptic medication was discontinued 1 year after surgery. Her seizures recurred 6 years after the initial resection, coinciding with the birth of her sixth child. Despite medical therapy she remained refractory and experienced 3–4 complex partial seizures per month. Repeat evaluation Semiology: She had the same aura as before surgery and loss of consciousness, but the look of terror and right sided clonic activity late in the seizure were not present. Scalp video-EEG: The interictal EEG showed left temporal continuous theta slowing and rare right sphenoidal sharp waves. The ictal EEG revealed a right sphenoidal ictal onset with rhythmic theta spiking. Semiology was consistent with an automotor seizure with loss of consciousness. MRI: This showed the prior left temporal resection, with 1 cm hippocampal resection and 4.5 cm lateral temporal resection. Neuropsychological testing: This showed average visuospatial memory and poor verbal memory.

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(a)

(b) Figure 149.2 (a) Saggital T1-weighted MRI revealing the prior area of resection (white arrow) in a patient with medically refractory aphasic seizures. Note the superior temporal gyrus was spared. (b) Representation of the intracranial implant with inferior frontal, orbitofrontal, lateral temporal and basal temporal subdural electrodes covering the possible epileptogenic regions. Ictal onset was noted behind the resection margin with rapid spread to the anterior superior temporal gyrus. No language function was identified within these regions with electrocortical stimulation. The patient had the superior temporal and middle temporal gyrus resected beyond the ictal onset.

Surgical plan The patient initially had left temporal lobe epilepsy which had responded to a left temporal resection with a limited mesial resection. However, the re-evaluation EEG data suggested an irritative zone and ictal onset zone within the right anterior temporal lobe. There are two main possible explanations for this. Either she still had left mesial temporal lobe epilepsy with preferential spread to the right temporal lobe due to the prior resection, or developed a new epileptogenic zone in the right temporal lobe. Less likely, an orbitofrontal epileptogenic zone

had developed. To address these possibilities the patient was implanted with depth electrodes in the hippocampus and subdural strip electrodes in both left and right temporal lobes. In addition, orbitofrontal subdural strip electrodes were placed bilaterally. Results With intracranial video-EEG monitoring, the patient had four complex partial seizures arising from the right anterior hippocampus and six subclinical seizures arising from the left

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Surgical failures: pre-surgical evaluation posterior hippocampus. Due to the bilateral nature of her disease and the predominance of clinical seizures now emanating from the right hippocampus, she was not offered further resection. This case illustrates the potential for progression of disease which can occur in epilepsy and the need to consider the development of de novo epileptogenic zones after failed epilepsy surgery. Case 2 A 53-year-old right-handed woman developed epilepsy at age 12. She initially had nocturnal generalized tonic-clonic seizures occurring 1–2 times per year despite medical treatment. Then, at the age of 27, she was involved in a motor vehicle accident which resulted in abdominal trauma, but she denied CNS trauma. However, after this accident she developed complex partial (automotor) seizures. Observers now reported a sudden loss of awareness which occurred without a warning. She then looked fearful, having hand and verbal automatisms. Despite medical treatment, she continued to have 2–4 seizures per week while the generalized tonic-clonic seizures continued at 1–2 per year. First evaluation Video-EEG: The interictal EEG showed right and left sphenoidal sharp waves, with 10 right-sided sharp waves for every one on the left. The ictal semiology was as described above. Ictal EEG showed bilateral attenuation of background frequencies at onset and then either an independent right or left temporal seizure discharge. MRI: This showed increased T2 signal in the left temporaloccipital gyrus, located 5 cm from the temporal tip. Neuropsychological testing: This showed impaired naming and verbal memory. Wada test: This showed left hemisphere dominance for language. Initial surgery The patient had intracranial video-EEG monitoring using bilateral mesial temporal depth electrodes and bilateral temporal lobe subdural strips. The interictal EEG data revealed bilateral hippocampal and amygdala epileptiform activity. Multiple complex partial seizures were recorded with left posterior hippocampal onset followed by spread to the right temporal lobe in 15–30 seconds. She then had a left anterior temporal lobectomy. After surgery, she continued to have 1–2

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complex partial seizures per week and the frequency of generalized tonic-clonic seizures increased to once per month. Repeat evaluation Neuropsychological testing: This showed significant verbal memory decline and severe anomia compared to the preoperative data. MRI: This showed residual left basal temporal T2 signal hyperintensity within the temporo-occipital gyrus. Video-EEG: This was not performed since the seizure semiology had not changed and the patient had a residual structural lesion. Surgical plan The patient was taken back to the operating room approximately 1 year after the first surgery with resection of the residual basal temporal lesion. Results The patient had three possible seizures several months after the second operation, and has been seizure free for the next 19 years. Her neuropsychological measures improved after her second surgery, with resolution of the anomia and improvement in verbal memory. Multiple follow-up EEGs have been devoid of epileptiform activity. This case illustrates the need to completely excise an epileptogenic lesion and that extensive basal temporal resection can be performed safely in the dominant hemisphere with improvement in neuropsychological functioning if seizures can be abolished.

Conclusion Epilepsy surgery is an effective option for many patients with medical refractory epilepsy, but current techniques do not assure a successful outcome. Further surgery may be possible in individuals who fail to fully respond, and approximately half benefit from reoperation. However, better tools and prognostic indicators must be devised to help guide the reoperation and predict which patients are apt to benefit. Until then, an individualized approach must be employed. The evaluation should aim at developing a reasonable hypothesis regarding the location of the remaining epileptogenic cortex, devising a safe strategy for intracranial investigation should this be needed, and planning an effective operation that minimizes the chances of producing a neurological deficit.

REFERENCES 1. 2. 3. 4. 5. 6.

Jeha LE, Najm I, Bingaman W et al. Surgical outcome and prognostic factors of frontal lobe epilepsy surgery. Brain 2007;130:574–84. Spencer SS, Berg AT, Vickrey BG et al. Initial outcomes in the multicenter study of epilepsy surgery. Neurology 2003;61:1680–5. Jeha LE, Najm IM, Bingaman WE et al. Predictors of outcome after temporal lobectomy for the treatment of intractable epilepsy. Neurology 2006;66:1938–40. Sperling MR, O’Connor MJ, Saykin AJ, Plummer C. Temporal lobectomy for refractory epilepsy. JAMA 1996;276:470–5. González-Martínez JA, Srikijvilaikul T, Nair D, Bingaman W. Longterm seizure outcome in reoperation after failure of epilepsy surgery. Neurosurgery 2007;60:873–80. Awad IA, Nayel MH, Lüders H. Second operation after the failure of previous resection for epilepsy. Neurosurgery 1991;28:510–18.

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Salanova V, Markand O, Worth R. Temporal lobe epilepsy: analysis of failures and the role of reoperation. Acta Neurol Scand 2005;111:126–33. Germano IM, Poulin N, Olivier A. Reoperation for recurrent temporal lobe epilepsy. J Neurosurg 1994;81:31–6. Holmes MD, Wilensky AJ, Ojemann LM, Ojemann GA. Predicting outcome following reoperation for medically intractable epilepsy. Seizure 1999;8:103–6. Salanova V, Quesney F, Rasmussen T, Andermann F, Olivier A. Reevaluation of surgical failures and the role of reoperation in 39 patients with frontal lobe epilepsy. Epilepsia 1994;35:70–80. Wyler AR, Hermann BP, Richey ET. Results of reoperation for failed epilepsy surgery. J Neurosurg 1989;71:815–19.

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Siegel AM, Cascino GD, Meyer FB et al. Resective reoperation for failed epilepsy surgery: seizure outcome in 64 patients. Neurology 2004;63:2298–302. Rasmussen TB. Surgical treatment of complex partial seizures: results, lessons, and problems. Epilepsia 1983;24(Suppl. 1): S65–S76. Glosser G, Roberts D, Glosser DS. Nonepileptic seizures after resective epilepsy surgery. Epilepsia 1999;40:1750–4. Hennessy MJ, Elwes RDC, Binnie CD, Polkey CE. Failed surgery for epilepsy: a study of persistence and recurrence of seizures following temporal resection. Brain 2000;123:2445–66.

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Kirchberger K, Hummel C, Stefan H. Postoperative multichannel magnetoencephalography in patients with recurrent seizures after epilepsy surgery. Acta Neurol Scand 1998;98:1–7. Mohamed IS, Otsubo H, Ochi A et al. Utility of magnetoencephalography in the evaluation of recurrent seizures after epilepsy surgery. Epilepsia 2007;Epub:1–10. Detre JA. fMRI: application in epilepsy. Epilepsia 2004;45 (Suppl. 4):S26–S31. Skidmore CT, Lee C, Sperling MR. Re-operation for epilepsy: does response to the first surgery predict outcomes. Neurology 2006;66(Suppl. 2):A88(abst).

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Reoperation after failed epilepsy surgery A Boongird, JA González-Martínez, and WE Bingaman

Introduction Surgical failure is defined by the inability of surgical intervention to accomplish the surgical goals, whether they are diagnostic or therapeutic in nature. Diagnostic procedures include subdural and/or depth electrode implantations for identification of epileptic tissue, while therapeutic procedures can be subdivided into those which may improve seizures (palliative) and those intended to stop seizures (curative). The seizure freedom rate after a palliative procedure such as vagal nerve stimulator (VNS) implantation is considerably low.1–3 Residual seizures after VNS implantation therefore would not necessarily be considered a ‘surgical failure’. In contrast, resective surgery for a focal epilepsy carries a much greater chance for curing seizures, especially if there is an associated lesion on neuroimaging.4 The term ‘surgical failure’ in resective cases is defined in this chapter as persistent or recurrent seizures after resective epilepsy surgery. Surgical failure rates for common epilepsy surgery procedures such as selective amygdalohippocampectomy or standard anterior temporal lobectomy are well characterized in the literature, with many reports citing widely varying outcomes after resective surgery. These outcomes seem to differ widely from center to center based on underlying substrate, surgical experience and method, outcome grading scheme used, and volume of cases. It is not the aim of this chapter to validate surgical therapy for epilepsy, but rather to explore some common reasons for failure and the potential for improving seizure control with re-operation in selected patients. Additionally, the time-period for diagnosis of surgical failure needs some consideration. Early versus late recurrenceof seizures is poorly understood. In general, surgical failure should be defined as identification of seizure(s) following the operation, with persistence of habitual seizures perhaps the most important criteria for clinical diagnosis of surgical failure.5 Prediction of surgical failure differs from patient to patient and should be individualized to the clinical scenario. The ‘running down phenomenon’ should be kept in mind, especially in patients experiencing major effects on clinical seizures.6–8 Siegel et al. reported 8 of 64 patients that were initially free of seizures after the first surgery for a mean of 4.6 years, followed by late recurrence and reoperation.9 Other studies also confirm the decreasing success of epilepsy surgery over time.10 These results underscore the necessity of long-term follow-up after surgery for epilepsy.

Frequency of surgical failure and reoperation The incidence of surgical failure is different from center to center because of referral bias, criteria for defining surgical success, number of cases, and different surgical experiences and strategies. Munari et al. reported 131 of 344 (38%) patients having persistence of seizures immediately after operation. This number might be lower if using different criteria to define outcome.11 The incidence of surgical failure was also reported in relation to specific locations of surgery. For example, Hennessy reported 51 of 282 patients (18.1%) experiencing persistent or recurrent seizures following temporal resections.12 The incidence of reoperation reported varies from 4.3–14%, depending on individual center practices.9,13,14 Diagnostic procedures are also associated with a chance for failure. Experience at our center from January 1997 through June 2005 included approximately 1440 epilepsy operations, in which 250 procedures were diagnostic, 190 procedures palliative, and about 1000 procedures for curative aims. Among 234 cases of subdural electrode evaluation and 17 cases for bilateral temporal depth electrodes, 30 patients (12%) underwent subdural electrodes removal without surgical resection and ten cases underwent depth electrodes removal without resection. Surgical failure after resective surgery remains challenging. At our institution, among 1000 resective operations within the same period of study, about 15% of patients still experience persistence of disabling seizures after the first surgery. Ninetytwo patients underwent reoperation and within this group, 26 patients (28%) were referred from outside institutions for further evaluation and management. Although these numbers are in line with other published reports on reoperation after failed epilepsy surgery, the true frequency of failure and success after reoperation will remain unknown until the epilepsy community has a standardized method of defining and recording outcomes. In this regard, a national database specific to outcomes after epilepsy surgery is needed.

Possible causes of surgical failure and the surgical approaches for reoperation For diagnostic procedures, the two main reasons for failure to localize the epileptogenic zone (EZ) are the diffuse nature of specific types of intractable epilepsy syndromes and the anatomical limitations of electrode implantation (insular cortex, 1425

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interhemispheric surfaces, posterior basal orbitofrontal region). The first may be considered a failure in the preoperative evaluation and most often occurs due to the clinician’s inability to accurately localize the epileptogenic zone. The second is surgical technique related and potentially avoidable. The possibility of combined depth electrode and subdural electrode implantation may be a better method in approaching these difficult anatomical areas. Alternatively, stereoelectroencephalography may be a better method for accessing difficult to access or more widespread cortical regions.15 Incorrect localization of the epileptogenic zone During the presurgical work-up, the epileptologist formulates a hypothesis of the epileptogenic zone by using clinical semiology, neurophysiology, and anatomical and functional neuroimaging. Non-lesional cases and those with discordant data require assumptions based on the interpretation of preoperative data. In most of these cases, further diagnostic invasive recording is necessary prior to establishing surgical resective candidacy. With these particular cases, surgical failure has been reported as higher compared to the more straightforward lesional case.16 When the preoperative data is discordant and/or there is no lesion present to steer surgical resection, the chances of incorrect localization or perhaps better termed incomplete characterization of the epileptogenic zone is more likely.16 Additional reasons for incorrect localization of the

epileptogenic zone include misinterpretation of preoperative data and presence of dual pathology on imaging. The following clinical example helps to demonstrate how incorrect characterization of the EZ might occur. In case 1, clinical semiology starts with an aura of ‘a scary feeling in my chest’ or a hard-to-describe sensation for seconds to a few minutes. This is followed by elevation of both arms and legs with tonic stiffening. Typical seizure duration is 20–30 seconds. Seizures occur mostly out of sleep, about 2–20 times per night. Neurophysiology revealed interictal sharp waves in the right frontotemporal region and non-localizable ictal onset. Magnetic resonance imaging (MRI) of the brain revealed a slightly hyperintense area on fluid-attenuated inversion recovery sequences at the depth of the right inferior frontal sulcus, most likely reflecting a malformation of cortical development. Because of the semiology, lack of electroencephalographic (EEG) ictal onset, and potential for a widespread malformative lesion, invasive mapping was recommended. Two 8×8 subdural electrodes (covering right fronto-parietal convexity area, including the abnormal area) were used for invasive monitoring. The mesial frontal regions were not covered. The EEG onset was characterized by diffuse attenuation of the background activity and was simultaneous to the clinical onset. Focal EEG changes were seen no earlier than 1–2 seconds after the clinical onset when beta-range rhythmic discharges arose from posterior fronto-temporal electrodes and evolved into repetitive spike waves over the adjacent area (Figure 150.1).

Area over lesion

Ictal EEG +10 sec: Rhythmic alpha SB 4–7,12–14 +14 sec: Spreading SA 53–55,SB31,39

Figure 150.1

Demonstrating the lesional MRI and ictal EEG findings in relation to the area of the overlying lesion.

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Reoperation after failed epilepsy surgery (a)

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Figure 150.2 Comparison of extent of left orbito-frontal resection between two operations. a. Initial frontal resection based on invasive recording data, b. Second resection of additional cortical tissue in region of initial resection.

The case illustrated demonstrates several salient points that may lead to the incorrect localization of the EZ and thus reduce the chances of a seizure-free outcome. First, the EZ may be more widespread than the lesion, when present. Similarly, the EEG data gathered via scalp or invasive recording may also not correlate with the lesion and/or the EZ. Surgical limitations in the number and location of invasive electrodes implanted may influence the data gathered and the hypotheses from this data. Finally, when a lesion is present (especially cortical malformations) it may or may not coincide with the EZ. In the final synthesis of data and operative plan, the epileptologist and surgeon must decide on the extent of tissue that needs to be removed and it is this human factor where likely most incorrect localizations of the EZ occurs. As mentioned earlier, surgical accessibility to some cortical regions is limited, especially for surface electrodes (subdural recordings). For example, the mesial frontal and parietal regions, cingulate gyri, orbital frontal, and mesial temporal areas are

difficult to access in a comprehensive fashion because of the size and inability to directly visualize the areas of interest. Figure 150.2 is an example of left basal frontal lobe epilepsy with a seizure free outcome achieved after two resections in the same region. This patient experienced a recurrence of habitual hypermotor seizures 3 months after undergoing an initial resection of left orbito-frontal cortex identified by an invasive subdural electrode evaluation. Following seizure recurrence, more extensive resection of the same cortical area under awake conditions led to long-term seizure freedom. Pathology revealed malformation of cortical development from both specimens. Due to the limitations of subdural electrode evaluation in specific areas of the brain as previously described above, the combination of subdural electrodes and depth electrodes may play a role for improved localization of the epileptogenic zone (Figure 150.3). In this example, the patient had a right posterior frontal seizure onset with a normal MRI. Implantation of

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1 - Early Ictal onset C - Face Motor B - Hand Motor D - Hand Sensory

Figure 150.3 Demonstrates the combination of subdural and depth electrodes for an extraoperative brain mapping (upper photo) and intraoperative electrocorticography (ECoG) of the insular lobe (lower photo) during the resection.

a combination of surface electrodes and intra-cortical electrodes in the insular cortex were utilized to document an insular ictal onset with an early spreading pattern to the surface subdural electrodes. The pathology report showed malformation of cortical development (MCD). The patient experienced seizure freedom after surgery. Limitations in the epileptogenic zone surgical resection The epileptogenic zone may involve eloquent cortex and resection of such may possibly lead to a permanent neurologic deficit. Invasive monitoring with subdural electrodes can provide information defining epileptic cortex and functional cortex and may lead to potential surgical extirpation of the epileptogenic zone. Despite accurate functional mapping, surgery in and around eloquent cortex carries risks of neurologic decline and this must be adequately discussed with patients and families prior to surgical treatment. Despite these risks, surgery can be performed with minimal deficits in some areas of sensorimotor cortex. For example, if the seizure onset zone

arose from the sensorimotor face area, surgery can be performed without significant permanent neurological deficit.17 Multiple subpial transections (MST) can be performed on the eloquent cortex in selected cases. The Yale group reported a 42% seizure frequency reduction after MST.18 Other surgical options including vagal nerve stimulation (VNS), responsive cortical stimulation, and deep brain stimulation (DBS) can be considered for palliative aims. Example 2 Left central lobe intractable epilepsy arose from a malformation of cortical development (MCD) involving motor and language cortex Figure 150.4a. A partial lesionectomy with preservation of hand function after invasive monitoring did not alleviate seizure frequency or severity Figure 150.4b. Other options including vagal nerve stimulation and deep brain stimulation targeting the subthalamic nucleus were performed in an attempt to stop the epilepsia partialis continua that developed after the biopsy procedure. Eventually a

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(a)

(b)

(c)

Figure 150.4 a Preoperative MRI of left frontal lobe malformation of cortical development. b. MRI after biopsy procedure, c. final postoperative resection.

lesionectomy completely removing the abnormal cortex was undertaken with successful cessation of the seizures Figure 150.4c. Postoperatively the patient had a significant right hemiplegia and motor aphasia. Recovery of ambulation and language occurred over 12 months. His hand function remains with poor fine motor control. Postsurgical extension of the epileptogenic zone Postsurgical processes in the epileptic brain are poorly understood. Cortical re-organization, kindling, and maturation or extension of the epileptogenic zone are processes potentially explaining seizure recurrence. Rasmussen reported the latent period between brain injury and onset of recurring seizures can vary from a few months up to decades.8 The underlying mechanism of this latent period is still unknown. Most of the epileptic processes occur in the region of the previous area of pathology such as tumor recurrence, signal changes in MCD, maturation of cortical scarring. However, secondary epileptogenicity can arise from remote areas within the network such as the contralateral hippocampus. For example, Hennessy reported 25% of surgical failures in mesial temporal sclerosis cases had seizure onsets exclusively in the contralateral temporal region.12

Weiser reported a patient seizure free for 11 years following stereotactic amygdalotomy who then experienced recurrent complex partial seizure arising from the residual hippocampus. Hippocampectomy regained seizure freedom for at least 9.5 years.19 This example may indicate a new seizure type arising from a new epileptogenic zone or maturation of the previous epileptogenic zone. Incomplete resection or disconnection of the epileptogenic zone Penfield and Jasper first described the role of residual hippocampus resection for the treatment of surgical failure in temporal lobe epilepsy.20 Rasmussen revealed 45% of 121 patients had remarkable seizure reduction after further cortical excision.8 Many series confirmed the role of residual epileptogenic lesion removal and long term seizure freedom.21–23 Surgical resection, if possible, for dual pathology with proof of independent foci should be recommended for long-term seizure freedom.25 For curative or palliative aims following hemispherectomy, an incomplete disconnection can be the reason for persistence or recurrence of seizures. Postoperative MRI provides useful information for incomplete anatomical disconnection (Figure 150.5). Electroencephalography (EEG) can be difficult to interpret especially following functional

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(b)

Figure 150.5 Demonstrates two cases of incomplete corpus callosum disconnection causing recurrence of disabling seizures at 6 months and 2 weeks respectively following the first surgery (a – Genu area, b – Splenium area).

hemispherectomy. Clinical semiology is very helpful to determine whether or not the seizure onset is arising from the previously resected hemisphere.

Technical difficulties and complications of using invasive electrodes in reoperation Foramen ovale electrodes The electrodes are placed at base of middle fossa (extracranial). Previous intracranial surgery should not be a contraindication for the placement of these electrodes. Subdural electrodes The main surgical difficulties for placement of subdural electrodes in previous surgery are dural adhesions with the cortical vessels and distortion of anatomical landmark structures. Careful sharp dissection is necessary, especially when opening adhered dura over major cortical vessels (sylvian fissure). The risk of bone flap infection is also higher in reoperated cases. Watertight dural closure should be accomplished in order to reduce the incidence of CSF leak and postoperative meningitis. Intensive care unit stays during the first 24 hours are routinely recommended for serial neurological examination.

Depth electrodes Invasive depth electrodes in re-operation cases may carry higher risk of bleeding because of adhesions and anatomical distortion. Depth electrodes should be inserted utilizing stereotactic guidance while observing the precautions of any stereotactic procedure (minimizing crossing of pial planes, avoiding traversing CSF spaces, etc.). Other technical difficulties The key to reducing complications during redo-surgery is to find reliable anatomic landmarks in order to orient the surgeon, for example pericallosal artery and corpus callosum. Surgical navigation helps in areas where reliable landmarks are not readily identifiable such as identification of perirolandic cortex and anatomic language areas. Issues that affect stereotactic navigation such as brain shift should be kept in mind as possible technical limitations. Re-operation in vagal nerve stimulation The risk of vagal nerve injury may be higher for redo VNS surgery. The main reasons for reoperation are infection and lead failure identified by high lead impedance during device interrogation. Exploration and/or removal or revision of the electrode is often hampered by adhesions and scarring around the

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Reoperation after failed epilepsy surgery vagus nerve. Redo VNS should be carefully performed under loupe magnification with normal nerve identified above or below the previous operative site. Macdonald recommended using microsurgical dissection for complete removal of the helical electrode from the vagus nerve without apparent physiological consequences.26

Outcome of re-operation and its complications The overall seizure-free outcome for lesionectomy is reported as 70–80%.23,27 Seizure-free rates after re-operation were described from 20–60%.9,28–30 The surgical strategies of reoperation for surgical failure vary across individual patients and epilepsy centers. However, two aspects of surgical outcome after re-operation were reviewed. The first aspect is the location of reoperation, which is sub-classified into intralobar resection (same lobe as the first operation), multilobar resection, and distant resection. Shaver reported a 62% seizure-free rate for intralobar resection as compared to 44% seizure-free rate for distant resection or multilobar resection.29 The second aspect is imaging, which is sub-classified into non-lesional, single lesion, and multiple lesions. For temporal lobe surgery, residual mesial structures were commonly reported as a cause of surgical failure during the early 1990s. Intralobar resection for residual mesial structures may accomplish a 50–60% seizure-free rate.21,22,31 Tailored resection based on neurophysiological data and/or functional mapping can be an ideal surgical option for re-operation especially in the dominant hemisphere.32 Intraoperative hippocampal electrocorticography was also reported for tailored hippocampal resection to maximize seizure-free outcome while leaving a portion of the hippocampus insitu. Hennessy reported 70% of mesial temporal sclerosis had postoperative seizures arising in the same hemisphere of the resection with

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85% of those arising from nearby temporal lobe regions. Interestingly, neocortical seizure onset was more frequently found than residual hippocampal seizure onset. Dual pathology was reported in up to 15%, especially in patients with congenital lesions.33 As our technology improves, the causes of surgical failure may be shifting from technical operative failures to different causes such as large epileptogenic zones, dual pathology, recurrence of tumor, and limited ability for resection to preserve function.28 Salanova reported the unfavorable factors after reoperation in temporal lobe surgery including a history of head injury or encephalitis and posterior temporal localization. Predictors for favorable outcome after re-operation included anterior temporal localization and abnormal imaging studies.14 For frontal lobe epilepsy, Salanova reported 39 of 284 (14%) patients underwent re-operation with a 20% seizurefree rate. The main cause of surgical failure was a large epileptogenic zone, which was demonstrated by residual postresection electrocorticographic spikes.13 Re-operation after hemispherectomy had been reported in a few series. Cortical dysplasia is the most common pathological substrate of surgical failure.34,35 In these cases, a more complete tissue removal operation such as tailored anatomical hemispherectomy may be a better surgical option at the first surgery.35 In cases of surgical failure after functional hemispherectomy, residual tissue was commonly found at the basal posterior frontal and insular regions. Surgical removal of the residual tissue, especially if it is dysplastic should be considered for maximal seizure-free outcome.36 The risk of developing postoperative hydrocephalus should be considered for anatomical hemispherectomy. Acknowledgment The authors specially thank to Ann Warbel for a great support with the epilepsy patients’ database.

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8.

9.

Nakken KO, Henriksen O, Roste GK, Lossius R. Vagal nerve stimulation – the Norwegian experience. Seizure 2003;12:37–41. Morris GL. III, Mueller WM. Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation Study Group E01–E05. Neurology 1999;53:1731–5. Boon P, Vonck K, de Reuck J, Caemaert J. Vagus nerve stimulation for refractory epilepsy. Seizure 2002;11 Suppl A:448–55. Berkovic SF, McIntosh AM, Kalnins RM et al. Preoperative MRI predicts outcome of temporal lobectomy: an actuarial analysis. Neurology 1995;45:1358–63. Lüders HO, Murphy D, Awad I et al. Quantitative analysis of seizure frequency 1 week and 6, 12, and 24 months after surgery of epilepsy. Epilepsia. 1994;35(6):1174–8. Salanova V, Andermann F, Rasmussen T, Olivier A, Quesney L. The running down phenomenon in temporal lobe epilepsy. Brain 1996;119 (Pt 3):989–96. Salanova V, Markand O, Worth R. Longitudinal follow-up in 145 patients with medically refractory temporal lobe epilepsy treated surgically between 1984 and 1995. Epilepsia 1999;40:1417–23. Rasmussen T. Cortical Resection for medically refactory focal epilepsy: results, lessons, and questions. In: Rasmussen T, Marino R, eds. Functional Neurosurgery. New York: Raven Press, 1979:253–269. Siegel AM, Cascino GD, Meyer FB et al. Resective reoperation for failed epilepsy surgery: seizure outcome in 64 patients. Neurology 2004;63:2298–302.

10. 11. 12.

13. 14. 15. 16.

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Gonzalez-Martinez JA, Srikijvilaikul T, Nair D, Bingaman WE. Long-term seizure outcome in reoperation after failure of epilepsy surgery. Neurosurgery 2007 May;60(5):873–80. Munari C, Berta E, Tassi L et al. Analysis of failures and reoperations in resective epilepsy surgery. Adv Neurol 2000;84: 605–14. Hennessy MJ, Elwes RD, Binnie CD, Polkey CE. Failed surgery for epilepsy. A study of persistence and recurrence of seizures following temporal resection. Brain 2000;123 Pt 12: 2445–66. Salanova V, Quesney LF, Rasmussen T, Andermann F, Olivier A. Reevaluation of surgical failures and the role of reoperation in 39 patients with frontal lobe epilepsy. Epilepsia 1994;35:70–80. Salanova V, Markand O, Worth R. Temporal lobe epilepsy: analysis of failures and the role of reoperation. Acta Neurol Scand 2005;111:126–33. Munari C, Hoffmann D, Francione S et al. Stereo-electroencephalography methodology: advantages and limits. Acta Neurol Scand Suppl. 1994;152:56–67, discussion 68–9. Cohen-Gadol AA, Wilhelmi BG, Collignon F et al. Long-term outcome of epilepsy surgery among 399 patients with nonlesional seizure foci including mesial temporal lobe sclerosis. J Neurosurg. 2006;104(4):513–24. Lehman R, Andermann F, Olivier A et al. Seizures with onset in the sensorimotor face area: clinical patterns and results of surgical treatment in 20 patients. Epilepsia 1994;35:1117–24.

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Mulligan LP, Spencer DD, Spencer SS. Multiple subpial transections: the Yale experience. Epilepsia 2001;42:226–9. Wieser HG. Mesial temporal lobe epilepsy versus amygdalar epilepsy: late seizure recurrence after initially successful amygdalotomy and regained seizure control following hippocampectomy. Epileptic Disord 2000;2:141–52. Penfield WJH. Epilepsy and the Functional Anatomy of the Human Brain. Boston: Little Brown, 1954. Awad IA, Nayel MH, Lüders HO. Second operation after the failure of previous resection for epilepsy. Neurosurgery 1991;28:510–18. Germano IM, Poulin N, Olivier A. Reoperation for recurrent temporal lobe epilepsy. J Neurosurg 1994;81:31–6. Fried I, Kim JH, Spencer DD. Limbic and neocortical gliomas associated with intractable seizures: a distinct clinicopathological group. Neurosurgery 1994;34:815–23; discussion 823–4. Li LM, Cendes F, Andermann F, et al. Surgical outcome in patients with epilepsy and dual pathology. Brain 1999;122 (Pt 5):799–805. Cascino GD, Jack CR Jr, Parisi JE et al. Operative strategy in patients with MRI-identified dual pathology and temporal lobe epilepsy. Epilepsy Res 1993;14:175–82. MacDonald J, Couldwell WT. Revision of vagal nerve stimulator electrodes: technical approach. Acta Neurochir (Wien) 2004;146:567–70; discussion 570. Bourgeois M, Sainte-Rose C, Lellouch-Tubiana A, et al. Surgery of epilepsy associated with focal lesions in childhood. J Neurosurg 1999;90:833–42.

28. 29. 30. 31.

32. 33 34. 35. 36.

Schwartz TH, Spencer DD. Strategies for reoperation after comprehensive epilepsy surgery. J Neurosurg 2001;95:615–23. Shaver EG, Harvey AS, Morrison G et al. Results and complications after reoperation for failed epilepsy surgery in children. Pediatr Neurosurg 1997;27:194–202. Tanaka T, Yonemasu Y, Olivier A, Andermann F. Clinical analysis of reoperation in cases of complex partial seizures. No Shinkei Geka 1989;17:933–7. Jooma R, Yeh HS, Privitera MD, Gartner M. Lesionectomy versus electrophysiologically guided resection for temporal lobe tumors manifesting with complex partial seizures. J Neurosurg 1995;83:231–6. Siegel AM, Roberts DW, Harbaugh RE, Williamson PD. Pure lesionectomy versus tailored epilepsy surgery in treatment of cavernous malformations presenting with epilepsy. Neurosurg Rev 2000;23:80–3. Salanova V, Markand O, Worth R. Temporal lobe epilepsy: analysis of patients with dual pathology. Acta Neurol Scand 2004;109:126–31. Cook SW, Nguyen ST, Hu B et al. Cerebral hemispherectomy in pediatric patients with epilepsy: comparison of three techniques by pathological substrate in 115 patients. J Neurosurg 2004;100:125–41. Carreno M, Wyllie E, Bingaman W et al. Seizure outcome after functional hemispherectomy for malformations of cortical development. Neurology 2001;57:331–3. Mittal S, Farmer JP, Rosenblatt B et al. Intractable epilepsy after a functional hemispherectomy: important lessons from an unusual case. Case report. J Neurosurg 2001;94:510–4.

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SECTION 21 Case presentations

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Lesional mesial temporal epilepsy case discussions J Mani and IM Najm

Introduction Lesional mesial temporal epilepsy is by far, the commonest cause of medically intractable partial epilepsy. Mesial temporal sclerosis (MTS) has been identified as the most frequent pathological feature in surgically treatable mesial temporal lobe epilepsy. Mesial temporal epilepsy (mTLE) syndrome is also the epilepsy most frequently associated with drug resistance. It has very good surgical prognosis in suitable candidates. The establishment of surgical candidacy requires the unambiguous demonstration of the mTLE syndrome associated with MTS, by comprehensive presurgical evaluation. In this chapter we document the case stories of two patients with mesial temporal sclerosis who had presurgical evaluation followed by surgery, one of the non dominant temporal lobe and the second of the dominant temporal lobe.

Patient 1: clinical details

these medications. She had previously been tried on Lamotrigine and Acetazolamide without success. Medical history and epilepsy risk factors Perinatal history was notable for neonatal blood transfusion due to Rhesus incompatibility. There was no report of febrile seizures, intracranial infection, or significant head injury. Family history was remarkable in that LN’s brother had a single febrile seizure. Social history Ms LN had recently lost two jobs in quick succession and was unemployed. She lived with her husband and three children. Clinical examination The general physical and neurological examination were unremarkable

History

Brain imaging

Seizure description and frequency Ms LN, a 38-year-old, right-handed woman was evaluated for intractable seizures. Her seizure history goes back about 20 years when she developed auras, which she described as a déjà vu sensation occurring about once or twice per month, invariably around her menstrual period. These were brief sensations, lasting 10–15 seconds of familiarity in unfamiliar situations. She took no notice of these events until about a year ago. Over the 18 months prior to her evaluation, the episodes changed in character. The more recent subjective sensations consisted of a hot flushed feeling in the head with a sensation of déjà vu that progressed to loss of awareness. Observers had noted reduced responsiveness with rolling movements of her finger tips, with drooling and chewing. Ms LN had no recollection of this however, and the last event that she remembered of her seizure was the déjà vu sensation. Seizures clustered around her menstrual period, occurring about three to five times a month. There was no history suggestive of a generalized motor seizure, though she did lose control of her urine in one of the episodes. Between events, Ms LN is in good health. Seizures continued despite two antiepileptic medications in therapeutic doses, Carbamazepine 1200 mg/day and Levetiracetam 2500 mg/day. LN complained of excessive sleepiness on

Magnetic resonance imaging (Figure 151.1a, b) Brain magnetic resonance imaging was performed on a 1.5 Tesla Siemens SP Scanner (Erlangen, Germany). T1-weighted coronal images showed bilaterally small hippocampi with increased signal in the right hippocampal body on FLAIR sequences. Positron emission tomography (Figure 151.2) PET study showed reduced Fluorodeoxyglucose uptake in the right mesial temporal structures.

Electrophysiology A 20 minute scalp EEG did not reveal any epileptiform activity. Video EEG monitoring Ms LN underwent video-EEG evaluation after withdrawal of antiepileptic drugs using the 10–20 system of scalp electrode placement with additional 10–10 coverage over the bitemporal regions and with sphenoidal electrodes. 1435

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(a)

(b)

Figure 151.1 Coronal images through the body of the hippocampi showing biolaterally small hippocampi (T1) with increased signal (FLAIR) in the right hippocampus consistent with predominant right hippocampal sclerosis.

Interictal activity (Figure 151.3a, b) Runs of intermittent slow activity at 3–4 Hz lasting 3–4 seconds were noted in the right temporal region. These runs were more frequent in drowsiness. Sharp waves were exclusively right temporal with maximum amplitude at the sphenoidal (SP2) electrode. Ictal activity Clinical seizure: aura- automotor seizure (loss of awareness) Five typical seizures were recorded over a period of 24 hours. All the episodes were stereotyped. LN recognized an aura and pushed the button at seizure onset. She was able to declare verbally that she was ‘having an aura’. She then had florid mouth and bilateral hand automatisms but continued to follow some verbal and nonverbal commands during the early phase. She was able to appropriately verbalize her name when asked, during the early phase despite the oral automatisms. She subsequently became confused and partially unresponsive during the late phase of the seizure. Immediately after the end of the seizure, LN was able to describe the aura which she called a ‘hot flush that spread across her head’ with increased salivation. However, she has no recollection of the events after the aura. No postictal tiredness or confusion was noted. The average duration of the clinical event was approximately 1 minute. This type of seizure would be described under the ILAE system as a simple partial seizure that evolved into a complex partial seizure. Under the semiological classification system this would be described as cephalic aura- automotor seizure. The seizure semiology is consistent with temporal lobe involvement, but has no clear lateralizing motor features. However, the preserved awareness and appropriate verbalization during the early phase are consistent with a nondominant temporal lobe origin.

EEG seizure (Figure 151.4a, b) The ictal pattern on EEG began with rhythmic sharp waves at 1 Hz over the right temporal region, maximum at the sphenoidal electrode. These evolved into rhythmic spikes at 3–4 Hz that then evolved into a sharply contoured theta rhythm (6 Hz) that increased in amplitude but remained localized to the right anterior temporal region without contralateral spread. The clinical and EEG onsets were simultaneous. The duration of the seizure was approximately 60 seconds.

Neuropsychology Preoperative neuropsychological assessment using the Wechsler Adult Intelligence and Memory Scales III edition revealed a full Scale IQ 118; 116 on the verbal measure, 117 on the visual measure. Verbal memory scores were 111 for the immediate and 99 for the delayed with a delayed recognition score of 90. Visual immediate and delayed scores were 106 and 97, respectively.

Analysis In summary, data from presurgical evaluation was concordant for a right mesial temporal epileptogenic zone. Seizure semiology was consistent with nondominant temporal lobe origin. Déjà vu sensations that LN reported are commonly associated with epilepsies of the temporal lobes. Isolated auras are reported to be highly specific of mTLE,1 and in general, are more common in right TLE.2,3 Oroalimentary and hand automatisms are typical signs in TLE. Preserved ictal consciousness despite involuntary automatisms is a rare finding, but is strongly associated with the primary epileptogenic zone in the nondominant hemisphere.4 Electrophysiology clearly demonstrated the irritative zone to be in the right temporal lobe, in view of the stable morphology and distribution of the right anterior

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Figure 151.2

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Fluorodeoxyglucose PET shows reduced radioactive tracer uptake in the right mesial and basal temporal regions.

temporal spikes. The temporal alpha pattern on the ictal EEG with a maximum in the anterior temporal electrodes confirmed that the seizures (ictal onset zone) were right mesial temporal in origin. This was corroborated by MRI, which revealed right mesial temporal sclerosis. Functional imaging also revealed hypometabolism in the same region. The neuropsychological scores were not strongly lateralized to the right side. Thus the presurgical evaluation was strongly indicative of right mesial temporal lobe epilepsy. In view of the strong evidence for right mesial temporal lobe epilepsy, the presurgical team was unanimous in its

recommendation for right temporal lobectomy. The high preoperative visual memory scores was not considered a deterrent for surgery of the nondominant temporal lobe.

Surgery Ms LN underwent right temporal lobectomy that included a resection of the lateral temporal lobe extending 5 cm from the temporal pole with removal of the mesial structures. Histopathology was consistent with hippocampal sclerosis.

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(a)

(b) Figure 151.3 (a and b) Interictal scalp EEG tracing on a bipolar montage shows right temporal slowing with sharp waves in the same region having a maximum negativity as SP2.

Post-operative outcome Ms LN was seizure and aura free at the 6-month follow-up visit. Postoperative MRI revealed resection of the temporal lobe including the mesial structures. Neuropsychological evaluation at 6 months revealed a Full Scale IQ of 121 (superior), a Verbal Comprehension Index of 105 (average), a Perceptual Organization Index of 128 (superior), and a Processing Speed Index of 120 (superior), Auditory Immediate Memory Index

of 105, an Auditory Delayed Memory Index of 94, and an Auditory Delayed Recognition Index of 100, Visual Immediate Memory Index of 97 (average) and a Visual Delayed Memory Index of 75 (borderline). These scores were corrected for practice effect and a significant decline was noted in the visual delayed memory scores. In spite of this change, the patient denied having experienced a significant change in her cognitive status or memory as a consequence of her right temporal lobectomy.

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(a)

(b) Figure 151.4 (a and b) SP2 maximum.

Ictal rhythms at seizure onset and after 20 seconds documenting the right temporal seizure rhythm with an

Patient 2: clinical details History: Seizure description and frequency Ms DN, a 49-year-old right-handed registered nurse had intractable epilepsy since childhood. Her first seizure occurred at the age of 1 year in the context of high-grade fever secondary to pneumonia. Rare seizures persisted until age 9.

These were described as episodes of staring followed by generalized body shaking. She was seizure free on a combination of phenytoin and phenobarbital for many years. Antiepileptic medications were tapered and discontinued at age 28. Seizures recurred at age 31 during the eighth month of DN’s second pregnancy. The seizure frequency increased from one to two per year in the first 3 years of recurrence to two per month in the year prior to the presurgical evaluation.

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DN reported an aura which she described as ‘a sick feeling in my stomach’ and ‘a little light headedness,’ which lasted for 1–2 min. This was usually followed by loss of awareness. ‘All I know is that I do pass out’. Observers reported that she was unresponsive, and then had jerking of her limbs (more marked in the lower limbs) for seizures that lasted more than 30 seconds. She occasionally bit her tongue during seizures but had never been incontinent. There was no significant postictal confusion, but DN had language difficulties. ‘When I’m starting to come out of it I know what is happening around me, but I cannot talk’. For example she was able to identify in her mind that she was looking at a computer, but could not ‘get the thought related to my speech’. This difficulty in speaking lasted for 30–90 seconds. There was no history of generalized motor seizures or status epilepticus. Medical history and epilepsy risk factors DN had hypertension, depression and chronic back pain. She worked as a part-time registered nurse and continued to drive. Seizures persisted despite a trial of three different antiepileptic drugs (Phenytoin, Phenobarbital, Oxcarbazepine) in the past and the present combination of Lamictal 900 mg/day and Phenytoin 500 mg/day.

Brain imaging Magnetic resonance imaging (Figure 151.5a, b) MR imaging of the brain in a 1.5 Tesla Siemens SP scanner (Erlangen, Germany) revealed left mesial temporal sclerosis in the form of a shrunken left hippocampus (head, body, and tail) in T1 coronal images and increased hyperintensity of the left mesial temporal structures on FLAIR imaging.

(a)

Positron emission tomography (Figure 151.6) An interictal PET study of the brain showed reduced fluorodeoxyglucose uptake in the left mesial temporal structures and the anterior temporal neocortex.

Electrophysiology Routine EEGs documented intermittent slowing and occasional sharp transients in the left temporal region. Video EEG evaluation Ms DN underwent video-EEG evaluation with discontinuation of antiepileptic medications over a period of 8 days using 10-10 system of scalp electrodes and additional sphenoidal electrodes. Interictal activity (Figure 151.7) Interictal recording revealed intermittent left temporal slowing at 5–7 Hz lasting 2–3 seconds in sleep and wakefulness. Rare left temporal spikes were recorded which were maximum at the sphenoidal electrode. Ictal activity (Figure 151.8a, b) Clinical seizures: automotor seizure (loss of awareness) Two of the three typical seizures recorded occurred out of wakefulness. DN did not recognize the onset of her seizures. The seizure began with a prolonged period of staring. She then had chewing and swallowing movements. She was tested towards the end of the clinical seizure and was partially attentive but had difficulty following commands. After the end of the EEG seizure, DN was fully attentive but had difficulty

(b)

Figure 151.5 (a and b) Coronal images through the body of the hippocampi showing a smaller left hippocampal body (T1 image) with increased signal (FLAIR) consistent with left hippocampal sclerosis.

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Figure 151.6

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Fluorodeoxyglucose PET shows reduced radioactive tracer uptake in the left mesial and basal temporal regions.

saying her name, repeating words and naming a pen. She was however able to stick out her tongue and point to her nose when instructed. This phase lasted for 90 seconds. She later reported being aware of the testing but being unable to speak. This seizure would be labeled a complex partial seizure in the ILAE classification. In the semiological seizure classification this would be an automotor seizure with loss of awareness. LN had classical postictal aphasia which lateralized the seizure to the left hemisphere. EEG seizures Ictal EEG patterns were stereotyped in all the three seizures.

EEG onset was marked by a rhythmic theta frequency discharge over the left temporal chain, maximal at Sp1. This evolved over 15 seconds to rhythmic spiking over the left hemisphere, that continued for another 25 seconds before slowing to a delta frequency rhythm with sharp components. The delta slowed further, and became smoothly contoured before the end of the EEG seizure. There was no significant involvement of the opposite side in the initial and spiking phase, and modest involvement with a low-amplitude deltafrequency rhythm in the latter part of the seizure. Duration of EEG seizure was 1 min 28 sec.

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(a)

(b) Figure 151.7 Interictal scalp EEG tracing on a bipolar montage shows left temporal slowing with sharp waves in the same region having a maximum negativity as left sphenoidal electrode SP1.

Neuropsychology

spheres, with delayed memory scores of 80 and 78 for verbal and visual material respectively.

Neuropsychological examination using the Wechsler Adult Intelligence and Memory Scales Version III revealed an average level of preoperative functioning with no asymmetry of verbal and visual scores. The Full Scale Intelligence Quotient (IQ) was 97 with the Verbal IQ at 98 and Performance IQ at 94. Scores for Immediate Memory were 77 and 75 in the verbal and visual

Analysis In summary, the preoperative evaluation provided evidence of left temporal lobe epilepsy, with complete concordance

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(a)

(b) Figure 151.8 (a and b) Ictal rhythms at seizure onset and after 25 seconds documenting the left temporal seizure rhythm with a left sphenoidal (SP1) maximum.

between seizure descriptions by history, interictal EEG, observed clinical semiology, ictal EEG and neuroimaging. Epigastic auras are very common in mTLE but are not specific for mesial temporal seizure origin.5 Though the seizure semiology in itself was not lateralizing, LN had a striking postictal aphasia. Post ictal aphasia has been consistently associated with seizure onset in the language dominant hemisphere.3,6–8

The neuropsychological scores did not lateralize memory deficits. In view of the average preoperative verbal memory scores and the presence of significant hippocampal sclerosis on MRI, it was predicted that Ms LN would have only a small risk for memory decline. It was concluded that no Wada test was necessary. DN was offered a left anterior temporal lobectomy.

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Textbook of epilepsy surgery Seizure semiology in MTLE Ictal semiology is a reflection of the activation of the symptomatogenic zone(s). The symptomatogenic zone is usually located in the proximity of the epileptogenic zone but very frequently it does not overlap with the epileptogenic zone. It is essential to remember that no single symptom or EEG feature in isolation is diagnostic of mesial temporal cortical activity. It is therefore crucial not to evaluate any symptom in isolation, but to consider the sequence and context of their occurrence.5

Figure 151.9 Postoperative coronal T1 image showing the resection of the lateral and mesial left temporal structures (6-month postoperative image).

Surgery A left temporal lobectomy was performed under general anesthesia. Four and a half centimeters of the lateral temporal lobe were removed with resection of the amygdala and the hippocampus. The parahippocampal gyrus was also resected. DN had an uneventful postoperative course. Histopathology revealed hippocampal sclerosis.

Post-operative outcome Ms DN was seizure free at the 6-month follow-up visit. Phenytoin was discontinued and she was maintained on Lamictal monotherapy. DN continued to do well at the 1-year follow-up visit. She had a single seizure in the 10th month after surgery. Follow-up neuropsychological assessment showed improvement in raw scores for all subsets of performance but these were not considered significant after correction for practice effects.

Discussion The essential purpose of the presurgical evaluation in lesional mTLE surgery is to demonstrate the overlap between the epileptogenic lesion and the epileptogenic zone.

EEG in mTLE Interictal discharges in hippocampal sclerosis have a very localized field which may be missed by scalp electrodes.9 When recorded in the scalp-EEG, they are highly restricted to the anterior temporal electrodes. True anterior temporal electrodes help increase the likelihood of recording temporal interctal epileptiform discharges (IEDs). Sphenoidal electrodes and anterior temporal electrodes help in the differentiation between neocortical temporal epilepsy (spikes have higher amplitude in mid-temporal electrodes) and mesial/anterior temporal epilepsy (spikes have a relatively higher amplitude in sphenoidal and anterior temporal electrodes). Frequent posterior temporal or extratemporal sharp waves may decrease the certainty of the diagnosis of hippocampal sclerosis. Ictal rhythms in the form of rhythmic theta (Figure 151.4a) or alpha activity (Figure 151.8a) within the first 30 seconds of the electrographic or clinical seizure onset are observed in approximately 80% of patients with mTLE and have a high lateralizing value.10,11 However these patterns are significantly more common in patients with moderate to marked hippocampal atrophy rather than those with mild hippocampal atrophy.12 Neocortical ictal onset patterns may be indistinguishable from those of mesial temporal origin, but some authors have suggested that the 5–9 Hz inferotemporal rhythm is more specific for hippocampal onset seizures.13 In patients with history and ictal symptoms suggestive of mTLE, interictal discharges can reliably lateralize the seizure focus if they are consistently unilateral and concordant with the MRI identified unilateral hippocampal atrophy. Concordance of MRI and interictal EEG is more closely associated with good surgical outcome than concordance of MRI and ictal EEG findings with nonlateralized interictal EEG.14 Studies indicate that noninvasive ictal EEG recordings do not improve seizure localization in patients with suspected TLE in whom MRI and interictal EEG are concordant.15 Neuropsychological outcome in mTLE Cognitive outcome after temporal lobe surgery has been recently evaluated in multivariate analyses.16,17 Dominant hemisphere surgery, extent of mesial temporal sclerosis on volumetric MRI and good baseline memory scores on neuropsychological testing were associated with a greater risk of memory decline following surgery. IAP memory scores did not contribute to the prediction of memory deficits in one study,16 but ipsilateral IAP memory score was an independent predictor of outcome in another study.17

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Conclusion Lesional mesial temporal lobe epilepsy lends itself to a simple and fairly standardized presurgical work-up and promises an excellent surgical outcome. In patients with intractable focal epilepsy and MTS on MR imaging, it is tempting to assume that the MTS is identical to the epileptic region. However it has been shown that the positive predictive value of MTS alone is not satisfactory.18 Hence it is essential to establish the overlap of the

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epileptogenic lesion with the irritative zone, the seizure onset zone and the functional deficit zones, by complementary multimodality testing. Such a demonstration of concordance may permit more selective surgery such as a selective amygdalohippocampectomy. The aim of a limited resection would be to limit postoperative functional deficits especially in cases with dominant temporal lobe epilepsy. The value of selective over more extensive temporal lobe resections in limiting deficits and in relative seizure outcome is still a matter of intense debate.19,20

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Wieser HG, Williamson PD. Ictal semiology. In: a Englj Jr ed. Surgical Treatment of Epilepsies. New York: Raven Press, 1993:161–71. Fakhoury T, Abou-Khalil B, Peguero E. Differentiating clinical features of right and left temporal lobe seizures. Epilepsia 1994;35(5): 1038–44. Steinhoff BJ, Schindler M, Herrendorf G et al. The lateralizing value of ictal clinical symptoms in uniregional temporal lobe epilepsy. Eur Neurol 1998;39(2):72–9. Ebner A, Dinner DS, Noachtar S, Lüders HO. Automatisms with preserved responsiveness: a Neurology 1995;45(1):61–4. Kotagal P. Seizure symptomatology in temporal lobe seizures In: Luders HO, Ed. Epilepsy Surgery. New York: Raven Press, 1992: 143–6. Penfield W, Jasper H. Epilepsy and the Functional Anatomy of the Human Brain. Boston: Little Brown and Company, 1954. Serafetidines EA, Falconer MA. Speech disturbances in epileptic patients: a study of 100 epileptic patients submitted to anterior temporal lobectomy. Brain 1963;86:333–46. King DW, Ajmone-Marson C. Clinical features and ictal patterns in patients with EEG temporal lobe foci. Ann Neurol 1977(2):138–47. So, NK. Interictal electroencephalography in temporal lobe epilepsy. In Lüders HO, Comair YG, eds. Epilepsy Surgery. Philadelphia: Lippincott Williams & Wilkins, 2001:393–402. Risinger MW, Engel J Jr, Van Ness PC, Henry TR, Crandall PH. Ictal localization of temporal lobe seizures with scalp/sphenoidal recordings. Neurology 1989;39(10):1288–93. Walczak TS, Radtke RA, Lewis DV. Accuracy and interobserver reliability of scalp ictal EEG. Neurology 1992;42(12):2279–85.

12. 13. 14. 15.

16. 17. 18.

19. 20.

Vossler DG, Kraemer DL, Knowlton RC et al. Temporal ictal electroencephalographic frequency correlates with hippocampal atrophy and sclerosis. Ann Neurol 1998;43(6):756–62. Ebersole JS, Pacia SV. Localization of temporal lobe foci by ictal EEG patterns. Epilepsia 1996;37(4):386–99. Gilliam F, Bowling S, Bilir E et al. Association of combined MRI, interictal EEG, and ictal EEG results with outcome and pathology after temporal lobectomy. Epilepsia 1997;38(12):1315–20. Cendes F, Li LM, Watson C et al. Is ictal recording mandatory in temporal lobe epilepsy? Not when the interictal electroencephalogram and hippocampal atrophy coincide. Arch Neurol 2000;57(4): 497–500. Chelune GJ, Najm IM. Risk factors associated with postsurgical decrements in memory. In: Luders HO and Comair Y, eds. Epilepsy Surgery, 2nd edn. Philadelphia: Lippincott-Raven, 2001:497–504. Stroup E, Langfitt J, Berg M et al. Predicting verbal memory decline following anterior temporal lobectomy (ATL). Neurology 2003;60(8):1266–73. Gilliam F, Faught E, Martin R et al. Predictive value of MRI-identified mesial temporal sclerosis for surgical outcome in temporal lobe epilepsy: an intent-to-treat analysis. Epilepsia 2000;41(8): 963–6. Helmstaedter C, Reuber M, Elger CC. Interaction of cognitive aging and memory deficits related to epilepsy surgery. Ann Neurol 2002;52(1):89–94. Gleissner U, Helmstaedter C, Schramm J, Elger CE. Memory outcome after selective amygdalohippocampectomy in patients with temporal lobe epilepsy: one-year follow-up. Epilepsia 2004; 45(8): 960–2.

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A patient with nonlesional mesial temporal lobe epilepsy A Ray, G Kalamangalam, and HO Lüders

Clinical history The patient was a 14-year-old right-handed female whose seizures started at the age of 9 years. Seizures were characterized by a blank stare, followed by repetitive semi-purposeful movements of her hands and lip-smacking (manual and oral automatisms). No preictal aura was reported. Observers reported that she was unable to speak during the seizure; she was amnestic for the seizure afterwards. She would usually fall asleep in the postictal period, though on occasion she would be awake and combative. Seizures lasted approximately 1 minute; seizure frequency varied from weekly to as many as seven seizures per day. There was no history of generalized motor seizures. There was no past history of febrile seizures, significant head trauma, or intracranial infection. Her health otherwise was excellent. There was no family history of epilepsy or other neurological disease. The patient had failed combinations of multiple antiepileptic drugs (AEDs) including zonisamide, topiramate, levetiracetam, carbamazepine, and phenobarbital. Previous EEGs had shown sharp waves at the left anterior temporal electrodes (F7, T7).

Figure 152.1

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General physical, and complete neurologic, examination was normal.

Noninvasive video-EEG monitoring Recordings were performed with the usual 10–20 scalp electrode coverage with additional sphenoidal electrodes. Interictal EEG Spikes, regional left temporal, maximum at the left sphenoidal (Sp1) electrode (Figure 152.1); 100% of discharges. Ictal EEG Four seizures were recorded. Clinical seizures These were characterized by blank staring, florid oral automatisms, and symmetric automatisms of the upper extremities. The patient could not speak or follow commands during seizures.

Left temporal spikes (location marked by grey dots) on scalp EEG, maximum at the left sphenoidal (Sp1) electrode.

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A patient with nonlesional mesial temporal lobe epilepsy In this phase progressed to clonic movements of the right side of the face. The patient was aphasic in the postictal period and wiped her nose with her left hand. In the ILAE classification system, the patient would be regarded as having complex partial seizures, as there appeared to be an ‘alteration of consciousness’ during the seizure. However under the semiological classification system1 followed in the Cleveland Clinic, the patient would be classified as having automotor seizures progressing to right face clonic seizures, with lateralizing signs of postictal aphasia and postictal nose-wipe. The latter two features, and the right face clonic activity, suggested a dominant (left) hemisphere seizure onset.2,3 EEG seizures Regional left temporal. Seizures began with brief electrodecrement over the left temporal region. This was followed (usually within approximately 10 seconds) by rhythmic theta activity over the left temporal region, maximal over the left sphenoidal (Sp1) electrode. Theta activity usually lasted between 30–40 seconds followed by postictal slowing, again maximal over the left temporal region (Figure 152.2). High-resolution brain MRI Normal T1-weighted and FLAIR coronal sequences. In particular, there was no evidence of shrinkage or asymmetry of hippocampal volumes, or hippocampal high signal (Figure 152.3).

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PET (positron emission tomographic) scan Left temporal hypometabolism (Figure 152.4). Ictal SPECT (single photon emission computed tomographic) scan Injection was performed at 35 seconds after EEG seizure onset. Intense ictal hyperperfusion (20–25%) was observed in the left temporal region (Figure 152.5). Neuropsychological evaluation This is detailed in Table 152.3 (left-hand columns). Memory was mildly impaired overall, with low-average impairment of verbal immediate memory (with delayed verbal recall relatively spared), and impairment of both immediate and delayed visual recall. Full-scale and verbal IQ were both in the normal range, with performance IQ scored in the low-average range. Overall, the patient was judged to function in the average range of intellectual ability, with an advantage for verbal, over nonverbal, material. Memory scores also reflected an advantage for verbal over visual tasks. This pattern was considered unusual in view of her right-handedness and putative left temporal lobe epilepsy. She was deemed to be at risk for decline in her verbal memory if subjected to left anterior temporal lobectomy.

Figure 152.2 EEG seizure on scalp EEG. Top left: Baseline: sleep in the first half of the page followed by arousal. Top right: Clinical onset followed about 8 seconds later by EEG seizure onset characterized by brief electrodecrement. Bottom left: EEG Onset + 30 seconds: theta rhythms are seen over the left temporal region, maximum over the Sp1. Bottom right: Seizure rhythms continue in the first half of the page, terminating in the middle of the page. Postictal slowing follows, again maximal over the left temporal region.

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Figure 152.3 Brain MRI. Left image shows T1-weighted volumetric coronal sequences. Right image is a T2-weighted coronal study. Hippocampi are normal in volume and appearance.

Figure 152.4

(Interictal) PET scan: left temporal hypometabolism.

Figure 152.5 Ictal SPECT scan: left temporal ictal hyperperfusion. Axial (top two) and coronal (bottom) images.

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A patient with nonlesional mesial temporal lobe epilepsy

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Intracarotid amobarbital (Wada) testing Results are summarized in Table 152.1. There was left hemispheric dominance for language, and bilaterally intact memory representation. Together with the preoperative neuropsychological evaluation, this emphasized the risk for some decline in verbal memory following left temporal lobe resection. Summary of evaluation and further management The patient’s history and seizure semiology suggested left temporal lobe epilepsy. Interictal EEG showed a single population of epileptiform discharges, maximum over the left sphenoidal electrode; ictal EEG rhythms were best developed over the left sphenoidal electrode (with the earliest changes of electrodecrement also over the left temporal region). The electrographic findings were thus of left mesial temporal lobe epilepsy. Interictal PET and ictal SPECT were concordant. However, the lack of an MRI lesion, the relatively preserved verbal memory scores on the neuropsychological evaluation, and bilateral memory representation on Wada put her at risk for memory decline following a standard left anterior temporal lobectomy. Following discussion at the epilepsy patient management conference, it was recommended that the patient undergo invasive evaluation with subdural grid electrodes prior to resective surgery. This would allow precise localization of the ictal onset zone, allowing a tailored resection sparing eloquent cortical areas identified by cortical stimulation mapping.

Figure 152.6 Schematic diagram showing A, B, C and D subdural electrode plate positions.

●

●

Invasive video-EEG monitoring Four subdural grids were placed at craniotomy (Figure 152.6). The A-plate (8 × 8) covered the lateral aspect of the inferior left frontal lobe and the adjacent left temporal lobe. The posterior edge of this plate overlapped the central sulcus. The B-plate (4 × 4) covered the left orbitofrontal region as well as the anteroinferior aspect of the left frontal lobe. The C-plate (2 × 6) was placed over the left midbasal temporal region. The D-plate (1 × 6) covered the left basal temporooccipital region. The position of electrodes was confirmed by 3D reconstructed MRI (Figure 152.7). Interictal EEG Recordings were reviewed in a referential montage to an electrode on the A-plate (SA59), presumed distant from the irritative zone. Two populations of epileptiform activity were observed.

Table 152.1

Spikes, left mesial temporal: These were the most frequent (70% of discharges) and present over the C-plate. These were usually maximum over C1 and C7 (Figure 152.8), and occasionally over C10. Spikes, left anterior temporal: This independent population was present over the A-plate and comprised 30% of all discharges. Spikes were usually maximum over the A8, A16 or A23 electrodes (Figure 152.9).

Ictal EEG Five seizures were recorded. Semiologically, these seizures were identical to those seen during the noninvasive evaluation, including one that progressed from an automotor phase involving oral and upper extremity automatisms to clonic activity of the right side of the face. Ictal EEG change preceded clinical symptoms by 7–8 seconds but on occasion by up to 30 seconds. The first EEG changes seen were poly-spikes (Figure 152.10) and paroxysmal fast activity over the left mesial temporal electrodes (C1>C2) followed by diffuse suppression over the left frontotemporal region (anteroinferior A-plate and entire C-plate) as well as the left orbitofrontal (B-plate) region. About 20 seconds after

Wada test

First verbal response Memory retention score

Left Injection

Right Injection

1 min 18 seconds after injection (followed by perseveration until 1 minute 37 seconds) 11/12 (92%)

12 seconds after injection 12/12 (100%)

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Figure 152.7 3D reconstructed images of electrode locations. These were obtained by superimposing the patient’s preoperative brain MRI on a further MRI obtained after subdural electrode placement.

Figure 152.8 Intracranial EEG of spikes on the C-plate (the main spike population). The top figure shows spike-polyspike discharges with maxima over the C1–2 electrodes (also seen at C7–8). The bottom figure shows spikes with maxima over the C7–8 electrodes (also seen at C1–2).

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Figure 152.9 Intracranial EEG showing spikes on the A-plate (the other spike population seen in this patient). The top image shows spikes with maxima over A15–16 electrodes (also seen at A7–8). The bottom image shows spikes over A23–24 electrodes (also seen at A15–16).

EEG seizure onset, theta rhythms were seen over the basal temporal region (C-plate), followed by similar rhythms over the lateral temporal neocortex (A-plate). Rhythms slowed down to delta frequency about 40 seconds after EEG seizure onset and finally diffuse suppression was seen (Figure 152.11). Evoked potential studies Median nerve SSEPs localized the central sulcus between the A59 and A57 electrodes.

Cortical stimulation mapping Receptive language function was localized to mid- and posterior temporal regions (A29, A37–39, A62–63), with the patient having difficulty with speech comprehension on stimulation of this area. Face and tongue motor responses were recorded from the A-plate above the sylvian fissure (A45, A53). Visual symptoms were reported on stimulation of the temporoparietal region (A54, A56, A61). A brief (5–8 second) seizure with clonic movements of the right face, was provoked by stimulation of the A36 electrode. Results of cortical stimulation are summarized in Table 152.2.

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Figure 152.10 Intracranial EEG seizure. The top image demonstrates the EEG seizure onset with a polyspike discharge at the C1 electrode. This is followed by rhythmic spiking (bottom image) at the C-plate, maximally seen over the mesial temporal electrodes (C1–3, C7–8). Also appreciated, in the second half of the bottom image is a diffuse suppression over the entire C-plate along with paroxysmal fast activity, again best appreciated over the C1 electrode.

Summary of invasive evaluation Left mesial temporal lobe epilepsy was confirmed. The majority of interictal discharges originated from the left mesial temporal region with the remaining discharges from the left anterior temporal lobe. The first EEG changes during seizures were over the left mesial temporal electrodes, confirming the latter as the ictal onset zone. Seizures spread rapidly to the basal temporal, followed by lateral temporal neocortex. Language function was localized to the mid to posterior temporal regions, well away from the ictal onset zone. Overall summary; surgical strategy The noninvasive and the invasive video-EEG monitoring were both suggestive of left mesial temporal lobe epilepsy. Concern remained about the relatively high preoperative neuropsychological verbal memory scores as well as the bilateral memory representation on Wada. However, from

the point of view of seizure control, a left temporal lobectomy was felt to be the optimal procedure. Informed consent for this procedure was taken after the risks and benefits of the procedure were explained to the patient and her family.

Epilepsy surgery The patient underwent a 4.5-cm left temporal lobectomy. A standard subpial technique was employed for dissection down to the temporal horn. The lateral temporal lobe was then amputated followed by resection of the left amygdala and the left hippocampus. Histopathology (Figure 152.12) Left temporal lobe: mild cortical dysplasia. Left amygdala: microscopic dysplastic foci. Left hippocampus: no significant pathology.

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Figure 152.11 Intracranial seizure progression at 20 (left panel), 40 (middle panel) and 60 seconds (right panel) following EEG seizure onset. The top images demonstrate seizure rhythms over the C-plate and the bottom images demonstrate simultaneous seizure rhythms at the A-plate.

Follow-up No postoperative motor deficits were observed. Seizure outcome was excellent, with no seizures during a 4-year outpatient followup period. The patient now has driving privileges. She remains on zonisamide 200 mg daily. Repeat neuropsychological evaluation was performed once, 6 months after surgery. The patient elected against having a further interval evaluation. Details of the former appear in Table 152.3 (right-hand column). Overall memory remained impaired, with a slight postoperative deterioration. However, this was entirely due to a significant (and expected) drop in both immediate and delayed verbal recall. Visual memory, on the other hand improved considerably, for both immediate and delayed items. This pattern carried over to IQ testing, with verbal IQ dropping modestly, but performance and full-scale IQ improving over preoperative scores. In conclusion, the patient experienced an overall improvement from her epilepsy surgery in terms of physiological distress. Mood and adjustment issues were of some persisting concern when she was last interviewed.

MRI is now considered relatively straightforward. Most centers report good seizure outcome from anterior temporal lobectomy in a typical case; postoperative neuropsychological deficits are thought to be somewhat mitigated by the presence of HS. Temporal lobe epilepsy in a patient with a normal MRI is more challenging; identification of the ictal onset zone requires further investigation, and postoperative neuropsychological deficits are of more concern. Epilepsy surgery centers vary in their approach to this issue; at the Cleveland Clinic, subdural grid evaluation similar to that performed in this patient is the favored invasive electroencephalographic approach for purposes of localization. Controversies regarding neuropsychological issues are outlined below. An early report of Penfield and Milner4 described memory decline in two patients following standard unilateral left temporal resection. Subsequent reports5,6 have documented

Discussion The management of a patient with mesial temporal lobe epilepsy associated with hippocampal sclerosis (HS) on brain

Table 152.2

Cortical stimulation

Symptom elicited

Electrodes stimulated

Difficulty with comprehension Tongue and face motor response Visual symptoms Right face clonic seizure

A29, A37–39, A62–63 A45, A53 A54, A56, A61 A36

Figure 152.12 Neuronal cytomegaly seen at layer 6 of the temporal neocortex suggestive of cortical dysplasia. No significant pathology was seen in the hippocampus.

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Pre- and postoperative neuropsychological evaluation

Neuropsychological parameter

Presurgical evaluation

6-month postoperative evaluation

Overall memory

74 (4th percentile; mild impairment)

Verbal immediate memory Verbal delayed memory

78 (7th percentile; low-average to mildly impaired) 97 (42nd percentile; average)

Visual immediate memory Visual delayed memory Full Scale IQ Verbal IQ Performance IQ

69 85 90 98 83

68 (2nd percentile; significant impairment) 54 (0.1 percentile; significant impairment) 54 (0.1 percentile; significant impairment) 100 (50th percentile; average) 103 (58th percentile; average) 93 (average) 89 (low-average) 99 (average)

(2nd percentile; impaired) (16th percentile; low-average) (average) (average) (low-average)

similar findings. Prediction of which patients are at particular risk for postoperative memory decline has prompted two explanatory neuropsychological models.7 The functional reserve model This model, now somewhat dated, postulated that memory function in the normal (i.e. contralateral to the epileptic) temporal lobe (the ‘functional reserve’) was predictive of postoperative memory decline. Thus, poor memory function of the contralateral (normal) temporal lobe on Wada testing predicted postoperative memory decline. This model was based on the observation8,9 that patients who passed the Wada memory test with ipsilateral injection (i.e. demonstrated adequate contralateral functional reserve), did not have significant postoperative memory complaints. This observation was however contradicted by the study of Wyllie and co-workers,10 who found no significant differences in postoperative memory outcome in patients who had passed or failed the Wada memory test after ipsilateral injection. The functional adequacy model According to this model,11–13 good ipsilateral memory scores on the Wada test predict poor memory outcomes after temporal lobectomy. This correlates with MRI hippocampal volumetric studies that suggest that patients with larger hippocampi experience more memory decline after left temporal resection.14 Neuropathologic studies also suggest

that higher degrees of hippocampal sclerosis are associated with less postoperative memory decline after dominant temporal resection.15 However, it has also been demonstrated that patients with unequivocal hippocampal sclerosis on brain MRI and good preoperative verbal memory scores experience memory decline after dominant temporal lobe resection.18,19 Thus, it appears that good preoperative verbal memory scores and a structurally normal dominant hippocampus are independent predictors of post-operative memory decline.20,21 Synthesis While the functional adequacy model appeared sound in the 1990s, towards the end of that decade and the early years of the current century, the validity of this model was also questioned. Various studies22–24 demonstrated that good preoperative right side memory scores on the Wada test in fact predicted a favorable memory outcome after dominant temporal lobectomy, if the age of seizure onset was taken into account. It has been postulated that early damage to the dominant temporal lobe possibly results in transfer of memory to the right temporal lobe resulting in a better postoperative memory outcome. In summary, while there is no clear consensus on which of these above models is correct, it may be that the risk of memory decline in individual patients is along a spectrum between these two extremes. Our patient’s outcome was concordant with the functional adequacy model, possibly in view of her relatively late onset of seizures.


Lüders HO, Acharya J, Baumgartner C et al. Semiological seizure classification. Epilepsia 1998;39(9):1006–13. Gabr M, Lüders HO, Dinner D et al. Speech manifestations in lateralization of temporal lobe seizures. Ann Neurol 1989;25(1):82–7. Leutmezer F, Serles W, Lehrner J et al. Postictal nose wiping: a lateralizing sign in temporal lobe complex partial seizures. Neurology 1998;51(4):1175–7. Penfield W, Jasper H. Epilepsy and the Functional Anatomy of the Human Brain. Boston: Brown, Little and Co., 1954. Serafetinides EA, Falconer MA. Some observations on memory impairment after temporal lobectomy for epilepsy. J Neurol Neurosurg Psychiatry 1962;25:251–5.

6. 7.

8.

Walker AE. Recent memory impairment in unilateral temporal lesions. AMA Arch Neurol Psychiatry 1957;78(6):543–52. Kubu CS, Lineweaver TT, Chelune GJ. The role of neuropsychological assessment in the presurgical evaluation of epilepsy surgery candidates. In: Rosenow F and Lüders HO, eds. Presurgical Assessment of the Epilepsies with Clinical Neurophysiology and Functional Imaging Handbook of Clinical Neurophysiology, Vol 3. 1st edn. Amsterdam: Elsevier BV, 2004; 245–56. Klove H, Grabow JD, Trites RL. Evaluation of memory functions with intracarotid sodium amytal. Trans Am Neurol Assoc 1969;94: 76–80.

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A patient with nonlesional mesial temporal lobe epilepsy 9. 10. 11. 12.

13. 14. 15.

16.

Blume WT, Grabow JD, Darley FL, Aronson AE. Intracarotid amobarbital test of language and memory before temporal lobectomy for seizure control. Neurology 1973;23(8):812–9. Wyllie E, Naugle R, Awad IA et al. Intracarotid amobarbital procedure: I. Prediction of decreased modality-specific memory scores after temporal lobectomy. Epilepsia 1991;32(6):857–64. Chelune GJ. Hippocampal adequacy versus functional reserve: predicting memory functions following temporal lobectomy. Arch Clin Neuropsychol 1995;10(5):413–32. Kneebone AC, Chelune GJ, Dinner DS et al. Intracarotid amobarbital procedure as a predictor of material-specific memory change after anterior temporal lobectomy. Epilepsia 1995;36(9): 857–65. Loring DW, Meador KJ, Lee GP et al. Wada memory asymmetries predict verbal memory decline after anterior temporal lobectomy. Neurology 1995;45(7):1329–33. Trenerry MR, Jack CR Jr, Ivnik RJ et al. MRI hippocampal volumes and memory function before and after temporal lobectomy. Neurology 1993;43(9):1800–5. Oxbury J, Oxbury S. Neuropsychology: memory and hippocampal pathology. In: Reynolds EH and Trimble MR, eds. The Bridge Between Neurology and Psychiatry. Edinburgh: Churchill Livingstone, 1989;136–150. Hermann BP, Wyler AR, Somes G et al. Pathological status of the mesial temporal lobe predicts memory outcome from left anterior temporal lobectomy. Neurosurgery 1992;31(4):652–7.

17. 18. 19. 20. 21. 22. 23.

24.

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Hermann BP, Wyler AR, Somes G et al. Declarative memory following anterior temporal lobectomy in humans. Behav Neurosci 1994;108(1):3–10. LoGalbo A, Sawrie S, Roth DL et al. Verbal memory outcome in patients with normal preoperative verbal memory and left mesial temporal sclerosis. Epilepsy Behav 2005;6(3):337–41. Loring DW, Meador KJ, Lee GP, Smith JR. Structural versus functional prediction of memory change following anterior temporal lobectomy. Epilepsy Behav 2004;5(2):264–8. Chelune GJ, Najm IM. Risk factors associated with postsurgical decrements in memory. In: Lüders HO, Comair Y, eds. Epilepsy Surgery 2nd edn. Philadelphia: Lippincott-Raven, 2001; 497–504. Stroup E, Langfitt J, Berg M et al. Predicting verbal memory decline following anterior temporal lobectomy (ATL). Neurology 2003; 60(8):1266–73. Jokeit H, Ebner A, Holthausen H et al. Individual prediction of change in delayed recall of prose passages after left-sided anterior temporal lobectomy. Neurology 1997;49(2):481–7. Bell BD, Davies KG, Haltiner AM, Walters GL. Intracarotid amobarbital procedure and prediction of postoperative memory in patients with left temporal lobe epilepsy and hippocampal sclerosis. Epilepsia 2000;41(8):992–7. Sabsevitz DS, Swanson SJ, Morris GL et al. Memory outcome after left anterior temporal lobectomy in patients with expected and reversed Wada memory asymmetry scores. Epilepsia 2001; 42(11):1408–15.

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Patient with bitemporal lobe epilepsy AV Alexopoulos and HO Lüders

History of present illness The patient is a 30-year-old right-handed woman, who presents for evaluation of poorly-controlled seizures. Her birth and development were normal. She reports a history of minor head trauma without associated loss of consciousness at the age of 5 years. Otherwise, she has no identifiable risk factors for epilepsy. Her history of seizures starts around the age of 20 years. Seizures consist of initial loss of awareness, a fixed stare and hand automatisms (described by her husband as ‘rubbing her hands together’). The patient does not report an aura and is amnestic for events during seizures. Average duration is 2 to 3 minutes, followed by a brief period of postictal confusion. Seizure frequency is approximately 1–2/week (predominantly around her menses). Exact seizure frequency has been difficult to estimate, as the patient may remain unaware of her seizures, when no one is with her. On one occasion, a seizure while cooking resulted in first degree burns of both hands. Several years ago the patient used to have episodes of ‘smelling something like ammonia’; these spells were not clearly linked to her habitual seizures and have not recurred in recent years. The patient is a high school graduate, who went on to complete all but three classes for an associate’s degree in general studies. According to her account she was forced to stop taking classes because of continued seizures and medication side effects. She then worked for several years as an assistant at a group home for handicapped children, but has been able to do so in the last 4 years. She is married and lives with her husband and their four children. She reports that seizures have taken away her independence, as she is afraid to go out on her own and ‘... can’t do the things I want to do with the kids’. She has a history of two seizure-related motor vehicle accidents in the past and is not allowed to drive. Her father provides transportation when her husband is at work. The patient does not smoke and does not consume alcohol. She denies use of any other recreational or illicit drugs. Her general physical and neurological examination is unremarkable. Formal psychological evaluation reveals that the patient has been depressed for several years in response to her ongoing, seizures and the multiple consequences associated with uncontrolled epilepsy including interference with college, employment and driving. She is currently on antidepressant therapy with a selective serotonin and norepinephrine 1456

reuptake inhibitor (venlafaxine) and participates in bimonthly counseling. Past medical history is otherwise unremarkable with the exception of a previous cholecystectomy and surgical removal of an ovarian cyst. Chronic anticonvulsant therapy consists of a combination of topiramate (500 mg/d) and valproic acid (1,000 mg/day). She has failed maximum tolerated doses of carbamazepine, levetiracetam, and phenytoin in the past. She is not under treatment for any other active medical condition. The patient is considering epilepsy surgery and expresses motivation to return to college in the future (she states that she would be interested in pursuing a degree in psychology and working to support single mothers and their children).

Presurgical investigations As seizures proved resistant to multiple antiepileptic medications the patient was admitted to the epilepsy monitoring unit for a noninvasive video-EEG evaluation using a combination of scalp and sphenoidal electrodes. Interictal EEG (Figure 153.1) showed sharp waves arising independently from the left and right anterior temporal regions (maximum at the ipsilateral sphenoidal electrode), with an estimated left (Sp1) to right (Sp2) ratio of approximately 60:40 overall (during one week of recording). No other temporal or extratemporal spike foci were noted. All recorded seizures had similar electroclinical features and were associated with a stereotyped ictal EEG, characterized by a rhythmic buildup of 5–6 Hz rhythmic theta localized in the left temporal region maximal in the left sphenoidal electrode (Figures 153.2a and b). Ictal patterns remained restricted in the left temporal distribution throughout the seizure without spreading to other brain regions. None of the recorded ictal patterns showed evidence of right hemisphere lateralization. Semiologically all of the patient’s recorded episodes were classified as automotor seizures. Her typical seizures were punctuated by an initial motionless stare heralding a period of unresponsiveness. Oral (lip-smacking) and distal hand automatisms were observed with all seizures, starting approximately 15–20 seconds after clinical onset. There were no other motor manifestations. Such seizures are most frequently seen with temporal lobe epilepsies.1,2 Detailed semiological analysis of video recordings did not reveal any distinct lateralizing signs. During the noninvasive evaluation a total of nine seizures were recorded, six of which

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Patient with bitemporal lobe epilepsy

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Figure 153.1 Scalp-EEG tracings demonstrating interictal, independent left (dark arrow) and right (white arrow) anterior temporal spikes, maximum at the ipsilateral sphenoidal electrode as seen on a longitudinal bipolar montage (the temporal chains have been extended with the addition of sphenoidal electrodes).

arose from sleep and three from wakefulness. No secondarily generalized seizures were recorded. The patient did not press the seizure button with any of these spells. Seizure duration based on EEG ranged from 30 to 80 seconds. Postictally, she was noted to be confused for a brief period lasting less than a minute. The patient was amnestic of her seizures. Results of noninvasive video-EEG studies pointed to a left temporal seizure focus, and prompted referral for further presurgical investigation (phase 1.5 testing), which included a high-resolution anatomical MRI with thin cuts through the temporal lobes (temporal lobe epilepsy protocol),3 an interictal FDG-PET study and formal, standardized neuropsychological evaluation. Initial qualitative review of the patient’s MRI did not reveal clear asymmetries of hippocampal size and/or signal intensity (a subtle decrease in the size of the right hippocampos was questioned). Careful visual inspection of contiguous 3D slices, however, provided no evidence to suggest unilateral atrophy, developmental dysplasia or a subtle mass lesion within the temporal lobes (Figure 153.3). On quantitative analysis the hippocampal formations were found to be volumetrically symmetrical.3 Axial and coronal interictal 18FDG-PET images (coregistered to the patient’s MRI) demonstrated bilateral hypometabolism involving the left and right mesial temporal regions. In addition, a small area of restricted hypermetabolism was seen within the region of the left amygdala (extending to a lesser degree to the left temporal pole). Otherwise, metabolic activity throughout the cortex and subcortical structures was uniform and symmetric (Figure 153.4). The presence of bilateral hypometabolism on 18FDG-PET is suggestive of an interictal functional deficit zone involving the left and right temporal regions and has been associated with bitemporal or less commonly diffuse or extratemporal

seizure foci.4–6 The patient’s interictal PET study was unusual in that it also showed a distinct hypermetabolic focus in the region of the left amygdala. No electroencephalographic or clinical seizures were recorded during acquisition of these PET images, as confirmed by concurrent scalp EEG recordings (which started approximately 20 minutes before injection of radiotracer and continued for a period of 60 minutes). Preoperative neuropsychological testing was notable for mild diffuse dysfunction involving multiple cognitive domains (Figure 153.5a). In addition, there were indications of at least mild level of psychological distress characterized by symptoms a verbal and nonverbal memory tests administered. Auditory memory index scores fell in the impaired range, and visual memory index scores ranged from mildly impaired to the lower end of the borderline range (Figures 153.5b and c). The interpreting neuropsychologist suggested that some of the patient’s difficulties on testing may be attributable to her uncontrolled seizures, level of psychological distress and/or medication adverse effects. The results of this extensive preoperative neuropsychological battery did not reveal a lateralized pattern of impairment and were consistent with other preoperative evidence pointing to ‘bilateral mesial temporal dysfunction’. Because memory function was significantly impaired it was felt that the patient would be at relatively little risk for decline, if she were to have a left (presumably dominant) temporal lobectomy. Summary of presurgical evaluation and surgical plan The patient’s noninvasive EEG recordings incriminated the left temporal region. Her structural MRI, however, did not provide lateralizing information in support of a left temporal epileptogenic focus. Furthermore, interictal EEG, interictal PET and preoperative neuropsychological findings indicated a bilateral functional deficit zone involving both mesial

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(a)

(b) Figure 153.2 Scalp video-EEG evaluation: Two consecutive 10-second scalp-EEG tracings of a typical seizure occurring out of wakefulness, characterized by arrest of activity followed by unresponsiveness and oral automatisms (same montage as seen in Figure 153.1). (a) Electrographic onset with the emergence of initially arrhythmic, sharply contoured delta activity at the left temporal region (left sphenoidal electrode); (b) Evolving ictal pattern: a well-developed left temporal rhythmic discharge (5–6 Hz) is seen within 10 seconds of electrographic onset. As the seizure progresses the left temporal ictal discharge appears to gradually slow down, and ends after a total duration of ∼40 seconds (not shown).

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Figure 153.3 Preoperative MRI: Coronal high-resolution T1-weighted and corresponding T2-weighted images at the level of the hippocampal head depicting the normal basal and lateral surface of both temporal lobes along with the hippocampal formations. Qualitative visual analysis of preoperative MRI images did not reveal any clear asymmetries of hippocampal size and/or signal intensity. The neuroradiologist suggested a subtle decrease in the size of the right hippocampal head, but this was not confirmed upon reviewing the reformatted 3D MPRAGE images. The two hippocampi were volumetrically symmetrical on formal quantitative analysis.

Figure 153.4 Coronal and axial preoperative interictal 18FDG-PET images (coregistered to the patient’s MRI) demonstrate bilateral hypometabolism involving the left and right mesial temporal regions. In addition, a small area of restricted hypermetabolism is present within the region of the left amygdala (double arrow). This restricted area of increased uptake overshadows any evidence of lateralized/asymmetric temporal hypometabolism. Otherwise, metabolic activity throughout the cortex and subcortical structures is uniform and symmetric.

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(a)

(b) Figure 153.5 Preoperative neuropsychological battery results. The shadowed area corresponds to the mean ± 1SD of normative values. (a) Overall, the cognitive data suggest a pattern of a mild, diffuse dysfunction involving multiple-cognitive domains. Indicators of general level of ability, depicted on the left, include: the Reading score based on the WRAT (Wide Range Achievement Test), the Information and Vocabulary subtest scores based on the WAIS-III (Wechsler Adult Intelligence Scale-Third Edition), and the FSIQ (Full Scale IQ) results of the WAIS-III. Two of the factor index scores derived from the WAIS-III, the VCI (Verbal Comprehension Index) and POI (Perceptual Organization Index) are plotted on the right. The WAIS-III yielded a full scale IQ of 77 with a VCI of 76 and a POI of 84; the difference between VCI and POI is not statistically significant; (b) Both verbal and visual memory scores were below normal, without evidence of significant discrepancy between the two sides.

Continued

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(c) Figure 153.5

cont’d (c) Material-specific verbal and visual memory subtest scores.

temporal regions. During review of this case in the interdisciplinary patient management conference, participants noted the bitemporal interictal sharp waves and lack of an unequivocal abnormality on MRI. Most noninvasive tests were suggestive of bitemporal dysfunction. It was also noted that aside from the curious left-sided ‘hot spot’ on the interictal PET, the MRI and semiology of recorded seizures failed to provide any additional lateralizing information. It was therefore decided to proceed with an invasive evaluation with bitemporal depth electrodes to confirm or refute the hypothesis that all of the patient’s habitual seizures arise from the left temporal lobe.7,8 Concepts and implications related to the presence of unitemporal versus independent bitemporal seizure foci were reviewed with the patient and her family, and the patient’s expectations of surgery were clearly discussed.9,10

of the depth-recorded spikes originated from the right hippocampus (with an approximate left-to-right ratio of 25:75). A total of 30 electrographic seizures were recorded during the period of stereotactic depth investigation. All seizures were characterized by a focal onset8 involving the left anterior hippocampus (nine seizures, Figure 153.9) or the right anterior hippocampus (17 seizures, Figure 153.10) or the left amygdalar contacts (four seizures). The majority (almost 70%) of the 13 left-sided seizures (Figure 153.9) were reflected

Invasive evaluation Three pairs of depth electrodes were inserted symmetrically by an orthogonal approach. Each depth electrode consisted of eight platinum contacts (with a contact diameter of 1mm; AdTech, Racine, WI, USA) located 5mm apart.11 They penetrated the temporal lobe horizontally through the middle temporal gyrus, and their tips (most distal contacts) were aimed at the amygdala, anterior hippocampus and mid/posterior hippocampus (Figure 153.6). Invasive video-EEG evaluation with bitemporal depth (and 10–20 scalp) electrodes Interictal depth EEG showed frequent, independent bitemporal abnormalities with spikes arising from the left and right hippocampal contacts (Figures 153.7 and 153.8). In contrast to the noninvasive findings (on sphenoidal electrodes) the majority

Figure 153.6 Skull X-ray following placement of pairs of temporal depth electrodes targeting bilaterally the amygdala, and the anterior and posterior hippocampus.

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(a)

(b) Figure 153.7 Simultaneous scalp and depth electrode recordings depicting interictal epileptiform activity arising from the left anterior temporal region: (a) Depth electrodes in the left mesial temporal structures (LAM = left amygdalar, LAH = left anterior hippocampus and LPH = left posterior hippocampus; contact 1 is the most distal and contact 8 the most proximal electrode). Referential montage using the extracranial vertex (Pz) electrode as reference. Interictal spikes appear to form a dipole with maximum negativity at the most distal left anterior (and posterior) hippocampal contacts and positivity at the left amygdalar electrodes; (b) The same interictal discharges as reflected on the scalp on this longitudinal bipolar montage (note that the standard T7 and T8 electrodes have been replaced by the adjacent C5 and C6 on the international 10–10 system to allow for concurrent depth and surface EEG recordings).

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Figure 153.8 Simultaneous scalp and depth electrode recordings depicting independent interictal epileptiform activity arising from the right anterior temporal region (Abbreviations as for Figure 153.7. RAM = right amygdalar, RAH = right anterior hippocampus and RPH = right posterior hippocampus depth electrodes). Interictal spike appears to form a dipole with a maximum negativity at the most distal left posterior hippocampal contacts and positivity at the right amygdalar electrodes. Note that the right-sided anterior temporal epileptiform discharge has a less conspicuous appearance on scalp electrodes, compared to the left-sided abnormalities (compare with Figure 153.7).

on scalp electrodes. Right-sided seizures were typically not reflected on the scalp except for occasional right temporal delta/theta slowing. A clinical accompaniment was observed with all nine leftsided seizures. Clinically these were similar to the seizures captured during the noninvasive video-EEG study, and lasted for less than 90 seconds. Most right-sided seizures were subclinical except for one clearly dialeptic seizure, which was recognized by the patient’s husband as one of her habitual spells. Electrographic seizures lasted for 70–120 seconds except for one seizure, which was sustained for a period of 3.5 minutes. Almost half of these subclinical seizures were identified by the technologist or nursing staff on the basis of EEG changes. When tested, the patient appeared to respond promptly and appropriately to verbal and nonverbal commands. There were no outward manifestations and no evidence to suggest speech or cognitive impairment. Summary of invasive evaluation and surgical plan The invasive evaluation lends support to the presumptive noninvasive diagnosis of bitemporal epileptogenicity and demonstrates independent interictal activity and electrographic as well as clinical seizures arising from the left and right mesial temporal structures. Prolonged recordings with bitemporal depth electrodes showed that the vast majority of electrographic seizures from the right temporal contacts occurred in the absence of clinical signs. On the other hand, seizures emanating from the left temporal contacts were almost always associated with alteration of awareness. It was also noted that left temporal onset seizures persisted after

resumption of full doses of antiepileptic medications during the latter part of invasive video-EEG recordings. Thus, the left mesial temporal region constitutes the predominant epileptogenic focus responsible for the majority of the patient’s habitual seizures. Given the patient’s seizure burden and lack of good alternative therapeutic options it was decided to proceed with a left temporal resection. Pathology and outcome Rare seizures were noted by the patient and her family at the 6- and 9-month postoperative follow-up intervals – an estimated total of 4 seizure-days corresponding to a class II Engel12 or class 4 Wieser seizure outcome.13 No further seizures were reported at 12 months and following adjustment of the patient’s antiepileptic medications. Although, the patient has experienced 2–3-month periods of seizure freedom following surgery, she has not been completely seizure free for longer periods of time, and has not been allowed to resume driving. Neither the patient nor her relatives noticed any significant memory changes following surgery. However at the time of this report the patient has not had a formal postoperative neuropsychological assessment.14 As she has recently relocated efforts are being made to have her come back for testing at our institution. Pathology only showed nonspecific changes characterized by a mild degree of gliosis and neuronal loss involving the CA4 (cornus ammonis or Ammon’s horn, subfield 4) region of the left hippocampus. The neuropathologist commented that the specimen was ‘somewhat fragmented’, and that qualitatively there was evidence for a mild degree of neuronal loss.

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(a)

(b) Figure 153.9 Invasive video-EEG evaluation: Bitemporal depth electrode tracings of a typical automotor seizure as displayed on a bipolar montage connecting adjacent depth electrode contacts (10-second epochs). Note that ‘bad’ electrode contacts (such as the left-sided LAM1 and LAH6 in this instance and RAM2, RAM8, RAH5, RAH6, and RPH6) have been omitted to facilitate visual analysis. (a) Electrographic onset with spike discharges – similar to the patient’s interictal activity (see Figure 153.7a) – but now accompanied by an emerging low voltage fast (alpha-beta) rhythm. This rhythm is first seen at the most distal left anterior hippocampal contacts (Figure 153.9a). Sustained fast-rhythmic activity involves the most distal left anterior and posterior hippocampal contacts (not shown). At the time, that this activity spreads to involve the left amygdalar leads an ictal pattern becomes apparent on the scalp electrodes, and the seizure follows its stereotyped electroclinical evolution (similar to Figure 153.2); (b) Approximately 70 seconds after the appearance of ictal activity on the left-sided contacts, a fast ictal rhythm is now seen on the right-sided depth electrodes, which persists after the end of the left-sided seizure. Note, that at the end of the left-sided ictal pattern the patient appears to recover clinically and is again responsive and able to follow commands in spite of evolving right-sided ictal activity.

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(a)

(b) Figure 153.10 Bitemporal depth electrode tracings showing a typical subclinical electrographic seizure originating from the right hippocampus (same montage as Figure 153.9). (a) Onset in the latter half of the page punctuated by a spike discharge with superimposed, evolving low voltage fast activity arising from the most distal right anterior hippocampal contacts; (b) Involvement of the right posterior hippocampal contacts and evolution to repetitive high amplitude spiking is seen 20 seconds later. (Total duration of ictal activity: approximately 70seconds).

Detailed histopathological analysis of the amygdala was not feasible because of tissue fragmentation during surgery. It was felt that the amygdala section also showed evidence of mild gliosis and cell loss. Interestingly, a few microglial nodules were seen in the amygdalar area. Such nodules have been likened to ‘the tombstones of dying neurons’ and are occasionally seen in patients with temporal lobe epilepsy.15 The resected temporal specimen did not show

any other pathological abnormalities outside the mesial temporal area.

Discussion The patient has bitemporal lobe epilepsy as defined by bitemporal depth EEG recordings, which demonstrate independent

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seizure onsets arising from each temporal lobe.16,17 The clinical history, video-EEG monitoring results, neuroimaging and neuropsychological evaluation support this diagnosis. The observed seizure semiology with arrest of activity, staring and altered responsiveness followed by automatisms is typical of temporal lobe epilepsy.1,18,19 In this case, neither the patient herself nor other observers provided a history of aura. Such lack of aura experience has been correlated with bitemporal dysfunction in patients with temporal lobe epilepsy.20–22 Temporal lobe epilepsy is frequently a bilateral disease.2,16,23 Up to one-third (or more) of patients with surgically-proven unitemporal epilepsy present evidence of bilateral irritability in the form of bilateral independent interictal epileptiform abnormalities.7,8,24,25 Temporal lobe seizures can propagate directly to the contralateral temporal region as evidenced by scalp or intracranial recordings.23,26,27 Moreover, structural and/or functional neuroimaging reveals a spectrum of bitemporal abnormalities.2,5,28 Bilateral atrophy may be seen in approximately 10% of patients with intractable focal epilepsy and MRI evidence of hippocampal atrophy.29 Finally, bilateral hippocampal neuropathological abnormalities are a common autopsy finding in patients with a clinical diagnosis of temporal lobe seizures.24,30,31 The ictal and interictal electroencephalographic findings suggest that the epileptogenic zone resides within the mesial temporal region. Indeed, hippocampal epilepsy is often accompanied by a highly characteristic epileptiform abnormality with maximal amplitude in the anterior and inferior temporal region.24 These findings have been described as ‘the interictal EEG signature’ of epilepsy arising from the mesial temporal limbic structures,19 and are best seen using basal derivations (such as sphenoidal electrodes; Figure 153.1). Bilateral independent temporal interictal epileptiform discharges (IEDs) are seen in approximately one third of patients with temporal lobe epilepsy.8,32–34 The majority of patients with bitemporal IEDs have seizures arising exclusively (or with a strong predominance) from a single temporal lobe.8,35 On that ground, most patients with bitemporal IEDs on surface EEG may be appropriate candidates for surgical treatment with anterior temporal lobectomy. At the same time, the probability of independent seizure onset from both temporal regions is higher in the presence of bitemporal IEDs.33,36 The degree of lateralization of independent bitemporal IEDs on scalp EEG may predict the likelihood of unitemporal seizure onset and/or favorable surgical outcome following anterior temporal lobectomy.37 Chung and colleagues reviewed the operative seizure outcome in the second year after temporal lobectomy in 52 patients with preoperative evidence of bitemporal IEDs (interictal spikes and sharp waves). The authors established that there was a significant and progressive decrease in the number of good operative results that mirrored increasingly lower degrees of lateralization. The risk for poorer operative results was found to be considerably higher in patients with less than 90% lateralization of temporal IEDs, even in cases where subsequent depth electroencephalography indicated that all recorded seizures emerged from a single temporal lobe.33 It should be noted, however, that such measures of IED lateralization are susceptible to sampling effects and may be affected by a number of other factors, including sleep stage and antiepileptic drug levels.38–40

In cases of suspected bitemporal lobe epilepsy or temporal lobe epilepsy with inconclusive lateralization, investigation with bitemporal intracranial depth electrodes may show that the patient’s habitual seizures arise exclusively or predominantly from one temporal lobe.8 Hirsch and colleagues performed a retrospective review of a large cohort of 166 consecutive patients studied with stereotactic depth electroencephalography. In this series 87 patients were found to have seizures arising from a single temporal lobe (unitemporal group), while 23 patients had seizures arising independently from either temporal lobe (bitemporal group). When comparing these two groups the authors did not find any statistically significant differences in terms of age at onset of seizures, duration of epilepsy, localization of scalp EEG abnormalities, surgical results or pathological findings. It was noted, however, that the bitemporal group had significantly fewer patients with a history of febrile seizures.16 No history of febrile seizures was reported in our patient or her immediate family. The typical ictal pattern seen with scalp EEG recordings consists of rhythmic theta activity in one sphenoidal electrode evident at the onset of the automotor or dialeptic temporal lobe seizure.79 When present on scalp-sphenoidal electrode derivations such strictly defined, unilateral temporal ictal patterns can correctly predict the findings of depth electrode investigations in 82 to 94% of patients.79 However, the reliability of scalp/sphenoidal ictal EEG recordings is considerably reduced in patients with bitemporal IEDs, in whom ictal scalpsphenoidal EEG is significantly less likely to predict the correct side of surgery (only 64 to 77% of the time in one study).41 Patients with suspected temporal lobe epilepsy should undergo detailed MRI studies that consist of multiple coronal T1, T2 and FLAIR (fluid-attenuated inversion recovery) images, sagittal T1 images, and axial T2 and FLAIR images. Coronal three-dimensional T1-weighted MP-RAGE (magnetization-prepared rapid gradient echo) sections with a 2 mm thickness and no interslice gap should be acquired and used for anatomical reconstruction. In the case discussed here, qualitative visual analysis suggested a subtle abnormality involving the right hippocampus (questionable decrease in size). In addition to visual inspection the volumes of the left and right hippocampal formations were measured from the coronal sections following standard anatomic guidelines.42 Absolute measures of hippocampal volumes were compared to normative data obtained from a sample of healthy volunteers.43 Although both right and left hippocampal volumes were relatively decreased, this decrease did not exceed two standard deviations, when compared to normative data. Furthermore, the right hippocampus al volume was slightly smaller, but the volumetric asymmetry between the two sides was not significant (volumetrically symmetrical ‘normal’ hippocampi). Previous studies suggest that temporal epilepsy may exhibit a spectrum of volumetric abnormalities ranging from bilateral asymmetrical or symmetrical hippocampal atrophy, to unilateral atrophy or no atrophy.44 Our patient belongs to the challenging latter group – i.e., patients ‘with marginal MRI abnormalities that approach the limit of normal variation’.45 Prognosis following temporal lobectomy in the nonlesional group is regarded as least favorable,46 but postoperative seizure freedom or worthwhile improvement occurs. In a study of 74 consecutive patients with pharmacoresistant TLE, investigators

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Patient with bitemporal lobe epilepsy performed preoperative bilateral volumetric MRI measurements of the mesial temporal structures. Patients were divided into three groups according to volumetric findings: unilateral atrophy (63.5% of the patients), bilateral atrophy (23%) or no atrophy (13.5%) of the amygdalohippocampal formation. Surgical outcome was assessed at least 1 year after surgery. Excellent results – class I or II outcome using a modified Engel’s classification12 – were observed in 93.6% of patients with unilateral atrophy, 61.7% of those with bilateral atrophy and only 50% of the group with no significant atrophy of the amygdalohippocampal formation.47 The presence of bilateral hypometabolism on 18FDG-PET suggests that the ‘functional deficit zone’ involves both the left and right mesial temporal regions.4,48 In a study of 15 patients with temporal lobe epilepsy Koutroumanidis and colleagues reported that the finding of symmetric or even asymmetric bitemporal hypometabolism was associated with bilateral independent seizure onset in almost half of these patients – especially when involving the inferior temporal gyrus.5 Most human epilepsy studies have utilized 18FDG-PET imaging to examine cerebral metabolic rates for glucose during the interictal state.49,50 In this case however, the interictal PET study was also notable for the presence of a distinct and unusual, small hypermetabolic focus in the region of the left amygdala (extending to a lesser degree to the left temporal pole) (Figure 153.4). No electroencephalographic or clinical seizures and no repetitive epileptiform discharges were recorded from scalp electrodes during acquisition of these PET images. It has been suggested that prolonged discharges confined to the amygdala and/or hippocampus may not be reflected on the surface EEG.2,51 During her invasive evaluation it was estimated that less than 25% of the patient’s depth-recorded, leftsided interictal spikes were visible on scalp electrodes. This lack of interictal epileptiform abnormalities on scalp recordings, while concurrent depth recordings show spiking activity, has been attributed to the distance separating scalp electrodes from a putative generator in the amygdalo-hippocampal complex.51,52 It is also known that the amygdala tends to behave as a closed electrical field,53–55 a fact that may contribute to discrepant scalp versus invasive recordings. Neuropsychological testing commonly reveals an asymmetry in memory functions in patients with unilateral mesial temporal lobe epilepsy. Memory deficits are typically materialspecific for the temporal lobe primarily involved,2,19 but patients with mesial temporal lobe epilepsy may manifest a more generalized cognitive impairment.56 Neuropsychological testing suggestive of bilateral or more diffuse functional deficit zones may identify surgical candidates with a poorer surgical outcome, presumably related to more extensive or diffuse epileptogenic zone(s).57 Neuropsychological data in our patient were nondiagnostic in terms of lateralization, and suggested bilaterally decreased memory function. The presence of independent bitemporal seizure foci has been associated with impairments of both verbal and spatial memory.5,24,58 Patients with bitemporal epilepsy may have increased difficulties recalling personal events and may show a pattern of general memory impairments. Hence, it has been suggested that from a functional standpoint, patients with bitemporal epilepsy may be regarded as partially amnestic.58 In surgical decision making it is also important to consider and discuss the concept of ‘apparent bitemporal

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epileptogenicity’:59 several authors have reported that seizure onset in a posterior epileptogenic focus can masquerade as bitemporal epilepsy.16,60,61 In a recent study the Montreal group presented six patients with nonlesional focal epilepsy, who failed anterior temporal lobectomy despite localized EEG findings pointing to the anterior and inferomesial temporal region. It was noted that all six patients reported a soma tosensory aura, a clinical feature suggestive of a more posterior temporoparietal symptomatogenic origin.62 Because of their inherently narrow scope, invasive recordings with bitemporal depth electrodes may fail to disclose a posterior or other epileptogenic focus outside the temporal regions.8 If the apparent bilateral EEG onset in mesial/basal structures results from a posterior epileptogenic region with variable propagation to these structures, then resection targeting the anteromesial temporal lobe (i.e., the site of propagation) is destined to fail.59 Notwithstanding these limitations, there was no evidence from the noninvasive evaluation to suggest a posterior temporal or extratemporal focus in our case. Preoperative MRI did not reveal any structural abnormalities outside the temporal lobes. Furthermore, neither the patient’s surface EEG nor her interictal PET studies were suggestive of an extratemporal focus. Prolonged interictal scalp EEG recordings did not disclose additional spike foci outside the bilateral inferomesial regions. Ictal scalp EEG recordings were localized early on during seizures to the left (or right) temporal region and no diffuse or nonlocalizing patterns were recorded. Finally, the patient’s stereotyped clinical semiology was not suggestive of a temporoparietal or extratemporal origin.63 Eccher and colleagues recently reviewed the Cleveland Clinic surgical database from 1990 to 2001 and identified a total of 105 patients, who underwent unilateral temporal lobectomy despite evidence of bitemporal epileptiform abnormalities (bilateral interictal spikes and/or seizures) on the preoperative surface EEG evaluation. In this cohort the majority of patients 48.6% (51/105, group A) had evidence of unilateral scalp EEG seizures and bilateral interictal epileptiform discharges. Another 24.8% (26/105, group C) had evidence of scalp EEG seizures arising independently from the left and right hemispheres. The remaining 26.7% (28/105, group B) presented with bilateral interictal spikes and a mixture of EEG seizures which consisted of strictly unilateral as well as nonlateralizable seizures–in the absence of scalp EEG evidence for strictly contralateral seizures (Eccher MAR et al.64 and personal communication). Roughly one-third of patients in this cohort 32.3% (34/105) underwent an invasive evaluation with bilateral subdural and depth electrodes prior to surgery. Of note, seizure freedom at last followup (for duration of follow-up ranging from 2 years to more than 10 years) was found to be similar in the three groups: 58.8% for group A (30/51), 57.1% for group B (16/28), and 65.4% for group C (17/26). Regression analysis suggested that the following four factors were associated with a higher likelihood of postoperative seizure recurrence: a history of secondarily generalized seizures, a positive family history of epilepsy, the absence of a history of febrile convulsions, and a preoperative seizure frequency that exceeded 20 seizures/month. Invasive recordings revealed bilateral independent ictal onsets on depth electrodes in 23.5% of the patients referred for invasive evaluations (8/34). Four of these eight patients remained seizure free at last follow-up.64

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The patient discussed here did not undergo a Wada test (intracarotid amobarbital procedure, IAP). Whether IAP testing provides meaningful clinical information that aids in predicting postoperative memory changes is controversial, more so in cases of suspected bitemporal epilepsy.65 The IAP protocol used at our institution was evaluated in a study of 72 consecutive patients with unilateral temporal lobe epilepsy (39 left ATL and 33 right ATL). Neither the contralateral injection IAP memory score (a measure of functional adequacy) nor the ipsilateral injection IAP memory score (a measure of functional reserve) were shown to significantly predict verbal memory outcome, based on a model of backward stepwise regression analysis.66 This model showed that the only variables predicting postoperative verbal memory were MRI hippocampal volume ratio, baseline verbal memory and side of surgery. A more recent study at our institution examined 12 patients with unilateral left (dominant) TLE who showed neuropsychological evidence of poor presurgical verbal and visual memory scores. None of these patients demonstrated a reliably meaningful decline in delayed verbal memory score following left ATL.67 As expected, most reports review the value of presurgical studies (including Wada testing) in patients with a unilateral temporal lobe seizure focus. Consequently, very limitedinformation exists about the value of presurgical studies in predicting morbidity in patients with bitemporal epilepsies. The incidence of TLE without an identifiable pathological substrate is difficult to estimate. Significant bias (sampling and ascertainment bias, for example) confound results of reported surgical series and autopsy studies.68,69 Wieser points out that in patients without definite/specific histopathological abnormalities one cannot exclude the origin of seizures outside the resected temporal lobe–given that the surgical outcome in this group tends to be worse compared with patients with demonstrable pathological changes in the resected surgical specimen.70 It has been estimated that approximately 10% of resected temporal specimens in patients with suspected temporal lobe epilepsy (TLE) show no significant histopathological abnormalities.70 Ongoing surgical experience with TLE suggests that the absence of mesial temporal sclerosis is more common than previously suspected.69 Such observations have led to the use of the term ‘paradoxical TLE’ or ‘cryptogenic TLE’ for these patients, because of the paucity of appreciable neuronal loss.71 Lastly, hippocampal sclerosis can be so mild that it cannot be identified on structural MRI despite the use

of high-resolution imaging, and in some cases it may even not be detectable by routine histopathological examination.19 Patients with bitemporal epilepsy without a predominant seizure focus are not considered candidates for resective surgery. Several authors have reported on the use of alternative therapies such as chronic vagus nerve stimulation72 or experimental deep brain stimulation applied directly to the amygdalohippocampal structures73,74 or to various modulatory subcortical structures such as the anterior nucleus of the thalamus75,76 and the subthalamic nucleus.77 An interesting neurosurgical approach, which may hold promise for patients with bitemporal epilepsy, is under development in Japan. The technique entails transection of the hippocampus in a manner similar to that of multiple subpial transections, performed under intraoperative electrocorticographic guidance. A recent report only included patients with unilateral temporal lobe epilepsy, and intact preoperative material specific memory function in the presence of a structurally normal-appearing hippocampus. The authors express their intent to further explore this technique in bitemporal lobe epilepsy encouraged by their positive, albeit very preliminary, seizure and functional results in patients with unitemporal seizures.78

Summary A 30-year-old patient with a history of poorly-controlled seizures starting at the age of 20 years is presented. Her seizures consist of initial alteration of awareness and staring followed by bimanual and oral automatisms and a brief period of postictal confusion. Seizures have persisted despite multiple trials of appropriately chosen antiepileptic medications resulting in significant psychosocial disability. A comprehensive noninvasive presurgical evaluation raised concerns for bitemporal epileptogenicity. Subsequent invasive evaluation with bilateral temporal depth electrodes demonstrated electrographic seizures arising from both the left and right temporal lobes. However, the majority of the patient’s disabling clinical seizures were shown to originate from the left amygdalohippocampal complex. A left anterior temporal lobectomy was performed. One year later, the patient reports significant benefit in terms of seizure control, although at her last follow-up she has not achieved seizure freedom for a period longer than 6 months.

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Alsaadi TM, Laxer KD, Barbaro NM, Marks WJ Jr, Garcia PA. Vagus nerve stimulation for the treatment of bilateral independent temporal lobe epilepsy. Epilepsia 2001;42:954–6. Vonck K, Boon P, Claeys P et al. Long-term deep brain stimulation for refractory temporal lobe epilepsy. Epilepsia 2005;46(Suppl 5): 98–9. Fountas KN, Smith JR, Murro AM et al. Implantation of a closedloop stimulation in the management of medically refractory focal epilepsy: a technical note. Stereotact Funct Neurosurg 2005;83: 153–8. Kerrigan JF, Litt B, Fisher RS et al. Electrical stimulation of the anterior nucleus of the thalamus for the treatment of intractable epilepsy. Epilepsia 2004;45:346–54. Osorio I, Overman J, Giftakis J, Wilkinson SB. High Frequency Thalamic Stimulation for Inoperable Mesial Temporal Epilepsy. Epilepsia. 2007;48:1561–71. Neme S, Montgomery EB, Jr, Rezai A, Wilson K, Lüders HO. Subthalamic nucleus stimulation in patients with intractable epilepsy: the Cleveland experience. In: Lüders HO, ed. Deep Brain Stimulation and Epilepsy. London: Martin Dunitz, 2004;349–55. Shimizu H, Kawai K, Sunaga S, Sugano H, Yamada T (2006) Hippocampal transection for treatment of left temporal lobe epilepsy with preservation of verbal memory. J Clin Neurosci 2006;13:322–8. Risinger MW, Engel J Jr, Van Ness PC, Henry TR, Crandall PH. Ictal localization of temporal lobe seizures with scalp/sphenoidal recordings. Neurology 1989;39:1288–93.

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Patient with lesional neocortical focal epilepsy B Abou-Khalil

Case presentation A 42-year-old right-handed man presented for evaluation and treatment of seizures since age 10. He could not remember his initial seizures well. They started with a strange feeling in the head that he could not describe. He would then lose awareness and have picking motions of the hands. After the seizure, he would be very tired. Epilepsy was diagnosed, but seizures were never controlled for more than 1 year, and they changed over time. At the time of last presentation he had a consistent aura which he now described as a feeling like a ‘pop’ in his head. The aura would last 5–10 seconds, then he would lose awareness and would be noted to stare and to purse and smack his lips. He would repeat ‘what’ over and over. He fumbled and picked with either hand. He hummed at times. He reported seizure duration as 20 seconds, after which he was confused and had slurred speech for about 1 minute. He did report word finding difficulty postictally for about 5–10 minutes. He tended to have seizures in clusters. For example, 30 seizures had occurred in the previous year, but he had eight seizures in 1 month before presentation. In addition, he averaged about three isolated auras per month. He had had only four secondarily generalized tonicclonic seizures in his life, all in one year, in 1984. With these, his wife thought that he had head-turning to one side, but she could not remember which side. At presentation, he was taking lamotrigine, 200 mg three times a day, and carbamazepine, 500 mg in the morning and 600 mg at night. He had failed treatment with phenytoin, valproate, and tiagabine. He thought that his medications were all in combinations never in monotherapy. Past medical history revealed no clear risk factors for epilepsy, with the exception of a positive family history of seizures in one of his two sisters and in one paternal cousin. In both instances, seizures were outgrown. He had been a heavy drinker in the past, but had stopped drinking 20 years previously. The review of systems was notable for complaints of memory loss, depression, and irritable mood. Social history indicated that he graduated from high school with average grades. He was self-employed as a farmer. He had been married for 21 years with one 13-year-old daughter. General and neurological examinations were completely normal, including mental status, cranial nerves, motor system, reflexes and sensory system.

Review of past evaluations indicated that he had had an MRI that was reported normal. No other outside data were available. The patient was interested in a definitive treatment for his seizures, and had heard about epilepsy surgery. He underwent a complete presurgical evaluation. MRI revealed a 20-mm lesion that had increased T2 signal in the center and decreased signal in the surround, suggesting old hemorrhage (Figure 154.1). This lesion was abutting the interior aspect of the left petrous pyramid laterally. There was no hippocampal sclerosis. 18F-Fluorodeoxyglucose positron emission tomography (PET) scan revealed a zone of reduced FDG uptake over the inferolateral region of the left temporal lobe, corresponding to the MRI lesion (Figure 154.2). Inpatient video-EEG monitoring for 4 days in conjunction with medication withdrawal recorded six partial onset seizures, two of which secondarily generalized. Five events began in sleep, and were characterized by arousal with restless movements, glancing around, initial fumbling with the left hand in two events, right arm dystonic posturing or immobility of the right arm in four events, and lip-smacking and chewing in three events. In the two seizures that generalized, there was adversive head and eye deviation to the right in

Figure 154.1 MRI shows a probable left inferior-lateral temporal cavernous angioma (arrow).

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Figure 154.2 FDG PET (axial top row; coronal bottom row) shows a defect in FDG uptake in the left inferior-lateral temporal region, corresponding to the MRI lesion (arrows).

transition to generalization. There was nose-wiping postictally with the left hand in one event. The associated ictal onset was consistently left temporal, but with predominance in the left sphenoidal electrode (Figure 154.3). Interictally, there were independent epileptiform discharges recorded from the left mesial-basal and lateral anterior-mid temporal region (with mesial-basal predominance), and from the left posterior and mid lateral temporal region with variable involvement of the left posterior quadrant. Finally, there was intermittent irregular left temporal slow activity (Figures 154.4 and 154.5). Neuropsychological testing (see Table 154.1) revealed borderline abilities, with significantly stronger aptitude for nonverbal skills in comparison to verbal skills. He also had stronger visual memory skills in comparison to verbal recall on the Wechsler Memory Scale WMS-III. He did not do well with either Rey-O Complex Figure. Recall or Buschke Selective Reminding Recall. The intracarotid sodium amobarbital procedure was performed with 125 mg of sodium amobarbital on each side, with about 30 minutes between injections. The left hemisphere was injected first. The patient developed global aphasia for more than 7 minutes, indicating left hemisphere dominance for language. He had only dysarthria (no language impairment) with right injection. He passed memory testing marginally with both left and right injection.

Summary of presurgical evaluation and surgical plan The lateralization of the epileptogenic zone was confident to the left hemisphere, based on the combination of MRI and PET findings, seizure semiology (the strongest lateralizing signs were the right arm dystonic posturing and the versive head turning to the right in transition to generalization – the postictal aphasia was also an important features derived from the history), interictal epileptoform discharges, ictal EEG onset, and interictal slow activity. However, there was a discrepancy between the imaging findings which indicated a neocortical temporal structural and functional lesion, and the ictal EEG onset which favored a mesial-basal seizure onset. The EEG interictal epileptiform abnormalities were consistent with independent lateral temporal and mesialbasal temporal irritative zones. The aura of ‘pop’ in the head can be considered a cephalic aura. It is nonspecific with respect to localization, but may be more common with neocortical seizure foci. The remainder of the seizure semiology was consistent with mesial temporal seizures, but seizures can spread and the predominant seizure semiology may actually reflect involvement of structures after seizure spread. Since cavernous angiomas are highly epiletogenic, it was felt that the left neocortical temporal cavernous angioma was most probably the epileptogenic lesion. It is also not

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Figure 154.3 Ictal onset on an average referential montage. There was initially a voltage attenuation in conjunction with muscle artifact. The first definite rhythmic ictal activity was in the theta range. It was left temporal, with voltage predominance at Sp1.

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Figure 154.4 Interictal epileptiform activity was recorded independently from the left mesial-basal-anterior temporal and the left posterior-mid-temporal regions (a series of discharges from each field are illustrated).

unusual to see mesial-basal temporal epileptiform discharges with neocortical epilepsy, whether neocortical temporal or extratemporal. The posterior temporal interictal epileptiform discharges may reflect irritative activity from around

Figure 154.5 Postoperative MRI demonstrating extent of resection (see arrow).

the lesion itself, while the sphenoidal electrode discharges could represent a form of secondary epileptogenesis. We had the option of either pursuing the presurgical investigation with invasive monitoring, using subdural grid electrodes for recording seizures and localizing language cortex, or proceeding with a lesionectomy since the lesion was surgically accessible. With the latter choice, an invasive evaluation could be pursued if seizures persisted. It was decided to proceed without invasive monitoring. The patient was left hemisphere dominant for language, but since the lesion was in the inferior temporal gyrus, the risk to language was felt to be minimal, and it seemed reasonable to proceed with a lesionectomy, including hemosiderin stained margins of the lesion, without mapping language functions. One other decision was whether to extend the resection to remove the hippocampus, in view of the mesial-basal temporal irritative zone by EEG. This case illustrates a frequent dilemma that occurs with lateral temporal neocortical lesions, when the EEG supports a mesial-basal seizure origin and predominant epileptiform activity. When there is associated hippocampal sclerosis by MRI (dual pathology), there is evidence that surgical outcome is better with removal of both the neocortical lesion and the sclerotic hippocampus. In this particular patient, the ipsilateral hippocampus appeared to be structurally normal, even though it may have participated in seizure propagation. Therefore, it was decided to perform a lesionectomy sparing the hippocampus.

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Patient with lesional neocortical focal epilepsy Table 154.1

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Selected neuropsychological measures

Area/test

Score

Age/education expected

72 87 77 68 91 97 86

100 100 100 100 100 100 100

68 81 64 75 33.5/36 6.5/36 6.5/36 7/12 by 8th trial 1/12 after 30 min delay

100 ± 15 100 ± 15 100 ± 15 100 ± 15 ≥32/36 ≥32/36 17/36 ≥10/12 8/12

32/60 3 errors

≥52/60 0 errors

Intelligence – WAIS-III Verbal IQ Performance IQ Full-scale IQ Verbal comprehension Perceptual organization Working memory Processing speed

± ± ± ± ± ± ±

15 15 15 15 15 15 15

Memory– Wechsler Memory Scale-III Immediate auditory Immediate visual Delayed auditory Delayed visual Rey-O-Complex figure copy Rey-O-Complex figure immediate recall Rey-O-Complex figure delayed recall Buschke Selective Reminding Task-immediate Buschke Selective Reminding Task-delayed recall Language Boston naming test Reitan Aphasia Screening

Surgical procedure and surgical outcome Surgery performed 28 months before this report was a left image-guided craniotomy for resection of the temporal lesion. It was performed under general anesthesia. The skin incision was made from the posterior aspect of the zygoma superiorly over the top of the ear for about 4 centimeters. Dissection was carried down to the squamous portion of the temporal bone. A craniectomy defect was created with a drill, exposing the inferior temporal gyrus and petrous apex area. After opening the dura, hemosiderin stained tissue was seen, along with a rather large vein presumed to be the vein of Labbe. The pia was separated from the inferior aspect of the vein, and the vein was retracted superiorly, then the hemosiderin stained area of the inferior temporal gyrus was slowly removed using bipolar and suction. The lesion measured 2–3 centimeters in diameter. Eventually, the entire nidus around the vascular lesion was delineated with a pedicle arising off the floor of the temporal lobe just over the petrous apex. The lesion was resected. The remaining portion of any hemosiderin stained brain was then aspirated. The wound was then irrigated and closed. The anatomic pathology was cavernous angioma. A postoperative MRI showed almost complete resection of the lesion (Figure 154.5). There were no immediate postoperative seizures. There were no neurological deficits and specifically no difficulties with word finding or naming. On follow-up visit 3 months postoperatively, the patient reported no full-fledged seizures. However, he did report some isolated auras lasting a few seconds, occurring two to three times a month. He was now on lamotrigine, 300 mg twice daily. When he returned 6 months

after surgery, he reported only a single possible aura, about 3 weeks before the visit, during the whole 3-month interval. At the 1-year postoperative visit he reported that seizure auras had recurred, sometimes up to three to four times per week. He said that they lasted only a second or so. He remained on lamotrigine, 300 mg twice daily. He continues to be selfemployed as a farmer, working full-time. He reports no decline in his function. The favorable outcome with respect to disappearance of disabling seizures supports the decision to limit the surgery to lesionectomy with removal of hemosiderin-stained margins, sparing the structurally normal hippocampus. However, the residual auras suggest that the epileptogenic zone may not have been fully resected.

Video seizure description The patient was lying with eyes closed. He suddenly opened his eyes and reached for the event button, but did not push it. He seemed to freeze, staring straight ahead, with his right hand fisted around the event button. He then looked slightly to the left. He pursed his lips and had slight chewing motions, while his right hand continued to hold the event button in a fist, the right elbow flexed and the hand held up in the air, with a rotatory component consistent with a dystonic posture. He then began to have restless fumbling and picking motions with the left hand and restless motions of the legs and trunk. The right hand remained fisted, holding the event button. As he sat on the bed, he began to make rhythmic grunting sounds and had versive eye and head deviation to the right. This was followed by secondary generalization.

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Patient with nonlesional neocortical epilepsy L Tassi and GL Russo

Summary We present the case of a 9-year-old boy, with a negative personal and familial history, who started having seizures at the age of 3 years. From the beginning, seizures have always been characterized by asymmetrical spasms, predominant on the left side. Brain MR was normal. His neurological examination was normal, but the IQ, 78 at the first evaluation (35 months) dropped to 55 three years later. Interictal EEGs showed since the beginning, a continuous slow wave and spike and wave activity, well localized in the right frontal region. We performed a stereo-EEG investigation, and on the basis of anatomo-electro-clinical correlation, a frontal corticectomy. The histological examination showed an architectural dysplasia, and since then the patient is seizure free (more than 1 year).

Clinical data Clinical history G.F., when referred to our epilepsy surgery center, was a righthanded 9-year-old boy without any personal or familial antecedent for epilepsy, and normal delivery after a physiologic pregnancy. Psychomotor development was normal until the onset of seizures. Ictal episodes started at 2 years and 9 months and from the beginning were characterized by a sudden bilateral elevation of the arms, predominant on the left side, sometime associated with a left oculo-cephalic deviation. Fits were very brief (1 second) and tended to present in clusters, lasting about 10 minutes, at the end of which no postictal deficit was present. Seizure frequency rapidly worsened (1–5 series a day) during the following 2 months, until a pharmacological treatment (GVG) was started and induced a 2-month seizure-free period. After that, episodes started again, occurring more than once a day only during wakefulness; they were always characterized by a cluster of spasms (abrupt asymmetric arms elevation with a left predominance) lasting 5–15 minutes during which the boy became more and more restless and was slightly pale and polypnoic; speech was preserved all along the cluster. No more prolonged seizure-free interval has been obtained by drug treatment which, after GVG, included VPA, CBZ, LEV, TPM, Hydrocortison, and CLB, in various associations. 1476

Neurological and neuropsychological investigation Neurological examination was normal except for cognitive functions. Serial neuropsychological evaluations documented a progressive decline in global IQ (Griffiths) from the very beginning of the illness (35 months: 78) with a sensible drop at 1 year (72) but namely at 2-year follow-up, when it was 55. Preoperative evaluation showed a language deficit, and a loss in verbal and non-verbal memory. Furthermore there were a difficulty in visuo-spatial perception and motor ability. Neuroimaging MR evaluation, performed following our protocol also included some additional cuts targeting the right frontal lobe. The following sequences were obtained: transverse spinecho double-echo of the entire brain and axial TSE inversion recovery (Figure 155.1), coronal turbo spin-echo (TSE) T2-weighted (W), coronal TSE fluid-attenuated inversionrecovery (FLAIR) T2W and coronal TSE inversion recovery (IR) T1W (Figure 155.2). Additional FLAIR images in the sagittal plane were acquired. The MR was totally normal. Video-EEG recordings Long-term video-EEG monitoring allowed a further definition of interictal EEG features and, mainly the evaluation of three series of ‘asymmetric spasms’. Interictal EEG was characterized by a mid amplitude posterior background rhythm at 8–9 Hz, symmetric and reactive to eye opening. Electrical activity was quite peculiar over the right frontal region, where theta-delta waves were almost constantly recorded, without arrest reaction but with the frequent intermixing of spikes and spike-and-waves (Figure 155.3a, b). This actual ‘electrical’ status epilepticus did not vary during wake and sleep cycle, almost always being present over the right fronto-temporal region. The three ictal clusters recorded, lasting from 1 minute 16 seconds to 5 minutes 33 seconds, were characterized by a progressive restlessness, then interrupted by sudden, brief, abrupt movements (left arm, left shoulder, a forced inspiration) with different entity, sometimes unperceivable.

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Patient with nonlesional neocortical epilepsy

Figure 155.1 noticed.

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Preoperative brain MR showing an axial TSE inversion recovery (3 mm slices). No anatomical abnormalities were

On the EEG slow activities were gradually replaced by a non-tonic rhythmic activity (Figure 155.4a), localized on the right fronto-temporal region, and by the appearance of rhythmic high-amplitude slow-wave surcharged by a low-voltage fast activity (Figure 155.4b); these last, maintaining a clear right fronto-temporal predominance, represented the electrical correlate of the motor ictal manifestation. A concomitant increase of generalized slow-spike and waves have to also be noticed. At the end of clinical manifestations, EEG recovery was prompt and without postictal slowing.

Summary of presurgical evaluation The clinical ictal semiology (including the presence of ‘asymmetric spasms’ predominantly localized on the left side of the body, associated with–or preceded by–an irritability and presenting in cluster with a high daily frequency) suggested a right hemispheric localization of the epileptogenic zone but could not indicate its lobar predominance. EEG interictal and ictal features, notwithstanding a fast and consistent contralateral spread, demonstrated a constant right fronto-temporal involvement.

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Figure 155.2

Preoperative MR, including coronal inversion recovery (a) and coronal FLAIR (b). The MR was completely normal.

MR was normal. On these electro-clinical basis, a right frontal (-temporal) epileptogenic zone represented the most likelihood localization hypothesis, and stereo-EEG exploration by mean of stereotactically implanted intracerebral electrodes was judged necessary for verifying this hypothesis and, possibly, define the actual extension of the surgical exeresis. The implantation strategy – once the lateralisation defined on clear electro-clinical basis – mainly followed the indications coming from EEG, showing a widespread right frontotemporal origin of ictal discharges.

Stereo-EEG investigation An unilateral, right fronto-temporal exploration was then realized, after an arteriographic study, by means of 14 multileads electrodes, ranging from five to 18 contacts (Figure 155.5). Invasive recordings (interictal and ictal) The patient was monitored for 7 consecutive days, during which seven series of spontaneous ‘spasms’ have been recorded. No ictal manifestations were induced by electrical stimulations.

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(a)

Fp1 – F7 F7 _ T3 T3 – T5 T5 – O1 Fp2 – F8 F8 – T4 T4 – T6 T6 – O2 Fp1 – F3 F3 – C3 C3 – P3 P3 – O1 Fp2 F4 F4 – C4 C4 – P4 P4 – O2 Fz – Cz F7 – F3 F3 – Fz Fz – F4 F4 – F8 T3 – C3 C3 – Cz Cz – C4 C4 – T4 T5 – P3 P3 – P4 P4 – T6 EKG Delt Sx

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(b)

Figure 155.3 Interictal scalp activity: 8 Hz background activity, symmetrical. High-amplitude repetitive slow-waves and slow-spike and waves on the fronto-temporal regions, predominant on the right side (a). Slow-waves on the right fronto-temporal region may assume a rhythmic aspect (b).

(a)

Fp1 – F7 F7 – T3 T3 – T5 T5 – O1 Fp2 – F8 F8 – T4 T4 – T6 T6 – O2 Fp1 – F3 F3 – C3 C3 – P3 P3 – O1 Fp2 – F4 F4 – C4 C4 – P4 P4 – O2 Fz – Cz F7 – F3 F3 – Fz Fz – F4 F4 – F8 T3 – C3 C3 – Cz Cz – C4 C4 – T4 T5 – P3 P3 – P4 P4 – T6 EKG Delt Sx Delt Dx

(b)

Figure 155.4 In the period immediately preceding ictal manifestation (a), there was a cut-down of slow-waves and a build-up of fast rhythmic activity, clustering in brief sequences. The first ‘spasm’ (red arrow) corresponds to a high-amplitude slow-wave probably preceded by and mixed with a rhythmic fast activity on the right fronto-temporal region (b). (See Color plates.)

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(a)

K

(c)

(d)

(e)

(f)

J Y M

F E

H

N =

L

= R

T

G

O

B

(g)

(h)

(i)

(j)

(k)

(l)

(m)

(n)

(b) J

Y

K

M F E R

H N

=

L

=

G O T B

Figure 155.5 Lateral (a) and antero-posterior (b) views of the stereotactic scheme, according to the bicommissural reference system, of the SEEG exploration of this patient. Electrodes are indicated with either circled dots or dashed lines labelled by upper case letters. (c–f) T1-weighted 3D postimplantation MRI, sagittal slices from mesial to lateral. (g–n) same MRI, coronal slices from posterior to anterior. Intracerebral electrodes sample the following structures, from external to internal contacts: B: middle temporal gyrus, hippocampus, parahippocampal gyrus. T: superior temporal gyrus, Heschl’s gyri. R: inferior frontal gyrus, insular cortex. G: inferior frontal gyrus, genu of cingulated gyrus. H: inferior frontal sulcus, anterior cingulated gyrus. N: precentral gyrus, central cingulated gyrus. M: middle frontal gyrus, mesial frontal cortex. F: middle frontal gyrus, mesial frontal cortex. O: inferior frontal gyrus, frontoorbital gyri, mesial frontal cortex. E: frontal pole. L: frontal pole. Y: superior frontal sulcus, fronto-orbital cortex. J: superior frontal gyrus, mesial frontal cortex. K: superior frontal gyrus, mesial frontal cortex.

The interictal activity (Figure 155.6a) is characterized by the presence of very frequent slow waves (theta delta) and slow–spike and waves localized on the orbital region, the frontal pole, the very anterior part of the cingulated gyrus and the anterior part of the first, second and third frontal gyri. HPN doesn’t modify the pathological activity and ILS was ineffective. During sleep (Figure 155.6b) slow–spike and waves become more frequent and intermingled by the presence of some ‘flattenings’, mostly localized on the orbital region and the frontal pole. During ictal episodes, as in surface recordings, ictal symptoms are preceded by clear electrical modifications: a dramatic reduction of slow waves, and the appearance of 1–2 seconds rhythmic fusiform discharges (Figure 155.7a), well localized, on the frontal pole and the orbital region. Progressively these discharges involve the anterior part of F1, F2, and F3 as well as the anterior part of the cingulated gyrus (Figure 155.7b).

Later a low-voltage fast activity appears concomitantly with the fusiform anterior discharges (Figure 155.8a), involving almost all the explored structures, but only when a highamplitude slow wave emerges, the clinical ‘spasm’ becomes evident (Figure 155.8b). Then the EEG becomes slower and slower (Figure 155.9a), and at the end of the episode, no postictal slow–waves were noticed, and it exists an impressive decrease of the previous interictal slow activity (Figure 155.9b). Video The boy, seated in the bed, is doing his homework with his father. Since 13.47.50 (10 seconds after the beginning of the fusiform fast activity in the anterior part of the frontal lobe) he becomes confused, restless, and he speaks with a feeble voice. The first spasm is at 13.49.21, and the last one at 13.52.22.

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Mes. Orb. Ant. F3 Ant F2-F3 F Pole F Pole F Pole F Pole F3 Mes. Orb. Mes. Orb. Ant F1-F2 Ant. F1-F2 Mid. F1 Mid. F2 Mid. F1 Mid. F1 Ant Cing. Mid. F3 Mid. F3 Post. F1 Post. F1 Post. F1 Post. F2 Post. F2 Post. F3 Post. F3 Mid. T1 Hippo. Mid. T2 Left Delt. Right Delt.

Mes. Orb. Ant. F3 Ant F2-F3 F Pole F Pole F Pole Genu Cing. F3 Mes. Orb. Mes. Orb. Ant F1-F2 Ant. F1-F2 Mid. F1 Mid. F2 Mid. F2 Mid. F1 Mid. F1 Ant Cing. Mid. F3 Post. F1 Post. F1 Post. F1-F2 Post. F2 Centr. Cing. PreC Gyrus Insula Post. F3 Mid. T1 Hippo. Mid. T2 EKG

(a)

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(b)

Figure 155.6 Stereo-EEG recording, during wakefulness (a) and sleep (b), demonstrating the presence of persistent slow waves and slow spike and waves in the anterior part of the frontal lobe, worsening during sleep. Mes Orb: mesial orbital region. Ant: anterior. F2: second frontal circumvolution. F3: third frontal circumvolution. F: frontal. Mid: middle. F1: first frontal circumvolution. Ant Cing: anterior part of the cingulated gyrus. Post: posterior. Mid. T1: middle part of the first temporal gyrus. Hippo: hippocampus. Mid. T2: middle part of the second temporal gyrus. Delt: deltoid. Genu Cing: genu of the cingulated gyrus. Centr. Cing: central part of the cingulated gyrus. PreC Gyrus: precentral gyrus.

(a)


(b)

Figure 155.7 Stereo-EEG recordings, showing the onset of fusiform fast activity (a), becoming more and more frequent (b), well localized in the frontal pole and the mesial orbital regions.

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(a)


(b)

Figure 155.8 Stereo-EEG recordings: the fusiform activities are associated with a faster activity, spreading to the posterior part of the frontal lobe, as well as to the temporal structures, with no symptoms, except for the irritability (a). The first spasm (red arrow) coincide with a high-amplitude slow wave. (See Color plates.)

(a)


(b)

Figure 155.9 Stereo-EEG recordings: slow waves grow up and the spasms are repetitive (red arrows) (a). At the end of the cluster, the total and abrupt disappearance of the slow activities is the main electrical feature. (See Color plates.)

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Figure 155.10

Postoperative MR, coronal TSE inversion recovery (3 mm slices), demonstrating the right frontal corticetomy.

Electrical intracerebral stimulations The neurophysiological mapping obtained by electrical stimulations, pointed out clonic jerks (hand motor area) in the right hand, only in contact R6–7 (posterior F3). No other clinical or electrical effect has been induced.

Definition of epileptogenic zone and surgical plan According to the electro-clinical data obtained during the stereo-EEG, the definition of the epileptogenic zone was mainly based on the following electrical features: ●

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slow waves and spike and waves were prevalently localized on the frontal pole, the orbital region, the anterior part of the cingulated gyrus and the anterior third of F1, F2, and F3;

●

●

during sleep, on the same regions, we noticed spike and waves intermingled with brief periods of flattening; ictal symptomatology was preceded (in some cases 2–3 minutes before) by the appearance of rhythmic fusiform discharges, always localized on the frontal pole and the orbital region, and then involving the anterior part of F1, F2, and F3, and the anterior part of the cingulated gyrus; these localized electrical modifications have always been the prelude for a widespread (almost all the explored structures) electrical change, characterized by an high-amplitude slow wave associated with the motor ictal phenomena.

Therefore we proposed a right frontal corticectomy, including the frontal pole, the orbital cortex, the cingulated gyrus and the superior, middle and inferior frontal circumvolutions, up to the projection of the electrode H, expecting a good outcome concerning seizure freedom. On the other hand, the evolution of cognitive functions could be hardly anticipated in

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Figure 155.11

Postoperative MR, transverse turbo spin-echo (TSE) T2-weighted.

view of the electrical ‘status epilepticus’ persistent from the beginning of the epilepsy.

Surgical procedure Anatomo-pathological results The histological examination showed a laminar cortical disruption, configuring an architectural focal cortical dysplasia (Type Ia), well localized in the gyrus rectus and in the very anterior part of the second and third frontal circumvolutions. A gliosis was also present in all the surgical specimens. Postoperative MR The postoperative MR (Figures 155.10 and 155.11) illustrates the frontal corticectomy, complying with the presurgical plan.

Outcome Since the intervention the patient is seizure free (18 months). The pharmacological treatment is unchanged. Follow-up The postoperative EEG shows the disappearance of the continuous slow-waves and slow-spike and waves which characterized the two fronto-temporal regions with a right side predominance. The first neuropsychological (6 months of follow-up) fails in putting in evidence a remarkable variation concerning the IQ, which is now assessed at 58; however the boy is more attentive and concerned with the proposed tests. A further evaluation is scheduled two years after the intervention.

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Patient with extensive malformation of cortical development DK Lachhwani

Case history DC was 8 weeks old when he presented to our practice with medically refractory epilepsy. Seizures had started on day 3 of life and were increasing in frequency and intensity despite use of multiple antiepileptic medications. His current seizures were occurring daily in clusters, with 10–30 seizures per cluster and five seizure clusters every day. Mother described the individual seizures as facial grimacing and tonic stiffening of all four extremities, followed by rapid eye blinking lasting up to 30 seconds. During some seizures, the eye blinking was more noticeable on the right side. After the cluster of seizures, DC was tired and exhausted for 2–3 hours with very few spontaneous movements. Initial seizures were very brief and involved a subtle flexion of trunk and facial grimacing, lasting < 3–5 seconds. These occurred sporadically, a few times per day. By the second week of life, episodes had picked up in intensity and DC had lost the sparkle in his eyes. A diagnosis of infantile spasms was made when a stronger episode was witnessed in the pediatrician's office. DC suffered a cardiac arrest while being transported to the nearest hospital from the pediatrician's office, however he was successfully resuscitated. Since then, he had mostly remained in the hospital for management of refractory epilepsy, before being transferred to our epilepsy service. Attempts to discharge him home had failed, and he would inadvertently present to the emergency room within 24 hours of discharge with an intense seizure cluster or an acute life-threatening emergency due to cyanosis, respiratory depression, and bradycardia. Antenatal and perinatal course Mother had received adequate perinatal care with close follow-up due to polyhydramnios. DC was born at 36 weeks of gestation, with a birth weight of 6 lbs 3 oz. His postnatal course was unremarkable and he was discharged home on day 2 with no concerns. Neurodevelopment His development had been delayed. At 8 weeks of age, he made eye contact and registered his mother’s presence; however he did not have a social smile and had little head control. Mother felt that this was largely due to heavy doses of medications and frequent seizures. She noted that on days with fewer or less intense seizures, he looked brighter and attempted to hold his head better.

Epilepsy risk factors No history of head trauma or meningitis. Medications He was on therapeutic doses of four antiepileptic medications – lamotrigine, leviteracetam, oxcarbazepine, and phenobarbital. He had previously failed a trial of phenytoin and intravenous pyridoxine. Family history DC’s mother had a history of cerebral vascular malformation and had experienced two generalized motor seizures. She remained seizure free on oxcarbazepine. Two maternal first cousins had history of seizures; one with febrile seizures and the other with epilepsy of unknown etiology. Pertinent positive findings on physical exam Length and head circumference were appropriate for age. (Weight 4.7 kilograms.) Airway conducted sounds suggestive of moderate to severe resistance in the upper airways. Subtle decrease in spontaneous movements and mild hypotonia of the right upper extremity was noted. He also showed an intermittent fisting with flexion of thumb across the palm in the right hand. Strength and reflex testing did not demonstrate any obvious asymmetry.

Non-invasive epilepsy evaluation Interictal abnormalities Modified hypsarrhythmia, lateralized left hemisphere. This was characterized by high amplitude (50–200 uV) bursts of multiregional (F7, P3, F3) spikes, and spikes lateralized to the left hemisphere which occupied 40–50% of the record. In between the bursts, there was a generalized, continuous slowing (20–40 µV). Rarely (20–30 recorded per day) characterized by clusters of sudden forward head flexion associated with bilateral arm and leg flexion, lasting for 1–5 seconds at a time were seen. 1485

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Fp1–F7 50 uV F7–T7 T7–P7 P7–O1 Fp2–F8 F8–T8 T8–P8 P8–O2 Fp1–F3 F3–C3 C3–P3 P3–O1 Fp2–F4 F4–C4 C4–P4 P4–O2 Fz–Cz Cz–Pz

Figure 156.1

Interictal EEG showing modified hyppsarrhythmia involving left hemisphere.

Clusters lasted 2–30 minutes each, and consisted of a spasm every 10–20 seconds. EEG seizure Generalized (20–30 per day recorded) ictal pattern, characterized by diffuse electrodecrement followed by superimposed low-amplitude (10–50 µV) paroxysmal fast (20–40 Hz) activity, lasting 2–5 seconds.

Second clinical seizure Right face clonic followed by generalized clonic seizure (20–30 recorded per day): Intermixed with the spasms described above, DC would have episodes of arrest of activity, bilateral eye blinking, right face pulling followed by right arm extension prior to a more generalized clonic pattern.


Figure 156.2

Ictal EEG showing diffuse electrodecrement during epileptic spasm.

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Patient with extensive malformation of cortical development

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Figure 156.3 myoclonia.

Ictal EEG showing evolution of the ictal rhythms over left hemisphere coinciding with bilateral (right>left) eyelid

EEG seizure Ictal pattern was lateralized to the left hemisphere and showed rhythmic (3–4 Hz) high amplitude(50–300 µV) spike- and slow-wave complexes starting at C3 or P3 before becoming diffuse and evolving within the left hemisphere or both hemispheres. MRI brain Extensive malformation of cortical development involving the left cerebral hemisphere. FDG PET scan Moderately increased FDG uptake in the dysmorphic left hemisphere. Neuropsychological assessment Due to the young age, and the frequency of seizures, the Bayley Scales of Infant Development were not attempted. Mother’s responses to The Vineland Adaptive Behavior Scales suggested that the motor and cognitive skills were within the adequate adaptive level range for a two-month infant. Pediatric ENT consultation Congenital Pyriform aperture stenosis, resulting in severe compromise of air exchange through nasal passages. This was felt to have contributed to previously observed life threatening apnea and bradycardia episodes during seizures.

had left hemispheric epilepsy due to an underlying cerebral malformation, since 3 days of age, with medically refractory clinical and EEG status epilepticus. At presentation he had a subtle left hemiparesis, but no other fixed neurological deficits. Experts were unanimous that continued medication trials were likely to be futile and would expose him to a significant risk of morbidity and mortality due to refractory status epilepticus. His risks were further compounded due to his very young age and a comorbid congenital upper airway stenosis (predisposing to airway obstruction and bradycardia during seizures). Therefore, surgical correction of the airway malformation followed by surgical removal of the brain malformation (left hemispherectomy), was felt to be the preferred treatment option. His young age (2 months, 4.7 kg weight) was a significant mitigating factor, and it was appreciated that this would add to the risk inherent to brain surgery involving a large resection. It was also realized that epilepsy surgery would result in worsening of the pre-existing subtle hemiparesis and a new fixed homonymous visual field deficit. Overall, it was felt that the risk of continued refractory status epilepticus would outweigh the surgical risks and therefore epilepsy surgery should be pursued imminently. Bioethics team was urged to meet the family to highlight the complicating features of the case before pursuing any treatment options. The family elected surgery.

Further management considerations Summary of epilepsy evaluation and plan The discussion at patient management conference included experts in pediatric and adult epilepsy, neurosurgical team, neuropsychologists, neuroradiologists, bioethicists, and other support staff. The group unanimously appreciated that DC

Identification of surgical candidates Careful attention to clinical details is impertinent when evaluating and treating patients with epilepsy. It is well known that infantile spasms may be the presenting feature of focal epileptogenic substrates.1 Careful investigation for the underlying cause and an accurate diagnosis of the epilepsy syndrome

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F

F

Figure 156.4 Axial MRI T2-weighted image showing diffuse left hemispheric malformation of cortical development and corresponding FDG-PET scan showing increased FDG. uptake in the dysplastic hemisphere.

(focal vs multifocal or generalized) is very important for the planning of treatment strategy. Indicators of focal epilepsy in our case include the asymmetric features in motor manifestation of the seizures as well as a subtle hemiparesis on neurological exam. Such clinical details indicating possible focal epilepsy syndrome may not always be evident in very young patients and therefore, a video-EEG evaluation, MRI brain and other adjunctive neuroimaging tests are important investigative tools that must be considered early in the course of investigation of infants with epilepsy. Refractory status epilepticus Medically refractory status epilepticus has significant morbidity and mortality risks associated with it. Currently accepted line of treatment involves high dose suppressive therapy with intravenous medications.2,3 The improvement in our capability to offer multidisciplinary symptomatic and supportive care for very young patients in an intensive care unit enables us to prolong medical management form several days to several weeks. However this approach is not without a heavy price. In one study2 authors found universal morbidity at follow-up in children who survived prolonged high-dose suppressive therapy. None of the children in this series returned to baseline neurological function and all of them continued to have epilepsy.2 Just as morbidity rates are very high, the risk to life is also substantial during the course of aggressive and prolonged pharmacotherapy for unremitting seizures. Mortality rates as a result of refractory status epilepticus may range from 16–43.5%.4–6 Unfortunately, the paradigm of aggressive and prolonged medical management with intravenous agents may be the only recourse for patients with non-existent surgical options. However, symptomatic refractory status epilepticus with available surgical options need not be subject to a similar stratagem. In favorable surgical candidates, resective surgery may offer an immediate cure from status epilepticus as well as future epilepsy.7,8 This approach is not commonly utilized.

Until recently, the literature referring to such surgical experience was limited to rare case reports or very small case series.9–13 Lately, experienced pediatric epilepsy centers have published more data supporting the role of resective approach to symptomatic refractory status epilepticus. In one series, status was stopped in all patients after surgery, 67% patients continued to be seizure free at follow-up and 33% had a significant improvement in their seizures.7 Another surgical series found seizure control in >71% patients at most recent follow-up.8 Status epilepticus is an acute medical emergency and surgical removal of epileptogenic cortex during such a crisis is a delicate decision, fraught with potential for complications. The hesitancy to pursue surgery is valid, and only centers with adequate medical and surgical experience with complicated cases may be suited to offer such expertise. Authors of the above mentioned study reported that the morbidity related to the surgical intervention was seen in a third of the patients, and none of the patients died.7 This rate of morbidity due to epilepsy surgery in refractory status epilepticus is certainly not any worse than the frequency of complications related to prolonged medical therapy, and further underscores that only comprehensive epilepsy centers with expertise may be well suited for exploring surgical options in this patient subpopulation.2,5 Upper airway disease The objective influence of additional comorbid medical conditions on the overall risk of status epilepticus per se is not quantifiable due to lack of specific data. It may be reasonable to assume that the odds would favor an increased risk of complications when there are other concomitant medical problems. The presence of a congenital stenosis of the pyriform aperture predisposed this young infant to acute life threatening apnea and bradycardia episodes during seizure clusters. Indeed, these resulted in at least one episode of cardiopulmonary arrest needing resuscitation and several other emergency room visits culminating in endotracheal intubation to

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Patient with extensive malformation of cortical development stabilize respiration. Risk of hypoxemic ischemic cerebral insult seemed cumulative and compounded the pre-existing morbidity risks related to status epilepticus itself. Body weight Very young patients have a relatively small blood volume and are less well adapted to withstand major surgical stress. Traditionally, surgical teams are inclined to defer major surgical procedures until the age of one year or a body weight of 10 kilograms is achieved, to offset some of the increased surgical risks noted at a lower body weight and younger age. Estimated blood volume of less than 400 cc in our patient (average blood volume 80 cc/kg, operative body weight 4.7 kg) immature and delicate intracranial tissues of an 8-week-old; are factors that elevate the surgical of bleeding, DIC, or shock associated with large resections such as hemispherectomy. Surgical interventions in younger infants carry immense gravity and these are best relegated to the judgment of only the most experienced surgical teams. Under extreme circumstances, when the risks of not doing surgery (i.e., continued medical management) outweigh the operative risks, resective surgery may become a consideration in the hands of experienced personnel. Developmental plasticity Early intervention to control seizures is especially relevant in infancy for reasons of neuronal plasticity – a virtue which rapidly declines during early childhood.14 One of the factors determining good neurocognitive outcome in infants with epileptic spasms, is the ability to rapidly control seizures after onset of epilepsy.15 On the other hand infants with poorly controlled seizures are more likely to have an irreversible epileptic encephalopathy.16 It is also recognized that if an immature brain suffers a regional insult, it stands a better chance to compensate for this insult and transfer the impairment in function to preserved areas. For instance, transfer of language to the non-dominant hemisphere is more likely if the injury to the language dominant hemisphere is incurred in early childhood rather than later in life. The plasticity of a young brain offers this unique and somewhat narrow window of opportunity to improve upon development, if an intervention to halt seizures is made early. It also offers the best chance to recover function by recruiting the adaptive potential of preserved areas. Early identification of medically refractory epilepsy should therefore, prompt a diligent evaluation for surgical options. Compelling data suggest that failure of two antiepileptic drugs implicates medical refractoriness and while this cautions against the futility of further AED trials, it also provides an opportunity to consider alternate options early in the course of epilepsy. Neurological deficits Expected neurological deficits as a result of surgery in this young infant included worsening of a subtle pre-existing hemiparesis and a homonymous hemianopia. The prospect of continued status with no clear endpoint with medical management, exposure to mortality risk of acute life-threatening events and imminent neurocognitive morbidity were unique features urging

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towards surgical intervention. Even though these may seem exceedingly pressing reasons, the sensitivity and perceptions regarding fixed neurological deficits are unique to each clinical challenge and must be adequately addressed with aid of medical ethics and other appropriate team members. Surgical procedures Congenital pyriform stenosis Prior to the epilepsy surgery, a midfacial degloving procedure involving bilateral medial maxillectomies was performed with an uneventful recovery. This was done with the goal to achieve physiological upper airway patency and relieve the underlying congenital stenosis. Anatomic vs functional hemispherectomy Anatomic hemispherectomy was preferred over a functional disconnection in our patient. Experience at our and other specialized epilepsy centers suggests that patients with large, hemispheric cortical malformations may not achieve complete seizure freedom after functional hemispherectomy.19,20 In our series authors reported that an incomplete disconnection after functional hemispherectomy was the single statistically significant variable associated with persistent seizures postoperatively.19 Revision to an anatomic hemispherectomy resulted in improved outcome in previously failed patients and authors advocate an anatomic removal of the malformed hemisphere as the preferred procedure of choice.19 Brain histopathology This showed a severe cortical dysplasia with microcalcifications and gliosis.

Outcome Immediate post operative Status epilepticus was stopped immediately following surgery. After acute convalescence, DC was discharged home on antiepileptic medications with no further seizures and a stable respiratory status. Eighteen months later At most recent follow-up, DC remains seizure free with reduction of his seizure medications. Neuropsychological testing was performed at 10-months’ age. He had a normal cognitive development for age and was noted to have a strong propensity for language development. His motor development lagged on account of the hemiparesis. His family shares that he has a very bright and cheerful disposition and that he continues to make developmental progress.

Summary and conclusion Infantile spasms may result from a focal epileptogenic substrate and careful evaluation including attention to clinical detail, neurophysiological and neuroimaging data is important. If a focal epileptogenic substrate is appreciated and

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seizures are medically refractory, an early intervention may offer the best chance for seizure relief and neurodevelepmental rehabilitation due to the plasticity of an immature brain. Undertaking a major neurosurgical procedure in the midst of a medical emergency such as status epilepticus needs careful

consideration due to several compounding factors and may be offered at centers with multispeciality state of the art expertise. In the hands of an experienced team, status epilepticus need not delay epilepsy surgery for carefully selected candidates and may even be life saving.

REFERENCES 1. 2. 3. 4. 5. 6. 7.

8. 9. 10.

Chugani HT, Conti JR. Etiologic classification of infantile spasms in 140 cases: role of positron emission tomography. J Child Neurol 1996;11(1):44–8. Sahin M, Menache CC, Holmes GL, Riviello JJ Jr. Prolonged treatment for acute symptomatic refractory status epilepticus: outcome in children. Neurology 2003; 61(3):398–401. Claassen J, Hirsch LJ, Emerson RG, Mayer SA. Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia 2002; 43(2):146–53. Gilbert DL, Gartside PS, Glauser TA. Efficacy and mortality in treatment of refractory generalized convulsive status epilepticus in children: a meta-analysis. J Child Neurol 1999; 14(9):602–9. Kim SJ, Lee DY, Kim JS. Neurologic outcomes of pediatric epileptic patients with pentobarbital coma. Pediatr Neurol 2001; 25(3):217–20. Sahin M, Menache CC, Holmes GL, Riviello JJ. Outcome of severe refractory status epilepticus in children. Epilepsia 2001; 42(11):1461–7. Alexopoulos A, Lachhwani DK, Gupta A, Kotagal P, Harrison AM, Bingaman W, Wyllie E. Resective surgery to treat refractory status epilepticus in children with focal epileptogenesis. Neurology 2005;64:567–70. Koh S, Mathern GW, Glasser G et al. Status epilepticus and frequent seizures: incidence and clinical characteristics in pediatric epilepsy surgery patients. Epilepsia 2005;46(12):1950–4. D’Giano CH, Del CG, Pomata H, Rabinowicz AL. Treatment of refractory partial status epilepticus with multiple subpial transection: case report. Seizure 2001;10(5):382–5. Desbiens R, Berkovic SF, Dubeau F, et al. Life-threatening focal status epilepticus due to occult cortical dysplasia. Arch Neurol 1993;50(7):695–700.

11. 12. 13. 14. 15.

16. 17.

18. 19. 20.

Gorman DG, Shields WD, Shewmon DA et al. Neurosurgical treatment of refractory status epilepticus. Epilepsia 1992;33(3):546–9. Krsek P, Tichy M, Belsan T et al. Life-saving epilepsy surgery for status epilepticus caused by cortical dysplasia. Epileptic Disord 2002;4(3):203–8. Ma X, Liporace J, O’Connor MJ, Sperling MR. Neurosurgical treatment of medically intractable status epilepticus. Epilepsy Res 2001;46(1):33–8. Chugani HT. A critical period of brain development: studies of cerebral glucose utilization with PET. Prev Med 1998; 27(2):184–8. Asarnow RF, LoPresti C, Guthrie D et al. Developmental outcomes in children receiving resection surgery for medically intractable infantile spasms. Dev Med Child Neurol 1997;39(7):430–40. Caplan R, Siddarth P, Mathern G et al. Developmental outcome with and without successful intervention. Int Rev Neurobiol 2002; 49:269–84. Camfield PR, Camfield CS, Gordon K, Dooley JM. If a first antiepileptic drug fails to control a child’s epilepsy, what are the chances of success with the next drug? J Pediatr 1997; 131(6):821–4. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342(5):314–19. Gonzalez-Martinez JA, Gupta A, Kotagal P et al. Hemispherectomy for catastrophic epilepsy in infants. Epilepsia 2005;46(9):1518–25. Di Rocco C, Iannelli A. Hemimegalencephaly and intractable epilepsy: complications of hemispherectomy and their correlations with the surgical technique. A report on 15 cases. Pediatr Neurosurg 2000;33(4):198–207.

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Hemispherectomy in a patient with catastrophic epilepsy A Gupta

Introduction Hemispherectomy is a not uncommon surgery that is performed usually in infants and children for the treatment of intractable epilepsy. This procedure, often quoted as being radical in the media and journal articles, is obviously reserved for catastrophic epilepsies that usually present with daily and some times life-threatening seizures or status epilepticus, progressive or malignant course, rapid cognitive decline, neurological deficits, lack of seizure response and toxicity from multiple antiepileptic medications, poor prediction for prognosis and mortality risk (unless surgery is imminently considered), and parental anxiety and stress. Common indications for hemispherectomy are congenital hemispheric malformations such as hemimegalencephaly or extensive cortical dysplasias, perinatal ischemic stroke, Rassmussen’s encephalitis, and Sturge-Weber syndrome.1 The goal of this chapter is to present an instructive case to illustrate important presurgical findings, decision-making steps, and surgical planning in an infant who underwent hemispherectomy. This case also exemplifies some of the unique aspects of evaluating infants who are candidates for surgery (also see Chapter 46). Hemispherectomy procedure and techniques are discussed elsewhere in this book (see Chapter 121).

Case history and examination A 6-month-old female baby presented with daily seizures that began soon after her birth. This was mother’s first and twin pregnancy induced by in vitro fertilization. She was on ovulation stimulation agents before pregnancy. Pregnancy was uneventful except for mild gestational diabetes managed by dietary modifications. Around 36 weeks period of gestation, mother went into spontaneous labor. However, the labor failed to progress, and twins were delivered by cesarean section. The first twin, our patient, was 2 kg birth weight and required supplemental blow-by oxygen for a few minutes after birth. The second twin was noted to be pink and active at birth with no subsequent medical concerns after delivery. In the nursery, on the second day after birth, it became clear from repeated observations that the infant was having seizures. Initially, her seizures were behavior arrest, rapid eye fluttering, facial twitching, and multifocal clonic movements (all extremities) occurring for 20–45 seconds 5–6 times a day. Medication management failed to control her seizures while

parents went through many frightening procedures, hospital admissions, emergency room visits, nutritional and feeding difficulties, and researching on their daughter’s condition. Around the age of 6 weeks, she developed typical infantile (epileptic) spasms and her epilepsy took a course for the worse. Her seizures (described above) were now mixed with infantile spasms in clusters of 5–10 seizures every few seconds lasting for 2–5 minutes. She was having 30–60 clusters daily by the time she was referred for surgery. During this time, she attained no developmental milestones, did not smile or even make eye contact with the parents, became hypotonic laying in bed sleepy and encephalopathic, was supplemented by nasogastric tube for failure to thrive, and was taking Valproate, Phenobarb, and Levetiracetam in toxic doses along with a ketogenic diet. She had previously failed to respond to Topiramate and Clonazepam. Parents also noted decreased spontaneous movements in the right arm and leg. It was now clear to the treating physicians and the parents that the child’s condition demanded some critical decisions. At this point, the child was referred for surgical options. At the time of our first examination at 6 months of age, she was an encephalopathic infant with severe developmental delay and generalized hypotonia. Her weight was 7 kg. Her scalp examination and head circumference were normal. She had one or more seizure clusters every hour. Repeated observations and careful examinations revealed right hemiparesis with extreme paucity of right hand and finger movements, but without any asymmetry in the deep tendon reflexes, tone or plantar responses (generalized hyptonia and hyporeflexia). Skin examination revealed a linear nevus on the bridge of the nose and small overgrowth over the left lip (Figure 157.1) suggesting a diagnosis of Epidermal Nevus Syndrome. Dilated eye examination was normal. Visual tracking or field deficits were untestable.

Presurgical evaluation Video-EEG evaluation at 6 months of age showed absence of normal awake rhythms and physiological sleep elements. The interictal EEG showed high-voltage, almost continuous sharp waves (1–2 per second) in the bioccipital regions with maximum in the left occipital region (Figures 157.2 and 157.3). Many clusters of seizures were recorded with behavior arrest, whole-body stiffening, rapid eye fluttering, and multifocal clonic jerking. Ictal onset (Figure 157.4) was again noted in 1491

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Figure 157.1 Facial photograph of the infant with arrows showing linear nevus in the midline over the bridge of the nose and overgrowth of the left lip ipsilateral to the hemimegalencephaly.

the bioccipital regions, however, maximum distribution was in the left occipito-parietal and mesial parietal channels. A brain MRI (Figure 157.5) revealed left hemimegalencephaly, agenesis of corpus callosum, and midline lipoma confirming the diagnosis of Epidermal Nevus Syndrome. No abnormalities were noted in the right cerebral hemisphere. Brain FDGPET showed marked left cerebral hypometabolism concordant with the MRI and EEG findings. Only limited neuropsychological evaluation was possible by parental report, and it revealed profound developmental delay.

Epilepsy management conference and decision making The case was presented and discussed in the Epilepsy Management Conference. It was the consensus that the infant had catastrophic left hemispheric epilepsy and surgery could have been considered even earlier given the diagnosis and expected intractability of her epilepsy. The burden of seizures, degree of encephalopathy and developmental delay, toxic doses of multiple antiepileptic medications, pre-existing right motor deficit, and the etiology argue favorably in considering urgent left hemispherectomy.2 No further studies such as invasive recordings were needed to refine surgical strategy. Extensive resective surgery in the face of small size (weight 7 kg) and encephalopathic state would entail higher perioperative risks of mortality and morbidity. However, the risk of mortality from surgery compares favorably to nonsurgical options, and is likely to be only higher if surgery is further delayed or not performed. The literature suggests 50% chance

of seizure freedom with additional 20–30% chances of >75% seizure improvement on lesser medications.2,3 It is likely that the patient will remain developmentally delayed, however, significant gains in global development and affect are expected. All this information was presented to the parents who were already on the verge of giving up on their child. After considering benefits, risks and no promising nonsurgical alternatives in the future, they agreed to proceed with hemispherectomy, the thought of which they had so far resisted.

Surgery and outcome A modified left anatomic hemispherectomy was performed (Figure 157.6). Perioperative course was unremarkable for any acute complication. The child did not have any seizure in the acute postoperative period. She was discharged from the hospital with intensive motor rehab and intervention for cognitive development. Two years since surgery, the child remains seizure free. She was on one medication in low doses at the 2-year follow-up visit. At two and a half years of age, she made significant motor and cognitive gains. She was learning to stand and did not yet have any clear words with meaning. Surgical pathology showed increase bulkiness of the resected left hemispheric tissue with thick and smooth gray matter in the left occipital, parietal and temporal lobes. Predominant microscopic findings included lack of cortical organization, dysmorphic neurons, regions of polymicrogyric cortex, and areas of nodular neuronal heterotopia. Numerous islands of microcalcifications were noted in the subcortical white matter. These findings confirmed the diagnosis of hemimegalencephaly.

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Ictal onset

Figure 157.2–4 Interictal EEG showing high voltage repetitive generalized (maximum bioccipital) sharp waves every 1–2 seconds (Figure 157.2) maximum in the left and mesial occipital (O1 and Pz) regions. On increasing the voltage gain, left hemispheric burst suppression pattern (modified hypsarrhythmia) is seen with relative preservation of the faster frequencies over the right hemisphere. Ictal onset (Figure 157.3) showed a burst of high voltage generalized sharp waves maximum in the left occipital and mesial parietal electrodes followed by emergence of sharp alpha in the same region. Note that due to hemimegalencephaly and protrusion of left parieto-occipital region across the midline, the mesial parietal (Pz) electrode is most likely over the left parieto-occipital lobe (Figure 157.4).

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Figure 157.5 T1 weighted brain MRI of the infant showing left hemimegalencephaly with left hemispheric enlargement, thickened cortex, poor gray-white differentiation, and a midline lipoma with hypoplastic corpus callosum. Right hemisphere appeared normal on MRI.

Figure 157.6 Postoperative brain MRI showing modified anatomic hemispherectomy with resection and disconnection of the brain except for insular region and deep gray nuclei.

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Hemispherectomy in a patient with catastrophic epilepsy

Discussion Our case illustrates several unique age-related aspects of infants who are candidates for epilepsy surgery (discussed in Chapter 49). First, the clinical course was catastrophic from the onset to the time of surgery. Beginning life with daily seizures due to extensive brain malformation (hemimegalencephaly) was further complicated by the toxic doses of antiepileptic medications, stupor state with encephalopathy, feeding difficulties and failure to thrive. This rendered accurate assessment of motor function, visual function, and neuropsychological assessment difficult, if not impossible. In addition, the stress of taking care of such an infant for new parents, especially so in the presence of a normal twin sibling, can not be underestimated. There usually is tremendous grief, guilt, anger, with psychosocial and economic impact on the family, and the family may be averse to making decisions for surgery (often considered more risky) early on in the course. Second, the intractability of seizures in infants such as our case is not just a function of time and trial of medications, but also, the evaluation of underlying etiology. Daily seizures that begin at birth due to hemimegalencephaly are most unlikely to respond to medical management, and surgical planning should start at the time of diagnosis. Surgical timing is crucial, and recent studies suggest that consideration for early surgery reduces the impact of daily seizures and encephalopathy on cognition and developmental outcome.4 With advances in pediatric anesthesia, critical care, neurosurgery, and epilepsy management, tertiary care centers with experience in pediatric epilepsy are able to operate with low mortality and morbidity even in infants weighing

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