Neurosurgery - PDF Free Download (2024)

European Manual of Medicine

Neurosurgery C. B. Lumenta, C. Di Rocco, J. Haase, J. J. A. Mooij Editors

. Arnold W U. Ganzer Series Editors

Christianto B. Lumenta Concezio Di Rocco Jens Haase Jan Jakob A. Mooij Editors

Neurosurgery

123

Series Editors

Volume Editors

Professor Dr. Wolfgang Arnold Department of Otorhinolaryngology, Head and Neck Surgery Technical University of Munich Klinikum rechts der Isar 81675 München Germany Email: [emailprotected]

Professor Dr. Christianto B. Lumenta Department of Neurosurgery Bogenhausen Academic Teaching Hospital Technical University of Munich Englschalkinger Straße 77 81925 München Germany E-mail: [emailprotected]

Professor Dr. Uwe Ganzer Department of Otorhinolaryngology, Head and Neck Surgery University of Düsseldorf 40225 Düsseldorf Germany Email: [emailprotected]

Professor Concezio Di Rocco, MD Istituto di Neurochirurgica Università Cattolica del Sacro Cuore Policlinico Gemelli Largo Gemelli 8 00168 Rome Italy E-mail: [emailprotected]

ISBN 978-3-540-79564-3 e-ISBN 978-3-540-79565-0

Professor Jens Haase, MD Institute of Health Science and Technology, Faculties of Engineering, Science and Medicine Aalborg University Fredrik Bajers vej 7 D3 9220 Aalborg East Denmark E-mail: [emailprotected]

DOI 10.1007/978-3-540-79565-0 Springer Heidelberg Dordrecht London New York Library of Congress Control Number: 2009938543 © Springer-Verlag Berlin Heidelberg 2010 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover design: Frido Steinen-Broo, eStudioCalamar, Figueres/Berlin, Spain/Germany Typesetting and production: le-tex publishing services GmbH, Leipzig, Germany

Professor Jan Jakob A. Mooij, MD Department of Neurosurgery University of Groningen Medical Centre UMCG POB 30.001 9700 RB Groningen The Netherlands E-mail: [emailprotected]

Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

Foreword of the Series Editors

The European Manual of Medicine series was founded on the premise of offering residents as well as specialised clinicians the latest and most up-to-date information on diagnosis and treatment in Europe. In contrast to existing textbooks, the European Manual of Medicine series aims to find a consensus on the demands of modern European medicine based on the “logbooks” recommended by the Union of European Medical Societies (UEMS). Therefore, identical for each discipline, diagnostic and therapeutic principles are recommended as “recommended European standards”. To fulfil these demands, we – together with Springer – recruit editors who are well established and recognised in their specialities. For each volume, at least three editors from different European countries are invited to bring the high clinical and scientific standards of their respective disciplines to the book. Wherever possible, the book editors were asked to follow a standardised structure for each chapter so as to guarantee the reader easy and quick access to the material. High-quality illustrations and figures should provide additional useful information. For the interested reader, detailed references allow him or her to further investigate areas of individual interest. The series editors are deeply grateful to Springer, especially to Mrs. Gabriele Schroeder, Mrs. Waltraud Leuchtenberger and Mrs. Stephanie Benko for their support and assistance in the realisation of this project from the early stages. The third volume of the European Manual of Medicine series is Neuro surgery. The aim is to provide neurosurgery trainees with a comprehensive, yet condensed, guide to the core knowledge required in this speciality, and to give them the ability to work in their speciality in the entire European Union. The volume editors Prof. Christianto B. Lumenta, Munich/Germany; Prof. Concezio Di Rocco, Rome/Italy; Prof. Jens Haase, Aalborg/Denmark; and Prof. Jan Jakob A. Mooij, Groningen/The Netherlands, leading European experts in Neurosurgery, recruited contributors from different European countries to compile a textbook that fulfils our original concept of the European Manual of Medicine series.

Wolfgang Arnold Uwe Ganzer Munich/Düsseldorf Fall 2009

Preface

In a highly specialized field of medicine such as neurosurgery, specific knowledge is needed, and residents in training for neurosurgery also need to have such knowledge. As we know, there are differences in the training programmes in the various EU countries, making it difficult to standardize medical training in the specialized field of neurosurgery. The basis for an international European consensus in neurosurgery is set out in this manual. The book is written for residents as well as for students and other physicians with special interest in neurosurgery. Attempts were made to incorporate details of diagnostic and therapeutic procedures in different neurosurgical cases depending on the localization (cranial, spinal, peripheral nerves), with consideration of congenital defects and paediatric neurosurgical disorders, of functional and stereotactic neurosurgery as well as of critical neurosurgical care. The chapters on each organ contain the basics in anatomy and physiology. The book is structured with a clear description of the entities and their neurosurgical treatment options. With better understanding of specific neurosurgical problems, the reader will be able to provide patients with better medical care. In preparing for the board examination, the resident will have a European standard for stepwise management of neurosurgical problems. Munich, Germany Rome, Italy Aalborg, Denmark Groningen, The Netherlands

C. B. Lumenta C. Di Rocco J .Haase J. J. A. Mooij Summer 2009

VII

Contents

Introduction

2.2.4

Edited by Christianto B. Lumenta 1.1

Introduction to Neurosurgery . . . . . . . 3 References .. . . . . . . . . . . . . . . . . . . . . . . . . 3

Training and Education

2.1.3 2.1.4 2.1.5 2.1.6 2.1.6.1

2.1.6.2 2.1.6.3 2.1.6.4 2.1.6.5 2.1.7 2.1.8 2.1.9 2.2

2.2.1 2.2.2 2.2.3

Training in Neurosurgery . . . . . . . . . . . 7 Introduction .. . . . . . . . . . . . . . . . . . . . . . . 7 Goals of a Neurosurgical Training Programme .. . . . . . . . . . . . . . . . . . . . . . . . 7 Length of Training . . . . . . . . . . . . . . . . . . 7 Contents of Training . . . . . . . . . . . . . . . . 7 The Training Programme . . . . . . . . . . . . 7 The Training Institution . . . . . . . . . . . . . 8 Requirements for Training Institutions with Regard to Equipment and Educational Facilities .. . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Institutional Quality Management Provisions . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Responsibilities of a Training Programme Director . . . . . . . . . . . . . . . . 9 Responsibilities of Trainers .. . . . . . . . . . 9 Requirements for Trainees . . . . . . . . . . . 9 Periodic Progress Evaluation . . . . . . . . . 10 Certification at Completion of Training . . . . . . . . . . . . . . . . . . . . . . . . . 10 Subspecialisation .. . . . . . . . . . . . . . . . . . . 10 R eferences .. . . . . . . . . . . . . . . . . . . . . . . . . 16 Basic Training in Technical Skills: Introduction to Learning ‘Surgical Skills’ in a Constructive Way .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Introduction to ‘Basic Training Skills’ .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Learning: Theories . . . . . . . . . . . . . . . . . . Length of Training Periods .. . . . . . . . . .

2.2.6

19 20 21 21

The Neurocranium

Edited by Christianto B. Lumenta 2.1 2.1.1 2.1.2

2.2.5

Magnification of Surgical Dexterity . . . . . . . . . . . . . . . . . . . . . . . . . . . Virtual Reality as Part of the Learning Process .. . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . R eferences .. . . . . . . . . . . . . . . . . . . . . . . . .

Edited by Christianto B. Lumenta, Jan Jakob A. Mooij and Concezio Di Rocco 3.1 3.1.1 3.1.1.1 3.1.1.2 3.1.1.3 3.1.1.4 3.1.2 3.1.3 3.1.3.1 3.1.3.2 3.1.3.3 3.1.3.4 3.1.4 3.1.4.1 3.1.4.2 3.1.5 3.1.5.1 3.1.5.2

17 17 17 18

3.1.5.3 3.1.5.4 3.1.5.5

Basics .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . The Skull and Its Solid Contents . . . . . . The Cerebral Blood Vessels .. . . . . . . . . . The Cerebrospinal Fluid and Ventricle System . . . . . . . . . . . . . . . . The Cranial Nerves .. . . . . . . . . . . . . . . . . Pathophysiology . . . . . . . . . . . . . . . . . . . . Clinical Symptomatology . . . . . . . . . . . . Sensorimotor Deficit . . . . . . . . . . . . . . . . Speech Disturbances .. . . . . . . . . . . . . . . . Optic Function Disturbance .. . . . . . . . . Cerebellar Symptomatology .. . . . . . . . . General Clinical Examination .. . . . . . . The Present and the Past Histories of the Patient and the Family .. . . . . . . . The Neurological Examination . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . . . Cerebral Diagnostics . . . . . . . . . . . . . . . . Radiology: Fundamentals of Cranial Neuroimaging . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . . . Electroencephalography . . . . . . . . . . . . . Suggested Reading . . . . . . . . . . . . . . . . . . Evoked Potentials and Their Use in Neurosurgical Practice . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . . . Radionuclide Imaging Studies .. . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . . . Cerebrospinal Fluid Diagnostics .. . . . . Selected Reading .. . . . . . . . . . . . . . . . . . .

27 27 27 28 29 31 31 32 32 33 33 33 33 33 33 34 34 34 43 43 46 46 51 52 55 56 59

Contents

3.2 3.2.1 3.2.1.1 3.2.1.2 3.2.1.3 3.2.1.4 3.2.2 3.2.2.1 3.2.2.2 3.2.2.3 3.2.2.4 3.2.2.5 3.2.3 3.2.3.1 3.2.3.2 3.2.3.3 3.2.3.4 3.2.4 3.2.4.1 3.2.4.2 3.2.4.3 3.2.4.4 3.2.5 3.2.5.1 3.2.5.2 3.2.5.3 3.2.5.4 3.2.5.5 3.2.5.6 3.2.6 3.2.6.1 3.2.6.2 3.2.6.3 3.2.6.4 3.2.7

Brain Tumors .. . . . . . . . . . . . . . . . . . . . Classification and Biology of Brain Tumors .. . . . . . . . . . . . . . . . . . Introduction .. . . . . . . . . . . . . . . . . . . . . Morphology, Prognosis, and Clinical Malignancy .. . . . . . . . . . Genetics .. . . . . . . . . . . . . . . . . . . . . . . . . Single Entities .. . . . . . . . . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . Epidemiology of Brain Tumours .. . . Basics . . . . . . . . . . . . . . . . . . . . . . . . . . . . Definitions . . . . . . . . . . . . . . . . . . . . . . . Epidemiology of Brain Tumours in Adults . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology of Brain Tumours in Children . . . . . . . . . . . . . . . . . . . . . . . Special Remarks .. . . . . . . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . General Principles of Surgery on Brain Tumors .. . . . . . . . . . . . . . . . . Indications for Surgery . . . . . . . . . . . . Aim of Surgery .. . . . . . . . . . . . . . . . . . . Results of Surgery . . . . . . . . . . . . . . . . . Microsurgical Instruments .. . . . . . . . Stereotactic Biopsy . . . . . . . . . . . . . . . . Introduction .. . . . . . . . . . . . . . . . . . . . . Technique of Frame-Based Stereotactic Biopsy . . . . . . . . . . . . . . . . Indications . . . . . . . . . . . . . . . . . . . . . . . Complications . . . . . . . . . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . Supratentorial Brain Tumors in Adults . . . . . . . . . . . . . . . . . . . . . . . . . Neuroepithelial Tumors .. . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . Meningiomas .. . . . . . . . . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . Lymphomas . . . . . . . . . . . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . Germ Cell Tumors . . . . . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . Tumors of the Sellar Region .. . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . Metastases . . . . . . . . . . . . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . Infratentorial Brain Tumours in Adults . . . . . . . . . . . . . . . . . . . . . . . . . Neuroepithelial Tumours . . . . . . . . . . Cerebellopontine Angle Tumours .. . Metastases .. . . . . . . . . . . . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . Pathologies of the Cranio-Cervical Junction . . . . Selected Reading .. . . . . . . . . . . . . . . . . Tumor of the Orbit .. . . . . . . . . . . . . . .

61 61 61

64 65 67 77 78 78 78

80 82 84 84

85 85 85 85 85 85 85

86 88 88 89

90 90 96 96 102 103 104 105 110 110 116 116 120

121 121 123 128 130

130 135 136

3.2.7.1 3.2.7.2 3.2.7.3 3.2.7.4 3.2.7.5 3.2.7.6 3.2.8 3.2.8.1 3.2.8.2 3.2.8.3 3.2.8.4 3.2.8.5 3.2.8.6 3.2.8.7 3.2.8.8 3.2.8.9 3.2.9 3.2.9.1 3.2.9.2 3.2.9.3 3.2.10 3.2.10.1 3.2.10.2 3.2.10.3 3.2.10.4 3.2.10.5 3.2.10.6 3.2.10.7 3.2.11 3.2.11.1 3.2.11.2 3.2.11.3 3.2.11.4 3.2.12 3.2.12.1 3.2.12.2 3.2.12.3 3.2.12.4 3.2.12.5

Introduction .. . . . . . . . . . . . . . . . . . . . . Symptoms . . . . . . . . . . . . . . . . . . . . . . . . Topographical Distribution . . . . . . . . Histology .. . . . . . . . . . . . . . . . . . . . . . . . Operative Approaches . . . . . . . . . . . . . European Recommendations .. . . . . . Selected Reading .. . . . . . . . . . . . . . . . . Pseudotumour Cerebri . . . . . . . . . . . . Basics . . . . . . . . . . . . . . . . . . . . . . . . . . . . Idiopathic Intracranial Hypertension . . . . . . . . . . . . . . . . . . . . . Diagnostic Procedures .. . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . Differential Diagnosis . . . . . . . . . . . . . Prognosis .. . . . . . . . . . . . . . . . . . . . . . . . Surgical Principles .. . . . . . . . . . . . . . . . Pseudotumour Cerebri, Secondary . . . . . . . . . . . . . . . . . . . . . . . . Special Remarks .. . . . . . . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . Pediatric Brain Tumors . . . . . . . . . . . . Infratentorial Brain Tumors in Children . . . . . . . . . . . . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . Supratentorial Brain Tumors in Children . . . . . . . . . . . . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . Congenital and Infantile Brain Tumors .. . . . . . . . . . . . . . . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . Radiotherapy . . . . . . . . . . . . . . . . . . . . . Introduction .. . . . . . . . . . . . . . . . . . . . . Mechanism of Action .. . . . . . . . . . . . . Standard Basic Equipment . . . . . . . . . Recent Developments .. . . . . . . . . . . . . Standard Approaches to Radiotherapy .. . . . . . . . . . . . . . . . . . The Late Consequences of Radiation Therapy to the Brain .. . Clinical and Research Developments . . . . . . . . . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . Chemotherapy for Brain Tumors . . . General Guidelines . . . . . . . . . . . . . . . Temozolomide .. . . . . . . . . . . . . . . . . . . PCV Chemotherapy .. . . . . . . . . . . . . . BCNU (Carmustine) . . . . . . . . . . . . . . Advantages and Limits of Adjuvant Treatments in Pediatric Brain Tumors .. . . . . . . . . Epidemiology .. . . . . . . . . . . . . . . . . . . . Background . . . . . . . . . . . . . . . . . . . . . . Adjuvant Treatment Options .. . . . . . Malignant Gliomas .. . . . . . . . . . . . . . . Low-Grade Gliomas .. . . . . . . . . . . . . .

136 136 136 136 138 138 139 140 140

140 141 142 143 143 143

144 145 145 146

146 150 150 158

158 163 163 163 163 164 164

164 165

165 166 167 167 167 169 170

170 170 171 171 172 172

Contents

3.2.12.6 3.2.12.7 3.2.13 3.2.13.1 3.2.13.2 3.2.13.3

Medulloblastoma/sPNETs .. . . . . . . . . Ependymoma .. . . . . . . . . . . . . . . . . . . . Novel Therapies .. . . . . . . . . . . . . . . . . . Targeting and Delivery . . . . . . . . . . . . Delivery .. . . . . . . . . . . . . . . . . . . . . . . . . Future Developments .. . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . .

173 175 176 176 178 178 178

3.3 3.3.1 3.3.1.1 3.3.1.2 3.3.1.3

Vascular Diseases .. . . . . . . . . . . . . . . . Aneurysms . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis .. . . . . . . . . . . . . . . . . . . . . Epidemiology .. . . . . . . . . . . . . . . . . . . . Symptomatology – Subarachnoid Haemorrhage .. . . . . . . . . . . . . . . . . . . . Diagnostic Procedures .. . . . . . . . . . . . Surgical Therapy . . . . . . . . . . . . . . . . . . Endovascular Therapy . . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . Arteriovenous Malformation .. . . . . . Pathogenesis .. . . . . . . . . . . . . . . . . . . . . Epidemiology .. . . . . . . . . . . . . . . . . . . . Symptomatology .. . . . . . . . . . . . . . . . . Diagnostic Procedures .. . . . . . . . . . . . Surgical Therapy . . . . . . . . . . . . . . . . . . Endovascular Therapy . . . . . . . . . . . . . Stereotactic Radiosurgery for Cerebral Arteriovenous Malformations .. . . . . . . . . . . . . . . . . . . Conservative Therapy . . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . Cavernoma .. . . . . . . . . . . . . . . . . . . . . . Characteristics .. . . . . . . . . . . . . . . . . . . Pathogenesis .. . . . . . . . . . . . . . . . . . . . . Epidemiology .. . . . . . . . . . . . . . . . . . . . Symptomatology .. . . . . . . . . . . . . . . . . Diagnostics .. . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . Conservative Treatment . . . . . . . . . . . Cranial Dural Arteriovenous Fistulas .. . . . . . . . . . . . . . . . . . . . . . . . . . Introduction .. . . . . . . . . . . . . . . . . . . . . Pathogenesis .. . . . . . . . . . . . . . . . . . . . . Classification . . . . . . . . . . . . . . . . . . . . . Diagnostic Procedures .. . . . . . . . . . . . Therapeutic Options .. . . . . . . . . . . . . . Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stenotic and Occlusive Vascular Disease .. . . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis .. . . . . . . . . . . . . . . . . . . . . Epidemiology .. . . . . . . . . . . . . . . . . . . . Symptomatology . . . . . . . . . . . . . . . . . Clinical Picture . . . . . . . . . . . . . . . . . . . Diagnostic Procedures . . . . . . . . . . . . Surgical and Neurointerventional Treatment . . . . . . . . . . . . . . . . . . . . . . . .

181 181 181 181

182 183 185 191 193 194 194 195 195 196 196 197

197 201 201 201 201 201 202 202 202 202 207

207 207 207 208 209 209 210

210 210 211 211 212 212

3.3.1.4 3.3.1.5 3.3.1.6 3.3.2 3.3.2.1 3.3.2.2 3.3.2.3 3.3.2.4 3.3.2.5 3.3.2.6 3.3.2.7 3.3.2.8 3.3.3 3.3.3.1 3.3.3.2 3.3.3.3 3.3.3.4 3.3.3.5 3.3.3.6 3.3.3.7 3.3.4 3.3.4.1 3.3.4.2 3.3.4.3 3.3.4.4 3.3.4.5 3.3.4.6 3.3.5 3.3.5.1 3.3.5.2 3.3.5.3 3.3.5.4 3.3.5.5 3.3.5.6

213

Non-Atherosclerotic Occlusive Disease .. . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.5.8 Mass Effect-Producing Ischemic Lesions .. . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.5.9 Acute Phase Treatment of Ischemic Stroke .. . . . . . . . . . . . . . . . 3.3.5.10 Conservative Therapy . . . . . . . . . . . . . 3.3.5.11 Anesthesia, Preoperative and Postoperative Management, Monitoring . . . . . . . . . . . . . . . . . . . . . . . 3.3.6 Spontaneous Intracerebral and Intracerebellar Haemorrhage in Adults . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.6.1 Pathogenesis .. . . . . . . . . . . . . . . . . . . . . 3.3.6.2 Causes . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.6.3 Epidemiology .. . . . . . . . . . . . . . . . . . . . 3.3.6.4 Symptomatology .. . . . . . . . . . . . . . . . . 3.3.6.5 Diagnostic Procedures .. . . . . . . . . . . . 3.3.6.6 Treatment . . . . . . . . . . . . . . . . . . . . . . . . References .. . . . . . . . . . . . . . . . . . . . . . . 3.3.7 Pediatric Vascular Lesions . . . . . . . . . 3.3.7.1 Pediatric Intracranial Arteriovenous Shunts .. . . . . . . . . . . . . 3.3.7.2 Intracranial Aneurysms in Children . . . . . . . . . . . . . . . . . . . . . . . 3.3.7.3 Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.5.7

3.4 3.4.1 3.4.1.1 3.4.1.2 3.4.1.3 3.4.1.4 3.4.1.5 3.4.2 3.4.2.1 3.4.2.2 3.4.2.3 3.4.2.4 3.4.3 3.4.3.1 3.4.3.2 3.4.3.3 3.4.3.4 3.4.3.5 3.4.4 3.4.4.1 3.4.4.2 3.4.4.3 3.4.4.4 3.4.4.5 3.4.5 3.4.5.1 3.4.5.2 3.4.5.3

Infectious Disease . . . . . . . . . . . . . . . . Infection of the Scalp .. . . . . . . . . . . . . Basics . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aetiology/Epidemiology . . . . . . . . . . Symptoms . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic Procedures .. . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . Osteomyelitis of the Skull . . . . . . . . . . Aetiology/Epidemiology .. . . . . . . . . . Symptoms . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic Procedures .. . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . Epidural Abscess .. . . . . . . . . . . . . . . . . Definition . . . . . . . . . . . . . . . . . . . . . . . . Aetiology/Epidemiology .. . . . . . . . . . Symptoms . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic Procedures .. . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . Subdural Empyema .. . . . . . . . . . . . . . . Definition . . . . . . . . . . . . . . . . . . . . . . . . Aetiology/Epidemiology .. . . . . . . . . . Symptoms . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic Procedures .. . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . Meningitis .. . . . . . . . . . . . . . . . . . . . . . . Definition . . . . . . . . . . . . . . . . . . . . . . . . Aetiology/Epidemiology .. . . . . . . . . . Symptoms . . . . . . . . . . . . . . . . . . . . . . . .

217 218 218 219 220

221 221 221 221 222 223 223 225 229

229 235 238

241 241 241 241 241 241 241 242 242 242 242 242 242 242 243 243 243 243 243 243 243 243 243 243 244 244 244 244

XII

Contents

3.4.5.4 3.4.6 3.4.6.1 3.4.6.2 3.4.6.3 3.4.6.4 3.4.7 3.4.7.1 3.4.7.2 3.4.7.3 3.4.7.4 3.4.7.5 3.5 3.5.1 3.5.1.1 3.5.1.2 3.5.2 3.5.3 3.5.3.1 3.5.3.2 3.5.3.3 3.5.3.4 3.5.3.5 3.5.3.6 3.5.4 3.5.4.1 3.5.4.2 3.5.4.3 3.5.4.4 3.5.5 3.5.5.1 3.5.5.2 3.5.6 3.5.6.1 3.5.6.2 3.5.6.3 3.5.7 3.5.7.1 3.5.7.2 3.5.7.3 3.5.7.4 3.5.7.5 3.5.7.6 3.5.7.7 3.5.8

Diagnostic Procedures and Treatment . . . . . . . . . . . . . . . . . . . . Brain Abscess .. . . . . . . . . . . . . . . . . . . . Aetiology/Epidemiology .. . . . . . . . . . Symptoms . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic Procedures .. . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . Encephalitis . . . . . . . . . . . . . . . . . . . . . . Definition . . . . . . . . . . . . . . . . . . . . . . . . Aetiology/Epidemiology .. . . . . . . . . . Symptoms . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic Procedures .. . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . General Principles and Pathophysiology of Head Injuries .. . . . . . . . . . . . . . . . . . . . . . . . . . Historical Perspective and Introduction .. . . . . . . . . . . . . . . . . Definitions, General Principles and Pathophysiology . . . . . . . . . . . . . . Epidemiology .. . . . . . . . . . . . . . . . . . . . Initial Assessment and Early Management . . . . . . . . . . . . Introduction .. . . . . . . . . . . . . . . . . . . . . Initial Assessment of the Head Injured Patient .. . . . . . . . Early Management . . . . . . . . . . . . . . . . Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . Classification . . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic Procedures .. . . . . . . . . . . . Computed Tomography . . . . . . . . . . . Magnetic Resonance Imaging . . . . . . Cerebral Angiography . . . . . . . . . . . . . Skull Radiography .. . . . . . . . . . . . . . . . General Principles of Treatment . . . . Minor and Moderate Injuries .. . . . . . Severe Injuries . . . . . . . . . . . . . . . . . . . . Skull Fractures and Open Injuries . . Linear Fractures .. . . . . . . . . . . . . . . . . . Depressed Fractures .. . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . CSF Fistulas . . . . . . . . . . . . . . . . . . . . . . Introduction .. . . . . . . . . . . . . . . . . . . . . Clinical Presentation . . . . . . . . . . . . . . Physical Examination .. . . . . . . . . . . . . Location of the Fistula .. . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . Non-Operative Management .. . . . . . Operative Treatment .. . . . . . . . . . . . . Penetrating Head Injuries .. . . . . . . . .

244 245 245 245 245 245 245 245 245 245 245 246 246

249 249 249 251 252 253 253

253 254 254 255 255 255 255 262 262 262 268 268 268 269 269 270 270 271 271 271 272 273 273 273 273 277

Introduction .. . . . . . . . . . . . . . . . . . . . . Pathophysiology . . . . . . . . . . . . . . . . . . Initial Examination . . . . . . . . . . . . . . . Operative Treatment . . . . . . . . . . . . . . Postoperative Treatment . . . . . . . . . . . Outcome . . . . . . . . . . . . . . . . . . . . . . . . . Traumatic Haematoma . . . . . . . . . . . . Epidural Haematoma .. . . . . . . . . . . . . Acute Subdural Haematoma . . . . . . . Parenchymal Lesions . . . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . B ooks . . . . . . . . . . . . . . . . . . . . . . . . . . . . Articles .. . . . . . . . . . . . . . . . . . . . . . . . . . Guidelines .. . . . . . . . . . . . . . . . . . . . . . . Useful Links . . . . . . . . . . . . . . . . . . . . . . 3.5.11 Head Injuries: Specific Aspects in Children . . . . . . . . . . . . . . . . . . . . . . . 3.5.11.1 Peculiar Aspects of Paediatric Traumatic Brain Injuries . . . . . . . . . . 3.5.11.2 Specific Types of Head Injuries in Newborns and Infants .. . . . . . . . . . 3.5.11.3 Medical Aspects . . . . . . . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . 3.5.8.1 3.5.8.2 3.5.8.3 3.5.8.4 3.5.8.5 3.5.8.6 3.5.9 3.5.9.1 3.5.9.2 3.5.9.3 3.5.10

3.6 3.6.1 3.6.1.1 3.6.1.2 3.6.1.3 3.6.1.4 3.6.1.5 3.6.1.6 3.6.1.7 3.6.1.8 3.6.1.9 3.6.2 3.6.2.1 3.6.2.2 3.6.2.3 3.6.2.4 3.6.2.5 3.6.2.6 3.6.3 3.6.3.1 3.6.3.2 3.6.3.3 3.6.3.4 3.6.4

Developmental and Acquired Anomalies .. . . . . . . . . . . . . . . . . . . . . . . Hydrocephalus in Adults .. . . . . . . . . . Basics . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic Procedures .. . . . . . . . . . . . Clinical Signs . . . . . . . . . . . . . . . . . . . . . Radiological Findings . . . . . . . . . . . . . Spinal Tap . . . . . . . . . . . . . . . . . . . . . . . . Continuous CSF Pressure Monitoring . . . . . . . . . . . . . . . . . . . . . . . CSF Dynamics .. . . . . . . . . . . . . . . . . . . Additional/Useful Diagnostic Procedures . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . Useful Links . . . . . . . . . . . . . . . . . . . . . . Congenital Arachnoid Cysts . . . . . . . Synonym . . . . . . . . . . . . . . . . . . . . . . . . . Definition and Etiology .. . . . . . . . . . . Intracranial Arachnoid Cysts .. . . . . . Supratentorial Arachnoid Cysts .. . . . Infratentorial Arachnoid Cysts . . . . . Intraspinal Arachnoid Cysts .. . . . . . . Chiari Malformations . . . . . . . . . . . . . Background . . . . . . . . . . . . . . . . . . . . . . Chiari 1 Malformation .. . . . . . . . . . . . Chiari 2 Malformation .. . . . . . . . . . . . Chiari 3 Malformation .. . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . Cranio-Vertebral Junction . . . . . . . . .

277 277 278 278 279 279 279 279 281 289 291 291 292 292 292

292 292 293 298 300

301 301 301 301 301 302 302

302 303

303 303 305 305 305 305 305 306 306 309 310 311 311 311 313 313 314 315

Contents

3.6.4.1

3.6.4.2

3.7 3.7.1 3.7.2 3.7.3 3.7.4 3.7.5 3.7.6 3.7.7 3.7.8

Definition, Embryology, Anatomy, Anomalies, Indications and Technical Notes for Posterior Arthrodesis .. . . . . . . . . . . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . Cranio-Cervical Junction Anomalies in the Paediatric Population .. . . . . . . . . . . . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . . Movement Rehabilitation for Trauma and Vascular Patients: Traumatic Brain Injury and Stroke . Introduction . . . . . . . . . . . . . . . . . . . . . Symptoms . . . . . . . . . . . . . . . . . . . . . . . . Immediate Treatment .. . . . . . . . . . . . . Prognosis .. . . . . . . . . . . . . . . . . . . . . . . . Restoration of the Functions of the Upper Extremities . . . . . . . . . . Restoration of the Functions of the Lower Extremities . . . . . . . . . . Orthoses for the Rehabilitation of Trauma and Vascular Patients .. . . Summary .. . . . . . . . . . . . . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . .

4.1.5.2 315 322 324 330

331 331 331 331 332

332 333 334 335 335

The Spine and Spinal Cord Edited by Jan Jakob A. Mooij 4.1 4.1.1 4.1.1.1 4.1.1.2 4.1.1.3 4.1.2 4.1.2.1 4.1.2.2 4.1.3 4.1.3.1 4.1.3.2 4.1.3.3 4.1.3.4 4.1.3.5 4.1.4 4.1.4.1 4.1.4.2 4.1.5 4.1.5.1

Basics .. . . . . . . . . . . . . . . . . . . . . . . . . . . Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . Spinal Column .. . . . . . . . . . . . . . . . . . . Spinal Cord .. . . . . . . . . . . . . . . . . . . . . . Meninges and Nerve Roots .. . . . . . . . Pathophysiology . . . . . . . . . . . . . . . . . . Degenerative Disc Disease . . . . . . . . . Spinal Stenosis .. . . . . . . . . . . . . . . . . . . Clinical Symptomatology . . . . . . . . . . Radiculopathy . . . . . . . . . . . . . . . . . . . . Myelopathy .. . . . . . . . . . . . . . . . . . . . . . Cauda Equina Syndrome .. . . . . . . . . . Low Back Pain . . . . . . . . . . . . . . . . . . . . Failed Back Syndrome . . . . . . . . . . . . . General Methods of Clinical Examination .. . . . . . . . . . . . . . . . . . . . . Inspection and Palpation .. . . . . . . . . . Specific Neurological Investigation .. . . . . . . . . . . . . . . . . . . . . References .. . . . . . . . . . . . . . . . . . . . . . . Radiology: Fundamentals of Spinal Neuroimaging .. . . . . . . . . . . Introduction .. . . . . . . . . . . . . . . . . . . . .

339 339 339 341 342 342 343 343 343 343 343 344 344 344

344 344 345 346 346 346

4.1.5.3 4.1.5.4 4.2 4.2.1 4.2.2 4.2.3 4.2.4 4.2.5 4.2.6 4.2.7 4.2.8 4.2.9 4.2.9.1 4.2.9.2 4.2.9.3 4.3 4.3.1 4.3.1.1 4.3.1.2 4.3.1.3 4.3.1.4 4.3.1.5 4.3.1.6 4.3.1.7 4.3.2 4.3.2.1 4.3.2.2 4.3.2.3 4.3.3 4.3.3.1 4.3.3.2 4.3.3.3 4.3.3.4 4.3.3.5 4.4 4.4.1 4.4.2

Special Characteristics of the Images . . . . . . . . . . . . . . . . . . . . . Guidelines and Technical Standards .. . . . . . . . . . . . . . . . . . . . . . . . Imaging in Spinal Disease .. . . . . . . . . References .. . . . . . . . . . . . . . . . . . . . . . .

347 347 349 351

Spinal Tumours .. . . . . . . . . . . . . . . . . . Pathological Anatomy . . . . . . . . . . . . . Epidemiology .. . . . . . . . . . . . . . . . . . . . Clinical Symptomatology . . . . . . . . . . General Principles of Surgery on Spinal Tumours . . . . . . . . . . . . . . . . Extradural Spinal Tumours .. . . . . . . . Intradural Extramedullary Spinal Tumours . . . . . . . . . . . . . . . . . . . . . . . . . Intramedullary Tumours .. . . . . . . . . . Prognosis .. . . . . . . . . . . . . . . . . . . . . . . . Specific Aspects of Spinal Tumours in Children . . . . . . . . . . . . . . Intramedullary Tumours .. . . . . . . . . . Intradural Extramedullary Tumours . . . . . . . . . . . . . . . . . . . . . . . . . Extradural Tumours .. . . . . . . . . . . . . . Selected Reading .. . . . . . . . . . . . . . . . .

353 353 353 354

Degenerative Disease . . . . . . . . . . . . . Cervical Spine . . . . . . . . . . . . . . . . . . . . Cervical Disc Herniation . . . . . . . . . . Cervical Spondylosis . . . . . . . . . . . . . . Cervical Spinal Stenosis .. . . . . . . . . . . Cervical Myelopathy . . . . . . . . . . . . . . Ossification of the Posterior Longitudinal Ligament . . . . . . . . . . . . Rheumatoid Arthritis .. . . . . . . . . . . . . Ankylosing Spondylitis . . . . . . . . . . . . Thoracic Spine . . . . . . . . . . . . . . . . . . . . Thoracic Disc Herniation . . . . . . . . . . Thoracic Spinal Canal Stenosis and Thoracic Myelopathy . . . . . . . . . . Scheuermann’s Disease (Juvenile Kyphosis) .. . . . . . . . . . . . . . . Lumbar Spine .. . . . . . . . . . . . . . . . . . . . Low Back Pain . . . . . . . . . . . . . . . . . . . . Lumbar Disc Herniation .. . . . . . . . . . Lumbar Spinal Canal Stenosis . . . . . . Spondylolisthesis, Spondylolysis .. . . Juxtafacet Cysts . . . . . . . . . . . . . . . . . . . References .. . . . . . . . . . . . . . . . . . . . . . .

373 373 373 374 375 376

377 378 380 380 380

354 355 359 363 365 366 366 370 370 370

381

382 382 382 383 386 387 388 389

Spinal Vascular Diseases . . . . . . . . . . 393 Introduction .. . . . . . . . . . . . . . . . . . . . . 393 Clinical Presentation . . . . . . . . . . . . . . 393

XIII

XIV

Contents

4.4.3 4.4.3.1 4.4.4 4.4.5 4.4.6 4.4.7 4.4.8 4.4.9 4.4.10 4.4.11 4.4.12

Dural Arteriovenous Fistulas .. . . . . . Pathophysiology . . . . . . . . . . . . . . . . . . Perimedullary Fistulas .. . . . . . . . . . . . Angiomas . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic Imaging . . . . . . . . . . . . . . . Endovascular Treatment .. . . . . . . . . . Surgical Treatment . . . . . . . . . . . . . . . . Recurrence . . . . . . . . . . . . . . . . . . . . . . . Cavernomas . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . European Recommendations .. . . . . . Suggested Reading . . . . . . . . . . . . . . . .

4.5 4.5.1

Infectious Disease of the Spine .. . . . Vertebral Body and Disc Infections .. . . . . . . . . . . . . . . . . . . . . . . . Definition . . . . . . . . . . . . . . . . . . . . . . . . Etiology/Epidemiology . . . . . . . . . . . . Symptoms . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic Procedures .. . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . Spinal Epidural Abscess .. . . . . . . . . . . Definition . . . . . . . . . . . . . . . . . . . . . . . . Etiology/Epidemiology . . . . . . . . . . . . Symptoms . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic Procedures .. . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . Transverse Myelitis and Human Immunodeficiency Virus Myelopathy .. . . . . . . . . . . . . . . . . . . . . . Definition . . . . . . . . . . . . . . . . . . . . . . . . Etiology/Epidemiology . . . . . . . . . . . . Symptoms . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic Procedures .. . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . References .. . . . . . . . . . . . . . . . . . . . . . .

399

Spinal Trauma .. . . . . . . . . . . . . . . . . . . Surgery of Cervical Spine Trauma . . Introduction .. . . . . . . . . . . . . . . . . . . . . Trauma of Upper Cervical Spine (C0–C2) .. . . . . . . . . . . . . . . . . . . . . . . . . Trauma of Subaxial Cervical Spine (C3–T1) . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . References .. . . . . . . . . . . . . . . . . . . . . . . Trauma of the Thoracolumbar Spine .. . . . . . . . . . . . . . . . . . . . . . . . . . . . Introduction .. . . . . . . . . . . . . . . . . . . . . Classifications and Review of the Recent Literature .. . . . . . . . . . . Indications for Fixation, Diagnostic Work-up and Defining Stability . . . . . . . . . . . . . . . . . . . . . . . . . . Historical Steps in Spinal Surgery .. .

403 403 403

4.5.1.1 4.5.1.2 4.5.1.3 4.5.1.4 4.5.1.5 4.5.2 4.5.2.1 4.5.2.2 4.5.2.3 4.5.2.4 4.5.2.5 4.5.3 4.5.3.1 4.5.3.2 4.5.3.3 4.5.3.4 4.5.3.5 4.6 4.6.1 4.6.1.1 4.6.1.2 4.6.1.3 4.6.1.4 4.6.2 4.6.2.1 4.6.2.2 4.6.2.3 4.6.2.4

394 394 394 394 394 395 395 395 395 396 396 396

399 399 399 399 399 400 400 400 400 400 400 401

401 401 401 401 401 401 401

403 409 412 412

Recent Clinical and Research Developments . . . . . . . 4.6.2.6 Late Problems .. . . . . . . . . . . . . . . . . . . . 4.6.2.7 Controversies About the Use of Steroids in Acute Spinal Cord Injuries .. . . . . . . . . . . . . . . . . . . . . . . . . . 4.6.2.8 Timing of Surgery .. . . . . . . . . . . . . . . . 4.6.2.9 Future Questions and Direction . . . . 4.6.2.10 Conclusion . . . . . . . . . . . . . . . . . . . . . . . R eferences .. . . . . . . . . . . . . . . . . . . . . . . 4.6.2.5

4.7 4.7.1 4.7.2 4.7.3 4.7.4 4.7.5 4.7.6 4.7.7

Syringomyelia . . . . . . . . . . . . . . . . . . . . Definition . . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology and Aetiology .. . . . Clinical Presentation . . . . . . . . . . . . . . Radiology and Differential Diagnosis .. . . . . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . Results of Treatment .. . . . . . . . . . . . . . Summary .. . . . . . . . . . . . . . . . . . . . . . . . References .. . . . . . . . . . . . . . . . . . . . . . .

Treatment and Rehabilitation of Patients with Spinal Cord Lesions .. . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.1 Epidemiology .. . . . . . . . . . . . . . . . . . . . 4.8.2 Survival and Causes of Death .. . . . . . 4.8.3 Prognosis After Traumatic Spinal Cord Lesion . . . . . . . . . . . . . . . . . . . . . . 4.8.3.1 Classification . . . . . . . . . . . . . . . . . . . . . 4.8.4 Consequences of a Spinal Cord Lesion . . . . . . . . . . . . 4.8.5 Acute Treatment of the Spinal Cord Lesion . . . . . . . . . . 4.8.5.1 Respiration . . . . . . . . . . . . . . . . . . . . . . . 4.8.5.2 Cardiovascular Issues .. . . . . . . . . . . . . 4.8.5.3 Pressure Ulcers . . . . . . . . . . . . . . . . . . . 4.8.5.4 Urological Management . . . . . . . . . . . 4.8.5.5 Bowel Management . . . . . . . . . . . . . . . 4.8.5.6 Sexual Function and Fertility .. . . . . . 4.8.5.7 Spasticity .. . . . . . . . . . . . . . . . . . . . . . . . 4.8.5.8 Pain .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8.5.9 Posttraumatic Syringomyelia . . . . . . . 4.8.5.10 Functional Electrical Stimulation .. . Suggested Reading . . . . . . . . . . . . . . . .

423 423

423 425 425 425 425

429 429 429 430

430 431 432 432 432

4.8

413 413

Peripheral Nerve Surgery

413

5.1

417 421

5.1.1

433 433 433 433 433 433

434 435 435 435 435 436 436 436 437 437 437 438

Edited by Jens Haase Basics: Aetiology, Pathophysiology, General Symptomatology and Diagnosis of Peripheral Nerve Injuries . . . . . . . 441 Aetiology .. . . . . . . . . . . . . . . . . . . . . . . . 441

Contents

5.1.1.1 5.1.1.2 5.1.2 5.1.2.1 5.1.2.2 5.1.3

Traumatic Injury .. . . . . . . . . . . . . . . . . Entrapment Neuropathies .. . . . . . . . . Pathophysiology . . . . . . . . . . . . . . . . . . Trauma .. . . . . . . . . . . . . . . . . . . . . . . . . . Entrapment .. . . . . . . . . . . . . . . . . . . . . . General Symptomatology and Diagnosis .. . . . . . . . . . . . . . . . . . . . References .. . . . . . . . . . . . . . . . . . . . . . .

5.2 5.2.1 5.2.2 5.2.2.1 5.2.2.2

Clinical Neurophysiology . . . . . . . . . Electromyography .. . . . . . . . . . . . . . . . Nerve Conduction Studies . . . . . . . . . Motor Nerve Conduction Studies .. . Sensory Nerve Conduction Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Application of Electromyography and Nerve Conduction Studies . . . . . . . . . . . . . . . Lower Motor Neurone Lesions . . . . . Peripheral Nerve Lesions . . . . . . . . . . Plexopathies . . . . . . . . . . . . . . . . . . . . . . Radiculopathy . . . . . . . . . . . . . . . . . . . . Spinal Lesions .. . . . . . . . . . . . . . . . . . . . Upper Motor Neurone Lesions . . . . . Suggested Reading . . . . . . . . . . . . . . . .

5.2.3 5.2.3.1 5.2.3.2 5.2.3.3 5.2.3.4 5.2.3.5 5.2.3.6 5.3 5.3.1 5.3.2 5.3.2.1 5.3.2.2 5.3.2.3 5.3.2.4 5.3.2.5 5.3.2.6 5.3.2.7 5.3.3 5.4 5.4.1 5.4.1.1 5.4.1.2 5.4.1.3 5.4.1.4 5.4.2 5.4.2.1 5.4.3 5.4.3.1 5.4.3.2 5.4.3.3 5.4.3.4 5.4.3.5

Therapy of Peripheral Nerve Lesions .. . . . . . . . . . . . . . . . . . . . . . . . . . Compression Syndrome, Entrapment Neuropathies .. . . . . . . . . Trauma .. . . . . . . . . . . . . . . . . . . . . . . . . . Timing of Surgery .. . . . . . . . . . . . . . . . Principles of Surgery . . . . . . . . . . . . . . Suture Techniques .. . . . . . . . . . . . . . . . Nerve Grafting .. . . . . . . . . . . . . . . . . . . Nerve Conduits . . . . . . . . . . . . . . . . . . . End-to-side Suture . . . . . . . . . . . . . . . . Direct Motor Neurotisation . . . . . . . . Conservative Treatment . . . . . . . . . . . Nerve Compression Syndromes in the Extremities .. . . . . . . . . . . . . . . . Upper Extremities .. . . . . . . . . . . . . . . . Median Nerve .. . . . . . . . . . . . . . . . . . . . Ulnar Nerve . . . . . . . . . . . . . . . . . . . . . . Radial Nerve .. . . . . . . . . . . . . . . . . . . . . Brachial Plexus .. . . . . . . . . . . . . . . . . . . Trunk Region .. . . . . . . . . . . . . . . . . . . . Lower Pelvic Plexus Lesions .. . . . . . . Lower Extremities .. . . . . . . . . . . . . . . . Femoral Nerve .. . . . . . . . . . . . . . . . . . . Sciatic Nerve .. . . . . . . . . . . . . . . . . . . . . Saphenous Nerve .. . . . . . . . . . . . . . . . . Peroneal Nerve .. . . . . . . . . . . . . . . . . . . Posterior Tibial Nerve . . . . . . . . . . . . .

441 441 442 442 442

443 443

5.4.3.6

Plantar Digital Nerve .. . . . . . . . . . . . . 463 References .. . . . . . . . . . . . . . . . . . . . . . . 463

5.5 5.5.1 5.5.2 5.5.3 5.5.4

Peripheral Nerve Tumours . . . . . . . . Schwannoma . . . . . . . . . . . . . . . . . . . . . Neurofibroma .. . . . . . . . . . . . . . . . . . . . Perineurioma .. . . . . . . . . . . . . . . . . . . . Malignant Peripheral Nerve Sheath Tumour . . . . . . . . . . . . . . . . . . . Other Tumours . . . . . . . . . . . . . . . . . . . Treatment of Peripheral Nerve Tumours . . . . . . . . . . . . . . . . . . . . . . . . . Suggested Reading . . . . . . . . . . . . . . . .

Autonomic Nervous System . . . . . . . Introduction .. . . . . . . . . . . . . . . . . . . . . Primary Hyperhidrosis . . . . . . . . . . . . Complex Regional Pain Syndrome . . . . . . . . . . . . . . . . . . . . . . . . References .. . . . . . . . . . . . . . . . . . . . . . .

469 469 470

445 445 446 446

5.5.5 5.5.6

446

5.6 5.6.1 5.6.2 5.6.3

447 447 448 448 448 449 449 449

467 467 467 468

468 468 468 468

470 470

Cranial Nerves Edited by Jan Jakob A. Mooij 6.1

Cranial Nerve Deficits . . . . . . . . . . . . 473

451

6.2

451 451 451 451 452 453 453 453 453 453

6.2.1 6.2.1.1 6.2.1.2 6.2.1.3

455 455 455 457 457 458 462 462 462 462 462 462 463 463

Cranial Nerve Compression Syndromes . . . . . . . . . . . . . . . . . . . . . . . Trigeminal Neuralgia .. . . . . . . . . . . . . Signs and Symptoms .. . . . . . . . . . . . . . Cause . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adjuvant Diagnostics and Differential Diagnosis . . . . . . . . . Therapeutic Options .. . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . Hemifacial Spasm .. . . . . . . . . . . . . . . . Signs and Symptoms .. . . . . . . . . . . . . . Cause . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adjuvant Diagnostics .. . . . . . . . . . . . . Therapeutic Options .. . . . . . . . . . . . . . Results .. . . . . . . . . . . . . . . . . . . . . . . . . . Tinnitus/Vertigo . . . . . . . . . . . . . . . . . . Signs and Symptoms .. . . . . . . . . . . . . . Cause . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adjuvant Diagnosis . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . Glossopharyngeal Neuralgia . . . . . . . Signs and Symptoms .. . . . . . . . . . . . . . Cause . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adjuvant Diagnosis . . . . . . . . . . . . . . . Therapeutic Options .. . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . .

6.2.1.4 6.2.1.5 6.2.2 6.2.2.1 6.2.2.2 6.2.2.3 6.2.2.4 6.2.2.5 6.2.3 6.2.3.1 6.2.3.2 6.2.3.3 6.2.3.4 6.2.3.5 6.2.4 6.2.4.1 6.2.4.2 6.2.4.3 6.2.4.4 6.2.4.5

475 475 475 475

475 476 476 476 476 477 477 477 477 477 478 478 478 478 478 478 479 479 479 479 479

XVI

Contents

6.2.5

Other Neurovascular Compression Syndromes .. . . . . . . . . . 479

6.3

Conclusion .. . . . . . . . . . . . . . . . . . . . . . Suggested Reading . . . . . . . . . . . . . . . . Trigeminal Neuralgia .. . . . . . . . . . . . . Hemifacial Spasm .. . . . . . . . . . . . . . . . Tinnitus/Vertigo .. . . . . . . . . . . . . . . . . . Glossopharyngeal Neuralgia . . . . . . . . Combined Studies . . . . . . . . . . . . . . . . . Hypertension and Diabetes . . . . . . . . . Spasmodic Torticollis .. . . . . . . . . . . . . .

481 481 481 481 481 481 482 482 482

Congenital Defects and Childhood Disorders

7.2.2 7.2.2.1 7.2.2.2 7.2.2.3 7.2.2.4 7.2.2.5

Syndromic Craniosynostoses .. . . . . . Introduction .. . . . . . . . . . . . . . . . . . . . . Genetics .. . . . . . . . . . . . . . . . . . . . . . . . . Main Syndromes .. . . . . . . . . . . . . . . . . Functional Aspects .. . . . . . . . . . . . . . . Management Principles .. . . . . . . . . . . Suggested Reading . . . . . . . . . . . . . . . .

522 522 523 523 526 526 528

7.3 7.3.1 7.3.1.1 7.3.1.2 7.3.2 7.3.3 7.3.4 7.3.5

Neurocutaneous Syndromes .. . . . . . Neurofibromatoses .. . . . . . . . . . . . . . . Neurofibromatosis Type 1 .. . . . . . . . . Neurofibromatosis Type 2 .. . . . . . . . . Tuberous Sclerosis Complex .. . . . . . Von Hippel–Lindau Disease . . . . . . . Sturge–Weber Syndrome .. . . . . . . . . . Hereditary Hemorrhagic Telangiectasia .. . . . . . . . . . . . . . . . . . . . Suggested Reading . . . . . . . . . . . . . . . .

529 529 529 531 533 535 535

7.4 7.4.1 7.4.2 7.4.3 7.4.4 7.4.5 7.4.6 7.4.7 7.4.8 7.4.8.1 7.4.8.2 7.4.8.3 7.4.9 7.4.10 7.4.11

Hydrocephalus . . . . . . . . . . . . . . . . . . . Definitions . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology . . . . . . . . . . . . . . . . . . Aetiology .. . . . . . . . . . . . . . . . . . . . . . . . Epidemiology .. . . . . . . . . . . . . . . . . . . . Clinical Symptoms . . . . . . . . . . . . . . . . Clinical Signs . . . . . . . . . . . . . . . . . . . . . Investigation .. . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . Surgical Options . . . . . . . . . . . . . . . . . . Shunt Valves .. . . . . . . . . . . . . . . . . . . . . Medical Treatment . . . . . . . . . . . . . . . . Complications . . . . . . . . . . . . . . . . . . . . Prognosis .. . . . . . . . . . . . . . . . . . . . . . . . Ongoing Care .. . . . . . . . . . . . . . . . . . . . Suggested Reading . . . . . . . . . . . . . . . .

Edited by Concezio Di Rocco 7.1 7.1.1 7.1.1.1 7.1.1.2 7.1.1.3 7.1.1.4 7.1.1.5 7.1.1.6 7.1.1.7 7.1.1.8 7.1.2 7.1.2.1 7.1.2.2 7.2 7.2.1 7.2.1.1 7.2.1.2 7.2.1.3 7.2.1.4 7.2.1.5 7.2.1.6 7.2.1.7 7.2.1.8 7.2.1.9 7.2.1.10 7.2.1.11 7.2.1.12 7.2.1.13

Cranial and Spinal Dysraphisms .. . Encephaloceles and Related Malformations .. . . . . . . . . . . . . . . . . . . Introduction: Concepts and Definitions . . . . . . . . . . . . . . . . . . . Anencephaly .. . . . . . . . . . . . . . . . . . . . . Encephalocele . . . . . . . . . . . . . . . . . . . . Cranial Meningocele . . . . . . . . . . . . . . Atretic Cephalocele .. . . . . . . . . . . . . . Scalp Defects . . . . . . . . . . . . . . . . . . . . . Sinus Pericranii . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . Suggested Reading . . . . . . . . . . . . . . . . Spinal Anomalies . . . . . . . . . . . . . . . . . Spina Bifida Aperta .. . . . . . . . . . . . . . . Spina Bifida Occulta .. . . . . . . . . . . . . . Suggested Reading . . . . . . . . . . . . . . . .

485

485 486 486 490 490 491 492 493 493 493 493 495 498

Craniosynostosis . . . . . . . . . . . . . . . . . Non-syndromic Craniosynostosis . . Introduction .. . . . . . . . . . . . . . . . . . . . . Classification . . . . . . . . . . . . . . . . . . . . . Prevalence .. . . . . . . . . . . . . . . . . . . . . . . Pathogenesis .. . . . . . . . . . . . . . . . . . . . . Functional Problems in Non-syndromic Craniosynostosis Diagnosis .. . . . . . . . . . . . . . . . . . . . . . . . Treatment: Indication and General Aspects .. . . . . . . . . . . . . . Postoperative Management . . . . . . . . Scaphocephaly .. . . . . . . . . . . . . . . . . . . Trigonocephaly . . . . . . . . . . . . . . . . . . . Plagiocephaly .. . . . . . . . . . . . . . . . . . . . Brachycephaly . . . . . . . . . . . . . . . . . . . . Non-synostotic Occipital Plagio cephaly and Lambdoid Synostosis . . Suggested Reading . . . . . . . . . . . . . . . .

501 501 501 501 501 502

485

. 503 506

506 509 509 511 513 514

515 517

536 537 539 539 539 539 541 541 541 541 541 542 542 542 542 542 543 543

Neuromodulation: Functional and Stereotactic Neurosurgery Edited by Jens Haase 8.1 8.1.1 8.1.1.1 8.1.1.2 8.1.1.3 8.1.1.4 8.1.1.5 8.1.2 8.1.2.1

Epilepsy .. . . . . . . . . . . . . . . . . . . . . . . . . Outcome and Long-Term Perspectives in Epilepsy Surgery .. . . Objective .. . . . . . . . . . . . . . . . . . . . . . . . Modern Literature Review . . . . . . . . . Recent Clinical and Research Development . . . . . . . . . . . . . . . . . . . . . Future Questions and Directions . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . Suggested Reading . . . . . . . . . . . . . . . . Epilepsy: Specific Aspects in Children . . . . . . . . . . . . . . . . . . . . . . . Drug-Resistant Epilepsy . . . . . . . . . . .

547 547 547 547

548 548 548 548

549 549

Contents

8.1.2.2 8.1.2.3 8.2 8.2.1 8.2.2 8.2.3 8.2.3.1 8.2.3.2 8.2.3.3 8.2.3.4 8.2.3.5 8.2.3.6 8.2.4 8.2.4.1 8.2.4.2 8.2.4.3 8.2.5 8.2.6 8.2.6.1 8.2.6.2 8.2.7 8.3 8.3.1 8.3.2 8.3.2.1 8.3.2.2 8.3.2.3 8.3.2.4 8.3.3 8.3.3.1 8.3.3.2 8.3.3.3 8.3.4 8.3.4.1 8.3.4.2 8.3.4.3 8.3.5

Catastrophic Seizures in Infancy and Childhood . . . . . . . . . . . . . . . . . . . 550 Main Etiological Forms .. . . . . . . . . . . 550 Suggested Reading . . . . . . . . . . . . . . . . 557 Pain .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Introduction .. . . . . . . . . . . . . . . . . . . . . Origin of Pain and Pain Phenomena .. . . . . . . . . . . . . . . . . . . . . . Experimental Methods for Pain Evaluation .. . . . . . . . . . . . . . . . . . . . . . . Estimation of Tactile Sensibility – von Frey Hair .. . . . . . . . . . . . . . . . . . . . Pressure Stimulation .. . . . . . . . . . . . . . Thermal Stimulation .. . . . . . . . . . . . . . Electrical Stimulation .. . . . . . . . . . . . . Chemical Stimulation . . . . . . . . . . . . . Temporal Summation . . . . . . . . . . . . . Experimental Methods for Quantitative Sensory Testing .. . . Psychophysical Determinations .. . . . Stimulus–Response Functions . . . . . Pain and Pain Tolerance Thresholds .. . . . . . . . . . . . . . . . . . . . . . . Rating Scales .. . . . . . . . . . . . . . . . . . . . . Conventional Neurophysiologic Techniques . . . . . . . . . . . . . . . . . . . . . . . Neurography .. . . . . . . . . . . . . . . . . . . . . Sensory-Evoked Potentials .. . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . Suggested Reading . . . . . . . . . . . . . . . .

559 559 559 560

560 560 561 561 561 561

562 562 562 562 563

Functional Stereotactic Neurosurgery for Movement Disorders: Deep Brain Stimulation . Introduction . . . . . . . . . . . . . . . . . . . . . Principles of DBS Surgery for Movement Disorders .. . . . . . . . . . Anatomy and Targets .. . . . . . . . . . . . . Hardware . . . . . . . . . . . . . . . . . . . . . . . . Operative Technique . . . . . . . . . . . . . . Hardware-Related Problems .. . . . . . . Patient Selection for Deep Brain Stimulation .. . . . . . . . . . . . . . . . . . . . . . Tremor .. . . . . . . . . . . . . . . . . . . . . . . . . . Parkinson’s Disease .. . . . . . . . . . . . . . . Dystonia . . . . . . . . . . . . . . . . . . . . . . . . . Results of Deep Brain Stimulation for Movement Disorders .. . . . . . . . . . Tremor .. . . . . . . . . . . . . . . . . . . . . . . . . . Parkinson’s Disease .. . . . . . . . . . . . . . . Dystonia . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and Perspectives . . . . . . S uggested Reading . . . . . . . . . . . . . . . .

563 563 563 565 565

567 567 567 567 568 568 571 571 571 572 572 572 572 573 574 574 575

8.4 8.4.1 8.4.2 8.4.3 8.4.3.1 8.4.4 8.4.4.1 8.4.5 8.4.5.1 8.4.5.2 8.4.5.3 8.4.6 8.4.6.1 8.4.6.2 8.4.6.3 8.4.6.4 8.4.7 8.4.7.1 8.4.7.2 8.4.7.3 8.5 8.5.1 8.5.2 8.5.3 8.5.4 8.5.4.1 8.5.4.2 8.5.4.3 8.5.4.4 8.5.4.5 8.5.5 8.6 8.6.1 8.6.2 8.6.3 8.6.4 8.6.5

8.6.6

Functional Applications of Radiosurgery . . . . . . . . . . . . . . . . . . Introduction .. . . . . . . . . . . . . . . . . . . . . Aims .. . . . . . . . . . . . . . . . . . . . . . . . . . . . Technique . . . . . . . . . . . . . . . . . . . . . . . . Indications . . . . . . . . . . . . . . . . . . . . . . . Pain .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Trigeminal Neuralgia .. . . . . . . . . . . . . Psychosurgery . . . . . . . . . . . . . . . . . . . . Indications . . . . . . . . . . . . . . . . . . . . . . . Anatomical Targets . . . . . . . . . . . . . . . Outcome . . . . . . . . . . . . . . . . . . . . . . . . . Movement Disorders . . . . . . . . . . . . . . Indications . . . . . . . . . . . . . . . . . . . . . . . Targets . . . . . . . . . . . . . . . . . . . . . . . . . . . Technique . . . . . . . . . . . . . . . . . . . . . . . . Outcome . . . . . . . . . . . . . . . . . . . . . . . . . Epilepsy .. . . . . . . . . . . . . . . . . . . . . . . . . Rationale .. . . . . . . . . . . . . . . . . . . . . . . . Mesial Temporal Sclerosis .. . . . . . . . . Hypothalamic Hamartoma .. . . . . . . . References .. . . . . . . . . . . . . . . . . . . . . . . Image-Guided Neurosurgery . . . . . . Introduction .. . . . . . . . . . . . . . . . . . . . . Technique of Frameless Neuronavigation . . . . . . . . . . . . . . . . . . Intraoperative Imaging . . . . . . . . . . . . Guidance for Neuronavigation with the BrainLAB VectorVision System . . . . . . . . . . . . . . . . . . . . . . . . . . . Hardware and Software .. . . . . . . . . . . Navigation Planning .. . . . . . . . . . . . . . Marker-Based Registration .. . . . . . . . Patient Registration . . . . . . . . . . . . . . . Navigation – Accuracy .. . . . . . . . . . . . Indication for Neuronavigation .. . . . Suggested Reading . . . . . . . . . . . . . . . . Spasticity and Muscles: Basics for Understanding the Different Treatment Modalities . . . . . . . . . . . . . Introduction .. . . . . . . . . . . . . . . . . . . . . Muscle Stiffness in Sitting Spastic Patients . . . . . . . . . . . . . . . . . . . . . . . . . . The Non-Reflex/Muscle Component .. . . . . . . . . . . . . . . . . . . . . . Reflex-Mediated Mechanical Muscle Responses .. . . . . . . . . . . . . . . . Neuropathology of the Increased Muscle Tone and Exaggerated Stretch Reflex at Rest in Spastic Patients . . . . . . . . . . . . . . . . . . . . . . . . . . The Threshold and Gain of the Pathologic Stretch Reflex .. . . .

577 577 577 577 577 577 577 577 577 577 577 577 578 578 578 578 578 578 578 578 578

579 579 579 580

584 584 584 584 585 585 585 587

591 591 591 592 593

593 593

XVII

XVIII

Contents

8.6.7 8.6.7.1 8.6.7.2 8.6.8

Muscle Stiffness During Walking in Spastic Patients .. . . . . . . . . . . . . . . . The Non-Reflex/Muscle Component .. . . . . . . . . . . . . . . . . . . . . . Muscle Reflexes During Spastic Walking . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Implications . . . . . . . . . . . . . . Suggested Reading . . . . . . . . . . . . . . . .

594 594 594 595 596

Critical Neurosurgical Care Edited by Christianto B. Lumenta 9.1 9.1.1 9.1.2 9.1.3 9.1.3.1 9.1.4 9.1.5 9.1.5.1 9.1.5.2 9.1.5.3 9.1.5.4 9.1.5.5 9.1.6 9.1.7 9.1.8 9.2 9.2.1 9.2.2 9.2.3 9.2.3.1 9.2.3.2 9.2.3.3 9.2.3.4 9.2.4 9.2.4.1 9.2.5 9.2.5.1 9.2.5.2 9.2.5.3

Consciousness Impairment .. . . . . . . Basics . . . . . . . . . . . . . . . . . . . . . . . . . . . . Definition of Consciousness .. . . . . . . Morphologic Correlate of Consciousness . . . . . . . . . . . . . . . . . . . . The Activating Reticular Ascending System .. . . . . . . . . . . . . . . . Mechanisms of Alterations in the State of Consciousness .. . . . . . Grading of Disturbances of Consciousness . . . . . . . . . . . . . . . . . Clouding of Consciousness . . . . . . . . Lethargy .. . . . . . . . . . . . . . . . . . . . . . . . . Obtundation .. . . . . . . . . . . . . . . . . . . . . Stupor .. . . . . . . . . . . . . . . . . . . . . . . . . . . Coma .. . . . . . . . . . . . . . . . . . . . . . . . . . . Grading of Coma .. . . . . . . . . . . . . . . . . Frequent Neurosurgical Causes of Altered Consciousness . . . . . . . . . . Approach to the Comatose Patient . . . . . . . . . . . . . . . . . . . . . . . . . . .

601 601 601

Intracranial Hypertension .. . . . . . . . Basics . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology . . . . . . . . . . . . . . . . . . Measurement Devices for Intracranial Pressure . . . . . . . . . . . Ventricular ICP Devices . . . . . . . . . . . Parenchymal ICP Devices .. . . . . . . . . Devices for Concurrent ICP Measurement and CSF Drainage .. . . European Standard . . . . . . . . . . . . . . . Selection of Patients for ICP Measurement . . . . . . . . . . . . . . . . . . . . . European Standard .. . . . . . . . . . . . . . . Treatment of Increased Intracranial Pressure . . . . . . . . . . . . . . Body Position .. . . . . . . . . . . . . . . . . . . . Sufficient Anesthesia and Analgesia .. . . . . . . . . . . . . . . . . . . . Drainage of Cerebrospinal Fluid .. . .

605 605 605

601 601 602

602 602 602 602 603 603 603

603 603

606 607 607 607 607 607 607 607 608 608 608

9.2.5.4 9.2.5.5 9.2.5.6 9.2.5.7 9.2.5.8 9.2.5.9 9.3 9.3.1 9.3.2 9.3.2.1 9.3.2.2 9.3.2.3 9.3.3 9.3.4 9.3.4.1 9.3.4.2 9.3.5 9.3.6 9.3.6.1 9.3.6.2 9.3.7 9.3.8 9.3.9 9.3.10 9.3.11 9.3.12 9.3.13 9.4 9.4.1 9.4.2 9.4.2.1 9.4.2.2 9.4.2.3 9.4.3 9.4.3.1 9.4.3.2 9.4.4 9.4.4.1

Cerebral Perfusion Pressure .. . . . . . . Moderate Hyperventilation . . . . . . . . Osmotherapeutics: Mannitol and Hypertonic Saline (NaCl 7.5%) . Barbiturates .. . . . . . . . . . . . . . . . . . . . . . Moderate Hypothermia .. . . . . . . . . . . Decompressive Craniectomy . . . . . . .

608 609

609 609 609 610

Water and Electrolyte Regulation . Introduction .. . . . . . . . . . . . . . . . . . . . . Basics . . . . . . . . . . . . . . . . . . . . . . . . . . . . Body Water . . . . . . . . . . . . . . . . . . . . . . Electrolytes .. . . . . . . . . . . . . . . . . . . . . . Osmolarity, Osmolality and Tonicity . . . . . . . . . . . . . . . . . . . . . . Regulation of Body Water and Osmolarity . . . . . . . . . . . . . . . . . . . Regulation of Sodium . . . . . . . . . . . . . The Renin–Angiotensin– Aldosterone System . . . . . . . . . . . . . . . Atrial Natriuretic Peptide (ANP) . . . Regulation of Potassium . . . . . . . . . . . Fluid Regulation in the Brain .. . . . . . The Blood–Brain Barrier .. . . . . . . . . . Fluid Regulation in the Brain with a Damaged Blood–Brain Barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . Changes of Sodium and Water Balance Following Surgery .. . . . . . . . Hypernatremia .. . . . . . . . . . . . . . . . . . . Hyponatremia . . . . . . . . . . . . . . . . . . . . Diabetes Insipidus .. . . . . . . . . . . . . . . . Syndrome of Inadequate ADH Secretion . . . . . . . . . . . . . . . . . . . . . . . . . Cerebral Salt-Wasting Syndrome . . . Differences Between CSWS and SIADH .. . . . . . . . . . . . . . . . . . . . . .

611 611 611 611 611

Temperature Regulation . . . . . . . . . . Introduction .. . . . . . . . . . . . . . . . . . . . . Normal Control of Thermoregulation .. . . . . . . . . . . . . . The Thermoafferent System . . . . . . . . The Integrating System . . . . . . . . . . . . The Effector System . . . . . . . . . . . . . . . Disturbances of Thermoregulation .. . . . . . . . . . . . . . . . Central Disturbances of Temperature Regulation .. . . . . . . . Effects of Anesthetics on Temperature Regulation . . . . . . . . Perioperative Hypothermia . . . . . . . . Early Changes of Body Temperature During Anesthesia .. . .

617 617

611 611 612

613 613 613 613 613

613

613 614 614 614

614 615 615

617 617 617 617

617 617 618 618 618

Contents

9.4.4.2 9.4.4.3 9.4.4.4 9.4.5 9.4.6 9.4.6.1 9.4.7

Late Changes of Body Temperature During Anesthesia .. . . Pathophysiological Effects of Hypothermia .. . . . . . . . . . . . . . . . . . Therapy and Prevention of the Perioperative Hypothermia Syndrome . . . . . . . . . . . . . . . . . . . . . . . . Drug-Induced Thermoregulation Imbalances . . . . . . . . . . . . . . . . . . . . . . . Hyperthermia .. . . . . . . . . . . . . . . . . . . . Malignant Hyperthermia . . . . . . . . . . Fever .. . . . . . . . . . . . . . . . . . . . . . . . . . . .

Respiration .. . . . . . . . . . . . . . . . . . . . . . Basics . . . . . . . . . . . . . . . . . . . . . . . . . . . . Central Disturbances of Breathing . Central Breathing Patterns .. . . . . . . . Cheyne–Stokes Respiration . . . . . . . . Apneustic Cluster and Ataxic Breathing .. . . . . . . . . . . . . . . . . . . . . . . . 9.5.3.3 Central Hyperventilation . . . . . . . . . . 9.5.3.4 Agonal Gasping .. . . . . . . . . . . . . . . . . . 9.5.4 Gas Exchange .. . . . . . . . . . . . . . . . . . . . 9.5.5 Indications for Intubation and Mechanical Ventilation . . . . . . . . 9.5.5.1 Intubation .. . . . . . . . . . . . . . . . . . . . . . . 9.5.5.2 Ventilation . . . . . . . . . . . . . . . . . . . . . . . 9.5.5.3 Tracheostomy .. . . . . . . . . . . . . . . . . . . . 9.5.5.4 When Not to Intubate . . . . . . . . . . . . . 9.5.6 Principal Modes of Mechanical Ventilation .. . . . . . . . . 9.5.6.1 Volume-Controlled Ventilation .. . . . 9.5.6.2 Pressure-Controlled Ventilation . . . . 9.5.6.3 Combined Ventilation Modes . . . . . . 9.5.6.4 Biphasic Positive Airway Pressure Ventilation . . . . . . . . . . . . . . . . . . . . . . . 9.5.7 Positive End-Expiratory Pressure .. . 9.5.8 Recommended Ventilator Settings for the Neurosurgical Patient .. . . . . . 9.5.8.1 Acute Lung Injury in Neurosurgical Patients . . . . . . . . . . 9.5.9 Side Effects of Mechanical Ventilation . . . . . . . . . . . . . . . . . . . . . . . 9.5.9.1 Effects on the Cardiovascular System . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.5.9.2 Effects of Mechanical Ventilation on the Kidneys .. . . . . . . . . . . . . . . . . . . 9.5.9.3 Effects of Mechanical Ventilation on the Digestive Organs . . . . . . . . . . . 9.5.9.4 Effects of Mechanical Ventilation on the Brain . . . . . . . . . . . . . . . . . . . . . . 9.5.10 Weaning from the Respirator . . . . . . 9.5.10.1 Prerequisites for Weaning in Neurosurgical Patients . . . . . . . . . . 9.5 9.5.1 9.5.2 9.5.3 9.5.3.1 9.5.3.2

618 618 618

9.5.10.2 Methods of Weaning from the Respirator . . . . . . . . . . . . . . . . . . . . 625 9.5.11 Extubation Criteria .. . . . . . . . . . . . . . . 625 9.6 9.6.1 9.6.2

618 618 618 619

9.6.3 9.6.4

621 621 621 621 621

621 621 621 622

9.6.6 9.6.6.1 9.6.6.2 9.6.6.3 9.6.6.4 9.6.6.5 9.6.6.6

622 622 622 622 623

623 623 623 623

623 623 624 624 624 624 624 624 624 625 625

9.6.5

9.7 9.7.1 9.7.1.1 9.7.2 9.7.2.1 9.7.2.2 9.7.2.3 9.7.2.4 9.7.3 9.7.3.1 9.7.3.2 9.7.3.3 9.7.3.4 9.7.4 9.7.4.1 9.7.4.2 9.7.4.3 9.7.4.4 9.8 9.8.1 9.8.2 9.8.3 9.8.3.1 9.8.3.2

Nutrition .. . . . . . . . . . . . . . . . . . . . . . . . Basics . . . . . . . . . . . . . . . . . . . . . . . . . . . . Effect of Nutrition on the Immune System and Outcome .. . . . . . . . . . . . . Effects of Stress and Malnutrition .. . Assessment of the Nutritional Need .. . . . . . . . . . . . . . . . . . . . . . . . . . . . When to Start Nutrition and How? . . . . . . . . . . . . . . . . . . . . . . . . What to Feed? . . . . . . . . . . . . . . . . . . . . Carbohydrates . . . . . . . . . . . . . . . . . . . . Protein .. . . . . . . . . . . . . . . . . . . . . . . . . . Lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . Immunonutrition . . . . . . . . . . . . . . . . . Vitamins and Trace Elements .. . . . . . Glucose Control .. . . . . . . . . . . . . . . . . . Multiresistant Infections in Neurointensive Care Patients . . . Basics . . . . . . . . . . . . . . . . . . . . . . . . . . . . Common Measures .. . . . . . . . . . . . . . . Methicillin-Resistant Staphylococcus aureus .. . . . . . . . . . . . Epidemiology .. . . . . . . . . . . . . . . . . . . . Clinical Significance .. . . . . . . . . . . . . . Diagnosis and Screening for MRSA . . . . . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . Vancomycin-Resistant Enterococcus . . . . . . . . . . . . . . . . . . . . . . Epidemiology .. . . . . . . . . . . . . . . . . . . . Clinical Significance .. . . . . . . . . . . . . . Diagnosis .. . . . . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . Extended Spectrum BetaLactamase-Induced Resistance .. . . . Epidemiology .. . . . . . . . . . . . . . . . . . . . Clinical Significance .. . . . . . . . . . . . . . Diagnosis .. . . . . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . Specific Aspects of Critical Care for Children .. . . . . . . . . . . . . . . . . . . . . Basics . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acute Pain Assessment in Paediatric Patients . . . . . . . . . . . . . . Post-operative Pain Management .. . By the Patient .. . . . . . . . . . . . . . . . . . . . By the Ladder .. . . . . . . . . . . . . . . . . . . .

627 627 627 627 627

627 628 628 628 628 628 628 628

631 631 631 631 631 631 632 632

632 632 632 632 632

632 632 633 633 633

635 635

635 636 636 636

XIX

Contents

9.8.4 9.8.4.1 9.8.4.2 9.8.4.3 9.8.4.4

Pharmacological Classification of Analgesic Drugs . . . . . . . . . . . . . . . . Non-opioid Analgesics . . . . . . . . . . . . Opioid Analgesics .. . . . . . . . . . . . . . . . Adjuvant Analgesics .. . . . . . . . . . . . . . Topical Analgesics .. . . . . . . . . . . . . . . .

638 638 638 640 640

9.8.5 9.8.6

Patient-Controlled Analgesia .. . . . . 641 Conclusions and Perspectives . . . . . . 641 Suggested Reading . . . . . . . . . . . . . . . . 641

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643

XXI

List of Contributors

Abrahamsen, Jan Department of Clinical Physiology Regionshospitalet Viborg Postboks 130 8800 Viborg Denmark E-mail: [emailprotected]

Bertalanffy, Helmut Department of Neurosurgery University Hospital Zurich Frauenklinikstrasse 10 8091 Zurich Switzerland E-mail: [emailprotected]

Arendt-Nielsen, Lars Center for Sensory-Motor Interaction Laboratory for Experimental Pain Research Institute for Heath Science and Technology Fredrik Bajersvej 7, D3 9220 Aalborg Denmark E-mail: [emailprotected]

Biering-Sørensen, Fin Righospitalet Blegdamsvej 9 2100 Copenhagen Denmark E-mail: [emailprotected]

Arnaud, Eric Craniofacial Unit Department of Paediatric Neurosurgery Hôpital Necker – Enfants Malades, Paris René Descartes University Paris France E-mail: [emailprotected] Battaglia, Domenica I. Pediatric Neurology Catholic University Medical School Rome Italy E-mail: [emailprotected] Beneš, Vladimir Department of Neurosurgery Central Military Hospital U Vojenske nemocnice 1200 16902 Prague 6 Czech Republic E-mail: [emailprotected]

Caldarelli, Massimo Department of Pediatric Neurosurgery Catholic University Medical School Largo A. Gemelli 8 00168 Rome Italy E-mail: [emailprotected] Capelle, Hans-Holger Department of Neurosurgery Medical School Hannover (MHH) Hannover Germany E-mail: [emailprotected] Chiaretti, Antonio Pediatric Intensive Care Unit Catholic University Medical School Largo A. Gemelli 8 00168 Rome Italy E-mail: [emailprotected]

XXII

List of Contributors

Cioni, Beatrice Istituto di Neurochirurgica Università Cattolica del Sacro Cuore, Policlinico Gemelli Largo Gemelli 8 00168 Rome Italy E-mail: [emailprotected]

George, Bernard Department of Neurosurgery Hôpital Lariboisière 2 rue Ambroise Paré 75475 Paris France E-mail: [emailprotected]

Di Rocco, Concezio Istituto di Neurochirurgica Università Cattolica del Sacro Cuore, Policlinico Gemelli Largo A. Gemelli 8 00168 Rome Italy E-mail: [emailprotected]

Gerlach, Rüdiger Klinik für Neurochirurgie Johann Wolfgang Goethe-Universität Schleusenweg 2–16 60528 Frankfurt/Main Germany E-mail: [emailprotected]

Di Rocco, Federico Department of Paediatric Neurosurgery Hôpital Necker – Enfants Malades, Paris René Descartes University Paris France E-mail: [emailprotected]

Gjerris, Flemming Department of Neurosurgery Rigshospitalet Blegdamsvej 9 2100 Copenhagen Denmark E-mail: [emailprotected]

Espinosa de Rueda Ruiz, Mariano Regional Unit of Interventional Neuroradiology, Servicio de Radiodiagnóstico Hospital Universitario Virgen de la Arrixaca 30120 El Palmar, Murcia Spain E-mail: [emailprotected]

Grill, Jacques Pediatric Oncology Department Institut Gustave Roussy Villejuif France E-mail: [emailprotected]

Fuglsang-Frederiksen, Anders Department of Clinical Neurophysiology Aarhus University Hospital Norrebrogade 44, Building 10 8000 Aarhus C Denmark E-mail: [emailprotected] Garnett, Matthew Department of Paediatric Neurosurgery Hôpital Necker – Enfants Malades, Paris René Descartes University Paris France Genovese, Orazio Pediatric Intensive Care Unit Catholic University Medical School Largo A. Gemelli 8 00168 Rome Italy E-mail: [emailprotected]

Gumprecht, Hartmut Department of Neurosurgery Bogenhausen Academic Teaching Hospital Technical University of Munich Englschalkinger Straße 77 81925 Munich Germany E-mail: [emailprotected] [emailprotected] Haase, Jens Institute of Health Science and Technology, Faculties of Engineering, Science and Medicine Aalborg University Fredrik Bajers vej 7 D3 9220 Aalborg East Denmark E-mail: [emailprotected]

List of Contributors

Hänggi, Daniel Vaskuläre Neurochirurgie und Schädelbasischirurgie Neurochirurgische Klinik Heinrich Heine Universität Düsseldorf Moorenstraße 5 40225 Düsseldorf Germany E-mail: [emailprotected] Hansen, Peter Orm Department of Clinical Neurophysiology Aarhus University Hospital Norrebrogade 44, Building 10 8000 AarhusC Denmark E-mail: [emailprotected] Hassler, Werner-Erwin Neurochirurgische Klinik Klinikum Duisburg gGmbH Zu den Rehwiesen 9 47055 Duisburg Germany E-mail: [emailprotected] Holm, Ida E. Department of Pathology Aalborg University Hospital Reberbanegade 9000 Aalborg Denmark E-mail: [emailprotected] Hoving, Eelco Department of Neurosurgery University of Groningen Medical Centre UMCG POB 30001 9700 RB Groningen The Netherlands E-mail: [emailprotected] Journée, H.L. Department of Neurosurgery University of Groningen Medical Centre (UMCG) PO Box 30001 9700 RB Groningen The Netherlands E-mail: [emailprotected] Kaech, Denis L. Department of Neurosurgery Kantonsspital Graubünden 7000 Chur Switzerland E-mail: [emailprotected]

Kemeny, Andras National Centre for Stereotactic Radiosurgery Sheffield U.K. E-mail: [emailprotected] Kiwit, Jürgen Neurochirurgische Klinik HELIOS Klinikum Berlin Schwanebecker Chaussee 50 13125 Berlin E-mail: [emailprotected] Klekamp, Jörg Department of Neurosurgery Christliches Krankenhaus Quakenbrück e.V. Danziger Straße 2 49610 Quakenbrück Germany E-mail: [emailprotected] Krammer, Matthias J. Department of Neurosurgery Bogenhausen Academic Teaching Hospital Technical University of Munich Englschalkinger Straße 77 81925 München Germany E-mail: [emailprotected] Krauss, Joachim K. Department of Neurosurgery Medical School Hannover Carl-Neuberg-Str. 1 30625 Hannover Germany E-mail: [emailprotected] Lange, Bent Ortopaedkirurgien Dronninglund Sygehus Noerregade 19 9310 Dronninglund Denmark E-mail: [emailprotected] Lasjaunias, Pierre † Centre Hôpitalier Université de Bicêtre Departement de Neuroradiologie et Therapeutique 78 Rue du Général Leclerc 94275 Le Kremlin-Bicêtre France

XXIII

XXIV

List of Contributors

Lindsay, Ken 14 Kenmure Road Giffnock, Glasgow, G46 6TU UK E-mail: [emailprotected] Lumenta, Christianto B. Department of Neurosurgery Bogenhausen Academic Teaching Hospital Technical University of Munich Englschalkinger Straße 77 81925 München Germany E-mail: [emailprotected] Marquardt, Gerhard Neurosurgical Clinic Goethe-University Schleusenweg 2-16 60528 Frankfurt am Main Germany Martínez-Lage, Juan F. Regional Service of Neurosurgery Virgen de la Arrixaca University Hospital E-30120 El Palmar, Murcia Spain E-mail: [emailprotected] Massimi, Luca Department of Pediatric Neurosurgery Catholic University Medical School Largo A. Gemelli 8 00168 Rome Italy E-mail: [emailprotected] Mathijssen, Irene Department of Plastic and Reconstructive Surgery Erasmus University Medical Centre Rotterdam Rotterdam The Netherlands E-mail: [emailprotected] Mennel, H.D. Department of Neuropathology Medical Center of Pathology Philipps-University Marburg Baldingerstraße 35043 Marburg Germany E-mail: [emailprotected]

Miller, Dorothea Klinik für Neurochirurgie Universitätsklinikum Essen Hufelandstraße 55 45147 Essen Germany E-mail: [emailprotected] Mooij, Jan Jakob A. Department of Neurosurgery University of Groningen Medical Centre UMCG PO Box 30.001 9700 RB Groningen The Netherlands E-mail: [emailprotected] Moreno Diéguez, Antonio Regional Unit of Interventional Neuroradiology, Servicio de Radiodiagnóstico Hospital Universitario Virgen de la Arrixaca 30120 El Palmar, Murcia Spain E-mail: [emailprotected] Pamir, M. Necmettin Department of Neurosurgery Acibadem Hospital Kozyatagi Inönü Cad Okur Sok 20 Kozytagi 34742 Istanbul Turkey E-mail: [emailprotected] Parrilla Reverter, Guillermo Regional Unit of Interventional Neuroradiology, Servicio de Radiodiagnóstico Hospital Universitario Virgen de la Arrixaca 30120 El Palmar, Murcia Spain E-mail: [emailprotected] Pérez-Espejo, Miguel Angel Regional Service of Neurosurgery Virgen de la Arrixaca University Hospital Murcia Spain E-mail: [emailprotected] Piastra, Marco Pediatric Intensive Care Unit Catholic University Medical School Rome Italy E-mail: [emailprotected]

List of Contributors

Piek, Jürgen Abteilung für Neurochirurgie Chirurgische Universitätsklinik Rostock Postfach 10 08 88 18057 Rostock, MV Germany E-mail: [emailprotected]

Ridola, Vita Division of Pediatric Oncology Catholic University Medical School Largo A. Gemelli 8 00168 Rome Italy E-mail: [emailprotected]

Pietrini, Domenico Pediatric Intensive Care Unit Catholic University Medical School Rome Italy E-mail: [emailprotected]

Romano, Dario Institute of Neurosurgery Catholic University of Rome Largo A. Gemelli 8 00168 Rome Italy E-mail: [emailprotected]

Popovic, Dejan B. Center for Sensory and Motor Interaction (SMI) Department of Health Sciences and Technology Aalborg University Denmark E-mail: [emailprotected] Puget, Stephanie Department of Paediatric Neurosurgery Hôpital Necker – Enfants Malades, Paris René Descartes University Paris France Rampling, Roy P. Beatson Oncology Centre Western Infirmary Glasgow, G11 6NT UK E-mail: [emailprotected] Renier, Dominique Department of Paediatric Neurosurgery Hôpital Necker – Enfants Malades, Paris René Descartes University Paris France E-mail: [emailprotected] Reulen, Hans-Jürgen Schwojerstraße 19 81249 München Germany E-mail: [emailprotected]

Roujeau, Thomas Department of Paediatric Neurosurgery Hôpital Necker – Enfants Malades, Paris René Descartes University Paris France Sainte-Rose, Christian Department of Pediatric Neurosurgery Hopital Necker – Enfants Malades 149, rue de Sèvres 75743 Paris Cedex 15 France E-mail: [emailprotected] Schick, Uta Neurochirurgische Klinik Klinikum Duisburg gGmbH Zu den Rehwiesen 9 47055 Duisburg Germany E-mail: [emailprotected] [emailprotected] Schmid-Elsaesser, R. † Neurochirurgische Klinik und Poliklinik Klinikum der Universität München-Großhadern Marchioninistraße 15 81377 Munich Germany Schürer, Ludwig Department of Neurosurgery Bogenhausen Academic Teaching Hospital Technical University of Munich Englschalkinger Str. 77 D-81925 München Germany E-mail: [emailprotected]

XXV

XXVI

List of Contributors

Seifert, Volker Department of Neurosurgery University Hospital Johann-Wolfgang-Goethe University Schleusenweg 2–16 60528 Frankfurt Germany E-mail: [emailprotected]

Trost, Hans Axel Klinik für Neurochirurgie Klinikum Bayreuth GmbH – Betriebsstätte Hohe Warte Hohe Warte 8 95445 Bayreuth Germany E-mail: [emailprotected]

Sinkjaer, Thomas The Danish National Research Foundation Holbergsgade 14, 1. sal 1057 Copenhagen K Denmark E-mail: [emailprotected]

van den Bent, Martin J. Neuro-Oncology Unit Daniel den Hoed Oncology Center PO Box 5201 3008 AE Rotterdam The Netherlands E-mail: [emailprotected]

Steiger, Hans-Jakob Department of Neurosurgery Heinrich-Heine-University Düsseldorf Moorenstraße 5 40225 Düsseldorf Germany E-mail: [emailprotected] Suchomel, Petr Department of Neurosurgery Neurocenter, Regional Hospital Husova Street, 10 46063 Liberec Czech Republic E-mail: [emailprotected]; [emailprotected] Sure, Ulrich Klinik für Neurochirurgie Universitätsklinikum Essen Hufelandstraße 55 45122 Essen Germany E-mail: [emailprotected] Tamburrini, Gianpiero Department of Pediatric Neurosurgery Catholic University Medical School Largo Gemelli 8 Rome Italy E-mail: [emailprotected] Thompson, Dominic N.P. Department of Neurosurgery Great Ormond Street Hospital London UK E-mail: [emailprotected]

van Dijk, J. Marc C. Department of Neurosurgery University of Groningen Medical Centre UMCG POB 30.001 9700 RB Groningen The Netherlands E-mail: [emailprotected] van Veelen-Vincent, Marie Lise C. Department of Pediatric Neurosurgery Sophia Children’s Hospital Erasmus University Medical Centre Rotterdam Dr. Molewaterplein 60 Rotterdam The Netherlands E-mail: [emailprotected] Visocchi, Massimiliano Institute of Neurosurgery Catholic University Rome Largo A. Gemelli 8 00168 Rome Italy E-mail: [emailprotected] Westphal, Manfred Neurochirurgische Klinik Universitäts-Krankenhaus Eppendorf Martinistraße 52 20246 Hamburg Germany E-mail: [emailprotected]

List of Contributors

Wolf, Stefan Department of Neurosurgery Bogenhausen Academic Teaching Hospital Technical University of Munich Englschalkinger Str. 77 D-81925 München Germany E-mail: [emailprotected] Zamarro Parra, Joaquín Regional Unit of Interventional Neuroradiology, Servicio de Radiodiagnóstico Hospital Universitario Virgen de la Arrixaca 30120 El Palmar, Murcia Spain E-mail: [emailprotected] [emailprotected]

Zerah, Michel Department of Paediatric Neurosurgery Hôpital Necker – Enfants Malades, Paris René Descartes University Paris France

XXVII

1.1 Introduction to Neurosurgery Christianto B. Lumenta

Neurosurgery is defined as a special field of operative treatment of space-occupying lesions, such as tumors, infection, or hematomas, malformations, degenerative changes, injuries, and other surgically reachable entities of the central, peripheral, and vegetative nervous system and the associated necessary diagnostic procedures. Modern neurosurgery is count as one of the newer fields of medicine, comparable to the fields of urology, orthopedic surgery, or vascular surgery which are now separated from the field of “general surgery” [1]. Nevertheless, the beginnings of neurosurgery go back to Stone Age times. Old Egyptian medicine had experience of and treatment guidelines for skull diseases 3,000 years bc. Since the middle of the nineteenth century archeologists have found, in different parts of the world, the remains of human skulls that have undergone trepanation and show evidence that the individuals have survived the procedure. Probably the procedures were for ritual purposes or for the treatment of some head injuries. Surgery on the nervous system, however, was reserved for more recent times. In the second half of the nineteenth century topographic anatomy was introduced after the development of asepsis and anesthesia. The first successful brain surgery was performed by R.Godlee in 1884, while, one year before, McEwen had removed a spinal tumor. Modern neurosurgery could be realized after the development of examination methods such as myelography by W.Dandy in 1919, cerebral angiography by E.Moniz in 1927, electroencephalography by Berger in 1927, and echoencephalography by Leksell in 1953. With the beginning of the computer era in the 1970s, computed tomography was developed by Ambrose and Hounsfield, followed by magnetic resonance imaging (MRI) with the

possibility for functional MRI, MRI spectroscopy, depiction of the pyramidal tract, and so on. The results of brain surgery were improved after the introduction of clips and diathermy by Cushing at the beginning of the twentieth century. Modern neurosurgery, however, began with the introduction of the microscope, modern anesthesiology, and neurointensive management. Progress continued with the development of the ultrasonic aspirator, laser technology, neuroendoscopy, neuronavigation, and image-guided surgery. Functional neurosurgery for the treatment of pain and movement disorders changed from ablative procedures to electrode stimulation techniques. Despite these rapid advances, in the last two decades the special field of neurosurgery has had to compete with other disciplines in the treatment of some conditions, such as stereotactic radiosurgery for the treatment of arteriovenous malformations (AVM) or small and well-defined brain tumors (metastasis, vestibular schwannoma, etc.), and endovascular neuroradiology for the treatment of intracranial aneurysms and AVM. Nanotechnology and molecular biology will bring in alternative treatments for many neurooncologic diseases. The most difficult cases, however, will be reserved for the neurosurgeon. As a consequence of all these developments, it is very important to have standards in the training of neurosurgical residents and in basic training for the technical skills. References 1. Reinbek (1991) Stammbaum der Medizin. Einhorn-Presse, Hamburg

2.1 Training in Neurosurgery Hans-Jürgen Reulen

2.1.1

Introduction

National authorities and professional bodies have the responsibility for monitoring and recognising training institutions and to provide certification or recognition of medical specialists. The European Union of Medical Specialists (UEMS) is the responsible authority in the EU for harmonisation and improvement of the quality of training of medical specialists. Harmonisation is a necessary prerequisite to enable free movement of medical specialists in the countries of the EU. The European Neurosurgical Training Charter of the UEMS [1] summarises the requirements and standards for training in neurosurgery. National organisations are strongly recommended to adopt these requirements in their national guidelines. In the following, all referrals are made to the European Neurosurgical Training Charter. Departments in the process of developing or improving their training programme may find comprehensive information in Training in neurosurgery in the countries of the EU, a guide to organize a training program [2].

2.1.2 Goals of a Neurosurgical Training Programme The main goal is to provide a trainee with a broad knowledge base, the necessary operative and procedural skills and experiences, as well as professional judgement as preparation for independent neurosurgical practice. Further goals are to teach self-criticism, critical assessment of his/her results, and the ability to undertake self-directed learning, which will eventually lead to continued expert practice and professionalism.

Of these four years at least three years should be spent in a UEMS member state and not less than three years in the same recognised programme. Training must include adequate exposure to intensive care and to paediatric neurosurgery. Because of the future reduction in the hours of work there may be a need to extend the training time in clinical neurosurgery from four to five years. Up to a total of two years may be spent in related disciplines (in a surgical discipline, neurology, neuropaediatrics, neuroradiology, neuropathology, neurophysiology) and/or activities including research in neurosciences.

2.1.4 Contents of Training The contents of training are described in the classical textbooks, encompassing knowledge in: • General basics of surgery • Complete neurological investigation tests and procedures • Neurosurgical diseases, their diagnosis, prognosis, treatment indications, and their operative and nonoperative treatment (including intensive care and possible complications) • Conservative and operative treatment of head injuries and the spine/spinal cord • Microsurgical operative techniques and neuronavigation • Indications for and the interpretation of modern neuroradiological examination techniques (CT, MRI, myelography, angiography), as well as Doppler sonography and ultrasound • Quality control (morbidity and mortality conference, infection control, risk management)

2.1.5 The Training Programme 2.1.3 Length of Training Neurosurgical training requires a minimum duration of six years which includes a minimum of four years training in clinical neurosurgery in an accredited programme.

• There should be a written Training Curriculum describing the contents and aims in each year of training. A structured Surgical Training Plan can be helpful to provide a systematic escalation of surgical competence

2.1 Training in Neurosurgery

•

• •

•

and responsibilities. Emphasis should be placed on adequate time allocated for study and tuition independent of clinical duties. There should be established Rotation Periods covering all main areas of neurosurgery. Each rotation should have clearly defined goals with regard to responsibilities in patient care, knowledge and operative experience. During each rotation a trainee should be assigned to a specific trainer. There should be a documented Education Programme with lectures, clinical presentations, neuropathological and neuroradiological conferences, a journal club, a morbidity and mortality conference, teaching meetings including subspecialties, and teaching in ethics, administration, management and economics. It is recommended that trainees participate at least once a year in a national/European training course, in a hands-on course or a national neurosurgical meeting, respectively. Each trainee must keep an authorised logbook (meeting the standards of the UEMS/European Association of Neurosurgical Societies [EANS] logbook) for documentation of his/her operative experience. The trainee will have to demonstrate that he/she has assisted in a wide range of cases, which should include a balance of trainer-assisted and personal cases under supervision. The logbook must be supervised and signed regularly by the respective trainer, and it must be available at Board examination. Trainees should be encouraged to participate in research and to develop an understanding of research methodology. In academic programmes, clinical and/ or basic research opportunities must be available to trainees with appropriate faculty supervision.

2.1.6 The Training Institution A training institution must have national recognition in accordance with the standards of the UEMS Training Charter. Participation of training institutions in the European accreditation process at present is voluntary and, if compliant, indicates that the department and the training programme fulfil the European Standards of Excellence for Education in Neurosurgery. Units that cannot comply with the minimum standards of the UEMS Training Charter (case volume and mixture, number of trainers and beds, etc. as listed below) and cannot offer the full spectrum of neurosurgery cannot be training centres on their own. It is recommended that they develop a common training programme in cooperation with a larger department. Highly specialised centres can be included in the rotation of a recognised training centre.

2.1.6.1

Requirements for Training Institutions with Regard to Equipment and Educational Facilities

• There must be a referral base sufficient to provide an adequate case volume and mixture to support the training programme. • There must be a minimum of four trainers (including the chairman/programme director). • There must be at least 30 neurosurgical beds and in addition critical care beds (7–10/million population). • There must be at least two designated, fully staffed operating theatres (neurosurgically trained staff), appropriately equipped and with 24-h availability. • There must be an operating microscope with CCTV for each theatre. The following are deemed essential equipment: ultrasonic aspirator, image guidance and/ or ultrasound, a stereotactic system, radiological imaging, and endoscopy equipment. • Neurosurgical theatres should be covered by anaesthetists with a special interest in neuroanaesthesia. Anaesthesia coverage should be available at all times for neurosurgery. • There must be designated and fully staffed neurosurgical intensive care beds. Neurosurgical intensive care may be managed by neurosurgery or there may be joint responsibility between neurosurgery and anaesthesia. • There must be an emergency unit with 24-h admission. • There must be outpatient clinics where non-emergency patients are seen before and after surgery. • There must be exposure to paediatric neurosurgery as a mandatory component of a training programme. Where this does not form part of the routine work of a neurosurgical department, a 6-month secondment to an appropriate programme should be arranged (It must be recognised that in some European countries paediatrics requires special training and a protected environment). • There should be opportunity to obtain experience in functional neurosurgery either within the department or in another neurosurgical department specialising in this field. • All main specialities (neurology, surgery/traumatology, anaesthesiology, radiology, neuroradiology, neuropathology, radiotherapy, internal medicine, paediatrics) must be present to provide the trainee with the opportunity of developing his/her skills in a team approach to patient care. • There should be an easily accessible library, with an adequate selection of books and journals on neurosurgery, as well as facilities for computer literature searches.

2.1.6 The Training Institution

2.1.6.2

Institutional Quality Management Provisions

A training institution must have an internal system of quality assurance. There should be written guidelines concerning patient care and patient information (patient’s consent), referrals, medical records, documentation, oncall and back-up schedules, days off, residents’ working schedules, attendance at conferences and educational activities). An example may be found in [2]. There must be a structured procedure for the reporting of adverse events in the form of a mortality and morbidity conference; and the hospital should have an infection control committee and a drugs and therapeutics committee. 2.1.6.3

Responsibilities of a Training Programme Director

The training programme director does not need to be the head of the training institution. He/she must be a certified specialist of a minimum of five years, and demonstrate evidence of continuing professional development. The Programme Director must establish a transparent and fair appointment process for trainees. A training agreement (contract) should be completed and signed by the director and the trainee at the beginning of training. The programme director should provide the trainee with a written Training Curriculum of his/her training (see Sect.2.1.5). The promotion of an ethos of a high level of professional conduct and ethics within the training programme is essential. The programme director has to: • Organise and coordinate a balanced training programme with established rotations ensuring that the trainee will have exposure to all aspects of neurosurgery. The programme must be written and available to trainees and trainers. • Ensure that there is dedicated time allocated to the trainers for training and that the trainers fulfil their training responsibilities. • Ensure that there is dedicated time for trainees to attend educational meetings and approved courses, and that trainees can fulfil all training obligations. • Ensure that the individual trainee’s documentation (training portfolio) is up to date. • Organise a transparent and fair semi-annual progress evaluation of trainees. • Provide valid documentation as to satisfactory completion of training.

2.1.6.4

Responsibilities of Trainers

Trainers should be certified specialists and possess the necessary administrative, teaching and clinical skills, and commitment to instruct and support their trainees. They have to: • Set realistic aims and objectives for a rotation period • Supervise the day-to-day work of the trainee on the ward, in the outpatient clinic and in the operating theatre • Support the trainee’s operative and clinical progress and provide feedback • Assess and report on the trainee’s progress at the end of each rotation (progress evaluation) • Inform the programme director of problems at an early stage 2.1.6.5

Requirements for Trainees

• Trainees during their training must be exposed to at least four different trainers and the full spectrum of neurosurgical procedures. • The attached Operative List (Appendix1) summarises the minimal and optimal numbers of so-called key procedures that trainees should have performed on completion of training. In addition to this mandatory list of operative procedures, the trainee should have assisted in or partly performed operations for pituitary adenomas, complex basal meningiomas, aneurysms, arteriovenous malformations, acoustic neurinomas, paediatric procedures, intramedullary tumours, etc. (see assistant figures in Appendix1) [3]. • Trainees should be directly involved in the pre- and postoperative management of these patients and should have a detailed understanding of the preoperative investigations. • Many of the above procedures demand the use of the operating microscope that the trainee must be fully familiar with. • The trainee must learn to record and document patient history, examinations and investigative findings, obtain patients’ consent for operative procedures, clearly detailing the reasons for performing the procedure and the risks involved, as well as learn to communicate with patients and relatives and pass on distressing information (e.g. malignancies or bereavement) in a sensitive and caring manner. • He/she must maintain an operative logbook detailing his/her involvement in all cases. He/she should ensure that the goals and objectives of each rotation are met, that all problems are discussed with the assigned trainer and that copies of the progress evaluation forms are stored. Also it is recommended to keep a record of courses attended, publications and/or presentations (training portfolio).

2.1 Training in Neurosurgery

• A neurosurgical training record (Appendix2) lists the cumulative operative experiences done by a trainee and shows the ‘competence level’ of each procedure expected at the end of training [4]. On completion of training the trainee tabulates his/her cumulative operative totals and indicates his/her level of competence. The training director certifies an adequate competency level for each procedure by signing the training record.

2.1.7 Periodic Progress Evaluation Periodic evaluation at 6-month intervals or at the end of a rotation period is an objective and fair instrument to ensure that trainees progress satisfactorily throughout the training. The logbook is used as supporting documentation. The trainer produces a written summary, using a structured format (Trainee Evaluation Form), and discusses with the trainee whether: • Agreed goals have been met during the past rotation • Specific knowledge, operative totals and all other aspects of training have been reached • Any weak areas have been identified that require intensified supervision, advice and support. Failure to meet the agreed target must be brought to the attention of the training programme director. In addition, the further development of training should be discussed and aims and objectives for the next rotation may be formulated. The Evaluation Sheet must be signed by the trainer/programme director and trainee and kept in the trainee’s portfolio. In future a separate (anonymous) evaluation of their training by the trainees may become helpful to receive the feedback of the trainees concerning clinical and operative training, teaching, supervision and support, feedback of progress and career advice.

2.1.8 Certification at Completion of Training An application for certification as a specialist must be sent to the national authority responsible for recognition/ certification as a medical specialist. The application must include: • Details of previous training posts, including dates, duration and trainers • Satisfactory cumulative operative totals performed by the trainee (logbook and operative list) • Signed Progress Evaluation Forms for each rotation/ training period

• List of training courses attended, hands-on courses, meetings, etc. • Letter from the programme director providing valid documentary evidence of the satisfactory completion of training • Specific additional requirements may exist in individual countries (list of publications, list of presentations at meetings, reviews, expert opinion, etc.) Many countries in Europe now have a compulsory written (MCQ) and oral examination, with the majority having an oral board examination. At present the level of such examinations varies considerably, and a common standard is needed urgently. It should be underlined that the EANS/UEMS offers a written and oral European Board Examination of high standard twice a year. Countries that do not have a full board examination in place may use the European written and/or oral examination as an equivalent, or organise their national examination with the support and advice of the EANS/UEMS Examination Committee.

2.1.9 Subspecialisation Competence in complex procedures exceeding the knowledge and operative totals required at the end of training can be developed after completion of training within the framework of a 12- to 18-month subspecialisation fellowship. The definition and organisation of subspecialisation is presently being discussed in a UEMS/ EANS committee and will be published in Acta Neurochirurgica.

Appendix 1 The New Operative Figures for Trainees Key Procedures

In order to make neurosurgical training comparable in the various European countries, key procedures have been defined. Every trainee at the end of training should be able to perform these procedures independently, i. e. with a trainer supervising but not making a significant decision/practical manoeuvre during the operation. The list is detailed and ensures that a trainee has acquired broad operative experience (Appendix 1). With these key procedures, a certain standard of training is guaranteed and in future will become more and more important as subspecialty areas are developed. Societies may wish to include additional key procedures and certainly can do so.

Appendix 1

Minimum and Optimum Figures

Minimum figures should be attained. It is of great importance that within the specific categories the trainee acquires sufficient experience. If the minimum of one key procedure is not fully met, this can be counterbalanced by a comparable key procedure of the same area. The minimum operative total for each area should be attained. The optimum figures are provided as a goal for a good training programme and also to allow for competencybased training. It takes into account that trainees progress at varying rates. For some operations only ‘optimum’ figures are indicated. National societies may define such operations as key procedures. If minimum figures are not achieved, smaller departments may need to arrange a rotation of their trainees for part of their training with larger departments.

Assistant Figures

For many years, opinions among trainers have differed considerably as to whether each trainee should have performed complex operations personally, such as aneurysms, AVMs, acoustic neuromas, spinal intramedullary tumours, basal meningiomas, brain tumours in children, etc. To solve this problem, a separate list of assistant figures is included (Appendix 1, assistant figures). This list contains procedures that trainees have to assist in or perform in part but with no obligation to perform them personally/independently. Most of these procedures will be learned either after finishing residency or in a subsequent subspecialty programme. The requirement of the assistant figures ensures that trainees are exposed to such complex diseases during their training and become familiar with the diagnostic procedures, the treatment options and the follow-up required. The specified minimum figures should be attained.

Appendix 1 Neurosurgical Training Requirements – Adults a Operative totals

Minimum

Optimum

Burr holes: external ventricular drainage/ICP monitoring/reservoir

Chronic subdural haematoma

Craniotomy: extradural/subdural/intracerebral haematoma/contusions

Head injuries

Total

Depressed skull fracture

Dural repair (CSF fistula)

Cranioplasty

Meningioma

Pituitary adenoma (transsphenoidal/transcranial)

Other benign lesions (epidermoid, arachnoidal cyst, etc.)

Primary and metastatic tumours

Chiari malformation/posterior fossa decompression

Other benign lesions (epidermoid, arachnoidal cyst, von Hippel-Lindau, etc.)

Supratentorial tumours and lesions (excluding stereotactic procedures)

Total

Intrinsic tumours: primary/metastatic

Posterior fossa lesions

Total

I t is of great importance that within the specific areas there is sufficient experience. If the minimum of one key procedure is not fully met, it can be counterbalanced by a comparable key procedure of the same area. The minimum operative total of each area should be attained

For some operations only ‘optimum’ figures are given. Some national societies may define such operations as key procedures

In a few European countries peripheral nerve procedures have, in the past, not been a mandatory requirement

2.1 Training in Neurosurgery

Appendix 1 Neurosurgical Training Requirements – Adults a Operative totals

Infection (cranial/spinal)

Total

Abscess/subdural empyema 5.

Vascular

Total

Craniotomy: arteriovenous malformations (AVM)

Cavernous angioma

Haematoma (spontaneous intracerebral/intracerebellar)

Shunting procedure, initial

Shunt revision

Hydrocephalus (≥16years)

Total

Spine

Total

145

Cervical instrumentation (anterior/posterior)

Lumbar disc disease/spondylosis: lumbar disc

Laminotomy/laminectomy for spondylosis

Lumbar instrumentation

Spinal tumours: extradural

Spinal tumours: intradural extramedullary

Spinal tumours: instrumentation in vertebral tumours

Spinal trauma: decompression/instrumentation

10.

Cervical disc disease/spondylosis: anterior decompression/foraminotomy

External ventricular drainage

Optimum

Craniotomy: aneurysm

Endoscopic fenestrations 7.

Minimum

Injection techniques/radiofrequency lesion

Microvascular decompression

Trigeminal and other neuralgias

Stereotactic and functional neurosurgery

Total

Stereotactic tumour biopsy

Surgery for epilepsy

Therapeutic electrostimulation (peripheral nerve, spinal)

Implantation of ports/pumps for intrathecal drug delivery

Peripheral nerve

Total

Craniotomy supratentorial

Craniotomy posterior fossa

Entrapment decompression/transposition 11.

Computer-aided interventions (not the procedures)

Total

12.

Basic techniques

Total

For some operations only ‘optimum’ figures are given. Some national societies may define such operations as key procedures

In a few European countries peripheral nerve procedures have, in the past, not been a mandatory requirement

Appendix 1

Appendix 1 Neurosurgical Training Requirements – Paediatric through 15Years of Age Operative totals

Minimum

Optimum

External ventricular drainage

Shunting procedure

Hydrocephalus and congenital malformation

Total

Head and spine injuries

Total

Burr holes: ICP monitoring/drainage/reservoir

Chronic subdural haematoma/hygroma

Extradural/subdural haematomas

Brain tumours and lesions

Total

Supratentorial tumours a

For some operations only ‘optimum’ figures are given. Some national societies may define such operations as key procedures

Appendix 1 Neurosurgical Training Requirements – Assistant Figures Procedure

Number

Craniopharyngioma

Pituitary adenomas (transsphenoidal + transcranial)

Acoustic neurinoma

Complex basal/posterior fossa meningioma

Craniotomy: aneurysm

Craniotomy: AVM

Occlusive: endarterectomy

Thoracic disc disease

Spinal tumours: intramedullary

Thalamotomy, pallidotomy/stimulation technique

Implantation of ports/pumps for intrathecal drug delivery

Single suture craniosynostosis

Paediatric infratentorial tumours

Meningocele/meningomyelocele

Tethering syndromes

Spinal dysraphism

2 a

Peripheral nerve sutures (with graft) a

In a few European countries peripheral nerve procedures have, in the past, not been a mandatory requirement

2.1 Training in Neurosurgery

Appendix2 Neurosurgical Training Record

Nature of operation – Adults

Head Injuries Burr holes ext. ventricular drainage /ICP-monitoring/reservoir Chronic subdural haematoma Craniotomy -extradural/subdural/intracerebral haematoma/ contusions Depressed skull fracture Dural repair (CSF fistula) Cranioplasty

Supratent.Tumours + Lesions (excl. stereotactic procedures) Intrinsic tumours – primary / metastatic Meningioma – vault Meningioma – parasagittal Meningioma – complex basal Pituitary adenoma (transphen. – transcranial) Craniopharyngioma Other benign lesions (epidermoid, arachnoidal cyst, etc.)

Posterior Fossa Lesions Primary and metastatic tumours (cerebellar hemisphere) Arnold Chiari malformation/ Posterior fossa decompression Acoustic neurinoma Other benign lesions (epidermoid, arachnoidal cyst, H. Lindau, etc.)

Infection (cranial – spinal) Abscess / subdural empyema

Vascular Craniotomy Aneurysm Craniotomy AVM Cavernous angioma Haematoma (spontaneous intracerebral/intracerebellar) Carotid endarterectomy

Hydrocephalus (≥ 16 years) Shunting procedure, initial Shunt-revision Endoscopic fenestrations External ventricular drainage

T Operative Totals T

Minimum Competency level end of 6th Year A

Training Director's signature

Appendix2

Nature of operation – Adults

Spine

T Operative Totals T

Minimum Competency level end of 6th Year A

Training Director's signature

Cervical disc disease/Spondylosis: anterior decompr./foraminotomy Cervical instrumentation (anterior/posterior) Lumbar disc disease/ Spondylosis: lumbar disc – laminotomy/laminectomy for spondylosis – lumbar instrumentation Thoracic disc disease Spinal Tumours: Extradural – Intradural extramedullary – Intradural intramedullary – Instrumentation in vertebral tumours Spinal Trauma: Decompression/Instrumentation 8.

Trigeminal and other Neuralgias Injection techniques/RF-lesion Microvascular decompression

Stereotactic and Functional Neurosurgery Stereotactic tumour biopsy Thalamotomy, Pallidotomy/Stimulation technique Surgery for epilepsy Therapeutic electrostimulation (peripheral nerve, spinal) Implantation of ports/pumps for intrathecal drug delivery

10. Peripheral Nerve Entrapment decompression/transposition Peripheral nerve sutures (with graft) 11. Computer-aided interventions (not the procedures) 12. Basic Techniques Craniotomy supratentorial Craniotomy posterior fossa Transsphenoidal approach Definitions: T = The trainee has done the operation. The supervising consultant must not have made a decision/practical manoeuvre significantly affecting the execution of the operation. TS = The trainee has done the operation but the supervising consultant has made a significant decision/practical manoeuvre during the operation. C = The trainee has performed component parts during the operation under supervision of a senior surgeon: positioning, operative approach (i. e. craniotomy, opening) closure, drainage, draping, instructions for postoperative care. A = The trainee is the principal assistant during the operation. Competency levels: 1 = should have assisted in, but is unable to perform the procedure 2 = competent to perform procedure under direct supervision 3 = competent to perform procedure without direct supervision

2.1 Training in Neurosurgery

Operative totals – Paediatric through 15 ys

1. Hydrocephalus and Congenital Malformation

Operative Totals Competency levels end of 6th year T

A+C 1

Training director's signature

External ventricular drainage Shunting procedure: Meningomyelocele Tethering syndromes Spinal dysraphism 2. Head and Spine Injuries Burr holes, ICP-monitoring/drainage/reservoir Chronic subdural haematoma/hygroma Extra-/subdural haematoma 3. Supra- and/or infratentorial tumours and lesions Supratentorial and/or infratentorial tumours Definitions: T = The trainee has done the operation. The supervising consultant must not have made a decision/practical manoeuvre significantly affecting the execution of the operation. TS = The trainee has done the operation but the supervising consultant has made a significant decision/practical manoeuvre during the operation. C = The trainee has performed component parts during the operation under supervision of a senior surgeon: positioning, operative approach (i. e. craniotomy, opening) closure, drainage, draping, instructions for postoperative care. A = The trainee is the principal assistant during the operation. Competency levels: 1 = should have assisted in, but is unable to perform the procedure 2 = competent to perform procedure under direct supervision 3 = competent to perform procedure without direct supervision

R eferences 1. Steers J, Reulen HJ, Lindsay K, et al (2004) UEMS charter on training of medical specialists in the EU: the new Neurosurgical Training Charter (2004). Acta Neurochir 90:3–11 2. Reulen HJ, et al. (2004) Training in neurosurgery in the countries of the EU. Springer, Wien New York

3. Reulen HJ, Lindsay K (2006) The new operative figures for trainees. Acta Neurochir 148:103–105 4. Reulen HJ, Lindsay KW (2007) UEMS charter on training of medical specialists in the EU: the neurosurgical training charter (2nd edn). Acta Neurochir 149:843–855

2.2 Basic Training in Technical Skills: Introduction to Learning ‘Surgical Skills’ in a Constructive Way Jens Haase

That one, when in truth shall succeed in bringing a man to a destination, first and foremost you have to be careful to find him where he is and start from there. This is the secret of all art of assistance, and anyone who cannot understand this is conceited when he thinks that he can help others. (Fragment of a straightforward message: Danish philosopher, Soren Kierkegaard 1856)

2.2.1 Introduction to ‘Basic Training Skills’ What is a good surgeon? This question cannot be easily, sincerely or precisely answered despite the fact that we ‘all know’ [54]. I assume that we all agree that a surgeon needs manual dexterity. Dexterity usually refers to skills and ease in physical activity especially manual activity which in the context of surgical dexterity should be understood as motor skills [1, 16]. Dexterity is closely connected to performance in surgery although a strict definition is not obtainable [46, 54]. Conventional surgical teaching is a daily working relationship between experienced teachers and trainees [6]. A young MD’s training has been described as an opportunity to have access to patients, but experience as such, without training, increases only confidence and not competence [14]. Traditional teaching makes steep learning curves take place during interaction with real patients. This is not acceptable in modern societies as we know that the first surgical procedures performed by an inexperienced surgeon carry greater risks for the patient and often even unacceptable risks [11]. We have therefore tried to establish different methods of learning surgical skills such as manual dexterity.

2.2.2 Learning: Theories Concerning learning and teaching, the so-called instructional approach has become synonymous with effective cognitive growth=learning [8]. Teaching neurosurgical skills today must be based on the concept: not to teach, but to facilitate learning and development of the abilities the trainee possesses.

Much surgical experience consists of procedural knowledge in the form of perceptual-motor or spatial skills that cannot be expressed verbally or in writing [49]. How we shall function in a microsurgical brain habitat teaches us that we must learn the true three-dimensional (3D) anatomy of the brain and not rely on simple pictures in our books. By spatial training in 3D models we learn where this anatomy is within the skull enhancing our chances of finding our designated targets more safely without complicated neuronavigation [20]. Learning in general is also tied to the motivation of the trainee, and effective learning of surgical skills depends on creating the right environment for learning. We have to accept that learning is connected with mental and emotional growth in which information access plays only a subordinate role [31]. Learners = trainees should therefore be viewed as active constructors rather than passive recipients of knowledge. In modern learning sciences, learning is a construct of the trainee’s ‘personality’ and of the surroundings in which the trainee functions. It has been documented that surgeons need a certain psychological and personal profile in order to become true experts in their field, as is the case with world-class athletes. Unless surgeons are prepared to learn and hence develop professionally, all training is doomed. The teacher’s role is merely to support. In this ‘enzymatic’ way they facilitate the learner in the process of ‘learning’ [37]. It is therefore nowadays also accepted that even the teachers need to learn to perform as teachers [6]. We must ask ourselves these questions: • How do we learn? • What is the purpose of this for me? These philosophical questions bring us far away from the concept of surgery. The Dreyfus brothers [14] argue that learning can be seen as a stepwise development through five stages. Briefly summarised these are as follows: 1. Novices act on the basis of context-independent elements and rules. 2. Advanced beginners begin to take account of situational factors, which they have learned to identify and interpret on the basis of their own experience from similar situations.

2.2 Basic Training in Technical Skills: Introduction to Learning ‘Surgical Skills’ in a Constructive Way

3. Competent performers are characterised by the involved

choice of goals and plans as a basis for their actions. Goals and plans are used to structure and store masses of both context-dependent and context-independent information. 4. Proficient performers identify problems, set goals and plan intuitively from their own experientially based perspective, and these choices are checked by analytical evaluation prior to action. 5. Experts whose behaviour is building on intuitive, holistic and synchronic judgements in a way that, in a given situation, releases an adequate picture of the problem together with goal, plan, decision, and action in one instant and with no division into phases. This is the level of true human expertise. Experts are therefore characterised by a flowing, effortless performance, unhindered by analytical deliberation.

To these you may add a sixth level: 6. Innovator experts: Here we find persons who also understand the necessity of a debriefing session after a performance in order to consider the adequacy of old skills in order to develop new ones. In this way these experts become true innovators of new techniques. Classical ‘information feeding’ of declarative knowledge will never take us above the first level of proficiency, i. e. novices. Information is NOT knowledge!! It is an error to assume that possessing a vast quantity of information is the same as having knowledge and understanding. Every 6–8years our scientific knowledge has doubled! In a setting where more trainees must learn more and more in less and less time, this places an unrealistically high burden on the teachers and is a rather cost-intensive way of teaching. From the second level on, the learning development depends on practical training, and in this process, declarative knowledge only supports the learning development up to the third, or perhaps fourth, level. It is therefore a prerequisite for the trainee to have a personal goal for the learning per se. Based on that, he/she has to develop a subset of tasks to be rehearsed. This learning is a groupmonitored and group-oriented process and not a simple ‘result-oriented’ task [12, 20, 21]. The ‘lonely wolf ’ training, which has been the standard set up in medicine for many years, is outdated. A prerequisite for making declarative choices is that the trainee learns to make the decision that seems ‘right’, that the trainee does not seek power over other trainees and that a disappointing result of a training session is considered a sign of a ‘failure of the training process’ and not a personal failure of the trainee [4, 9, 22, 44, 49]. Neurosurgeons have learned to be independent, and therefore tend to be very individualistic – which makes

it difficult for most physicians to work together in a cooperative situation or in practice. (James I. Ausmann 1997) By organising the surgical performance teaching in a structured systematic system based on problem-based learning and by introducing virtual reality (VR) learning methods, we can enhance speed and effect of learning basic dexterity and visualisation skills needed to perform surgery at the expert level [3, 23, 54]. It is well known that pilots are tested for both abilities and for psychological behaviour before they are introduced into a training programme. The same should perhaps also be a natural part of any surgical training programme [3, 40].

2.2.3 Length of Training Periods Learning automatic dexterity = procedural memory, also means that we must learn these skills in a continuous manner. Although much surgical interference during an operation depends on declarative knowledge in terms of solid background knowledge of anatomy, physiology, pathology and surgical techniques and procedures, the ‘true’ surgical performance is significantly a procedural knowledge of ‘knowing how’ [15, 20, 37]. Procedural memory is stored in the cerebellum and basal ganglia. All training aimed at obtaining this procedural knowledge must be tailored to this fact. The performance of a motor function is through reaction in the premotor and motor centres of the brain. In addition we have the supplementary motor area (SMA) on the mesial part of the frontal lobes where we visualise our movements. We can literally think of a specific movement, visualise it (without performing it) and see this SMA area light up on functional imaging [18]. In surgery our movements should be as automatic as they are when we are writing with a pen or riding a bicycle. It is further shown that training the non-dominant hand leads to a higher performance increase. Non-dominant left-hand stimulation also increases 3D space observation. Therefore rehearsal of movements via SMA and with the left hand may be of benefit for surgeons [41]. As MerleauPonty points out: ‘A movement is learned when the body has understood it, that is, when it has incorporated it into its “world”, and to move one’s body is to aim at things through it; it is to allow oneself to respond to their call, which is made upon it independently of any representation.’ [14]. Learning to play a piano from simple notes (procedural knowledge) and in a standard fashion can be achieved in 5–7weeks by continuous training. This procedural skill of playing the piano stays with you for life and the novice can proceed in the learning from there.

2.2.4 Magnification of Surgical Dexterity

This also means that we can learn movements or tasks by visualising them without being in a real operating theatre. Studies suggest that humans may form internal models of these primitive movements, which they can combine into more complex tasks. So when a task is broken down and learned in simple steps, rather than ‘all at once’, learning a complex task can be faster, and even performance improves [35, 36, 40]. One dexterity skill, which is often used, is moving a curved needle precisely along its own form. You may rehearse this in the air or through a piece of rubber or cloth, not necessarily through a human vessel or a rat vessel [39]. From our own microsurgical learning system at the Microsurgical Laboratory at Aalborg University Hospital, we have realised that it takes around 400h of microsurgical training, from scratch, to be able to carry out, for example, a free flap transfer on a rabbit. When spending 8h daily rehearsing in the laboratory, this means that it takes at least 50days of training to become fully educated! Not 24h as is the standard of a hands-on course.

2.2.4 Magnification of Surgical Dexterity Competence in surgery depends on a plethora of factors and skills, and one among these is to perform surgery with the aid of the microscope, i. e. with magnification [44, 46]. When introduced to endoscope techniques, these are so different from daily life dexterities that all trainees understand the necessity for learning to use the endoscope before carrying out endoscope operative procedures on patients [17, 19, 29, 49]. For neurosurgeons the use of the microscope is nowadays essential; however it is often thought of being a simple tool for surgery, a tool that needs no ‘training’ to be used [5, 35]. This is a grave mistake. Microsurgical techniques are specific tasks carried out in a specific microenvironment, a microhabitat created by the operative microscope [24]. Therefore our goal settings include performance using specific microsurgical instruments in this habitat, a task that demands a better understanding of the microscope. The microsurgical habitat lacks definition of sizes, which gives rise to perceptual problems in training [13]. The operative microscope has an enormous effect on surgical performance as it offers excellent light at the surgical stage under all circ*mstances with preservation of true 3D imaging, in contrast to endoscope surgery. The lenses of modern microscopes are of outstanding quality so that the images we receive at our retinas are perfect. For microsurgery the surgeon needs to be able to control hand/finger tremor at the micro level and to master changed hand–eye coordination with angles rotated and distances magnified by the microscope. The learning of

microsurgical techniques or skills requires the surgeon to learn to work in a microsurgical environment using and understanding microsurgical instruments serving as interfaces between hand/brain and the target. When the surgeon becomes familiar with a new tool (instrument), this tool will become ‘internalised’, forming a ‘functional organ’ together with the surgeon’s hand [28]. While the two terms ‘tool’ and ‘interface’ are far from having identical meanings, the tool can thus now be thought of as an interface between the holistic surgeon and the object (e.g. the patient that is to be operated on). However, in this process of internalisation of the microsurgical instruments, the surgeon has to develop specific skills in order to use the tool. The surgeon must also learn to control the behaviour of tissues and threads involved. Despite the fact that microscopes have been on the market for more than 35years, surgeons still forget the simple adjustments of these instruments, most pronounced in the continuous balancing of the microscope. In modern microscopes, this balancing is constant despite the position of any part of the microscope. Movements are augmented server driven in some, which decreases the muscle power needed to adjust the position and thereby reduces fatigue and tremor [26]. The surgeon that grabs the microscope and some microsurgical instruments and trusts that he/she can carry out the microsurgical procedure has not fully understood this paradigm, and disasters will follow. Experiments have shown major differences in touch sensing among inexperienced and experienced surgeons/ students [10] documenting this problem. For accurate control the trainee must develop new motor strategies involving only the fine motion of the fingers [18]. Arm movements used in macrosurgery induce too much tremor. The overwhelming use of the operative microscope’s ‘zoom function’ delays the learning of micro sizes and thereby our functionality in the micro space. If we position a structure of known size in the operative training field this could facilitate the understanding of sizes. What is the length of the tip of an instrument? Measure it, watch it using the microscope with variable magnification and it will help to develop these skills of determining sizes. For the beginner, fixed magnification settings should therefore be used from a didactic point of view. The operative microscope is however only a part of the normal macro habitat – the operation room. Although the microscopes may be similar and therefore easy to learn to use, all operative rooms are different, which makes surgical rehearsal difficult compared with what aeroplane pilots experience – all their co*ckpits = macrohabitats are equal! The solution to the problem of timing is to accept that the pace of learning, of whatever skill, is a personal one. This means that all our dexterity learning should be self-administered, self-monitored and continuous [7, 17, 39, 50].

2.2 Basic Training in Technical Skills: Introduction to Learning ‘Surgical Skills’ in a Constructive Way

2.2.5 Virtual Reality as Part of the Learning Process Surgeons need to learn how to use all the modern technological facilities that exist today including information technology (IT) and virtual reality (VR). VR is defined as an artificial world resembling ‘real life’ (RL) [52, 53]. Most research is that which changes the way we think about an issue or a technical problem. The data explosion we all must deal with needs to be more manageable, more coherent and more meaningful to give us a superior performance [24, 30, 40]. We will filter more and more of the surgical ‘chaff ’, allowing truly imaginative and creative research results, whether clinical or basic, to have their appropriate input [2, 47]. One of the goals of surgical media management should be to decrease the volume of data distributed and thereby increase the significance of new information presented. We must reduce the ‘information fatigue syndrome’ that is so common today [2]. Virtual reality gives a substantial contribution to interactive learning environments. Virtuality in this context should be used according to its meaning ‘potential/possible’, making it a medium for communication of surgical skills. This is in accordance with our own findings with the Dextroscope training [5, 24, 30]. It combines the realism (as in a video recording) with the manipulative reality as in simulation programs. Virtual reality is a desired technology for those applications in which reality does not exist (yet), cannot be accessed, or is too dangerous or expensive to disclose [24, 30]. VR gives us the possibility to rehearse complications before they occur and without injuring patients [25, 32, 50]. VR has also been described as a tool that allows a ‘broadening [of] our channels of sensation and communication’ [52]. The power of VR as a learning tool comes from the possibilities to explore cause-and-effect relationships in a safe environment, and to understand and prepare for various difficult scenarios [16]. Learning in a VR world is interactive and not merely receptive. Learning in the VR space also lacks the stressed atmosphere of the operating theatre and is therefore an optimal educational environment for the novice surgeon [3, 17, 34]. Within high-risk organisations such as the military and the aircraft, nuclear and chemical industries, the opportunities to learn are not only through normal learning means but also always with simulation included [27]. The VR environment can also allow the trainee to practice a skill several times as a refresher course. Surgeons and pilots that continuously make a certain type of mistake generally make more of other types of mistakes too. Findings have also proved skill acquisition by VR training in that subjects with lower spatial abilities dem-

onstrated a significant positive transfer from a simulatorbased training task to a similar real world robotic operations task [50]. As already stated, the trainee must develop a plan for his/her dexterity training. A key point in surgical training today is to set personal dexterity goals, develop personal methods/protocols for reaching these goals, secure validation of how the goals are reached and learn to perform these dexterity tasks in settings that simulate the operating theatre environment with all its distraction [4, 6, 35, 42]. VR can be employed to test the essential abilities of a surgical candidate, and to test and train his/her surgical skills in order to orchestrate his/her actions in a new surgical habitat. Subjects with higher spatial skills did not response as positively from training in a simulated environment. Virtual reality systems introduce the alluring possibility of a completely objective measurement and assessment of the trainee’s ability [44, 46, 48, 51]. VR also makes it possible to track training developments, being an electronic and digital environment. This enhances the opportunities of the trainee to receive feedback from ‘a supervisor’ that is always available and thus gives the possibility of tracking development in training and rehearsal. In Lufthansa they showed that 75% of all failures were caused by non-human errors, only 13% by technical mistakes and 12% were due to environmental causes. The personality of a neurosurgeon influences the operative outcome significantly – but is never tested today [38]. To me the purpose of our new technology is to broaden our channels of sensation and communication, allowing us to experience reality more fully and making us more creative in the face of life’s challenges. I think it is plausible to suggest that progress toward this goal may depend more on technology expanded sensual experience than on computer-supported reason. (John Waterworth) Surgery is today a ‘high-risk’ task. In high-risk surgery, surgeons are facing special demands in terms of both physical stress and emotional stress. VR introduces the possibilities for learning surgical performance in a setting where failures will not lead to human disasters. Another important feature of surgery is preparedness and control of stress, e.g. mental status of the surgeon. If we make surgical mistakes, such as occluding a vessel by suturing, rupture of an aneurysm during dissection or not being able to localise our target, this will not injure our virtual models as it would a real patient. We know from athletes that one of the most important issues for them to be ready for an Olympic gold medal is to have dealt with all possible mistakes and thus know that they can manage the situation. We know that 70% of surgeons tend to feel that they can cope with a surgical procedure even when tired,

2.2.6 Conclusion

whereas only 26% of aeroplane pilots think the same [45]. By making the mistakes, experience grows and perfection is developed. For surgeons this is only morally allowed in a VR scenario [24, 37]. In every surgical procedure there are a few key steps that the trainee is more likely to perform incorrectly leading to complications. VR is therefore considered a new medium for communication of surgical skills. The value of a surgical simulator and of continuous training is analogous to the proven value of a flight simulator [27]. A surgical simulator should train surgeons for principal pitfalls. However, the transfer of learning from such contexts to that of the operating theatre may not be as easy as is assumed by many medical training programmes [19, 36, 39, 41, 43, 44, 49, 50]. The fast propagation of www-based tele-learning can benefit from the VR prospects in the coming years, as VR programs can now be accessed by the most common web browsers such as Explorer, Safari, Mozilla, etc. [33, 43, 47]. Virtual reality will replace the customary physical congregation for lectures, workshops, scientific communications and personal interactions. Features of virtual conferences will quite easily include lectures, workshops and poster presentations [2]. If the goal of the educational experience is to foster excitement about a subject or to encourage learning though exploration, VR may be worth the expense.

2.2.6 Conclusion In surgery one trains at random, based on a time-based system; some trainees will devote a significant amount of time to their education while others will rely on relatively passive knowledge receiving. There is often no plan for developing surgical skills and absolutely no information in the training on the role different working spaces gives us. We know today that 70% of all mistakes and unintended failures are linked to human errors. Therefore a close evaluation of the surgical skills/task performances must be included in future education. A considerable amount of evidence proves that training by computerised models facilitates the learning process [5, 16, 24, 29, 30, 33–35, 40, 53]. We cannot depend on the techniques and information learned during a short training period being adequate for an entire career: learning surgical skills is a lifelong task. If we do not learn from our mistakes we are doomed to continue with these.

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2.2 Basic Training in Technical Skills: Introduction to Learning ‘Surgical Skills’ in a Constructive Way

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2.2.6 Conclusion

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3.1 Basics

3.1.1

Anatomy

Christianto B. Lumenta 3.1.1.1

The Skull and Its Solid Contents

The central nervous system has a hard and a soft cover: the skull and the meninges (Figs.3.1.1–3.1.4). The skull is divided into the neurocranium and the viscerocranium. The neurocranium encloses the brain, and is formed by the frontal, parietal, temporal, occipital sphenoid and ethmoid bones. The frontal, both parietal, a small part of the temporal and a large part of the occipital bone make up the skullcap, while the orbital roof, the sphenoid, the petrosal, and the suboccipital bones constitute the skull base, which is divided into anterior, middle and posterior fossa. The cranial bones are connected by cranial sutures: the sutura coronalis, the sagittalis and the lambdoidea. In childhood the sutures have not been ossified; therefore, on X-ray films the sutures seem to be gaping. We call the gap the fontanel, which is closed by the end of the second year of life. The cranial bone is covered by layer of skin called the pericranium. The brain is covered by the soft meninges, which consists of three layers: the dura mater, the arachnoidea and the pia mater. The whole nervous system is divided into the central nervous system, which includes the brain and the spinal cord, the peripheral nerves and the vegetative nervous system. The brain consists of three parts: the cerebrum, the cerebellum and the brain-stem. All body functions are controlled by the cerebrum, while the brain-stem plays the role of an instinctive control system. The cerebellum coordinates all movement impulses coming from the cerebrum, before they reach the muscle via the spinal cord and peripheral nerves. The cerebrum is in humans the largest part of the brain. It has four lobes: the frontal, parietal, temporal and occipital lobes. The cerebral cortex is structured out of the sulci and gyri. The sulcus centralis differentiates the frontal lobe from the parietal one, and the Sylvian fissure

(sulcus lateralis) is the border between the frontal and parietal lobes and the temporal one. The sulcus parieto-occipitalis marks off the parietal lobe from the occipital one. There is, however, no border between the temporal and occipital lobes. If we perform a section through the brain, we recognise the grey and the white matter, in which grey-coloured areas are also localised (brain nuclei). The most important area for the motoric function is the gyrus precentralis. The nerve cells localised to this gyrus nerve cells are the origins of the pyramidal tract, the most important tract of the arbitrary motoric system. Eighty-five percent of the pyramidal tract crosses to the contralateral side at a small mound at the medulla oblongata. In fact, the pyramidal tract goes straight to the anterior horn cells of the spinal cord, but all motoric functions are controlled by connections between the precentral gyrus and other centres of the brain, especially the cerebellum. The connection tracts between each brain zone are called association and commissural tracts. The most important commissural tracts, which connect the two hemispheres to each other, are localised to the corpus callosum, which can be recognised as white structure in the median section of the brain. While the precentral gyrus represents the motoric control of the body, the postcentral gyrus is responsible for sensoric control, with defined functional areas for different body parts. The two hemispheres are functionally dissimilar; in the normal case of a right-handed person the left hemisphere is the dominant one. The motoric speech centre of Broca – its disturbance causes so-called motoric aphasia – is localised to the lateral part of the frontal lobe, while the sensoric speech centre of Wernicke is situated in the temporal lobe below the Sylvian fissure. A disturbance of the Wernicke speech centre leads to so-called sensoric aphasia, i.e. to be unable to understand. The cerebellum is localised to the posterior fossa, it has two hemispheres and a middle part (vermis; Fig.3.1.5). The connection tracts between the cerebrum and the cerebellum pass the cerebellar peduncles. The main functions of the cerebellum are to coordinate and to control all movements of the body. The following brain areas belong to the brain-stem: • The diencephalon: consisting of the thalamus, hypothalamus and corpus pineale

3.1 Basics

• The mesencephalon, including the lamina quadrigemina • The tegmentum and crura cerebri • The pons and medulla oblongata The unarbitrary control of all life functions is performed in the reflex centres of the brain-stem, which consists of the main parts of the tracts to and from the cerebrum. The pituitary gland is localised in the middle fossa and divided into: • The adenohypophysis, which produces: – Growth hormone (somatotropin, STH, GH) – –Adrenocorticotropic hormone (ACTH) – Follicle-stimulating hormone (FSH) – Luteinising hormone (LH) – Interstitial cells-stimulating hormone (ICSH) – Thyrotropin hormone (TSH) – Prolactin • The neurohypophysis, which transfers the hormones that are produced in the hypothalamus into the blood circulation: – Anti-diuretic hormone (ADH) – Oxytocin The centre of cardiac and blood circulation and the breath function is localised in the medulla oblongata. 3.1.1.2

The Cerebral Blood Vessels

Fig.3.1.1 The lateral (top) and the medial (bottom) views of the left hemisphere with each brain region

The arterial intracranial blood vessel system (Fig.3.1.6) consists of: • The two internal carotid arteries (ICA) with their branches: the ophthalmic artery (OA), the posterior communicating artery (PCommA), the anterior choroidal artery (AChoA), the anterior cerebral artery (ACA) and the middle cerebral artery (MCA) • The two vertebral arteries (VA) linked to the basilar artery (BA) with its branches: the posterior cerebral artery (PCA), the superior cerebellar artery (SCA), the anterior inferior cerebellar artery (AICA) and the posterior inferior cerebellar artery (PICA) The two internal carotid arteries are connected by the anterior communicating artery (ACommA), and the basilar artery is connected to the carotid arteries by the posterior communicating arteries. We call this structure at the skull-base the circulus arteriosus or the circle of Willis. The ACA, MCA and PCA come from this circle. The large venous system of the brain is called the venous sinus, which is a duplication of the dura: the superior sagittal sinus (SSS) and the rectus sinus (RS) → the confluens sinuum (CS) → the transverse sinus (TS) → the sigmoid sinus (SS) → the jugular vein (JV).

Fig.3.1.2 The basal view of the brain without the cerebellum

3.1.1 Anatomy

Fig.3.1.3 The brain gyri (top) and sulci (bottom) in lateral and medial view

3.1.1.3

The Cerebrospinal Fluid and Ventricle System

Cerebrospinal fluid (CSF) is produced in the ventricles by the plexus choroideus, and washes around the central nervous system within the subarachnoid space.

The CSF circulates in the ventricle system of the brain: • From both lateral ventricles via the foramen of Monro to • The third ventricle via the aqueduct to

3.1 Basics

Fig.3.1.4 Localisation of motor and sensory cortex as well as of motor speech and sensory area

Fig.3.1.5 The cerebellum: view from the top and from below

3.1.2 Pathophysiology

• The fourth ventricle via the foramen of Magendie (medially) and the foramina of Luschka (laterally) to • The spinal canal Resorption of the CSF takes place in the arachnoid, in Pachioni’s granulations, and in the root sheath of the spinal nerves. The amount of CSF in adults is around 120–180ml. 3.1.1.4

Fig.3.1.6 The arteries at the base of the brain

The Cranial Nerves

All 12 cranial nerves (Figs. 3.1.7, 3.1.8) come directly from the brain: • CN 1: the olfactory nerve → the smell function • CN 2: the optic nerve → vision • CN 3: the oculomotor nerve → movement of the eye ball and pupil reaction • CN 4: the trochlear nerve → rotation of the eye ball laterally and downwards • CN 5: the trigeminal nerve → sensory function of the face and the mastication function • CN 6: abducent nerve → rotation of the eye ball laterally • CN 7: facial nerve → the mimic function • CN 8: vestibulocochlear nerve → the balance and hearing functions • CN 9: glossopharyngeal nerve → taste and the swallowing function • CN 10: vagal nerve → sensory and motoric function of the tongue and mouth floor, as well as the parasympathetic function • CN 11: accessory nerve → head flexion and shoulder elevation • CN 12: hypoglossal nerve → tongue movement

3.1.2 Pathophysiology

Christianto B. Lumenta

Fig.3.1.7 The cranial nerves

Although the weight of the brain is around just 2% of that of the whole body, it needs around 20% of the cardiac minute volume for its blood flow. The cerebral blood flow (CBF) remains constant, as long as the systolic blood pressure is not lower than 60mmHg and not higher than 150mmHg, the so-called autoregulation of the brain. It controls the width of the blood vessels in the brain depending on the pH, pO2 and pCO2 values of the blood, and thus the CBF. A shock occurs if the systolic blood pressure falls below 60mmHg. This situation leads to a disturbance of the brain’s autoregulation. The CBF and the brain blood volume decrease. The result is unconsciousness or irreversible brain function damage, if it persists.

3.1 Basics

Fig.3.1.8 The skull base. Left: the entry zones of the cranial nerves (foramina). Right: the dissected cranial nerves

A long period of increase in the blood pressure of more than 150mmHg also leads to general changes of the brain vessels, e.g. arteriosclerosis. The brain, which consists of three components: brain tissue, CSF and intracranial blood, is surrounded by the rigid skull, which is not able to compensate for any elastic pressure changes. Because of this, an increase in volume within the skull leads to an increase in the intracranial pressure. In the case of intracranial haemorrhage, the blood volume increases and consequently the intracranial pressure too. A similar situation is present in the case of increased CSF volume due to hydrocephalus or in the case of increased brain tissue volume due to a mass lesion such as a tumour. The normal intracranial pressure is around 5–15mmHg or 50–200mm H2O. A cerebral oedema occurs as a reaction to brain damage. In a cytotoxic brain oedema, the tissue water increases in the glial cells (intracellular), in the case of a vasogenic oedema, the water content between the white matter tissue increases (interstitial).

A raised ICP with decreased cerebral blood flow causes an accumulation of acid metabolite products → acidosis → cytotoxic brain oedema → raised ICP; therefore, a pathophysiologic vicious circle occurs. Vasogenic brain oedema is based on brain vessel damage caused by severe head injury, ischemic brain infarction, brain tumour etc.

3.1.3 Clinical Symptomatology

Christianto B. Lumenta 3.1.3.1

Sensorimotor Deficit

The supplementary motor area (SMA) is the cortical centre of the pyramidal system. There is a regulation circle around the primary and the supplemental motor area as well as the cerebellum. Due to this fact, a tumour in the SMA can cause the symptom of gait disturbance. A lesion

3.1.4 General Clinical Examination

of the SMA leads to spastic hemiparesis on the contralateral side. All voluntary movements start at the pre-central gyrus, the primary motor cortex. A lesion in this area causes a flabby contralateral hemiparesis. The primary somatosensory cortex is localised to the post-central gyrus. A lesion of this area leads to a decreased perception for pain, temperature, pressure and touch as well as loss of discriminative perception and of position sensitive. 3.1.3.2

Speech Disturbances

A lesion of the basal pre-central gyrus next to the Sylvian fissure (Brodmann field 44, Broca’s area) in the left hemisphere of a right-handed person leads to motor aphasia, the patient can understand, but cannot speak, although the speech muscles are not weak. In sensory aphasia the patient loses their understanding of words, names and sentences due to a lesion in the temporo-parietal region on the left of a right-handed person (Wernicke’s area). In the case of apraxia the voluntary movements are not disturbed by a paresis. The symptom occurs due to a lesion in the SMA. The patient neglects the extremities, normally those on the left. 3.1.3.3

Optic Function Disturbance

The primary visual cortex is localised to the sulcus calcarinus at the occipital lobe. A hom*onymous hemianopia occurs in the case of a lesion in this area. A lesion of the optic nerve leads to vision disturbance, and one of the chiasm to bitemporal hemianopia. Functional disturbance of the CN 3, 4 and 6 leads to diplopia. 3.1.3.4

Cerebellar Symptomatology

Ataxia, dys- or adiadochokinesis, intention tremor, and hypotonic muscle of the ipsilateral side are the typical cerebellar symptoms. In addition to the focal symptoms described, one has to differentiate between general and distant symptoms. Very early, a mass lesion leads to raised ICP due to a blockade of the CSF circulation somewhere in the skull, or distant symptoms occur due to transtentorial herniation or due to incarceration of the vessels. Other symptoms are caused by pressure to the hypothalamus or to the brainstem. Because of this, it is very important to analyse the first symptoms and the following ones as they develop. Raised ICP is characterised by headache, vomiting, bradycardia and papillary oedema. The patient is increasingly somnolent and in the final stage, unconscious.

3.1.4 General Clinical Examination

Christianto B. Lumenta There is currently an increasing tendency among young residents to rely upon the modern diagnostic tools such CT, MRI, PET scans etc., whilst neglecting neurologic evaluation. Only through careful neurological history and examination can the use of special diagnostic procedures be applied to their best advantage. These procedures are often costly to the patient and in time consumption for diagnostic personnel. Complications and discomfort may accompany their use. Only the careful clinician will be able to evaluate the various tests in light of the patient’s complaints and findings. 3.1.4.1

The Present and the Past Histories of the Patient and the Family

The examiner should first ascertain whether the patient’s complaints develop spontaneously or after trauma, whether the onset was recent or remote, and whether there was a progression or regression of the findings. Because of possible defects in judgement and memory, the patient’s version may not always be reliable. He or she may also omit details of the history for psychiatric reasons or even economic gain, and he or she may exaggerate. Since many neurological conditions are recurrent and have a genetic background, the past and family histories make up an important part of the evaluation. 3.1.4.2

The Neurological Examination

The assessment of blood pressure, pulse rate and respiration (vital signs) should be a part of any neurological examination. The objective of the examination of the sensorium is to determine the level of consciousness and the general mental, emotional and intellectual make-up of the patient. The European standard for assessing the level of consciousness is the Glasgow Coma Scale, which was introduced in 1976 by Teasdale and Jennett [1]. The cranial nerves, the sensorimotor system, the reflexes, the cerebellum, speech and coordination must be examined. The examiner must come to the conclusion that due to the tests the findings are normal or there are signs of intracranial mass lesion with deficit, such as functional impairment of the cranial nerve(s), hemiparesis with flaccid or spastic weakness, hemihypoesthesia or gait disturbance, dysdiadochokinesis etc.

3.1 Basics

With these results, neurological examination can be followed by further appropriate radiological and other cerebral diagnostic measures. Selected Reading

after discussion of these protocols with radiologists (e.g. a skeletal survey for a myeloma). Some authors still consider it helpful in evaluating the sella turcica in preoperative planning. Skull films are not indicated routinely for headache, pituitary problems, nasal trauma or sinus disease. 3.1.5.1.1.2 Computed Tomography

1. Teasdale G, Bennett B (1974) Assessment of coma and impaired consciousness. A practical scale. Lancet 2(7872): 81–84

3.1.5 Cerebral Diagnostics 3.1.5.1

Radiology: Fundamentals of Cranial Neuroimaging

Joaquín Zamarro Parra, Mariano Espinosa de Rueda Ruíz, Guillermo Parrilla Reverter and Antonio Moreno Diéguez The following section is intended to familiarise the neurosurgeon with different imaging techniques in an easy manner, and to be a guide to the key imaging findings in the main pathologies. In order to stick to the essentials a neurosurgeon will need in his first steps in neuroradiology, we have reduced the physics, technical details and many atypical presentations of different pathologies to a minimum. We will focus only on the requisites for understanding the techniques, and on the most important general features of the different pathologies, as they will be thoroughly explained in detail in their specific chapters. This should make this chapter easy and fun to read for the first approach in the first year, and maybe serve as a fast review of the requisites for neuroimaging in later years. The aim is to make it easy for you to diagnose these main pathologies and to make basic differential diagnoses. 3.1.5.1.1

Fundamentals of Neuroimaging Techniques

3.1.5.1.1.1 Plain X-Rays

Many would say (I would) that plain skull X-rays have no place in an emergency and a limited place in any other situation. Due to the accessibility and amount of information given by CT and MRI, skull plain X-ray images are almost never used in neurosurgery if a CT can be performed instead. Nevertheless, it can be helpful in evaluating shunts, cranial sutures in children, looking for metallic foreign bodies prior to performing MRI and as part of an imaging protocol for specific clinical problems

Introduced in the mid 1970s, computed tomography (CT) changed the diagnostic approach of neurosurgeons, neurologists and any doctor in emergency and nonemergency medicine. CT is based on X-ray attenuation of tissues acquired in a tomographic way. The information displayed on CT images in grey scale for every pixel is related to the different X-ray attenuation properties of each tissue, dependent on the “radiodensity” of the atoms of the tissue. This is represented on an arbitrary scale (the Hounsfield scale, in Hounsfield units – H) in which bone is +1,000H, air –1,000H and water 0H. Other useful attenuation coefficients are: blood, approximately +100H, brain, +30 H and fat, –100 H. The higher number of Hounsfield units, the whiter the pixel will be displayed, and the more “hyperdense” it will be called. The lower numbers of Hounsfield units will be darker, and will be called “hypodense”. After the addition of intravenous contrast, tissues that enhance will appear whiter. To start with, CT was always axial CT. Acquisition was made while the table was still, then the table would move to the next position, and data were acquired again, and so on. Nowadays, most acquisitions will be made in a helical way. That is, the highly collimated X-ray will be spinning and acquiring while the table moves continuously. These data are later transformed by a computer using mathematical algorithms that allow further reconstructions. Axial CT used to have much better image quality, and studies such as those of brain parenchyma, ear, paranasal sinuses and others would be performed axially. The quality of the new machines is almost identical using the helical and axial methods, even though brain parenchyma is still studied using axial acquisition. This is important to know, as you can improve the image quality of a non-collaborating patient if you make the acquisition helically instead of axially, as it is faster and less sensitive to movement. Computed tomography is a very good imaging modality for evaluating bones and blood. It is very fast, needs little preparation, acquisition can be performed in about 12s, and it is very useful for non-collaborating patients. Multidetector CT also allows reformatting in slices as small as 0.5–0.6cm and reformatting in different planes (multi-planar-reconstruction [MPR]) even after the normal axial data acquisition. That way, you can make thinner slices without acquiring new data and without radiating the patient again. This is called “volumetric CT acquisition”, which can be useful in non-cooperative patients, or in the study of subtle changes or small lesions

3.1.5 Cerebral Diagnostics

such as hyperacute stroke, infectious small cysts (cysticerci), paranasal study, fractures etc. Brain perfusion CT (BPCT) techniques for stroke and tumours and angio-CT techniques for intracranial and neck vessels are used on an everyday basis in most hospitals. BPCT is performed by acquiring data on the same table position, without moving it, and injecting a bolus of intravenous iodinated contrast. We radiate and get information about a slice, whether it is thinner or thicker (64row CT covers slices as thick as 4cm, or up to 8cm with special table movement techniques, and future CT multidetectors will cover the whole brain). This way we “lose” information in the “z-axis” (cranio-caudally), but we gain the temporal aspect, which will allow us to study the haemodynamics of this slice of parenchyma, and indicate in which location biopsy of a neoplastic lesion is most likely to give higher diagnostic rentability, or to assess the functional status and viability of brain parenchyma in stroke patients (see Sect.3.1.5.1.2.3 later in this chapter). Computed tomography plays a key role in emergency imaging of the head. There is controversy with regard to studies about what clinical factors to use in order to reduce the amount of cranial CTs being performed in emergencies. Some say there are, others say there are no symptoms or signs that can reduce the amount of cranial CTs carried out in emergencies without missing patients with significant intracranial lesions. CT is indicated to diagnose intracranial haemorrhage, skull fractures, oedema, mass lesions, hydrocephalus, and arterial and venous infarction. It is the imaging modality to choose in head injury, as it will give information about brain, bones (including cranium, face, orbit etc.) and soft tissues. If neoplastic illness is suspected, intravenous contrast administration is advised. Normal intact blood–brain barrier is impermeable to any contrast agents injected. Areas with impaired (e.g. tumour, infection, vascular anomaly) blood–brain barrier are permeable to contrast agents and show greater enhancement than normal areas. 3.1.5.1.1.3 Magnetic Resonance

Discussion of MRI physics is beyond the scope of this forum. MR is not based on X-rays, but on radiofrequency and magnetic stimulation. Medical MRI relies on the relaxation properties of excited hydrogen nuclei in water and lipids. The MR image depends on the amount of protons (H) of each tissue that will produce a signal that will be received by antennas/arrays. H2O (water) will therefore be very important for image formation, and for contrast between structures. Bone will show little signal and brain and CSF will show a greater amount of signal. In order to selectively obtain image voxels (volume picture elements) of the subject, orthogonal magnetic gradients are applied. Although it is relatively common to apply gradients in the principal axes of a patient, MR al-

lows flexible orientations for images. Magnetic gradients are generated by three orthogonal coils, oriented in the x, y and z directions. The scanners used in medicine have a typical magnetic field strength of 0.2 to 3Teslas. On the image, the white pixels are called hyperintense, and the dark ones hypointense. Different types of acquisition of MR imaging give different information. Here are some tips regarding some of these sequences: • T1-weighted images give a lot of anatomical information as well as information about venous sinus permeability or pathologic blood. CSF is dark and fat is white in T1-weighted sequences. Lesions bright in T1weighted sequences are: fat (lipoma, dermoid), subacute haemorrhage (metHb), metastatic melanoma (melanotic), protein-containing fluid (colloid cyst) and paramagnetic agents (gadolinium). • T2-weighted images give information about oedema, arteries and sinus permeability. Water is white in T2weighted sequences, fat appears intermediate to dark, and haematomas have a variable signal intensity. Some dark lesions on T2-weighted images are acute haemorrhage (deoxyHb), haemosiderin, iron and mucinous lesions. A proton density-weighted image is an image dependent primarily on the density of protons in the imaging volume. The higher the number of protons in a given unit of tissue, the brighter the signal is. • Proton density-weighted images have excellent grey matter–white matter contrast, as their brain–CSF contrast is much lower. It is good to study basal nuclei anatomy and differentiate lacunar infarctions from Virchow-Robin spaces, and to evaluate gliosis. • FLAIR (fluid attenuation inversion recovery) is also called the “dark fluid technique”. It is used to remove the effects of fluid from the resulting images. Lesions that are normally covered by bright fluid signals on T2-weighted images are made visible by FLAIR. Its use is very common in many specific illnesses, and is very important in some of them, such as multiple sclerosis. • Diffusion is the process by which molecules or other particles intermingle and migrate due to their random thermal motion. Diffusion-weighted imaging (DWI) is sensitive to diffusion, because the diffusion of water molecules along a field gradient reduces the MR signal. In areas of lower diffusion the signal loss is less intense and the display from these areas is brighter. This will show images in which areas of rapid proton diffusion can be distinguished from areas with slow diffusion. Multislice diffusion-weighted imaging is today a standard for imaging brain infarction. The whole brain can be scanned within seconds. Certain illnesses show restrictions of diffusion, for example demyelinisation and cytotoxic oedema. Areas of cerebral infarction have decreased apparent diffusion, which results in

3.1 Basics

increased signal intensity on diffusion-weighted MRI scans. Diffusion-weighted imaging has been demonstrated to be more sensitive for the early detection of stroke than standard pulse sequences. If neoplastic illness is suspected, intravenous contrast administration is advised. Gadolinium is a non-iodinated contrast material that is hyperintense on T1-weighted images and hypointense on T2-weighted images. Normal intact blood–brain barrier is impermeable to injected contrast agents. Areas with impaired (e.g. tumour, infection, vascular anomaly) blood–brain barrier are permeable to contrast agents and show greater enhancement than normal areas. It is also possible to evaluate blood flow and CSF flow, perform MR angiography and MR perfusion. Brain perfusion MR (BPMR) techniques for stroke and tumours and angio-MR techniques for intracranial and neck vessels are used on an everyday basis in most hospitals, although they are not as easily accessible as CT techniques in some smaller hospitals. It allows us to study the haemodynamics of the parenchyma, and indicate in which location biopsy of a neoplastic lesion is most likely to give higher diagnostic rentability, or to assess the functional status and viability of brain parenchyma in stroke patients (see Sect.3.1.5.1.2.3 later in this chapter). Perfusion MRI techniques are sensitive to microscopic levels of blood flow. Contrast-enhanced relative cerebral blood volume (rCBV) is the most used type of perfusion imaging. Gadolinium is a suitable agent for perfusion imaging. The rapid passage of contrast agent through the capillary bed will induce a T2*-weighted MRI signal drop within a brain region caused by spin dephasing. The signal decrease is used to compute the relative perfusion to that region. Since the transit time of the bolus through the tissue is only a few seconds, high temporal resolution imaging is required to obtain sequential images during the washin and wash-out of the contrast material and, therefore, resolve the first pass of the tracer. The basis of spectroscopy was discovered by Edward Purcell and Felix Bloch in 1946. Magnetic resonance spectroscopy (MRS) is an analytical tool, based on nuclei that have a spin (nuclei with an odd number of neutrons and/or protons) like 1H, 13C, 17O, 19F, 31P etc. Through nuclear magnetic principles such as precession, chemical shift etc., the analysis of the content, purity, and molecular structure of a sample is possible. The spectrum produced by this process contains a number of peaks; the highs and the positions of these peaks allow exact analysis. Unknown compounds can be matched against spectral libraries. Even very complex organic compounds such as enzymes and proteins can be determined. This information will allow differential diagnosis of different lesions, such as glioma, metastasis, meningioma, abscesses etc., depending on the metabolites found on the lesion.

3.1.5.1.1.4 Cerebral Angiography

Cerebral angiography was first performed by Egas Moniz in 1927. This is an alias of Antonio Caetano de Abreu Freire (1874, Avanca, Portugal). He was awarded the Nobel Prize in medicine in 1949 for his work in describing the effects of prefrontal leukotomy in psychotic patients. Out of a total of nine patients, he successfully obtained angiographic images of two, one of whom demonstrated a fatal complication of the procedure. It was first used to evaluate intracranial mass effect from intracranial neoplasm or oedema, or to diagnose ventricular enlargement or shift. Nowadays, it is used specifically to study brain vessels. This includes the study of sub-arachnoid haemorrhage and many vascular diseases, such as aneurysms, non-aneurysmal sub-arachnoid haemorrhage, dissections, arteriovenous malformations (AVMs) of the brain and spine, arteriovenous fistulas, vasculitis and other vascular diseases. New possibilities arise from advances in materials as microcatheters, coils, stents, embolic agents, new balloons etc. Not only diagnosis, but also treatment can be achieved by endovascular means. Interventional neuroradiologists can now treat many illnesses, such as aneurysms, with a deposition of coils, close arteries or veins in order to treat aneurysms or dural fistulas with coils or balloons, treat epistaxis with embolic solid agents (particles), treat vasospasm after subarachnoid haemorrhage, close the feeders of brain AVMs with embolic liquid agents, or use direct intra-arterial fibrinolytic agents to treat thromboembolic events. All this work is achieved more efficiently and the patient gains greater benefit when there is close team work between neuroradiologists, neurosurgeons, radiosurg eons and neurologists, as a combined treatment is often the best approach to some of these lesions. A very good example of this need for a combined approach is brain AVMs, as they can be (and often are) treated sequentially by neuroradiologists, neurosurgeons and radiosurgeons. 3.1.5.1.2 Key Imaging Findings in Main Cranial Pathologies 3.1.5.1.2.1 Cranial Trauma

Trauma is one of the most important causes of mortality and morbidity in the modern world. It is the leading cause of death in children and young adults in the United States, over 50% of them from head injury. Computed tomography is very important in the evaluation of head trauma, and is the first technique to use. It is very fast (with an acquisition time of less than 1min), very sensitive to blood and good for studying bones, air (pneumocephalus) and radiologically dense foreign bodies. To maximise the diagnostic capabilities of CT in cranial trauma the images should be reviewed in different windows

3.1.5 Cerebral Diagnostics

to better visualise from narrower to wider windows early signs of stroke, parenchyma, blood and bone/air/fat. 3.1.5.1.2.1.1 Skull Fractures

Computed tomography is capable of diagnosing the three types of skull fractures, linear, depressed and diastatic. Specific reconstruction algorithms and filters will help to visualise linear and small fractures. Skull fractures may be associated with haematomas, contusions, pneumocephalus or foreign bodies, all of which can also be studied using CT. When there is an overlying scalp laceration leading to potential communication between the intracranial space and the environment, the fractures are called “open”. Otherwise they are called “closed”. Key imaging findings:

• Conspicuous fractures need no explanation on how to diagnose them. • For others, on normal CT slices look for air inside the skull (pneumocephalus), or lack of air where it should normally be, such as paranasal sinuses, mastoid cells, middle ear, or the external auditory canal. • Providing there was no pathology prior to trauma, the liquid filling these spaces may be CSF or blood, which will be hyperdense to CSF. • Look also for subdural/epidural haematomas or brain contusions. • Then look for the fracture in the vicinity of these findings on thin-slice CT with a specific bone filter/reconstruction algorithm. • You will see them as lines on bones without cortical bone. • Differentiate them from normal sutures or nerve paths (they have cortical bone; if there is any doubt, check for the same line on the contralateral side). • After that, check for associated lesions on parenchyma windows or nerve course disruption. • Remember to check on the mandible, temporo-mandibular joint (TMJ) and the orbit. • For the latter two it is better to use multi-planar reconstructions to study them on coronal, sagittal and oblique views. 3.1.5.1.2.1.2 Epidural Haematoma

Epidural haematoma (EDH) is a collection of blood between the skull and the dura, usually from arterial shearing, and rarely from veins/dural sinus. Key imaging findings:

• A biconvex (lentiform) hyperdense mass between bone and brain. • It displaces the brain tissue. • It is bound by suture lines, and will only rarely cross them. • It may cross the midline.

• These last two facilitate differential diagnosis with subdural haematoma. • Usually unilateral (95%) and supratentorial (95%), and associated with fracture in 90%. 3.1.5.1.2.1.3 Subdural Haematoma

Subdural haematoma (SDH) is a collection of blood between the dura and the arachnoid. It is caused by the tearing of the bridging veins (often after acute changes in head velocity associated with parenchymal lesions). Chronic SDHs may occur without trauma or as a result of minor trauma, especially in an elderly patient. Key imaging findings:

• A subdural haematoma is a crescent-shaped mass between the bone and brain and is often associated with other lesions (70%). • The density will decrease approximately 1.5h/day. • It can cross sutures, but not the midline (it does not cross dural insertions). • Always remember to check on the falx and the tentorium for small subdural haematomas. • CT findings are different depending on the age of the bleeding: – Hyperacute SDH: heterogeneous (40%) or hyperdense (60%). If heterogeneous, the hypodense part represents CSF or unclotted blood (acute bleeding). – Acute SDH (several days): hyperdense. – Subacute SDH (2 days to 2 weeks): isodense to brain. Be careful with subacute SDHs; because they are isodense to brain, they can be missed. The way to differentiate them from brain and to diagnose them is to check that the grey matter and sulci are in touch with bone or CSF, and the grey–white matter union is not medially displaced. Otherwise, there may be interposed subacute SDHs. If in doubt, intravenous iodinated contrast can show displaced veins and the dural capsule. – Chronic SDH (weeks to months): it can be hom*ogeneously hypodense; sometimes you can see a horizontal line separating hyperdense (inferior) and hypodense (superior) liquid in chronic SDHs in patients with anticoagulation treatment or coagulation illnesses, and heterogeneously hypo-/ isodense, with trabeculae, and may be calcified. It can also be a heterogeneous mixture of hyper- and hypodensities if there is a chronic SDH with recurrent haemorrhage representing CSF or unclotted blood (acute bleeding). – Changes with age of the haematoma can also be observed as changes in the intensity of signal on MR, but this is not commonly used in an emergency setting, and its use for child abuse dating has been questioned by some authors.

3.1 Basics

3.1.5.1.2.1.4 Traumatic Subarachnoid Haemorrhage

Subarachnoid haemorrhage (SAH) is blood between the arachnoid membrane and the pia mater of the brain. It is present in most cases of moderate to severe head trauma, which is the most common cause of SAH. Key imaging findings:

• Hyperdensity that follows the sulci over the cerebral convexities or (less commonly) in the CSF cisterns at the base of the brain. • Always look in the interpeduncular cistern and occipital horns. • Check in the vicinity of the SAH for fractures and for associated primary parenchymal brain injury such as contusions, which, together with the history of the trauma and the location of the SAH, will help in the differential diagnosis with SAH caused by an aneurysm. 3.1.5.1.2.1.5 Primary Parenchymal Brain Injury

Primary injury is defined as the injury produced at the moment of trauma as a direct consequence of the traumatic force. Secondary lesions are usually a consequence of primary ones. Primary lesions are those of the scalp, fractures, extra-axial haemorrhages, direct vascular lesions and primary parenchymal brain injury. Primary parenchymal brain injury can be divided into diffuse axonal injury, cortical contusions, parenchymal haematomas and subcortical grey matter lesions. 3.1.5.1.2.1.5.1 Diffuse Axonal Injury This pathological mechanism is a shearing injury to axons as a result of acceleration/deceleration or rotatory forces applied to the head. Typical locations of diffuse axonal injury (DAI) are at the grey–white junction, the corpus callosum, or the dorsolateral brainstem, fornix, basal nuclei, and the internal capsule. Key imaging findings:

• Computed tomography is often normal, mostly in mild DAI. • It can show mild brain oedema or micro-haemorrhage (20–50%) in the prior locations, or mass lesions (10%). • If CT is normal, and the patient is neurologically impaired, MR should be performed. • MR is more sensitive than CT in detecting DAI, which is better visualised on T2- and FLAIR-weighted images as multiple, poorly defined, hyperintense areas located in the white matter. • On T2*-weighted images they will be hypointense. 3.1.5.1.2.1.5.2 Cortical Contusions Cortical contusions are haemorrhages resulting from the brain hitting the skull. Therefore, they are frequently

found at the frontal and temporal poles. They are often associated with depressed skull fractures and are the most common parenchymal lesions. Key imaging findings:

• Early CT can be normal. • On non-contrast CT they appear as heterogeneously hyperdense areas within the brain tissue, with blood and oedema. • The oedema will become more conspicuous in further CTs. • MR is more sensitive in diagnosing them. 3.1.5.1.2.1.5.3 Parenchymal Haematomas Parenchymal haematomas are caused by the rupture of the small parenchymal vessels, and are not related to cortical contusions. They can occur some days after the trauma. Key imaging findings:

• Hyperdense blood on the white matter of the frontal and temporal lobes or basal nuclei. 3.1.5.1.2.1.5.4 Grey Subcortical Matter Lesions Grey subcortical matter lesions are odd primary brain injuries, caused by the rupture of the penetrating vessels. They are only seen in severe trauma. Key imaging findings:

• Multiple petechial haemorrhages on basal nuclei (hyperdense on non-contrast CT). 3.1.5.1.2.2 Intracranial Haemorrhage

Intracranial haemorrhage (ICH) can occur as a result of many situations such as hypertension, haemorrhagic infarction (arterial or venous), ruptured cerebral aneurysm, AVM, arteriovenous dural fistulas, amyloid angiopathy, haemorrhagic tumours or cysts, encephalitis, trauma or vasculitis. CT is the image strategy to use, as it is easily accessible, fast, and sensitive to the presence or absence of blood. 3.1.5.1.2.2.1 Parenchymal Haematomas

Hypertensive, haemorrhagic infarction and tumours. 3.1.5.1.2.2.1.1 Hypertensive Haematomas Hypertension is the most common cause of intracerebral haemorrhage in the adult population. Key imaging findings:

• Hyperdensity is located in the basal ganglia, especially in the putamen, followed by the thalamus, pons, cerebellum, and subcortical white matter. • You should ask the patient and family about hypertension history and check on CT for radiologic signs of hypertension such as lacunar infarctions and small vessel leukoencephalopathy.

3.1.5 Cerebral Diagnostics

3.1.5.1.2.2.1.2 Haemorrhagic Infarction Haemorrhagic infarction can result from either arterial (5–15% within 48 h, caused by reperfusion) or venous infarcts. Key imaging findings:

• On non-contrast CT, arterial infarction will show hypodensity with a vascular distribution caused by ischaemia, and hyperdensity if it is haemorrhagic. • Venous infarcts demonstrate patchy areas of oedema (hypodense, hyperintense on T2-weighted and FLAIR images) that do not show vascular distribution; they are often bilateral and often associated with haemorrhages (hyperdense, hyperintense on T1-weighted images, hypointense T2-, T2*-weighted images). 3.1.5.1.2.2.1.3 Intracranial Haemorrhage Intracranial tumours may present as ICH. Contributing factors include neovascularity, necrosis, direct vascular invasion, and a coagulopathic state. Primary tumours prone to haemorrhage include glioblastoma multiforme, oligodendroglioma, pituitary adenoma and haemangioblastoma. Metastases particularly prone to haemorrhage include melanoma, renal cell carcinoma and choriocarcinoma, as well as lung carcinoma. Key imaging findings:

• Extensive oedema surrounding a haematoma should raise the suspicion that there may be an underlying lesion. • Contrast CT or MRI should be performed in this situation and any known primary extracranial tumour should be checked for. 3.1.5.1.2.2.2 Subarachnoid Haemorrhage and Vascular Malformations, Aneurysms, Benign SAH, AVM, Cavernomas, Venous Angiomas, Capillary Telangiectasias

Intracranial vascular malformations are normally divided into four or five types, depending on whether or not you include aneurysms: aneurysms, AVMs, cavernous angiomas, capillary telangiectasias, and venous angiomas. 3.1.5.1.2.2.2.1 Aneurysms A ruptured intracranial aneurysm is the most common cause of non-traumatic SAH. CT is the first imaging strategy for diagnosis of SAH. MRI is also useful for detecting acute subarachnoid haemorrhage, but it has a heterogeneous appearance on MRI sequences, depending on the age of the SAH; T2*-weighted sequences are very sensitive to blood. Once SAH is diagnosed, angiography should be performed. In some institutions, angioCT is performed as soon as the SAH is diagnosed, as it is also a good diagnostic tool and will diagnose most aneurysms. MR angiography is also useful, mostly in evaluat-

ing the three-dimensional anatomy of giant aneurysms in relation to the brain or cranial nerves. If angio-CT and angio-MR are not available in your hospital, angiography should be performed as soon as possible. Angiography remains the gold standard for the diagnosis of cerebral aneurysm. Key imaging findings:

• On non-contrast CT, acute SAH is hyperdense compared with brain. • After 1week, blood has cleared from the CSF and is therefore not visible on CT. • Depending on the location of the SAH, the location of the aneurysm can be suspected: basal cisterns – aneurysms in the Circle of Willis, posterior communicating artery; Sylvian fissure – middle cerebral artery, terminal internal carotid, posterior communicating artery aneurysms; interhemispheric fissure – anterior cerebral and anterior communicating artery aneurysms; fourth ventricle – posterior inferior cerebellar artery aneurysms. • The study of aneurysmatic SAH is better performed by angiography. • Angiography should include both carotid and both vertebral arteries (called “four vessels angiography”), as well as the three communicating arteries (some authors call this “seven vessels angiography”). • Information given should always include location, size and shape of the aneurysm, neck size, perforating arteries, possibility of collateral circulation, vasospasm, the possibility of more than one aneurysm and accessibility for treatment, endovascular or surgical based on proximal vessel status (internal carotid artery, common carotid artery), arteries arising from the sac of the aneurysm, the ratio dome–neck, etc. To determine which aneurysm has ruptured when multiple aneurysms are present, it is helpful to correlate aneurysm location with the clot location. Ruptured aneurysms tend to be larger, more irregular, or have outpouchings. 3.1.5.1.2.2.2.2 Benign, Perimesencephalic or Idiopathic SAH Benign, perimesencephalic or idiopathic SAH – if no lesion is found on angiography, benign or idiopathic SAH is diagnosed. Key imaging findings:

• Often located perimesencephalically, it is thought to be caused by venous rupture, probably due to thrombosis. • They have a good prognosis. • Always check for aneurysms, arteriovenous fistulas, AVMs, and dural fistulas of the cervical spine or spine tumours before diagnosing benign SAH.

3.1 Basics

3.1.5.1.2.2.2.3 Arteriovenous Malformations Arteriovenous malformations (AVMs) are direct artery to vein fistulae. They are thought to cause haemorrhage at a rate of 4% per year. They usually have tortuous feeding arteries, a dense nidus, and large draining veins that may be seen on CT. AVMs may have associated feeding artery or venous drainage aneurysms secondary to the high flow. If the AVM is treated, these flow-related aneurysms will regress. AVMs most commonly present as an ICH or seizure and less commonly as a focal neurologic deficit from vascular steal or mass effect. Key imaging findings:

• Arteriovenous malformations appear isodense on CT with occasional calcifications on non-contrast studies and enhancement of serpentine vessels after contrast administration. • MRI will show flow voids, and is useful in defining the cerebral anatomy around the AVM as well as the oedema it is causing. • The typical appearance of AVM on MRI is a tight “honeycomb” of flow-voids. • If an AVM is suspected the patient should undergo cerebral angiography to define the number, location and size of the feeding arteries, the size and location of the nidus, the number and size of the draining veinsrelated aneurysms or stenosis and degree of fistulous component. • All these items are important in deciding how to treat the AVM.

treated. They are collections of veins within the periventricular white matter that empty into a larger, transcortical draining vein. Key imaging findings:

• They may not be visible on non-contrast CT, and subtle on MR, but appear as a tuft of vessels near the ventricle on contrast CT or MRI. • Angiography shows normal arterial phase and venous structures with a “Medusa head” appearance. • They are sometimes associated with cavernous angiomas, which are the ones supposed to be really responsible for the rare “bleeding venous angiomas” reported. 3.1.5.1.2.2.2.6 Capillary Telangiectasias Capillary telangiectasias are nests of dilated capillaries that may have normal brain tissue interposed. These are often found in the pons, but also in the cerebral cortex or spinal cord. Key imaging findings:

• On CT and angiography they are usually not visible. • On MRI, capillary telangiectasias may be absent or show small, poorly defined areas of enhancement. • They may be invisible on angiography or show small areas of vascular blush. 3.1.5.1.2.3 Occlusive Cerebrovascular Disease

• The classic popcorn-like appearance on CT and MRI is caused by haemorrhage of multiple ages and calcification. • There is often a classical haemosiderin ring (a hypointense ring on T2-weighted images). • Cavernous angiomas have a very variable appearance. • Always check on a T2* sequence to look for other cavernomas (seen as hypointense on T2*). • They are angiographically not visible, slow-flow lesions, and show minimal or no enhancement. • They are angiographically invisible. • They are sometimes associated with venous angiomas.

Ischaemic stroke continues to be a major cause of death and disability throughout the world. The most frequent cause of ischaemic stroke is atherothrombosis, and the most frequent location of the plaque is the carotid bifurcation. Also related to neurosurgery, patients with subarachnoid haemorrhage are at risk of serious morbidity and mortality from ischaemia and infarct secondary to cerebral vasospasm. The role of neuroimaging in the evaluation of acute stroke has changed dramatically over the past decade. Previously, it was used to provide anatomic imaging that indicated the presence or absence of acute cerebral ischaemia and excluded lesions that produce symptoms or signs mimicking those of stroke, such as haemorrhage and neoplasms. The introduction of thrombolysis has changed the goals of neuroimaging from providing anatomic information to providing physiologic information to determine which patients might benefit from therapy. CT should be performed for the immediate diagnosis of stroke to exclude haemorrhagic and other causes of neurologic deficit, and perfusion studies should be performed after that.

3.1.5.1.2.2.2.5 Venous Angiomas Venous angiomas are thought to be extreme variants of normality and do not bleed. Therefore, they should not be

• Hyperacute (≤ 12 h) cerebral infarcts were typically said not to be detected on CT scans, but nowadays are

3.1.5.1.2.2.2.4 Cavernous Angiomas Cavernous angiomas are composed of cystic vascular sinusoids lined with a vascular endothelium monolayer and no interposed neural tissue. They can present as haemorrhage (0.5% per year) or seizure. Key imaging findings:

Key imaging findings:

3.1.5 Cerebral Diagnostics

• • • •

often detected as subtle changes in cortical–subcortical (grey–white matter) differentiation or the very subtle effacement of the sulci. Occasionally, a hyperdense artery is visible or the basal nuclei become hypodense. Acute infarcts (12–24 h) will show loss of cortical– subcortical (grey–white matter) differentiation or sulcal effacement. At 24–72h the infarct becomes a more defined, wedgeshaped hypodense area, and it becomes oedematous. At 4–7days the infarct becomes more hypodense and will show gyral enhancement after contrast administration. Later scans (months to years) will show an area of encephalomalacia and volume loss.

Computed tomographic perfusion studies can delineate ischaemic zones, the infarct core (supposedly “dead”), “penumbra” and mismatch. In particular, significant emphasis has been placed on the delineation of the ischaemic penumbra, also called “tissue at risk”, as it is theoretically the salvageable parenchyma. Mismatch on BPCT is measured by comparing cerebral blood flow (ischaemic parenchyma) with cerebral blood volume (supposedly similar to diffusion, both supposedly dead parenchyma, although it has now been seen that it is not always dead). Computed tomographic angiography can define the occlusion site, depict arterial dissection, grade collateral blood flow, and characterise atherosclerotic disease. Computed tomography offers a number of practical advantages over other cerebral perfusion imaging methods, including its wide availability. Using perfusion CT and CT angiography to define new individualised strategies for acute reperfusion will allow more acute stroke patients to benefit from thrombolytic therapy. Magnetic resonance imaging demonstrates hyperacute and acute infarction better than CT. Diffusion will be restricted almost from the beginning of ischaemia. MRI will show sulcal effacement and loss of grey–white differentiation at ≤12h. From 12 to 24h, the area of the infarct develops hyperintensity on T2-weighted images. Contrast enhancement of the affected parenchyma begins to appear at 24–72h, and becomes more striking between days 4 and 7. MRI perfusion and diffusion studies can delineate ischaemic zones, penumbra and mismatch (between diffusion and perfusion). Diffusion is supposedly dead parenchyma, but recent experience shows that it is not always so. Angiography plays an important role in ischemic cerebrovascular disease. It is the gold standard for diagnosing ischaemic disease of the main arteries. It may be used to treat patients with mechanical thrombus extraction techniques and intra-arterial thrombolytic agents in the hyperacute state. It can also be used to diagnose carotid extraor intra-cranial stenosis and to decide the better treatment option (pharmacological, surgical or endovascular).

3.1.5.1.2.4 Intracranial Tumours

Describing the imaging characteristics of each type of brain tumour is beyond the scope of this discussion. Nevertheless, we will provide an overview of the characteristic imaging features of common primary brain tumours and metastatic tumours. 3.1.5.1.2.4.1 Intra-Axial Tumours

Intra-axial tumours can be divided in primary and metastatic tumours. Primary tumours include gliomas (astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, oligodendroglioma, and ependymoma), tumours of neuronal origin, pineal region tumours and CNS lymphomas. Metastatic disease may affect not only the brain parenchyma, but also the leptomeninges and calvarium. 3.1.5.1.2.4.1.1 Primary Tumours 3.1.5.1.2.4.1.1.1 Gliomas Gliomas represent approximately 40% of all intracranial tumours. Astrocytic tumours are the most common of the glial tumours. Typically, they are infiltrative or diffuse, but some specific subtypes are circ*mscribed. Infiltrative astrocytic tumours include astrocytomas, anaplastic astrocytomas, glioblastoma multiforme, oligodendroglioma and ependymoma. Circ*mscribed tumours of astrocytic origin include pilocytic astrocytomas and subependymal giant cell astrocytomas. Key imaging findings:

• On non-contrast CT, gliomas may be evident only as white matter oedema or an ill-defined isodense white matter lesion. • They are usually found supratentorially in adults, but more frequently infratentorially in children. • With the addition of contrast, low-grade astrocytomas enhance poorly. • Anaplastic astrocytomas and glioblastomas show stronger enhancement patterns and may have areas of heterogeneity. • These high-grade gliomas often show spread of oedema or enhancement along white matter tracts such as the corpus callosum, which indicates infiltration of the tumour into normal brain. • They may also show central areas of haemorrhage or necrosis. On MRI, low-grade astrocytomas are iso- or hypointense on T1-weighted images and hom*ogeneously hyperintense on T2. • They may show minimal to no enhancement with gadolinium. • Anaplastic astrocytomas and glioblastoma multiforme are iso- to hypointense on T1 and heterogeneous on T2, with strong heterogeneous enhancement. • The T2 signals are more sensitive to oedema, which often correlates with the degree of tumour infiltration.

3.1 Basics

3.1.5.1.2.4.1.1.2 Pilocytic Astrocytomas Pilocytic astrocytomas are tumours of glial origin and are more common in children and young adults. Key imaging findings:

• Well-circ*mscribed tumours located near the third or fourth ventricles that arise from the cerebellum and optic chiasm/hypothalamus. • They frequently appear cystic with an enhancing, solid mural nodule, without surrounding oedema. • The cyst is hypodense, hyperintense on T2-weighted and FLAIR images, and hyperintense to CSF on T1weighted images. • Check for leptomeningeal spread on contrast-enhanced MRI. 3.1.5.1.2.4.1.1.3 Oligodendrogliomas Oligodendrogliomas are relatively slow-growing tumours arising from oligodendrocytes. Key imaging findings:

• Heterogeneous, enhancing mass in the cerebral hemispheres (especially frontal lobes), often with calcification. 3.1.5.1.2.4.1.1.4 Ependymomas Ependymomas are derived from ependymal cells, which line the ventricular system. Key imaging findings:

• Most of these tumours are found infratentorially, arising in the fourth ventricle (<3years old). • The supratentorial ependymomas (> 3 years old) are usually found outside the ventricular system and may resemble astrocytomas on imaging. • Fourth ventricular ependymomas are isodense with some areas of hyperdensity representing calcification (50%) on non-contrast CT and mildly heterogeneously enhancing on MRI. • They appear to “fill” the ventricles, may extend up or down the fourth ventricle, and have a “plastic” appearance. • They are iso/hypointense on T2-weighted MRI. Check for hydrocephalus, which occurs very often. 3.1.5.1.2.4.1.2 Metastases Metastases represent one-quarter to one-third of all adult brain tumours. Common metastases to brain include lung, breast, melanoma, renal cell carcinoma, and gastrointestinal (GI), and genitourinary (GU) tumours. Between 60 and 85% of all metastases are multiple. Key imaging findings:

• On non-contrast CT, metastases are iso- or hyperdense lesions usually found at the grey–white matter junction, but which can occur anywhere in the brain.

• With contrast administration, metastases will enhance either hom*ogeneously or peripherally. • On MRI, most metastases are hypointense on T1weighted images, hyperintense on T2-weighted images and enhance with gadolinium in the same pattern as on CT. • Cerebral metastasis should be considered first in the differential diagnosis of any patient with multiple lesions, since primary brain tumours are usually solitary. • Extensive vasogenic oedema generally surrounds the tumour. If the metastases are haemorrhagic, you will have to consider them when you find parenchymal haematoma surrounded by extensive oedema. • Metastases prone to being intra-axial are those from the lung, breast, melanoma and colon; extra-axial are usually those from the breast, lymphoma, prostate and neuroblastoma; and metastases that are haemorrhagic are melanoma and kidney, thyroid and choriocarcinoma. • Although less common, a cerebral abscess may mimic metastases on imaging and should be ruled out either clinically or by biopsy, diffusion or spectroscopy. 3.1.5.1.2.4.2 Extra-Axial Tumours

The distinction between intra-axial and extra-axial tumours is important in surgical planning and prognosis. Extra-axial tumours are generally benign tumours, such as meningiomas, vestibular schwannomas, pituitary tumours, dermoids and epidermoids. Malignant extra-axial tumours include metastases, malignant meningioma, sarcoma and chordoma. 3.1.5.1.2.4.2.1 Meningiomas Meningiomas are the most common primary intracranial tumour of non-glial origin. They are derived from arachnoidal cap cells and can be found on any surface carrying arachnoid tissue. The most common locations are the sagittal sinus (parasagittal), the cerebral convexity, the sphenoid ridge, the olfactory groove and the posterior fossa. Key imaging findings:

• Plain skull films may show hyperostosis adjacent to a meningioma and dilated vascular channels leading to the tumour. • CT will show a well-circ*mscribed, hyperdense mass that abuts the dura. • Some meningiomas show calcification on CT and demonstrate peritumoral oedema. • They enhance strongly with intravenous contrast. • On MRI, meningiomas are isointense to brain, enhance strongly and often have a dural tail corresponding to the migration of tumour cells. • Angiography can demonstrate an extracranial blood supply as well as parasitised pial vessels.

3.1.5 Cerebral Diagnostics

• There may be a persistent vascular blush. • Angiography can help decide if presurgical embolisation for surgical comfort is safe and advisable. 3.1.5.1.2.4.2.2 Vestibular Schwannoma Vestibular schwannoma, or acoustic neuroma, is a benign tumour arising from the nerve sheath of the vestibular portion of the eighth cranial nerve. Key imaging findings:

• They are seen only in the cerebellopontine angle, often with extension into the internal acoustic canal (IAC). • On CT they are iso- or hypodense and enhance strongly. • The bone windows may show widening of the IAC. On MRI, vestibular schwannomas are well-circ*mscribed, enhancing masses that extend into the IAC. • They are hyperintense on T2-weighted images. • Meningiomas should be considered in the differential diagnosis: schwannomas are lesions centreed on the IAC, with widening of the IAC, no dural tail, noncalcified, iso/hyperdense to brain and hyperintense on T2-weighted images; meningiomas have a dural tail, hyperostosis, they are isointense to cortex on T2weighted images, calcified and are not centred on the IAC, with no widening of the IAC. 3.1.5.1.2.4.2.3 Pituitary Adenomas Pituitary adenomas represent approximately 10% of all primary intracranial tumours. They are grouped into microadenomas (≤10mm) and macroadenomas (> 10mm). Most adenomas are slow-growing and 50% are endocrinologically active, the most common type being the prolactinoma.

Key imaging findings:

• Microadenomas appear hypodense on contrast-enhanced CT and MRI because there is stronger enhancement of normal pituitary. • Macroadenomas appear as isodense intra- and suprasellar masses that enhance strongly on CT and MRI. • Cysts, haemorrhage, or necrosis may also be seen in the macroadenoma. 3.1.5.1.2.5 Hydrocephalus

Hydrocephalus is a condition in which the ventricles become enlarged and intracranial pressure becomes elevated. It is commonly divided into two types: communicating, which is due to the inability of the arachnoid granulations to adequately absorb CSF and non-communicating, which is caused by an obstruction of CSF flow within the ventricles. Communicating hydrocephalus may occur after subarachnoid haemorrhage if the subarachnoid blood and its by-products impair the function of the arachnoid villi. Nowadays, these concepts are changing, and hydrocephalus is supposedly caused by the abnormal pulsatility

of CSF, which would explain why ventriculostomy may help in hydrocephalus treatment. Key imaging findings:

• On non-contrast CT and MRI, these patients have symmetric enlargement of all ventricles, which is particularly noticeable in the third ventricle and temporal horns of the lateral ventricles. • Non-communicating hydrocephalus may occur with intraventricular tumours or cysts. • In these cases there is enlargement of the ventricles proximal to the occlusion and normal-sized ventricles distally. 3.1.5.1.2.6 Cerebral Abscess

Cerebral abscesses are foci of parenchymal bacterial infections that result from contiguous spread, direct inoculation, or haematogenous spread. Haematogenous spread from an extracranial site such as the lung often results in multiple lesions, whereas local spread from mastoid air cells or paranasal sinuses usually creates a solitary lesion. Key imaging findings:

• The appearance on CT or MRI depends on the age of the abscess. • In the early cerebritis stage of a cerebral abscess (3–5days), CT or MRI may show a small, ill-defined area of mild enhancement at the grey–white interface. • From 5days to 2weeks, the late cerebritis stage develops, and CT and MRI show a thin ring of enhancement around a necrotic centre. During the early and late capsule stages (weeks to months), a thicker, more defined ring of enhancement forms, with a surrounding area of oedema. On diffusion images it shows restriction (hyperintense). Selected Reading 1. Scott W (2002) Magnetic resonance imaging of the brain and spine, 3rd edn. Lippincott Williams & Wilkins, Philadelphia 2. Osborn A, Blaser S, Salzmann K (1997) Diagnostic imaging: brain. In: Morris, P (ed) Practical neuroangiography. Lippincott Williams & Wilkins, Philadelphia

3.1.5.2

Electroencephalography

Anders Fuglsang-Frederiksen, Peter Orm Hansen Electroencephalography (EEG) is the recording of electrical activity generated in the cerebral cortex. The signal is a summation of excitatory and inhibitory synaptic potentials on cortical neurones. These potentials

3.1 Basics

rely on the functionality of cortical neurones as well as afferent input to the cortex from subcortical structures, e.g. the thalamus. Abnormalities on the electroencephalogram may reflect either disturbance of cortical neurones or the subcortical input to cortical neurones. Many abnormalities seen in the electroencephalogram are non-specific, as different diseases may produce similar EEG abnormalities. It is not possible from the scalprecorded potentials to identify the mechanism disturbing the synaptic events responsible for abnormal EEG waves. Furthermore, electrical activity is not equally well recorded in every part of the brain: inter-hemispheric and mesial cerebral cortices, as well as the basal parts of the brain, are less responsive to the scalp electrodes than the cortex over the lateral convexities and potentials originating from the surface of the gyri are more readily recorded than those originating from the sulci. Consequently, a large cortical area must be involved in a disturbance in order to be shown on the electroencephalogram. In addition, electrical abnormalities may be of such low amplitude that scalp electrodes do not detect them. Despite these limitations, some abnormalities seen on EEG are suggestive of specific diseases, e.g. epilepsy, metabolic encephalopathy and herpes encephalitis. Approximately 20 electrodes placed symmetrically on the scalp in the midline and on both sides of the head in a standardised way (10–20 system) pick up the electrical signals. For standard purposes surface electrodes are often used, but needle or wire electrodes are used under certain circ*mstances. The recording electrodes are interconnected, and the potential difference between pairs (or groups) of electrodes is either printed on paper or digitised and stored for inspection. The duration of standard EEG is 30–45min. The patient is awake, but with eyes closed. Several provocations are applied to the patient in order to provoke EEG abnormalities not otherwise seen: stroboscopic flash stimulation (1–60 Hz), hyperventilation and sleep (or a doze). In patients with decreased consciousness, reactivity to applied stimuli (commands, eye opening, painful tactile stimuli) is tested. The frequency of EEG activity is referred to as alpha activity if it is in the range 8–13 Hz. Activity with frequencies above 13Hz is referred to as beta activity. Slow wave activity is known as theta activity when the frequency is within the range 4–7Hz and as delta activity when it is below 4Hz. The electroencephalogram is traditionally displayed (or printed) as eight or 16 continuous graphs showing the spatial and temporal distribution of the electrical activity recorded. In the case of digital EEG, the arrangements of pairs (or groups) of electrodes can be changed during inspection in order to examine different parts of the cerebral cortex and elucidate various aspects of its electrical activity.

The normal EEG has an amplitude of 10–100 μV. Frequency varies according to different activities. In the adult who is awake, 8–13Hz activity is seen. Eye opening, drowsiness and mental activity attenuate the activity. Activity above 13Hz may normally be seen in the frontal regions and is more pronounced in patients receiving, for example, benzodiazepines. Small amounts of activity ranging from 4 to 7Hz are normally seen in the temporal regions, especially in children, young people and after the age of 50–60years. Activity below 4Hz is not normally seen in adults except during the deeper stages of sleep. In newborn and young children low frequency activity dominates, but disappears with maturation. The abnormal EEG is characterised by either low amplitude of background activity, excessive slow activity (<8Hz) or spikes and sharp waves (high amplitude potentials of short duration). Abnormal EEG activity may appear focal, diffuse or generalised. Low amplitude indicates cortical disturbance. When localised it may correlate to atrophy, porencephaly and subdural haematoma. General attenuation of amplitude is associated with more diffuse depression of cortical activity, as seen in degenerative brain disorders and following cerebral anoxia. In its most pronounced form no electrocerebral activity is recorded, which may support the diagnosis of brain death. Focal slow waves correlate to a localised brain lesion, e.g. tumour, infarct and haemorrhage. When the slow activity is more diffusely distributed, disturbance of afferent input to cortical neurones, as seen following lesions in the posterior fossa or hydrocephalus, may be suspected. In encephalopathy, e. g. encephalitis, slow waves are often seen to be diffuse or generalised. Spikes and sharp waves are seen in patients suffering epilepsy – either during seizure or inter-ictally. They may appear generalised, often followed by a high amplitude slow wave as in absence epilepsy or during generalised tonic-clonic seizures. Localised spikes and sharp waves may be suggestive of a focal cortical lesion, e.g. tumour, infarct or abscess, but can also be seen without any structural lesion. Spikes may be seen in complex discharges appearing repetitively in one hemisphere (periodic lateralised epileptiform discharges, PLEDs) which may be associated with a hemisphere lesion, e.g. tumour, infarct, metabolic encephalopathy and herpes encephalitis. 3.1.5.2.1 Clinical Application

Electroencephalography is a dynamic examination in which brain function is measured over time. It may detect abnormalities not necessarily related to structural lesions in the brain, as in encephalitis, encephalopathy and idiopathic epilepsy, where MRI and CT may not show abnormalities. Compared with other tests of brain physiology (e.g. functional MRI and positron emission

3.1.5 Cerebral Diagnostics

tomography), EEG has a much shorter temporal delay (a few milliseconds). EEG is readily available and has relatively few resource requirements. Technologists have to be trained to place electrodes correctly and to detect and eliminate artefacts. High quality recording, in addition to systematic and rational interpretation of the electroencephalogram, is also of critical importance to the usefulness of EEG. Electroencephalography is intended to answer specific questions about the brain function and is not just a screening procedure, and so clinical information on the patient and a precisely formulated questionnaire need to be available in order to design the EEG examination and to interpret the encephalogram.

the adjacent non-neoplastic, transformed brain tissue. Abnormalities are caused by destruction of the neurone by tumour growth or by metabolic changes induced by changes in blood flow. More diffuse EEG changes are seen in patients with increased intracerebral pressure and hydrocephalus. After head trauma, transitory generalised slowing of the background activity is frequently seen. If the changes persist, it suggests a cerebral contusion even if no structural abnormalities are seen on CT. During the first 3months, it is not possible from the EEG to predict whether or not post-traumatic epilepsy will develop. In subdural haematoma low amplitude background activity may be seen unilaterally. 3.1.5.2.4 Decreased Consciousness

3.1.5.2.2 Epilepsy

Electroencephalography is used to classify different types of epilepsy in order to optimise medical treatment and to make a prognosis. Most electroencephalograms of patients with suspected epilepsy are not obtained during a seizure, but electrical abnormalities are often found inter-ictally. However, inter-ictal findings have to be interpreted with care, as there is only a vague correlation with the recurrence of the seizures. Some patients, with a doubtless clinical diagnosis of epilepsy, show normal electroencephalograms, even on repeated examination. The abnormalities seen in epilepsy are spikes and sharp waves in addition to increased slow wave activity. These latter findings are non-specific, and are also seen in encephalopathy, brain tumour, migraine and following head trauma, and therefore need to be interpreted together with clinical information. In order to precisely locate cortical epileptic foci prior to epilepsy surgery, EEG may be performed after craniotomy with specialised electrodes on the surface of the brain (electrocorticography). 3.1.5.2.3 Focal Brain Lesions

Electroencephalography is no longer central in the diagnosis of focal brain lesions, as imaging techniques have developed and spread widely. The role of EEG is to detect neuronal electrical dysfunction in the absence of (macroscopic) structural lesions, as well as to assess dysfunction created by known lesions (e.g. electrocorticography is done as intraoperative monitoring to search for epileptic foci in the vicinity of a cortical tumour, in order to include the electrically abnormal cortex in the removal). The abnormalities seen in focal brain lesions are slow focal activity, with or without spike activity. The changes are non-specific, but a focal lesion is particularly suspected when slow wave activity occurs continuously with variable amplitude and shape, and if it is present both in the waking and sleeping states. Brain tumours are electrically quiet, and associated EEG abnormalities are localised to

In comatose patients, EEG can provide useful prognostic information and detect potentially treatable causes. EEG is useful to determine whether or not apparent decreased consciousness may be caused by reasons other than altered brain electrophysiology, i.e. psychogenic mechanisms or locked-in syndrome. EEG can also be utilised to evaluate the extent of pathology causing impaired consciousness (focal, multifocal or diffuse). In addition, EEG is often applied to prove progress in cerebral function, despite minor or no change in the clinical evaluation, as electrophysiological improvements may precede clinical betterment. Moreover, EEG may recognise epileptic activity in patients with impaired consciousness, e.g. nonconvulsive seizures or “status epilepticus” and periodic discharges (e.g. PLEDs). Non-convulsive status epilepticus is a condition that is often overlooked in neurosurgical intensive care units, and is associated with a worse outcome. About 20% of patients in neurosurgical intensive care units because of moderate to severe head trauma may develop convulsive and non-convulsive seizures during the first 2weeks. The non-convulsive seizures are not detected if an electroencephalographic examination is not performed. This raises the question of continuous electroencephalographic recording in intensive care units to diagnose potentially treatable conditions, which, if left untreated, will worsen the neurological condition, e.g. non-convulsive seizure and cerebral ischaemia at a reversible stage. Continuous electroencephalographic recording in intensive care units also implies the possibility of directing the depth of anaesthesia in, for example, patients with head injury. In comatose patients, the EEG may contain prognostic data, as poor outcome is associated with alpha coma, burst suppression and periodic discharges. Alpha coma is the appearance in a comatose patient of rhythmic activity of normal frequency (8–13Hz), often with maximal amplitude frontally, but showing no reactivity to eye opening or other stimuli. Burst suppression indicates generalised bursts of slow wave activity of high amplitude, with or

3.1 Basics

without spikes, occurring repetitively and separated by intervals with a pronounced decrease in amplitude – and sometimes electrocerebral inactivity. The periodic discharges seen in comatose patients are generalised spikes and sharp waves appearing repetitively once or twice every second. These EEG characteristics, which indicate a bad prognosis, are non-specific, and may also be seen in reversible, relatively benign conditions such as deep anaesthesia, drug overdose and hepatic or renal failure.

3.1.5.2.7 Brain Death

Brain death is the clinical diagnosis of irreversible loss of brain function. On EEG brain death is characterised by electrocerebral inactivity. Electrocerebral inactivity is non-specific, and is also seen in, for example, severe hypothermia and overdose of CNS depressants. In the right clinical context, electrocerebral inactivity supports the brain death diagnosis. Therefore, similar to other EEG abnormalities, clinical information must be taken into consideration when an EEG is interpreted.

3.1.5.2.5 Metabolic Encephalopathy

Metabolic derangement diffusely affects neuronal activity in the brain, and is a common cause of impaired consciousness. The abnormalities seen in metabolic encephalopathies depend on the degree of derangement and ranges from a slight decrease in the frequency of the background activity (8–9 Hz) to continuous slow wave activity (0.5–3Hz) with a spike and sharp waves. The EEG abnormalities reflect the clinical findings in the patients ranging from mildly decreased alertness to deep coma. The EEG changes seen in metabolic encephalopathies are non-specific, but may provide information on the aetiology: slow wave activity appearing as bilateral, synchronous triphasic potentials of high amplitude is suggestive of a metabolic cause of the altered state of consciousness. Decreased energy metabolism, seen in hypothyroidism, anoxia and hypothermia, often correlate to generalised attenuation of amplitude of the background activity. Plenty of generalised, rhythmic activity of >13Hz suggests intoxication with central nervous system depressants. 3.1.5.2.6 CNS Infections

Continuous, slow focal activity and PLEDs in the frontal or temporal regions are characteristic EEG changes seen in patents with herpes encephalitis. The changes often appear during the first 2 weeks of the disease and may precede changes on CT. Diffuse slow wave activity is seen in the encephalitis of other viral causes than herpes virus. Even though these changes are non-specific, doubt will be raised if the EEG of a patient with suspected encephalitis turns out to be normal. In viral meningitis no consistent changes are seen, but in bacterial meningitis reduced frequency and decreased amplitude of background activity may be seen. The EEG changes seen in meningitis reflect that inflammation of the meninges has spread to the brain tissue, i.e. meningoencephalitis. In cerebritis, EEG changes are often seen before a cerebral abscess is formed and visualised on CT. EEG abnormalities include slow focal wave activity with or without spikes and sharp waves.

Suggested Reading 1. Aminoff MJ (1999) Electroencephalography: general and clinical applications. In: Aminoff MJ (ed) Electrodiagnosis in clinical neurology, 4th edn. Churchill Livingstone, Philadelphia, pp 37–80 2. Vespa P (2005) Continuous EEG monitoring for the detection of seizures in traumatic brain injury, infarction, and intracerebral hemorrhage: “to detect and protect”. J Clin Neurophysiol 22(2):99–106 3. Claassen J, Mayer SA, Hirsch LJ (2005) Continuous EEG monitoring in patients with subarachnoid hemorrhage. J Clin Neurophys 22(2):92–98

3.1.5.3

Evoked Potentials and Their Use in Neurosurgical Practice

Jan Jakob A. Mooij, H.L. Journée 3.1.5.3.1 Introduction

• Evoked potentials form a variety of induced neurophysiological responses that can evaluate the function of certain specific components of the central and/ or peripheral nervous system. Therefore, they can be used in the diagnostic work-up of various neurological symptoms and diseases. • In neurosurgical practice, they are useful for the monitoring of certain functions that are at risk during surgical procedures. • Intraoperative monitoring in general is based on the reversibility of “events”, abnormal values that are recognised during such monitoring; reversibility means that there is a time frame during which measures can ideally be taken to restore the system back to normal. A well-known example is the constant measurement of blood pressure during surgery, where on the detection of deviating values measures are taken to restore the pressure immediately by adapting fluid delivery, drug application etc. • In a comparable way, evoked potentials measurement can be used as a specific monitoring tool during neu-

3.1.5 Cerebral Diagnostics

rosurgery, but also during other kinds of surgery, like scoliosis surgery or thoraco-abdominal vascular surgery. • The various evoked potentials that are currently in use for this purpose will be dealt with in this chapter. 3.1.5.3.2 Somatosensory Evoked Potentials

Somatosensory evoked potentials (SSEPs) are elicited by electrically stimulating a peripheral nerve – mostly the median nerve at the wrist and/or the tibial nerve at the ankle – and recorded on the scalp in the sensory area. In the case of median nerve stimulation, responses can also be recorded for the neck area (see Fig.3.1.9). In order to obtain responses, an averaging technique is necessary, using 50–300 stimuli; this takes time, 30 s

20 ms

C z’

to 3min, which means that changes are detected with a delay. With the SSEPs one measures the conduction along the peripheral nerves, dorsal columns and central sensory pathways of the nervous system. The conduction time of action potentials from the neck to the scalp is defined as the central conduction time (CCT). Intraoperative SSEP measurements are used in brain surgery (aneurysms, tumours, cortical surface mapping, posterior fossa/brain stem procedures), in surgery involving the spinal cord (tumours, vascular malformations) and the vertebral column (scoliosis, reconstructions) [1, 2]. In thoraco-abdominal vascular surgery the spinal cord can be at risk as well, due to interference with the vascular supply to the cord, which is the reason why SSEPs are also used in these procedures in some centres [3–6].

C 4’

0.001 mV

cct N20

Fz L

R Fz

C 3’

C z’

P/N 14

Neck electrode

C 4’

N. medianus stim.

N. tibialis stim.

Fig.3.1.9 Set-up of somatosensory evoked potentials (SSEP) monitoring. Stimulation electrodes are placed on the median nerve at the wrist, or on the posterior tibial nerve at the ankle. Stimulation is usually performed with 200-μs wide rectangular monophasic pulses of 20–30mA at a rate of 2–4Hz. Details of the parameters are given in Table3.1.1. Recording electrodes are mounted on the scalp, C3 and C4 for median nerve stimulation, and C’z for tibial nerve stimulation, with the position Fz as a reference. A dorsally placed neck electrode detects a locally generated positive peak, P14. The central conduction time (cct) is defined as the time difference between the negative cortical peak, N20, measured at C3 or C4, and P14. The cct is usually 5.5ms and depends markedly on the temperature. Between 50 and 300 signals have to be averaged in order to obtain a clear response wave. Continuous stimulation can be performed, especially during periods of risk, leading to a continuous update of the averaged signal, called running averaging

3.1 Basics

When “events” are detected (see above) the surgeon and the anaesthetist can react, for example by raising the blood pressure, by relaxing retractors, removing temporary clips or by changing the position and angle of the vertebral column. The reliability of the method depends on the aim of the monitoring. Only the sensory system is tested; thus, inadvertent immanent or permanent damage to the motor system cannot be detected [7, 8]. Somatosensory evoked potentials signals are sensitive to anaesthetic drugs; therefore, no inhalation anaesthesia should be used, and it is important to have stable anaesthesia and baseline recordings with adequate setting of stimulus and recording parameters in each individual patient. The operating room is not very “monitoring friendly”, which means that interference with for example 50- or 60-Hz electromagnetic waves may disturb or lengthen the averaging process. This results in less reliable monitoring. Some basic values for SSEP monitoring are given in Table3.1.1. An example of intraoperative SSEP monitoring is shown in Fig.3.1.10. 3.1.5.3.3 Motor Evoked Potentials

Motor evoked potentials (MEPs) are elicited by the transcranial stimulation of axons in the corticospinal tract, and are recorded by the transcutaneous or intramuscular measurement of muscle action potentials in relevant muscles. The stimulation can be performed magnetically or electrically. Magnetic stimulation is used in patients who are awake for diagnostic work-up in the clinical neurophysiology unit. In the intraoperative situation, magnetic stimulation is cumbersome. Instead, transcutaneous needle electrodes and electrical stimula-

tion can easily be used with a patient under anaesthesia, while such stimulation hurts in the patient who is awake. This is called transcranial electrical stimulation (TES). Opinions differ with regard to what is stimulated when: proximal axons of the motor neurones of the pyramidal track, more distal parts of the axons, or association fibres in the cortex as well. This will depend on the strength of the stimulation, the montage and the polarity of the electrodes [9–12]. For the muscle recording a set of four to eight muscles is chosen, in the arm and leg. Depending on the situation, other muscles (facial, for example) can also be monitored. With MEPs there is a one-to-one relationship between stimulus and response. The stimulus needs to consist of a train of four to seven pulses, with a short inter-pulse interval (see Table3.1.1). There is hardly any delay between the “event”, when it occurs, and the recording of it, as long as frequent stimulation is performed. Besides recording from the muscles, it is also possible to record from the spinal cord, epidurally, depending on the surgery and the accessibility of that area. These responses are called D-waves (from “direct”). The setting and mounting of the electrodes is shown in Fig.3.1.11. Motor evoked potentials monitoring is used in cranial and spinal surgery as with SSEP monitoring. The technique provides direct information on the motor system and is therefore most appropriate when the motor system is at risk. Combined monitoring with SSEPs can easily be performed, thus providing information on both the sensory and motor tracts. Motor evoked potentials are, like SSEPs, sensitive to anaesthetic agents, especially the volatile ones. Moreover, muscle relaxants have to be used very carefully; with no relaxant there might be unacceptable movement of the patient, and with normal relaxation there will be no

Table3.1.1 Generalised settings and warning criteria for the intraoperative use of evoked potential modalities. The montage choice of transcranial electrical stimulation (TES) electrodes depends on the type of surgery. SSEP somatosensory evoked potentials, MEP motor evoked potentials, BAEP brainstem auditory evoked potentials Stimulation

SSEP

MEP (by TES) BAEP

Recording electrodes Active

Reference

Amplitude from baseline * absolute criterium

Latency increase

<50% [2]

>10%

Arm

Median nerve

Contralateral C3 or C4

Leg

Tibial nerve

Cz’

mMEP C3/C4 D-wave C1/C2 Cz’–Fz Ear phones

Warning levels

Muscle belly

<20% [16]

Epidural electrode contact

<50% [17]

Proximal

Distal

Ipsilateral A1 or A2

0.6 and 1.0ms [14]

3.1.5 Cerebral Diagnostics Start resection tumour ventral of C7

11:10

(Metastasis Grawitz tumour)

1µV

12:00 SSEP’s legs disappear spontaneously

12:10

Fig.3.1.10 Example of a temporary SSEP event. A 55-year-old male patient during surgical removal of an intraspinal metastasis of a Grawitz tumour, ventrally located at C7. Shown are the SSEPs from stimulation of the posterior tibial nerves on both sides. The SSEPs disappeared spontaneously, while the SSEPs from the upper extremity and all the motor evoked potentials (MEPs) showed a slight decrease in amplitude or remained unchanged. The tibial SSEPs were restored after raising the blood pressure

Blood pressure raised

12:20

12:30

100 ms

Left tibial SSEP

Right tibial SSEP

muscle response at all. Therefore, the setting of a baseline response with stable anaesthesia is very important. In the case of unacceptable movement, partial but stable relaxation levels may be considered. Achieving this can be time-consuming, and the reliability of motor potentials monitoring may be affected. Good interaction among the physiologist, anaesthetist and surgeon is mandatory for successful MEP monitoring and for rendering it a useful and reliable tool. Basic values for MEP monitoring are given in Table3.1.1. An example of intraoperative MEP monitoring is given in Fig.3.1.12. 3.1.5.3.4 Visual Evoked Potentials

Visual evoked potentials (VEPs) are elicited by stimuli to the eyes, and recorded through surface or needle electrodes on the occipital scalp. The stimulus can be shown as a flash, or as an alternating chequerboard image. The latter can only be applied

in a patient who is awake. Similar to the SSEP, the setup needs an averaging technique, with 200–300 stimuli given at 1–2Hz. VEP measurements are routinely used in the clinical neurophysiologic units for diagnostic purposes in several neurological or ophthalmologic entities, for example, when multiple sclerosis is suspected. Actually, the whole visual system, from the retina to the occipital cortex, is included and tested [2]. In a surgical situation with patients under anaesthesia, flash stimuli can be delivered through closed eyelids using goggles with built-in LED devices. Unfortunately, the VEPs (three typical peaks) can be so variable and unstable – primarily due to the anaesthetics – that they may show too many false-positive and -negative changes, making them unreliable. Therefore, most practitioners who have been using intraoperative VEPs (mainly for anterior base procedures) have stopped the application of VEP monitoring. Therefore, we will not show any details or examples here.

3.1 Basics 2 ms

C4 L

C3 Transcranial electrical stimulator

R Fz

Corticospinal tract

0.03 mV

Epidural MEP

1mV

MEP m.tib. ant.

3.1.5.3.5 Brainstem Auditory Evoked Potentials

Brainstem auditory evoked potentials (BAEPs) are elicited by auditory input – clicks – to the external auditory canal, and recorded by electrodes on the scalp (vertex) related to electrodes on the earlobes (Fig. 3.1.13). The recordings are difficult and need an averaging of 1,000– 3,000 signals. The click rates used (at a hearing level of 70–100 dB) are between 10 and 30 pulses per second; thus, responses are ideally obtained at between 30 and 300s. BAEPs give information about the whole auditory system, which comprises conduction to the inner ear, the cochlea, the cochlear nerve and the central auditory pathways. With optimal filtering techniques, five waves can usually be discerned (see Fig. 3.1.13). Each stands

2 ms

Motor neuron

MEP m.abd. poll. br

20 ms

Fig.3.1.11 Set-up of motor evoked potentials monitoring. Transcranial electrical stimulation (TES) through skin/needle electrodes at C3 and C4, the anode (+) being the stimulus for the corticospinal tract axons. TES stimuli consist of trains of four to seven pulses/train with a 1- to 4-ms inter-stimulus interval depending on the voltage or current stimulation [10]. Stimuli are mostly performed at a rate of 1–0.5Hz, especially during the critical periods of the surgery. General specifications are shown in Table3.1.1. Recording is performed by needle or surface electrodes in/on a series of muscles in the arm, hand (for example the musculus abductor pollicis brevis, m.abd.poll.br) and leg (musculus tibialis anterior, m.tib.ant.). During open spinal surgery, epidural electrodes can be placed below (and above) the area at risk, for example, in the case of an intramedullary tumour. The figure shows that in the case of muscle recordings, two synapses are involved: one at the motor neuron, and one at the motor endplate in the muscle. In epidural recordings (D-waves), no synapses are involved, rendering the monitoring in that situation insensitive to anaesthesia or relaxation. Epidural recordings also show late responses, called I-waves, which are the result of the stimulation of associated fibres in the cortex, instead of the axons in the corticospinal tract directly

for a specific part of the neuronal pathway that is being checked. Brainstem auditory evoked potentials are used in patients who are awake for testing and differentiating among various types of hearing loss. Intraoperative monitoring by BAEPs is used in surgery for acoustic tumours, and procedures in the posterior fossa where the brainstem is involved or at risk [2, 13–15]. Some centres have experience with direct recordings on the cochlear nerve, which bypasses the need for averaging. In that situation, however, only the first part of the neuronal acoustic pathway is monitored. Sensitivity to interference by anaesthetics is comparable to that in MEP and SSEP monitoring. With the use

3.1.5 Cerebral Diagnostics

Start resection tumour

10 : 27 11 : 13 11 : 24 11 : 41 11 : 52 12 : 11 12 : 37 13 : 2 13 : 24 13 : 53 14 : 39 15 : 46 16 : 44 17 : 5 17 : 20 17 : 48 18 : 2 18 : 29 18 : 32 18 : 38

1mV

Increase propofol level Decrease to original level

50 ms

Left tibial muscle

Right tibial muscle

Fig.3.1.12 Example of temporary TES-mMEP events bilaterally in the tibial muscles. Intraoperative neurophysiological monitoring during resection of an intramedullary tumour (ependymoma) at thoracic levels T1–T2 of a 59-year-old male patient with preoperatively progressive pyramidal signs. The events consisted of nearby abolished but still present MEPs related to a temporary increase of the propofol level because of spontaneous movements. The tibial MEPs recovered after restoring the original propofol dosage 0.5 µV Medial geniculatum

I 1.7

Inferior colliculus Lat lem

Sup. olivary nucleus

III 3.8

V 5.7 ms

Ear

Cochlear nuclei

of total intravenous anaesthesia (TIVA) it should not be a problem. However, in many patients with acoustic tumours and preoperative hearing loss, the potentials are difficult or impossible to obtain. Moreover, the cochlear nerve is more vulnerable to manipulation than any other nerve, which makes reversibility in the case of “events” more problematic, and less accessible for useful monitoring. Indirect trauma, by cerebellar retraction for example, is however easily detected and mostly reversible, making BAEP monitoring especially useful for surgery in the posterior fossa where the cochlear nerve itself is not in-

Fig.3.1.13 Brainstem auditory evoked potentials (BAEPs) monitoring set-up. Stimulation is performed by continuous acoustic clicks (70–100dB) in the external meatus of the ear, with a repetition rate of 10–30Hz. BAEP recording at A1 or A2 (active electrodes) at the ear lobes and centrally Cz (reference). After averaging 1,000–3,000 signals, a response like that shown is obtained, with five peaks, the fourth one not very visible in many situations. The relation between the peak and the anatomical localisation of its origin is shown

volved directly. Settings for BAEP monitoring are shown in Table3.1.1. Selected Reading 1. Mooij JJ, Buchthal A, Belopavlovic M (1987) Somatosensory evoked potential monitoring of temporary middle cerebral artery occlusion during aneurysm operation. Neurosurgery 21:492–496

3.1 Basics

2. Moller AR (2006) Intraoperative neurophysiological monitoring. Humana Press, Totowa 3. Weigang E, Hartert M, von Samson P, Sircar R, Pitzer K, Genstorfer J, Zentner J, Beyersdorf F (2005) Thoracoabdominal aortic aneurysm repair: interplay of spinal cord protecting modalities. Eur J Vasc Endovasc Surg 30(6):624–631 4. MacDonald DB, Janusz M (2002) An approach to intraoperative neurophysiologic monitoring of thoracoabdominal aneurysm surgery, J Clin Neurophysiol 19:43–54 5. Nuwer MR, Dawson EG, Carlson LG, Kanim LE, Sherman JE (1995) Somatosensory evoked potential spinal cord monitoring reduces neurologic deficits after scoliosis surgery: results of a large multicenter survey. Electroencephalogr Clin Neurophysiol 96:6–11 6. Chiappa KH, Hill RA (1997) Short latency somatosensory evoked potentials. Evoked potentials in clinical medicine. Lippincott-Raven, Philadelphia/New York, pp 341–423 7. Wiedemayer H, Sandalcioglu IE, Armbruster W, Regel J, Schaefer H, Stolke D (2004) False negative findings in intraoperative SEP monitoring: analysis of 658 consecutive neurosurgical cases and review of published reports. J Neurol Neurosurg Psychiatry 75:280–286 8. Toleikis JR, Carlvin AO, Shapiro DE, Schafer MF (1993) The use of dermatomal evoked responses during surgical procedures that use intrapedicular fixation of the lumbosacral spine. Spine 18:2401–2407 9. Deletis V (2002) Intraoperative neurophysiology and methodologies used to monitor the functional integrity of the motor system. In: Deletis V, Shills JL (eds) Neurophysiology in neurosurgery. Academic Press, New York, pp 25–51 10. MacDonald DB (2006) Intraoperative motor evoked potential monitoring: overview and update. J Clin Monit Comput 20:347–377 11. Szelenyi A, Langer D, Kothbauer K, De Camargo AB, Flamm ES, Deletis V (2006) Monitoring of muscle motor evoked potentials during cerebral aneurysm surgery: intraoperative changes and postoperative outcome. J Neurosurg 105:675–681 12. Neuloh G, Pechstein U, Cedzich C, Schramm J (2004) Motor evoked potential monitoring with supratentorial surgery. Neurosurgery 54:1061–1070 13. Sindou MP (2005) Microvascular decompression for primary hemifacial spasm. Importance of intraoperative neurophysiological monitoring, Acta Neurochir (Wien) 147:1019–1026 14. Polo G, Fischer C, Sindou MP, Marneffe V (2004) Brainstem auditory evoked potential monitoring during microvascular decompression for hemifacial spasm: intraoperative brainstem auditory evoked potential changes and warning values to prevent hearing loss – prospective study in a consecutive series of 84 patients, Neurosurgery 54:97–104 15. Chiappa KH (1997) Brain stem auditory EPS: methodology. Evoked potentials in clinical medicine. Lippincott-Raven, Philadelphia, pp 157–197

16. Langeloo D, Lelivelt A, Journee HL, Slappendel R, de Kleuver M (2003) Transcranial electrical motor-evoked potential monitoring during surgery for spinal deformity – a study of 145 patients. Spine 28:1043–1050 17. Kothbauer K (2002) Motor evoked potential monitoring for intramedullary spinal cord tumor surgery. In: Deletis V, Shills JL (eds) Neurophysiology in neurosurgery. Academic Press, New York, pp 72–117

3.1.5.4

Radionuclide Imaging Studies

Jan Abrahamsen Nuclear medicine is often used to study cerebral physiology, while radiological examinations (MRI and CT) are most often used for anatomical studies. 3.1.5.4.1 Gamma Camera Scintigraphy (SPECT ) and PET Scanning

For the purpose of nuclear medicine examinations, radioactive isotopes (radionuclides) are used. Due to their nuclear instability, they decay in different ways (for instance with gamma-ray radiation or positron emission). Most studies of the cerebrum are made tomographically with a rotating camera (Fig.3.1.14). This technique is either called single photon emission computed tomography (SPECT), referring to the most often used radionuclide, 99mTc (a single photon emitter) or positron emission tomography (PET) referring to the isotopes decaying by positron emission. 3.1.5.4.2 Radionuclides for PET

The detection of gamma rays from the annihilation process originating from the collision of a positron with an electron is made by a PET scanner. The most commonly used positron emitters are oxygen (15O), carbon (11C), nitrogen (13N) and fluorine (18F). These radionuclides are produced by a cyclotron. The cyclotron and PET scanners are not currently available in all departments of nuclear medicine. The PET radionuclides provide the possibility to measure blood flow quantitatively in different regions of the brain. With the 15O, the oxygen metabolism can be measured, e.g. the metabolic rate for oxygen. Such studies have been used to predict the survival of patients with cerebral gliomas. 3.1.5.4.3 Radionuclides for SPECT

The radionuclides most commonly used for cerebral studies are technetium (99mTc), iodide (123I), xenon (133Xe) and thallium (201Tl), which all decay with the emission of

3.1.5 Cerebral Diagnostics

Fig.3.1.14 Gamma camera with single photon emission computed tomography (SPECT) possibilities. Rotating twoheaded gamma camera

gamma rays to be detected by the SPECT gamma camera (Fig.3.1.14). A molybdenum/technetium generator is delivered to departments of nuclear medicine each week. The ready availability of 99mTc at a reasonable cost from such a generator combined with the physical characteristics both for imaging and dosimetry makes 99mTc superior to any other radionuclide. The use of 99mTc-labelled agent is therefore often requested. The radionuclides are in one way or another combined with a target-seeking molecule. The target could be the cerebral cells, receptors, or membrane transporters. Thus, the radionuclides are used as tracers, which give the possibility to trace the target-seeking molecule. For instance, in order to evaluate cerebral perfusion, 99mTc is incorporated into a molecule passing through the blood–brain barrier and accumulating in the cerebral cells.

may give rise to a steal phenomenon. By comparison with an rCBF study without added Diamox, a cerebral perfusion reserve can be detected. The territory at risk of stroke can be estimated by using this Diamox test (Fig.3.1.16). Quantitative CBF studies are also valuable as preoperative mapping of, for instance, the language centre prior to removal of a nearby tumour. For quantitative assessment of cerebral blood flow, 133Xe (Fig.3.1.16) or the PET tracer H215O is used.

3.1.5.4.4 Measurement of Cerebral Blood Flow

The two most widely used tracers for regional cerebral blood flow (rCBF) studies are 99mTc-labelled hexamethylpropylene amine oxime (99mTc-HMPAO; Fig.3.1.15) and 99m Tc-labelled ethylcysteinate dimer (99mTc-ECD). For both these lipophilic labelled agents the mechanism of retention in the brain is the conversion to more hydrophilic compounds, trapping them in the brain tissue. The rCBF studies are especially valuable in examinations for stroke, transitory cerebral ischaemia (TCI), dementia, epilepsy and Alzheimer’s disease. This physiological test (rCBF) often demonstrates changes prior to anatomic changes. To study the cerebral haemodynamic, two perfusion studies (one with and one without Diamox®) are needed. Diamox dilates cerebral vessels and

Fig. 3.1.15 Regional cerebral blood flow using the 99mTc-labelled hexamethylpropylene amine oxime (HMPAO)

3.1 Basics

Fig. 3.1.16 Quantitative cerebral blood flow estimated with 133Xe before and after Diamox®

3.1.5.4.5 Radionuclide Demonstration of Brain Tumours

Cells that depend on glucose metabolism are easily visualised with 18F-1 abelled deoxyglucose (18FDG) due to their high glucose turnover. The metabolism in tumours can thus be shown by giving 18FDG intravenously. Furthermore, the brain itself is dependent on glucose metabolism. It is, however, possible to visualise a cerebral tumour even when the background metabolism is high. In particular, postoperatively and after radiation therapy, it is difficult to evaluate MRI and CT scans due to tissue scarring. A residual tumour or a recurrence will depend on glucose metabolism, while scar tissue will show only a limited glucose uptake. 18FDG will thus show a still viable tumour amongst the scar tissue (Fig.3.1.17). Cerebral infection will also have a high glucose turnover. It may thus be difficult to differentiate between cerebral tumours and abscesses. 3.1.5.4.6 Neuroreceptor Imaging

Both ligands for SPECT and PET imaging are available. For several years it has been possible to obtain imaging receptors for dopamine, serotonin, histamine, benzodiazepine, morphine, acetylcholine (muscarinergic, nicotinergic), noradrenaline, amino acids (GABA), steroids, purines and somatostatins, as well as several other neuropeptides. A huge variety of radiolabelled agonists and antagonists have been developed for the purpose of studying the localisation and in some cases the functions of these receptors. Given the high number of radiolabelled receptor ligands it has been possible to study clinical entities such

as Alzheimer’s disease, epilepsy, Parkinson’s disease (Fig.3.1.18), depression, alcoholism, Giles de la Tourette syndrome, schizophrenia, tardive dyskinesia, neurografting of foetal mesencephalic tissue, olivopontocerebellar atrophy, panic disorders etc. Neurotransmitter transporters for dopamine (Fig.3.1.18) and serotonin have also been labelled with radionuclides, as have some neurotransmitter enzymes. 3.1.5.4.7 SPECT/CT and PET/CT, in Contrast to MRI and PET

At present, most new scanners are combinations of either SPECT/CT or PET/CT. These new possibilities create a combination of physiology and anatomy. MRI is especially appropriate for anatomic brain investigations and even better than CT. A combination of PET and MRI would be a very strong new tool for diagnosing cerebral tumours. For the time being, however, PET and MRI data are acquired with two scanners and a combined image is obtained by image fusion (Fig.3.1.18). However, a combination of PET/MRI has recently been introduced. No validated clinical examinations have yet been reported using this new combination of scanners. It seems evident that molecular imaging, i.e. visualising molecular structures, will attract much attention in years to come. With the combined techniques (SPECT/CT, PET/CT, PET/ MRI) molecular processes can be referred to the correct anatomic localisation. This will bring hope for a better understanding of the underlying pathophysiology of cerebral diseases.

3.1.5 Cerebral Diagnostics

Fig.3.1.17a–c Magnetic resonance imaging (MRI), positron emission tomography (PET) and MRI-PET image fusion. a Tumour recidive: MRI. b Tumour recidive: PET. c Tumour recidive, image fusion MRI-PET

Fig.3.1.18 Parkinson’s disease: the presynaptic dopamine transporters are labelled with 123I-ioflupane (DaTSCAN) showing the caudate and putamen. Increasing severity (a–d) of Parkinson’s disease is shown

Acknowledgements

Selected Reading

The author would like to thank the Rigshospitalet in Copenhagen, Denmark for providing the images.

1. Ell PJ, Gambhir SS (eds) (2004) Nuclear medicine in clinical diagnosis and treatment, 3rd edn. Churchill Livingston, London, pp 1235–1493

3.1 Basics

3.1.5.5

Cerebrospinal Fluid Diagnostics

Flemming Gjerris 3.1.5.5.1 Basics

Even if the use of computed tomography and high-resolution magnetic resonance imaging is expanding, analysis of the cerebrospinal fluid (CSF) by a lumbar or ventricular puncture is still an important investigation in many different neurosurgical and neurological conditions. 3.1.5.5.2. The Cerebrospinal Fluid

(ICP) and the dimensions of the brain. Measurements of the CSF volume in vivo using the MR technique in normal persons produce a total CSF volume ranging from 57 to 286 ml. The total CSF volume increases with age in both sexes, mostly as an increase in the cortical sulcal volume. The ventricular CSF volume ranges between 6.8 and 30ml and correlates with the total CSF volume. The intracranial pressure (ICP) is normally maintained by the resistance factor of CSF outflow [6, 7]. An increased amount of CSF (hydrocephalus) presupposes a reverse volume change in one of the other intracranial volumes, the so-called Monro–Kellie doctrine. 3.1.5.5.2.4 CSF Absorption

3.1.5.5.2.1 Anatomy of the CSF Pathways

The anatomy is well known. CSF flows caudally in the ventricular system [6, 7]. The cilial movements of the ependyma, the respiratory and arterial pulsations, and the pressure gradients between the ventricular and sub arachnoid system and the venous side of the sinuses result in a flow of CSF. The driving forces for these pressure gradients are probably created by the continuous CSF formation and maintained by the arterial pressure pulsations of the brain (the CSF pump). The CSF ends up in the arachnoid villi or around the brain capillaries. 3.1.5.5.2.2 CSF Formation

The main production site of CSF (70–80%) is the choroid plexus in the two lateral, the third and the fourth ventricles. The choroidal formation is either a filtration across the endothelial capillary wall or an active secretion (sodium and bicarbonate) by the choroidal epithelium. The CSF formation is influenced by aquaporine1, enzyme inhibitors, the autonomic nervous system and the choroidal blood flow. The extrachoroidal part of CSF begins as interstitial fluid seeping away from the brain either transependymal to the ventricles or transpial to the intracranial and intraspinal subarachnoid spaces [7]. The CSF formation rate is about 0.35ml/min, a total of 500ml/day, and may be inhibited by steroids, acetazolamide, diuretics, low temperature and changes in CSF osmolality. Humans have the highest overall rate of formation of CSF of all species. 3.1.5.5.2.3 CSF Composition and Volume

Cerebrospinal fluid resembles an ultrafiltrate of plasma, and the concentration of the single solute (protein, transmitter etc.) differs very much in the different CSF compartments [6]. Cranio-caudal gradients (even gradients in the opposite direction) exist for different proteins, amines and neuro-transmitters, which makes it difficult to interpret data based on concentrations measured at the lumbar level [6]. Intracranial CSF volumes are linked intimately to the formation rate, circulation and resistance to CSF outflow (Rout) and with factors such as intracranial pressure

The CSF is either absorbed through the arachnoid villi to the brain sinuses [6, 7], along the spinal (15%) villi, through the brain capillaries [9], helped by the recently discovered aquaporins, probably aquaporin4 [7, 18], or via a lymphatic route in animals [13]. There is a linear relationship between CSF absorption and ICP, and CSF absorption depends on the transvillus or the transcapillary pressure gradients. It is possible, that the aquaporins, besides facilitating the water absorption, may also work against a pressure gradient, which may explain the resorption through the capillaries in patients with hydrocephalus or increased intracranial pressure. 3.1.5.5.2.5 Resistance to CSF Outflow

The resistance of CSF outflow (Rout) can be measured by isotope dilution methods or by bolus, infusion or perfusion techniques [6, 7, 18]. Humans have the lowest outflow resistance of all species. Rout measurements can be used for evaluation of shunting in patients with hydrocephalus and idiopathic intracranial hypertension [6, 18]. 3.1.5.5.3 Lumbar Puncture

The techniques of lumbar and ventricular puncture are described, together with the macroscopic findings, which are important for neurosurgeons. Laboratory analyses of CSF can be found in various textbooks or review papers [1–4, 8, 10–12, 14, 16]. The indications and contraindications for lumbar puncture are clear. The technique of lumbar puncture is simple, but withdrawal of CSF can still be dangerous, even fatal, and in many cases the diagnostic information acquired is limited. A lumbar puncture should be carried out if specific information is expected from the CSF ana lysis for the present disease. It should no longer be used for diagnostic purposes in patients with brain tumours or subdural haematomas. 3.1.5.5.3.1 Contraindications

The contraindications, although very clear, are still disregarded with surprising regularity.

3.1.5 Cerebral Diagnostics

3.1.5.5.3.1.1 Local Infection

Infected small lesions near the puncture site can be transferred in to the meninges. 3.1.5.5.3.1.2 Elevated ICP (Fresh Bilateral Papilloedema)

Persistent ignorance of this rule sooner or later causes fatalities from brain herniation. Symptoms and signs suggesting a space-occupying process, e.g. a tumour in the posterior fossa, might give incipient brain stem compression, whether there is papilloedema or not. This should be suspected when there is intense headache, drowsiness, vomiting, slowing of the pulse rate, neck stiffness or episodes of faintness, and should be ruled out by CT or MRI before lumbar puncture. Patients with papilloedema, but with no space-occupying brain lesion, are not in danger, i.e. idiopathic intracranial hypertension, subarachnoid haemorrhage and meningeal carcinomatosis of a lumbar puncture [6, 7]. 3.1.5.5.3.2 Technique (Recommended European Standard)

For a normal diagnostic procedure the patient should lie flat on his side with his back at the edge of the bed (Fig.3.1.19 [15]). The iliac crests must be maintained vertically above each other. The body is slightly curled up (flexion of the hips and knees) to separate the spinous processes and a line is drawn, joining the tops of the iliac crests. It usually intersects at the L3–L4 or L4–L5 space. Mark the space, clean the skin aseptically and use local anaesthesia with a fine needle in the skin and the interspinous ligament. Wait at least 2min and many painful lumbar punctures are avoided. Remember to tell the patient that piercing the dura may cause a stab of pain. Introduce a 20- to 22-gauge needle (an atraumatic cannula with a special tip) with the stiletto exactly in the midline and in between two spinal processes, and pointing slightly towards the head of the patient. Push the needle with the cutting edge in a cranio-caudal direction to minimise the cut in the dura (Fig.3.1.19) slowly, but firmly, forwards. A characteristic jerk is felt as the needle enters the dura, usually at a depth of 5–6 cm. Push the needle a further 2–3 mm inwards, withdraw the stiletto and allow a few drops of CSF to escape. When the fluid is obtained the pressure monitor is attached. Remember to replace the stiletto before removing the needle to avoid unintentional crushing of a nerve root, and never use a syringe to withdraw CSF.

tension or abdominal compression in an obese patient. Queckenstedt’s test is no longer of any use. 3.1.5.5.3.4 Complications

The most common complication is the so-called post lumbar puncture syndrome, which occurs in up to 30% of cases and includes back pain, headache, nausea and dizziness. It usually continues for 3–5days, but can persist for months. Bed rest (24–48h) with the legs elevated usually has an effect in some cases, but the most effective treatment is an epidural blood patch. 3.1.5.5.4 Cisternal and Ventricular Puncture 3.1.5.5.4.1 Cisternal Puncture

Cisternal puncture is an uncommon procedure today. It is mostly used when CSF examination is vital and lumbar puncture has failed. The contraindications are the same as for lumbar puncture, and the procedure should only be carried out by specially trained personnel. 3.1.5.5.4.2 Ventricular Puncture

This procedure is only in use in neurosurgical clinics or intensive care units, often as a standard procedure for ICP monitoring. The technique is mentioned in Chap.3.2.8. [5], Fig. 3.2.80. 3.1.5.5.5 CSF Composition During Normal and Pathological Conditions 3.1.5.5.5.1 Appearance and Blood Pigment

Allow CSF to drip slowly into one or two tubes, usually between 5 and 10ml and look at it, first held up to the light, and then against a white coat. Normal CSF is clear

3.1.5.5.3.3 The Pressure

Variations in the pressure of pulsations and respiration are seen. The normal pressure is below 200 mm of water or 15mmHg and CSF should flow out of the cannula freely on coughing and abdominal pressure. The pressure is low below a complete spinal block and a block at the foramen magnum. A high pressure is commonly due to

Fig.3.1.19 Lumbar puncture. Position of the patient and anatomical demonstration of the structures passed by the lumbar puncture needle; drawing by Bo Jespersen [15]

3.1 Basics

and colourless like tap water. During pathological conditions it can be cloudy, bloody or xanthochromic. A cloudy fluid is seen with an increase in the cell count above 200– 400/μl. A smoky or “snowy” appearance may be due to large numbers of red cells. The blood-stained fluid of the first few drops is mostly due to lesions of the local veins during the puncture. If the fluid remains equally bloodstained, it probably indicates an acute subarachnoid haemorrhage. The CSF must be centrifuged immediately. If the supernatant fluid is colourless this is unlikely to be anything, but traumatic or very near to the peak of the SAH. CSF usually turns out to be xanthochromic in SAH 6–12 h after the time of the bleeding, caused by breakdown products from the haemoglobin. It can also be seen in CSF with a high content of protein (neurinoma, Guillain–Barré syndrome). If the collected CSF clots, it is often caused by pure blood from a traumatic puncture or a very high proteinous fluid content. Blood in CSF caused by a stabbing lumbar puncture, repeated lumbar punctures or myelography results in an increase in the white cell count, which may persist for up to 2–3weeks. Some common findings in neurological and neurosurgical diseases are shown in Table3.1.2.

3.1.5.5.5.2 Leucocytes

The cells must be counted as soon as possible. Abnormal is more than 3 cells/μl or if the cells are polymorphonuclear. Polymorphonuclear and mononuclear pleocytosis, see other textbooks. 3.1.5.5.5.3 Tumour Cells

Tumour cells are important findings in patients with different malignant diseases affecting the brain or spinal cord, i.e. medulloblastoma. 3.1.5.5.5.4 Glucose, Proteins, Protein Fractions, Bacteriology and Virology

See textbooks or review papers [1–4, 8, 10–12, 14, 16]. 3.1.5.5.6 Special Remarks

Lumbar puncture is still safe if precautions are taken. A parallel blood sample is always necessary for a complete CSF study, if analysis of CSF is to remain fundamental in the diagnosis of many neurosurgical and neurological diseases.

Table3.1.2 Cerebrospinal fluid findings in normalcy and common neurosurgical and neurological diseases Disease

Appearance

Normal

Protein

Sugar

Clear, colourless 70 –200mm H2O 0–3 leucocytes, 5–15mmHg 0 erythrocytes

0.30 – 0.85g/l

⅓ –½ of fasting blood sugar

SAH

Bloody, yellow

Increased

Many red and white cells

Slightly increased

Normal

Leucocytes may increase

Purulent meningitis

Yellowish, cloudy

Increased

Polymorphonuclear cells. > 3,000

Increased

Low

Bacteria

Mononuclear meningitis

Clear or slightly opalescent

Normal or increased

Many monocytes

Slightly increased

Normal

Possible vira

Brain abscess

Clear or slightly opalescent

Increased

Normal or slightly increased

Increased

Normal or decreased

Meningeal symptoms when breakthrough to ventricular system

IIH

Clear, colourless Increased

Normal

Drastically increased

Normal

Spinal tumour; Yellowish, below block of spontaneous CSF space coagulating

Pressure

Normal or low

Cell contents

Polyradiculitis

Clear, colourless Normal

Normal, few leucocytes

Normal or slightly increased

Increased after days

Multiple sclerosis

Clear, colourless Normal

Normal, a few leucocytes

Normal or slightly increased

Normal

Other findings

Oligoclonal IgG bands

3.1.5 Cerebral Diagnostics

Selected Reading 1. Aminoff MJ, Greenberg DA, Simon RP (2007) Clinical neurology, 6th edn. McGraw-Hill, New York, p 2300 2. Blennow K (2005) CSF biomarkers for Alzheimer’s disease: use in early diagnosis and evaluation of drug treatment. Expert Rev Mol Diagn 5:661–672 3. Bogousslavsky J, Fisher M (eds) (1998) Textbook of neurology. Butterworth & Heinemann, Boston, p 674 4. Fonteh AN, Harrington RJ, Huhmer AF, Biringer RG, Riggins JN, Harrington MG (2006) Identification of disease markers in human cerebrospinal fluid using lipidomic and proteomic methods. Dis Markers 22:39–64 5. Gjerris F (2007) Idiopathic intracranial hypertension. In: Lumenta C, Di Rocco C (eds) European manual of medicine. Springer, Berlin Heidelberg New York, in print 6. Gjerris F (2000) Hydrocephalus in adults. In: Kay AH, Black PM (eds) Operative neurosurgery. Churchill Livingstone, London, pp 1236–1247 7. Gjerris F, Børgesen SE (2000) Pathophysiology of the CSF circulation. In: Crockard A, Hayward R, Hoff JT (eds) Neurosurgery – the scientific basis of clinical practice, 3rd edn. Blackwell Science, Boston, pp 147–168 8. Goetz CG (2007) Textbook of clinical neurology, 3rd edn. Saunders, Chicago, pp 1300

9. Greitz D (1993) Cerebrospinal fluid circulation and associated intracranial dynamics. A radiologic investigation using MR imaging and radionuclide cisternography. Acta Radiol Suppl 386:1–23 10. Harrington MG (2006) Cerebrospinal fluid biomarkers in primary headache disorders. Headache 46:1075–1087 11. http://www.emedicine.com/neuro/contents.htm 12. Huhmer AF, Biringer RG, Amato H, Fonteh AN, Harrington MG (2006) Protein analysis in human cerebrospinal fluid: physiological aspects, current progress and future challenges. Dis Markers 22:3–26 13. Johnston MG, Boulton M, Flessner M (2000) Cerebrospinal fluid absorption revisited: do extracranial lymphatics play a role? Neuroscientist 6:77–85 14. Link H, Huang YM (2006) Oligoclonal bands in multiple sclerosis cerebrospinal fluid: an update on methodology and clinical usefulness. J Neuroimmunol 180:17–28 15. Paulson OB, Gjerris F, Sørensen PS (2004) Klinisk neurologi og neurokirurgi, 4th edn. FADL, Copenhagen, pp 648 16. Schapira A (2006) Neurology and clinical neuroscience. Mosby, New York, p 1664 17. Skau M, Brennum J, Gjerris, Jensen R (2006) What is new about idiopathic intracranial hypertension? An updated review of mechanism and treatment. Cephalgia 26:384–398 18. Stephensen H (2006) Adult hydrocephalus (thesis). Vasastadens Bokbinderi, Gothenburg

3.2 Brain Tumors

3.2.1 Classification and Biology of Brain Tumors

H.D. Mennel 3.2.1.1

Introduction

The classification of brain tumors has had a long history. Both general pathology and neurosurgery have influenced the description and classification of tumors of the nervous system. Whereas neurosurgery attempts to “classify” tumors for practical reasons, pathology offer general rules for doing so. Early attempts were made on the histogenetic level due to the collaboration between Percival Bailey and Harvey Cushing, but the emphasis was soon changed to the outcome of the patients. Thus, the prognosis has been one of the leading viewpoints of classification since the beginning [1].

Therefore, as well as the histogenetic considerations, different grading systems were established, mainly in the years between 1949 and 1960 [2–4]. Thereafter, the work of the WHO unified the concepts and nomenclature, gathering together different groups of experts. The results of these initiatives were presented in three issues of the WHO Classification of Brain Tumors, the last edition being in 2007 [5–8]. Few tumors have been added to this 2007 edition. The different entities of this WHO classification are shown in Table3.2.1. In addition to the WHO classification based on descriptive morphology, a sort of grading system has been added that provides some indications regarding the mean postoperative course of individual tumors. The latest draft includes a rearrangement of entities, especially in the group of gliomas, which are now arranged according to increasing grades (of malignancy). More recent developments have changed our attitude toward brain tumor biology in many respects. The advent of immunohistochemistry brought new insight into his-

Table3.2.1 List of tumor entities following the WHO classification, 2007 draft [8] WHO Classification of Tumours of the Nervous System TUMOURS OF NEUROEPITHELIAL TISSUE Astrocytic tumours

Other neuroepithelial tumours

Pilocytic astrocytoma

Astroblastoma

–– Pilomyxoid astrocytoma

Chordoid glioma of the third ventricle

Subependymal giant cell astrocytoma

Angiocentric glioma

Pleomorphic xanthoastrocytoma Diffuse astrocytoma

Neuronal and mixed neuronal-glial tumours

–– Fibrillary astrocytoma

Dysplastic gangliocytoma of cerebellum (Lhermitte-Duclos)

–– Gemistocytic astrocytoma

Desmoplastic infantile astrocytoma/ganglioglioma

–– Protoplasmic astrocytoma

Dysembryoplastic neuroepithelial tumour

Anaplastic astrocytoma

Gangliocytoma

Glioblastoma

Ganglioglioma

–– Giant cell glioblastoma

Anaplastic ganglioglioma

–– Gliosarcoma

Central neurocytoma

Gliomatosis cerebri

Extraventricular neurocytoma Cerebellar liponeurocytoma

3.2 Brain Tumors

Table3.2.1 (continued) List of tumor entities following the WHO classification, 2007 draft [8] TUMOURS OF NEUROEPITHELIAL TISSUE Oligodendroglial tumours

Papillary glioneuronal tumour

Oligodendroglioma

Rosette-forming glioneuronal tumour of the fourth ventricle

Anaplastic oligodendroglioma

Paraganglioma

Oligoastrocytic tumours

Tumours of the pineal region

Oligoastrocytoma

Pineocytoma

Anaplastic oligoastrocytoma

Pineal parenchymal tumour of intermediate differentiation Pineoblastoma

Ependymal tumours

Papillary tumour of the pineal region

Subependymoma Myxopapillary ependymoma

Embryonal tumours

Ependymoma

Medulloblastoma

–– Cellular

–– Desmoplastic/nodular medulloblastoma

–– Papillary

–– Medulloblastoma with extensive nodularity

–– Clear cell

–– Anaplastic medulloblastoma

–– Tanycytic

–– Large cell medulloblastoma

Anaplastic ependymoma

CNS primitive neuroectodermal tumour –– CNS Neuroblastoma

Choroid plexus tumours

–– CNS Ganglioneuroblastoma

Choroid plexus papilloma

–– Medulloepithelioma

Atypical choroid plexus papilloma

–– Ependymoblastoma

Choroid plexus carcinoma

Atypical teratoid/rhabdoid tumour

TUMOURS OF CRANIAL AND PARASPINAL NERVES Schwannoma (neurilemmoma, neurinoma)

Malignant peripheral nerve sheath tumours (MPNST)

–– Cellular

–– Epithelioid MPNST

–– Plexiform

–– MPNST with mesenchymal differentiation

–– Melanotic

–– Melanotic MPNST –– MPNST with glandular differentiation

Neurofibroma –– Plexiform Perineurioma –– Perineurioma, NOS –– Malignant perineurioma TUMOURS OF THE MENINGES Tumours of meningothelial cells

Mesenchymal tumours

Meningioma

Lipoma

–– Meningothelial

Angiolipoma

–– Fibrous (fibroblastic)

Hibernoma

3.2.1 Classification and Biology of Brain Tumors

Table3.2.1 (continued) List of tumor entities following the WHO classification, 2007 draft [8] TUMOURS OF THE MENINGES –– Transitional (mixed)

Liposarcoma

–– Psammomatous

Solitary fibrous tumour

–– Angiomatous

Fibrosarcoma

–– Microcystic

Malignant fibrous histiocytoma

–– Secretory

Leiomyoma

–– Lymphoplasmacyte-rich

Leiomyosarcoma

–– Metaplastic

Rhabdomyoma

–– Chordoid

Rhabdomyosarcoma

–– Clear cell

Chondroma

–– Atypical

Chondrosarcoma

–– Papillary

Osteoma

–– Rhabdoid

Osteosarcoma

–– Anaplastic (malignant)

Osteochondroma Haemangioma

Primary melanocytic lesions

Epithelioid haemangioendothelioma

Diffuse melanocytosis

Haemangiopericytoma

Melanocytoma

Anaplastic haemangiopericytoma

Malignant melanoma

Angiosarcoma

Meningeal melanomatosis

Kaposi sarcoma Ewing sarcoma – PNET

Other neoplasms related to the meninges Haemangioblastoma LYMPHOMAS AND HAEMATOPOIETIC NEOPLASMS Malignant lymphomas Plasmacytoma Granulocytic sarcoma GERM CELL TUMOURS

TUMOURS OF THE SELLAR REGION

Germinoma

Craniopharyngioma

Embryonal carcinoma

–– Adamantinomatous

Yolk sac tumour

–– Papillary

Choriocarcinoma

Granular cell tumour

Teratoma

Pituicytoma

–– Mature

Spindle cell oncocytoma of the adenohypophysis

–– Immature –– Teratoma with malignant transformation Mixed germ cell tumour METASTATIC TUMOURS

3.2 Brain Tumors

tology and histogenetics of individual tumors [9]. Also, proliferation markers such as Ki 67 (MIB 1) have gained increasing influence on the determination of the innate biological behavior of the tumors [10, 11]. Furthermore, tumor genetics are exerting an increasing impact upon the pathological aspects as well as on the prognosis of the tumors. In this field, a final breakthrough has not yet been achieved, but, in certain regions of interest, progress has been made concerning the correlation of molecular and genetic data with the pathology and clinical behavior of tumors, e. g., in the case of the MYC amplification and tumor progression in childhood peripheral adrenal neuroblastoma [12]. On the whole, genetic data have tremendously enlarged our knowledge of tumor growth and pathogenesis; one outstanding example is the stepwise genetic alterations occurring during tumor progression, e. g., in gliomas (see Sect. 3.2.1.3). Equally, in gliomas, the MGMT (O6-methylguanine-DNA methyltransferase) promoter methylation may indicate a better outcome in glioblastoma patients, when treated with temozolomide [13]. Thus, the “methylation status” of malignant gliomas may nowadays be included in routine molecular investigations in this tumor group. 3.2.1.2

Morphology, Prognosis, and Clinical Malignancy

Early descriptions led to a nomenclature that is still broadly used today, despite the ongoing changes in concepts and names. Thus, increasing anaplasia has been thought to push back the line of differentiation that is achieved stepwise during ontogenesis. Many expressions such as glioblastoma, neuroblastoma, medulloepithelioma, and medulloblastoma have been coined following this line of thinking. The underlying dogma maintains that higher anaplasia (dedifferentiation) means increased malignancy. This general rule of descriptive oncology is only partly true, has numerous exceptions, and is particularly difficult under special conditions such as tumor growth within the intracranial space [14]. Therefore, a more pragmatic approach proved to be necessary and successful. The “biologic” connotation of the nomenclature had to be abandoned in parts and empiric definitions of biological entities established instead. The situation is even more complicated, because in intracranial tumor growth, biological “intrinsic” behavior and so-called clinical malignancy interact much more than in other locations in the field of oncology. Thus, the prognostic considerations are based on both clinical and pathological information. In therapy studies over the last few years, the high impact of clinical data (in addition to grading by morphology) became obvious [15]. However, conventional morphology, nowadays enriched by immu-

nohistochemical markers of tissue derivation and proliferation estimation, contributes greatly to the evaluation of the patients’ general prognosis. Particularly in supratentorial gliomas in adults, increasing anaplasia can be found both on the cellular and the tissular level. This anaplasia has been known as “cellular and tissular pleomorphism.” It led to the introduction of the group of “pleomorphic gliomas” (today anaplastic astrocytoma, oligodendroglioma, and mixed glioma), which is intermediate between the glioma, with a better prognosis, and the malignant glioblastoma [16]. Cellular pleomorphism means varying sizes and forms of nuclei and cells. Anaplastic gliomas exhibit a wide range of pleomorphic cells up to the formation of giant cells. Tissular pleomorphism is defined as the increasing formation of neovascularization and the occurrence of necrotic areas typically seen in glioblastomas. Thus, in adult supratentorial gliomas, by increasing cellular and architectural pleomorphism (anaplasia) three grades can be easily distinguished and roughly correlated with mean postoperative survival [17]. A simplified survey of adult supratentorial gliomas, with grades and mean postoperative survival figures, is shown in Table3.2.2. The general idea behind this sort of approach to grading tumors is that other intracranial new growths, by their natural course, can be compared with the three grades of supratentorial gliomas of the adult and thus receive a corresponding – or in the case of benign behavior – an even lower grade, i. e., grade I. The latter holds true for childhood glioma, formerly known as (polar) spongioblastoma, today called pilocytic astrocytoma. Historically, this grading with mixed morphological and clinical

Table 3.2.2 Survey of the morphology and survival times of the supratentorial gliomas of the adult [15] GRADE

III

CYTOLOGY Isomorphic

Pleomorphous Pleomorphous

HISTOLOGY Isomorphic

Vascular Vascular –– Proliferation –– Proliferation – Necrosis

ENTITIES

Astrocytoma Anaplastic

Glioblastoma

–– Astrocytoma

SURVIVAL (YEARS)

Oligodendroglioma

Anaplastic –– Oligodendroglioma

Mixed Glioma

Anaplastic –– Mixed Glioma

3.2.1 Classification and Biology of Brain Tumors

Table3.2.3 Survival chart of the different intracranial tumors. Nomenclature and scheme according to Zülch [16] Degree of malignancy

Prognosis after “total” removal

Tumors Extracerebral

Intracerebral

Neurilemmoma Meningioma Craniopharyngioma Pituitary adenoma Others

Astrocytoma, pilocytic Ependymoma of the ventricles Choroid plexus papilloma Gangliocytoma (temporobasal) Hemangioblastoma

Grade I benign *

Cure or at least survival time of 5 or more years

Grade II semibenign **

Postoperative survival time: 3–5years

Grade III relatively malignant ***

Postoperative survival time: 2–3years

Pituitary adenocarcinoma, Meningioma, anaplastic “Neurosarcoma”

Astrocytoma, anaplastic Oligodendroglioma, anaplastic Ependymoma, anaplastic Gangliocytoma, anaplastic Germinoma

Grade IV highly malignant ****

Postoperative survival time: 6–15months

Sarcomas and other highly malignant local extensions

Glioblastoma Medulloblastoma Sarcoma, primary

viewpoints was introduced by K.J. Zülch. He established a chart of mean survival periods for different intracranial tumors and attributed four grades, but avoided forcing every entity into one of them. This chart is shown in Table3.2.3 [4, 5, 18]. Similar systems had been developed previously [2]. In particular, the three-grade scheme by Ringertz [3] acknowledged the fact that gliomas (and ependymomas) develop stepwise into glioblastomas. The (re)discovery of the concept of secondary glioblastoma and the genetic cascade of events that accompany the different steps have confirmed the earlier notion of increasing pleomorphism in gliomas [18]. Since its first draft in 1979, the WHO classification has also introduced [5] a modified four-grade system for many intracranial tumors; however, this is optional at this time. The latest edition gives grades for almost all tumors and stresses the continuous evolution of secondary glioblastoma as well as that of oligodendrogliomas and meningiomas of increasing malignancy [7, 8].

Neurilemmoma, anaplastic Meningioma, anaplastic

3.2.1.3

Astrocytoma Oligodendroglioma Ependymoma (cerebral, extraventricular) Choroid plexus papilloma Ganglioglioma

Genetics

The true indicator of benign or malignant behavior must be found in genetic alterations that are obviously much closer to the proliferation apparatus than the derived phenotypic features. One of the intracranial tumor entities has been a first candidate for genetic changes; namely, the meningioma, which presented alterations in the rough number of chromosomes. The first investigation showed that chromosome 22 was involved, a chromosome that played a role in the hereditary tumor syndrome of von Recklinghausen’s disease [19]. Accordingly, spontaneous meningiomas may exhibit mutations of different sorts in the NF 2 gene on chromosome 22q, which is considered to act as a suppressor [20]. Several other genetic loci in meningiomas are affected as well, but there are some indications that few are associated with increased malignancy. Thus, it has become possible to conceive a tentative stepwise progression toward more aggressiveness on the

3.2 Brain Tumors

Table 3.2.4 Tentative list of genetic events in meningioma of different grades [7]

Arachnoidal cell NF2 mutation/loss 22q Meningioma, grade I Losses of 1p, 6q, 10q, 14q, 18q Gains of 1q, 9q, 12q 15q, 17q, 20q Atypical meningioma, grade II Losses of 6q, 9p,10q,14q Amplification 17q Rare mutations TP53, PTEN Anaplastic (malignant) meningioma grade III

molecular level. A pertinent scheme taken from the 2000 edition of the WHO classification is given in Table3.2.4. A very similar chart of events in tumor progression was established for the secondary glioblastoma. This term was coined for clinical and also morphological reasons in 1940 by H. J. Scherer [21]. Its real occurrence has only been corroborated with the advent of molecular genetics, despite the fact that some histological differences may be found, especially regarding the extent of ischemic necroses [22]. In addition, there are possible clinical differences concerning the age at onset and the clinical course, but the most striking distinction between the more frequent primary (de novo) glioblastoma and the glioblastoma that arises through malignant changes of more benign astrocytomas concerns the genetic level. Thus, EGF-R overexpression or amplification is the hallmark of de novo growing glioblastomas, whereas in secondary glioblastoma, a cascade of genetic events is reached step by step [18]. Table3.2.5 illustrates this.

Table3.2.5 Genetic evolution in primary and secondary glioblastoma [8]

Differentiated astrocytes or precursor cells WHO grade II

Low-grade astrocytoma TP53 mutation (59%) 5.1 years

WHO grade III

Clinical history < 3 months 68% < 6 months 84%

Anaplastic astrocytoma TP53 mutation (53%) 1.9 years

WHO grade IV

Secondary glioblastoma LOH 10q (63%) EGFR amplification (8%) P16 INK4a deletion (19%) TP53 mutation (65%) PTEN mutation (4%)

5% of cases

Primary glioblastoma (de novo) LOH 10q (70%) EGFR amplification (36%) P16 INK4a deletion (31%) TP53 mutation (28%) PTEN mutation (25%) 95% of cases

3.2.1 Classification and Biology of Brain Tumors

In particular, the evolutionary steps of astrocytomas undergoing anaplasia to become the highly malignant glioblastoma form the basis of the above-mentioned increasing pleomorphism of the supratentorial gliomas in the adult. Consequently, the benign childhood glioma, the pilocytic astrocytoma, has no genetic similarity to the molecular findings shown above. Obviously, p53 mutation, so common in adult diffuse astrocytoma, does not play a significant role in pilocytic astrocytoma [23]. It must be mentioned that familial tumor syndromes have long been known to involve the central and peripheral nervous system. It is beyond the scope of this presentation to go into details regarding genetic data of both sporadic and familial nervous system tumors. It should be pointed out, however, that the most widely known syndromes, neurofibromatosis types 1 and 2 (mutations in the gene NF1 on chromosome 17q11 and NF2 on 22q12), von Hippel–Lindau syndrome (mutation on the VHL gene on chromosome 3p25) and tuberous sclerosis (two altered genes TSC1 and 2 on 9p34 and 16p13), and others, have contributed greatly to our better understanding of the pathogenesis of tumor growth and initiation. 3.2.1.4

Single Entities

Fig. 3.2.1 Brain stem tumors in children are often pilocytic astrocytomas, but may be more malignant, such as this tumor, representing a malignant glioma. However, they behave malignantly clinically independently from biological dignity, as they usually cannot be removed when growing next to vital centers

ever, is not a sign of greater malignancy. A variant with a marked mucoid matrix has been described and was recently named pilomyxoid astrocytoma. Its biological behavior is obviously more aggressive (grade II) than that of the common pilocytic astrocytoma (grade I).

3.2.1.4.1 Pilocytic Astrocytoma

Pilocytic astrocytoma is an astrocytic tumor that constitutes about 5% of intracranial tumors; it occurs preferentially in young people in midline sites. Synonyms are (uni)polar spongioblastoma, juvenile astrocytoma, and Bergstrand tumor. In the cerebellum the tumor can usually be removed, whereas in other locations of the midline such as the chiasma opticum, thalamus, and brain stem there may be difficulties. Growth within the spinal cord is also possible (so-called glial rod). Pilocytic astrocytoma is classified grade I in the WHO classification. Malignant change has been described, but seems to be extremely rare (Fig.3.2.1). Pilocytic astrocytoma may, however, be a good example of diverging biological and clinical malignancy. Pilocytic astrocytoma may be grossly firm or cystic depending on the site of growth. It is composed of bipolar astrocytes that taper into curly glial fibers (pilocytic = hairy cells). If looser growth is possible, multipolar cells may be formed. Usually, the tumor is rich in glial fibers. The cytological hallmark of the tumor is the so-called Rosenthal fiber, a degenerated glial fiber product. The corresponding formations are known as the “granulated bodies” and are also considered as sequelae of glial degeneration. Regressive changes such as small calcifications and the formation of larger cysts occur. Often, there is considerable variability in newly formed vasculature, which, together with some cellular pleomorphism, may give the impression of aggressiveness; this (moderate) anaplasia, how-

3.2.1.4.2 Diffuse Astrocytomas

Diffuse astrocytomas are supratentorial gliomas that occur in earlier adulthood. They account for 5–10% of intracranial new growths. A slight male preponderance has been noted. Astrocytomas are firm tumors; some of them form abundant minute cysts. These tumors receive grade II in the WHO classification. With this grading a recurrence-free interval of about 5years is to be expected. There are slightly differing prognoses concerning the subgroups (see below), but all behave in such a way that their grouping as grade II seems most appropriate. Fibrillary, protoplasmic, and gemistocytic diffuse astrocytomas can be distinguished according to their cytology. Fibrillary astrocytomas are of low cell density, with naked nuclei embedded within a loose glial fiber network. This variety often forms small cysts, when the meshes of the network rupture (Fig. 3.2.2). There are many small capillaries; mitoses are typically absent. In the protoplasmic variant the somata of the astrocytes, in addition to their extensions, are visible with aniline dyes, with impregnation, and with immunohistochemistry (Fig. 3.2.3). Gemistocytic astrocytomas contain a wealth of huge cells with abundant cytoplasm and coarse fibers (Fig 3.2.4). In the latter tumors, some vascular proliferation may be seen. The pleomorphic xanthoastrocytoma may have very variegated features resembling the glioblastoma, but has a favorable prognosis (grade II).

3.2 Brain Tumors

Fig.3.2.2a,b Diffuse adult fibrillary astrocytomas most often grow in a loose network and may form small, microscopically visible cysts that in this case are surrounded by tumor cells with very slender astrocytic processes

Fig. 3.2.3 Protoplasmic astrocytomas exhibit well recognizable cellular shapes and coarse glial fibrils

Fig. 3.2.4a,b Gemistocytic astrocytomas are full of large cells with eosinophilic cytoplasm (a). These tumors invariably express the astrocytic marker glial fibrillary acidic protein (GFAP) (b)

3.2.1 Classification and Biology of Brain Tumors

3.2.1.4.3 Oligodendrogliomas

One to five percent of intracranial tumors are thought to be oligodendrogliomas, with an age peak of about 40years and, again, a slight prevalence of the male. These tumors are mostly found in the cerebral hemispheres, occasionally extending into the cerebral cortex. The cytological picture is very uniform. Cells have small round dark nuclei that are situated in the center of small holes; the whole arrangement is known as “honeycomb” formation (Fig.3.2.5). This tumor tends to form calcifications that can even be visible on conventional X-rays. Oligodendrogliomas are classed as grade II in the WHO classification. Recurrence free-intervals are generally 5years or more, and a good response with regard to certain drug protocols has been reported [24]. Mixed gliomas contain both astrocytic and oligodendroglial cells to variable extents. Since a considerable proportion of the oligodendroglial component confers a better prognosis and chemotherapy sensitivity, the composition of mixed glioma has to be analyzed skillfully.

The hallmark of anaplastic gliomas are variegated cell shapes and increased newly formed vasculature. The cellular pleomorphism is marked by the variable size and shape of the tumor cells (Fig. 3.2.6); giant cells may be formed. Mitoses and their pathological forms occur. Otherwise, anaplastic gliomas show the histological criteria of their more benign counterparts. Vascular proliferation may be present in anaplastic gliomas; in anaplastic oligodendrogliomas in particular the occurrence of microvascular proliferation, and even small necroses, is compatible with the diagnosis. However, necroses belong rather to the glioblastoma feature. Anaplastic gliomas are classed as grade III in the WHO classification. Their recurrence-free postoperative interval is considered to be about 2years. They are treated similarly to glioblastomas, but since anaplastic oligodendrogliomas have a better prognosis, the composition of the anaplastic gliomas has to be analyzed thoroughly. 3.2.1.4.5 Glioblastoma (Multiforme)

Anaplastic gliomas may be considered intermediate between diffuse (isomorphic) gliomas and the highly anaplastic glioblastoma (multiforme). Pleomorphic (pleomorphous) glioma is a synonym emphasizing the variegation in cellularity and histology. Anaplastic gliomas comprise anaplastic astrocytomas, anaplastic oligodendrogliomas, and anaplastic mixed gliomas. The clinical course and epidemiological data, as well as the gross localization, are thought to be intermediate between diffuse glioma and glioblastoma.

Glioblastoma is a malignant adult intracranial tumor. It accounts for 10–15% of all intracranial tumors. There is a clear male preponderance of 6:4. The location of the glioblastoma in the brain is mostly supratentorial, but brain stem and spinal cord tumors have been found incidentally. Within the brain, temporal and other “lobar” locations are typical. Another characteristic growth pattern is that in butterfly manner, where the tumor spreads through the corpus callosum and grows in both hemispheres. Macroscopically, glioblastoma is variegated in color (glioblastoma multiforme); necroses may be whitish or yel-

Fig. 3.2.5 The hallmark of low-grade oligodendrogliomas is the monomorphic formation of so-called honeycomb or plant cell architecture. In addition, small capillaries are found within the tumor

Fig.3.2.6 Anaplastic astrocytomas are of an astrocytic nature, but with increased cellularity, formation of giant cells, and a higher proliferation rate, as indicated by the increased number of mitoses

3.2.1.4.4 Anaplastic Gliomas

3.2 Brain Tumors

low and fresh or old hemorrhage may be seen (Fig.3.2.7). The cellular content is usually very pleomorphous. Often small round cells constitute the major cell population (globuliform) or bipolar cells prevail (fusiform). In addition, identifiable protoplasmic or gemistocytic astrocytes are observed. Giant cells are common; if they predominate, the tumor is often named “giant cell glioblastoma.” The separation of this entity proved reasonable because of few differences compared with ordinary glioblastoma in the genetic make-up [25]. The histology of the tumor is marked by two regularly occurring features: prominent newly formed vasculature and necroses. Neovascularization is found in different formations: microvessels may form glomeruli and huge sinusoidal vessels may occur. Necroses are either large areas or small band-like foci surrounded by tumor cells, forming pseudopalisades. Large “territorial” necroses occur preferentially in de novo formed glioblastomas, whereas small serpiginous ones are found in primary and secondary glioblastomas. The cells forming pseudopalisades are thought to produce hypoxia-driven growth factors for neovascularization [26]. The classical method of visualizing such newly formed vessels is the staining of reticulin fibers, which nicely depicts vessels of all sizes. If the reticulin-stained fibers transgressed the vasculature, the tumor was considered to contain a “sarcomatous component” or was even called “gliosarcoma.” Gliosarcoma was considered in the former WHO classification as a separate entity, but is now a subgroup of the glioblastoma, with a frank mesodermal component, proven by reticulin stain. It has been shown repeatedly that the genetic alterations in gliosarcoma are almost identical to those of primary glioblastoma; in the gliomatous and sarcomatous parts of the same tumor the findings were the same [27]. Glioblastoma, and even more so,

gliosarcoma, have to be separated from the benign pleomorphic xanthoastrocytoma (see Sect.3.2.1.4.2), a tumor with features that can all be found in malignant gliomas, except for signs of rapid growth [28]. To distinguish between them, the immunohistochemical visualization of proliferation markers is very helpful.

Ependymoma and papilloma of the choroid plexus are localized within or near the ventricles of the brain (Fig.3.2.8). Both tumors preferentially occur in children or young adults, but some are also found in the elderly. Both tumors may have a papillary structure on gross inspection. Histologically, ependymomas group around vessels. The most prominent feature is the perivascular arrangement of cells, leaving free the zone between the endothelium and the cellular cuffs (pseudorosettes). Several subgroups can be distinguished by histopathology: papillary, clear cell, tanycytic, cellular, and myxopapillary. Some ependymomas form short ependymal channels and true rosettes that both mimic the architecture of the ependymal lining (Fig.3.2.9). A tumor with similarities to ependymoma is the socalled subependymoma [29], presenting with small clusters of round cells within a glial matrix and facultative formation of microscopic cysts. Papillary choroid plexus tumors are by their make-up very similar to normal choroid plexus, but may be much larger; the stroma and the superficial cells may be enlarged and/or thickened. Ependymomas are usually classified as grade II; i. e., recurrence is possible after a few years. The myxopapillary variant, as well as the subependymomas and most

Fig.3.2.7 Glioblastomas multiforme often develop visible necroses in the center and a rim of irregularly proliferating cells at the periphery, as seen here in a glioblastoma of the thalamus

Fig.3.2.8 Ependymomas grow in or next to the ventricular lumen in different parts of the brain, here in the third and lateral ventricle of the forebrain

3.2.1.4.6 Ependymoma and Papilloma of the Choroid Plexus

3.2.1 Classification and Biology of Brain Tumors

Fig.3.2.9 Anaplastic ependymomas are of high cellular density and higher mitotic activity, but show the ground structure of the repetitive pattern, as is seen in other tumors of this type

Fig. 3.2.10 Perivascular pseudorosettes within a malignant ependymoma allow the diagnosis of this otherwise diffusely arranged, highly cellular neoplasm

of the plexus tumors, are classified as grade I. Malignant ependymomas (anaplastic ependymomas, WHO grade III) share features with anaplastic gliomas, especially high proliferation indices (Fig.3.2.10). Malignant plexus tumors (plexus carcinomas, WHO grade III) are equally polymitotic. The ependymoblastoma, an embryonal childhood tumor with the hallmark of layered rosettes is considered to correspond to WHO grade IV. 3.2.1.4.7 Tumors of the Pineal Parenchyma

Tumors of the pineal parenchyma comprise the pineocytoma on the benign and the pineoblastoma on the malignant side. Tumors of pineal origin represent less than 0.5% of intracranial neoplasms, and half of them are pineocytomas, half pineoblastomas. Harmless pineal cysts may be considered to be inert tumors at this site. Pineocytomas are composed of small cells resembling pineal parenchymal cells. They are layered in sheets, but occasionally also form characteristic “large” rosettes. Pineoblastomas, in contrast, are less differentiated, polymitotic small cell tumors that can be compared to medulloblastomas and are included in the primitive neuroectodermal tumor group. Accordingly, the tumor cells have the polygonal shape of medulloblastoma cells and some rosette formations, cellular columns, and islands may be seen (Fig.3.2.11). In pineocytoma and pineoblastoma differentiation along the neuronal and glial line has been described. Pineocytomas receive grade II classification, but the course is often favorable. Pineoblastomas are classed as grade IV, as are other members of the primitive neuroectodermal tumor group. An intermediate form – pineal parenchymal tumor of intermediate differentiation – is included in the WHO classification, but without any comment concern-

Fig.3.2.11 Malignant tumors in the pineal gland with an aspect of low differentiation and mitotic activity are called pineoblastoma

ing its actual clinical course. The designation “pinealoma” – isomorphic and anisomorphic – is no longer used. Most of the tumors diagnosed as pinealoma were in fact germinomas. 3.2.1.4.8 Medulloblastomas

Medulloblastomas are tumors with a clear-cut peak of occurrence in children at the age of 7–9 years, a location – by definition – within the fossa cerebri posterior, and a malignant course. Medulloblastomas in the adult are less frequent and are clustered around 30years of age. Sixtysix percent of affected children and adults are male. Most medulloblastomas are localized in and probably arise from the vermis of the cerebellum, possibly extend-

3.2 Brain Tumors

ing into the fourth ventricle (Fig.3.2.12). Specimens that occupy the cerebellar hemispheres are often associated with later onset and desmoplastic behavior. The nuclei of the tumor cells of these neoplasms are described as round to oval, carrot- or bean-shaped, hyperchromatic, and often presenting with mitotic figures. A typical but not constant feature is the so-called neuroblastic rosette and possible differentiation along the neuronal line is assumed; ganglion cell perikarya have been observed. A special formation is the occurrence of abundant reticulin fibers leaving free pale islands. This variant is now called desmoplastic medulloblastoma (formerly also arachnoidal sarcoma). Another, more recently described variety is the medulloblastoma, with extensive nodularity and advanced neuronal differentiation. Fur-

thermore, a large cell variant, medullomyoblastomas with focal myoblastic differentiation and melanotic medulloblastoma with pigmentations were treated as separate entities. Tumors with less differentiated histological features, often known as “blue” tumors, that grow in the supratentorial compartment, today receive the label of PNET – primitive neuroepithelial tumor (Fig. 3.2.13). In PNET, as in other primitive tumors – pineoblastoma, medulloblastoma – various lines of differentiation, neuronal in the first instance, can be recognized. PNET and the mesenchymal–osteogenic Ewing sarcoma are considered to be identical because they present with the same immunophenotype [30]. All tumors of this group are malignant and as classified as WHO grade IV. Medulloblastomas tend to produce metastases through the spinal fluid pathway. Progress in the management of childhood medulloblastomas has been achieved in the last few decades. 3.2.1.4.9 Neuronal Tumors

Fig.3.2.12 Medulloblastomas typically grow in the vermis of the cerebellum, extending into the fourth ventricle

Fig.3.2.13 In these diffusely arranged primitive neuroepithelial tumors (PNETs), the mitotic activity is similar to that found in medulloblastomas

Neuronal tumors form a heterogeneous group. They include the olfactory neuroblastoma, the adrenal neuroblastoma, and other tumors of the sympathetic nervous system, as well as centrally occurring neuroblastomas, ganglioneuroblastomas, gangliogliomas, and gangliocytomas. The central neurocytoma of the third ventricle (formerly foramen of Monroe ependymoma) has been shown to be neuronal [31]. As one can see from the nomenclature, these tumors cover a wide range of malignancy grades. In addition, some partly malformative, partly tumorous conditions are included, such as the dysembryogenetic neuroepithelial tumor, a lesion often found in connection with epilepsy neurosurgery, but with an uncertain definition [32]. A similar, highly benign lesion is the desmoplastic infantile ganglioglioma (DIG), today used synonymously with infantile desmoplastic astrocytoma (DIA). All these tumors have overt or partial neuronal differentiation that can be unraveled by either conventional staining (Nissl stain; Fig. 3.2.14) or the formation of axons in mature gangliocytomas or gangliogliomas, or immunohistochemistry, or even electron microscopy in other cases. According to the heterogeneity of the group, varying morphological pictures are encountered; the common denominator is the proof of neuronal derivation. Similarly, the share of actively proliferating cells varies considerably, as measured by mitotic figures or Ki 67 (MiB-1) immunohistochemistry. Highly malignant neuroblastomas and almost nonproliferating dysembryoplastic neuroepithelial tumors (DNT) are included. Of the intracranial tumors, olfactory and other neuroblastomas are classed as grade IV, ganglioneuroblastoma and anaplastic ganglioglioma grade III, ganglioglioma and central neurocytoma mostly fall within grade II,

3.2.1 Classification and Biology of Brain Tumors

Fig. 3.2.14 Gangliocytomas consist of mature ganglion cells with large nuclei that may be recognized using the cresyl violet “Nissl” stain

Fig. 3.2.15 Neurinoma, schwannoma or neurilemmoma are composed of bipolar Schwann cell-like elements that form palisades, i. e., rows of tumor cell nuclei leaving fibrillary parts free between them

whereas gangliocytoma, DNT and DIG, receive grade I of the WHO classification.

Neurofibromas are characterized by the participation of connective cells and tissue in the histological picture. The mostly peripherally occurring tumor of the nerves with onion bulb formation is called the perineurioma. Schwannomas and the tumors mentioned here are all classed as grade I in the WHO classification. The malignant variant of these Schwann cell neoplasms is designated the malignant peripheral nerve sheath tumor (MPNST). It is graded III or IV in the WHO classification. MPNST corresponds to the earlier malignant neurinomas, neurosarcomas, neurogenic sarcomas or malignant neurofibromas.

3.2.1.4.10 Schwannomas

The terms neurinoma and neurilemmoma are used synonymously. These tumors grow within the cranial and spinal cavities and peripherally, but are objects mostly of neurosurgical intervention. Nerve roots are the main site; the overwhelming majority within the intracranial space are so-called acoustic nerve root schwannomas that in fact take their origin from the vestibular part of the eighth brain nerve. Spinal roots may be affected within and outside the column; these tumors then grow in a dumb-bell manner. Solitary peripheral schwannomas are found in connection with any peripheral nerve. A special gross growth pattern, mostly on the periphery, is the nodular or plexiform neurinoma. Schwannomas account for 5–10% of nervous system tumors. They occur preferentially in the elderly, and there is a small female preponderance. Grossly, the tumors tend to be firm. Schwannomas have two histologic patterns; namely, a reticular growth pattern (Antoni B) and the more common fibrillary variant (Antoni A). This fibrillary pattern is formed by the dense layering of slender bipolar cell nuclei surrounded by a cytoplasmic sheath tapering on both ends into fibrillary-like extensions. The nuclei may even be arranged in parallel rows (Fig. 3.2.15), called palisades, which are not so common, but highly characteristic of schwannomas. Short roundish bodies with nuclei roughly arranged in palisades are known as Verocay bodies.

3.2.1.4.11 Meningiomas

These tumors of the meninges are frequent. They constitute about 15–25% of primary intracranial tumors. They are tumors that occur in older people, and some special locations and even some morphological subgroups show a high female preponderance. Meningiomas arise in some typical locations that may be associated with neurological syndromes; therefore, olfactory groove meningiomas lead to early anosmia, whereas parasagittal meningioma may be followed by paraplegia mimicking a spinal location. Large meningiomas of the cerebral convexities may produce ipsilateral hemiparesis, and a well-documented but rare event is the intraventricular location of this tumor. Gross meningiomas are well demarcated (Fig.3.2.16) and firm, often adherent to the meninges and/or bone. Some tumors are lobulated. So-called infiltration of the dura mater and the bones of the skull is of uncertain significance with regard to malignant behavior. Some meningiomas grow as flat masses – en plaque.

3.2 Brain Tumors

The main histological feature of the meningioma is its tendency to “cover”: virtually all structures, single cells, small vessels or minute calcifications are surrounded by layers of covering cells. Thus, a wealth of concentric onion bulb formations can be seen in quite a number of meningiomas. A second, almost constant feature is the meningioma cell with round to oval pale nucleus and frequently with central clearing. Notwithstanding those more common features there are many subtypes, the most common being the endotheliomatous (meningotheliomatous), fibrous, transitional, and angiomatous varieties. Meningiomas with abundant formation of calcospherites are described as psammomatous; they are an example of high female and site prevalence. They occur in females typically in the 60–70 age group and are mostly located in the thoracic spinal cord. Further rarer subtypes are the cystic meningioma, the secretory variant with PAS-positive secretory products (pseudopsammoma bodies), the lymphoplasmacyte-rich meningioma and the metaplastic meningioma usually with focal mesenchymal differentiation. All these subgroups are classed as grade I in the WHO classification if there are no overt signs of advanced growth. There are few subtypes that by their histological nature are classed as grade II. The chordoid meningioma in parts resembles the chordoma and the clear cell meningioma, whose “empty” cytoplasm contains glycogen. Rhabdoid and papillary meningioma are classed as grade III, but they are both rare. Thus, there are three grades. Most common meningiomas are classed as grade I; grade II meningiomas may be any of the aforementioned with signs of higher proliferation, especially mitotic activity. They are called atypical meningiomas. Together with the chordoid and clear cell subgroups described they form the grade II group of

meningiomas in the WHO classification. Highly proliferating or invasive meningioma of any type or papillary and rhabdoid subtypes are included in grade III. Grade III meningiomas of any subtype are named anaplastic or malignant meningioma. The differential diagnosis of meningiomas includes mesodermal and vascular tumors. Benign and malignant mesodermal tumors occur in the meninges and occasionally in the brain. Somewhat more frequent are hemangiopericytomas of the meninges, formerly known as hemangiopericytic meningiomas. They correspond mostly to grade III in the WHO classification. Another neoplasm that is found in the leptomeninges with diffuse spread is primary diffuse melanosis of the brain, a condition with a poor prognosis.

Fig.3.2.16a,b Meningiomas are tumors of the cerebral coverings that grow within the intracranial space and may compress considerably the adjacent brain, but often do not invade the

brain or spinal cord (a). Histologically, onion bulb formations and psammoma bodies can often be found. The cells contain the intermediary filament vimentin (b)

3.2.1.4.12 Vascular Tumors

There are two true vascular tumors in the intracranial space; namely, the hemangiopericytoma, already alluded to in connection with the meningiomas and the hemangioblastoma Lindau. The hemangiopericytoma does not differ from specimens in other locations of the body, both with regard to morphology and to biological behavior, apart from the fact of its intracranial site with imminent pressure (Fig.3.2.17). The angioblastoma Lindau is found in the fossa posterior, seldom in the brain stem and spinal cord. It accounts for 1–2% of intracranial tumors. Its first symptoms often appear in the 30+ age group, but earlier onset is not uncommon. When growing within the hemispheres of the cerebellum, angioblastomas tend to undergo cystic transformation. Only small tumors grow regularly in a compact fashion. The histology of angioblastoma consists of a wealth of

3.2.1 Classification and Biology of Brain Tumors

Fig. 3.2.17 Hemangiopericytoma of the meninges show the histology of this tumor in other sites, namely a dense reticulin network next to the abundant vessels, demonstrated by silver impregnation methods

Fig.3.2.18 In the pineal gland, germinomas of the midline occur that are characterized by a two-fold cellular nature. Small lymphocytic cells surround large tumorous cells, thus yielding the characteristic biphasic cytology of this entity

vessels of different sizes; mostly, however, capillaries and interstitial cells. The latter may contain fat droplets. Thus, the histological picture is uniform: endothelial cells, basem*nt lamina (reticulin-stained), and interstitial cells. All hemangiopericytomas are considered to be classed as grade II or frequently grade III. Angioblastoma Lindau is classed as grade I. It is a matter of convention whether or not cerebellar angioblastoma might always be considered as the forme fruste of the von Hippel–Lindau phakomatosis.

ferentiated tissues, whereas the immature form consists fully or partly of immature fetal tissue. Mature teratomas are considered benign; their immature counterparts are less so, but can obviously undergo tumor “maturation.” In addition, teratomas with malignant transformation have been described that in addition contain sarcoma or carcinoma. Yolk sac tumors also resemble the specimens found in gonadal sites; some of their constituents express alpha fetoprotein. The latter tumors have an unfavorable course.

3.2.1.4.13 Germ Cell Tumors

3.2.1.4.14 Tumors of the Pituitary

Germ cell tumors are found in midline locations within the nervous system. One of the more conspicuous neoplasms of this group is the germinoma. It arises in the pineal site and is the most frequent tumor at this site. Furthermore, germinomas may be detected in the hypothalamic region and elsewhere in the midline (formerly known as ectopic pinealoma). Germinomas, like other germ cell tumors, are more common in children and young people, and there is a clear male preponderance in teratomas and germinomas. Germinomas present with two cell types. Large cells that occasionally show mitotic figures are the true tumor cells. Small cells occurring in clusters or diffusely intermingled with the tumor cells lead to the characteristic picture (Fig. 3.2.18). Other germ cell tumors, such as embryonal carcinomas or choriocarcinomas, have the morphologies of their gonadal or extragonadal forms elsewhere. Teratomas are tumors that differentiate along more than one germ line be it ecto-, meso- or entodermal. Their mature form has formations that are found in fully dif-

Tumors of the pituitary are pituitary adenomas and their very rare malignant forms are known as pituitary carcinomas and craniopharyngiomas. Pituitary adenomas are endocrinologically active or silent tumors, possibly leading to acromegaly or Cushing’s syndrome, etc. They belong to the more frequent intracranial tumors (8–12%), there is no clear cut monophasic age peak, and there is equal distribution between males and females. Pituitary adenomas either form sheets of monomorphic small round cells (Fig.3.2.19) or may exhibit some papillary formations. Craniopharyngiomas occur in children and adults, the male–female ratio is balanced (Fig.3.2.20). In addition, few cysts occur in this site, the most common being Rathke’s cleft cyst. Pituitary adenomas are classified as endocrinologically active if they produce prolactin or growth hormone (frequently) or ACTH (seldom) or other hormones (extremely seldom). The pertinent cell populations in the tumors may be identified by special stains, immunohistochemistry or electron microscopy. But a one-to-one correlation from morphology to endocrinological chang-

3.2 Brain Tumors

Fig.3.2.19 Pituitary adenomas, hormonally either active or inactive, consist of a dense population of small cells that are poorly delineated and form monomorphic sheets

Fig.3.2.20 Craniopharyngioma are often cystic and show several regressive features visible to the naked eye

es should not be expected. Craniopharyngiomas contain bands of partly stratified epithelium; two forms, papillary and adamantinomatous, may be distinguished and have slightly different histological features and varying age distribution and recurrence rates, the latter forming wet keratin and calcifications, the former almost exclusively occurring in adults. Pituitary adenomas and both forms of craniopharyngiomas are classed as grade I. Pituitary carcinomas, which are extremely rare, receive grade IV. Rathke’s pouch cleft is not a proper tumor, but may be considered as a forme fruste of a craniopharyngioma.

tioned. Most are malformative cysts such as the enterogenic cyst, bronchogenic cyst, and colloid cyst of the third ventricle. Some hamartomas, the so-called glioma nasi, and the cysts of the dermoid or epidermoid may be gathered within the same rubric. Since these are not true tumors, no grading is given. There are several categories in the latest 2007 WHO Classification of Tumours of the Nervous System (Table 3.2.1) that are not specifically addressed in the text, as they are rather uncommon or contentious. Further information can be found in the cited or other textbooks.

3.2.1.4.15 Miscellaneous

Metastases to the brain from distant carcinomas are frequent (Fig.3.2.21). Most often the brain is the metastatic goal of tumors of the lungs, breast, kidney, gastrointestinal tract, and as a direct extension of the pharynx. Obviously, a tumor with high metastatic potential to the brain is the chorionepitheliom, which, however, is infrequent as a primary tumor. A similarly high rate of brain affiliation is observed in malignant melanoma of the skin and other localizations. Malignant lymphomas may stem from cerebral or subarachnoidal seedings or arise primarily in the brain (Fig.3.2.22). Both malignant lymphomas and carcinomas are prone to inducing neoplastic meningitis (leukemic or carcinomatous). On the opposite side of the spectrum of intracranial space-occupying lesions there are a variety of cysts (Fig. 3.2.23), some of which have already been men-

Fig. 3.2.21 Metastatic tumors to the brain are often multiple and tend to grow in different places

3.2.1 Classification and Biology of Brain Tumors

Fig. 3.2.22 Cerebral primary or metastatic lymphomas are characterized by a perivascular assembly of neoplastic lymphocytes almost exclusively of the B cell type

Fig.3.2.23 Different sorts of intracranial cysts may be visualized using cytokeratin antibodies that show this epithelial marker, sometimes within the cyst lining

Selected Reading

11. Ohgaki H, Reifenberger G, Nomura K, Kleihues P (2001) Gliomas. In: Gospodarowicz MK, Henson DE, Hutter RVP, O’Sullivan B, Sobin LH, Wittekind C (eds) Prognostic factors in cancer, 2nd edn. Wiley-Liss, New York, pp 725–743 12. Schwab M, Ellison J, Busch M, Rosenau W, Varmus HE, Bishop JM (1984) Enhanced expression of the human gene N-myc consequent to amplification of DNA may contribute to malignant progression of neuroblastoma. Proc Natl Acad Sci USA 81:4940–4944 13. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller, M, Kroos JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from telozolomide in glioblastoma. N Engl J Med 352:997–1003 14. Zülch KJ (1975) Atlas of gross neurosurgical pathology. Springer, Berlin Heidelberg New York 15. Krauseneck P (1998) Neuroonkologie. Akt Neurol 25:219–226 16. Zülch KJ (1986) Brain tumors their biology and pathology. Springer, Berlin Heidelberg New York 17. Mennel HD, Plate KH (1991) Morphologie und Prognose bei intrakraniellen Tumoren. Fortschr Neurol Psychiatr 59:35–42 18. Kleihues P, Ohgaki H (1999) Primary and secondary glioblastoma: from concept to clinical diagnosis. Neurooncology 1:44–51 19. Zankl H, Zang KD (1972) Cytological and cytogenetic studies on brain tumors. 4. Identification of the missing G chromosome in human meningiomas as no 22 by fluorescence techniques. Humangenetik 14:167–169 20. Lekanne D, Bianchi AB, Groen NA, Warringa UL, Seizinger BR, Hagemeier A, van Drunen E, Bootsma D,

1. Mennel HD (1993) Einteilungsprinzip intrakranieller Tumoren. Eine unbedingte Voraussetzung zur Therapie. TW Neurol Psychiatr 7:320–335 2. Kernohan JW, Mabon RF, Svien HJ, Adson AW (1949) A simplified classification of the gliomas. Symposium on a new simplified concept of gliomas. Proc Staff Meet Mayo Clin 24:71–75 3. Ringertz N (1950) Grading of gliomas. Acta Pathol Microbiol Scand 27:51–64 4. Zülch KJ, Wechsler W (1968) Pathology and classification of gliomas. Prog Neurol Surg 2:1–84 5. Zülch KJ (1979) Histological typing of brain tumors. WHO, Geneva 6. Kleihues P, Burger PC, Scheithauer BW (eds) (1993) Histological typing of tumors of the central nervous system. Springer, Berlin Heidelberg New York 7. Kleihues P, Cavenee WK (eds) (2000) Pathology and genetics tumors of the nervous system. IARC, Lyons 8. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds) (2007) WHO Classification of Tumours of the Central Nervous System. IARC, Lyon+ 9. Mennel HD (1988) Geschwülste des zentralen und peripheren Nervensystems. In: Doerr W, Seifert G (eds) Spezielle pathologische Anatomie, vol 13/III. Pathologie des Nervensystems III, pp 215–542 10. Cattoretti G, Becker MHG, Key G, Duchrow M, Schlüter C, Gerdes J (1992) Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol 168:357–363

3.2 Brain Tumors

Koper JW, Avezaat CJ, Kley N (1994) Frequent NF2 gene transcript mutations in sporadic meningiomas and vestibular schwannomas. Am J Hum Genet 54:1022–1029 21. Scherer HJ (1940) Cerebral astrocytomas and their derivatives. Am J Cancer 40:159–198 22. Tohma Y, Gratas C, Van Meir EG, Desbaillets I, Tenan M, Tachibana O, Kleihues P, Ohgaki H (1998) Necrogenesis and Fas/APO-1(CD95) expression in primary (de novo) and secondary glioblastoma. J Neuropathol Exp Neurol 57:239–245 23. Ohgaki H, Eibl RH, Schwab M, Reichel MB, Mariani L, Gehring M, Petersen I, Holl T, Wiestler OD, Kleihues P (1993) Mutations of the p53 tumor suppressor gene in neoplasms of the human nervous system. Mol Carcinog 8:74–80 24. Cairncross JG, Laperiere NJ (1989) Low grade glioma. To treat or not to treat? Arch Neurol 46:1238–1239 25. Peraud A, Watanabe K, Schwechheimer K, Yonekawa K, Kleihues P, Ohgaki H (1999) Genetic profile of the giant cell glioblastoma. Lab Invest 79:123–129 26. Plate KH, Breier G, Weich HA, Mennel HD, Risau W (1994) Vascular endothelial growth factor and glioma angiogenesis: coordinate induction of VEGF receptors, distribution of VEGF protein and possible in vivo regulatory mechanisms. Int J Cancer 59:520–529 27. Biernat W, Agguzzi A, Sure U, Grant JW, Kleihues P, Hegi ME (1995) Identical mutations of the p53 tumor suppressor gene in the gliomatous and the sarcomatous components of gliosarcomas suggest a common origin from glial cells. J Neuropathol Exp Neurol 54:651–656 28. Kepes JJ, Rubinstein LJ, Eng LF (1979) Pleomorphic xanthoastrocytoma: a distinctive meningocerebral glioma of young subjects with relatively favorable prognosis; a study of 12 cases. Cancer 44:1839–1852 29. Scheinker IM (1945) Subependymoma: a newly recognized tumor of subependymal derivation. J Neurosurg 2:232–240 30. Fletcher CDM, Unni KK, Mertens F (eds) (2002) WHO classification of tumours: pathology and genetics of soft tissues and bone. IARC, Lyon 31. Hassoun J, Gambarelli D, Grisoli F, Pellet W, Salamon G, Pellisier JF, Toga M (1982) Central neurocytoma. An electron microscopic study of two cases. Acta Neuropathol (Berl) 56:151–156 32. Daumas-Duport C, Scheithauer BW, Chodkiewicz JP, Laws ER Jr, Vedrenne C (1988) Dysembryoblastic neuroepithelial tumor: a surgically curable tumor of young patients with intractable partial seizures. Report of thirty nine cases. Neurosurgery 23:545–556

3.2.2 Epidemiology of Brain Tumours

Flemming Gjerris 3.2.2.1

Basics

The treatment of primary brain tumours in adults and children is a challenge for neurosurgeons, paediatricians and neuro-oncologists. It is important to have a thorough knowledge of the frequency, taxonomy and prognosis of brain tumours. Epidemiology of intracranial (brain) neoplasms is thus a study of the occurrence of brain tumours in a distinct population or region [1, 2]. The compilation of all the different cases within one region is dependent on the organisation of the medical services, on neuropathological traditions, on tumour taxonomy, on the availability of cancer and mortality registration systems, and finally on the different rules in a single country. The neuropathological classification of primary brain tumours is described in Sect.3.2.1. During the last 20years, modern imaging methods such as roentgen computed tomography (CT) and magnetic resonance imaging (MRI) have been of great help in the verification and planning of treatment or follow-up of patients with brain tumours. 3.2.2.2 Definitions 3.2.2.2.1 Definitions and Age Limits

• A brain tumour is an intracranial neoplasm verified by histology, operation, autopsy or by imaging methods, and arises from the brain itself or from the meninges, and grows inside the skull. Tumours located in the skull only, i. e. dermoids and granulomas, are not included. Arteriovenous malformations of the brain are not neoplasms and should not be incorporated into the classification of brain tumours. • The age limits used for adults are the age groups above 14years of age, i. e. 15–99 or more. • The age limits for children are the 15 year groups from 0 to 14years of age. • Supratentorial location is the space above the tentorial incisura and includes the anterior and medial fossa of the skull and the brain above the tentorium. • Infratentorial location is the posterior fossa space, including the cerebellum, brainstem and the adjacent parts of the skull base. • Imaging verification by CT or MR in the supratentorial area should only be performed for deep-seated tumours, i. e. in the basal ganglia or pineal area and in the posterior fossa for brain stem tumours, mostly due to the rather high risk related to a biopsy. In all

3.2.2 Epidemiology of Brain Tumours

• •

•

other intracranial regions a tumour should always be verified by histology in an attempt to plan and apply the best treatment. Prevalence and incidence are the two major measures of disease frequency. Prevalence is the number of persons alive with a brain tumour in a population divided by the total population at risk within that time; for example, in Denmark 2,500 persons out of 5.3million people = 50 per 100,000 per year. The prevalence depends on two factors, i. e. incidence and duration of the disease, so a variation in prevalence may reflect a change in incidence or outcome or both. The cumulative incidence is observed for an equal period of time and is the probability of developing a brain tumour in a population. It is defined as the number of new brain tumours during a period of time (generally 1 year) divided by the population at risk within that time (Fig.3.2.24). The incidence rates are usually expressed per 100,000 persons of a standardised European population. As an illustrative example, Denmark has 4.4 million adults and about 1 million children below 15years of age. The annual incidence is 440 per 4.4million adults = 10 per 100,000 adults, and 35 per 1million children = 3.5 per 100,000 children. The incidence density is the average risk of developing a brain tumour in a population, i. e. the number of new brain tumours per year divided by the population at the beginning of the time interval, e. g. 400 per 5.3million = 9 per 100,000 per year. The incidence density is used when persons are observed for different lengths of time. Mortality (death) rate is the number of persons dying of a brain tumour during a period of time divided by the population at risk within that time.

Fig. 3.2.24 European incidence rates standardised according to age of brain and CNS tumours, by sex, Great Britain, 1975–2003; modified from [15], with permission

3.2.2.2.2 Further Epidemiologic Concepts

The frequency of brain tumours can be investigated by cohort or case-control studies [1, 2, 7]. The cohort study is a follow-up (retrospective) investigation or a prospective analysis in which groups of individuals are identified and followed over time [5, 6]. The case-control study identifies persons with brain tumours, uses a similar age group of individuals without brain tumour as controls and evaluates survival, disability rate and social events. These are retrospective in nature and compare a sample of cases with exposures of interest, i. e. diet and vaccinations [4]. The retrospective (casecontrol) study identifies children by whether or not they have a brain tumour. Thus, a case-control study might be based on only 50 children with a specific brain tumour and a similar number of controls. The advantage, besides its low cost, is that it provides an opportunity to explore multiple hypotheses. If parental exposure is a risk factor for brain tumours in children, it is necessary to determine how much of the increased risk reflects exposure before conception, during pregnancy and after birth. Correlational (ecological) studies explore the rate of brain tumours in a population area and compare this with a geographic distribution of suspected risk factors. The principle goal is to find the causes of a brain tumour so that preventive measures may be implemented. Only prospective studies can provide accurate information about exposure, but are incredibly expensive. For example, for every 100,000 children under the age of 15years investigated, only 3 or 4 children will manifest a brain tumour each year [6, 17]. The occurrence of brain tumours in populations is not an indiscriminate phenomenon. It depends on many causes, e. g. biology, exposure and the dose–response relationship. Brain tumours can be induced in experimental animals via the intracerebral or other routes of different compounds, e. g. aromatic hydrocarbons and nitrosoureas [12, 13], which exert their carcinogenicity in different ways. Foetal animals are more susceptible to chemical oncogenesis than adult animals. Adult persons in some occupations are at increased risk of central nervous system tumours, e. g. lead smelters and petrochemical workers [13]. Different risk factors are described, of which only a few are mentioned here, e. g. immunosuppression, postnatal irradiation, viral exposition, gender and gene disorders. People who are immunosuppressed are at risk of developing lymphomas or sarcomas in the brain. Reports of central nervous system tumours have implicated therapeutic radiation as a risk factor [6], e. g. irradiation of the head for a malignant brain tumour during childhood appears to result in an increased risk of meningiomas and other intracranial tumours. In laboratory animals, viral infections increase the risk of brain tumours, and the

3.2 Brain Tumors

younger the age at inoculation, the greater the incidence of multiple tumours [4]. Polio vaccine contaminated with simian virus-40 (SV-40) can be oncogenic. SV-40 is a papovavirus with which some live polio vaccines were contaminated. Increased occurrence of ependymomas and plexus papillomas has been described in animals after SV-40 contamination, but has not been found in children vaccinated for polio with SV-40-contaminated vaccine [4]. Men are at greater risk of brain tumours than women [15]. Compared with male/female ratio in the paediatric population, the incidence figures only disclose a very slight preponderance in boys [5, 6]. Some genetic factors are known, e. g. von Recklinghausen’s neurofibromatosis (Table3.2.6). The reader can calculate the frequency of brain tumours using the above given numbers and can compute the incidence figures for adults and children in their own country, if stable bio-statistical figures for the population, adults and children are known. For elaboration of these definitions; see the following textbooks of epidemiology [1, 2, 7, 16, 19, 20]. The reason why a specific brain tumour might develop is unknown in most cases. 3.2.2.3

Epidemiology of Brain Tumours in Adults

Brain tumours are not very common, and many more than 50% of all brain tumours are metastatic (most common are from cancer of the lung [50%], breast [15%], melanoma [10%] and kidney [8%]), and the number is still increasing due to longer survival in patients with a cancer like the breast, kidney and prostate, or better diagnostic methods such as MRI (Sects. 3.2.5.6. and 3.2.6.3).

3.2.2.3.1 Incidence Rates of Primary Brain Tumours

Over the years 1980 to 2000, incidence rates of primary brain tumours have increased in adults [8, 15], caused by either improved diagnoses or a real change in incidence (Fig.3.2.24). The rise found in persons above the age of 64years is only a very modest increase, probably caused by better diagnostics using CT and MRI. In 2003 in the UK the crude incidence rate (Fig.3.2.25) per 100,000 of the population was 8.5 for males and 7.2 for females and the age-standardised rate in Europe per 100,000 of the population was 7.9 for males and 5.1 for females, numbers that are similar over the world. The different age peaks are well illustrated in Fig.3.2.24. Primary intracranial tumours are not among the most common tumours and constitute only 2–3% of all malignancies, with an incidence of 8–10 per 100,000 inhabitants in Europe and North America [14]. In adults, brain tumour figures from cancer registry studies are dependent on the rate of notification, which is high in many European countries and North America. However, a lack of clarity regarding the criteria for tumour definitions, the considerable variation in age ranges that are accepted as childhood, and the selection of materials, make comparison of incidence, classification, and survival difficult in many series. Statistical surveys very often include spinal tumours, but the low incidence of primary spine tumours implies only a slight increase in the total number, especially in children. The incidence rates for different primary brain tumours are fairly similar all over the world; an exception is a very high rate of pinealomas in Japan and the high rate of lymphomas in AIDS patients. In adults glioblastomas and meningiomas are the most frequent and the distribution of the different types is shown in Table3.2.7. A number of gene disorders or familial syndromes are shown in Table3.2.6.

Table3.2.6 Gene disorders and primary brain tumours Gene disorder

Tumour type

Place

Von Hippel-Lindau’s disease

Haemangioblastoma

Cerebellum, brain stem, spinal cord

Neurofibromatosis type 1

Astrocytoma, optic – chiasmal glioma

Midline, chiasmal area

Neurofibromatosis type 2

Schwannoma, meningioma, glioma

Cerebellopontine angle, overall intracranial

Tuberose sclerosis

Subependymal giant cell astrocytoma

Third and lateral ventricles

Sturge-Weber disease

Plexus papilloma

Ventricular system

Gorlin syndrome

Medulloblastoma

Cerebellum

Turcot syndrome

Medulloblastoma, glioblastoma

Cerebellum, cerebral hemispheres

Gardener’s syndrome (familial gliomas)

Glioma

Brain

Li-Fraumeni syndrome

Glioma

Brain

3.2.2 Epidemiology of Brain Tumours

Table 3.2.7 Histological types and frequency of the most common primary brain tumours Histology

Frequency (%)

Glioblastoma multiforme

20–25

Astrocytoma, anaplastic

3–5

Astrocytoma, juvenile or diffuse, low grade

Fig.3.2.25 Numbers of new cases and age-specific incidence rates of brain and other CNS tumours, by sex, UK, 2003; modified from [15], with permission

18–20

Ependymoma, low grade or anaplastic

3–5

Oligodendroglioma, low and high grade

2–4

Medulloblastoma

2–4

Meningioma

15–18

Schwannoma

6–8

Pituitary adenoma

6–8

Pinealoma, low and high grade

1–2

Angioblastoma

< 1

3.2.2.3.2 Distribution in Connection with Location and Histology

Papilloma

< 1

Epidermoid

< 1

3.2.2.3.2.1 Overall Remarks on Location and Histology

Craniopharyngioma

< 2

Primitive neuroepithelial tumours (PNET)

< 2

Lipoma

< 1

Other types

< 2

Primary brain tumours are classified according to their localisation. The intracranial space is for convenience divided into the supratentorial and infratentorial spaces. In adults 80–85% of the tumours will be placed in the supratentorial space and 15–20% in the posterior fossa. Histology rather than the anatomical location defines brain tumours today. The different classifications are described in Chap. 3.2.1 and the WHO classification has been used for many years [9]. The pathological classification is based on the tissue of origin and the morphological criteria for malignancy are anaplasia, invasiveness, recurrence and metastatic growth. All the different histologic types of brain tumours are shown in Tables3.2.7 and 3.2.8. Tumours, mostly neuroepithelial, are divided by degree of malignancy according to histological features into four malignancy groups, I–IV, where grade I includes juvenile astrocytomas and ependymomas, grade II diffuse astrocytomas, ependymomas and oligodendrogliomas, grade III anaplastic astrocytomas, ependymomas and oligodendrogliomas, and grade IV glioblastomas. 3.2.2.3.2.2 The Supratentorial Space 3.2.2.3.2.2.1 Sellar, Chiasmal and Pineal Region

These midline tumours account for 8–12% of all intracranial neoplasms. Pituitary adenomas (6–8%) are the most common followed by craniopharyngiomas (5%), pinealomas and chiasmal gliomas. Pinealomas occur mostly in young adults, i. e. germinomas. Ependymomas and papillomas are found in the third ventricle.

3.2.2.3.2.2.2 Cerebral Hemispheres and Lateral Ventricles

The most frequent tumours are astrocytomas, glioblastomas, ependymomas and oligodendrogliomas. Glioblastomas are slightly more common in males. Meningiomas are benign tumours, arising from the arachnoid membrane and found all over the inside of the dura. They are seldom found in the lateral ventricles. Meningiomas are doubly frequent in females as in males. Atypical meningiomas are uncommon and often associated with recurrence. Ependymomas and giant cell astrocytomas are found in the ventricles. 3.2.2.3.2.3 The Infratentorial Space 3.2.2.3.2.3.1 Cerebellum and Fourth Ventricle

The most common tumours are astrocytomas, grades II to III, ependymomas, haemangioblastomas and dermoids. 3.2.2.3.2.3.2 Brain Stem

These tumours are rather uncommon in adults and are mostly astrocytomas grades II to III. 3.2.2.3.2.3.3 Cerebellopontine Angle

Cerebellopontine angle tumours are most often meningiomas and schwannomas.

3.2 Brain Tumors

Table3.2.8 Location and histology of the most common primary brain tumours in adults and children Histology

Location

Supratentorial

Infratentorial

3.2.2.4

Adults

Children

Sellar

Pituitary adenoma Craniopharyngioma

Craniopharyngioma Glioma, optic chiasm

Third ventricle

Glioma Ependymoma

Astrocytoma, juvenile or diffuse Ependymoma

Pineal region

Pineoblastoma Pinealoma Meningioma

Pinealoma/pineocytoma Germinoma, teratoma Astrocytoma

Cerebral hemispheres

Glioblastoma Astrocytoma, low grade Astrocytoma, anaplastic Oligodendroglioma

Astrocytoma, juvenile/diffuse Astrocytoma, anaplastic Spongioblastoma Oligodendroglioma

Lateral ventricles

Ependymoma Meningioma

Plexus papilloma Ependymomas

Cerebellum

Astrocytoma, pilocytic Astrocytoma, diffuse Angioblastoma

Medulloblastoma Astrocytoma, pilocytic Angioblastoma Dermoid cyst

Fourth ventricle

Meningioma Ependymoma

Medulloblastoma Ependymoma Papilloma

Brain stem

Astrocytoma, anaplastic Astrocytoma, diffuse

Cerebellopontine angle

Schwannoma Meningioma Epidermoid cyst Glomus tumour

Ependymoma Papilloma Schwannoma Lipoma

Epidemiology of Brain Tumours in Children

In children brain tumours are the second most common type of tumour after leukaemia, i. e. about 25%. The natural history of a brain tumour includes a continual growth of the tumour, which means that almost every child will sooner or later come to medical attention. This also means that detection biases are infrequent. The rate of histological verification is in many older publications as high as 85–90%, but autopsy has decreased in many European countries during the last two decades. In specific noneloquent locations, i. e. the basal nuclei and brain stem, many tumours are verified by CT or MRI only. Metastasis to the brain is very uncommon in children.

3.2.2.4.1

Incidence Rates

The frequency of brain tumours in childhood reported in the previous literature is mostly based on materials from single departments, i. e. paediatric and neurosurgical clinics, neuropathological institutes or on reports referring to selected histological tumour types and only give a limited view of the epidemiological patterns. The annual incidence rates all over the world differ a little, probably due to registration matters. The rates for the Scandinavian countries, UK, The Netherlands and North America are very close. Other studies use the age of 20 as the upper age limit for childhood. First, acceptance of this high upper age limit will cause inclusion of supratentorial tumours, typically found in adults, and secondly, comparison between individual studies in some countries is difficult as most population statistics take the end of the 14th year as the upper age limit of childhood [3, 5]. Materials based on cancer registry studies or population materials

3.2.2 Epidemiology of Brain Tumours

have shown an annual incidence of brain tumours of between 2.2 and 3.5 per 100,000 in children below 15years of age, with an average incidence of 3.5 per 100,000 for boys and 2.5 per 100,000 for girls [10, 11]. Other reports show differences both in location and histological typing, mostly due to varying age ranges for childhood [6, 21]. The age peak of brain tumours in childhood is illustrated in Fig.3.2.25. Three epidemiological studies of brain tumours in children in Denmark for the years 1935–1959, 1960–1984 and 1980–1996 have shown that the number of tumours or different tumour types did not change during the first 50years, but increased during the last 10years of study [5, 6, 17]. The increased incidence rate of brain tumours in children is found in several countries. It is uncertain whether the increase is biologically real or is due to improved diagnostic methods, but the data strongly suggest that the incidence rate of brain tumours among Danish children aged 0–4 years has truly increased. Statistics from Denmark, Germany, Sweden and the UK indicate that improved diagnostic methods are unlikely explanations for the registered increases in incidence rates [10, 11, 17]. The most pronounced increase was seen for astrocytomas and primitive neuroectodermal tumours [11, 17].

Histology and anatomical location define brain tumours in children today, the International Classification of Diseases for Oncology (ICD-O) is in use. The majority of the tumours (80%) originate from neuroepithelial tissue. Astrocytomas are the most common, followed by medulloblastomas, ependymomas and oligodendrogliomas. In the most malignant ones differentiation between medulloblastomas, ependymoblastomas and sarcomas can be almost impossible, and many neuropathologists prefer to classify many of them as PNET (primitive neuroectodermal tumours). PNET are highly malignant and particularly seen in the cerebral hemispheres in infants. Pituitary adenomas, schwannomas and meningiomas are very uncommon in childhood [5, 6, 18].

3.2.2.4.2 Distribution in Connection with Location and Histology

The cerebral hemispheres are the second most common site (20%) and 40% of all intracranial neoplasms in infants are found here. They are usually astrocytomas, ependymomas, oligodendrogliomas, glioblastomas and PNET (Table3.2.8). Meningiomas are very uncommon.

3.2.2.4.2.1 Overall Remarks on Location and Histology

Thirty years ago intracranial tumours in children were described as being far more frequent in the infratentorial than in the supratentorial compartment, and in particular tumours of the cerebral hemispheres were reported less frequently. Later reports from Sweden, the UK and Denmark show that supratentorial tumours now constitute about 45% of all childhood intracranial tumours [6, 11]. Many authors have found identical rates of supratentorial and infratentorial tumours, but they had an upper age limit for childhood of 17years, which implies a rise in the number of supratentorial tumours [6]. The only wellknown cause of brain tumours in children is heredity, as shown in Table3.2.6. Half of the tumours in the supratentorial space are located in the midline and the other half in the lateral space. In children 75% of posterior fossa tumours are localised in the cerebellum or fourth ventricle, 20% in the brain stem and less than 2% in the cerebellopontine angle. Nearly the same distribution is found in cancer registry materials in Europe and North America [14, 17]. The most distinct differences in intracranial tumour types between children and adults are shown in the Table3.2.8.

3.2.2.4.2.2 Supratentorial Space 3.2.2.4.2.2.1 Sellar, Chiasmal and Pineal Regions

Tumours of these regions account for more than 10% of all intracranial neoplasms in children. Craniopharyngiomas constitute about 5% of all childhood brain tumours, pinealomas about 2% and chiasmal gliomas between 2 and 4%, and they often manifest during the first 5years of life with a familial predisposition. 3.2.2.4.2.2.2 Cerebral Hemispheres and Lateral Ventricles

3.2.2.4.2.3 Infratentorial Space 3.2.2.4.2.3.1 Cerebellar Tumours

Approximately 45% of childhood brain tumours arise in cerebellum. Juvenile and diffuse astrocytomas are the most frequent, followed by medulloblastomas, ependymomas, haemangioblastomas and plexus papillomas. 3.2.2.4.2.3.2 Brain Stem Tumours

These tumours are low grade or anaplastic astrocytomas. They are most common in the pons, infiltrating the cranial nerve nuclei and growing intrinsically along the long fibre tracts. Often, exophytic masses protrude into the fourth ventricle, which might enable biopsy or partial removal. 3.2.2.4.2.3.3 Cerebellopontine Angle Tumours

Cerebellopontine angle tumours are seldom seen in children [5, 6]. It is mostly acoustic schwannomas (nearly always in the 10–14years age group), epidermoids, dermoids and lipomas.

3.2 Brain Tumors

3.2.2.5 Special Remarks Primary brain tumours represent 2–3% of all cancers, with a yearly incidence of 8–10 per 100,000 adults, 20 per 100,000 adults above the age of 64years and 3.5 per 100,000 children. With the estimated increase in incidence in children, an average annual number of 40 new primary brain tumours per one million children is to be expected in a future European child population. Eighteen of these will be placed in the supratentorial area, 18 in the cerebellum and 3–4 in the brain stem or cerebellopontine angle. CT and MRI make it possible to establish the location and size of the tumour, and probably also to get an impression of the tumour type in question. Far and wide, knowledge of the epidemiology and a uniform standardised classification system for primary brain tumours in both children and adults are necessary tools for the correct treatment of the individual, for the evaluation of the long-term prognosis in different tumour types, and for a comparison of rates of tumours among different centres and countries. It also provides the possibility of analysing difficult cases over a long period, to evaluate and identify different types of exposure, and to treat high-risk groups. Cancer registry studies have shown that a low incidence of a type of brain tumour corresponds to a poor prognosis and that joint European efforts in multicentres and follow-up studies are necessary. After decades of research, we know a little more about the epidemiology and causes of primary brain tumours. Trends in brain tumour incidence have been influenced by technological advances in imaging and subsequent increased detection, especially in elderly people and children. Molecular epidemiologic studies of common genes and their possible interaction with different types of environmental exposure will hopefully provide new information on the incidence and causes of primary brain tumours. Selected Reading 1. Adami H, Hunter D, Trichopoulos D (2002). Textbook of cancer epidemiology. Oxford University Press, Oxford 2. Cassidy J, Bissett D, Spence RAJ (eds) (2006) Oxford handbook of oncology, 2nd edn, Oxford University Press, Oxford 3. Dreifaldt AC, Carlberg M, Hardell L (2004) Increasing incidence rates of childhood malignant diseases in Sweden during the period 1960–1998. Eur J Cancer 40:1351–1360 4. Engels EA, Katki H, Nielsen NM, Winther JF, Hjalgrim H, Gjerris F, Rosenberg PS, Frisch M (2003) Cancer incidence in Denmark following exposure to poliovirus vaccine contaminated with simian virus 40. J Nat Cancer Inst 95:532–539

5. Gjerris F, Harmsen A, Klinken L, Reske-Nielsen E (1978) Incidence and long-term survival of children with intracranial tumours treated in Denmark 1935–1959. Brit J Cancer 38:442–451 6. Gjerris F, Agerlin N, Buhl L, Børgesen SE, Haase J, Johansen H, Klinken L, Mortensen AC, Møller C, Ovesen N, Reske-Nielsen E, Schmidt K (1998) Epidemiology and prognosis of intracranial tumours in children in Denmark 1960–84. Childs Nerv Syst 14:302–311 7. Hebel JR, McCarter RJ (2006) A study guide to epidemiology and biostatistics. James and Bartlett, Boston 8. http://info.cancerresearchuk.org/cancerstats/types/brain 9. Jellinger K (1987) Pathology of human intracranial neoplasia. In: Jellinger K (ed) Therapy of malignant brain tumours. Springer, Vienna 10. Kaatsch P, Rickert CH, Kuhl J, Schuz J, Michaelis J (2001) Population-based epidemiologic data on brain tumours in German children. Cancer 92:3155–3164 11. Lannering B, Marky I, Nordborg C (1990) Brain tumors in childhood and adolescence in west Sweden 1970–1984. Epidemiology and survival. Cancer 66:604–609 12. Lilienfeld DW, Stolley PD (1994) Foundations of epidemiology, 3rd edn. Oxford University Press, New York 13. Merrill RM, Timmreck TC (2004) Introduction to epidemiology, 4th edn. James and Bartlett, Boston 14. Muir C, Waterhouse J, Mack T, Powell J, Whelan S (1987) Cancer incidence in five continents, vol V. IARC Scientific Publications No. 88. International Agency for Research on Cancer, Lyon 15. Office for National Statistics (2006) Cancer statistics registrations: Registrations of cancer diagnosed in 2003, England. Series MB1 no.34. 2006. National Statistics, London 16. Oleckno WA (2002) Essential epidemiology: principles and application. Waveland Press, Long Grove 17. Raaschou-Nielsen O, Sørensen M, Carstensen H, Jensen T, Bernhardtsen T, Gjerris F, Schmiegelow K (2006) Increasing incidence of childhood tumours of the central nervous system in Denmark 1980–1996. Br J Cancer 95:416–422 18. Rochat P, Johansen HH, Gjerris F (2004) Long-term followup of children with meningiomas in Denmark 1935–84. J Neurosurg (Pediatrics) 100:179–182 19. Rothman KJ, Greeland S (1998) Modern epidemiology, 2nd edn. Lippincott-Raven, Philadelphia 20. Szklo M, Nieto FJ (2004) Epidemiology, beyond the basis. James and Bartlett, Boston 21. Viscomi S, Pastore G, Mosso ML, Terracini B, Madon E, Magnani C, Merletti F (2003) Population-based survival after childhood cancer diagnosed during 1970–98: a report from the Childhood Cancer Registry of Piedmont, Italy. Haematologica 88:974–982

3.2.4 Stereotactic Biopsy

3.2.3 General Principles of Surgery on Brain Tumors

Christianto B. Lumenta 3.2.3.1

Indications for Surgery

The indication for surgery depends on the location of the tumor: it must be easily approachable and removable. Other important factors are the size and the growth factor of the tumor, and whether or not hydrocephalus is present. The Karnofsky performance scale and the age of the patient also have to be taken into consideration. In an infiltratively growing glioma palliative surgery is indicated, while curative surgery can be performed in low grade, non-glial tumors like meningioma, neurinoma, etc. The surgeon should decide on the radicality of the surgery, i. e., stereotactic biopsy, partial, subtotal or total exstirpation of the tumor. 3.2.3.2

Aim of Surgery

The aim of surgery is: • To remove as much as possible of the tumor • To improve the quality of life • To postpone the clinical worsening • To improve the conditions for adjuvant therapies 3.2.3.3

Results of Surgery

The results of surgery correlate significantly with the techniques used: • Operating microscope • Navigation system • Endoscope • Intraoperative imaging • Intraoperative neurophysiologic monitoring Another important type of equipment is microsurgical instruments. 3.2.3.4

Microsurgical Instruments

• Craniotomy instruments (high speed drill system), retractor system, micro-instruments: forceps, scissors, knifes, dissectors, micro irrigation systems, etc. • Ultrasonic aspirator allows a demolition followed by extraction of the tumor tissue. • Instruments used very frequently are a monopolar instrument for cutting and a bipolar instrument for hemostasis.

• Similar to the instruments that are used very frequently, laser also plays also a role in cutting, shrinking and hemostasis in specific tumors. The common types are Nd-YAG, CO2, holmium and argon laser.

3.2.4 Stereotactic Biopsy

Christianto B. Lumenta, Hartmut Gumprecht, Matthias J. KRAMMER 3.2.4.1

Introduction

Stereotactic techniques are employed to collect biopsies from a brain lesion for diagnostic evaluation by means of minimally invasive techniques. Mathematical calculations are used to define a target point within the three dimensional space of the brain. The calculation of a target point relates to a Cartesian coordinates system. This mathematical concept identifies a point in space by its relationship to three planes intersecting at right angles to each other and intersecting at a common point. The concept forms the basis for identifying a stereotactic target by the three coordinates: lateral (x) anterior-posterior (y), and vertical (z) [7]. Historically, at the end of the 19th century, Professor Zernov, as one of the first, constructed the encephalometer [27], an apparatus designed to calculate the surface anatomy of the brain. In 1908, Horsley and Clarke published a report on the application of a stereotactic apparatus in animals [10]. Using mathematical calculations and a frame fixed to the head of the animals, a target point could be defined. Spiegel and co-workers introduced stereotactic operations as a clinical method in humans in 1947 [22]. As a fundamental modification they used intraoperative X-rays to visualise intracerebral landmarks like the third ventricle to define a target point. In 1952, Spiegel presented an atlas of the human brain for stereotactic surgery that illustrated the relevant anatomical structures. The basis for target point calculation was the commissura posterior. Later, the necessity of two intracerebral benchmarks, the commissura anterior and posterior, was postulated [23]. Visualisation of intracerebral structures was realised by pneumoencephalography [20, 21]. Over the years, various stereotactic systems were developed [1, 5, 9, 14, 18, 19]. With the introduction of computed tomography (CT) into clinical use [11] it was possible to visualise pathological structures and a target point directly. This expanded the indications for stereotactic procedures. The development of a fiducial system was the breakthrough in CT-based stereotaxy. This fiducial system consists of three sets of rods, arranged in an N-shaped configuration and containing all the information for

3.2 Brain Tumors

three-dimensional targeting of each two-dimensional CT plane. The height of the slice, the z coordinate, could be determined by the position of the diagonal centre rod relative to the vertical rod. The BRW system incorporated this principle first [5]. The most popular stereotactic system in Europe is based on the “centre of arc” principle, designed by Lars Leksell [14, 15]. A semicircular arc with a moveable probe carrier is attached to the base ring. The arc can swing in an anterior–posterior direction and an intracranial target can be approached from any entry point on the patient’s head.

3.2.4.2

Technique of Frame-Based Stereotactic Biopsy

Nowadays, CT- and MRI-compatible stereotactic frames are available. In our department we use an arc-centred stereotactic system manufactured by Zeppelin Surgical Instruments®, Pullach, Germany. This equipment is easy-to-handle and consists of a base frame, the Z-posts, the fiducial plates and the arc with the targeting probe (Fig. 3.2.26). The fiducial plates are equipped with Nshaped rods as described previously (Fig.3.2.27). The image slices are acquired parallel to the base frame. If the

Fig.3.2.26a,b The stereotaxy apparatus consists of a a base frame, the Z-posts, the fiducial plates and the arc with b the targeting probe

Fig. 3.2.27 The fiducial plates are equipped with N-shaped rods, as described in the text

Fig.3.2.28 Calculation of the X- and Y-values directly from the image slice

3.2.4 Stereotactic Biopsy

Fig.3.2.29 The Z-value (distance from the base frame to target point) is calculated by measuring the distance of the diagonal rod to the vertical rod

frame is attached rigidly to the CT couch, the values of X (lateral position) and Y (anteroposterior position) can be calculated directly from the image slice (Fig.3.2.28). The Z-value (distance from the base frame to target point) is calculated by measuring the distance of the diagonal rod to the vertical rod (Fig.3.2.29). The rods on the fiducial plate are arranged like a 90° triangle. Therefore, the red line (C) is equal to the green line (B), which marks the distance to the frame base (A), the Z-value. If the frame is not fixed to the CT table, the values for X, Y and Z are calculated using a mathematical formula. Alternatively, various types of computer software are available that allow the calculation of a trajectory with sophisticated 3D computer graphics. The advantage of software calculation is the virtual simulation of the trajectory. Relevant brain areas (Fig.3.2.30) can be spared, with assessment of the three-plane view. After calculation of the target point, the values of the coordinates are transferred to the stereotactic apparatus. We perform a 0.5-cm skin incision and then a twist

Fig.3.2.30 The virtual simulation of the trajectory by the software based on MR images

3.2 Brain Tumors

drill trepanation of the skull with perforation of the dura (Fig. 3.2.31). Afterwards, the biopsy probe is advanced to the target point and two to three biopsies are taken. Another biopsy is taken along the trajectory before and behind the target point, depending on the size of the lesion. Subsequently, we obtain histological results from the cross-section of the lesion. In most cases we use a side-cutting aspirator called a Sedan needle for biopsy sampling (Fig.3.2.32). This instrument provides a 1-cm biopsy cylinder. In brain stem lesions a 2-mm forceps is used (Fig.3.2.33). The planning of a target point and the trajectory is performed individually in each patient. This is dependent on the shape and, of course, on the localisation of the lesion. In most patients the planning can be sufficiently performed with CT data. In low-grade glioma and other lesions with no or marginal contrast enhancement in particular the diagnostic yield can be improved using MRI planning and image fusion with PET scans [3, 8, 16].

Biopsies can be taken from pathological structures in almost any supra- or infratentorial region of the brain. Normally, the shortest distance from the skull to the target point should be used, sparing eloquent brain areas and critical vascular structures. Lesions within the basal ganglia and most brain stem lesions can be reached using a coronal approach. 3.2.4.3

Indications

The indication for a stereotactic biopsy is the intention to obtain a histopathological diagnosis of an unknown cerebral tumour in patients in whom an open tumour resection is not the “first choice” therapy. Included in this group are patients with lesions in critical brain areas like the basal ganglia, the brain stem and the motor- or language-related cortex, as well as lesions with a diffuse spread, multifocal lesions with suspected metastatic disease, brain-related disease or lymphoma, as well as AIDS-related pathological brain lesions. The need for histological differentiation between tumour relapse and radionecrosis is also an indication for stereotactic biopsy. Even a cerebral abscess can be treated by stereotactic biopsy. First, an extraction of the infectious material should be performed for further examination of the abscess and then a catheter should be placed for abscess irrigation. 3.2.4.4

Complications

Fig.3.2.31 The twist drill

The complications of stereotactic biopsy are haemorrhage, deterioration of the neurological status, seizure and infection. Bleeding can occur at the entry site in terms of a subdural or epidural haematoma, along the trajectory and at the biopsy site. Neurological deficits may occur when the lesion or a bleeding is directly localised in an eloquent

Fig.3.2.32 The Sedan needle

Fig.3.2.33 The biopsy forceps

3.2.4 Stereotactic Biopsy

brain area like the basal ganglia, the brain stem, the motor or visual cortex and the speech area. Furthermore, new neurological deficits can be elicited by miscalculation of the trajectory crossing relevant brain structures. We prefer general anaesthesia to local anaesthesia because the patient cannot move and possibly displace the frame and can be sedated in the case of a surgery-related seizure. We do not administer a prophylactic anticonvulsant loading dose. The risk of a superficial or deep infection in stereotactic biopsy is very low. In general, the risk of complications [2, 6, 12, 26], like bleeding, transient or permanent neurological deficits or even death, is low. The mortality rate for the biopsy of supratentorial lesions is below 1% and approximately 4% for brain stem tumours. Therefore, stereotactic biopsy is a safe and reliable diagnostic tool, with a diagnostic potential reported in the literature ranging from 83 to 93% [4, 13, 17, 24, 25]. Selected Reading 1. Bailey P, Stein SN (1951) A stereotactic apparatus for use on the human brain. AMA scientific exhibit, Atlantic City 2. Bernstein M, Parrent AG (1994) Complications of CT-guided stereotactic biopsy of intra-axial brain lesions. J Neurosurg 81:165–168 3. Bittar RG, Olivier A, Sadikot AF, Andermann F, Pike GB, Reutens DC (1999) Presurgical motor and somatosensory cortex mapping with functional magnetic resonance imaging and positron emission tomography. J Neurosurg 91(6):915–921 4. Blaauw G, Braakman R (1988) Pitfalls in diagnostic brain surgery. Acta Neurochir (Wien) Suppl 42:161–165 5. Brown RA, Roberts TS, Osborn AG (1980) Stereotactic frame and computer software for CT-directed neurosurgical localization. Invest Radiol 15:308–312 6. Cook RJ, Guthrie BL (1993) Complications of stereotactic biopsy. Perspect Neurol Surg 4:131–140 7. Gildenberg PL (1988) General concept of stereotactic surgery. In Lunsford LD (ed) Modern stereotactic neurosurgery. Oston Martinus Nijhoff, pp 3–12 8. Hara T, Kondo T, Hara T, Kosaka N (2003) Use of 18F-choline and 11C-cholin as contrast agents in positron emission tomography imaging-guided stereotactic biopsy sampling of gliomas. J Neurosurg 99:474–479 9. Hecaen H, Thalairach T, David M, Dell MB (1949) Memoires originaux: Coagulation limiteses du thalamus dans les algies du syndrome thalamique. Rev Neurol (Paris) 81: 917–931 10. Horsley V; Clarke RH (1908) The structure and the function of the cerebellum examined by a new method. Brain 31:45

11. Hounsfield GN, Ambrose J, Perry BJ, Bridges C (1973) Computerized transverse axial scanning (tomography). Br J Radiol 46:1016–1051 12. Kelly PJ (1991) Tumor stereotaxis. Saunders, Philadelphia, pp 183–223 13. Kleihues P, Volk B, Anagnostopoulos J, Kiessling M (1984) Morphologic evaluation of stereotactic brain tumour biopsies. Acta Neurochir (Wien) Suppl 33:171–181 14. Leksell L (1949) A stereotactic apparatus for intracranial surgery. Acta Chir Scand 99:229–233 15. Leksell L (1971) Stereotaxis and radiosurgery: an operative system. Thomas, Springfield 16. Mosskin M, Ericson K, Hindmarsh T, von Holst H, Collins VP, Bergstrom M, Eriksson L, Johnstrom P (1989) Positron emission tomography compared with magnetic resonance imaging and computed tomography in supratentorial gliomas using multiple stereotactic biopsies as reference. Acta Radiol 30(3):225–232 17. Mundinger F (1985) CT-stereotactic biopsy of intracranial processes. Acta Neurochir (Wien) Suppl 35:70–74 18. Narabayashi H (1952) Stereotactic instrument for operation on the human basal ganglia. Psychiatr Neurol Jpn 54:669–671 19. Riechert T, Wolff M (1951) Über ein neues Zielgerät zur intrakraniellen elektrischen Ableitung und Ausschaltung. Arch Psychiatr Z Neurol 186:225–230 20. Spiegel EA, Wycis HT (1950) Pallido-thalamothomy in chorea. Arch Neurol Psychiatr 64:495–496 21. Spiegel EA, Wycis HT (1952) Stereoencephalotomy. I. Grune & Stratton, New York 22. Spiegel EA, Wycis HT, Marks M, Lee AJ (1947) Stereotaxic apparatus for operations on the human brain. Science 106:349–350 23. Talairach J, David M, Tournoux P, Corredor H, Kvasina T (1957) Atlas d’anatomie Stèrèotaxique. Repérage radiologique indirect des noyaux gris centraux des regions mésencéphalo-sous-optique et hypothalamique de l’homme. Masson et Cie, Paris 24. Thomas DGT, Nouby RM (1989) Experience in 300 cases of CT-directed stereotactic surgery for lesion biopsy and aspiration of haematoma. Br J Neurosurg 3:321–326 25. Ungersböck K, Schmidbauer M, Budka H, Kitz K, Grunert P, Koos W (1989) Stereotaktische Biopsie intrakranieller Prozesse: Validität der histologischen Diagnostik. Wien Klein Wochenschr 101:376–380 26. Voges J, Schröder R, Treuer H, Pastyr O, Schlegel W, Lorenz WJ, Sturm V (1993) CT-guided and computer assisted stereotactic biopsy: technique, results, indications. Acta Neurochir (Wien) 125:142–149 27. Zernov DN (1889) Encephalometer: device for estimation of parts of brain in human. Proc Soc Physiomed Moscow Univ 2:70–80

3.2 Brain Tumors

3.2.5 Supratentorial Brain Tumors in Adults

Manfred Westphal 3.2.5.1

Neuroepithelial Tumors

3.2.5.1.1 Basics

Neuroepithelial tumors arise from the glial component of the brain. The largest group consists of the astrocytomas, followed by the oligodendrogliomas. Mixed entities exist. Ependymomas are comparatively rare and tend to occur more frequently in children. Glial tumors are classified according to the WHO system [6]. Grade I astrocytomas are synonymous with pilocytic tumors and occur mostly in children. Their preferred location is the optic chiasm and the optic pathway including the hypothalamus. The other preferred location is the cerebellum and tumors there tend to be cystic. Another variant is the brain stem glioma, which is frequently a grade I astrocytoma. Grade II astrocytomas, synonymous with the diffuse astrocytoma, occur anywhere in the hemispheres and are typical of young adulthood. These tumors tend to progress over time to grade III astrocytomas (anaplastic astrocytomas) or grade IV astrocytomas (glioblastomas). The underlying mechanism is the sequential progressive acquisition of genetic aberrations. Grade III astrocytomas tend to occur anywhere in the brain and are more frequent in younger adults. Grade IV astrocytomas (glioblastomas) have their peak incidence in the sixth and seventh decades of life. They either originate from lower grade lesions or arise de novo anywhere in the brain.

Grade II oligodendrogliomas occur anywhere in the brain, have a different set of genetic aberrations from astrocytomas and also progress to grade III tumors over time (anaplastic oligodendrogliomas). They tend to occur in adulthood with peak incidences before the sixth decade. Mixed gliomas or oligoastrocytomas contain both components and occur in grades II and III tumors. The genetic distinction between the different tumor types [5] and the existence of the mixed variant has raised the question as to whether there are different kinds of tumor stem cells. Ependymomas come as grade I (synonymous with subependymoma), grade II, and grade III (anaplastic ependymomas) [16]. They can be found throughout the ventricular system and in adults are more frequent in the lateral ventricles and in the third ventricle, whereas in children they tend to be in the infratentorial compartment (Fig.3.2.34). They are the most frequent intramedullary tumor. 3.2.5.1.2 Epidemiology

There is limited epidemiological information about gliomas in Europe [15, 17]. However, extrapolating data from regional registries and the North American data bases [1], around 30,000 new cases of malignant glioma can be expected in Europe every year. The numbers for lowgrade gliomas are much lower, but due to longer life expectancies, the prevalence increases accordingly. As there are incongruences between the inclusion of pediatric patients and age cut-offs for the epidemiological data collections, and in addition no European standard for the separation between WHO grade I and II, any number from any regional cancer registry in Europe is meaningless.

Fig. 3.2.34a–c Anaplastic ependymoma in a 16-month-old boy that arose from the roof of the fourth ventricle. a,b MRI with gadolinium preresection and c postresection

3.2.5 Supratentorial Brain Tumors in Adults

There are no etiological clues to the origin of these tumors, not environmental, nutritional or occupational. A hereditary component has only been very vaguely implied and familial gliomas are very rare [17]. 3.2.5.1.3 Symptoms

Gliomas become symptomatic with a broad range of symptoms. Low-grade tumors (WHO II) tend to lead to seizures, including the whole spectrum of possible seizure types. As these tumors grow slowly, they will rarely produce a focal neurological deficit before becoming symptomatic with a seizure. Higher grade tumors also cause seizures, but due to their more rapid growth and more aggressive behavior, they frequently lead to progressively and rapidly evolving focal neurological deficits. Depending on the location this could be dysphasia, hemiparesis, a visual field deficit or cognitive problems, just to name a few. With increasing size, the tumors will cause intracranial hypertension, which in turn will lead to decreasing levels of consciousness, brain stem compression with central dysregulation of blood pressure, and other vegetative functions. Singultus is already a grave sign of advanced raised intracranial pressure or brain stem compression. 3.2.5.1.4 Complications

Except for the occasional pilocytic astrocytoma, gliomas are eventually fatal. The intrinsic property of the glioma cells to migrate through the brain will lead to invasion and eventually to involvement and functional impairment of vital structures, excluding any further therapeutic option once all possible therapies have been applied. During the disease, a period of profound disorientation may occur, necessitating continuous care and supervision. Systemic metastases of gliomas are the exception. Whereas glioblastomas have been seen in transplanted organs donated by glioblastoma patients, lifetime development of extracranial metastases has only been reported for a number of anaplastic oligodendrogliomas, which tend to metastasize to the lung and bone marrow. 3.2.5.1.5 Diagnosis

When a patient is suspected of harboring a glioma based on the neurological symptoms mentioned above, the first step will be imaging, and it is mandatory today that an MRI scan is performed because it allows a highly probable estimate of the histological diagnosis to be obtained using today’s routine modalities, such as spectroscopy [8]. Also, MRI is helpful with distinguishing a glioma from other lesions, especially metastases, which tend to frequently occur as multiple lesions. With the refinement

of the MRI techniques, there is no real need for any other modality, such as PET or SPECT, in the initial setting. Those modalities may be useful for monitoring therapy. If a tissue diagnosis is required for a nonresectable tumor, this will be obtained by stereotactic biopsy [7]. Immunohistochemistry, and to an increasing extent, molecular genetics, will secure the differential diagnosis. There is no role for electrophysiology in the establishment of the correct diagnosis, nor are there tests for serum or CSF. 3.2.5.1.6 Therapy

Therapy for gliomas is interdisciplinary. Most tumors will be resected as radically as is safely possible, but some are primarily unresectable (mostly midline tumors) and these will be biopsied to obtain a proper tissue diagnosis before they go on to conservative, nonsurgical treatments. 3.2.5.1.6.1 Conservative Treatment

Apart from treating the tumor, it may be necessary to treat collateral edema. This is done with dexamethasone at an initial dose of 4 × 4mg/day, which then tapers according to the improvement or stabilization of the neurological status. It is frequently possible, and should be the goal, to get patients off steroids completely after successful treatment; however, there may be a need to reinitiate therapy in the case of symptomatic recurrence. Seizure prophylaxis with anticonvulsive drugs is mandatory in those patients who become symptomatic with a seizure. The prophylaxis may be tapered and eventually withdrawn after a tumor is removed. The predictive value of EEG is questionable. There is a wide range of drugs that only in the past 5 years has seen several new additions [4]. Most commonly, valproic acid will be used, but other substances, like phenytoin and carbamazepine, are also still used. Prophylaxis should be as short as possible. In the case of slowly progressing low-grade glioma, the nature of the seizures may change and an adaptation of anticonvulsive therapy may become necessary, sometimes leading to complex combinations. Non-surgical tumor therapy rests on radiotherapy and chemotherapy. Radiation regularly follows the resection of a high-grade glioma and 54Gy are applied in 1.8-Gy fractions over 6weeks to the tumor area plus a 2-cm margin. Chemotherapy is also offered to patients who have recurrences or progression not eligible for further surgery, or those patients who have nonresectable tumors that are histologically confirmed by stereotactic biopsy (Fig.3.2.35) [2]. A wide range of chemotherapeutics has been used, but all with marginal efficacy in the newly diagnosed patient, as well as in the situation of recurrence. Chemotherapy in general is regarded as salvage therapy, but nevertheless is frequently given as the last resort. Recently, the combination with radiotherapy in the treat-

3.2 Brain Tumors

Fig.3.2.35 Rapidly evolving, diffusely infiltrative lesion, in the left paracallosal, peritrigonal, subangular region, that is not amenable to meaningful resection. Stereotactic biopsy confirmed glioblastoma; therefore, primary radiochemotherapy was administered

ment of newly diagnosed patients has been shown to extend survival has become the standard and a subgroup analysis showed that the efficacy is mostly due to cases in which there is hypermethylation-mediated silencing of the MGMT gene [3, 13]. 3.2.5.1.6.2 Surgical Therapy

The role of surgery for gliomas, low-grade as well as highgrade, has been questioned for a long time, but evidence has now been produced as a collateral result from the phase III trial with fluorescence-guided resection of newly diagnosed glioblastoma [12], showing that the extent of resection correlates with survival [11a]. Prior studies coming to that conclusion were mostly retrospective or uncontrolled or even meta-analyses [9, 10]. Technically, there are few limitations of surgical resection, as any area in the brain can be easily accessed. However, there are definite functional/anatomical limitations due to the direct involvement of functionally important structures, and in particular, tumors crossing the midline or involving the basic ganglia, as well as the cerebral peduncles, are not good candidates (Fig. 3.2.35). In general, not only resectability (anticipated morbidity) has to be considered, but also the wish of the patient and his or her general condition including age, Karnofsky performance score, and collateral diseases. The principles of resection are standardized and include microsurgery, minimal invasiveness, image guidance, and where applicable, intraoperative monitoring by electrophysiological means or awake surgery. For pilocytic astrocytomas of the optic system, partial resection may be an option to obtain decompression of frontobasal structures and reconstitute the CSF pathways (Fig.3.2.36). Residuals from pilocytic astrocytomas have

been known to remain stable for long periods and even spontaneously regress (see sections on pediatrics). A surgical resection is by definition incomplete because of the invasive nature of the disease, but in surgical candidates it is frequently possible to resect all contrast enhancement of a WHO grade III or IV lesion (Fig.3.2.37) or all of the hypointensity in the case of seemingly welldelineated low-grade gliomas, of which there seems to be a truly locally confined subtype [11]. With regard to low-grade gliomas, only those that seem to be compact will be good candidates, but not the diffusely infiltrating variants (Fig. 3.2.38a). Frequently, the indication will be associated with the attempt to control seizures (Fig.3.2.38b). As for high-grade gliomas, the resection can be supplemented with intracavitary drug application [14] or experimental therapies. In newly diagnosed patients this will be followed by standard external beam radiotherapy. In the situation of recurrence, any decision regarding reoperation follows the same rules as for the initial treatment, but has to take into account the course of the disease, the time to recurrence, and the judgment by the patient as to whether the first operation was seen to be a beneficial measure. 3.2.5.1.7 Differential Diagnosis

In the case of doubt about the nature of a lesion, there are now numerous neuroradiological techniques that allow distinctions to be made, and if there is still insufficient information or nonresolvable controversy, a stereotactic biopsy can be performed [7]. For noncontrast-enhancing lesions, the major differential is an encephalitic lesion or a postencephalitic state.

3.2.5 Supratentorial Brain Tumors in Adults

Fig.3.2.36 Incomplete resection of an optic pathway astrocytoma (WHO I) that is followed up with no further therapy. The goal was the disobliteration of the CSF pathway, which was achieved without incurring visual, endocrine or diencephalic problems

Fig. 3.2.37 Subependymal glioblastoma of the posterior thalamic region (top row) that was debulked via a transventricular approach (bottom row) with actual improvement of a pre-existing moderate hemiparesis

3.2 Brain Tumors

Fig.3.2.38 a Progression of a mixed glioma (WHO grade II), over a period of years after two extensive left-sided temporal resections, that turned into a grade III tumor within 5years and is stable in a state of diffuse hemispheric infiltration after radiotherapy. b Diffusely infiltrating low-grade glioma with a 10-year

history of slow progression throughout the hemisphere and into the brain stem. Partial resection of the temporomesial portions of the tumor was necessary to change the symptomatology of epileptic seizures

For contrast-enhancing lesions, the differential diagnosis between glioblastoma and metastasis may be difficult (Fig.3.2.39), or lymphoma and very rarely an acute inflammatory lesion in the context of multiple sclerosis. In deep-seated lesions, a stereotactic biopsy should be performed. A brain abscess or granulomatous disease is rarely mistaken for a glioma (Fig.3.2.40). MR spectroscopy can distinguish between those and tumors.

that are symptomatic, progressive or cause mass effect are removed with an attempt at a gross total resection. Lesions that are incidental, stable, and asymptomatic can be watched or undergo a stereotactic biopsy, after which the histological diagnosis determines further treatment options. Low-grade lesions are followed at regular intervals. High-grade lesions are radiated after biopsy or gross total removal. For glioblastomas, radiation is combined with chemotherapy with temozolomide. When lesions recur, reoperation can be indicated in patients with a good quality of life and in lesions that do not pose an additional risk during resection; however, European practice is rather inhom*ogeneous with regard to this condition.

3.2.5.1.8 European Standard of Care for Neuroepithelial Tumors

For diagnosis and treatment planning, enhanced MRI and preferably MR spectroscopy are necessary. Lesions

3.2.5 Supratentorial Brain Tumors in Adults

Fig.3.2.39 a Typical gadolinium-enhanced MRI of a glioblastoma. b Irregular cystic lesion with contrast-enhancing margins that turned out to be the metastasis of a urothelium carcinoma

Fig.3.2.40 Cystic, contrast-enhancing lesion in the brain stem that was believed to be a malignant glioma, but which increased in size within a few days and turned out to be an abscess

3.2 Brain Tumors

Selected Reading 1. CBTRUS (2004) Statistical report: primary brain tumors in the United States, 1997–2001. Central Brain Tumor Registry in the United States 2. Grossman SA, Batara JF (2004) Current management of glioblastoma multiforme. Semin Oncol 31:635–644 3. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003 4. Hildebrand J (2004) Management of epileptic seizures. Curr Opin Oncol 16:314–317 5. Jeuken JW, Sprenger SH, Boerman RH, von Deimling A, Teepen HL, van Overbeeke JJ, Wesseling P (2001) Subtyping of oligo-astrocytic tumours by comparative genomic hybridization. J Pathol 194:81–87 6. Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC, Cavenee WK (2002) The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 61:215–225; discussion 226–219 7. Kondziolka D, Lunsford LD (1999) The role of stereotactic biopsy in the management of gliomas. J Neurooncol 42:205–213 8. Law M, Hamburger M, Johnson G, Inglese M, Londono A, Golfinos J, Zagzag D, Knopp EA (2004) Differentiating surgical from non-surgical lesions using perfusion MR imaging and proton MR spectroscopic imaging. Technol Cancer Res Treat 3:557–565 9. Laws ER, Shaffrey ME, Morris A, Anderson FA Jr (2003) Surgical management of intracranial gliomas – does radical resection improve outcome? Acta Neurochir Suppl 85:47–53 10. Piepmeier J, Baehring JM (2004) Surgical resection for patients with benign primary brain tumors and low grade gliomas. J Neurooncol 69:55–65 11. Schramm J, Luyken C, Urbach H, Fimmers R, Blumcke I (2004) Evidence for a clinically distinct new subtype of grade II astrocytomas in patients with long-term epilepsy. Neurosurgery 55:340–347; discussion 347–348 11a. Stummer W, Reulen HJ, Meinel T, Pichlmeier U, Schumacher W, Tonn JC, Rhode V, Oppel F, Turowski B, Woiciechowsky C, Franz K, Pietsch T, ALA-Glioma Study Group (2008) Extent of resection and survival in glioblastoma multiforme: identification of an adjustment for bias. Neurosurgery 62(3):564–576 12. Stummer W, Reulen HJ, Novotny A, Stepp H, Tonn JC (2003) Fluorescence-guided resections of malignant gliomas – an overview. Acta Neurochir Suppl 88:9–12 13. Stupp R, van den Bent MJ, Hegi ME (2005) Optimal role of temozolomide in the treatment of malignant gliomas. Curr Neurol Neurosci Rep 5:198–206 14. Westphal M, Hilt DC, Bortey E, Delavault P, Olivares R, Warnke PC, Whittle IR, Jaaskelainen J, Ram Z (2003) A phase 3 trial of local chemotherapy with biodegradable

carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neurooncology 5:79–88 15. Westphal M, Ekman M, Andlin-Sobocki P, Lönn S, Heese O (2009) Brain tumor epidemiology in the European Union: a critical assessment. Acta Neurochir, in revision. 16. Wiestler OD, Schiffer D, Coons S, Prayson RA, Rosenblum MK (2000) Ependymoma. In: Kleihues P, Cavanee W (eds) Tumours of the nervous system: pathology and genetics. IARC, Lyon 17. Wrensch M, Minn Y, Chew T, Bondy M, Berger MS (2002) Epidemiology of primary brain tumors: current concepts and review of the literature. Neurooncology 4:278–299

3.2.5.2

Meningiomas

3.2.5.2.1 Basics

Meningiomas arise from the arachnoid cover cells of the brain. They can occur anywhere around the brain and may also be located in the ventricles. They are classified according to the WHO system [24]. Grade I meningiomas make up 80% of this type of tumor. There are at least nine histological subtypes, which, however, have not been shown to be relevant to prognosis [24]. Grade II meningiomas (atypical meningiomas) tend to have a higher cellularity and increased signs of proliferative activity, and tend to have a higher incidence of recurrence. Grade III meningiomas (anaplastic meningiomas, papillary meningioma) are aggressive malignant tumors with a tendency to metastasize. Genetically, it was found that deletions on chromosome 22 or losses of the whole chromosome are an early event in the disease. Genetic progression to more aggressive types is possible over time in repeatedly recurring cases, but is not the rule, as in astrocytomas, and has to be considered a rare event [22]. 3.2.5.2.2 Epidemiology

Meningiomas are more frequent in women (2.5:1 femaleto-male ratio). They typically occur in the older age group with a peak incidence in the sixth decade and beyond. There are also pediatric meningiomas, but they tend to occur more frequently in boys and have a preferential ventricular location. There is limited epidemiological information about meningiomas in Europe. However, extrapolating data from regional registries and the North American databases are available. Many affected patients will be able to live nearly normal lives with the disease, but with the necessity of being under continuous surveillance. Ionizing radiation has been the most definitive factor associated with the etiology of meningiomas [30]. A hereditary component has been discussed [14], but is definitely present in patients with type 2 neurofibromatosis [23].

3.2.5 Supratentorial Brain Tumors in Adults

3.2.5.2.3 Symptoms

Meningiomas have a broad range of symptoms. Depending on their location, they cause seizures [3] (temporomesial, perirolandic), focal neurological deficits, symptoms of obstructive hydrocephalus, visual field impairment or behavioral disorders (large frontobasal tumors). Many meningiomas are asymptomatic and are found incidentally. There is no specific neurological symptom or syndromic complex associated with meningiomas.

debate on the role of hormonal replacement therapy in postmenopausal women with regard to the growth, progression or recurrence of meningiomas [16, 37]. 3.2.5.2.4.2 Pregnancy

In the course of a pregnancy one has to be aware of rapidly expanding lesions that may even hemorrhage intratumorally, leading to an emergency situation for mother and fetus (Fig.3.2.41) [38]. 3.2.5.2.4.3 Associated Stroke

3.2.5.2.4 Complications 3.2.5.2.4.1 Hormonal Influence

Meningiomas are more frequent in women and there is the as yet unresolved problem of how the increased levels of steroid hormone receptors lock into the biological behavior of meningiomas [34]. Consequently, there is

Encasem*nt of the carotid artery and subsequent severe stenosis or even complete obliteration may lead to stroke (Fig.3.2.42). 3.2.5.2.4.4 Optic Nerve Involvement

Encasem*nt of the optic nerve will lead to blindness (Fig.3.2.42).

Fig.3.2.41 Thirty-one-year-old woman in the 32nd week of gestation who became unconscious with a generalized seizure and had to undergo emergency tumor removal combined with a cesarean section

Fig.3.2.42 Progressive recurrent meningioma with encasem*nt of the left optic nerve that originated from the residual of a much larger tumor. Slow progression of this lesion eventually led to blindness in the left eye. The tumor was treated with radiosurgery

3.2 Brain Tumors

3.2.5.2.4.5 Spinal Cord Compression

Meningiomas at the craniocervical junction that may have gone unnoticed for a long time can lead to acute paraplegia in the situation of a whiplash injury (Fig.3.2.43). 3.2.5.2.4.6 Cancer Metastases

Possibly in relation to the unresolved hormonal dependence, there is also a relationship with breast cancer metastases, which appear to be able to preferentially hone in on meningiomas. Therefore, in any incidentally discovered meningioma in a woman who is affected with breast

cancer there is an additional reason for it to be removed to prevent that from happening (Fig.3.2.44). 3.2.5.2.5 Diagnosis

The suspected diagnosis will be established from neuroimaging and it is mandatory today that an MRI scan is performed to allow the relevant information to be obtained in all three planes, which will allow the assessment of the invasion or involvement of neighboring structures such as the venous sinuses or cranial nerves [19]. Men-

Fig.3.2.43 Meningioma of the craniocervical junction which could be removed without sequelae. MRI with and without Gd (left and middle) in the sagittal and coronary plane (right)

Fig.3.2.44 Coincidence of metastasis from mammary carcinoma and meningioma. Meningioma of the craniocervical junction caused bilateral leg weakness and hypoesthesia

3.2.5 Supratentorial Brain Tumors in Adults

ingiomas are hom*ogenously enhancing lesions that as a rule have a broad attachment to the dura of the convexity or the skull base. They may be calcified, which may be seen on an additional CT scan. Surrounding intracranial edema may be present, indicating breakdown of the arachnoid plane. This may be present in some cases all around the meningioma, but is most pronounced around the secretory variant (Fig.3.2.45) [7]. MR spectroscopy may give additional clues [11]. Angiography is no longer part of the routine evaluation of meningiomas. If it is performed for specific reasons, blood supply from the external carotid artery will be found as a rule. Should the blood supply come from the internal carotid, other differential diagnoses have to be considered: either a more malignant variant of meningioma, like papillary meningioma or meningiosarcoma, or also hemangiopericytoma (see Sect.3.2.5.2.9). 3.2.5.2.6 Therapy

Therapy for meningiomas is mostly surgical [1, 2]. Most tumors will be resected as radically as is safely possible [9] and radicality is still captured according to the Simpson [32] grading system. Some meningiomas are primarily unresectable (mostly skull base tumors) and these will be treated by combined surgical and radiosurgical strategies [6, 9].

3.2.5.2.6.1 Conservative Treatment

An incidental meningioma that has been definitively asymptomatic after a thorough case history has been established may be observed with neuroimaging at appropriate time intervals, which should be 6months in young adults and up to a year in patients over 70. Thereafter, the intervals will be adjusted according to the emerging growth characteristics. This is different when the incidental discovery is a fortuitous event, as in a suprasellar meningioma that has not yet caused symptoms, but shows displacement and compression of the optic chiasm or analogous cases in the posterior fossa. Early treatment should be advised. While observing an asymptomatic meningioma, stable disease may be present for a long time. Special attention has to be given to the perimenopausal period, during which proliferation dynamics can change. Seizure prophylaxis with anticonvulsive drugs can be necessary in some patients who became symptomatic with a seizure. As long as the tumor causing the seizure activity is still in place, it needs to be continued. Radiosurgery has its established role in the treatment of residual tumors at the skull base [6] or as primary treatment of well-contained cavernous sinus meningiomas that are limited to that compartment or optic sheath meningiomas [4]. Frequently, radiosurgery will be combined with surgical resection within the limits of what is safely possible [36]. Endovascular embolization, used alone, has not found its way into the established treatment schemes. It may be used preoperatively in selected cases [5, 28, 29]. There is no role for chemotherapy in grade I and II tumors. In these cases, when there is no surgical option and all other measures, such as radiosurgery, have been exhausted, experimental treatment with hydroxy-urea can be attempted, which has shown anecdotal efficacy, but has never been proven to be efficacious in a controlled clinical trial [25, 26]. Likewise, all hormone-based treatments have not been efficacious [12]. For anaplastic tumors, there are limited reports on chemotherapy, but the success is limited and temporary stabilization is the maximum achievement [9, 10, 20]. 3.2.5.2.6.2 Surgical Therapy

Fig.3.2.45 Meningioma with massive edema caused very mild aphasia. The midline shift is pronounced and in this case caused by the edema more than by the tumor

The role of surgery for meningiomas is well established. Resection of meningiomas with Simpson grade I resections should lead to a definitive cure in most cases [2]. The principles of resection are standardized and include microsurgery, minimal invasiveness, image guidance, and where applicable, intraoperative monitoring by electrophysiological means. The paradigm to obtain maximal radicality, even with the help of bypass surgery and intracranial grafting for severed cranial nerves. has been left behind [6]. Nevertheless, there are complex skull base lesions that may require interdisciplinary ap-

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proaches involving ophthalmic surgeons, maxillofacial surgeons or ENT colleagues for what can be considered the removable part. Nonresectable portions of tumor, either in the wall of major sinuses or at the skull base, will be left for close observation. They may remain unchanged for many years. Should regrowth or progression be clearly documented, a focal radiation should be offered to the patient and the planning should occur between both the radiotherapist and the neurosurgeon as an interdisciplinary effort.

sheath of the sinus, this will be sharply dissected and then coagulated. If there is growth throughout the whole wall and anticipated removal would leave a hole too large to be easily grafted with periosteum, the infiltrative part is left behind and watched. In the case of further growth, two alternative approaches might be taken. One is to wait until the sinus is obliterated, which usually occurs slowly with concomitant formation of sufficient collaterals. Then, the residual tumor can be taken out en bloc. The other less preferable approach is treatment with focal irradiation.

3.2.5.2.6.2.1 Surgical Resection of Convexity Meningiomas

3.2.5.2.6.2.4 Frontobasal Meningiomas

The incision is planned so that the entire area of the tumor origin is exposed. Dura is removed together with the tumor and replaced with grafted periosteum. 3.2.5.2.6.2.2 Surgical Resection of Sphenoid Wing Meningiomas

Usually, a pterional approach is taken and the Sylvian fissure split. The exophytic part is removed, including the dura, and bone is drilled as far as possible, sometimes removing the lateral wall of the orbit and opening the superior orbital fissure. Reconstruction uses methyl methacrylate or titanium mesh and periosteum (Fig.3.2.46). 3.2.5.2.6.2.3 Sagittal and Falcine Meningiomas

Exposure of the sinus anterior and posterior to the lesion is planned to go far enough laterally on both sides so that the interhemispheric space can be entered from both sides. In the case of an obliterated sinus, after removal of the exophytic part of the tumor, the sinus will be secured and divided anterior and posterior to the tumor, and the infiltrated part removed, including a generous portion of the falx. When there is no involvement, the inferior sagittal sinus should be spared, as it may serve as important collateral. In the case of involvement of only the external

The approaches taken vary according to the lesion and its extension and include anything from a small frontobasolateral craniotomy to large pterional, orbitofrontozygomatic and even bifrontal transbasal approaches. Most suprasellar meningiomas and olfactory meningiomas can be approached via a pterional craniotomy. Care should be taken to coagulate and scrape any dura to minimize the incidence of recurrences. When extending towards the optic canal, this might need to be opened to allow mobilization of the nerve and removal of affected dura. In the case of compression of the chiasm any displacement of neural structures should be minimal but the tumor should be debulked from the inside to gradually decompress the neural structures. Large olfactory meningiomas may penetrate the skull base requiring replacement of the cribriform plate with a bone graft taken as split bone from the lamina externa of the bone flap (Fig.3.2.47) [8]. 3.2.5.2.6.2.5 Adjuncts to Surgical Resection 3.2.5.2.6.2.5.1 Preoperative Embolization

This has a value in cases where significant blood supply comes from areas which will only be exposed late during surgery. These are few cases and the experience with it are mixed [5, 28, 29]. Should it be used, there needs to be increased awareness for swelling which is dangerous

Fig.3.2.46 Typical, mostly intraosseous right-sided sphenoid wing meningioma. These tumors usually have a parenchymal component at the base of the middle fossa

3.2.5 Supratentorial Brain Tumors in Adults

Fig.3.2.47 Typical olfactory meningioma

in cases where brain stem compression is already present or herniation is imminent in the case of large bifrontal or temporal lesions which already have significant amounts of edema. 3.2.5.2.6.2.5.2 Radiosurgery Radiosurgery is mostly used in combination with surgery although sometimes also as primary modality [13]. Treatment planning and field control for radiation has made significant advances in the last decades and high intensity radiation can now be safely administered to even very critical regions like the cavernous sinus which has complex neighborhood relationships to the optic and hypothalamic structures [18]. The debate, whether single dose radiosurgical treatment by gamma knife or LINAC or whether a fractionated regimen are better is still undecided and intensity modulated schedules are too early in the follow up period to comment [9, 36]. 3.2.5.2.7 Differential Diagnosis

There are almost no durally attached intracranial tumors which can be mistaken for meningioma. The only other tumor resembling meningioma is hemangiopericytoma which has as differentiating characteristics destruction of bone, frequently a very inhom*ogeneous structure, blood supply from the internal carotid and always pronounced edema [15]. Lymphomas and metastases can occur in principle anywhere, thus also as dural neoplasms [21, 31, 33, 35]. The overall medical history of the patient needs to be considered when shape and other structural characteristics suggest that kind of differential diagnosis.

3.2.5.2.8 Prognosis

The prognosis of meningiomas is generally favorable. Most patients can expect to be cured or at least in long term control of their disease. The disease may locally progress with little therapeutic options and that is in particular the case for optic nerve meningiomas which cannot be resected and are only partially controlled by radiotherapy. Recurrence rates are low for convexity grade I meningiomas but high for meningiomas of the skull base or midline. Atypical meningiomas (WHO grade II) need closer monitoring and stringent follow-up but may have the same good prognosis as grade I tumors,- only with the necessity of several therapeutic interventions over the lifetime. Anaplastic meningiomas have a poor prognosis [27]. Even with all combined modalities like resection, radiation and chemotherapy the median survival in most published series is less than four years particularly due to the tendency to metastasize [17, 27]. 3.2.5.2.9 Hemangiopericytoma

This tumor is not an exclusively dural neoplasm but deserves special consideration in this context because dural manifestation represents a major subgroup. The tumor often mimics meningioma but shows more bone erosion and blood supply from the internal carotid as well as edema. Treatment is similar to meningiomas and ranks resection as the major means to reduce tumor. These tumors have, however, a high rate of local recurrence but show some degree of increased local control after resection and local irradiation. Chemotherapy is frequently used especially after metastases are found. The prognosis is better than for anaplastic meningiomas but is still unfavorable in the long run.

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Selected Reading 1. Al-Mefti O (1991) Meningiomas. Raven, New York 2. Al-Mefti O (1998) Operative atlas of meningioma. Lippincott-Raven, Philadelphia 3. Beaumont A, Whittle IR (2000) The pathogenesis of tumour associated epilepsy. Acta Neurochir (Wien) 142:1–15 4. Becker G, Jeremic B, Pitz S, Buchgeister M, Wilhelm H, Schiefer U, Paulsen F, Zrenner E, Bamberg M (2002) Stereotactic fractionated radiotherapy in patients with optic nerve sheath meningioma. Int J Radiat Oncol Biol Phys 54:1422–1429 5. Bendszus M, Rao G, Burger R, Schaller C, Scheinemann K, Warmuth-Metz M, Hofmann E, Schramm J, Roosen K, Solymosi L (2000) Is there a benefit of preoperative meningioma embolization? Neurosurgery 47:1306–1311; discussion 1311–1302 6. Brock M (2005) The heroes return to earth. Surg Neurol 63:590–591 7. Buhl R, Hugo HH, Mehdorn HM (Brain oedema in secretory meningiomas. J Clin Neurosci 8 [Suppl 1]:19–21 8. Bull WJ, Vandevender D, Cimino VG (2003) Reconstruction of defects of the cranial base. Tech Neurosurg 9:106–112 9. Chamberlain MC, Blumenthal DT (2004) Intracranial meningiomas: diagnosis and treatment. Expert Rev Neurother 4:641–648 10. Chamberlain MC, Tsao-Wei DD, Groshen S (2004) Temozolomide for treatment-resistant recurrent meningioma. Neurology 62:1210–1212 11. Fountas KN, Kapsalaki EZ, Gotsis SD, Kapsalakis JZ, Smisson HF III, Johnston KW, Robinson JS Jr, Papadakis N (2000) In vivo proton magnetic resonance spectroscopy of brain tumors. Stereotact Funct Neurosurg 74:83–94 12. Grunberg SM (1994) Role of antiprogestational therapy for meningiomas. Hum Reprod 9 [Suppl 1]:202–207 13. Hart DJ, Gianotta SL (2003) Complex cranial base meningioma: combined management. Tech Neurosurg 9:86–92 14. Hemminki K, Li X (2003) Familial risks in nervous system tumors. Cancer Epidemiol Biomarkers Prev 12:1137–1142 15. Jääskeläinen J, Louis DN, Paulus W, Haltia M (2000) Haem angiopericytoma. In: Kleihues P, Cavanee WK (eds) Tumors of the central nervous system: pathology and genetics. IARC, Lyon 16. Jhawar BS, Fuchs CS, Colditz GA, Stampfer MJ (2003) Sex steroid hormone exposures and risk for meningioma. J Neurosurg 99:848–853 17. Kaminski JM, Movsas B, King E, Yang C, Kronz JD, Alli PM, Williams J, Brem H (2001) Metastatic meningioma to the lung with multiple pleural metastases. Am J Clin Oncol 24:579–582 18. Kondziolka D, Nathoo N, Flickinger JC, Niranjan A, Maitz AH, Lunsford LD (2003) Long-term results after radiosurgery for benign intracranial tumors. Neurosurgery 53:815–821; discussion 821–812

19. Kremer S, Grand S, Remy C, Pasquier B, Benabid AL, Bracard S, Le Bas JF (2004) Contribution of dynamic contrast MR imaging to the differentiation between dural metastasis and meningioma. Neuroradiology 46:642–648 20. Kyritsis AP (1996) Chemotherapy for meningiomas. J Neurooncol 29:269–272 21. Laidlaw JD, Kumar A, Chan A (2004) Dural metastases mimicking meningioma. Case report and review of the literature. J Clin Neurosci 11:780–783 22. Lamszus K (2004) Meningioma pathology, genetics, and biology. J Neuropathol Exp Neurol 63:275–286 23. Lamszus K, Vahldiek F, Mautner VF, Schichor C, Tonn J, Stavrou D, Fillbrandt R, Westphal M, Kluwe L (2000) Allelic losses in neurofibromatosis 2-associated meningiomas. J Neuropathol Exp Neurol 59:504–512 24. Louis DN, Scheithauer BW, Budka H, von Deimling A, Kepes JJ (2000) Meningiomas. In: Kleihues P, Cavanee WK (eds) Tumours of the nervous system : pathology and genetics. IARC, Lyon 25. Loven D, Hardoff R, Sever ZB, Steinmetz AP, Gornish M, Rappaport ZH, Fenig E, Ram Z, Sulkes A (2004) Non-resectable slow-growing meningiomas treated by hydroxyurea. J Neurooncol 67:221–226 26. Mason WP, Gentili F, Macdonald DR, Hariharan S, Cruz CR, Abrey LE (2002) Stabilization of disease progression by hydroxyurea in patients with recurrent or unresectable meningioma. J Neurosurg 97:341–346 27. Modha A, Gutin PH (2005) Diagnosis and treatment of atypical and anaplastic meningiomas: a review. Neurosurgery 57:538–550; discussion 538–550 28. Probst EN, Grzyska U, Westphal M, Zeumer H (1999) Preoperative embolization of intracranial meningiomas with a fibrin glue preparation. AJNR Am J Neuroradiol 20:1695–1702 29. Rosen CL, Ammerman JM, Sekhar LN, Bank WO (2002) Outcome analysis of preoperative embolization in cranial base surgery. Acta Neurochir (Wien) 144:1157–1164 30. Sadetzki S, Flint-Richter P, Ben-Tal T, Nass D (2002) Radiation-induced meningioma: a descriptive study of 253 cases. J Neurosurg 97:1078–1082 31. Sijens PE, Oudkerk M (2002) Diagnosing dural metastases. Neuroradiology 44:275; author reply 276 32. Simpson D (1957) The recurrence of intracranial meningiomas after surgical treatment. J Neurol Neurosurg Psychiatry 20:22–29 33. Stark AM, Mehdorn HM (2004) Images in neuro-oncology: dural metastases. J Neurooncol 68:11 34. Swensen R, Kirsch W (2002) Brain neoplasms in women: a review. Clin Obstet Gynecol 45:904–927 35. Tagle P, Villanueva P, Torrealba G, Huete I (2002) Intracranial metastasis or meningioma? An uncommon clinical diagnostic dilemma. Surg Neurol 58:241–245 36. Tonn JC (2004) Microneurosurgery and radiosurgery – an attractive combination. Acta Neurochir Suppl 91:103–108

3.2.5 Supratentorial Brain Tumors in Adults

37. Wahab M, Al-Azzawi F (2003) Meningioma and hormonal influences. Climacteric 6:285–292 38. Wan WL, Geller JL, Feldon SE, Sadun AA (1990) Visual loss caused by rapidly progressive intracranial meningiomas during pregnancy. Ophthalmology 97:18–21

ment of PCNSL, it is acknowledged that in older patients, in addition to or synchronous with, chemotherapy, it appears to cause unacceptable neurocognitive deficits. This complication is avoided by not including WBRT in elderly patients [4, 5]

3.2.5.3

3.2.5.3.5 Diagnosis

Lymphomas

3.2.5.3.1 Basics

The origin of primary lymphomas of the central nervous system (PCNSL) have for a long time been a matter of debate. It is still not agreed from where the cell of origin is derived, but it is agreed that expansion and progression is intracerebral. Most are of the B cell type [7]. T cell lymphoma is rare [9]. In addition, there are increasing numbers of CNS lymphoma associated with immunosuppression, either in the context of an HIV infection or in patients who have received an organ transplant [2]. 3.2.5.3.2 Epidemiology

Primary lymphomas of the CNS are most common in the older age groups. There is an increasing incidence that has given rise to much debate about the possible causes, none of which, however, could be firmly established. The last reported incidence describes PCNSL constituting 6% of all primary intracranial neoplasms [7].

The suspected diagnosis will be established from neuroimaging and it is mandatory today that an MRI scan be performed. Lymphomas are characteristically located in the periventricular white matter (Figs.3.2.48, 3.2.49), but may also have extensive cortical presentation. They are usually primarily hyperintense and characteristically hom*ogeneous in appearance; thus, they can be mistaken for meningioma when located cortically. They have, however, unclear “foggy” margins (Fig.3.2.49) and are almost never necrotic or cystic. Contrast enhancement is also hom*ogeneous. Multiple lesions are possible. There are patients with only arachnoidal enhancement. The PCNSL is truly a neuroradiological chameleon that is almost certainly diagnosed when presenting with a typical appearance, but then there is such a broad range of possible appearances, that in rare instances it can mimic almost any other lesion [6]. When PCNSL is suspected, no steroids should be given before tissue diagnosis. Histology is usually es-

3.2.5.3.3 Symptoms

Lymphomas usually become symptomatic with seizures or a rapidly progressive focal neurological deficit. The symptoms are not generally different from any other parenchymal intracerebral lesion and none is specific to or pathognomonic for lymphoma. 3.2.5.3.4 Complications

Most complications of PCNSL are associated with treatment. Lymphomas are by their nature frequently associated with perifocal edema. Although lymphoma can often be suspected from the imaging characteristics (see below) or an associated disease context (see above), unfortunately, steroids are often given as a reflex to the edema seen on the T2-weighted MRI. This may lead to disappearance of the lesion (ghost tumors) and no diagnosis can be made. Without such a diagnosis, however, the appropriate therapy cannot be started. Stopping the steroids will allow the lesion to reappear, but more aggressive clones may already have been selected. While there is still ongoing debate regarding the roles of whole brain radiation treatment (WBRT) in the treat-

Fig.3.2.48 Gadolinium-enhanced T1-weighted MRI of a typical left-sided paraventricular, deep white matter lesion with hom*ogeneous enhancement, no necrosis and fuzzy edges, which was biopsied and proven to be PCNSL

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Fig.3.2.49 Another case of biopsy-proven PCNSL that involves a large subependymal paratrigonal territory and extends diffusely into the corpus callosum

tablished with a stereotactic biopsy. Occasionally, PCNSL are removed because the diagnosis is not suspected or the lesion is considered to be space-occupying [1]. 3.2.5.3.6 Therapy

Therapy for CNS lymphomas is nonsurgical except when for space occupation removal is felt necessary [1]. Different regimens for chemotherapy and radiation and combinations thereof have been evaluated over the last few decades. The most accepted regimens are based on risk adaptation and aggressive chemotherapy, both intraventricular and systemic, and additional radiation, depending on the performance of the patient [4, 8]. Methotrexate features prominently in the current regimens, but there are current extrapolations from the treatment for systemic lymphoma with monoclonal antibodies and also blood–brain barrier disruption [10], which may have specific implications for this tumor type as it has a physiology that accounts for different pharmaco*kinetics than those known from intrinsic brain tumors [11]. Surgical removal adds no additional benefit to the current chemotherapy regimens [1]. 3.2.5.3.7 Differential Diagnosis

Lymphomas need to be distinguished from metastases and sometimes from anaplastic gliomas. Also, inflammatory lesions, and especially large foci of multiple sclerosis, have to be excluded because therapy is very different from that of lymphoma. Careful evaluation of the case history and additional investigations like CSF chemistry for inflammatory lesions or MR spectroscopy may help to distinguish between different entities.

3.2.5.3.8 Prognosis

The prognosis of lymphomas is still considered unfavorable. However, there is a tendency toward increasing survival with the more intense, risk-adapted therapy regimens, new reagents based on experience gained from systemic lymphomas or derived from insights into tumor physiology, and even long-term remission with an acceptable quality of life has been observed [3, 10, 11]. 3.2.5.3.9 European Standard for the Treatment of PCNSL

• When the presence of PCNSL is suspected, no steroids are given before tissue diagnosis is established. • Tissue diagnosis is established by stereotactic biopsy. • Risk-adapted chemotherapy protocols of variable intensity are the current gold standard of treatment. • Surgical resection for lymphoma is unusual and is the consequence of highly individual circ*mstances. Selected Reading 1. Bellinzona M, Roser F, Ostertag H, Gaab RM, Saini M (2005) Surgical removal of primary central nervous system lymphomas (PCNSL) presenting as space occupying lesions: a series of 33 cases. Eur J Surg Oncol 31:100–105 2. Castellano-Sanchez AA, Li S, Qian J, Lagoo A, Weir E, Brat DJ (2004) Primary central nervous system posttransplant lymphoproliferative disorders. Am J Clin Pathol 121:246–253 3. DeAngelis LM (2003) Primary central nervous system lymphoma: a curable brain tumor. J Clin Oncol 21:4471–4473

3.2.5 Supratentorial Brain Tumors in Adults

4. DeAngelis LM, Hormigo A (2004) Treatment of primary central nervous system lymphoma. Semin Oncol 31:684–692 5. Fliessbach K, Helmstaedter C, Urbach H, Althaus A, Pels H, Linnebank M, Juergens A, Glasmacher A, Schmidt-Wolf IG, Klockgether T, Schlegel U (2005) Neuropsychological outcome after chemotherapy for primary CNS lymphoma: a prospective study. Neurology 64:1184–1188 6. Kuker W, Nagele T, Korfel A, Heckl S, Thiel E, Bamberg M, Weller M, Herrlinger U (2005) Primary central nervous system lymphomas (PCNSL): MRI features at presentation in 100 patients. J Neurooncol 72:169–177 7. Paulus W, Jellinger K, Morgello S, Deckert-Schlüter M (2000) Malignant lymphomas. In: Kleihues P, Cavanee W (eds) Pathology and genetics tumors of the nervous system. IARC, Lyon, pp 198–203 8. Pels H, Schmidt-Wolf IG, Glasmacher A, Schulz H, Engert A, Diehl V, Zellner A, Schackert G, Reichmann H, Kroschinsky F, Vogt-Schaden M, Egerer G, Bode U, Schaller C, Deckert M, Fimmers R, Helmstaedter C, Atasoy A, Klockgether T, Schlegel U (2003) Primary central nervous system lymphoma: results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy. J Clin Oncol 21:4489–4495 9. Shenkier TN, Blay JY, O’Neill BP, Poortmans P, Thiel E, Jahnke K, Abrey LE, Neuwelt E, Tsang R, Batchelor T, Harris N, Ferreri AJ, Ponzoni M, O’Brien P, Rubenstein J, Connors JM (2005) Primary CNS lymphoma of T-cell origin: a descriptive analysis from the International Primary CNS Lymphoma Collaborative Group. J Clin Oncol 23:2233–2239 10. Soussain C, Hoang-Xuan K, Doolittle ND (2005) New treatment approaches in primary central nervous system lymphoma. Hematol Oncol Clin North Am 19:719–728, vii 11. Warnke PC, Timmer J, Ostertag CB, Kopitzki K (2005) Capillary physiology and drug delivery in central nervous system lymphomas. Ann Neurol 57:136–139

3.2.5.4

Germ Cell Tumors

3.2.5.4.1 Basics

Germ cell tumors occur mostly in the pediatric population. They originate from embryonal tissue and are generally divided into proper germ cell tumors and the so-called non-germinomatous germ cell tumors, which include yolk-sac tumors, teratoma, teratocarcinoma, embryonal carcinoma, and choriocarcinoma [11]. 3.2.5.4.2 Epidemiology

Germ cell tumors are rare. There are regional differences with the highest incidence apparently in Japan. The peak incidence is in Asia, where they constitute 2% of all intracranial tumors, but only 0.2% to 0.5% elsewhere [11]. There is a slight predominance of germinomas in males, but no gender difference for the other tumors. No environmental clues have been described and no genetic syndromes are associated with this tumor group. 3.2.5.4.3 Symptoms

Germinomas arise usually in the pineal region and/or in the suprasellar region, particularly in relation to the pituitary stalk. Therefore, the symptoms are those of chronic or even acute hydrocephalus from compression of the Sylvian aqueduct, hormonal disorders, with diabetes insipidus and pituitary insufficiency, or visual disorders caused by chiasmatic compression. It has been proposed that the combination of diabetes insipidus with a pineal lesion, even in the absence of neuroradiological evidence of hypothalamic involvement, is certain to be associated with germinoma [13]. This has to be questioned as the combination has also been seen with histologically proven pineocytoma, leaving the cause of germinoma unresolved (Fig.3.2.50).

Fig.3.2.50 Biopsy-proven pineocytoma in a 1.5-year-old boy with diabetes insipidus in whom germinoma was suspected, but no treatment was started before tissue diagnosis, which turned out to be different from the initial assumption

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The other group, the non-germinomatous germ cell tumors, frequently produce high levels of hormones like alpha feto-protein or beta human chorionic gonadotropin (HCG), which can lead to precocious puberty.

tive sequelae are such that most modern studies try to delay or eliminate radiation [6], although there are studies from radiotherapists that contradict that view [9]. Spontaneous hematogenic metastases are a rare complication [12].

3.2.5.4.4 Complications

As with most other entities, many complications may arise from therapy. Initially, acute hydrocephalus occurs due to pressure on the Sylvian aqueduct. This may force immediate intervention, but should not lead to implantation of a shunt, as this can be complicated by systemic metastases [1]. Hemorrhage may occur spontaneously or in conjunction with stereotactic biopsy [14]. As the pineal region tumors are extremely heterogeneous, endoscopic or stereotactic biopsy may provide an inadequate sample [6], and therefore mixed tumors are either underestimated (pineocytoma instead of pineoblastoma) or overestimated (germinoma instead of mature teratoma with germinomatous components (Fig.3.2.51). Treatment for germinomas includes radiotherapy, which in most cases includes the whole brain or even the spinal cord in craniospinal radiation and the neurocogni-

3.2.5.4.5 Diagnosis

A major component of the diagnostic procedure is neuroimaging. It is mandatory today that an MRI scan be performed, especially to obtain information on the displacement of the Sylvian aqueduct in the sagittal plane and the relationship with the quadrigeminal plate. As for the features of the lesion itself, there are no specific clues or characteristics that allow diagnose a germinoma, a non-germinomatous germ cell tumor or a pineal parenchymal tumor to be diagnosed with any certainty [8]. An additional cranial CT might be useful for determining the extent of calcification. Simultaneous lesions in the pineal region and the suprasellar cistern very strongly hint at pure germinoma (Fig. 3.2.52). A lesion confined to the suprasellar cistern may also be a granuloma and may need to be biopsied to establish the diagnosis (Fig.3.2.53). Lesions within the pineal region cannot be subclassified based on the morphology alone, as all germinomas and non-germinomatous germinomas may be partly cystic, present with perilesional edema, and have patchy contrast enhancement (Fig.3.2.52). The only clue pointing toward a possible teratoma is extreme heterogeneity (Figs.3.2.51, 3.2.54). Biochemical markers in serum or CSF may be very helpful in establishing the final diagnosis. Cerebrospinal fluid markers and cytology can only be obtained when there is clearly no sign of CSF pathway obstruction. Otherwise, when serum samples show ambiguous results and CSF sampling is required, CSF might be obtained during stereotactic or endoscopic biopsy, which has taken on a significant role in the recent years, as it also allows ventriculostomy at the time of biopsy and allows the necessity of any shunting to be circumvented [10, 15]. 3.2.5.4.6 Therapy

Fig.3.2.51 Mixed teratoma with germinoma in a young man. Because of its heterogeneity the lesion was approached for open resection, which was abandoned when during the procedure a frozen section showed a germinoma. Later, a teratoma with immature features was seen in additional specimens and after radiation, the tumor maintained a formidable size, most likely constituting a mature teratoma for which patient and family refused further treatment

Therapy for germinomas and non-germinomatous germ cell lesions is complex and requires an interactive interdisciplinary team [4, 5]. The most important element is a safe and representative tissue diagnosis, which can be obtained by stereotactic or endoscopic biopsy, but will be most reliable when the lesion is surgically excised whenever possible and is not a pure germinoma [2]. If a pure germinoma can be assumed to be present, radiation will be initiated as the first line of therapy [7], but may be preceded by chemotherapy to further increase the efficacy of radiation, which may then be confined to

3.2.5 Supratentorial Brain Tumors in Adults

the involved field [7]. Rapid and sustained resolution is to be expected (Fig.3.2.55). For non-germinomatous germ cell tumors, there is first combinatorial chemotherapy and radiation. Should there still be tumor present, surgery should be performed to remove the remaining solid part. Afterward, another chemotherapy regimen should be given to consolidate the treatment [7]. The treatment efficacy greatly improved when the experiences gained from the treatment of adult germ cell tumors were combined with the pediatric experience. Focal radiation has been frequently mentioned over the last decade, particularly as an alternative to surgical removal, which was considered to carry too high a risk. It cannot be denied that radiosurgery has its place in the treatment of many tumors and also plays some role in recurrent or otherwise exhaustively treated pineal region tumors [3]. The argument, however, cannot be that surgery is too risky, as in those centers in which this highly standardized operation is performed regularly, the morbidity is very low when using the classical supracerebellar, infratentorial approach (Fig.3.2.56) [2]. 3.2.5.4.7 Differential Diagnosis

Fig. 3.2.52 Hypothalamic granuloma with severe water and electrolyte imbalance and eating disorder as well as mental alterations

In the pineal region, pineal parenchymal tumors such as pineocytoma or pineoblastoma need to be distinguished. They have no markers, but the neuroimaging appearance overlaps with the other tumor types so that in any case a biopsy, preferably a resection for a marker negative tumor is advised, providing enough sample to not miss the intermediate type, which may easily progress to an aggressive lesion (Fig.3.2.56). Pineocytomas may also be cystic and thus not distinguishable from pineal cysts, which in turn may cause aqueductal compression and even hemorrhage (Fig.3.2.57).

Fig.3.2.53 Germinoma with inhom*ogeneous appearance, which is located in the pineal region as well as in the suprasellar region, with additional manifestation in the fourth ventricle. The simultaneous suprasellar and pineal location is very typical of germinoma

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Fig.3.2.54 Very inhom*ogeneous tumor in the quadrigeminal cistern apposed to the pineal gland that turned out to be a mature teratoma and was completely resected

Fig.3.2.55 Typical biopsy-proven germinoma filling the whole third ventricle, which responded well to standard treatment

3.2.5 Supratentorial Brain Tumors in Adults

Fig.3.2.56 a Axial and b sagittal Gadolinium-enhanced T1-weighted MRI showing a cystic pineal parenchymal tumor of intermediate differentiation, which was completely resected by c,d the supracerebellar approach

Fig.3.2.57 Pineal cyst with signs of hemorrhage and chronic hydrocephalus due to compression of the Sylvian aqueduct

In the suprasellar region, granulomas are more frequent than elsewhere (Fig.3.2.52). They are also markernegative and indirect inflammatory signs in the CSF are absent or ambiguous. They may respond to steroids, but the response may be slow; therefore, a lack of response does not exclude that possibility.

3.2.5.4.8 Prognosis

The prognosis for pure germinomas is generally excellent with correct treatment and long-term control or cures are frequent. As for the mature teratomas, the prognosis is also excellent when completely resected. With the anaplastic non-germinomatous germ cell tumors, the prognosis

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is uncertain because no large series with hom*ogeneous treatment regimens have bee published. There is reason to believe, though, that with appropriate combinations of chemotherapeutics, surgery and radiation the prognosis improves and long-term control is possible [5]. 3.2.5.4.9 European Standard for the Treatment of Germ Cell Tumors

• Upon detection of a pineal tumor, serum and possibly CSF markers should be obtained. • Hydrocephalus is treated by third ventriculostomy, strictly avoiding shunting. • Tissue diagnosis is made from biopsy or after open surgical resection. • Resection techniques have been refined and are safe. • Germinomas are treated with radiation therapy, which may be preceded by chemotherapy. • Non-germinomatous germ cell tumors are resected when mature and treated by a combination of surgery, chemotherapy, and radiation when immature. The same holds true for pineal parenchymal tumors.

germinoma: a multi-institutional retrospective review of 126 patients. Int J Radiat Oncol Biol Phys 58:705–713 10. Reddy AT, Wellons JC III, Allen JC, Fiveash JB, Abdullatif H, Braune KW, Grabb PA (2004) Refining the staging evaluation of pineal region germinoma using neuroendoscopy and the presence of preoperative diabetes insipidus. Neurooncology 6:127–133 11. Rosenblum MK, Matsutani M, Van Meir EG (2000) CNS germ cell tumors. In: Kleihues P, Cavanee W (eds) Pathology and genetics of tumors of the nervous system. IARC, Lyon, pp 208–214 12. Saif MW, Takimoto CH (2003) Pineal germinoma followed by hematogenous metastases. South Med J 96:117–119 13. Wellons JC III, Reddy AT, Tubbs RS, Abdullatif H, Oakes WJ, Blount JP, Grabb PA (2004) Neuroendoscopic findings in patients with intracranial germinomas correlating with diabetes insipidus. J Neurosurg 100:430–436 14. Wong TT, Yen SH, Ho DM, Chang FC, Chang KP (2003) Pineal germinoma with intratumoral hemorrhage after neuroendoscopic tumor biopsy. Childs Nerv Syst 19:769–772 15. Yurtseven T, Ersahin Y, Demirtas E, Mutluer S (2003) Neuroendoscopic biopsy for intraventricular tumors. Minim Invasive Neurosurg 46:293–299

Selected Reading 3.2.5.5 1. Altundag OO, Celik I, Kars A (2002) Pineal germ cell tumor metastasis via ventriculoperitoneal shunt. Am J Clin Oncol 25:104–105 2. Bruce JN, Ogden AT (2004) Surgical strategies for treating patients with pineal region tumors. J Neurooncol 69:221–236 3. Hasegawa T, Kondziolka D, Hadjipanayis CG, Flickinger JC, Lunsford LD (2003) Stereotactic radiosurgery for CNS nongerminomatous germ cell tumors. Report of four cases. Pediatr Neurosurg 38:329–333 4. Herrmann HD, Winkler D, Westphal M (1992) Treatment of tumours of the pineal region and posterior part of the third ventricle. Acta Neurochir (Wien) 116:137–146 5. Herrmann HD, Westphal M, Winkler K, Laas RW, Schulte FJ (1994) Treatment of nongerminomatous germ-cell tumors of the pineal region. Neurosurgery 34:524–529; discussion 529 6. Hooda BS, Finlay JL (1999) Recent advances in the diagnosis and treatment of central nervous system germ-cell tumours. Curr Opin Neurol 12:693–696 7. Kaur H, Singh D, Peereboom DM (2003) Primary central nervous system germ cell tumors. Curr Treat Options Oncol 4:491–498 8. Liang L, Korogi Y, Sugahara T, Ikushima I, Shigematsu Y, Okuda T, Takahashi M, Kochi M, Ushio Y (2002) MRI of intracranial germ-cell tumours. Neuroradiology 44:382–388 9. Ogawa K, Shikama N, Toita T, Nakamura K, Uno T, Onishi H, Itami J, Kakinohana Y, Kinjo T, Yoshii Y, Ito H, Murayama S (2004) Long-term results of radiotherapy for intracranial

Tumors of the Sellar Region

3.2.5.5.1 Basics

Sellar tumors originate from the proper contents of the sella, which is the pituitary gland, or from developmental residues there, or from the surrounding structures. The first group is thus the adenomas from the anterior lobe, which are either hormonally active or nonfunctional. The second type of tumor is the craniopharyngioma and tumors from the surrounding structures, which are mostly meningiomas or metastases and will be dealt with in that context elsewhere (Sects.3.2.5.2 and 3.2.5.6). Hormonally active tumors secrete prolactin, growth hormone, the adrenocorticotrophic hormone (ACTH), thyroid-stimulating hormone (TSH) or gonadotrophins (LH/FSH). Mixed hormone secretion is also known but rare. The inactive adenomas may still produce subunits of some hormones or inadequately processed precursor molecules. Pituitary adenomas are mostly restricted to the sellar area, but, without being histologically anaplastic in some cases, may also grow invasively into the cavernous sinus and compromise its contents. Anaplastic adenomas and pituitary carcinomas are rare and usually develop after a long history of recurrence and repeated multimodality treatment. Many different classification schemes exist, but only one was adopted by the WHO [6]. Craniopharyngiomas arise from residuals of the craniopharyngeal duct. They are frequently cystic and locally invasive. They occur in the sella, in the sella with extensive suprasellar extension, but also originate higher

3.2.5 Supratentorial Brain Tumors in Adults

up all along the pituitary stalk and at the base of the infundibulum. Histologically, they are made up of Rathke pouch epithelium and are classed as grade I according to the WHO, with only extremely rare instances of anaplasia [5]. 3.2.5.5.2 Epidemiology

Pituitary adenomas occur throughout life, although the proportion of children and patients over 70 affected is rather small. Craniopharyngiomas occur typically in children and then with a second incidence peak later in the seventh decade. No environmental clues have been described and no genetic syndromes are associated with either of these tumor groups. 3.2.5.5.3 Symptoms

For sellar tumors, there are some common, nonspecific symptoms and then there are symptoms that are specifically related to the endocrine activity of a tumor. The nonspecific symptoms are visual field disturbances caused by tumors compressing the optic chiasm from below. Also, compression of the optic nerves may cause severe loss of visual acuity and even blindness. A sudden hemorrhage into a tumor is a feared complication and immediately results in emergency treatment to rescue the patient from optic nerve compression and subsequent loss of vision. The other major common symptom for all sellar lesions large enough to exert pressure on the pituitary stalk or the gland itself is that of pituitary insufficiency, which is particularly dangerous when it affects the adrenal axis, perhaps eventually leading to an Addison crisis. Any mild compression of the gland due to a tumor that results in a lack of inhibitory control of the prolactin secretion can result in reactive hyperprolactinemia, which is different from hyperprolactinemia due to an active adenoma. This will lead to infertility or amenorrhea in women and loss of libido in men. Hormonally active pituitary adenomas have their characteristic symptoms depending on the hormone secreted. Prolactinomas cause infertility in females and amenorrhea, and when large with excessive hormone production, even galactorrhea. In males the most frequent presenting sign of prolactinomas is impotence, and with excessive prolactin secretion, gynecomasty. Growth hormone-producing adenomas typically present with acromegaly in the adult and with gigantism in children or teenagers. Adrenocorticotrophic hormone-producing adenomas cause hypercortisolism and this leads to the development of Cushing’s disease. Thyroid-stimulating hormone-secreting tumors result

in hyperthyroidism, whereas gonadotropin-secreting tumors also cause fertility problems. Craniopharyngiomas most often present with partial pituitary insufficiency and visual problems due to suprasellar extension and optic nerve/chiasm compression. There may be delayed puberty as well as impairment of pituitary/hypothalamic function, such as diabetes insipidus or eating disorders. 3.2.5.5.4 Complications

Hemorrhage into a large pituitary adenoma, which is also called pituitary apoplexy, can cause immediate loss of vision, headache, and severe impairment of pituitary function including diabetes insipidus [12]. Extension of very large adenomas or craniopharyngiomas into the third ventricle may lead to obstructive hydrocephalus because of the blockade of the foramen of Monro. This can lead to acutely raised intracranial pressure with herniation. Suprasellar extension into the third ventricle with hypothalamic compression may also cause severe imbalances of water and electrolytes. Hypo- or hypernatremia may result, with the related disturbances of consciousness and even severe brain edema may be a feared complication. Extensive supra- and retrosellar extension may affect the integrity of the mammillary bodies, either in the untreated state or later in the context of therapy leading to apathy and memory loss. There are also severe complications from insufficient treatment of hormonally active tumors. Longstanding severe Cushing’s disease causes hypertension, muscle wasting, and osteoporosis. Long-standing acromegaly causes severe diabetes with all the late effects and cardiomegaly with, eventually, fatal cardiomyopathy. The most feared treatment-related complication in ACTH-producing pituitary adenomas is the development of Nelson’s syndrome after adrenalectomy for Cushing’s disease, which has fortunately become extremely rare, but was more frequent during the days of insufficient transphenoidal surgery and poor endocrine diagnostics where adrenalectomies were performed. 3.2.5.5.5 Diagnosis

A major component of the diagnostic procedure is neuroimaging. It is mandatory today that an MRI scan be performed, especially to obtain information on the relationship with the optic chiasm and the pituitary stalk and possible invasion of the cavernous sinus. An additional cranial CT might be useful for determining the extent of calcification, especially for craniopharyngiomas. Adenomas are homgeneously enhancing, well-demarcated tumors that may just be visible in the pituitary and cause stalk deviation (Fig. 3.2.58) or fill the whole sella

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lumen or extend into the suprasellar region (Fig.3.2.59). They are only rarely cystic. In extreme cases they can extend to all neighboring structures and invade the cavernous sinus as well as the anterior skull base (Fig.3.2.60). Craniopharyngiomas are much more frequently cystic or multicystic. The cysts can be extremely heterogeneous in their imaging properties ranging from hyperintense

to hypointense, depending on the contents (Figs.3.2.61, 3.2.62). Calcifications are frequent. At least in primary tumors, the pituitary can often be seen in the sella, displaced or compressed into one corner. Hormonally active adenomas are diagnosed due to their endocrine syndromes [7]. All pituitary hormones can be easily measured; therefore, serum diagnostics are

Fig.3.2.58 Pituitary microadenoma contained in the sella with stalk deviation to the side of the tumor

Fig.3.2.59 Large inactive pituitary adenoma with extensive suprasellar extension, leading to the choice of a primarily transcranial approach

3.2.5 Supratentorial Brain Tumors in Adults

Fig.3.2.60 Very large human growth hormone-secreting adenoma with diffuse infiltration of the perisellar structures that was resistant to multimodal treatment

Fig. 3.2.61 Typical suprasellar craniopharyngioma, which has a very heterogeneous appearance on MRI, not only with a mix of cystic and solid components, but also cysts with variable signal intensities

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Fig.3.2.62 Almost exclusively cystic, mainly intrasellar, craniopharyngioma

routine. Measuring the prolactin levels is mandatory in large, newly diagnosed tumors because the levels will determine further decisions and will clearly distinguish between reactive hyperprolactinieia and prolactinoma. Only for ACTH, is there the possibility of ectopic hormone production in small cell lung carcinoma or other potentially paraneoplastic endocrine-active tumors. As at the same time, these adenomas may really be microadenomas that cannot be seen, even on high-resolution MR, catheterization of the petrosal sinus may be helpful in establishing at least by virtue of a central to peripheral gradient the diagnosis of central Cushing’s disease versus an ectopic syndrome [4].

3.2.5.5.6 Therapy 3.2.5.5.6.1 Conservative Treatment

Therapy for pituitary adenomas is constantly undergoing changes because of the increasing availability and efficacy of medical therapies [11]. Prolactin-secreting adenomas are mostly treated by dopamine agonists that need to be taken for many years, or even for life. This leads in most cases to complete long-term control, but there are still reasons mostly related to patient compliance and side effects why surgery is warranted [2]. Human growth hormone-secreting adenomas are nowadays also treated with drugs first. Somatostatins have been developed into long-acting agents so that treatment can be managed by most patients. Long-term control is possible, but intolerance to treatment or insufficient response still requires surgical intervention.

3.2.5 Supratentorial Brain Tumors in Adults

Medical treatment is insufficient for the other hormonally active adenomas, and there is no medical treatment for inactive adenomas or craniopharyngiomas. 3.2.5.5.6.2 Surgical Treatment

Pituitary adenomas are safely removed by selective microsurgical transsphenoidal adenomectomy [1]. Large suprasellar extensions may rarely require additional or primary transcranial intervention (Fig.3.2.59 [1]) Craniopharyngiomas are approached using the transsphenoidal approach when the tumor is intra- or intra-/ suprasellar [3], but frequently using the transcranial approach when there is major involvement of the third ventricle and hypothalamus. As the tumors are highly individual in their extension, there are many approaches that need to be taken, which range from pterional through bifrontal to transcallosal/transventricular. Literature series report effective gross total resection in 50–70% of cases. Recurrent tumors can frequently be reoperated, but thereafter radiotherapy must be considered. 3.2.5.5.6.3 Radiotherapy

Pituitary adenomas can grow invasively into the cavernous sinus, rendering them uncontrollable by surgery alone. In these cases, residual tumors or any tumor that shows signs of regrowth can be treated by conformal radiotherapy, either with single high-dose stereotactic radiosurgery by Gamma knife or LINAC, or in a fractionated regimen. Radiosurgery plays an increasing role in the overall management [8]. Craniopharyngiomas should also be irradiated upon recurrence and some groups already advocate radiation as the primary treatment without even risking initial surgery, which may incur morbidity due to hypothalamic injury. For mostly cystic craniopharyngiomas, instillation of radionuclides for interstitial radiation is successfully used by some centers. 3.2.5.5.7

Differential Diagnosis

In addition to intrinsic and extrinsic tumors, inflammatory lesions occur in the sella. Hypophysitis is rare and is characterized by the same symptoms as an intrasellar adenoma. It can also extend to the suprasellar plane and cause visual symptoms, and therefore the diagnosis is frequently made after surgery and not with imaging [9, 10]. Granulomas are even rarer and typically in closer proximity to the pituitary stalk. Likewise, germinomas may occur along the pituitary stalk and the diagnosis should be suspected when there is an additional lesion in the pineal region. Metastases can occur just as often in the sella or perisellar region as anywhere else. They tend to be locally invasive and frequently destruct bone. The diagnosis is more likely when an underlying primary tumor is known.

Meningiomas tend to have a broad attachment to the bony surroundings of the sella and also frequently show dural involvement over the tuberculum sellae or the sphenoid plane. 3.2.5.5.8

Prognosis

The prognosis for endocrine active pituitary adenomas is excellent, except for giant adenomas, which at the time of presentation are already invasive (Fig. 3.2.60). Inactive adenomas usually present later and with larger sizes; therefore, in these cases, recurrence is more frequent. Even with local invasiveness, the prognosis for long-term control is good when radiotherapy is included in the therapeutic strategies. Craniopharyngiomas have a tendency to recur even after gross total resection because of the invasive nature of the capsule, which may have digit-like processes into the surrounding parenchyma, which in the case of hypothalamic extension cannot be removed with any kind of safety margin. Therefore, there is a need for irradiation in subtotally resected or recurrent tumors [13, 14]. This, however, does not result in complete control in all cases and progression may still occur, but 10 year survival is over 90% in most series when combination therapy is used and patients are regularly followed up. 3.2.5.5.9 Generally Accepted Standard Treatment in Europe 3.2.5.5.9.1 Pituitary Adenomas

Prolactin and growth hormone-secreting tumors are first treated medically. Surgery is only indicated when medical therapy fails or the patients wish to circumvent their need for constant medication. All other adenomas are resected microsurgically, either transnasally or via the transcranial route when there is extensive suprasellar or parasellar extension. There is increasing use of the endoscope in transnasal surgery. Invasive tumor residuals or recurrences are treated by fractionated conformal radiotherapy. 3.2.5.5.9.2 Craniopharyngiomas

There is no consensus on the treatment of craniopharyngiomas. Small intrasellar lesions are resected transnasally. The majority of the suprasellar cystic craniopharyngiomas will also be resected. When residual tumor is present, resection is followed by radiation. In cases of radiologically complete resection radiotherapy may be withheld to wait and see whether there will be recurrence. Some centers advocate biopsy and radiation as the primary treatment. Also, interstitial radiation (brachytherapy) is given in some centers to treat cystic lesions.

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Selected Reading 1. Couldwell WT (2004) Transsphenoidal and transcranial surgery for pituitary adenomas. J Neurooncol 69:237–256 2. Couldwell WT, Weiss MH (2004) Medical and surgical management of microprolactinoma. Pituitary 7:31–32 3. Fahlbusch R, Honegger J, Paulus W, Huk W, Buchfelder M (1999) Surgical treatment of craniopharyngiomas: experience with 168 patients. J Neurosurg 90:237–250 4. Flitsch J, Ludecke DK, Knappe UJ, Grzyska U (2002) Cavernous sinus sampling in selected cases of Cushing’s disease. Exp Clin Endocrinol Diabetes 110:329–335 5. Janzer RC, Burger PC, Giangaspero F, Paulus W (2000) Craniopharyngioma. In: Kleihues P, Cavanee W (eds) Pathology and genetics of tumors of the central nervous system. IARC, Lyon 6. Kovacs K, Horvath E, Vidal S (2001) Classification of pituitary adenomas. J Neurooncol 54:121–127 7. Kreutzer J, Fahlbusch R (2004) Diagnosis and treatment of pituitary tumors. Curr Opin Neurol 17:693–703 8. Laws ER, Sheehan JP, Sheehan JM, Jagnathan J, Jane JA Jr, Oskouian R (2004) Stereotactic radiosurgery for pituitary adenomas: a review of the literature. J Neurooncol 69:257–272 9. Leung GK, Lopes MB, Thorner MO, Vance ML, Laws ER Jr (2004) Primary hypophysitis: a single-center experience in 16 cases. J Neurosurg 101:262–271 10. Ng WH, Gonzales M, Kaye AH (2003) Lymphocytic hypophysitis. J Clin Neurosci 10:409–413 11. Pickett CA (2005) Update on the medical management of pituitary adenomas. Curr Neurol Neurosci Rep 5:178–185 12. Sibal L, Ball SG, Connolly V, James RA, Kane P, Kelly WF, Kendall-Taylor P, Mathias D, Perros P, Quinton R, Vaidya B (2004) Pituitary apoplexy: a review of clinical presentation, management and outcome in 45 cases. Pituitary 7:157–163 13. Varlotto JM, Flickinger JC, Kondziolka D, Lunsford LD, Deutsch M (2002) External beam irradiation of craniopharyngiomas: long-term analysis of tumor control and morbidity. Int J Radiat Oncol Biol Phys 54:492–499 14. Wara WM, Sneed PK, Larson DA (1994) The role of radiation therapy in the treatment of craniopharyngioma. Pediatr Neurosurg 21 [Suppl 1]:98–100

3.2.5.6

Metastases

3.2.5.6.1 Basics

Metastases are the most frequent intracranial tumor entity. With increasingly improved control of systemic disease, there are a growing number of patients who will fail in the intracranial compartment during the course of the disease [2]. Brain metastases are hematogenic because there is no lymphatic system. It is speculated that a specific set of cell surface adhesion molecules is necessary for a tumor to metastasize to the brain. Not all primary tumors have equal potential to spread to the brain. Mela-

noma, bronchial carcinoma, mammary carcinoma, renal cell carcinoma, and colon carcinoma spread to the brain easily, whereas gastric carcinoma or prostate carcinoma only rarely spread intracranially. Metastases may be singular (only one metastasis known in the body) or solitary (only one metastasis known in the brain). Multiple lesions may be present. When they are all of a similar size, just one metastatic event is assumed (synchronously metastasizing), or when they are very different in size a metachronous event is postulated. 3.2.5.6.2 Epidemiology

With the increasing incidence of cancer in an aging population and increasingly successful systemic therapies, the incidence of brain metastases is rising and it can roughly be assumed that there are ten times as many brain metastases as primary brain tumors. The annual occurrence for the European Union is therefore estimated to be roughly 300,000 cases. 3.2.5.6.3 Symptoms

Metastases become symptomatic with a broad range of symptoms. Depending on their location, they cause seizures (temporomesial, perirolandic), focal neurological deficit, symptoms from obstructive hydrocephalus, visual field impairment, or behavioral disorders (large frontal tumors). Many metastases are asymptomatic when found and are discovered in the context of staging or routine follow-up for known disease. Twenty percent of metastases are found without a known primary and a clue as to where to look for a primary tumor is often only obtained after tissue diagnosis of the metastasis. 3.2.5.6.4 Complications

Hemorrhage into a large metastasis may have the same symptoms as a spontaneous intracerebral hemorrhage with a sudden neurological deficit, loss of consciousness or even herniation. Hemorrhage is not pathognomonic for a specific histology, but can occur with almost any histology. Shedding of cells on the surface of metastases exposed to CSF spaces may lead to spread within the CNS compartment and subsequent meningeal carcinomatosis (Fig.3.2.63). Extensive metastases may lead to increased protein concentrations in the CSF and consecutive malresorptive hydrocephalus. 3.2.5.6.5 Diagnosis

A major component of the diagnostic procedure is neuroimaging. Metastases may show contrast enhancement of varying intensity, and when centrally necrotic mimic

3.2.5 Supratentorial Brain Tumors in Adults

glioblastoma (Figs.3.2.64, 3.2.65). Multiplicity is always a strong indicator for metastases (Fig.3.2.66). It is mandatory today that an MRI scan be performed, in particular to obtain information about the extent of disease, which may be already untreatable by the time of diagnosis when

ten or more lesions are present. CT shows the lesions as well, but especially in the infratentorial compartment or the brain stem, MRI is superior (Fig.3.2.67). When there is a known tumor in the case history, the diagnosis is easier to suspect. Most often the diagnosis

Fig.3.2.63 Meningeal carcinomatosis in a patient with proven temporal metastasis from a bronchial adenocarcinoma

Fig.3.2.64 Typical appearance of a superficial metastasis; in this case, from a known renal cell carcinoma that had caused severe neuropsychological disturbances, which were rapidly resolving after complete removal

Fig.3.2.65 Largely cystic, centrally hypointense metastasis from a mammary carcinoma that, without specific case history, could also be taken for glioblastoma

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Fig.3.2.66 Metachronous metastases from colorectal cancer with coexisting large and small lesions

Fig.3.2.67 Adenocarcinoma of the lung with one cystic, symptomatic lesion in the right temporal region, which is shown on the CT (top left) as well as on the MRI (top right). The infratentorial lesion shows much better on the MRI scan

3.2.5 Supratentorial Brain Tumors in Adults

is made from tissue obtained either from a stereotactic biopsy or from resection. 3.2.5.6.6 Therapy

Treatment in general has to take into account the general status of the disease, options to treat or control the underlying disease, and the life expectancy, including quality of life. 3.2.5.6.6.1 Conservative Treatment

Chemotherapy plays only a limited but slowly growing role in the treatment of brain metastases [5]. Mainly, small cell lung carcinomas and some metastases from mammary carcinoma lend themselves to chemotherapy. For surgically untreatable cases there is whole brain radiation with or without chemotherapy [3, 10]. 3.2.5.6.6.2 Surgical Treatment

Resection of metastases has been shown in controlled studies to be of benefit, which is enhanced when radiotherapy is added [6, 7]. Resection is warranted in all lesions over 3 cm, lesions that are easily accessible and those that are surrounded by symptomatic extensive edema [12]. Also, infratentorial lesions that threaten to cause obstructive hydrocephalus are surgical indications, and can be considered even in complex locations like the pineal gland where resection immediately restores CSF pathways (Fig.3.2.68). Up to three lesions can easily be removed in one surgical setting, even in the infratentorial and supratentorial compartments with repositioning of the patient. Removal of brain metastases should be attempted in toto, possibly even with a small cover of perilesional white matter as a safety margin. The ability to do so also

determines the choice of additional treatment. Resection in toto is clearly impossible in large cystic lesions, which therefore have a higher tendency toward local recurrence, and in those cases additional radiation, either as whole brain or in the field involved, may be desirable. 3.2.5.6.6.3 Radiotherapy

As an alternative to surgery, stereotactic radiosurgery (SRS) has frequently been used [1, 4]. The lesions are ideally spherically shaped and when less than 3cm an ideal volume for focused irradiation. Multiple lesions can be treated in one setting. When the appropriate dose which may vary depending on the underlying histology is delivered, control is excellent, but the resolution of brain edema takes much longer than after surgical removal. SRS may be used in combination with surgery [8, 11] or whole brain radiotherapy [9]. Whole brain radiation is given when widespread disease is present and there is no other option. This may have severe neurocognitive sequelae. 3.2.5.6.7 Differential Diagnosis

Because of the contrast enhancement and central necrosis, metastases mimic high-grade glioma. Because of the spherical shape and the ring-like marginal enhancement, there can also possibly be uncertainty between metastasis and brain abscess. This is currently easily resolved with an ADC sequence in the MRI, which can very reliably distinguish between these entities. 3.2.5.6.8 Prognosis

The prognosis for patients with metastases is generally poor as most patients will succumb to their underlying

Fig.3.2.68 Metastasis in the pineal region with threatening occlusive hydrocephalus and compression of the quadrigeminal plate, which could be easily resected

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Fig.3.2.69 Diffuse multiple lesions, which leave no therapeutic options

disease within 1year. When the systemic disease can be controlled, and this appears to be increasingly the case, aggressive treatment of brain metastases may provide durable control and it is therefore indicated as much as aggressive treatment of gliomas is indicated. When widespread, untreatable cerebral involvement is present, survival falls within the range of 4–6weeks (Fig.3.2.69). 3.2.5.6.9 European Standard for Cerebral Metastasis

• When the patient is known to have cancer, thorough staging has to precede any discussion of therapeutic options. Cranial MRI is mandatory. • Control of the systemic disease is desirable when treatment of CNS metastasis is to be considered. There has to be a life expectancy of at least 6months. • Treatment of brain metastases is interdisciplinary and includes microsurgical resection, diagnostic stereotactic biopsy followed by radiation (whole brain or SRS), and chemotherapy, or any combination. • Shunting is to be avoided and in cases of obstructive hydrocephalus, third ventriculostomy may be indicated.

Selected Reading 1. Barker FG II (2005) Surgical and radiosurgical management of brain metastases. Surg Clin North Am 85:329–345 2. Burton A (2004) High incidence of brain metastases with trastuzumab treatment. Lancet Oncol 5:523 3. Kaal EC, Niel CG, Vecht CJ (2005) Therapeutic management of brain metastasis. Lancet Neurol 4:289–298 4. Koc M, McGregor J, Grecula J, Bauer CJ, Gupta N, Gah bauer RA (2005) Gamma Knife radiosurgery for intracranial metastatic melanoma: an analysis of survival and prognostic factors. J Neurooncol 71:307–313 5. Langer CJ, Mehta MP (2005) Current management of brain metastases, with a focus on systemic options. J Clin Oncol 23:6207–6219 6. Paek SH, Audu PB, Sperling MR, Cho J, Andrews DW (2005) Reevaluation of surgery for the treatment of brain metastases: review of 208 patients with single or multiple brain metastases treated at one institution with modern neurosurgical techniques. Neurosurgery 56:1021–1034; discussion 1021–1034 7. Patchell RA, Tibbs PA, Regine WF, Dempsey RJ, Mohiuddin M, Kryscio RJ, Markesbery WR, Foon KA, Young B (1998) Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA 280:1485–1489

3.2.6 Infratentorial Brain Tumours in Adults

8. Pollock BE, Brown PD, Foote RL, Stafford SL, Schomberg PJ (2003) Properly selected patients with multiple brain metastases may benefit from aggressive treatment of their intracranial disease. J Neurooncol 61:73–80 9. Shehata MK, Young B, Reid B, Patchell RA, St Clair W, Sims J, Sanders M, Meigooni A, Mohiuddin M, Regine WF (2004) Stereotactic radiosurgery of 468 brain metastases < or =2cm: implications for SRS dose and whole brain radiation therapy. Int J Radiat Oncol Biol Phys 59:87–93 10. Varlotto JM, Flickinger JC, Niranjan A, Bhatnagar A, Kondziolka D, Lunsford LD (2005) The impact of wholebrain radiation therapy on the long-term control and morbidity of patients surviving more than one year after gamma knife radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys 62:1125–1132 11. Vecil GG, Suki D, Maldaun MV, Lang FF, Sawaya R (2005) Resection of brain metastases previously treated with stereotactic radiosurgery. J Neurosurg 102:209–215 12. Westphal M, Heese O, de Wit M (2003) Intracranial metastases: therapeutic options. Ann Oncol 14 [Suppl 3]:iii4–10

the origins of those tumours rather than to morphological criteria will someday replace this classification system. Table3.2.9 gives an overview: Table 3.2.9 Neuroepithelial tumours of the cerebellum and brain stem I

Glial tumours 1. Astrocytic tumours Pilocytic astrocytoma Diffuse astrocytoma (fibrillary, protoplasmatic, gemistocytic) Anaplastic astrocytoma Glioblastoma multiforme Pleomorphic xanthoastrocytoma 2. Oligodendroglial tumours Oligodendroglioma Anaplastic oligodendroglioma 3. Mixed gliomas

3.2.6 Infratentorial Brain Tumours in Adults

Oligoastrocytoma Anaplastic oligoastrocytoma 4. Ependymal tumours

Infratentorial brain tumours represent about 15% of adult and about 60% of paediatric brain tumours. Those that include the group of medulloblastomas will be discussed in Sect.3.2.9.1. Tumours of the posterior fossa constitute a continuing challenge to the neurosurgeon due to the limited access options as well as the delicate anatomy of the cranial nerves and the brain stem nuclei and fibre tracts.

Myxopapillary ependymoma Subependymoma Ependymoma Anaplastic ependymoma 5. Neuroepithelial tumours of uncertain origin Astroblastoma

3.2.6.1

Gliomatosis cerebri

Neuroepithelial Tumours II

Neuronal and mixed neuronal-glial tumours

Jürgen Kiwit

1. Gangliocytoma

The oncological basics are discussed in Sect. 3.2.5.1. In general, all neuroepithelial tumours of the cerebral hemispheres can be found infratentorially as well. The WHO classification [6] is widely accepted, but is basically a morphological classification of tumours. Histological features determine the grading system, and there is general acceptance that the morphological grade of malignancy corresponds to the patient’s prognosis. WHO grade I tumours are considered benign lesions with low proliferative potential and possible cure after surgery. WHO grade II tumours infiltrate the surrounding brain, brain stem or cerebellum, have low mitotic activity, but tend to progress to a more malignant phenotype. WHO grade III and IV tumours show histological signs of malignancy, are mitotically highly active and have a universally fatal clinical course. Cytogenetic and molecular genetic classification systems that are prognostically valid and correspond to

2. Ganglioglioma 3. Desmoplastic infantile astrocytoma/ganglioglioma 4. Dysembryoplastic neuroepithelial tumour 5. Central neurocytoma 6. Cerebellar liponeurocytoma 7. Cerebellar paraganglioma (only case reports) III

Non-glial tumours 1. Embryonal tumours Ependymoblastoma Medulloblastoma 2. Choroid plexus tumours Choroid plexus papilloma Choroid plexus carcinoma

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3.2.6.1.1 Definition

Tumours arising from various neuroglial cells in the central nervous system. The traditional naming of neuroepithelial tumours corresponds to the presumed cell of origin, but concepts of tumourigenicity are rapidly changing. Rather than dedifferentiation from local cells it seems that glioma stem cells are capable of tumour initiation and tumour renewal. These stem cells have been characterized as CD 133-positive; the CD 133-negative cells, in contrast, show limited proliferative ability and no tumourigenicity. Glioma stem cells harbour extensive similarities to normal neural stem cells and recapitulate the genotype, gene expression patterns, and in vivo biology of human gliomas [8]. This might be the explanation for the infiltrative nature, chemoresistance pheno- and genotype and immunological masking of these tumours. On the other hand, tumours from different brain regions might have explicit distinct genetic signatures [10]. 3.2.6.1.2 Aetiology/Epidemiology

There are no reliable data regarding neuroepithelial tumours in Europe. About 8/100,000 individuals per year will develop primary supratentorial brain tumours. Infratentorial tumours represent about one tenth of these patients. In the paediatric population, posterior fossa tumours are much more frequent. 3.2.6.1.3 Symptoms

Signs and symptoms are related to neuroanatomy. They include headaches, general malaise, loss of appetite, nausea, vomiting, gait ataxia and dysarthria, and may develop over weeks and months. Obstruction of the ventricular foramina or the aqueduct may lead to acute increased intracranial pressure caused by occlusive hydrocephalus. 3.2.6.1.4 Clinical Course

All patients with infiltrating gliomas of the posterior fossa (except pilocytic astrocytoma) will eventually die due to the invasive nature of these tumours.

• Trans-oesophageal ultrasound to detect a patent oval foramen if surgery in the sitting position is planned (large tumours or those in the upper cerebellar vermis are best operated on via a supracerebellar, infratentorial approach) • Blood count, clotting times, electrolytes, liver function tests, creatinine, electrocardiography 3.2.6.1.5.2 Additional Useful Diagnostic Procedures

• Audiogram (VIII) and acoustic evoked potentials (AEPs) in selected cases • Visual field testing (perimeter) – only in cases of large tumours with hydrocephalus 3.2.6.1.6 Therapy 3.2.6.1.6.1 Conservative Treatment

• Whole brain radiotherapy (WBRT) with a fractionated technique • Dexamethasone (3 × 8 mg daily), tapering according to clinical status • PCV (procarbazine, CCNU and vincristine) therapy in patients with anaplastic oligodendroglioma with 1p 19q deletions • Temozolomide in cases of MGMT (methylguanine methyltransferase) gene silencing 3.2.6.1.6.2 Surgical Treatment

• Suboccipital craniotomy and tumour removal in cerebellar/vermis tumours • Open biopsy or partial removal in dorsal exophytic brain stem gliomas • Stereotactic biopsy in diffuse brain stem tumours (pons) 3.2.6.1.7 Differential Diagnosis

• • • •

Cerebellar abscess/inflammation Intra-axial metastases Ischaemic infarction of the cerebellum or brain stem Demyelination (e. g. multiple sclerosis)

3.2.6.1.5 Diagnostic Procedures 3.2.6.1.8 Prognosis 3.2.6.1.5.1 Recommended European Standard

• • • •

Careful medical history Neurological examination including long fibre tracts Cranial nerve function (II–XII) Motor evoked potentials (MEPs) and somatosensory evoked potentials (SEPs) • Cerebellar function including formal vestibular testing • Magnetic resonance imaging (MRI)

Malignant neuroepithelial tumours in the posterior fossa carry a serious prognosis, and malignant brain stem gliomas are always fatal within a few weeks or months, despite therapy. Chemotherapy has not influenced survival in the last 40years; however, molecular genetic typing of gliomas can help to define individuals who might benefit from adjuvant chemotherapy like temozolomide [3]. Low-grade tumours may show very slow progression and

3.2.6 Infratentorial Brain Tumours in Adults

patients can survive for years. There is no benefit to be gained from radiotherapy for this group. The subgroup of pilocytic astrocytoma carries an excellent prognosis after surgery, and the 10-year survival has been reported to be over 90%.

• • • •

3.2.6.1.9 Surgical Principles

3.2.6.2

3.2.6.1.9.1 Suboccipital Craniotomy

Jürgen Kiwit

• Make a midline linear skin incision for a large craniotomy extending laterally to the sigmoid sinus and cranially to the transverse sinus. In cases affecting only one cerebellar hemisphere perform a unilateral suboccipital craniectomy. If possible, retain the bone flap for reinsertion. Carry out the microsurgical opening of the dura. In the midline (cerebellar vermis or ventricular) approach, incise the dura of the suboccipital midline sinus bilaterally and carefully ligate the sinus. Protection of the cerebellar hemispheres with cotton or cellulose net (e. g. Tabotamp®) and opening of the cisterna magna may be necessary. • In cases involving the cerebellar vermis or fourth ventricle, identify the posterior inferior cerebral artery (PICA) and strictly confine to the midline. Opening the foramen of Magendie is usually no problem. Never coagulate near the medulla oblongata or foramen of Luschka, as sacrifice of even the smallest vessels may lead to serious neurological deficits. • Do not attempt to achieve primary dural closure as it usually does not work. Use a dural graft with running sutures to try to achieve watertight closure. Attempt to reinsert the original bone flap and fix with either miniplates/screws or clamps like Craniofix® 3.2.6.1.9.2 Technique

• Rigid fixation in a Mayfield clamp • Continuous MEP and SEP monitoring in cases involving the brain stem • Wax the emissary veins to avoid air embolism • Avoidance of cerebellar retraction by CSF release • Avoidance of bipolar coagulation close to the ventricular floor • Strictly no bipolar coagulation around the medulla and foramen of Luschka • Piecemeal removal of the tumour • Watertight closure of the dura with a dural graft 3.2.6.1.9.3 Useful Additional Therapeutic Considerations

• Precordial or trans-oesophageal ultrasound to detect air embolism • Palacos® closure of the bone defect and tight fixation if the original bone cannot be replaced

3.2.6.1.9.4 Possible Surgical Complications

CSF leakage (in approximately 10% of cases) Postoperative haemorrhage (approximately 1–2%) Postoperative hydrocephalus (1–3%) Wound infection (1–2%) Cerebellopontine Angle Tumours

Cerebellopontine angle (CPA) tumours occupy the space between the petrous bone laterally, the pons and medulla medially, and the cerebellar hemispheres posteriorly. Tumours in this region are nearly always benign. They represent a major challenge to the surgeon as they are closely related to the cranial nerves. Large tumours have to be operated on using the “windows” between the cranial nerve groups. The arachnoid membranes, and most importantly, the smallest nerve vessels, have to be strictly preserved. Never coagulate small bleeders in this area. A small cotton pad and a lot of patience will do. Positioning of the patient is dependent on the extent of the tumour. Small CPA tumours are best operated on in the supine position with the head fixed and rotated to the contralateral side. The cerebellar hemisphere will come down after opening of the subarachnoid space and CSF release, thus avoiding any retraction of the cerebellum. Tumours measuring up to 2 cm can be safely operated on in this position. Larger tumours should be operated on in a sitting position, the head being rotated to the ipsilateral side without tilt. The advantage of this position is the free drainage of blood and the good exposition of the petrous vein and upper CPA. Retraction is usually necessary, and this positioning may be impossible in cases of patent oval foramen or in cardiovascularly compromised patients. 3.2.6.2.1 Acoustic Neurinoma 3.2.6.2.1.1 Synonyms

• Acoustic neuroma • Vestibular schwannoma • Vestibular neurilemmoma 3.2.6.2.1.2 Definition

Tumours arising from the vestibular branches of the vestibulo-cochlear nerve (VIII), usually displacing the cochlear and facial nerve anteriorly. They are always histologically benign and can be classified according to Koos into four categories (Table3.2.10) [7]: Grading is closely related to symptoms and treatment results.

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Grade Morphology

axial imaging studies. A third group might exhibit rapid growth of > 1cm/year.

Purely intracanalicular lesions

3.2.6.2.1.6 Complications

II A

Tumours protruding into CPA <1cm

II B

Tumours protruding into CPA > 1.0–1.8cm not reaching the brain stem

III

Tumours up to 3cm contacting the brain stem

Tumours compressing the brain stem

Table3.2.10 Koos classification [7]

3.2.6.2.1.3 Aetiology/Epidemiology

About 1/100,000 individuals per year will develop symptomatic vestibular schwannoma, the tumour accounting for 6–8% of all intracranial tumours. The true prevalence, however, is likely to be higher. Incidental acoustic neurinomas can be found in up to 7/10,000 tumours in a large series of MRIs [1]. Although the exact mechanism of tumourigenesis is not fully understood, a malfunction of a tumour suppressor gene coding for schwannomin/merlin on chromosome 22q12 is responsible for the development of vestibular schwannomas. This seems to be true of the development of spontaneous unilateral tumours as well as for the bilateral tumours found in neurofibromatosis type II. 3.2.6.2.1.4 Symptoms

A declining hearing ability is the most common symptom that leads to the diagnosis of acoustic neurinoma. Usually, hearing declines over time, but 5–15% of patients complain of sudden or fluctuating hearing loss, most likely due to compromised blood flow to nerve and cochlea. Only 5% of patients presenting with acoustic neurinoma have normal hearing and speech discrimination. Rotational vertigo may be an early symptom; however, the gradual decline in vestibular function is usually well compensated by the contralateral labyrinthine system and central brain information processing. The facial nerve has a larger stretching tolerance than the cochlear portion of the eighth nerve; hence, facial weakness in small and even larger tumours is uncommon. Only 10% of patients, even those with large tumours (including Koos III and IV) present with unilateral facial weakness. More often facial dysaesthesia (up to 20%) can be observed due to cranial extension of the tumour contacting the trigeminal nerve. 3.2.6.2.1.5 Clinical Course

A considerable number of acoustic tumours will not grow or will grow at an extremely slow pace, considering the probably very high incidence of tumours. A second group might show slow growth defined as 0.2cm/year on

Complications in the natural course of the disease are rare, cystic tumours might deteriorate rapidly due to cyst filling or intratumoural haemorrhage. Large tumours will at some stage compress the fourth ventricle and aqueduct leading to occlusive hydrocephalus. 3.2.6.2.1.7 Diagnostic Procedures 3.2.6.2.1.7.1 Recommended European Standard

• Careful medical history including history of hearing dysfunction • Neurological examination including long fibre tracts • Cranial nerve function (II–XII) • Audiogram (VIII) and AEPs • Speech discrimination score measurements • Facial nerve function (VII) according to the House/ Brackmann scheme including electromyography [4] • Cerebellar function including formal vestibular testing • MRI • CT scan using the bone window technique to watch for bone erosion, widening of the internal acoustic meatus and relation of the jugular bulb to the meatus • Trans-oesophageal ultrasound to detect a patent oval foramen if surgery in sitting position is planned (tumours larger than 2cm) • Blood count, clotting times, electrolytes, liver function tests, creatinine, electrocardiography 3.2.6.2.1.7.2 Additional Useful Diagnostic Procedures

• Digital subtraction angiography (DSA) only in very large tumours or suspected glomus tumours • MEPs and SEPs in very large tumours compromising brain stem function • Visual field testing (perimeter) only in cases of large tumours with hydrocephalus 3.2.6.2.1.8 Therapy 3.2.6.2.1.8.1 Conservative Treatment

• Observation with serial imaging in elder patients as well as in “incidentalomas” • Radiosurgical treatment (e. g. Gamma Knife®) with 12–13Gy to the 50% isodose line • Fractionated stereotactic radiotherapy (e. g. LINAC – linear accelerator, frameless system) with up to 17Gy to the 80% isodose line 3.2.6.2.1.8.2 Surgical Treatment

• Suboccipital retro-mastoid craniotomy and tumour removal

3.2.6 Infratentorial Brain Tumours in Adults

1 2

b Fig.3.2.70 a Acoustic meningioma of the right cerebellopontine angle operated on in the supine position (with the head turned to the left). b Acoustic meningioma. 1 = facial nerve (VII),

2 = superior vestibular nerve (VIII) partially surrounded by the tumour, 3 = cochlear nerve (VIII), 4 = inferior vestibular nerve (VIII), 5 = internal auditory artery, 6 = tumour

3.2.6.2.1.9 Differential Diagnosis

necessary to open the cisterna magna. The anterior inferior cerebellar artery (AICA), nerves VII and VIII and the internal auditory artery (IAA) are identified. • The posterior meatus is opened and bone removed with a high-speed drill. The canalicular dura is opened and the tumour removed piecemeal removal without bipolar coagulation; the bleeding will stop when tumour is removed. Meticulous haemostasis, irrigation and functional control of the facial and cochlear nerves are ensured by monitoring.

3.2.6.2.1.10 Prognosis

• Rigid fixation in a Mayfield clamp • Continuous facial EMG monitoring (m. orbicularis oculi, m. orbicularis ori) • Continuous acoustic evoked potential registration • Suboccipital retro-mastoid craniotomy extending to the sigmoid sinus • Wax the mastoid cells to avoid CSF leakage; wax the emissary veins to avoid an air embolism • Avoidance of cerebellar retraction by CSF release • Avoidance of bipolar coagulation close to the cranial nerves and meatus • Identification of the facial (VII) and cochlear (VIII) nerves • Piecemeal removal of the tumour without any traction on the nerve • Watertight closure of the dura with a dural graft

Intracanalicular tumours are uniformly acoustic neurinomas, but meningiomas of the anterior internal meatus can mimic morphology and symptoms of these tumours (see Fig.3.2.70). In contrast to acoustic neurinomas, the facial and cochlear nerves are displaced posteriorly and are easily identified. • Meningioma of CPA • Glomus tumour • Epidermoid • Extra-axial metastasis Tumour control rate after radiosurgery is 95–98%; surgical tumour control is reported to be 90–95%. Hearing preservation in radiosurgery is reported to range from 60 to 70% compared with 80% in Surgical Centres of Excellence. Facial nerve function is better after radiotherapy compared with microsurgery for these tumours, i. e. 90 versus 80% in small tumours. 3.2.6.2.1.11 Surgical Principles 3.2.6.2.1.11.1 Suboccipital Retro-Mastoid Craniotomy

• A retro-mastoid linear skin incision is made, and a 3-cm craniotomy performed, extending laterally to the sigmoid sinus and cranially to the transverse sinus. The dura is opened microsurgically, avoiding sinus lesions. The cerebellar hemisphere is protected with cotton or cellulose net (e. g. Tabotamp®), the arachnoid cisterns are opened, and in large tumours it may be

3.2.6.2.1.11.2 Technique

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3.2.6.2.1.11.3 Useful Additional Therapeutic Considerations

• Precordial or trans-oesophageal ultrasound to detect air embolism • Palacos® closure of the bone defect and tight fixation 3.2.6.2.1.11.4 Possible Surgical Complications

• CSF leakage, either through the wound or through air cells opened intraoperatively via the Eustachian tube (approximately 10%) • Postoperative haemorrhage (approximately 1–2%) • Postoperative hydrocephalus (1–3%) • Wound infection (1–2%) 3.2.6.2.1.12 Special Remarks

There has been considerable debate on what is the best treatment option for small tumours, but the trend clearly favours radiosurgery due to the minimal treatment time, lower complication rate and excellent preservation of facial function. However, there is a small risk of delayed radiation-induced oncogenesis, with five cases of radiationrelated secondary malignancies having been reported. Looking at the large treatment numbers, the possible risk to a patient probably lies below 1:1,000. 3.2.6.2.2 CPA Meningioma/Petro-Clival Meningioma

angle and/or the clivus region. These tumours may reach large dimensions without causing any clinical symptoms and signs and are generally difficult to operate on. They tend to displace the cranial nerves posteriorly, which facilitates early identification of nerves, but makes removal difficult. The surgeon has to operate through the natural “windows” between the jugular foramen nerve group (IX, X, XI) caudally and the internal auditory meatus group (VII, VIII) as well as the trigeminal nerve (V) cranially (Fig.3.2.71). 3.2.6.2.2.3 Aetiology/Epidemiology

About 6/100,000 individuals per year will develop meningioma, the tumour accounting for 13–26% of all intracranial tumours. However, these data refer to supratentorial meningiomas, while posterior fossa meningiomas represent only 10% of this group. The true prevalence, therefore, should be between 0.5 and 1 per 100,000 individuals. The most common cytogenetic alteration in meningiomas is a loss of chromosome 22 in 60–70% of histologically benign WHO grade I tumours. Progression to more aggressive forms of meningioma is associated with deletion of 1p, 6p, 10q 14q and 18q in atypical meningiomas and 9p (CDKNA) for anaplastic meningioma. Women are affected more often than men with a female:male ratio of 2:1, and most tumours occur in the sixth or seventh decade of life. 3.2.6.2.2.4 Symptoms

3.2.6.2.2.1 Synonym

CPA meningioma.

3.2.6.2.2.2 Definition

Tumours arising from the meningeal cells of the petrous dura/arachnoid and growing into the cerebellopontine

There is no most common symptom leading to the diagnosis of posterior fossa meningioma. These tumours grow slowly and may stay asymptomatic for years. They can affect any cranial nerve leading to symptoms from nausea, vertigo, diminished hearing to facial weakness or facial dysaesthesia. Very rarely, the space-occupying mass has

Fig 3.2.71 a Petro-clival meningioma of the left side. Note the tumour stretching the lower cranial nerves and displacing the posterior inferior cerebellar artery (PICA) caudally. b Lower cranial nerves on the left after complete tumour removal

3.2.6 Infratentorial Brain Tumours in Adults

grown to such an extent that it compromises the foramina Luschka and Magendie, leading to acute hydrocephalus requiring emergency surgery. 3.2.6.2.2.5 Clinical Course

3.2.6.2.2.8.2 Surgical Treatment

• Suboccipital retro-mastoid craniotomy and tumour removal 3.2.6.2.2.9 Differential Diagnosis

Petro-clival meningiomas are slow-growing, but progressively devastating tumours. In very old patients, observation and regular clinical and imaging controls might be appropriate. In younger patients, surgical removal is the preferred treatment option.

• • • • •

3.2.6.2.2.6 Complications

3.2.6.2.2.10 P rognosis

Complications in the natural course of the disease are rare, patients may suffer from lower cranial nerve lesions predisposing to aspiration pneumonia. Rarely, hydrocephalus has to be treated when acute/subacute CSF obstruction is observed. 3.2.6.2.2.7 Diagnostic Procedures 3.2.6.2.2.7.1 Recommended European Standard

• • • • • • • • • •

Careful medical history Neurological examination including long fibre tracts Cranial nerve function (II–XII) Audiogram (VIII) and acoustic evoked potentials (AEPs) Cerebellar function including formal vestibular testing Magnetic resonance imaging (MRI) CT using the bone window technique to watch for bone erosion, infiltration of the dura and neighbouring bone, and widening of the internal acoustic meatus Trans-oesophageal ultrasound to detect a patent oval foramen if surgery in the sitting position is planned (in tumours larger than 3cm) Blood count, clotting times, electrolytes, liver function tests, creatinine, electrocardiography Digital subtraction angiography (DSA) to assess blood supply particularly for the tentorial branches of the internal carotid artery (ICA)

3.2.6.2.2.7.2 Additional Useful Diagnostic Procedures

• Motor evoked potentials (MEPs) and somatosensory evoked potentials (SEPs) in very large tumours compromising brain stem function • Visual field testing (perimeter) only in cases of large tumours with hydrocephalus • Speech discrimination only in cases of affected hearing • Facial nerve EMG only in cases of large tumours affecting facial nerve function 3.2.6.2.2.8 Therapy 3.2.6.2.2.8.1 Conservative Treatment

• Observation with serial imaging in older patients as well as in “incidentalomas”

Acoustic neurinomas Glomus tumour Chordoma Epidermoid Extra-axial metastasis

Depending on the WHO grade, benign meningiomas recur in 7–20% of cases, atypical meningiomas (grade II) in about 33% and anaplastic tumours graded WHO III in about 60–80% of all cases. Histological subtyping (meningothelial, fibroblastic, transitional etc.) plays no major role in the prognosis. Patients harbouring malignant meningiomas with brain invasion have short survival times down to only 2years. 3.2.6.2.2.11 Surgical Principles 3.2.6.2.2.11.1 Suboccipital Retro-Mastoid Craniotomy

• A retro-mastoid linear skin incision is made, and a craniotomy is performed, extending laterally to the sigmoid sinus and cranially to the transverse sinus. The dura is opened microsurgically, avoiding sinus lesions. The cerebellar hemisphere is protected with cotton or cellulose net (e. g. Tabotamp®), the arachnoid cisterns are opened, and in large tumours it may be necessary to open the cisterna magna. The PICA, AICA, internal auditory artery (IAA) and cranial nerves can usually be easily identified. • The posterior tumour capsule between cranial nerve groups is opened, the petrosal and other veins are protected, and cerebellar retraction is avoided if possible. The arachnoid membranes on cerebellum and brain stem are preserved. • The tumour is removed piecemeal without bipolar coagulation; the bleeding will stop when the tumour has been removed. Meticulous haemostasis, irrigation and functional control of the cranial nerves are ensured by monitoring. If feasible, the dural attachment of the tumour should be removed, and if necessary a dural graft with watertight closure with running sutures should be performed. Otherwise there will be coagulation of the tumourous dural attachment. 3.2.6.2.2.11.2 Technique

• Rigid fixation in a Mayfield clamp • Continuous facial EMG monitoring (m. orbicularis oculi, m. orbicularis ori) • Continuous acoustic evoked potential registration

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• Suboccipital retro-mastoid craniotomy extending to the sigmoid sinus • Wax mastoid cells to avoid a CSF leak, wax emissary veins to avoid air embolism • Avoidance of cerebellar retraction by CSF release • Avoidance of bipolar coagulation close to the cranial nerves and meatus • Identification of all cranial nerves • Piecemeal removal of the tumour without any traction on the nerve • Watertight closure of the dura with a dural graft • Reinsertion of the bone flap 3.2.6.2.2.11.3 Useful Additional Therapeutic Considerations

• Precordial or trans-oesophageal ultrasound to detect air embolism • Palacos® closure of the bone defect and tight fixation if reinsertion of the original bone flap is impossible 3.2.6.2.2.11.4 Possible Surgical Complications

• • • •

CSF leakage (in approximately 10–15% of cases) Postoperative haemorrhage (approximately 1–2%) Postoperative hydrocephalus (approximately 2–5%) Wound infection (1–2%)

3.2.6.3.2 Aetiology/Epidemiology

Metastases to the brain are the most common intracranial tumours in adults. Twenty to 40% of all cancer patients will develop brain metastases accounting for at least 100,000 to 150,000 new cases per year in Germany. Eighty percent of those will develop metastases to the cerebral hemispheres, 15% to the cerebellum and about 5% to the brain stem. The true incidence may be much higher, as MRI can detect even extremely small metastases with no clinical symptoms and signs. The most common primary tumours are lung (50%), breast (20%), melanoma (10%) and colon carcinoma (5%+). Principally, every malignancy can metastasise to the brain or the meninges. Most patients harbour multiple metastases at the time of the first diagnosis, but solitary metastases may also occur. 3.2.6.3.3 Symptoms

Brain stem tumours may cause cranial nerve signs when small and are generally detected early in the clinical course. Cerebellar tumours may reach a considerable size before becoming symptomatic; they often present with acute signs and symptoms of occlusive hydrocephalus and may require emergency surgery.

3.2.6.2.2.12 Special Remark

The rate of surgical complications may well be higher than the published figures, even in the most experienced hands. Complications such as CSF leakage are common [9]. Stereotactic radiosurgery is an option in recurrent or residual tumours, but not in primary cases as the tumours are usually too large.

3.2.6.3.4 Clinical Course

3.2.6.3

• Careful medical history including previous cancer treatment • Neurological examination including long fibre tracts • Cranial nerve function (II–XII) • Magnetic resonance imaging • CT using the bone window technique in cases involving bone • Trans-oesophageal ultrasound to detect a patent oval foramen if surgery in the sitting position is planned (large tumours) • Blood count, clotting times, electrolytes, liver function tests, creatinine, electrocardiography

The clinical course of metastatic disease to the posterior fossa is always devastating. 3.2.6.3.5 Diagnostic Procedures 3.2.6.3.5.1 Recommended European Standard

Metastases

Jürgen Kiwit 3.2.6.3.1 Definition

Metastases of the posterior fossa are neoplasms that originate in tissues outside the central nervous system and then spread to the cerebellar hemispheres, the brain stem or the subarachnoid space. In solitary lesions, such tumours should not be automatically diagnosed as metastases only because the patient is harbouring a malignancy. Appropriate treatment of curable benign tumours may be missed. In contrast, multiple posterior fossa lesions in widespread metastatic disease can usually be assumed to be of cancerous origin. In general, patients with metastatic disease to the posterior fossa have a very bad clinical prognosis with survival of only a few weeks or months.

3.2.6.3.5.2 Additional Useful Diagnostic Procedures

3.2.6 Infratentorial Brain Tumours in Adults

3.2.6.3.6 Therapy 3.2.6.3.6.1 Conservative Treatment

• Radiosurgical treatment (e. g. Gamma Knife®) with up to 20Gy is the treatment of choice for single brain stem metastases [2] • Whole brain radiotherapy (WBRT) using a fractionated technique • Dexamethasone (3 × 8 mg daily), tapering according to clinical status 3.2.6.3.6.2 Surgical Treatment

• Suboccipital craniotomy and tumour removal 3.2.6.3.7 Differential Diagnosis

In widespread metastatic disease and multiple posterior fossa lesions diagnosis of cerebellar/brain stem metastasis might be assumed. In solitary lesions stereotactic biopsy or removal should be considered. • Neuroectodermal tumours • Lymphoma • Cerebellar or brain stem abscess 3.2.6.3.8 Prognosis

The tumour control rate after radiosurgery is about 90%, but survival is no more than 10months after treatment. Even aggressive multimodal therapy, including surgery, stereotactic radiation and WBRT does not lengthen survival by more than 13months [5].

3.2.6.3.9 Surgical Principles 3.2.6.3.9.1 Suboccipital Craniotomy

• A midline linear skin incision is made, and a large craniotomy is performed, extending laterally to the sigmoid sinus and cranially to the transverse sinus. In small cerebellar metastases a unilateral suboccipital craniectomy is carried out. If possible, retain the bone flap for reinsertion. The dura is opened microsurgically. In the midline (cerebellar vermis or ventricular) approach, incise bilaterally the suboccipital midline sinus and carefully ligate the sinus. The cerebellar hemispheres are protected with cotton or cellulose net (e. g. Tabotamp®). It may be necessary to opening the cisterna magna. Microsurgical removal of metastases is usually not very demanding and technically quite easy (Fig.3.2.72). 3.2.6.3.9.2 Technique

• Rigid fixation in a Mayfield clamp • Continuous MEP and SEP monitoring in cases involving the ventricular floor • Wax the emissary veins to avoid an air embolism • Watertight closure of the dura with a dural graft 3.2.6.3.9.3 Useful Additional Therapeutic Considerations

• Precordial or trans-oesophageal ultrasound can be used to detect an air embolism in the sitting position • Palacos® closure of the bone defect and tight fixation if reinsertion of the original bone flap is not feasible

Fig. 3.2.72 a Left solitary cerebellar metastasis of lung cancer on coronal contrast-enhanced MRI. b Left solitary cerebellar metastasis of lung cancer on coronal contrast-enhanced MRI after removal

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3.2.6.3.9.4 Possible Surgical Complications

• • • •

CSF leakage (in approximately 10% of cases) Postoperative haemorrhage (approximately 1–2%) Postoperative hydrocephalus (1–3%) Wound infection (1–5%)

around osteoligamentous elements achieving the mobility as well as the stability of the junction between the head and the neck. Pathological changes affecting this region are various and numerous. Their treatment is often challenging. The goal must be as radical a treatment as possible with preservation or restoration of CCJ stability.

Selected Reading 3.2.6.4.1 1. Anderson TD, Loevner LA, Bigelow DC, Mirza N (2000) Prevalence of unsuspected acoustic neuroma found by magnetic resonance imaging. Otolaryngol Head Neck Surg 122:643–646 2. Fuentes S, Delsanti C, Metellus P, Peragut JC, Grisoli F, Regis J (2006) Brainstem metastases: management using gamma knife radiosurgery. Neurosurgery 58:37–42 3. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003 4. House J W, Brackmann D E (1985) Facial nerve grading system. Otolaryngol Head Neck Surg 93:184–193 5. Kanner AA, Suh JH, Siomin VE, Lee SY, Barnett GH, Vogelbaum MA (2003) Posterior fossa metastases: aggressive treatment improves survival. Stereotact Funct Neurosurg 81:18–23 6. Kleihues P, Cavenee WK (eds) (2000) Pathology and genetics of tumours of the nervous system. International Agency for Research on Cancer, Lyon 7. Koos WT, Day JD, Matula C, Levy DI (1998) Neurotopographic considerations in the microsurgical treatment of small acoustic neurinomas. J Neurosurg 88:506–512 8. Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM, Pastorino S, Purow BW, Christopher N, Zhang W, Park JK, Fine HA (2006) Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum cultured cell lines. Cancer Cell 9:391–403 9. Roberti F, Sekhar LN, Kalavakonda C, Wright DC (2001) Posterior fossa meningiomas: surgical experience in 161 cases. Surg Neurol 56:8–20 10. Sharma MK, Mansur DB, Reifenberger G, Perry A, Leonard JR, Aldape KD, Albin MG, Emnett RJ, Loeser S, Watson MA, Nagarajan R, Gutmann DH (2007) Distinct genetic signatures among pilocytic astrocytomas relate to their brain region origin. Cancer Res 67:890–900

3.2.6.4

Pathologies of the Cranio-Cervical Junction

Bernard George The cranio-cervical junction (CCJ) is a complex region with many important neurovascular structures in and

Definition

The CCJ includes: • The lower part of the intracranial cavity with the lower third of the clivus, occipital condyle and posterior margin of the foramen magnum (occipital bone) • The upper part of the cervical spine with the atlas and odontoid. The inferior limits are the body, laminae, and spinous process of C2. 3.2.6.4.2 Anatomy

The CCJ is embryologically made from multiple segments of ossification, some of which connect together [8]. In fact, the upper part with the lower clivus and condyle corresponds to a piece of spine rather than to a piece of the skull. It can be named C0. It is important to realize that the first two joints, C0–C1 and C1–C2, are much more anteriorly located than the lower cervical joints (C3–C7). In fact, they are almost entirely located before the neuraxis on the side of the odontoid. Therefore, the CCJ has two main walls: • The anterior wall with the clivus, the anterior arch of the atlas and the odontoid. This wall is reached directly via the transoral approach. • The lateral wall with the occipital condyle and lateral mass of the atlas and the two joints C1–C2 and C0–C1. On top of the occipital condyle the jugular tubercle is placed, which is the medial wall of the jugular foramen. This lateral wall is directly reached via the lateral approach (Figs. 3.2.73, 3.2.74). There is a third wall, the posterior one, which is weak and does not participate in the mobility and stability of the CCJ. It includes the squama of the occipital bone and the posterior arch of the atlas. It is reached via the standard posterior midline approach and can be removed without almost any consequences. The anterior midline (transoral) approach, as well as the posterior midline approach, has the same lateral limits, which are the vertebral arteries. As a consequence of this anatomical presentation, there is no intervertebral foramen and the C1 and C2 nerve roots merge behind the joints (and not in front as is the case lower in the neck). Thus, there is a wide free space lateral to the neuraxis behind the joints. Anatomical relations between the bony structures are in fact modified during head movements, especially the rotation. During head rotation, the atlas follows the

3.2.6 Infratentorial Brain Tumours in Adults

head movement and the C0–C1 joint does not participate. On the contrary, the axis does not follow the head, which rotates around the axis of the odontoid process and the C1–C2 joint moves a great deal. The vertebral artery (VA), which runs along the C1–C2 joint, is stretched on one side and compressed on the other. This is important to understand with regard to two occurrences: • Positioning of the patient for surgery • Intermittent compression of the VA, generally during rotation (Bow Hunter’s syndrome). Many variations and congenital anomalies can be observed at this level. The most common types may involve the bone: fusion of different, normally separate pieces and a supplementary piece of bone. The VA may also be the site of anomalies. Besides the variation in diameter with a dominant VA on one side and a minor (hypoplastic or atretic) VA on the other side (40%), a duplication with an

intradural course of the VA, a persistent congenital anastomosis with the carotid artery (pro-atlantal artery) and an extracranial origin of the posterior inferior cerebellar artery (PICA) are most commonly observed. Calcification or ossification of the atlanto-occipital membranes sometimes turns the groove of the VA on the posterior arch of the atlas into a tunnel and makes VA exposure more difficult. 3.2.6.4.3 Pathologies

Different pathologies may involve different structures. Excluding intra-axial lesions, pathologies may develop into either the intradural or the extradural space and the bony structures. They may be of different types [6, 7]: • Vascular: essentially aneurysm of the VA or the PICA, or much more rarely, dural arteriovenous fistulas. The

1 2 a

Fig.3.2.73a,b Coronal a MRI and b CT showing the lateral wall of the CCJ with: 1 atlas; 2 axis; O occipital condyle; T jugular tubercle; star internal jugular vein above and below the transverse process of C1; arrow vertebral artery

Fig.3.2.74 a 3D CT showing the location of the C0–C1 and C1–C2 joints (circles) and of the C3–C4 and C4–C5 joints (stars). b Angio-CT showing the course of the vertebral artery around the C0–C1 joint. c Axial MRI showing the limit of the vertebral artery groove (arrow)

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control of VA branches supplying highly vascularized tumors, especially glomus jugulare tumors, and revascularization of the distal VA in some cases of proximal occlusion, must also be considered in the vascular field. • Inflammatory and infectious: tuberculosis and rheumatoid arthritis are commonly observed at the CCJ level. They may have the features of pseudotumors, with cysts or a pannus compressing the neuraxis. • Degenerative: spondylosis of the C0–C1 or the C1–C2 joint is not frequent. The main problem for degenerative as well as for some inflammatory processes is to distinguish them from real tumors, so that aggressive surgical resection is adequately proposed. • Malformative: the CCJ is the site of many different bony malformations, sometimes associated with malformations of the nervous system (Chiari malformation, syringomyelia). All these pathologies may simulate a tumor producing symptoms related to permanent or intermittent compression of the nervous or vascular structures and present features of pseudotumors on imaging studies. Carrying out a biopsy before deciding on surgical resection is sometimes a good option. Tumors at the CCJ level are most commonly meningiomas for intradural ones and chordomas for those involving the bone or the extradural space (Tables3.2.11, 3.2.12). Intradural tumors to which the name foramen magnum tumors is generally given mostly include meningiomas and neurinomas. In fact, these tumors may also be partially or totally extradural. This is rarely observed for meningioma (10% and 3% respectively); it is more frequent in cases of neurinomas (49% and 37%). Besides these two main types of tumors, intradural extra-axial tumors may be hemangioblastomas, epidermoid cysts or ependymomas. Extradural tumors are mostly represented by bone tumors. If metastasis is excluded, chordomas are most frequently observed. Then primary bone tumors may be of different types, including for the most frequent ones, osteoid osteomas, aneurysmal cysts and plasmocytomas [1]. Chordomas are often located on the midline, but frequently extend laterally and even sometimes bilaterally [3]; therefore, requiring combined or staged surgical approaches (Tables3.2.11, 3.2.12) All these pathologies may require surgical treatment for two main reasons • Decompression of the nervous parenchyma (upper spinal cord, medulla oblongata, and lower cranial nerves) or much more rarely of the VA. • Instability of the CCJ. Sometimes the two factors are simultaneously observed and need to define a particular strategy in one or several surgical stages with one or several combined approaches.

3.2.6.4.4 Surgical Approaches

When dealing with a CCJ pathology, the surgeon must be able to apply any of all the main surgical approaches leading to the CCJ.

Table 3.2.11 Tumors of the cranio-cervical junction area. Personal series (Hopital Lariboisière, 2006) Intradural Meningioma

Extradural 104

Meningioma

Neurinoma

Others

Chordoma

Sarcoma

Pseudotumors

Metastasis

Osteoid osteoma Others

7 28

Table3.2.12 List of the main pathologies involving the bony structures of the cranio-cervical junction level * Neoplastic • Benign: – Aneurysmal cyst – Fibrous dysplasia – Osteoid osteoma – Osteoblastoma – Giant cell tumor – Histiocystosis – Osteochondroma

• Malignant: – Plasmocytoma – Metastasis – Hodgkin’s – Chordoma – Chondrosarcoma

* Developmental and acquired • Infections: • Metabolic: – Tuberculosis – Morquio’s syndrome • Inflammatory: • Genetic: – Rheumatoid arthritis – Down’s syndrome – Ankylosing spondylitis, – Osteogenesis psoriasis imperfecta – Sclerodermia – Achondroplasia – Synovial cyst – Neurofibromatosis – Amylosis * Congenital • • • • • • • •

Clivus segmentation Proatlas remnant Condylar invagin*tion Condylar hypoplasia Atlas assimilation or fusion Axis fusion Odontoid hypoplasia Ossiculum terminale

3.2.6 Infratentorial Brain Tumours in Adults

3.2.6.4.4.1 Anterior Approaches

The CCJ has an anterior wall that can be reached via the transoral approach. This approach, with all its variations (upper extension with transpalatal splitting and the transmaxillary combined Le Fort approach, and lower extension with the transglossal and transmandibular approaches) is useful for any midline lesion located before or in this anterior bony wall [4, 9]. It is a straightforward approach, deep, and therefore needs long instruments, but with no structures on the way; only the mucosa and prevertebral muscles have to be divided and laterally retracted. It has lateral limitations with the two VAs and for the upper opening, the jugular veins and internal carotid arteries (ICAs). It is certainly not indicated for lesions located behind the anterior bony wall and moreover for intradural lesions. In fact, to reach these lesions via the transoral approach, it is necessary to destroy the anterior bony wall, thus creating a previously non-existent instability. This problem can be avoided using lateral approaches. Then, closure of the dura is often difficult to achieve, with a high risk of CSF leak and meningitis. 3.2.6.4.4.2 Posterior Approaches

The posterior wall is rather weak compared with the anterior and lateral ones. It has little importance in CCJ instability. The direct route to this wall is the standard posterior midline approach, very well known by every neurosurgeon. It leads directly to the posterior midline of the CCJ area by splitting in between the two parts of the posterior cervical muscles dividing the avascular midline. It may be used for any extra- or intradural midline posterior lesion. It is limited laterally by the end of the VA groove in the posterior arch of the atlas and anteriorly by the neuraxis. 3.2.6.4.4.3 Lateral Approaches

The lateral wall of the CCJ consists mainly of the two joints, C0–C1 and C1–C2. It is in fact an anterolateral wall, since the line of these joints is at the level of the C2 vertebral body. There is no pedicle and no intervertebral foramen at the CCJ level; the C1 and C2 spinal nerve roots merge posterior to the joints, while lower spinal nerve roots merge anterior to them. Therefore, lateral approaches are directed to these joints, either turning around the posterior aspect of them (the posterolateral approach) or going straight to them (the anterolateral approach) [2, 5–7]. The posterolateral approach (Fig. 3.2.75) is in fact the lateral extent of the midline posterior approach, so that the VA groove is exposed and the resection of the occipital bone and posterior arch of the atlas reaches the posterior aspect of the occipital condyle and lateral mass of the atlas. The patient’s position can be sitting, prone or lateral; the skin incision is either vertical on the midline and curved at the occipital protuberance down to the

mastoid process, or oblique vertical from the top of the ear toward the posterior midline at the C5–C6 level. The bone is exposed subperiosteally so as to keep intact the periosteal sheath surrounding the VA. Then the bone can be safely removed above and/or below the VA. Following the course of the VA, the surgeon may penetrate into the subarachnoid space at the foramen magnum, first along the lateral aspect and then the anterior aspect of the medulla oblongata (MO). These spaces lateral and anterior to the MO are generally enlarged owing to tumoral development, making it still easier to access them. This posterolateral approach is therefore essentially designed for intradural tumors or for extradural pathologies that have developed behind the lateral wall of the CCJ. The lateral opening is extended toward this lateral wall, especially in cases of lesions anterior to the neuraxis. However, it is the exception that some drilling of the lateral mass of the atlas and/or of the occipital condyles has to be done. The anterolateral approach (Fig. 3.2.76) is similar to that used lower in the neck to expose the transverse processes and the VA. At the CCJ level the anterolateral approach goes to the C1 and C2 transverse processes and to the suboccipital (V3) VA segment. The field is opened between the medial aspect of the sterno-mastoid muscle (SM) and the lateral edge of the internal jugular vein. To get more space it is often useful to detach the SM and occasionally the posterior cervical muscles from the occipital bone. For this, the patient is in the supine position with the head slightly extended and rotated toward the opposite side. The skin incision follows the upper 10cm of the medial limit of the SM up to the tip of the mastoid process, then follows the mastoid process and the superior occipital crest toward the occipital protuberance. Once the field between the SM and the internal jugular vein is opened the accessory nerve (CN XI) must be identified and dissected, then retracted inferiorly with the fat pad covering the depth of the field. The transverse process of the atlas can be palpated 15mm below and before the tip of the mastoid process. It is freed from all the small muscles attached to it, thus providing a view of the C1–C2 and above C1 segments of the VA with the posterior arch of the atlas interposed between them. Transposition of the VA out of the transverse foramen permits exposure of the CCJ lateral wall with the two joints C0–C1 and C1–C2. More rotation of the head contralaterally brings the posterior part of the atlas and CCJ into view, while less rotation permits running in front of the joints and reaching the anterior wall of the CCJ (anterior arch of the atlas, the vertebral body of C2 and the odontoid process). This approach can be extended as necessary inferiorly to lower levels in the neck as the same anterolateral approach permits exposure and control of the entire cervical spine. It can also be extended superiorly to the jugular

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C1 C2

S T O

A b

* 2

Fig.3.2.75 a Schematic drawing of the skin incision and opening of the posterolateral approach (top). Operative view (bottom) of the posterolateral approach. The arrow indicates the midline. Star vertebral artery; M mastoid process; C2 lamina of C2; C1 posterior arch of the atlas. b Schematic drawing and

operative view of the posterolateral approach after bone resection (occipital bone and posterior arch of the atlas). 2 lamina of C2; A lateral mass of the atlas; star vertebral artery; O occipital condyle; T jugular tubercle; S sigmoid sinus

3.2.6 Infratentorial Brain Tumours in Adults

Fig.3.2.76 a Schematic drawing; b cadaver dissection and c operative view of the anterolateral approach with exposure of the jugular foramen. V internal jugular vein; G jugular gulf; S sigmoid sinus; star vertebral artery; N accessory nerve; D dura of the lateral posterior fossa

G D

N b

foramen and the posterior fossa. In this case a complementary opening of the posterior fossa via a retro-sigmoid approach is realized. The last possible extension is toward the petrous bone above the jugular foramen. This may be necessary in large tumors of this region, such as paragangliomas. Most of the time, the anterolateral approach is applied for tumors invading the bony elements of the anterior and lateral wall. It means that CCJ stability is already compromised and will be even more impaired after surgery; therefore, a stabilization procedure generally needs to be considered in the management of these patients, either in the same surgical stage or in a separate one. Circ*mstances must be quite exceptional to make a patient unstable who is preoperatively stable. It generally means that something was wrong in the strategy and the chosen surgical approach was not appropriate. Morbidity related to the exposure should be minimal. VA injury should remain the exception. If there is any reason to think that it may occur, the VA size should be considered: minor VA can be sacrificed without any consequences; equal or dominant VA should be tested by preoperative balloon occlusion. If the choice is to

include the ligation of the VA in the surgical planning (for instance to achieve a more radical tumoral resection) revascularization (saphenous vein bypass from the carotid artery) has to be considered in case of balloon occlusion test failure. Another morbidity may be related to damage of the accessory nerve (CN XI), especially owing to retraction of the SM muscle being too hard. At this level, a lesion to the sympathetic trunk very rarely leads to Horner’s syndrome. Morbidity in relation to the injury of other nerves (CN IX,X, XII) may be due to tumor resection, but not to exposure of the CCJ. Selected Reading 1. Bruneau M, Cornelius JF, George B (2005) Osteoid osteomas and osteoblastomas of the occipito-cervical junction. Spine 30:E567–571 2. Bruneau M, Cornelius JF, George B (2006) Anterolateral approach to the V3 segment of the vertebral artery. Neurosurgery 58:29–35

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3. Carpentier A, Polivka M, Blanquet A, George B (2002) Suboccipital and cervical chordomas. The value of aggressive treatment at first presentation. J Neurosurg 97:1070–1077 4. Crockard HA, Johnston F (1993) Development of transoral approaches to lesions of the skull base and craniovertebral junction. Neurosurg Quart 3:61–82 5. George B, Carpentier A (2001) Compression of and by the vertebral artery. In: Spetzler R (ed) Operative techniques in neurosurgery, vol 4. Saunders, Orlando, pp 202–218 6. George B, Blanquet A, Alves O (2002) The V3 segment of the vertebral artery. Surgery around the craniocervical junction. In: Spetzler R (ed) Operative techniques in neurosurgery, vol 5. Saunders, Orlando, pp 50–74 7. George B (2002) Extracranial vertebral artery anatomy and surgery. In: Pickard JD (ed) Advances and technical standards in neurosurgery, vol 27. Springer, Vienna, pp 179–211 8. Menezes AH (1998) Embryology, development and classification of disorders of the craniovertebral junction. In: Dickmans CA, Spetlez RF, Sonttag VKH (eds) Surgery of the craniovertebral junction. Thieme, New York, pp 3–12 9. Menezes AH, Van Gilder JC, Graf CJ, McDonnell DE (1980) Craniocervical abnormalities. A comprehensive surgical approach. J Neurosurg 63:444–455

3.2.7

Tumor of the Orbit

Werner-Erwin Hassler, Uta Schick 3.2.7.1

Introduction

A broad variety of tumors and pseudotumors can involve the small, well-defined orbit. Two-thirds of the lesions are benign and one-third are malignant. The proportion of malignant tumors is inverse to age due to the higher incidence of orbital metastases and lymphomas. In childhood more dermoid cysts and orbital capillary hemangiomas are seen. Neurosurgeons encounter more neural tumors such as meningiomas and optic pathway gliomas, ENT or head and neck surgeons more secondary lesions such as mucoceles and paranasal sinus neoplasms. Ophthalmologists experience a greater incidence of thyroidrelated orbitopathies and inflammatory pseudotumors. Only a few specialized centers have an overview of the broad variety of these rare lesions and possible minimally invasive surgical approaches. 3.2.7.2

Symptoms

• Proptosis • Visual field defect/loss of visual acuity • Diplopia, strabism

92% 74% 66%

• Pain • Lacrimation • Conjunctival edema

34% 23% 22%

Proptosis can be caused by any type of orbital process. Visual acuity is often reduced by malignant and inflammatory/infectious processes (79%), as well as by optic nerve gliomas (67%); it is less commonly reduced by meningiomas (45%). Pain is a prominent feature of inflammatory/infectious disorders (96%) and meningiomas (70%). The mean duration of symptoms before diagnosis is 4.2 months for malignant tumors, 15 months for gliomas, and 28 months for meningiomas. The mean age at manifestation is 19 years for optic gliomas, which is considerably lower than for schwannomas (42 years) or meningiomas (54 years). 3.2.7.3

Topographical Distribution

• Intraconal (optic nerve): optic nerve glioma, optic nerve sheath meningioma • Intraconal: cavernoma, schwannoma, metastases, lymphoma, lymphangioma • Extraconal: dermoid cyst, pleomorphic adenoma of the lacrimal gland, pseudotumor • Subperiosteal: mucocele • Sphenoid wing, bony orbit: meningioma, osteoma, malignant tumor, fibrous dysplasia • Orbital apex, superior orbital fissure, cavernous sinus: meningioma, cavernoma • Lacrimal gland, duct system: pleomorphic adenoma, carcinoma • Muscles: endocrine orbitopathy, rhabdomyosarcoma • Preseptal, lids: lymphomas, infections, lipoma The intraconal space is delimited by the conus, which connects the four rectus muscles to each other. The extraconal compartment surrounds the muscular conus like a tube. The subperiosteal compartment is defined as the space between the periosteum and the bony orbit. 3.2.7.4

Histology

3.2.7.4.1 Meningioma

The most common orbital tumor is a meningioma arising from the medial portion of the sphenoid wing, the anterior clinoid process, or the optic nerve sheath. They manifest themselves with gradual loss of visual acuity, accompanied by optic nerve atrophy or proptosis. The peak incidence is between the ages of 30 and 50. Patients with optic nerve sheath meningiomas should undergo

3.2.7 Tumor of the Orbit

decompression of the optic canal, intracranial tumor resection, and postoperative irradiation of the intraorbital part. The goals of surgery for spheno-orbital meningiomas are good cosmetic and functional results, good tumor control, and minimal morbidity. Aggressive resection in the cavernous sinus and superior orbital fissure is not recommended. Surgery should be performed as early and as radically as possible. Radiotherapy is an option for recurrences or subtotal resections.

3.2.7.4.4 Schwannoma

3.2.7.4.2 Vascular Lesions

3.2.7.4.6 Pleomorphic Adenoma

We distinguish between three types of hemodynamics. Most common are arteriovenous malformations characterized by direct low flow, such as cavernous hemangiomas, and treated by complete excision. Patients with capillary hemangiomas undergo spontaneous regression. Surgery is appropriate in well-circ*mscribed lesions. Direct antigrade high-flow lesions like AVMs are rare; patients undergo combined endovascular and surgical treatment. Venous flow lesions appear as distensible lesion with rich communication or nondistensible anomalies. Deep venous lesions should be treated if they cause severe pain, cosmetic disturbances or visual deterioration. No-flow lesions have little connection to the vascular system and include lymphangiomas or combined venous lymphatic malformations. Surgery may be helpful in distinct cases with intracystic hemorrhage. Hemangiopericytoma is a rare vascular wall tumor of adulthood. It behaves rather aggressively, is locally invasive, and undergoes malignant degeneration in 30% of cases, possibly triggering distant metastases. The prognosis is good as long as the tumor is diagnosed early and completely resected.

Schwannoma tends to develop on the sensory branches of peripheral nerves. This type of tumor is cured by complete surgical resection (Fig.3.2.77). 3.2.7.4.5 Fibrous Dysplasia

Fibrous dysplasia involves the bone of the optic canal and orbital roof. Decompression of the optic canal may be indicated.

Pleomorphic adenoma is the most common tumor of the lacrimal gland, and can be cured by total resection. Rupture of the capsule should be avoided. 3.2.7.4.7 Rhabdomyosarcoma

Rhabdomyosarcoma is the most common malignant orbital tumor in the first decade, is usually extraconal in the superior nasal quadrant, and may involve the conjunctiva, uvea, and the lid. This tumor has the best prognosis among all locations (3-year recurrence-free survival rate: 91%). Anteriorly located rhabdomyosarcoma can be completely resected; posteriorly situated ones are biopsied and then treated with combined radio- and chemotherapy. 3.2.7.4.8 Adenoid Cystic Carcinoma

Adenoid cystic carcinoma carries a poor prognosis and produces distant metastases and local recurrence. Treatment entails enucleation of the globe or brachytherapy.

3.2.7.4.3 Optic Nerve Glioma

Pilocytic astrocytoma usually arises in childhood, particularly in children with neurofibromatosis. The initial manifestation is usually visual impairment, in small children strabismus or nystagmus. Intraorbital tumors without useful vision or severe proptosis should be operated with transsection of the optic nerve just behind the globe and prechiasmatic transsection. Patients with intracranial tumors, involving the optic chiasm and hypothalamus, undergo subtotal resection, followed by chemotherapy in children below the age of 5years, external beam radiation or seed implantation in those over 5. Fig. 3.2.77 Axial enhanced MRI displays a medially located schwannoma with lateral displacement of the optic nerve

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3.2.7.4.9 Metastases

The primary tumor can be located in the breast, lung, prostate, GIT or kidney. Diplopia and pain are the main symptoms, and there is a short duration of symptoms until diagnosis. Treatment is palliative, as survival is poor. Confirmation by biopsy is required. 3.2.7.4.10 Lymphoma

Most are EMZL (extranodal marginal zone lymphoma) and have a good prognosis with biopsy and radiotherapy. DLCL (diffuse large cell lymphoma) is the least favorable type, and can be treated with chemotherapy. Twenty percent of EMZL and 50% of DLCL become systemic. 3.2.7.4.11 Dermoid Cysts

Fig. 3.2.78 Intraoperative view of the transconjunctival approach creating a corneal flap

3.2.7.5

3.2.7.6

Dermoid cysts are of congenital origin. Complete removal is required, otherwise recurrence is likely. Operative Approaches

The choice of approach depends on the location, size, demarcation, and histological type of the lesion (Fig.3.2.78, Table3.2.13). The least atraumatic approach should be chosen. In general, we distinguish between two types of approaches: transcranial or directly extracranial. Today, the transcranial approach is no longer used in most cases.

European Recommendations

Any patient with visual loss, proptosis, or impaired ocular motility should undergo MRI to detect or exclude an intraorbital or intracranial process. Patients found to have one of these rare tumors should be referred to a specialized center for further treatment. Collaboration across specialties, including ENT, maxillofacial surgery, ophthalmology, and neurosurgery, improves the chances of successful treatment.

Table3.2.13 Approaches to the orbit Approach

Indications

Advantages

Disadvantages

Lateral orbitotomy

Intra- and extraconal tumors, lateral and basal to the optic nerve; orbital apex, lacrimal gland tumors

Good exposure, well-tolerated procedure

Visible but minimal scar

Transethmoidal

Extraconal tumors medial to the optic nerve, traumatic injury of the optic canal

Well tolerated, usually used by ENT surgeons, no brain retraction

Limited exposure, approach through unsterile sinuses, more bleeding

Frontal transsinusoidal

Tumors or trauma of the frontal sinus, retention cysts, extraconal processes

Minimally invasive, particularly Visible scarring, risk for retention cysts of infection, limited indications

Transmaxillary

Basal lesions, intra- or (preferably) extraconal, contraction of the maxillary sinus

Well-tolerated, performed in collaboration with ENT surgeons

Limited exposure, hemorrhage, approach through unsterile sinuses

Transconjunctival

Basal, medial intra- and extraconal tumors, biopsy of intraconal processes

Minimally invasive, ideal for cavernomas, excellent cosmetic result

Only for highly experienced surgeons (collaboration with ophthalmologists is recommended)

3.2.7 Tumor of the Orbit

Table3.2.13 (continued) Approaches to the orbit Approach

Indications

Advantages

Disadvantages

Supraorbital via eyebrow incision

Well-circ*mscribed intra- and extraconal processes above the optic nerve

Minimally invasive extradural approach with minimal manipulation of the orbital structures and brain, no limitation of size, excellent cosmetic result

Hypesthesia for 8months (supraorbital nerve)

Subfrontal

Intraorbital optic nerve glioma, Good general exposure growing into the cranial cavity, lateral tumors of the optic nerve

Fronto-lateral, pterional Ideal approach for tumors of the superior orbital fissure, optic canal, orbital apex, and intraorbital optic nerve; tumors located dorsal to the optic nerve; and lateral extra- and intraconal tumors

Traumatizing approach, requiring brain retraction

Broad exposure, minimal No disadvantages brain retraction, good access to the extra- and intradural and intraorbital compartments

Pterional-extradural

Ideal for decompression Well-tolerated, no brain of the optic nerve in the optic retraction, clear exposure canal, suitable for periorbital tumors and for tumors near the superior and inferior orbital fissures and the cavernous sinus

Detailed anatomical knowledge is essential

Pterional-contralateral

Tumors of the medial orbital apex, aneurysms of the ophthalmic artery

Difficult without navigation, injury to the olfactory nerve is possible, may involve extensive brain retraction

Direct approach to medial processes

Acknowledgments We thank Prof. Brassel, Neuroradiology, for the neuro imaging. Selected Reading 1. Christ WM, Anderson JR, Meza JL, Fryer C, Raney RB, Ruyman FB, Breneman J et al. (2001) Intergroup rhabdomyosarcoma study IV: results for patients with nonmetastatic disease. J Clin Oncol 19:3091–3102 2. De Jesús O, Toledo MM (2001) Surgical management of meningioma en plaque of the sphenoid ridge. Surg Neurol 55:265–269 3. Gunalp I, Gunduz K (1995) Pediatric orbital tumors in Turkey. Ophthal Plast Reconstr Surg 11:193–199 4. Gunalp I, Gunduz K (1995) Vascular tumors of the orbit. Doc Ophthalmol 89:337–345 5. Hassler WE, Eggert H (1985) Extradural and intradural microsurgical approaches to lesions of the optic canal and the superior orbital fissure. Acta Neurochir (Wien) 74:87–93

6. Hejazi N, Hassler W, Farghaly F (1999) Transconjunctival microsurgical approach to the orbit: a retrospective preliminary review and analysis of experience with the first 15 operative cases. Neurosurg Quart 9:197–208 7. Lee S, Suh CO, Kim GE, Yang WI, Lee SY, Hahn JS, Park JO (2002) Role of radiotherapy for primary orbital lymphoma. Am J Clin Oncol 25:261–265 8. Maalouf T, Trouchaud-Michaud C, Angioi-Duprez K, George JL (1999) What has become of our idiopathic inflammatory pseudo-tumors of the orbit? Orbit 18:157–166 9. Maroon JC, Kennerdell JS, Vidovich DV, Abla A, Sternau L (1994) Recurrent spheno-orbital meningiomas. J Neurosurg 80:202–208 10. Mauriello JA, Flanagan JC (1990) Orbital inflammatory disease. In: Mauriello JA, Flanagan JC (eds) Management of orbital and ocular adnexal tumors and inflammations. Springer, Berlin Heidelberg New York, pp 19–46 11. Miller NR (2004) Primary tumours of the optic nerve and its sheath. Eye 18:1026–1037 12. Nutting CM, Jenkins CD, Norton AJ, Cree I, Rose GE, Plowman PN (2002) Primary orbital lymphoma. Hematol J 3:14–16

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13. Schick U, Bleyen J, Hassler W (2003) Treatment of orbital schwannomas and neurofibromas. Br J Neurosurg 17:541–545 14. Schick U, Bleyen J, Bani A, Hassler W (2006) Management of meningiomas en plaque of the sphenoid wing. J Neurosurg 104:208–214 15. Schick U, Dott U, Hassler W (2003) Surgical treatment of orbital cavernomas. Surg Neurol 60:234–244 16. Schick U, Dott U, Hassler W (2004) Surgical management of meningiomas involving the optic nerve sheath. J Neurosurg 101:951–959 17. Schick U, Hassler W (2004) Neurosurgical management of orbital inflammations and infections. Acta Neurochir 146:571–580 18. Shields JA, Shields CL, Brotman H, Carvalho C, Perez N, Eagle RC Jr (2001) Cancer metastatic to the orbit. The 2000 Robert M. Curts Lecture. Ophthal Plast Reconstr Surg 17:346–354 19. Shields CL, Shields JA, Carvalho C, Rundle O, Smith AF (2001) Conjunctival lymphoid tumors: clinical analysis of 117 cases and relationship to systemic lymphoma. Ophthalmology 108:979–984 20. Turbin RE, Pokorny K (2004) Diagnosis and treatment of orbital optic nerve sheath meningioma. Cancer Control 11:334–341

3.2.8 Pseudotumour Cerebri

Flemming Gjerris 3.2.8.1

Basics

The clinical syndrome of pseudotumour cerebri (PTC) is described by many authors, resulting today in the term idiopathic intracranial hypertension (IIH) for pseudotumour cerebri of unknown origin. There is no consensus on classification. Some authors prefer to divide intracranial hypertension into idiopathic (unknown = primary) and secondary intracranial hypertension, others into primary PTC = idiopathic intracranial hypertension and secondary PTC, where the aetiologies are multitudinous [6, 7]. When an aetiology is found, i. e. a drug or a venous sinus anomaly, the correct term is secondary PTC [7, 9]. Studies such as magnetic resonance imaging (MRI), MRCSF flow and cerebrospinal fluid (CSF) dynamics have resulted in a better understanding of the aetiology, pathogenesis and pathophysiology of the disease [9, 11]. 3.2.8.2

Idiopathic Intracranial Hypertension

3.2.8.2.1 Synonyms

Primary pseudotumour cerebri, benign intracranial hypertension, papilloedema of unknown cause.

3.2.8.2.2 Definition

Idiopathic intracranial hypertension is a condition of increased intracranial pressure (ICP) without any clinical, laboratory or radiological evidence of intracranial pathology and a completely normal composition of CSF. It is thus a diagnosis of exclusion and describes today a much more restricted group of patients than previously. The criteria are formulated in the International Headache Society’s classification of headache disorders [14]. 3.2.8.2.3 Epidemiology/Aetiology

The annual incidence of IIH is 1–2/100,000 in the general population with an increase up to 3/100,000 in the age group 15–44 in women. The female:male ratio differs between 4.3:1 and 15:1. It is found in all age groups and especially in obese females of childbearing age. Several studies have attempted to find an existence of proposed associations, but apart from obesity there is no convincing evidence. The different concomitant disorders, which can give a similar clinical picture (secondary PTC) have to be outlined by CT, MRI, MRV, angiography or lumbar puncture before the diagnosis of IIH can be safely proven. Ophthalmologists should always be part of the IIH team. 3.2.8.2.4 Pathogenesis and Pathophysiology

Idiopathic intracranial hypertension may be attributed to intra- and extracellular brain oedema, increased cerebral blood volume or compromised CSF resorption. Indirect evidence of brain oedema has been provided by MR studies showing increased water content and water apparent diffusion coefficients in subcortical white matter, which may result from the convective transependymal flow of water, but a recent study of more refined MR techniques could not reproduce these findings [8, 13]. In PET studies cerebral blood flow and regional cerebral blood volume are normal, even in patients with raised ICP. Idiopathic intracranial hypertension patients do not have increased CSF production. CT and MRI show a normal ventricular size and velocity-sensitive MR techniques demonstrate a normal CSF flow through the cerebral aqueduct. Many studies have demonstrated an increased CSF outflow resistance in 75–100% of IIH patients [9], in patients with Guillain–Barré syndrome or in intradural spinal tumours with a very high CSF protein concentration [11]. It has been proposed, that IIH patients have a defect in CSF resorption at the level of the arachnoid villi or in the capillaries in the brain cortical area, caused by some precipitating factors leading to brain water accumulation and a “stiff brain” or caused by agents or noxious events that might interfere with membrane water resorptive function (aquaporins) and brain water permeability [9]. The raised pressure on the cerebral veins could cause

3.2.8 Pseudotumour Cerebri

cerebral vasodilatation and increased cerebral blood volume, resulting in a further rise in ICP and Rout until the CSF absorptive level is again in equilibrium. Venous sinus hypertension may occasionally be caused by elevated central venous pressure. Obesity correlates directly to elevated central venous pressure and a secondary raised sinus pressure in some adipositas patients, but not in all [3, 6, 13].

3.2.8.2.5.3 Complications

3.2.8.2.5 Symptoms and Signs

3.2.8.3.1.1 Neuroimaging

3.2.8.2.5.1 Symptoms

The symptoms are headache, pulsatile, often reversible tinnitus, nausea, transitory visual obscurations varying from slight blurring to total loss of light perception and double vision. The obscurations are usually related to papilloedema. Nearly 90% of the patients have headache. The headache has an episodic onset and is aggravated in the morning and by physical activity. Obesity is seen, especially in young females, often with a significant weight gain 6–12 months prior to the symptoms of increased ICP. Less common symptoms are dizziness, vomiting and paraesthesia in the hands and feet. 3.2.8.2.5.2 Signs

No focal neurological signs except for those attributable to increased ICP, i. e. papilloedema, sixth nerve palsy and enlarged blind spots are found at the time of admission. Papilloedema is usually bilateral with blurring of the disc, diminished venous pulsation, protrusion of the optic disc and peripapillary haemorrhages or exudates. Early papilloedema is usually associated with normal visual acuity, although complaints of blurred vision may be present. Rare cases of IIH without papilloedema have been reported. Visual field defects appear in up to 96% of patients during the course of the disease. An enlarged blind spot is the most frequent, found in nearly all IIH patients. Often field defects are arcuate scotomas. Small visual defects are often asymptomatic. When the patient becomes aware of a visual problem, the extent of the defect has often evolved. Therefore, routine follow-up of patients with IIH should consist of visual acuity testing combined with visual field examination. The upper limit of the normal CSF opening pressure is defined as 200mm H2O or 15mmHg in the lateral decubitus position. An elevated steady-state ICP has been reported in nearly all IIH patients, but many patients have long periods of normal ICP between short periods of elevated ICP. Abnormal ICP wave-forms are present. Repeated lumbar puncture after previously normal pressure may be necessary. Pressure monitoring for several hours through a lumbar drain or an intracranial transducer is recommended.

In rare cases blindness may occur rapidly within a few days, which is why visual acuity should be monitored carefully when the diagnosis of IIH is established [3, 13]. 3.2.8.3

Diagnostic Procedures

3.2.8.3.1 Recommended European Standard

Computed tomography and MRI show a normal or even diminished ventricular system. MR venography may be necessary to exclude secondary PTC and is normal in IIH. 3.2.8.3.1.2 Cerebrospinal Fluid

The cerebrospinal fluid constituents (protein, sugar, cells, electrolytes) are within the normal ranges. Lumbar puncture should be performed after normal brain imaging and is of no risk in IIH patients. Post-lumbar puncture headache is not very common in IIH patients. Thirty to 120min of lumbar pressure monitoring is necessary and sufficient to reveal an increased steady-state ICP and abnormal pressure waves. Monitoring ICP with an epidural intrathecal or a subdural lumbar transducer for at least 6–24h is occasionally needed. 3.2.8.3.1.3 Ophthalmologic Investigations

Ophthalmoscopy, visual acuity and perimetry are necessary. All IIH patients should undergo regular testing of the visual fields with quantitative or automated perimetry. Fundus photography of the optical discs to follow the appearance over time requires collaboration with a trained ophthalmologist. 3.2.8.3.1.4 Additional/ Useful Diagnostic Procedures

Measurement of Rout by a lumbar computerised infusion method is of considerable diagnostic value and an important parameter in the surveillance of IIH patients [2, 11]. Rout measurements are reliable and can be repeated several times during the course of the disease with a minimum of inconvenience to the patient [11]. Demonstrating increased CSF outflow resistance (> 10mmHg × min × ml-1) with a lumbar infusion test helps to maintain the suspicion that intracranial hypertension exists despite normal CSF opening pressures. 3.2.8.3.2 Diagnosis of IIH

The clue to diagnosis is the history and imaging investigations. An algorithm for diagnosis of IIH is illustrated in Fig.3.2.79. Clinical examination, including a general medical examination as well as thoroughly neurological and ophthalmologic examinations, is mandatory.

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Symptoms of intracranial hypertension: Chronic daily headache Visual disturbances Pulsatile tinnitus Ophthalmoscopic examination Papilledema in a conscious, alert patient with no neurologic signs other than sixth nerve palsy

No papilledema

Differential diagnosis

Sustained clinical suspicion of intracranial hypertension

MRI, MRV Space-occupying lesion or hydrocephalus

Normal Sustained suspicion

Lumbar pressure meassuring > 200 mmH2O*

≤ 200 mmH2O* CSF examination Normal Differential diagnosis

Abnormal Differential diagnosis

CSF examination Normal IIH

Abnormal Differential diagnosis

* 200 mmH2O in the non-obese, 250 mmH2O in the obese

Fig.3.2.79 Algorithm for the diagnosis of idiopathic intracranial hypertension [13]

3.2.8.4

Therapy

3.2.8.4.1 Medical Treatment 3.2.8.4.1.1 Recommended European Standard

Standard treatment consists of carbonic anhydrase inhibitors such as acetazolamide (500–1,500 mg daily), which is very effective in most IIH cases. Side effects such as acroparaesthesias are dose-dependent. Less common are nausea, anorexia, hypokaliaemia and nephrolithiasis. When acetazolamide is insufficient or intolerable the diuretic furosemide (40–120 mg/day) combined with potassium may be considered. The effect is less specific and has only a small effect on CSF production. Repeated lumbar punctures may now be considered as obsolete and are not recommended. 3.2.8.4.1.2 Additional Therapeutic Strategies

Topiramate, a new anticonvulsant, also inhibits carbon anhydrase at clinically relevant doses. A clinical effect in

IIH cases has been reported. The role of corticosteroids in the treatment of IIH is still controversial. Weight loss reduces papilloedema, lowers CSF pressure and may be associated with relapses of IIH. 3.2.8.4.2 Surgical Treatment: Recommended European Standard

A common management error is delaying too long before surgery. Any waiting policy may be erroneous. Active surgical treatment is necessary to treat increased ICP and severe headache (most often CSF shunting) and to avoid permanent visual defects (shunting or optic nerve sheath decompression) [3, 10, 13]. 3.2.8.4.2.1 Shunt Operation

Cerebral spinal fluid shunting is usually effective in IIH, but shunt dysfunctions and infections are significant problems. The lumbo-peritoneal (L-P) shunt has a rather high complication rate, and many authors prefer ventric-

3.2.8 Pseudotumour Cerebri

ulo-peritoneal (V-P) shunting, in spite of the difficulty of cannulating a normal ventricular system [4, 5, 10]. 3.2.8.4.2.2 Optic Nerve Sheath Decompression

Initial improvement or stabilisation of visual function has been reported in many cases, but the postoperative complication rate is rather high, i. e. seizures, infection, focal brain damage, cosmetic disfigurement, visual deterioration. The long-term efficacy is uncertain and outcome reports suggest that optic nerve sheath fenestration may be less effective than CSF shunting. 3.2.8.5

Differential Diagnosis

Idiopathic intracranial hypertension is still a diagnosis of exclusion. Several conditions can present with signs of raised intracranial pressure alone (Table3.2.14). 3.2.8.6

Prognosis

Idiopathic intracranial hypertension is usually a self-limiting disorder with spontaneous remission in some cases. Several follow-up studies show that a few months of medical treatment in a large group of patients will improve the symptoms. Recurrence, even 5–15years after the first attack, is described in up to 10%. A chronic course of IIH with severe headache and visual disturbances for years is not uncommon and constitutes a therapeutic problem. Visual field defects are fairly common and permanent loss of visual function is the most serious complication. Less than 5% develop blindness in one or both eyes, the risk of which is related to duration of papilloedema. In most long-term monitored patients both ICP and Rout decrease or normalise [11]. The few shunted IIH patients also have a good prognosis for both vision and headache [5, 11].

3.2.8.7

Surgical Principles

3.2.8.7.1 Ventriculo-Peritoneal and Lumbo-Peritoneal Shunting 3.2.8.7.1.1 Exposure

The basic steps in a shunting procedure are: • Positioning of the patient • Draping of the operative field • Skin incisions • Head and skull • Insertion of the ventricular catheter • Tunnelling of the dome, valve and the distal catheter to the jaw angle, chest and abdomen • Insertion of the catheter into the peritoneal cavity The different steps of CSF shunting are described in neurosurgical textbooks such as Kay and Black [10], and in a short form here. 3.2.8.7.1.2 Positioning of the Patient

For a V-P shunt the patient is placed supine with the head turned to the left and with a 30° elevation. A fluffy cushion is placed under the neck and the upper part of the elevated right shoulder to flatten out the angle between the head and the chest, so that the subcutaneous tunnelling may be performed more easily. In L-P shunting the patient is placed on the side with free access to both the lumbar spine and the abdominal flank area. 3.2.8.7.1.3 Draping

The skin incisions should be outlined before skin draping. The hair of the skin is cut and not shaved. The skin is washed and prepared with iodine or a similar solution. 3.2.8.7.1.4 Skin Incision

The surgical drapes are placed a few centimetres from the incision sites and should not adhere to any tubes. The skin is then covered with a sticking, preferably iodinated, drapery.

Table 3.2.14 Most common causes of secondary pseudotumour cerebri. (Modified from [13]) Vascular diseases –– Cerebral venous sinus thrombosis –– Arteriovenous malformations CSF hyperviscosity –– Guillain–Barré syndrome –– Intradural or spinal cord tumours Infection –– Syphilis –– Meningitis/encephalitis –– HIV –– Toxicity

Circulatory –– Hypertension –– Congestive heart failure Neoplasms –– Gliomas –– Meningeal carcinomatosis –– Leukaemia –– Intradural spine tumours Others –– Sleep apnoea syndrome –– Respiratory disease with CO2 retention

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3.2.8.7.1.5 Head and Skull

toneum. This is elevated and opened very carefully. The catheter is pushed into the peritoneal cavity with light pressure, often to a length of 20cm. With any hindrance, or if the catheter curls up, it is very important to start afresh. The peritoneum is secured by a purse string suture, and the muscle fascia, subcutis and skin are closed in the usual way.

3.2.8.7.1.6 Insertion of the Ventricular Catheter

3.2.8.7.2 The Lumbo-Peritoneal Shunt

The cranial skin incision is placed 3 cm from the midline, usually 2cm in front of the right coronal suture. The advantages of the frontal region (non-dominant) are that the patient is supine and that the external turning points are clear (Fig.3.2.80). The periosteum is rongeured away, the burr hole made and the dura opened by a small crucial incision. The dural edges are thermocoagulated. The tip of the catheter should be directed to the middle part of the zygoma and in the other plane to the middle part of the nose or the medial corner of the left eye (Fig.3.2.80). The catheter is inserted in the right frontal horn, an approach with many advantages, i. e. short distance through the brain, access to the brain away from eloquent areas and the tip of the catheter far away from the choroid plexus. The ependyma is penetrated with the feeling of slight resistance. The catheter is fixed to the dome part with an angle connector and in some shunt types fixed to the pericranium.

The spine is moderately flexed to open the interlaminar spaces. A special one-piece shunt is used and the lumbar end can be placed using a percutaneous technique or by performing a small open laminectomy. The dome and peritoneal part are tunnelled subcutaneously from the lumbar spinal area to the side of the abdomen and placed in the peritoneal space. 3.2.8.7.3 Optic Nerve Sheath Decompression

The dome and valve are placed on the pericranium of the skull, not on the soft tissue structures of the neck, and allowed to fill with CSF. The CSF flow is tested by lowering the distal end of the tube below the level of the skull. The various skin incisions are closed in two layers.

If medical treatment has failed and disc swelling with visual field loss progresses, direct fenestration of the optic nerve sheaths via a medial or lateral orbitotomy is effective. The surgeon makes slits by cutting into the optic nerve sheath, which allows CSF to escape and thereby reducing the pressure around the optic nerve. The intracranial hypertension presumably persists [1]. Operative details are described in ophthalmologic textbooks.

3.2.8.7.1.8 Insertion of the Catheter in the Peritoneal Cavity

3.2.8.8

3.2.8.7.1.7 The Dome and Valve

The tunnelling of the catheter to the abdomen can be done either from the cranial or from the abdominal end. The abdominal skin incision is made in the midline below the xiphoid process or as a slight curvilinear incision 3cm below and along the curvature. The subcutaneous tissue is divided, the muscle fascia opened sharply and the muscle fibres divided by blunt dissection to the peri-

Pseudotumour Cerebri, Secondary

A pseudotumour, like the clinical picture, is seen in chronic meningo-encephalitis, cerebral sinus thrombosis, intrathoracic lesions, polyradiculitis and spinal cord tumours. Many other causes have been described, often associated with endocrine disorders or the use or cessation of different drugs (Tables 3.2.14, 3.2.15). Extremely

Fig.3.2.80 Directions for the correct placement of a cannula in the right frontal horn. (Modified from [10]; illustrator is consultant Bo Jespersen)

3.2.8 Pseudotumour Cerebri

Table 3.2.15 Proposed aetiological factors of conditions similar to idiopathic intracranial hypertension. (Modified from [13]) Exogenous factors

Endogenous factors

–– Tetracyclines –– Nitrofurantoin –– Nalidixic acid –– Sulfamethoxazole –– Penicillin –– Corticosteroid treatment and withdrawal –– NSAID in Bartter syndrome –– Mesalamine –– Lithium carbonate –– Amiodarone –– Chlordecone –– Cyclosporine –– Vitamin A –– rhGH and IGF-1

Endocrinology –– Irregular menstruation –– Pregnancy –– Oral contraceptives –– Turner –– Adrenal insufficiency –– Hyperthyroidism –– Hypothyroidism –– Hyperaldosteronism Haematology –– Anaemia –– Hypercoagulability Others –– Systemic lupus erythematosus –– Behcet’s disease –– Sleep apnoea –– Acute respiratory insufficiency

careful and sufficient clinical, ophthalmologic and imaging investigations are mandatory to exclude secondary causes of pseudotumour cerebri. Sinus obstructions are revealed by MR venography (MRV) or conventional angiography in up to 40% of cases. Thrombotic material appears strongly hyperintense in the first month, and chronic thromboses or partially recanalised sinuses are best recognisable on MRV. The recognition of sinus thrombosis has crucial therapeutic implications, as management is completely different from IIH. Endovascular treatment, i. e. thrombolysis and stent placement, are promising new therapies [12]. It is outside the scope of the present chapter to give a full review of secondary pseudotumour cerebri [3, 6, 13]. 3.2.8.9

Special Remarks

Idiopathic intracranial hypertension is a diagnosis of exclusion that has been puzzling health professionals for decades. The pathophysiology of IIH is not fully understood and no causal treatment exists. Research reports favour the presence of venous outflow abnormalities. Advances in diagnostic neuroimaging techniques and implication of manometry recordings particularly in relation to venous sinus pathology have demonstrated underlying causes in many of the cases conventionally classified as IIH. The disease usually resolves after a few months of medical treatment, but the risk of visual deterioration is considerable and some patients experience a chronic disabling course for years that limits their working and social capacity. When a feasible aetiology is pointed out,

i. e. a drug or a venous sinus anomaly, the correct term is secondary PTC and not IIH. Selected Reading 1. Acheson JF (2004) Optic nerve disorders: role of canal and nerve sheath decompression surgery. Eye 18:1169–1174 2. Albeck MJ, Skak C, Nielsen PR, Olsen KS, Børgesen SE, Gjerris F (1998) Age-dependency of resistance to cerebrospinal fluid outflow. J Neurosurg 89:275–278 3. Binder DK, Horton JC, Lawton MC, McDermott MW (2004) Idiopathic intracranial hypertension. Neurosurgery 54:538–552 4. Burgett RA, Purvin VA, Kawasaki A (1997) Lumboperitoneal shunting for pseudotumor cerebri. Neurology 49:734–739 5. Bynke G, Zemack G, Bynke H, Romner B (2004) Ventriculoperitoneal shunting for idiopathic intracranial hypertension. Neurology 63:1314–1316 6. Digre KB, Corbett JJ (2001) Idiopathic intracranial hypertension (pseudotumor cerebri): a reappraisal. Neurology 7:2–67 7. Fishman RA (1992) Cerebrospinal fluid in diseases of the nervous system. Saunders, Philadelphia 8. Gideon P, Sørensen PS, Thomsen C, Ståhlberg F, Gjerris F, Henriksen O (1995) Increased brain water self-diffusion in patients with idiopathic intracranial hypertension. Am J Neuroradiol 16:381–387 9. Gjerris F (1998) Hydrocephalus and other disorders of cerebrospinal fluid circulation. In: Bogousslavsky J, Fisher M (eds) Textbook of Neurology. Butterworth & Heinemann, Boston, pp 655–674

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10. Gjerris F (2000) Hydrocephalus in adults. In: Kay AH, Black PM (eds) Operative neurosurgery. Churchill Livingstone, London, pp 1236–1247 11. Gjerris F, Børgesen SE (2000) Pathophysiology of the CSF circulation. In: Crockard A, Hayward R, Hoff JT (eds) Neurosurgery – the scientific basis of clinical practice, 3rd edn. Blackwell Science, Boston, pp 147–168 12. Higgins JN, Cousins C, Owler BK, Sarkies N, Pickard JD (2003) Idiopathic intracranial hypertension: 12 cases treated by venous sinus stenting. J Neurol Neurosurg Psychiatry 74:1662–1666 13. Skau M, Brennum J, Gjerris, Jensen R (2006) What is new about idiopathic intracranial hypertension? An updated review of mechanism and treatment. Cephalgia 26:384–399 14. The International Classification of Headache Disorders (2004), 2nd edn. Cephalalgia 24 [Suppl 1]:9–160

3.2.9 Pediatric Brain Tumors 3.2.9.1

Infratentorial Brain Tumors in Children

Massimo Caldarelli, Concezio Di Rocco 3.2.9.1.1 Introduction

Three oncotypes, astrocytoma, medulloblastoma, and ependymoma, almost exclusively encompass the field of infratentorial tumors in the pediatric age. While cerebellar astrocytoma is mainly a surgically curable disease, a combination of surgery, radiation therapy, and, to a lesser extent, chemotherapy, constitutes the basis for the management of the other two forms. Local recurrence or CSF spread is negligible for the former, whereas this is almost the rule for the latter two, unless adjuvant therapy is given after surgical excision. Tumor characteristics at diagnosis, extent of surgical excision, and age of the patient are the leading factors that influence the possibility of cure. Clinical manifestations are common to all of them, and consist mainly of symptoms and signs of increased

ICP (headache, vomiting, and lethargy), mainly due to the frequently associated obstructive hydrocephalus (80% of cases), nuchal pain, torticollis, and more rarely, signs of cerebellar deficit and isolated cranial nerve deficits; multiple cranial nerve deficits and pyramidal syndrome are suggestive of brain stem glioma. Spinal or limb pain should suggest spinal seeding. 3.2.9.1.2 Astrocytomas

Cerebellar astrocytomas constitute about 5% of all intracranial pediatric tumors and approximately one-third of those located in the posterior cranial fossa; peak incidence between 6 and 8years, with a slight female preponderance. It is one of the few really surgically curable CNS tumors. Total resection assures 100% disease-free survivals at 10years; however, this is the case in only 70–80% of cases, due to the invasion of eloquent areas in the remaining cases. There are two main histological forms: pilocytic and diffuse. The first type (70%) is a pink-gray, translucent, solid and elastic mass lesion with frequent cyst formation; they are usually sharply marginated and well-demarcated from the cerebellar parenchyma, with a preferred location in the cerebellar vermis and prevalent extension toward one cerebellar hemisphere; intratumoral hemorrhage is rare. From a histological point of view, it is moderately cellular, with fibrillary cells oriented in bundles; cells are fusiform or elongated, uni- or bipolar; mitoses are absent. The second type (30%) is less well-demarcated from the cerebellar parenchyma; histologically presents pseudorosettes, hypercellularity, occasional mitoses, abundant necrosis, microcalcifications; and cyst formation is far less frequent than with the first type (25%). 3.2.9.1.2.1 Neuroimaging

The unenhanced CT appearance of pilocytic astrocytoma is of a well-demarcated, isodense or hypodense mass. Three main patterns can be recognized: a large cyst with a mural nodule; a solid tumor with cystic areas; and a cystic tumor surrounded by a thick solid neoplastic rim.

Fig.3.2.81a,b T1-weighted a axial and b sagittal contrast-enhanced (CE) images of an infratentorial pilocytic astrocytoma. Note the typical pattern of the cystic tumor with a mural nodule and the hom*ogenous bright contrast enhancement

3.2.9 Pediatric Brain Tumors

Intense, hom*ogeneous contrast enhancement (CE) is usually seen after contrast injection. Diffuse astrocytoma presents as an ill-defined, hom*ogeneous hypodensity, with occasional calcifications (20%). On basal MRI pilocytic astrocytoma appears as a hypointense mass on T1-weighted images and moderately hyperintense on T2-weighted images; there is a variable cyst signal according to the protein content of the cyst fluid; and intense, hom*ogeneous CE after Gadolinium injection (Fig. 3.2.81). On the other hand, a diffuse astrocytoma appears as an ill-defined hypointensity on T1-weighted images, a better defined hyperintensity on T2-weighted images; and there are sometimes patchy areas of CE after Gadolinium injection. 3.2.9.1.2.2 Therapy

Surgical excision is the elective treatment. In the case of cystic tumors, simple nodule excision may suffice if the cyst wall does not enhance on neuroradiological investigation; otherwise, the cyst wall must be removed together with the mural nodule. In the case of diffuse tumors, a close relationship with eloquent structures, namely the brain stem and cerebellar peduncles, can make surgical excision less radical (actually feasible in only 50–60% of cases). While survival at 25years is over 90% in the case of pilocytic astrocytoma, this percentage decreases to only 40% in patients with diffuse astrocytoma undergoing partial resection. Recurrences should be treated with repeated surgery. Radiation therapy plays a role after partial removal in children aged 3years or more, or after partial removal of a recurrence. Malignant transformation or CSF seeding of a benign astrocytoma is exceedingly rare. 3.2.9.1.3 Medulloblastomas

Medulloblastomas account for about 20% of all CNS pediatric tumors and approximately one-third of those within the posterior cranial fossa. The peak incidence is between 7 and 12years (median 9years). Boys are more affected than girls, with a sex ratio of 3.0 to 1.6. The most frequent location is the inferior cerebellar vermis with ex-

tension into the fourth ventricle. Less frequently, they are located within the cerebellar hemispheres or cerebellopontine angle. On gross examination a medulloblastoma (MB) appears as a well-circ*mscribed, grey reddish mass, soft or granular; nonetheless, cerebellar invasion does occur at its edges, and possibly at the cerebellar peduncles and brain stem in about 33% of cases. On occasion, they are more firm, due to the presence of abundant connective tissue. Histologically, MBs are composed of tightly packed, isomorphous, elongated cells, with round or oval nuclei, occasionally arranged to form pseudorosettes. Mitosis is frequent. Necrosis, calcifications, and cyst formation are uncommon. The presence of mature astrocytes or gangliocytes inside the tumor (expression of tumor multipotentiality) would be associated with a longer disease-free survival; other authors, on the contrary, deny this association, and in fact attribute a less favorable prognosis to this finding. Two main variants are described: classic and desmoplastic. Traditionally, the latter would be characterized by a larger amount of connective tissue (an expression of mesenchymal reaction to meningeal invasion), more frequent location in the cerebellar hemispheres, less aggressive behavior, and a higher incidence in older patients. Other observations, however, indicate that the desmoplastic variant is equally distributed in the hemispheres and vermis and does not carry a better prognosis. Recently, a further variant, “multinodular,” has been described, so called for its histological appearance; it occurs prevalently in very young children, and usually bears a more favorable prognosis. Generally, the biological behavior of MB is that of a highly malignant tumor, death occurring within 8–15months of onset of symptomatology with no treatment or surgery alone. 3.2.9.1.3.1 Neuroimaging

Medulloblastoma is a spontaneously hyperdense mass on unenhanced CT, with peripheral edema; rare necrosis or calcifications; and marked, hom*ogeneous CE. It is

Fig.3.2.82a,b T1-weighted a axial and b sagittal CE images of a medulloblastoma. Note the huge vermian tumor showing almost uniform contrast enhancement, with extensive infiltration of the dorsal aspect of the lower brain stem

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hypointense or isointense on T1-weighted images; shows notable decay on T2-weighted images; and is moderately to markedly hyperintense on T1-weighted images after Gadolinium injection (Fig.3.2.82). 3.2.9.1.3.2 Therapy

Surgical excision is the first step of treatment, and should be as radical as possible to give the patient the best chance of cure. In fact survival is directly related to the extent of surgical removal, with only 30% of patients receiving partial resection still alive at 5years, compared with 60% in the case of total removal, provided the same postoperative adjuvant treatment is given. At present, gross total resection is obtained in more than 60% of cases; operative mortality is 3–4%. Persistent hydrocephalus is observed in almost 20% of cases, in spite of gross total tumor removal. Third ventriculostomy can succeed in restoring CSF circulation in > 80% of cases, VP shunting representing the treatment in the remaining cases. Routine preoperative third ventriculostomy has been repeatedly criticized, and is no longer indicated. A permanent VP shunt does not constitute an adjunctive risk for extrathecal tumor spread, as previously suggested. Adequate treatment of hydrocephalus is mandatory to prevent the side effects of chemo- and radiation therapy, which can induce cerebral edema and decompensate an apparently stable ventricular dilatation. Tumor staging is fundamental for prognostic purposes and is based on the following criteria: • Extent of removal (more important than tumor size at diagnosis) • Presence of metastasis at diagnosis • Postoperative subarachnoid tumor spread • Negative early (within 48/72 h) postoperative CT/ MRI According to these criteria, 100% disease-free survival at 5years is expected in patients undergoing total resection, with negative postoperative CT/MRI investigation, and with no evidence of tumor spread; this percentage is reduced to 78% in the same situation, but with subtotal resection; and to 18% in the case of subtotal resection, with positive postoperative CT/MRI, and the presence of leptomeningeal spread. According to these criteria a distinction can be made between “standard” and “highrisk” patients (partial resection, presence of metastases at diagnosis, young age). Children less than 3 years old constitute a special problem as they cannot undergo radiation therapy and are treated only with high-dose chemotherapy. 3.2.9.1.3.2.1 Radiotherapy

Radiotherapy plays a fundamental role in the treatment of MB (only one-third of patients survive 5 years without this therapy). Its major adverse effects (hypopituitar-

ism; short stature; intellectual impairment, from learning disabilities to severe neurocognitive handicap) can be partially obviated by reducing the standard radiation dose (50–55 Gy to the posterior fossa, 35–40 Gy to the neuraxis) or by utilizing hyperfractionated irradiation in combination with chemotherapy. 3.2.9.1.3.2.2 Chemotherapy

Various chemotherapeutic drugs have been utilized over the years: vincristine, CCNU, cisplatin, busulfan, and thiopental. The role of chemotherapy in low-risk patients is still controversial; on the contrary, the survival of highrisk patients receiving chemotherapy is comparable with that of standard-risk patients. The possibility of replacing radiation therapy with chemotherapy has been investigated, but a definitive answer is still lacking. Certainly, chemotherapy plays a role in postponing for 1–2 years radiation therapy in infants and young children less than 3years old with nonmetastatic, totally resected MBs. Less convincing are the results in infants with diffuse disease and limited resection. At present, encouraging results are obtained with high-dose chemotherapy under the cover of bone marrow stem cell rescue. 3.2.9.1.4 Ependymomas

Ependymomas represent approximately 10% of all intracranial tumors, 60% of which are located within the posterior cranial fossa; they constitute 10–15% of posterior fossa tumors. The most common location (in 60%) is the fourth ventricle, as the tumor usually originates in its floor and extends into the cisterna magna and upper cervical canal. Less frequently (in 30%), they develop in a lateral position involving the foramen of Luschka and spread into the cerebellopontine angle; very rarely, the tumor originates in the roof of the fourth ventricle. At inspection, ependymomas appear as a reddish nodular or lobulated mass, occasionally with a cauliflower appearance, mainly extra-axial, but with discrete brain stem and cerebellar infiltration. The prevalent cisternal growth accounts for the frequent involvement (compression more than infiltration) of lower cranial nerves and vascular supply to the brain stem. From a histological point of view, the neoplastic cells are typically arranged in perivascular pseudorosettes; cytoplasm is scarce and mitoses rare. Histological classification remains controversial, the main differentiation being between ependymoma and anaplastic ependymoma (whose incidence varies widely from 7 to 89%). These tumors are often biphasic, with a prevalent benign appearance and small islands of more malignant cells. 3.2.9.1.4.1 Neuroimaging

Ependymomas are usually isodense on plain CT, with microcalcifications. Cysts and necrosis are rare. Contrast

3.2.9 Pediatric Brain Tumors

enhancement is partial and moderate. They are usually iso- or hypointense on T1-weighted MRI, with heterogeneous CE; and typically hyperintense on T2-weighted, proton density, and FLAIR images. 3.2.9.1.4.2 Therapy

Ependymoma is mainly a surgical disease, and the extent of surgical resection is the single most relevant factor influencing the long-term outcome. However, despite the availability of sophisticated operative tools, like ultrasound aspiration, which enable the neurosurgeons to be more aggressive, the actual feasibility of a gross total removal remains only 50%; surgical difficulties are caused by the intimate tumor relationship with brain stem, cranial nerves, and vessels; in particular, tractions on the floor of the fourth ventricle, while attempting radical removal, can provoke life-threatening cardiocirculatory reactions (alternating tachycardia and bradycardia, elevation in blood pressure), which account for the non-negligible operative mortality and elevated morbidity. Radiation therapy is standard adjuvant treatment in the case of partial resection and in children aged more than 3years. Local irradiation is thought to be sufficient, as the actual occurrence of metastases is lower than originally estimated. The optimal dose is controversial, as well as the need for this therapy in the case of total resection. Chemotherapy plays a marginal role. The prognosis of posterior fossa ependymoma continues to be poor with an overall 5-year disease-free survival of only 30–38%, which is worse than for medulloblastoma, despite its presumed better histology. Recurrences are frequent and are mainly local, with spinal spreading possible, but rare (<10%). Repeat surgery is the mainstay of treatment. 3.2.9.1.5 Brain Stem Gliomas

Brain stem gliomas are dealt with in Sect.3.2.6, but some remarks must be made on aspects concerning the pediatric age. Brain stem gliomas account for approximately 8–15% of all intracranial tumors in children, and 20% of those in the posterior cranial fossa. There are two peaks of incidence, in the first and fourth decades, and 27–77% of brain stem tumors occur in the pediatric age. They may present as a symmetrical enlargement of the pons (almost 60% of localizations), or less frequently as restricted growth involving one half of the pons, medulla or midbrain. 3.2.9.1.5.1 Histology

There are two main patterns: in approximately two-thirds of cases diffuse replacement of nervous tissue by small or large, fusiform, bipolar or gemistocytic astrocytes, either randomly dispersed or arranged in groups, with focal areas of anaplasia (fibrillary or gemistocytic astrocytoma,

anaplastic astrocytoma, glioblastoma); in the other third the typical pattern of pilocytic astrocytoma is prevalent. From a clinical stand point, brain stem gliomas are characterized by the association of lower cranial nerve deficits with signs of cerebellar or pyramidal tract deficits. Hydrocephalus is far less common than with other posterior fossa tumors. 3.2.9.1.5.2 Neuroimaging

The CT appearance of a brain stem glioma is that of diffuse brain stem enlargement with hypodense (36%), isodense (36%), or less frequently, mixed density (23%) signal. MRI appearance is that of a hypointense signal on T1-weighted images, and a hyperintense signal on T2weighted images with variable CE. What seems most important for surgical purposes is the tumor localization: • Type I: diffuse pontine tumors (55–60%) – usually hypointense on T1-weighted images and minimal or absent CE • Type II: intrinsic and focal tumors (10%) – solid or cystic, localized in the pons, medulla or midbrain • Type III: exophytic tumors (dorsal or lateral, 10–20%) • Type IV: cervicomedullary tumors (20%) 3.2.9.1.5.3 Therapy

While no surgery is advised for type I tumors (and also biopsy seems devoid of a practical significance), it does play a role in the other three forms, mainly characterized by a benign histology, where surgical removal may give a long life expectancy. Prognosis is a function of localization and histology, with an actuarial survival rate of only 6% at 10 years for type I lesions, and much more optimistic survival rates (up to 90%) for the other forms. Radiotherapy plays a major role in type I tumors (actually, the only possible treatment), although the prognosis is only marginally influenced. The role of chemotherapy is even more controversial. 3.2.9.1.6 Other Forms

Fourth ventricle papilloma is exceedingly rare in children, in contrast to supratentorial locations; it may be either located within the fourth ventricle or in the cerebellopontine angle; and hydrocephalus is usually present. Hemangioblastoma is seemingly rare in this age group, and often is a manifestation of the von Hippel–Lindau syndrome. Acoustic schwannomas are exceptional in children, unless associated with NF-2, in which case they are bilateral. The rare cerebellar gangliogliomas are more often hemispheric, also with cerebellar signs, and occasionally they may present with hemifacial and contralateral focal motor seizures (probably in relation to the presence of heterotopic, neoplastic ganglion cells). Hydrocephalus is rarely reported. Among the rarest forms are teratomas and dermoid or epidermoid cysts.

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Selected Reading 1. Di Rocco C (1999) Cerebellar astrocytoma. In: Choux M, Di Rocco C, Hockley AD, Walker ML (eds) Pediatric neurosurgery, Churchill Livingstone, pp 427–459 2. Albright AL (1999) Medulloblastomas. In: Albright L, Pollack I, Adelson D (eds) Principles and practice of pediatric neurosurgery. Thieme, New York, pp 591–608 3. Tomita T (2001) Ependymomas. In: McLone DG (ed) Pediatric neurosurgery, 3rd edn. Saunders, Philadelphia, pp 822–834 4. Choux M, Lena G, Do L (1999) Brainstem tumors. In: Choux M, Di Rocco C, Hockley AD, Walker ML (eds) Pediatric neurosurgery. Churchill Livingstone, New York, pp 471–491

3.2.9.2

Supratentorial Brain Tumors in Children

Massimo Caldarelli, Concezio Di Rocco Brain tumors are the most frequently occurring solid neoplasms, and the second most common cause of death (following traumas) in the pediatric age. Their incidence is 2–3 new cases per year per 100,000 children, with a reported rising annual incidence of 1% in the last 20years. In the first 2years of life supratentorial tumors predominate, as in the adult population, over infratentorial tumors, whereas from the third year on, the latter are more frequent. Supratentorial tumors represent approximately 40– 50% of all brain tumors in children. Neuroepithelial tumors account for about 80% of cases, the remaining 20% comprising craniopharyngiomas, germ cell tumors, meningiomas, and more rare oncotypes. For practical purposes, tumors of the cerebral hemispheres (cortex and underlying white matter) will be addressed separately from those occurring along the cerebral midline (diencephalon, hypothalamus) or within the ventricles. 3.2.9.2.1 Tumors of the Cerebral Hemispheres

Tumors of the cerebral hemispheres constitute approximately 30–40% of pediatric supratentorial tumors. Tumors of neuroepithelial origin (astrocytoma, ependymoma, and less frequently oligodendroglioma) are by far the most frequent. Among them, astrocytoma (predominantly low-grade pilocytic, fibrillary or protoplasmic) is the most frequent oncotype, followed by ependymoma, oligodendroglioma, mixed glioma, and ganglioglioma. In fact, since many pediatric tumors disclose a mixed population, histology often indicates the predominant

oncotype or the most aggressive. New entities such as dysembryoplastic neuroepithelial tumors (DNET), central neurocytomas, and desmoplastic infantile gangliogliomas (DIG) have been described. Furthermore, the cerebral hemispheres may harbor embryonal tumors such as primitive neuroectodermal tumor (PNET) and atypical teratoid/rhabdoid tumor (ATRT). Clinical manifestations vary according to tumor location and aggressiveness, and to the patient’s age. Symptoms and signs of increased ICP are late, unless the tumor grows rapidly. In children less than 2years old, irritability or lethargy, associated with macrocrania and bulging fontanel, may be the only clinical manifestation. Epilepsy is the main symptom in 40–70% of cases; while seizure semiology represents an important topographic criterion in older children and adolescents, its value is much less significant in young patients due to brain immaturity. Also, cranial asymmetry may be the revealing sign of a brain tumor. Among focal signs, motor or sensory disturbances, personality changes, deteriorating school performance, behavioral changes, and to a lesser extent, visual field defects are the most common. 3.2.9.2.1.1 Astrocytomas

Astrocytomas are predominantly (in about 80% of cases) low-grade tumors (pilocytic and fibrillary); however, the pilocytic variant is relatively less common than those in the infratentorial compartment. Cystic forms are found in 35–60% of cases, and predominate in patients with pilocytic astrocytoma; in contrast to its infratentorial counterpart, the cyst wall contains neoplastic tissue in up to 70% of cases. Anaplastic astrocytoma and glioblastoma multiforme together account for the remaining 20%. 3.2.9.2.1.1.1 Neuroimaging

Low-grade astrocytomas are usually iso- or hypodense on CT, with a moderate or absent mass effect, mostly scarcely or non-enhancing after contrast agent administration. The MRI appearance (Fig.3.2.83a,c) is that of an iso- or hypointense mass on T1-weighted images, with ill-defined borders, and hyperintense on T2-weighted images; usually there is scarce and patchy CE. Conversely, pilocytic astrocytomas, often deeply seated (in the thalamus or basal ganglia) and cystic, tend to present more distinct boundaries and marked CE, which does not represent a sign of malignancy, in contrast to what happens in adults. The CT appearance of high-grade tumors is that of a large isodense or hyperdense lesion that usually enhances hom*ogeneously; necrosis (with post-contrast ring enhancement), cyst formation, and hemorrhage are frequent. The MRI appearance is that of an iso-/hyperintense lesion on T1-weighted images, and hyperintense on T2-weighted images; CE is usually hom*ogeneous.

3.2.9 Pediatric Brain Tumors

Fig.3.2.83a–d T1-weighted a axial and c sagittal contrast-enhanced (CE) MRI of a supratentorial pilocytic astrocytoma. Note the peripheral ring enhancement of the tumor. b T2-weighted axial and d T1-weighted CE sagittal MRI of a typical supratentorial ependymoma with a mainly extra-ventricular location. Note the heterogeneous signal characteristics on basal MRI and the patchy contrast enhancement

3.2.9.2.1.1.2 Management

Surgical excision is the mainstay of treatment for lowgrade astrocytomas. Superficially located low-grade tumors bear a good prognosis after radical excision, with a long-term survival of 60–93% in most recent series and surgery-related mortality approaching 0%. At present, thanks to the introduction of neuronavigation, intraoperative ultrasonography, integration of functional imaging, and improvement in electrophysiological monitoring, surgical resection represents a safe option not only for superficial tumors (even when located in eloquent brain areas), but also for deeply seated tumors. Actually, most of the latter are low-grade astrocytomas, and also a subtotal resection can provide an elevated 5-year survival rate. Postoperative radiation therapy plays a minor role, if any, after total/subtotal excision of a low-grade astrocytoma. In fact, although radiotherapy is presently much safer than before, its utilization in children less than 5years of age should be regarded with caution, taking into account the significant immediate and later side effects of treatment. Follow-up MRI is the best way to monitor these children, and the possible tumor recurrence or progression should be managed by means of a second operation. Chemotherapy is utilized, especially in young children with a residual tumor as an alternative to radiation. There are multiple protocols including carboplatin and vincristine. Complete responses are few, whereas the rate of par-

tial responses or stable disease is high (progression-free survival 61–75% at 3years). The most relevant prognostic factors in low-grade astrocytoma are the histology and the patient’s age at diagnosis. Pilocytic tumors show 5- and 10-year disease-free survival of 85% and 79% respectively, compared with 51% and 23% for nonpilocytic tumors. With regard to age, the 2-year progression-free survival has been reported to be as high as 81% in children less than 5years of age, compared with 58% in older children. In another study, pediatric patients (<19years old) had a 5-year survival rate of 83%, compared with 35% in those aged 20–49years, and 12% in those aged > 50years. The management of high-grade astrocytoma is more uniform. Radical excision has proven to be superior to partial resection in children as well as in adults. The association with radiation and chemotherapy doubles the 5-year survival. Nevertheless, the prognosis is poor and parallels that observed in the adult population, with disease-free survival at 5 years of 20–40% for anaplastic astrocytoma, and only 5–15% for glioblastoma. 3.2.9.2.1.2 Ependymoma

Ependymomas are mostly paraventricular (in contrast to infratentorial forms) and predominate in boys less than 5years of age (approximately one-third of all CNS ependymomas). Generally, they present as well-differentiated tumor masses with a variable incidence of malignant

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forms. Although for practical purposes, one distinguishes between low-grade (grade II of the WHO classification) and high-grade (grades III and IV) ependymomas, the histological grade is not usually a reliable prognostic factor. Ependymomas are mostly well-demarcated and cystic (about 50%), but these features are not a sign of benignity; malignant forms tend to be more invasive, to grow significantly inside the ventricular space, and to be highly vascular. Histologically, ependymomas are characterized by a perivascular cell distribution with rosette or pseudorosette formation; malignant forms show increased cellularity and mitotic activity, and nuclear polymorphism; and necrosis, vascular proliferation, and endothelial hyperplasia are less reliable signs of malignancy. Ependymoblastoma is a poorly differentiated malignant form prevalently occurring in children, and represents the embryonic form of the ependymal tumor (PNET with ependymal differentiation, according to Rorke). The prognosis is invariably poor. 3.2.9.2.1.2.1 Neuroimaging

Ependymomas are either hypo- or isodense on basal CT; calcifications and cysts are very frequent. CE is usually heterogeneous. On MRI ependymomas are hypointense on T1-weighted images, and hyperintense on proton density and T2-weighted images. They are usually welldemarcated from the surrounding brain parenchyma, but with inhom*ogeneous signal characteristics owing to the presence of calcifications, microhemorrhages, mineralization, and increased vascularity. Also, with MRI, CE is usually inhom*ogeneous (Fig.3.2.83b,d). 3.2.9.2.1.2.2 Management

Surgical excision followed by radiotherapy is the mainstay of treatment for these tumors. As tumor recurrence is mainly local (spinal metastases are reported in only 10–13% of cases in most recent series), local irradiation can be a valid alternative to classical whole-brain irradiation. After complete treatment, the overall 5-year survival varies from 44 to 66%, and the 5-year progression-free survival from 23 to 61%. Adjuvant therapy, after total resection of low-grade ependymomas, is not recommended in young patients (who constitute the majority). Various chemotherapy regimens have been utilized over the years, but the results of currently available protocols remain quite disappointing, due to the lack of chemosensitivity of these tumors. The most relevant factor for the patient’s outcome is the extent of surgical resection, with 5-year survival of 80% for total resection, 48% for near total, and only 22% for partial. Also, tumor seeding seems influenced by the extent of removal, as no dissemination was found in 83% of totally resected tumors compared with 71% of those subtotally resected. The patient’s age is another important

factor as children less than 3years old show a significantly worse outcome than older children; however, this seems related to their inability to receive optimal treatment. 3.2.9.2.1.3 Oligodendroglioma

Oligodendrogliomas account for 2–3% of supratentorial tumors in children; when considered together with mixed gliomas, which are characterized by a mixture of two or three types of mature cells (oligoastrocytoma, oligoependymoma), their incidence reaches 9–30%. Calcification is usually abundant. Pediatric oligodendrogliomas have a predisposition to spontaneous hemorrhage due to their rich vascular bed. The grading system identifies a benign and an anaplastic form, the latter being more frequent than in the adult population. Furthermore, even benign forms may spread along CSF pathways. Histologically, they present as sheets of monomorphous cells with small round nuclei, surrounded by a clear cytoplasm; anaplastic nuclei and a variable degree of mitoses identify the malignant variants. Clinically, a history of seizures is present in 52–67% of cases. 3.2.9.2.1.3.1 Neuroimaging

Oligodendroglioma is usually hypodense on basal CT, with a variable degree of calcifications (the pattern of gyriform calcifications is pathognomonic) and cysts; CE is inhom*ogeneous. MRI characteristics are similar. 3.2.9.2.1.3.2 Management

Radical surgery is the most effective therapy. Unfortunately, the infiltrative nature of the tumor, and the presence of calcifications, can prevent radical removal; in such cases, as well as in cases of malignant forms, adjuvant radiotherapy is indicated. The effectiveness of chemotherapy is still under discussion. Five-year survival varies from 75 to 85%, but is significantly lower in anaplastic forms. 3.2.9.2.1.4 Ganglion Cell Tumor

Ganglion cell tumors include ganglioglioma, gangliocytoma, and desmoplastic infantile ganglioglioma (DIG). All these forms are characterized by a mixture of astrocytes and neurons. Together they constitute 1–7.5% of all primary CNS neoplasms. Gangliogliomas are more frequently found in children and young adults, with a peak incidence between 5 and 6years. More than 80% of the cases involve the mesial aspect of the temporal lobe, the amygdala, and the hippocampus. The predominant (in about 80% of the cases) seizure pattern is that of complex partial seizures; seizures may arise either from irritation of normal brain surrounding the tumor, or from its neuronal component. Neuropsychological tests show mild cognitive impairment in almost all the patients with temporal lesions and longstanding seizures. Verbal and visuo-spatial performance are the most frequently compromised functions for dominant and nondominant tumors respectively.

3.2.9 Pediatric Brain Tumors

Gangliogliomas are staged according to the WHO classification, grades I and II constituting 80–90% of the cases. Histologically, they consist of a mixture of glial cells and neurons; the former may be made up of mature astrocytes, gemistocytes or oligodendroglial cells; and the neurons are clearly heterotopic or atypical, showing disorientation, bizarre shapes, and nuclear hyperchromatism. Anaplastic gangliogliomas (WHO grade III) and ganglioblastomas (WHO grade IV) constitute less than 10% of all gangliogliomas. The glial component represents the malignant portion of the tumor in the majority of cases. Gangliocytomas are a far less common subgroup characterized by the presence of only abnormal neurons inside the tumor, and their clinical behavior parallels that of traditional gangliogliomas. The DIG is a distinct form of ganglioglioma peculiar to the pediatric age, occurring almost exclusively in children under 18months of age; they are usually large and cystic and they show diffuse arachnoidal infiltration. Nevertheless, their biological behavior is indolent and the clinical course may be unremarkable for a long time. 3.2.9.2.1.4.1 Neuroimaging

The CT appearance of gangliogliomas is usually that of a well-demarcated hypodense area, with absent perilesional edema, rare calcifications, and occasional cysts. In the case of cortical localization, scalloping of the inner skull table can be observed. On MRI they are usually isointense on T1-weighted and hyperintense on proton density and T2-weighted MRI (hyperintense in 30%). CE is usually moderate and hom*ogeneous. Anaplastic variants (WHO grade III) are spontaneously hyperdense on CT and hyperintense on T1-weighted MRI scans. A comparison of PET/MRI studies has revealed heterogeneous metabolic behavior in low-grade tumors, and increased metabolic activity in high-grade gangliogliomas.

3.2.9.2.1.4.2 Management

Radical excision, whenever feasible, is the treatment of choice and assures long-term survival or cure. In children with medically intractable epilepsy there is controversy as to whether simple lesionectomy or identification and resection of epileptogenic areas should be considered. Data from the literature suggest that tumor removal is indicated as the primary treatment in children with a short epileptogenic clinical history, reserving intraoperative mapping and more extensive resections for patients with long-standing seizures and multifocal EEG patterns. The role of adjuvant therapies in the case of incomplete removal remains uncertain. Radiotherapy after partial tumor removal is generally considered of little benefit. The 10-year actuarial survival rate for gangliogliomas of the cerebral hemispheres is more than 90% 3.2.9.2.1.5 Dysembryoplastic Neuroepithelial Tumors

Dysembryoplastic neuroepithelial tumors (DNETs) are rare neoplasms, with a male predominance, and are almost exclusively found in the pediatric age (1–19years, mean 9 years). Histologically, they resemble mixed tumors. Typical features are cortical location, multinodular architecture (the nodules consisting of areas resembling astrocytoma, oligodendroglioma, cortical dysplasia), the presence of specific neuronal elements disposed perpendicularly to the cortical surface. They are most frequently located in the temporal lobe and associated with longstanding seizure disorder (usually early onset partial seizures); neurological deficits are minimal or absent. 3.2.9.2.1.5.1 Neuroimaging

The CT appearance of DNET is usually that of a welldemarcated hypodense area, with focal calcifications, and calvarial erosion (typical “pseudocystic lesion”). On MRI (Fig. 3.2.84) they are hypointense on T1-weighted im-

Fig.3.2.84a,b Axial a T1-weighted and b T2-weighted images of a dysembryoplastic neuroepithelial tumor (DNET), demonstrating a well-demarcated lesion with low-intensity signal on T1-weighted images that becomes hyperintense on T2-weighted images

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ages and hyperintense on T2-weighted images; they may look like large cortical gyri. CE is usually uniform and marked. 3.2.9.2.1.5.2 Management

Radical excision, whenever feasible, is the treatment of choice, which also results in seizure control. No adjuvant treatment is indicated, even in the case of incomplete removal. 3.2.9.2.1.6 Embryonal Tumors

Embryonal tumors are small cell neoplasms with divergent differentiation; they include primitive neuroectodermal tumors (PNET), medulloepithelioma, neuroblastoma, and ATRT. In particular, PNETs are undifferentiated neoplasms, considered to originate from a common primitive neuroepithelial cell. They are relatively rare in the supratentorial compartment compared with the infratentorial one. PNETs are composed of poorly differentiated neuroepithelial cells with clusters of cells with astrocytic, ependymal, oligodendroglial, or neuronal differentiation. Necrosis, hemorrhage, and cyst formation are very common, and their clinical behavior parallels that of a medulloblastoma. Approximately two-thirds occur in children under 3years of age. 3.2.9.2.1.6.1 Neuroimaging

The CT appearance of PNET is that of a large isodense or hyperdense lesion that usually enhances hom*ogeneously (but less markedly than medulloblastoma). Necrosis, cyst formation, and hemorrhage are frequent. The MRI appearance is that of an iso-/hyperintense lesion on T1weighted images and hyperintense on T2-weighted images. CE is hom*ogeneous. 3.2.9.2.1.6.2 Management

Attempted radical surgery is the first step of treatment, as the entity of tumor removal seems to affect positively

disease-free survival. Surgery, however, must be integrated with chemotherapy (cisplatin, lomustine, and vincristine) and craniospinal irradiation, as in the case of medulloblastoma. Children less than 3 years of age are treated only with multiagent chemotherapy with the aim of postponing the time until irradiation can be administered. The prognosis is poor irrespective of treatment, with a median survival time of less than 1year. 3.2.9.2.1.7 Atypical Teratoid/Rhabdoid Tumors

Atypical teratoid/rhabdoid tumors (ATRT) are peculiar to the early pediatric age, three-quarters of them occurring in young children less than 3years of age. Histologically, they are largely similar to PNET, with a relevant malignant mesenchymal component (almost 30% of the tumor), and epithelial differentiation in a quarter of them. Neuroimaging (Fig.3.2.85) and treatment parallel those of PNET, with an even poorer prognosis. 3.2.9.2.1.8 Meningiomas

Meningiomas are predominantly observed in adulthood; nevertheless, they can also be found in children, constituting 1–3% of intracranial tumors in this age group, and 1–2% of all meningiomas. No gender predominance is observed in children, in contrast to adults in whom a clear female predominance is well-established. About 40% are associated with neurofibromatosis types 1 and 2 (often multiple in this case). About one-third of childhood meningiomas are purely intraparenchymal or intraventricular; they are mostly supratentorial (>80%) and about 20% intraventricular (see below); and they are frequently cystic. Giant forms are observed in > 40%. Up to 40% of pediatric meningiomas disclose malignant features (hemangiopericytoma, papillary meningioma). The peak of incidence in this case is about 3years (compared with 11years for classical forms), and they are more frequent in females. Some radiological aspects (hyperostosis, “dural tail”) are quite rare.

Fig.3.2.85a,b Axial a T2-weighted and b FLAIRcoronalimages of a huge ATRT. Note the heterogeneous signal characteristics of the lesion

3.2.9 Pediatric Brain Tumors

The treatment of choice is total resection, which is feasible in most cases (>80%); subtotal or partial resection will suffice in tumors involving the skull base. In these cases as well as in malignant forms postoperative radiotherapy is required. Recurrences after total resection are reported in 10–20% of cases, 70–80% after partial removal. 3.2.9.2.1.9 Teratomas

Teratomas are among the most frequently diagnosed hemispheric tumors in neonates and infants, as well as in the prenatal period (about one-third). Over 50% are found in the pineal region, while the remainder are suprasellar or intraventricular. They are usually large when they are first identified by ultrasound (US) or MRI. Histologically, they are composed of multiple tissues deriving from all (in 90%) or two of the three germ layers. The presence of cellular populations with embryonal features distinguishes the immature subtype. 3.2.9.2.1.9.1 Neuroimaging

The US appearance is that of a large cystic mass with heterogeneous echogenic characteristics, owing to the concomitant presence of calcified or cartilaginous components; increased vascularity with low-resistance flow may be demonstrated by color Doppler. Likewise, CT and MRI demonstrate a heterogeneous mass, with different signal characteristics (Fig.3.2.86). 3.2.9.2.1.9.2 Management

Surgical resection is the treatment of choice and it is curative in the case of mature teratoma; however, particularly in neonates and infants, the huge tumor size, and the already stabilized compromise of the surrounding brain structures, can prevent the feasibility of such radical surgery, not to mention the elevated surgery-related mortality and morbidity. Immature teratomas and teratocarcinomas have a poor prognosis, even though adjuvant therapy is provided.

3.2.9.2.2 Intraventricular Tumors

Tumors located inside the lateral and third ventricles originate both from the anatomical structures located within the ventricles or in their walls. They grow prevalently within the ventricular cavities and often remain silent for a long time until they reach a huge size or cause hydrocephalus. Focal signs are remarkably rare, although seizures may occur; the clinical picture is dominated by symptoms and signs of increased ICP. Tumors arising from intraventricular structures mainly consist of choroid plexus tumors; those originating from the ventricular walls include all the tumors described in the above sections, mainly ependymomas and astrocytomas. Intraventricular ependymomas account for about 20% of supratentorial ependymomas, and share with them the same characteristics and management. A peculiar form is the subependymoma, an exceedingly rare, truly benign tumor (WHO grade I) with a mixed population of ependymal and astrocytic cells. It originates from either the ventricular walls or the septum pellucidum, and appears as a well-circ*mscribed nodule on the ventricular walls. MRI appearance is that of an isointense lesion on T1-weighted images, and is hyperintense on T2-weighted images. Another intraventricular tumor with a similar location is the subependymal giant cell astrocytoma (SEGA), a benign lesion that is a manifestation of tuberous sclerosis, which is believed to derive from the neoplastic transformation of one of the subependymal nodules (typical of this neurocutaneous syndrome). Owing to their mostly intraventricular growth, they may remain asymptomatic for a long time, or indefinitely, unless they obstruct CSF flow and cause obstructive hydrocephalus. In this case tumor removal should be the first option rather than CSF shunting. Neurocytoma, a benign tumor consisting of mature neurons, seemingly originates in the septum pellucidum or ventricular walls, and grows inside the ventricles.

Fig.3.2.86 a Axial and b sagittal T1-weighted images of a congenital teratoma

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Other possible, though rare, intraventricular tumors are the meningioma and the teratoma. Intraventricular meningioma originates from the arachnoid tissue in relation to the choroid plexus. Characteristic of, although not exclusive to, the pediatric age, they may reach a huge size before becoming symptomatic, as with other intraventricular tumors. Hydrocephalus is not frequent, whereas exclusion and consequent dilatation of the temporal horn of the lateral ventricle are possibilities. 3.2.9.2.2.1 Choroid Plexus Papilloma

Choroid plexus papilloma is a rare tumor accounting for less than 1% of brain tumors overall, but for 5% of those occurring in the pediatric age; its incidence is even higher (10%) when only infancy and early childhood are considered. From another point of view, 70–90% of these tumors occur in the first 2years of life. They look like a lobulated, pink mass, varying in size from a small pedunculated lesion to a large one filling the ventricle completely. They are highly vascular, the arterial supply being contributed by the anterior and posterior choroidal arteries. Histologically, they consist of mature, benign choroidal cells quite similar to that constitute the normal choroid plexus, albeit with a higher cellularity. Increased cellularity with lack of differentiation, increased mitoses, vascular proliferation, and necrosis identify the malignant form of the choroid plexus tumor (carcinoma). Papillomas are typically associated with hydrocephalus that has a multiple pathogenesis. In fact, an overproduction of CSF (up to three to four times the normal amount produced by the choroid plexus) has been documented, but there is also the possibility of an obstruction to CSF flow (mainly for tumors located in the third and fourth ventricles), and a resorption defect, possibly

related to asymptomatic hemorrhage from the tumor, which in turn may lead to increased CSF protein content and fibrosis of the arachnoid villi. The latter mechanism may account for the persistence of hydrocephalus after tumor removal. 3.2.9.2.2.1.1 Neuroimaging

On CT the tumor appears as a lobulated, hypodense lesion filling the ventricle, which enhances brightly and hom*ogeneously. MRI gives similar information and may document directly the rich vascular supply to the mass (Fig.3.2.87). This aspect may be further investigated by means of MR angiography. 3.2.9.2.2.1.2 Management

Gross total resection is the mainstay of treatment, which may ensure definitive cure. The concomitant hydrocephalus may be treated before, concomitantly or after craniotomy; in the former instance, ventricular dilatation may facilitate the surgical approach to the lesion. The main advantage of preoperative shunting is that, while relieving the increased ICP, it allows an increase in the thickness of the cortical mantle, thus reducing the risk of post-craniotomy collapse. A possible complication of CSF shunting in this situation is the occurrence of ascites. This complication, peculiar to this particular tumor, may be explained on the basis of the increased protein content of the CSF (and consequently abdominal fluid), which is responsible for the reduced resorptive ability of the peritoneal membrane. The most relevant complications in choroid tumor surgery are intraoperative bleeding and brain collapse. Even a discrete hemorrhage can become life-threatening, when considering the limited blood volume of infants

Fig.3.2.87a–c Axial a T1-weighted and b T2-weighted images, and coronal CE c T2-weighted images of a huge choroid plexus papilloma of the lateral ventricle with associated hydrocephalus. Note the typical signal characteristics of the lesion and the bright enhancement after Gadolinium administration

3.2.9 Pediatric Brain Tumors

and young children. To prevent such a complication the arterial supply should be identified and divided prior to proceeding to tumor removal (possibly en bloc). To prevent persistent ventriculo-subarachnoid fistulae and brain collapse, the cortical incision may be obliterated with fibrin glue, after filling the ventricular chamber with saline. Another possibility is a temporary external drainage maintained for 5–7days after the operation. Complete surgical resection is curative for papillomas, although local recurrences have been rarely described. Carcinoma is more difficult to resect because of its infiltrative behavior and increased vascularity. Nevertheless, in this case, too, the aim of surgery should be gross total resection. Radiation and chemotherapy are indicated in the case of incomplete removals, with the well-known limitations related to the patient’s age. In the case of prenatal hydrocephalus the prognosis may be poor, in spite of successful surgical removal of the tumor. 3.2.9.2.3 Tumors of the Suprasellar Region

Two main tumors, the craniopharyngioma and the optic pathway/hypothalamic glioma, encompass the field of suprasellar region neoplasms diagnosed in the pediatric age. Their peculiar location accounts for the clinical symptomatology that translates into damage to the optic pathway and the hypothalamic–pituitary axis. Compression of the third ventricle and of the foramina of Monro justifies the associated obstructive hydrocephalus that frequently accompanies these lesions. 3.2.9.2.3.1 Craniopharyngioma

Craniopharyngioma is dealt with in Sect. 3.2.5.5; however, some of the characteristics peculiar to the pediatric age must be underlined. First of all, as many as 30–40% of craniopharyngiomas occur in children or adolescents less than 18 years of age, and consequently a large number of these tumors are treated in a pediatric neurosurgical environment. Pediatric craniopharyngiomas are usually of large or huge size, with abundant calcification (90%)

(Fig. 3.2.88a). Of the two histological variants, the adamantinous is prevalent in children, whereas the papillary is practically non-existent. Concerning the traditional surgical classification, the retrochiasmatic variant is more frequent, and accordingly hydrocephalus is much more frequently observed than in the adult population. Clinical manifestations include increased intracranial pressure in more than 50% of cases, related to both the huge tumor size and the concomitant hydrocephalus. Likewise, endocrine dysfunction is very frequently observed, short stature and growth retardation being the most common complaints. Ocular signs are less common (also considering the difficulty in demonstrating such dysfunction in young patients). 3.2.9.2.3.1.1 Management

Traditionally, radical surgery is the preferred treatment for this benign tumor, with the goal of curing the patient and avoiding tumor recurrence. However, the close relationship of the tumor with vital surrounding structures makes this goal only partially achievable. In many cases, operative morbidity, especially concerning the endocrinological function, is high following an aggressive surgical approach. Indeed, while long-term follow-up is good in terms of survival, the endocrinological sequelae, as well as postoperative neurological and behavioral changes relating to hypothalamic insult, can limit significantly the quality of life of these long-term survivors of radical (“successful”) craniopharyngioma surgery. Nevertheless, in most surgical series the judgment of a successful surgery is expressed only in terms of percentage of radical resection and recurrence rate. This evaluation may be very limited when dealing with children, as the life-long necessity of hormone replacement, pathologic obesity, and the detrimental effect on the intellect are major limiting factors for acceptable quality of life. Furthermore, total resection is not devoid of the risk of tumor recurrence. Recurrence is treated mainly by repeated surgery and with radiotherapy. Intracavitary radiotherapeutic agents, bleomycin, and more recently, in-

Fig.3.2.88 a Sagittal T1weighted image of a huge craniopharyngioma and b sagittal T1-weighted CE image of a midline pilocytic astrocytoma

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terferon alpha, seem to assure a definitive cure or tumor stabilization in purely cystic forms. In order to avoid the hypothalamic compromise, an increasing number of pediatric neurosurgeons are presently in favor of a less invasive surgical attitude for those craniopharyngiomas that, on preoperative MRI, clearly involve the hypothalamic structures; this means renouncing detaching the tumor capsule from the hypothalamus, and relying on radiotherapy for the treatment of possible regrowth.

indicated to reduce the mass effect (more radical removal in the case of severely impaired vision or amaurosis). Radiation therapy is more and more rarely utilized as an adjuvant treatment. On the contrary, single or multiagent chemotherapy (carboplatin and vincristine) represents a promising approach in the treatment of these tumors; although no definitive remission is obtained, the reduced growth rate may be considered a useful result. Nowadays, chemotherapy is regarded as the first-line treatment for these tumors.

3.2.9.2.3.2 Optic Pathway/Hypothalamic Gliomas

Optic pathway/hypothalamic gliomas are considered together because of the peculiar anatomy of the chiasmatic region and the consequent reciprocal involvement of the two structures in tumors in this area. They are the most frequent suprasellar tumors in the pediatric age. In most pediatric series they make up approximately 10% of supratentorial tumors. Age distribution is peculiar, as 80–90% of these neoplasms are diagnosed in the pediatric age, with a peak incidence at 2–4years for hypothalamic tumors, and slightly higher for optic nerve involvement. Histologically, they are mainly pilocytic astrocytomas, although fibrillary astrocytomas are observed on some occasions (Fig.3.2.88b). A peculiar aspect of these astrocytomas is their variable biological behavior. In fact, they can remain static and stable for years; they can shrink and eventually disappear, spontaneously or after biopsy; or they can behave as aggressive tumors with rapid increases in size and metastatic seeding, despite their histological benignity. Optic pathway gliomas may be a manifestation of neurofibromatosis type 1 (NF-1) in 15–20% of cases. The presence of NF-1 seems to confer a protective effect with regard to tumor progression. Clinical manifestations include visual acuity and visual field defects. A peculiar manifestation of the hypothalamic involvement, observed only in infants or children less than 3years of age, is the so-called hypothalamic cachexia (Russell’s syndrome), which can be present in up to 25% of cases. It is characterized by marked emaciation and loss of the subcutaneous fat, contrasting with normal height and almost normal muscle mass. 3.2.9.2.3.2.1 Management

Therapeutic options vary according to tumor location. Optic nerve gliomas involving only one nerve and with limited impairment of visual function are monitored by means of serial ophthalmologic evaluations and MRI. In the case of loss of visual acuity or growing intraorbital tumors (especially when responsible for marked exophthalmos), surgical excision is indicated, with the aim of preventing tumor spread to the opposite optic nerve and for cosmetic purposes. In the case of tumors located in the chiasm or hypothalamus, surgical debulking of the exophytic portion and removal of the cystic components are

Selected Reading 1. Rorke LB (1999) Pathology of brain and spinal cord tumors. In: Choux M, Di Rocco C, Hockley AD, Walker ML (eds) Pediatric neurosurgery, Churchill Livingstone, pp 395–426 2. Hockley AD, Sgouros S (1999) Tumors of the cerebral hemispheres. In: Choux M, Di Rocco C, Hockley AD, Walker ML (eds) Pediatric neurosurgery. Churchill Livingstone, New York, pp 493–507 3. Montes JL, Farmer JP (2001) Tumors of the cerebral hemispheres. In: McLone DG (ed) Pediatric neurosurgery, 3rd edn, Churchill Livingstone, New York, pp 738–750 4. Myseros JS, Reigel DH (2001) Intraventricular tumors. In: McLone DG (ed) Pediatric neurosurgery, 3rd edn, Churchill Livingstone, New York, pp 755–767 5. Caldarelli M, Pezzotta S (1999) Optic pathway and hypothalamic tumors. In: Choux M, Di Rocco C, Hockley AD, Walker ML (eds) Pediatric neurosurgery. Churchill Livingstone, London, pp 509–529

3.2.9.3

Congenital and Infantile Brain Tumors

Gianpiero TamburRini, Concezio Di Rocco 3.2.9.3.1 Definition

There is no definite agreement on the definition of congenital and infantile brain tumors. Solitare and Krigman [5] considered three distinct categories: • “Definite congenital tumors,” presenting or producing symptoms at birth • “Probable congenital tumors,” presenting or producing symptoms within the first week of life • “Possible congenital tumors,” presenting or producing symptoms during the first months of life. Advances in prenatal and neonatal diagnosis have led to an extension of this original classification. Jellinger and Sunder Plassman [4] consider as “definite congenital tumors” those producing symptoms within the first 2weeks of life, tumors first seen within the first year of life as “probably congenital,” and tumors seen in infants beyond

3.2.9 Pediatric Brain Tumors

1year of age as “possibly congenital.” Some authors, however, still refer to the Collins law stating that all intracranial tumors diagnosed up to the 9th month of life should be included in the category of congenital brain tumors, while other authors have put this cut-off age at 18months [1]. A further problem lies in the different biological behavior of some tumors. For example, medulloblastomas, teratomas, hamartomas, and craniopharyngiomas are known to be of congenital origin, but rarely manifest at an early age, suggesting that some pediatric neoplasms might be congenital in origin despite clinical manifestations occurring later than in infancy [2, 3]. 3.2.9.3.2 Epidemiology

The incidence of infantile brain neoplastic lesions has significantly changed in the last 15years thanks to advances in neuroimaging techniques. Their overall occurrence rate is actually reported to be up to 3.6 per 100,000 newborns, accounting for 0.04 to 0.18% of deaths in children under 1year of age [4]. In the Cooperative survey study of the International Society for Pediatric Neurosurgery in 1991 [1] it was confirmed that 15% of all pediatric brain tumors are diagnosed in infants. No significant differences were found among different geographic areas. The sex incidence was nearly equal, with a slight male predominance (males 54.2%; females 45.8%), and again, there were no significant differences among the different geographic areas. Two peaks of age were recorded, one

under 1month of age (13.9%) and the second toward the end of the first year. 3.2.9.3.3 Etiological and Molecular Biology Considerations

The regional prevalence of some histological types reported in different retrospective studies has led to racial and/or environmental effects to be considered in the pathogenesis of intracranial tumors in infants. A higher incidence of brain tumors in infancy has also been described among family members and siblings with cerebral neoplasms or other diseases of the nervous system, various associated congenital anomalies, birth defects, genetic factors and malformative factors (in 15% of cases), maternal exposure to ionizing radiation and toxic substances, and other kinds of cancer, have been reported in many series [4]. However, epidemiological investigations on large series have not always led to conclusive remarks. Since the early 1990s, a number of genes alterations have been individuated, most of which concern malignant tumors in which a more stable representation of genetic alterations has been reported (Table3.2.16) Data available for benign tumors are more uncertain; the most relevant are summarized in Table3.2.17. Similar to brain tumors of older children and adults most of the actual basic research on intracranial tumors of infancy has been directed toward the differentiation of tumor stem cells from their lineage-differentiated forms.

Table3.2.16 Genetic and protein alterations most frequently reported in primary malignant brain tumors of infancy Genetic and/or protein alterations

Detected rate

Clinical association

TrkC

48% of MB cases

Low expression  unfavorable outcome

erbB-2 (HER2)

84% of MB cases

High expression  unfavorable outcome

MYCC

42% of MB/PNET cases

High expression  unfavorable outcome

PTCH

8–10% of MB cases

Mutation  development of sporadic and nonsporadic desmoplastic MB

17p

35–50% of MB cases

Deletion  unknown significance; putative tumor suppressor gene locus

Beta-tubulin class III expression

15–20% of MB cases

MB differentiation in neuronal cells: indicator of lower aggressiveness

13q14 deletion

93% of pinealoblastoma Expression of trilateral retinoblastoma

22q11 deletion (hSNF5/INI1gene); 85% of AT/RTs 22 monosomy

Altered expression of SWI/SNF protein (oncosuppressor protein)

9p deletion

40% of malignant gliomas

Putative tumor suppressor gene locus

17q deletion

60% of PNETs

Putative tumor suppressor gene locus

+7, +12, and +20 (hyperdiploid chromosomes)

30–40% of choroid plexus carcinomas

Hyperdiploid state indicative of tumor aggressiveness

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Table3.2.17 Genetic and proteins alterations most frequently reported in primary benign brain tumors of infancy Genetic and/or protein alterations

Detected rate

Clinical association

22q11d13 breakpoint or 22 monosomy

28% of Ependymoma cases

Putative tumor suppressor gene locus

Reelin signaling and tuberin/insulin growth receptor pathways

30% of Ganglioglioma cases

Cellular division control proteins

C to T transition (C169) in a CpG dinucleotide of the NF2 gene

50% of NF2 meningeal tumors

Presentation of the disease in infancy

7,8,11 structural abnormalities

50% of pilocytic astrocytomas

Significance unknown

+7, +12, and +20 (hyperdiploid chromosomes) 30–40% of choroid plexus papillomas

The ability of tumor stem cells to self-renew in an extreme undifferentiated form is actually thought to be one of the main factors that can justify the resistance of malignant brain tumors to chemotherapeutic agents, and their tendency to recur in spite of combined multiple staged treatment protocols. 3.2.9.3.4 Anatomical Distribution

In contrast to what occurs in older children, congenital and infantile brain tumors have a significant predilection for the supratentorial compartment compared with the infratentorial space. In the Cooperative survey of the ISPN, published in 1991, supratentorial tumors accounted for 65.4% of the 840 collected cases and infratentorial tumors for 29.6% [1]. This kind of anatomical distribution has been confirmed by subsequent series. In the 20-year review of series of pediatric CNS tumors, Rickert et al. reported a supratentorial/infratentorial ratio varying from 1.5 to 9.0, with the exception of two series in which an almost equal distribution between the supratentorial and the infratentorial compartment was found [4]. A predominance for midline and ventricular/ periventricular tumors has been reported in most series; among hemispheric locations the frontal lobe appears to be more frequently affected. No definitive explanation of the prevalent location of congenital and infantile brain tumors along midline and ventricular structures has been found. One of the possibilities that has been claimed is their proximity to secondary germinal areas, where substantial cell proliferation occurs in the first 6months of extrauterine life; the neoplastic transformation interesting proliferating primitive cell populations physiologically would also explain the frequent finding of mixed populations and immature/aggressive tumors in this subset of patients. Another feature of brain tumors in infants, if compared with those occurring in older children, is their higher tendency to occupy more than one intracranial compartment. Their frequent origin from multiple cell

Hyperdiploid state indicative of atypical choroid plexus papillomas

lineages and the big tumor size often present at diagnosis may help to explain this finding. 3.2.9.3.5 Clinical Presentation

Advances in prenatal neuroimaging techniques (ultrasonography, MRI) have led to a significant improvement in the prenatal diagnosis of congenital intracranial tumors. Maternal and fetal signs that are considered important in this context are large-for-gestational-age uterus, polyhydramnios, rapidly evolving hydrocephalus, and hydrops [3]. A typical clinical presentation in neonates is stillbirth. In his review of perinatal brain tumors, Isaacs [4] reported that 21 of the 250 cases (21%) were stillborn. In infants clinical manifestations may be delayed; indeed the head enlargement and the plasticity of the developing brain often allow tumor growth without producing significant neurological changes [3, 4]. In the Cooperative Survey of the International Society for Pediatric Neurosurgery [1], the most common clinical findings that first lead to diagnosis of an intracranial tumor in the first year of life were signs of intracranial hypertension (41%) and seizures (12%). Macrocrania (64–82%) and vomiting (39.2–56%) were the most frequent symptoms found by Rickert et al. [4] in their review of the literature up to 1997. Associated congenital anomalies are most often located in the head, with cleft, lip or palate being most frequently involved [3, 4]. A review of neonatal brain tumors by Wakai et al. [5] revealed that of 230 cases, 23 (11.5%) had associated congenital malformations. As in older patients more malignant tumors usually have a shorter duration of symptoms and might be more frequently associated with an acute clinical onset. In this context the incidence of hemorrhages from malignant tumors at diagnosis has been reported to be as high as 14–18%, which is much higher than the rate otherwise seen in children and adults [2, 4]. The rapid tumor growth has been claimed to contribute to this rate, as has the presence of isoforms of vascular endothelial growth

3.2.9 Pediatric Brain Tumors

factors in specific histologic subtypes (i. e., glioblastomas, medulloblastomas). Severe anemia may be the dominant clinical feature in these specific cases. 3.2.9.3.6 Histological Types

Histological types of congenital and infantile brain tumors are significantly different from those found in the older child and adolescent. A further distinction should be made between tumors presenting at birth or in the first weeks of life and those diagnosed between the first month and the first year of age. Teratomas constitute between one-third and one-half of tumors diagnosed prenatally or in the first month of life. Their incidence progressively decreases when considering older patients [2, 3]. In the series by Wakai et al. [5] teratomas represented 54.4% of tumors diagnosed at birth or in the first week of life, but only 28.8% of all the tumors diagnosed between 1month

Fig.3.2.89 a Sagittal, b axial, and c coronal T1 MRI sequences after gadolinium injection of a 20-day-old baby with an immature intracranial teratoma. Anatomical structures of the anterior

and 1year of age (Fig.3.2.89). The second most common perinatal brain tumors are neuroepithelial tumors, which have been reported to have an incidence between 37.4% and 42.5%, most of them being astrocytomas (13–16%) and medulloblastomas (7–8%) [2, 3]. Choroid plexus papillomas (6–7%) and craniopharyngiomas (5–6%) are relatively frequent, while mesenchymal tumors are rare, the whole group constituting about 5% of all intracranial tumors in this age group [2, 3]. On the other hand, when dealing with brain tumors diagnosed between 1 month and 1year of age the most common histological types are neuroepithelial tumors. In the Cooperative Survey of the International Society for Pediatric Neurosurgery [1], astrocytomas (28.6%), ependymomas (11.4%; Fig.3.2.90), medulloblastomas (11.5%), and choroid plexus papillomas (10.6%) (Fig.3.2.91) were by far the most common oncologic types. Teratomas represented 5% and primitive neuroectodermal tumors 6.2%. Craniopharyngiomas

cranial fossa are almost completely replaced by the tumor; thus, the exact site of initial tumor growth cannot be determined

Fig.3.2.90 a Sagittal, b axial, and c coronal T1-weighted MRI sequences after gadolinium injection of a 3-month-old baby with an anaplastic ependymoma. The tumor has a multicystic appearance and extensive intraventricular growth

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Fig.3.2.91 a Sagittal, b coronal, and c axial T1-weighted MRI sequences after gadolinium injection of a 2-month-old baby with a choroid plexus papilloma. The prevalent intraventricular

growth, the connection with the choroid plexus (a, c), and the associated hydrocephalus are typical MRI features of this kind of lesion

were extremely rare (0.4%). Similar results have been reported by other authors in more recent related papers, the whole group of neuroepithelial tumors rating between 63 and 80% of the reported cases [3, 4].

puberty, undetected hypothyroidism, and poor nutrition. Fifty to 80% of children treated with craniospinal radiation for brain tumors will experience growth failure. On the contrary, preoperative and/or postoperative conventional chemotherapy has been used in adjunct to surgery in most series, particularly those dealing with more aggressive histologies or infiltrating lesions; in specific histological subtypes (i. e., medulloblastomas and ependymomas) its role is considered particularly important in delaying radiotherapy, although the influence of conventional chemotherapy on patients’ outcome has still not been completely clarified and improvement in survival rates has been reported. Chemotherapy has also been suggested as preoperative treatment in infants whose general condition is too grave for a major surgical procedure. A reduction of up to one-third of the tumor’s original size has been reported. Operative findings suggest that the main action of chemotherapeutic agents in this context may be on tumor vascularization, with the induction of fibrotic changes.

3.2.9.3.7 Treatment

Surgery is the main step in the treatment of neonatal and infantile brain tumors. The extent of tumor removal is directly related to the patient’s outcome. However, radical resections are conditioned by a frequently undefined and/or eloquent area tumor location and by their frequent multicompartmental extension [2–4]. This is particularly true for teratomas: anatomic landmarks cannot be determined in up to one-half of the cases and sites like the hypothalamus, the pineal or the suprasellar region are often involved [2, 3]. The difficulty in achieving a radical tumor resection is confirmed by data from the literature. Of the 886 cases of the International Society for Pediatric Neurosurgery survey [1] only 389 (43.9%) underwent total tumor removal. In 290 cases (32.7%) partial tumor removal could be achieved, while in 85 cases (9.5%) only a biopsy was carried out. Similar results have been reported by other authors quoting overall rates of total tumor resection between 27 and 58%, subtotal/partial resection between 17 and 46%, and biopsy between 5 and 20% [4, 5]. Radiotherapy is not advised at this early age, because of its long-term cognitive and endocrinological sequelae. Cognitive decline is progressive over at least a decade. The most common radiation-induced endocrinopathies are hypothyroidism and growth hormone deficiency. Treatment effects on growth are multifactorial and include growth hormone deficiency, spinal shortening, precocious

3.2.9.3.8 Prognosis

The patient-dependent factors that appear to be mostly related to survival rates are: • Age at diagnosis • General condition at diagnosis • Histological type of the tumor The role of patient age and general conditions at diagnosis has been underlined by Wakai et al. [5]; in this paper the overall survival rate among 200 infants reviewed from the literature was 7% if the tumor was diagnosed at birth, and 25.6% if the tumor was diagnosed between the first

3.2.10 Radiotherapy

week and the first 2months of life. Histology also resulted in an important clue. Table 3.2.18 summarizes the mean survival rates of congenital and infantile brain tumors compared with the most frequent histological types. Some comments should be added in order to better understand the results cited above: • The fair prognosis of infantile intracranial teratomas can be attributed to the presence in the majority of these patients of advanced disease at the time of diagnosis with multicompartmental tumor location and involvement of eloquent areas [2, 3]. • The wide range of survival rates reported for infants with medulloblastoma is influenced by patients’ selection criteria in the different series and time of patients’ data collection. In fact, advances in surgical techniques have led to a significant improvement in the extent of tumor removal in recent years, a factor that has been related to an improvement in survival rates; new chemotherapeutic regimens have also been claimed to contribute to more favorable results. • The restriction for radiotherapy before the third year of life contributes to the fair results obtained in infants with neoplastic lesions who are unresponsive to chemotherapeutic agents like ependymomas and malignant astrocytomas.

in utero development of associated hydrocephalus contributes to a poor outcome independently of the histological type of the tumor.

Concerning the quality of life, many authors have pointed out the high “price of survival” observed in infants with intracranial tumors; endocrinopathies have been reported in up to 70% of cases, and cognitive deficits have been described in 40–100% of long-term survivors. Again, the younger age and a more malignant histological type are significantly related to a worse outcome [2, 3]. Long-term

3.2.10.1 Introduction

Table3.2.18 Mean survival rates in most frequent congenital and infantile brain tumors Histology

Mean survival rate

Teratoma

7.2–12%

Benign astrocytoma

34–44.4%

Anaplastic astrocytoma and glioblastoma

2–14%

Primitive neuroectodermal tumors

5–12%

Choroid plexus papillomas

50–73%

Craniopharyngioma

8.8–23.5%

Medulloblastoma

7–42.1%

Ependymoma

3–9%

Ependymoblastoma

0–1%

Meningeal tumors

14–36%

Selected Reading 1. Di Rocco C, Iannelli A, Ceddia A (1991) Intracranial tumors of the first year of life. A cooperative survey of the 1986–1987 Education Committee of the ISPN. Childs Nerv Syst 7: 150–153 2. Isaacs H Jr (2002) I. Perinatal brain tumors: a review of 250 cases. Pediatr Neurol 27(4):249–261 3. Isaacs H Jr (2002) II. Perinatal brain tumors: a review of 250 cases. Pediatr Neurol 27(5):333–342 4. Rickert CH, Probst-Cousin S, Gullotta F (1997) Primary intracranial neoplasms of infancy and early childhood. Childs Nerv Syst 13:507–513 5. Wakai S, Arai T, Nagai M (1984) Congenital brain tumors. Surg Neurol 21:597–609

3.2.10 Radiotherapy

Roy P. Rampling

Radiotherapy is the treatment of disease using ionising radiation. It is normally directed at malignant disease, but some benign conditions (e. g. pituitary macroadenomas) are also treated. Most radiotherapy for brain tumours is delivered using postoperative, external beam X-rays. A variety of other techniques is possible including intraoperative radiotherapy, particle radiotherapy and brachytherapy. The value of radiotherapy depends largely on the intrinsic radiosensitivity of the tumour. It may be curative (e. g. in medulloblastomas, germ cell tumours), or prolong survival (e. g. in gliomas). The ambition is to deliver a maximal or curative dose to the entire tumour, whilst minimising the normal tissue damage [1]. 3.2.10.2 Mechanism of Action Radiotherapy is made selective by localising the highdose radiation to the tumour and by exploiting differences in the radiation response of normal and cancerous tissue. The important damage occurs in the DNA, which may be repaired or lead to cell death through a variety of mechanisms. Understanding and manipulating the molecular consequences of radiation exposure are leading to improvements in outcome [2, 3]. To exploit differences in repair and growth kinetics in

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response to radiation, the total dose is divided into smaller doses or “fractions”. In general, the more fractions delivered, the greater the differential one can achieve. Hence, radical treatments are given in 30 or more fractions, whilst palliative treatments comprise far fewer. 3.2.10.3 Standard Basic Equipment Central nervous system (CNS) irradiation should be performed on a linear accelerator of energy 4–6 MV. It should have the capability for beam conformation and intensity modulated radiotherapy (IMRT). There should be access to modern radiotherapy planning facilities based on CT, with image fusion and a simulator for palliative work and beam verification. Most radiotherapy is given at a rate of one fraction of 1.8–2.0Gy per day, 5days a week. For rapidly growing tumours there is a theoretical advantage to giving more than one fraction per day (accelerated radiotherapy). Also, by giving radiotherapy at low doses per fraction, a higher total dose can be given to normal tissue (hyperfractionated radiotherapy) with a better effect on the tumour. This may be effective in some paediatric tumours. In adult tumours neither accelerated nor hyperfractionated radiotherapy has been shown to be of greater benefit [4, 5]. 3.2.10.4 Recent Developments 3.2.10.4.1 Conformal Radiotherapy

Conformal radiotherapy means shaping each of the treatment beams to fit the tumour outline. This can be achieved using a (micro) multi-leaf collimator or cast lead blocks [6, 7]. 3.2.10.4.2 Beam Intensity Modulated Radiotherapy

Conventionally, the radiation dose intensity across any treatment beam is uniform. By using multiple beams with non-uniform (intensity modulated) profiles it is possible to create uniform doses in highly complex (even concave) volumes. This has advantages when working close to sensitive or vital structures [8–10] or when non-uniform dose distributions are desired, so-called dose painting [11]. 3.2.10.4.3 Stereotactic Radiosurgery/Radiotherapy

Stereotaxy in radiotherapy means localising a lesion for treatment with respect to an external co-ordinate system. With adequate patient fixation, stereotactic radiation can be delivered with an accuracy of better than 1mm. Using this system to eliminate vital structures from the beam, ablative doses of radiation can be given at a single applica-

tion Stereotactic Radiosurgery (SRS). Stereotactic Radiotherapy (SRT) uses the same method of localisation applied to conventionally fractionated radiotherapy [7, 12]. 3.2.10.4.4 Radiation Sensitisers

A variety of agents, which theoretically should sensitise tumour tissue to radiation, have been tried in the CNS. These include sensitisers at a subcellular level such as IUdR and hypoxic cell sensitisers such as misonidazole. None has been effective [13]. 3.2.10.5 Standard Approaches to Radiotherapy 3.2.10.5.1 High-Grade Glioma

Radiotherapy prolongs survival for patients with newly diagnosed high-grade glioma (HGG), e. g. [14]. Prognostic factors, including age, performance status, precise histology and to a lesser extent tumour size and resectability, operate in these patients, allowing their treatment to be optimised [15]. Patients who are most likely to benefit should be selected for maximal treatment, whilst those with a poor outlook can be given short courses of radiotherapy or none at all. Treatment should be delivered promptly after surgery. High-dose radiation is localised to the enhancing region or the resection rim plus approximately 2cm. Irradiating large volumes of brain unnecessarily, and whole brain radiotherapy, is no longer acceptable. Tumour resection may improve tolerance to radiation and reduce the need for steroids, which are frequently given during radiotherapy. The maximal standard treatment is 56–66 Gy in 5–7weeks. There is no evidence that increasing the intensity of treatment by using interstitial radiotherapy (iodine seeds) or stereotactic radiosurgery, or by using alternative fractionation schemes improves outcome [4]. Patients with poorer prognosis may be offered short course radiation (e. g. 30Gy in six fractions) It has been established that temozolomide given during and after radiation, improves survival in patients with glioblastoma [16]. In that study the 2-year survival was improved from 10 to 26% with improved “time to progression” and no detriment to quality of life. Patients with good performance status who had undergone tumour resection benefited most. This concomitant/adjuvant regime is now accepted as the standard of care for patients with glioblastoma in many countries. 3.2.10.5.2 Low-Grade Astrocytoma

It is a matter of common experience that radiotherapy can induce regression of low-grade gliomas and improve symptoms. However, the role of radiation is less clear than

3.2.10 Radiotherapy

in HGG. Large-scale trials of the EORTC and RTOG have established that radiotherapy, given at the time of the first diagnosis, does not improve survival, but does delay the time to tumour progression [17]. Intermediate dose treatment (45Gy) is as effective as higher doses (60Gy) [18, 19]. Furthermore, risk factors have been shown to predict those patients who might benefit from early treatment [20]. Patients with good prognostic indicators (age < 50, tumours < 6cm, not involving the midline, with a good performance status) may be kept under surveillance following initial diagnosis. When radiation is required, the irradiated volume should include the entire T2-weighted abnormality plus a 1- to 2-cm margin. Image fusion should be used to optimise target identification and CT planned, non-coplanar conformed fields should be used to optimise tumour coverage. The total radiation dose should be no more than 54Gy (typically 50Gy) with no more than 1.8Gy per fraction [17]. 3.2.10.5.3 Tumours Associated with Widespread Metastatic Potential

Some tumours tend to spread via the CSF (e. g. PNETs, some germ cell tumours). For these, radiation to the whole neuraxis may be required. A uniform radiation dose must be delivered to the entire meningeal surface and its contents with boost doses to the sites of original primary disease and to any bulky metastatic deposits. Patients should be planned using CT with compensators and customised shielding to reduce the risk of damage to vital structures and long-term complications. Typically, a parallel pair of fields irradiates the brain and upper cord with a matched single posterior field to the spine. In standard medulloblastoma treatment without chemotherapy the whole neuraxis receives 30–35 Gy and the tumour is boosted to 55Gy. Doses may be lowered when combined with chemotherapy. Refinements of treatment are the subjects of contemporary trials [21–23]. 3.2.10.5.4 Radiotherapy for Benign Tumours

Some benign tumours benefit from radiotherapy (meningioma, pituitary adenoma, craniopharyngioma). Longterm survival prospects are good so particular care must be taken with localisation and delivery using stereotaxy, conformality, IMRT and non-coplanar planning where appropriate. The minimum effective dose is delivered in fraction sizes less than 2Gy. SRS may also be used in some situations. 3.2.10.5.5 Metastases

Radiation is established in the management of brain metastases from systemic cancer, but is probably overused. Patient selection should be based on an accepted classi-

fication scheme [24]. Patients with multiple metastases and poor performance status (RPA 3) probably gain no benefit from treatment. Younger patients with better PS (RPA 2) should receive short-course radiation (20Gy in five fractions in 1week). Patients with solitary (or few) brain metastases, particularly if they have controlled systemic disease (RPA 1) should be considered for a radical approach to their intracranial disease. Surgery and stereotactic radiosurgery (SRS) to the index lesion appear to produce the same level of control for small tumours. The addition of whole brain radiotherapy reduces relapse within the brain [25] and may be beneficial [26–28]. 3.2.10.6 The Late Consequences of Radiation Therapy to the Brain Healthy brain adjacent to a tumour that is unavoidably irradiated is at risk of damage. The most important changes occur late after the delivery of radiation (6months to 10 years) and comprise white matter change, vascular damage, neuronal fallout, gliosis and calcification. Clinical manifestation may vary from minor cognitive deterioration to gross neurological deficit. The risks following carefully delivered and scheduled radiation have probably been overstated. In patients with low-grade glioma the late consequences may be modest in patients with no pre-irradiation deficit [29]. In patients with abnormal baseline cognitive function there may be improvement following radiation therapy [30]. 3.2.10.7 Clinical and Research Developments 3.2.10.7.1 Protons

Protons travelling in a medium deposit a large amount of energy in the final few millimetres of their path, known as the Bragg peak. This property can be used to deliver highly localised 3-D conformed dose distributions to tumours requiring high doses that lie immediately adjacent to vital structures. The most common applications in the CNS are chordomas of the clivus, and other skull base tumours. High-energy proton beams are expensive and the technique is available in very few centres [31]. 3.2.10.7.2 Brachytherapy

Brachytherapy, usually using temporary, high activity 125I seed implants, has been used to treat high-grade gliomas at relapse or as a boost at first presentation. Mature results have not confirmed the value of brachytherapy [32–34]. Implants have also been used to treat low-grade gliomas and iridium wire afterloading has been used for palliation in glioblastoma.

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3.2.10.7.3 Boron Neutron Capture Therapy

Boron neutron capture therapy (BNCT) relies on the capture interaction of very low-energy (thermal) or lowenergy (epithermal) neutrons with the stable isotope Boron-10 (10B). Capture causes the 10B to split, releasing α and lithium particles. N + 10B → 4He + 7Li Successful BNCT requires selective accumulation of 10B into brain tumours using boron labelled compounds such as 10B-BSA. Irradiation with low-energy neutrons releases short-range, high linear energy transfer (LET) particles in the vicinity of the tumour. The technique is under study in a few centres world-wide [35, 36]. 3.2.10.8

The Future of Radiation Therapy in the CNS

Radiation therapy is a major treatment modality in the management of many intrinsic, particularly malignant, brain tumours. This will remain true for the foreseeable future. However, we are approaching a limit beyond which technical improvement in the delivery of radiation will have little additional benefit. Future improvement will result from our increasing understanding of the mechanisms of cell cycle control and its response to radiation insult. Selected Reading 1. Rampling R (2008) Central Nervous system. In: Price P, Sikora K and Illidge T in Treatment of Cancer. Arnold, London, pp 287–319 2. Valerie K et al. (2000) Novel molecular targets for tumour radiosensitisation. Molecular radiation biology and oncology workshop: translation of molecular mechanisms into clinical radiotherapy. Int J Cancer 90(1):51–58 3. Jones B, Dale D (1999) Inclusion of molecular biotherapies with radical radiotherapy: modelling of combined modality treatment schedules. Int J Radiat Oncol Biol Physics 45(4):1025–1034 4. Rampling R (1998) Modern aspects of radiation therapy for glial tumours of the brain. Forum (Genova) 8:289–301 5. Rao R et al (2002) Safety of thrice daily hyperfractionated radiation and BCNU for high grade gliomas. Int J Radiat Oncol Biol Phys 53(2):376–384 6. Chan J et al. (2002) Survival and failure patterns of high grade gliomas after three dimensional conformal therapy. J Clin Oncol 20(6):1635–1642 7. Saren F et al (2002) Stereotactically guided conformal radiotherapy for progressive low grade tumours of childhood. Int J Radiat Oncol Biol Phys 53(1):43–51 8. Zhen W, Thompson RB, Enke CA (2002) Intensity-modulated radiotherapy (IMRT): the radiation oncologist’s perspective. Med Dosim 27(2):155–159

9. Intensity Modulated Radiation Therapy Collaborative Working Group (2001) Intensity modulated radiotherapy: current status and issues of interest. Int J Radiat Oncol Biol Phys 51(4):880–914 10. Thilmann C et al (2001) Intensity modulated radiotherapy with an integrated boost to the macroscopic tumour volume in the treatment of high grade gliomas. Int J Cancer 96(6):341–349 11. Suzuki M et al (2003) Feasibility study of the simultaneous integrated boost (SIB) method for malignant gliomas using intensity modulated radiotherapy. Jpn J Clin Oncol 33(6):271–277 12. Weil M (2001) Stereotactic radiosurgery for brain tumors. HematoOncol Clin North Am 15(6):1017–1026 13. Prados M et al (2004) Phase III randomised study of radiotherapy plus procarbazine, lomustine and vincristine with or without BUdR for treatment of anaplastic astrocytoma. Int J Radiat Oncol Biol Phys 58(4):1147–1153 14. Walker MD et al (1978) Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. J Neurosurg 49:333–343 15. Scott CB et al (1998) Validation and predictive power of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: a report using RTOG 90–06. Int J Radiat Oncol Biol Phys 40(1):51–55 16. Stupp R et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996 17. Karim A et al (2002) Randomized trial on the efficacy of radiotherapy for cerebral low grade glioma in the adult: European Organisation for Research and Treatment of Cancer study 22845 with the Medical Research Council study BRO4: an interim analysis. Int J Radiat Oncol Biol Phys 52(2):316–324 18. Karim ABMF et al (1996) A randomized trial on dose-response in radiation therapy of low-grade cerebral glioma: European Organization for Research and Treatment of Cancer (EORTC) study 22844. Int J Radiat Oncol Biol Phys 36(3):549–556 19. Shaw E et al. (2002) Prospective randomised trial of lowversus high dose radiation therapy in adults with supratentorial low grade glioma: initial report of a North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group Study. J Clin Oncol 20(9):2267–2276 20. Pignatti F et al (2002) Prognostic factors for survival in adult patients with cerebral low-grade glioma. J Clin Oncol 20(8):2076–2084 21. Pomery S et al (2002) Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415(6870):436–442 22. Packer R et al (1999) Treatment of children with medulloblastomas with reduced dose craniospinal radiation therapy and adjuvant chemotherapy: a Children’s Cancer Group Study. J Clin Oncol 17:2127–2136

3.2.11 Chemotherapy for Brain Tumors

23. SIOP (2002) A prospectively randomised controlled trial of hyperfractionated versus conventionally fractionated radiotherapy in standard risk medulloblastoma – a protocol 24. Gaspar LE et al (2000) Validation of the RTOG recursive partitioning analysis (RPA) classification for brain metastases. Int J Radiat Oncol Biol Phys 47(4):1001–1006 25. Shehata M et al. (2004) Stereotactic radiosurgery of 468 brain metastases < or +2cm implications for SRS dose and whole brain radiation therapy. Int J Radiat Oncol Biol Phys 59(1):87–93 26. Mehta MP, Tremont-Lukats I (2002) Evaluation and management of brain metastases. In: ASCO 38th Annual Meeting 2002. American Society of Clinical Oncology, Orlando 27. Patchell R (2002) Treatment of brain metastases. In: ASCO 2002. American Society of Clinical Oncology, Orlando 28. Patchell R et al (1998) Postoperative radiotherapy in the treatment of single metastases to the brain: a randomised trial. JAMA 280(17):1485–1489 29. Klein M et al. (2002) Effect of radiotherapy and other treatment-related factors on mid-term to long-term cognitive sequelae in low-grade gliomas: a comparative study. Lancet 360(9343):1361–1368 30. Brown P et al (2003) Effects of radiotherapy on cognitive function in patients with low grade glioma measured by the Folstein mini mental state examination. J Clin Oncol 21(13):2519–2524 31. Hug E et al (2002) Proton radiotherapy in the management of pediatric base of skull tumours. Int J Radiat Oncol Biol Phys 54(2):1017–1024 32. Patel S et al. (2000) Permanent iodine-125 interstitial implants for the treatment of recurrent glioblastoma multiforme. Neurosurgery 46(5):1123–130 33. Suh J, Barnett G (1999) Brachytherapy for brain tumor. Hematol Oncol Clin N Am 13(3):635–650 34. Selker R et al (2002) The Brain Tumour Group NIH trial 87–01: a randomised comparison of surgery, external beam radiotherapy and carmustine versus surgery, interstitial radiotherapy boost, external beam radiotherapy and carmustine. Neurosurgery 51(2):343–357 35. Barth R et al. (1999) Boron neutron capture therapy of brain tumors: an emerging therapeutic modality. Neurosurgery 44(3):433–450

36. Sauerwein W, Zurlo A (2002) The EORTC boron neutron capture therapy (BNCT) group: achievements and future projects. Eur J Cancer 38 [Supp 4]:S31–S3.

3.2.11 Chemotherapy for Brain Tumors

Martin J. van den Bent 3.2.11.1 General Guidelines • Before treatment, hematological, renal, and hepatic function must be checked. • Do not give chemotherapy in the presence of infections. • For females: preclude pregnancy if of fertile age; for both males and females: advice on contraception. Consider sem*n preservation. • The patient should be seen by a specialist with expertise on chemotherapy. • For scoring of toxicities see the Common Terminology Criteria for Adverse Events, http://ctep.cancer. gov/forms/CTCAEv3.pdf; Table3.2.19 displays hematological toxicity • The dosage is determined using the body surface area (BSA). In patients with a calculated body surface > 2.1, the BSA should be taken as 2.1. 3.2.11.2 Temozolomide 3.2.11.2.1 Treatment Schedule of Radiotherapy with Concomitant and Adjuvant Temozolomide for High-Grade Glioma (EORTC 26981 Schedule)

Treatment consists of two phases: concomitant radiotherapy and temozolomide chemotherapy, followed by six cycles of the classic regime of temozolomide chemotherapy days 1–5 every 4weeks.

Table3.2.19 Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0: hematological toxicities Adverse even, unit

Grade 1

Hemoglobin, mmol/L

< LLN-6.2 < LLN-3.0

Leukocytes, 10 /L 9

Grade 2

Grade 3

Grade 4

< 6.2–4.9

< 4.9–4.0

< 4.0

< 3.0–2.0

< 2.0–1.0

< 1.0

ANC, 10 /L

< LLN-1.5

< 1.5–1.0

< 1.0–0.5

< 0.5

Lymphocytes, 109/L

< LLN-0.8

< 0.8–0.5

< 0.5–0.2

< 0.2

CD4 count, /mm3

< LLN-500

< 500–200

< 200–50

< 50

< LLN-75

< 75–50

< 50–25

< 25

Platelets, 10 /L LLN: lower limit of normal

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ule of temozolomide on days1–5 every 4weeks for the dosing specifications.

3.2.11.2.1.1 Temozolomide in the Concomitant Phase

Radiotherapy (RT) 60 Gy (30 × 2 Gy) combined with temozolomide (daily 75 mg/m2). Expected duration: 6 weeks; concomitant temozolomide should not exceed 7weeks • Administer temozolomide 1 h before each session of RT on weekdays. At weekends etc. without RT temozolomide is to be continued and to be taken in the morning. • One hour before the first and second dose of temozolomide, anti-emetic prophylaxis with a 5-HT3-antagonist (e. g., 8mg ondansetron, 1mg granisetron) is recommended. During the concomitant radiochemotherapy with low-dose daily TMZ, continuation of anti-emetic prophylaxis beyond the first 2days is only occasionally necessary. • Pneumocystis jiroveci pneumonia (PCP) prophylaxis (960 mg cotrimoxazole three times a week or pentamidine inhalations) is indicated especially in patients using steroids, either during the entire concomitant phase or if CD4 counts are < 200/mm3. Prophylaxis should continue until patients have fully recovered from any lymphocytopenia (CTC grade ≤ 1). • During the radiotherapy patients should be monitored for toxicity once a week. – Weekly: complete blood count (Hb, Ht, WBC, ANC, platelets, CD4 counts if used for decision on PCP prophylaxis) – At the end of week four and prior to the start of adjuvant treatment: serum chemistries (renal, hepatic function, serum electrolytes, glucose) • Temozolomide delay and stopping rules in the concomitant phase (Table3.2.20).

3.2.11.2.2 Standard Temozolomide Chemotherapy for Recurrent Disease or Adjuvant Treatment

• Treatment is given according to the standard schedule of administration on days 1–5 every 4weeks: – The starting dose for the first adjuvant cycle is 150mg/m2/day on days1–5, with a single dose escalation to 200 mg/m2/day on days 1–5 in subsequent cycles in the event of no significant toxicity in the first cycle (all CTC non-hematological toxicity Grade ≤ 2 (except for alopecia, nausea, and vomiting) and with platelets ≥ 100 × 109/L and ANC ≥ 1.5 × 109/L). – For treatment of recurrent disease: In patients at the beginning of the next cycle who have undergone previous chemotherapy the starting dose for the first cycle will be 150mg/ m2/day on days 1–5, with a single dose escalation to 200 mg/m2/day in subsequent cycles in the event of no significant toxicity (see above). Chemo-naive patients start on 200 mg/m2/day on temozolomide on days1–5. – Three dose levels are used: 200mg/m2, 150mg/m2, and 100mg/m2 daily on days 1 to 5. • Duration of treatment: – In newly diagnosed glioma after concomitant chemo-irradiation a maximum of six cycles of adjuvant treatment. – For recurrent disease until progression or 12 cycles. • During standard days 1–5 temozolomide treatment anti-emetic prophylaxis with a 5-HT3-antagonist is recommended as nausea and vomiting may be severe, especially on days 1 and 2. Because 5-HT3-antagonist may induce constipation it is advised to give ondansetron (8mg) or granisetron (1mg) once or twice daily

3.2.11.2.1.2 Temozolomide in the Adjuvant Phase for Newly Diagnosed Glioma

The start of the first cycle will be scheduled 28 ± 3 days after the last day of radiotherapy. See the standard sched-

Table3.2.20 Temozolomide (TMZ) delay and stopping rules in the concomitant phase Toxicity ANC Platelets count

Value

CTCAE grade Action 9

2, 3

1, 2, 3

≥ 0.5 and < 1.5 × 10 /L ≥ 25 and < 100 × 10 /L

Delay TMZ until normalization

CTC non-hematological toxicity (except for alopecia, nausea, and vomiting) 2 ANC Platelets count

< 0.5 × 109/L 9

< 25 × 10 /L

CTC non-hematological toxicity (except for nausea, vomiting)

4 4 3, 4

Stop concomitant TMZ

3.2.11 Chemotherapy for Brain Tumors

•

on days 1–3; thereafter, only when needed, and to be taken 1h before temozolomide dosing. Before each treatment cycle with temozolomide a complete blood count (CBC) has to be obtained (within 72h before dosing). Check hematological parameters on day 21 in the first cycle or after dose increase. Reduce the dose one level in the case of nadir (usually around day 21) NCIC-CTC hematological toxicity grade 3 or 4; in the case of NCIC-CTC grade 3 nonhematological toxicity, or if the start of the next cycle is delayed thereby 3weeks because of toxicity. Stop treatment in the case of grade 3 cardiotoxicity, grade 4 hematological toxicity or grade 3 non-hematological toxicity at the dosage of 100 mg/m2 daily (500mg/m2 per cycle), or any non-hematological toxicity CTC grade 4 (except for nausea and vomiting). The next cycle can start if ANC ≥ 1.5 × 109/L and/or platelet count ≥ 100 × 109/L on day 29 = day 1 of the next cycle; and all non-hematological toxicities (except for alopecia) have resolved to CTC grade ≤ 1: – If not, delay the next cycle until resolved – If not resolved by 3weeks, discontinue treatment

3.2.11.2.3 Alternative Temozolomide Chemotherapy Dosing Regimen

• Several other temozolomide regimens have been used that allow a more dose-dense temozolomide administration, by giving temozolomide on more days every 4weeks. The most frequently used are: – One week on, 1 week off: alternatively 1 week of daily temozolomide and 1week of rest • Dose levels used: 100 mg/m2 daily, 125 mg/m2 daily, 150mg/m2 daily – Three weeks on, 1week off: alternatively 3weeks of daily temozolomide followed by 1week of rest • Dose levels used: 75 mg/m2 daily, 100 mg/m2 daily • Nausea and vomiting is often less troublesome than with the standard dosing regimen, lower dosages of anti-emetics can be tried; preferably 5HT3 antagonists are to be used • Fatigue, malaise, etc., may be more pronounced, which may increase after more cycles • Lymphopenia is a side effect of all dose-dense regimens. Monitoring of CD4+ counts is advised, with the administration of PCP prophylaxis if CD4+ counts fall below 200/mm3 (and continuation until recovery > 200mm3) • Start with lower dosages if these regimens are given after previous chemotherapy • Reduce dosage and start new cycles according to the guidelines given for the days 1–5 every 4 weeks schedule • Consider switching to standard days 1–5 every 4weeks dosage in the case of debilitating general symptoms

• Recommended duration of treatment in recurrent disease: up to 1year 3.2.11.3 PCV Chemotherapy • Each course of standard PCV chemotherapy consists of: – CCNU (lomustine), 110mg/m2 orally on day 1 with anti-emetics (domperidone or metoclopramide, if necessary ondansetron or a similar agent) – Procarbazine (Natulan), 60mg/m2 orally for 14days on each cycle, on days 8–21 – Vincristine, 1.4mg/m2 i. v. on days 8 and 29 of each cycle (maximum 2mg) • A full course of therapy will be repeated every 6weeks (42days), for a maximum of six cycles. • The efficacy of vincristine has been questioned, and is left out of the schedule by many physicians. • Toxicity consists mainly of cumulative myelosuppression, nausea, alopecia, fatigue, loss of appetite, liver disturbances, and polyneuropathy (vincristine). – Procarbazine may cause an allergic skin reaction. – The ingestion of tyramine-containing foods such as red wine, ripe cheese, and bananas during treatment with procarbazine may induce a hypertensive crisis (mono-amine oxidase effect), and patients should be warned not to use these products. Patients should also be warned for a disulfiram-like effect after the ingestion of alcohol (headache, flushes, and sweating). • The nausea and vomiting caused by the PCV scheme is usually manageable with conventional anti-emetic treatment, i. e., domperidone or metoclopramide. • Follow-up schedule: – Hematological parameters on days 1, 8, and 43 (= day 1 of the next cycles) – Serum chemistry before the start of each cycle • Dosage modifications: – If the regimen is used after previous combined chemo-irradiation with temozolomide: decrease the dosage of CCNU and procarbazine by 25% – In the case of white blood cell count < 3.0109/L or thrombocytes < 100 × 109/L at day1: • CCNU will be delayed 1week. In the case of persistent leukopenia < 3.0 × 109 or thrombocytopenia < 100 × 109 treatment will be delayed another week. If leukopenia or thrombopenia persist thereafter, discontinue chemotherapy. • In the case of a cycle having to be delayed for 2weeks for toxicity, reduce the dosage of CCNU and procarbazine by 25%. – Reduce the dosage of CCNU and procarbazine by 25% in the case of grade III/IV leuko- or granulocytopenia, or in the case of grade III/IV thrombocytopenia.

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– In the case of WBC < 3.0 × 109/L or thrombocytes

–

– – –

–

< 100 × 109/L at day8: • Both vincristine and procarbazine will be delayed for 1 week. In the case of persistent leukopenia < 3.0 × 109 or thrombocytopenia < 100 × 109 treatment will be delayed another week. If hematological abnormalities persist the patient comes off the treatment. Reduce the dosage of CCNU and procarbazine by 25% in the case of CTCAE (Common Toxicity Criteria for Adverse Events) vs 3 grade 2 or 3 nonhematological toxicity. Stop treatment in the case of: • CTCAE grade 3 cardiotoxicity • Grade 4 hematological toxicity or a CTCAE vs. 3 grade 3 non-hematological toxicity, despite dose reductions • Or any non-hematological toxicity CTCAE vs. 3 grade 4 (except for nausea and vomiting) In the case of an allergic skin reaction, procarbazine must be discontinued. Vincristine will be stopped in the case of a grade II neurotoxicity. Because of the cumulative myelosuppression of CCNU, continuation of treatment in the presence of marginal hematological abnormalities will result in more severe toxicity in subsequent cycles. As a rule, hepatic abnormalities improve slowly.

3.2.11.4 BCNU (Carmustine) Sixty mg/m2 on days 1–3 every 8weeks: • The most common regimen for BCNU (carmustine) is 130–200mg/m² every 6weeks, but an 8-week regimen at the dosage of 80mg/m² given days 1–3 proved to be feasible in a phase II study including 40 patients with high-grade glioma. A study on GBM patients pretreated with temozolomide (combined chemo-irradiation) observed significant hematological toxicity at this dose level and reduced the dosage to 60mg/m2 on days1–3 in 8-week cycles. • Major side effects are hematological toxicity, long-lasting liver toxicity, nausea, and pulmonary toxicity. • BCNU is administered intravenously on days1 to 3 at the dosage of 60mg/m2/day (dose per cycle 180mg/ m2) every 8weeks. Prescribe anti-emetics (metoclopramide, domperidone). • Contra-indications: a history of pulmonary disease that may affect pulmonary function, the patient should have their respiratory function evaluated by carbon monoxide diffusion capacity (DLCO), which must be more than 60% of the predicted value. • Follow-up schedule:

– Hematological parameters on days 21, 28, 35, 42,

and day 65 (= day 1 of the next cycles)

– Serum chemistry before the start of each cycle

• Dosage modifications: – In the case of WBC < 3.0 × 109/L or thrombocytes < 100 × 109/L at the start of new cycles: delay until recovery • If the hematological toxicity is not recovered within 2 weeks or if hematological toxicity recurs during a subsequent cycle to CTCAE grade ≥ 2, discontinue treatment. – In the case of hematological toxicity CTCAE grade 3, reduce the dosage of the next cycles by 25%. – In the case of hematological toxicity CTCAE grade 4: reduce the dosage of the next cycle by 50%. – For non-hematological toxicity: • Do not start the next cycle until all toxicities (except alopecia) have recovered to CTCAE grade 1 or less. • If liver toxicity is CTCAE grade 2, the dosage of the next cycles will be reduced by 25% after return to normal. • If liver toxicity is CTCAE grade 3, the dosage of the next cycles will be reduced by 50% after return to normal. • In the case of pulmonary toxicity grade 1 or 2, administer desmethylclomipramine (DCLO); if < 60% of predicted value, discontinue treatment. In the case of pulmonary toxicity grade 3 or 4, discontinue treatment. • In the case of any grade 4 or non-hepatic grade 3 non-hematological toxicity (except nausea, vomiting, and alopecia), discontinue treatment. • If the non-hematological toxicity is not recovered within 1month or if non-hematological toxicity recurs at a subsequent cycle to grade ≥ 2, discontinue treatment.

3.2.12 Advantages and Limits of Adjuvant Treatments in Pediatric Brain Tumors

Vita Ridola, Jacques Grill 3.2.12.1 Epidemiology Malignant brain tumors are the leading cause of cancer death among children and the second most common type of pediatric cancer after leukemia, comprising 20–25% of all childhood cancers. Astrocytomas account for 52% of childhood brain tumors, medulloblastoma/embryonal tumors account for 21%, ependymomas for 10%, and other gliomas for 15%.

3.2.12 Advantages and Limits of Adjuvant Treatments in Pediatric Brain Tumors

3.2.12.2 Background Gross total surgical removal alone is curative for lowgrade tumors and it is the optimal condition required to obtain a cure in the case of high-grade tumors. Nevertheless, surgery alone is rarely curative in patients with histologically malignant lesions. Adjuvant treatments such as chemotherapy and/or radiotherapy are needed to improve disease control for medulloblastomas and ependymomas, high-grade gliomas, tumors in deepseated midline structures, and for recurrent or metastatic disease. Despite advances in neurosurgery, oncology, and radiotherapy, pediatric brain tumors still pose considerable therapeutic challenges: • Intrinsic tumor resistance to adjuvant therapies, including chemotherapy and radiotherapy. • Inadequate drug delivery, given the presence of the blood–brain barrier. • Considerable heterogeneity both between different histologies and within one tumor type (i. e., there are at least four different types of medulloblastoma). • The benefit of potentially curative radiotherapy is offset by the significant and unacceptable long-term sequelae. 3.2.12.3 Adjuvant Treatment Options 3.2.12.3.1 Radiotherapy

For many childhood CNS tumors, radiotherapy plays an essential role. Frequently, these tumors cannot be completely cured with surgery because of their location or because of microscopic or macroscopic spread. Therefore, radiation therapy is frequently employed alone or as part of a multimodal treatment approach in combination with surgery and/or chemotherapy. Nonetheless, conventional radiotherapy is associated with worrying long-term side effects: • Late neurocognitive sequelae and intellectual impairment • Hearing loss • Endocrinological deficits of hypothalamic–pituitary axis (i. e., growth hormone deficiency) • Potential development of second malignancies Potentially long-term intellectual sequelae are a major concern for patients treated with CNS irradiation. The main risk factors for cognitive damage in irradiated children are: • Cranio-spinal irradiation (CSI): in cross-sectional comparative studies, less severe deficits in IQ have been shown in ependymoma patients irradiated on the posterior fossa alone than in medulloblastoma patients treated with cranio-spinal irradiation.

• Age: younger ages at the time of treatment are at a higher risk of IQ deficits with particularly devastating effects under the age of 3years. • Decline in IQ is progressive over time without reaching a “plateau,” in longitudinal studies. • Dose of cranio-spinal irradiation: IQ is significantly lower in children irradiated at a standard CSI dose of 35Gy than in those irradiated at a reduced dose of 24Gy. In order to decrease the late effects of radiotherapy, conformal radiation therapy techniques have been developed to deliver the high radiation dose to the tumor target with very little dose to the adjacent normal tissue. Included in such techniques are three-dimensional conformal radiotherapy, radiosurgery, intensity-modulated radiotherapy, and proton irradiation. 3.2.12.3.2 Chemotherapy

In the last few decades chemotherapy has been introduced into the treatment of pediatric brain tumors with the aim of: • Improving the prognosis • Postponing or avoiding radiotherapy in very young children • Decreasing the dose of cranio-spinal irradiation in MB/PNETs The most effective drugs are: platinum compounds, nitrosurea, cyclophosphamide, topoisomerase inhibitors such as CPT-11 or etoposide, busulfan, thiotepa, and other alkylating agents such as temozolomide. For chemosensitive tumors such as medulloblastoma and germ cell tumors, high-dose chemotherapy followed by autologous stem cell rescue has been used to achieve better survival rates in high-risk or relapsed patients, as well as to supplant CSI in very young children. High-dose chemotherapy regimens are frequently based on a combination of two or three drugs (thiotepa, melphalan, busulfan, carboplatin, etoposide, and cyclophosphamide). The use of a high systemic dose allows high concentration within the tumor, but leads to more severe toxicities. Myelosuppression is transient and is overcome by the use of stem cell rescue; however, other dose-limiting toxicities can occur, including those to the liver, lung, kidney, CNS, and cardiovascular system. Toxic deaths range from 5 to 10%, mainly due to infections, veno-occlusive disease, and multi-organ failure. Although standard chemotherapy kills most dividing cells in a tumor, it is not effective against cancer stem cells that are naturally resistant through their quiescence, capacity for DNA repair, and resistance to apoptosis. Consequently, at least some of the tumor stem cells can survive chemotherapy and result in regrowth of the tumor.

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Interactions can occur between antineoplastic agents and other drugs and can also be affected by the patient’s genetic polymorphism in metabolizing enzymes. Drugs interactions can modify the pharmaco*kinetics of chemotherapy agents and may significantly alter its efficacy or toxicity. For example, antiepileptic drugs and chemotherapeutics share common metabolic pathways via the hepatic cytochrome P450 isoenzymes (CYP). Phenytoin, carbamazepine, and phenobarbital are potent inducers of CYP that can cause a decrease in the serum concentration of chemotherapeutics, potentially compromising antitumor activity. Other agents, such as valproic acid, are enzyme inhibitors that can potentially increase the serum concentrations of anticancer drugs (e. g., cisplatin, nitrosourea). New antiepileptic drugs, such as gabapentin or levetiracetam, are not metabolized by CYP and do not interact with chemotherapy. Steroids may alter the blood–brain barrier and limit drug penetration, and some compounds, such as dexamethasone, can induce CYP and alter the pharmaco*kinetics of chemotherapy. Significant limitations are associated with the use of standard radiographic measurements as indicators of response in chemotherapy trials on brain tumors. There is a need to standardize the methodology to assess and simplify objective tumor response to treatment. Actually, the response rates can be derived from 1D (greatest length; RECIST criteria), 2D (two-dimensional: product of the two longest perpendicular diameters; WHO criteria), or 3D (three-dimensional: product of the longest perpendicular diameters in one plane and the longest orthogonal diameter to that plane). More recently, several new classes of anticancer drugs have been explored in clinical trials. These new drugs often act through different molecular pathways and they do not induce massive cell kill like standard chemotherapeutics; evaluating their therapeutic effect should also take into consideration endpoints such as duration of response, 6-month progression-free survival (PFS), and quality of life. 3.2.12.4 Malignant Gliomas High-grade gliomas (HGG; WHO grade III–IV) account for 15% of pediatric brain tumors, excluding brain stem tumors. They are characterized by histological features of glial origin, namely glioblastoma multiforme (GBM), anaplastic astrocytoma (AA), and oligodendroglioma, with high malignancy and a generally poor prognosis, despite multimodal treatment. Overall survival at 5years is at the best 40% in published series. • The current therapeutic management includes maximal tumor resection, whenever possible, followed by radiation therapy. Because chemotherapy has shown some benefit, inclusion in chemotherapy trials is ad-

•

vised, especially in patients who could not be completely resected. Different from adult patients, gross total resection is of major importance for prognosis: PFS at 5 years is 35% in patients who undergo a complete resection (26% for GBM and 44% for AA) compared with 17% in patients with incomplete resection (4% for GBM and 22% for AA). Radiation therapy is recommended in children with HGG and who are over 3years of age. The total dose of radiation to the tumor bed is up to 54–59.5Gy with a 2-cm margin with conventional fractionation. Craniospinal radiation therapy is performed only for the rare patients with disseminated disease at diagnosis. Chemotherapy has shown a very limited benefit in the treatment of high-grade gliomas. In a randomized CCG study radiotherapy plus adjuvant CCNU/ vincristine/prednisone results in a PFS at 5 years of 46% versus 18% in children treated with radiotherapy alone. High-dose chemotherapy, despite high acute toxicity, does not seem to improve the overall survival, with some exceptions for children with a minimal tumor burden at the time of treatment. Children younger than 3 years of age have been enrolled in prolonged chemotherapy regimens (BabyPOG; BabySFOP) with delayed radiotherapy. Fiveyear PFS and OS are 31–43% and 50–54% respectively. Cases of long-term survivors who did not receive radiotherapy are reported and overall survival is around 50% despite the avoidance of RT (no studies yet). Temozolomide has shown to be a promising agent against adult high-grade gliomas. Its low toxicity profile and good bioavailability after oral administration make it an interesting drug even if, at the moment, the results of pediatric studies are less encouraging than in adults.

3.2.12.5 Low-Grade Gliomas Low-grade gliomas (LGG; WHO grade I–II; Fig.3.2.92) are a heterogeneous group of tumors in which most have prolonged indolent phases, whereas some tumors progress quickly, and others are associated with neurofibromatosis type 1 (NF1) and rarely progress after the first decade of life. Primary surgery with gross total resection is the treatment of choice whenever possible (i. e., hemispheric, cerebellar, exophytic brain stem and spinal tumors). The extent of resection correlates with clinical evolution and PFS. In the case of recurrence, repeated attempts at total surgical removal can be performed before considering adjuvant therapy. Non-surgical treatment is not indicated for tumors that have been completely removed.

3.2.12 Advantages and Limits of Adjuvant Treatments in Pediatric Brain Tumors

For unresectable LGG (i. e., optic pathways; hypothalamus; thalamus; brain stem) chemotherapy and radiotherapy have to be considered, especially in cases of symptomatic, clinically or radiologically progressive lesions. In the case of stable disease at the moment of diagnosis, for unresectable tumors, such as optic pathway gliomas occasionally ascertained in the initial staging of NF1, a “wait and see” policy with close follow-up is currently adopted. In the setting of diffuse chiasmatic/hypothalamic tumors radiotherapy is effective for tumor control, with overall survival at 5years reaching 90%. Doses allowing favorable outcomes are in the range of 45–56Gy. Because of long-term radiation-induced side effects such as endocrinopathy, developmental abnormalities, neurocognitive impairment, and vasculopathy (there is a higher risk of “moya-moya” syndrome in NF1 patients who undergo RT), chemotherapy has been proposed to postpone or avoid radiotherapy, especially in young children. Actually, in patients less than 8years of age first-line treatment is deemed to be chemotherapy, based on the “Packer regimen” with carboplatin/vincristine association for at least 1 year. Median radiotherapy-free intervals obtained by chemotherapy are between 22 and 35months according to the different protocols. In a French study, 5-year radiotherapy-free survival was 61% employing a multidrug regimen. Progression-free survival at 5years is in the range of 34–40% in different chemotherapy protocols. For children older than 8years of age, radiotherapy at 50–54Gy can be considered the first-line treatment, but chemotherapy may still be proposed when the radiation field is too large. In NF1 patients leukemogenic chemotherapy (i. e., etoposide) and radiotherapy should be avoided as they

have an accrued risk of leukemia and cerebral vasculopathy. Leptomeningeal spread has been observed in 5 and 12% of cases at diagnosis or at progression respectively. It is an indication for treatment with chemotherapy or radiotherapy depending on the age of the patient. Multicentric disease can be more often associated with the pilomyxoid astrocytoma and the evolution of disease is extremely variable, with the potential for prolonged disease stabilization. Patients often require multiple lines of chemotherapy, possibly associated with repeated surgery. 3.2.12.6 Medulloblastoma/sPNETs Medulloblastoma (WHO grade IV; Fig.3.2.93) is a malignant, invasive primitive neuroectodermal tumor (PNET) arising in the cerebellum and it accounts for 16% of primary CNS tumors in childhood, with a peak incidence at 5years of age. Most (80%) arise in the median part of the cerebellum and the remaining 20% in the cerebellar hemispheres. Leptomeningeal dissemination is present in one-third to one-half of patients at diagnosis. At histopathology four main variants are recognized: classic MB; anaplastic/large cells MB, desmoplastic MB, and MB with extensive nodularity. Correct staging for children with MB includes: • Preoperative brain and spine MRI • Early postoperative brain CT or MRI with and without contrast (in the first 72h after surgery) • CSF cytology through lumbar puncture at 15days after surgery

Diagnosis

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Fig.3.2.92 Management of childhood low-grade gliomas (LGG)

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Regarding risk stratification, patients are currently classified as: • Standard risk: no metastases on cranio-spinal MRI + negative CSF cytology + absence of postsurgical residual disease on early postoperative CT/MRI and on surgical report. All these conditions are needed to be assigned to the standard risk group. • High risk: postsurgical residual disease and/or metastatic disease on cranio-spinal MRI and/or CSF cytology. Treatment protocols start with maximal surgical resection followed by adjuvant radiation and chemotherapy given the high radio- and chemo-sensibility of MB and the ineluctable poor prognosis of children treated with neurosurgical resection alone. Standard radiation therapy for MB is based on craniospinal irradiation (CSI) at 35Gy with a boost to the posterior fossa, assuring a total dose to this area of 50–55Gy and allowing a survival rate of about 50%. Randomized clinical trials have demonstrated an improved event-free survival (EFS) in patients with non-metastatic MB when chemotherapy is administered before radiotherapy compared with radiotherapy alone (EFS at 5years: 74 vs 60% respectively). In order to reduce the long-term neurocognitive sequelae associated with this amount of CSI, trials have been conducted to decrease the dose of CSI. Efforts to reduce CSI, without impairment of overall survival, have succeeded in standard risk patients only when a reduced dose of CSI has been coupled with adjuvant chemotherapy. The highest EFS ever published in standard risk MB patients has been reported by Packer et al. using vincristine during postoperative radiotherapy, with reduced CSI of 23.4Gy, and the combination of vincristine, cisplatin, and CCNU for eight 6-week cycles after completion of radiotherapy (EFS at 5years: 79%).

For high-risk patients, radiation treatment remains the essential component of therapy. Adjuvant chemotherapy adds a significant benefit in overall survival compared with radiotherapy alone. Nevertheless, in this setting of patients, the use of standard dose chemotherapy is not sufficient to allow the reduction of the cranio-spinal dosage under 35Gy. Five-year EFS in metastatic patients ranges between 40 and 67% when full-dose cranio-spinal radiotherapy is administered with adjuvant chemotherapy. Treatment approaches currently under investigation in this poor prognosis subset of patients include the use of: • Radiosensitizing agents such as carboplatin • High-dose chemotherapy with peripheral blood stem cell rescue • Hyperfractionated accelerated radiation therapy Supratentorial PNETs (sPNETs) account for 3–5% of childhood brain tumors and behave much more aggressively than their infratentorial counterparts. Outcome seems to be improved in recent studies adopting multimodality treatments after total resection. They are considered as high-risk PNETs and generally treated according to the same protocols of metastatic medulloblastomas. Non-metastatic PNETs of the pineal region seem to have a better prognosis than non-pineal sPNETs. Treatment of very young children under 3–5years of age with MB is still the greatest challenge for pediatric neuro-oncologists. Concerns about neurocognitive outcome, growth delay, and endocrinological deficits due to irradiation of the developing brain and cranio-spinal axis have led to the designing of treatment protocols based on chemotherapy in order to either delay or even avoid radiotherapy. The most common strategies have adopted: • Conventional chemotherapy • High-dose chemotherapy

Surgery < 3-5 years

> 3-5 years

Standard risk

High risk R+, M0

HR M+

Standard risk

CT alone

HD-CT + PF RT

CT ± HD CT + RT

CT + RT (PF + CSI at 24 Gy)

(PF + CSI) HDCT: high dose chemotherapy; PF RT: posterior fossa radiotherapy

Fig.3.2.93 Management of childhood medulloblastoma

3.2.12 Advantages and Limits of Adjuvant Treatments in Pediatric Brain Tumors

The EFS of infants in these studies delaying or avoiding irradiation are inferior to those obtained in older children, especially in cases of incomplete resection or metastatic tumor. Nevertheless, 30–50% of the patients with a completely resected local tumor can be cured without irradiation. The overall survival rates in standard-risk MB could reach those observed in older children, despite the omission or reduction of radiotherapy. Future prospective trials will evaluate histopathological characteristics and molecular markers (i. e., β-catenin, Trk-C, ErbB2, p53, c-Myc, OTIX-2) in order to allow better disease risk stratification and the identification of patients curable with less intensive therapy (such as desmoplastic MB) or, in contrast, with more aggressive treatment (such as anaplastic/large cells MB). 3.2.12.7 Ependymoma Ependymomas (Fig.3.2.94) occur in two thirds of cases in posterior fossa and one third of cases at the supratentorial level. Tumor grading is an important prognostic factor in some studies and is based on the distinction, according to the WHO classification, between differentiated (grade I–II WHO) ependymomas and anaplastic (grade III) ependymomas. To date, however, few groups use grading to stratify patient’s treatment. Seven per cent of children have leptomeningeal dissemination at diagnosis. In most cases tumor relapse occurs as a result of local failure. The most effective treatment for localized ependymoma is gross total resection followed by focal radiation therapy (53–59.4Gy). In children over 3years of age this treatment strategy results in 50–65% PFS at 5years.

Cranio-spinal irradiation (36Gy) is employed in patients with metastatic disease. Chemotherapy at standard or high doses has not shown any increase in overall survival. Phase II studies of single or combination drugs show the poor response of ependymomas to chemotherapy. In spite of this, chemotherapy has often been used in an adjuvant setting, especially: • In infants < 3–5 years with the aim of avoiding or delaying radiotherapy. With prolonged adjuvant chemotherapy (French study: BBSFOP protocol), 40% of patients are alive and radiotherapy-free at 2 years and 23% at 4 years; OS at 4 years is 74% in patients with complete resection and 35% after incomplete resection. RT can be safely deferred in children with radiological gross total resection until the time of progression. • A brief course of chemotherapy is given in patients with residual tumor after initial surgery in order to let children recover and plan the second surgery to achieve gross total resection. A few retrospective institutional studies report sporadic cases of long-term survivors, cured by surgery alone without any adjuvant treatment. These data need to be confirmed in large prospective series. Observation could be proposed, inside a treatment protocol, for patients with supratentorial, low-grade ependymomas after microscopically complete resection. There is a clear need for new markers defining relevant prognostic groups.

Initial surgery

< GTR

GTR

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Above 3 years

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Study risk factors for relapse

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Upfront window chemotherapy

Second look surgery

Fig.3.2.94 Management of childhood intracranial ependymoma

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3.2.13 Novel Therapies

Jan Jakob A. Mooij, Manfred Westphal Disappointment with the failure of so-called standard therapies for glioblastoma multiforme (GBM) – including chemotherapy – has led to a series of new concepts that form the basis of new ways to attack brain tumours in general and the GBM in particular. These “novel therapies” share two main concepts: specific targeting and dedicated delivery [33]. Failure of surgery is primarily due to a lack of boundaries to brain tumours [8]; failure of radiation and drug therapy is due to the variable stages of genetic aberrations in the tumour cells [13], their heterogeneity [27] and the impossibility of adequate delivery of drugs thanks to the blood–brain barrier (BBB) and the inconsistency of tissue resistance to diffusion, enhanced by the primarily lipophilic basis of the brain structure. 3.2.13.1 Targeting and Delivery The concept of targeting comprises a wide variation of therapeutic concepts based on specific properties of brain tumour cells that make them different from the surrounding tissue and also centred around the idea that drugs may be administered directly into the tumour, the resection cavity or the brain. Targeted therapy includes gene therapy- and gene technology-based approaches; therapies based on immunological properties and the immunological system in general; drug targeting using specific and tumour-unique membrane receptors, including the use of naturally occurring as well as artificial ligands and ligand-connected drugs; intracellular pathway interference, in particular, various membrane receptor-linked tyrosine–kinase pathways; interference with tumourrelated angiogenesis; interference with the migration properties of tumour cells into the surrounding matrix, which are essential for their survival and proliferation [5, 11, 21]. Targeted delivery includes specific methods intended to overcome the problems of the classical oral, intravenous or intra-arterial drug delivery that is hampered by the BBB and other forms of resistance mentioned above. Techniques that have evolved and have been developed into clinically applicable use are local delivery by direct intraparenchymal injections of viruses at the time of surgery [14], vector-producing cells [25], or slow-release polymers with chemotherapeutic agents [20]. Also, polymer wafers with sustained slow-release properties for BCNU have been used for intracavitary placement [34]. Intracavitary delivery via a catheter connected to a subgaleal reservoir is another option used for radioimmuno-

therapy [9]. Most recently, direct interstitial application of a drug via slow infusion with catheters, which is called convection enhanced delivery (CED), is finding its way into clinical trials [17]. In the next few paragraphs examples will be given of novel therapies based on this specific targeting, the advanced delivery methods and often the combination of both technologies. 3.2.13.1.1 Gene Therapyand Gene Technology-Based Therapies

In the context of brain tumours the concept of gene therapy is mostly based on strategies for transferring into tumour cells the so-called suicide genes – genes that force the cell to produce certain enzymes that could convert prodrugs into locally (intracellularly) killing substances. The most frequently explored approach has been the herpes simplex tyrosine kinase (HSTk) ganciclovir system. For transfection, retrovirus and adenovirus have been used. With the retrovirus system, worldwide multicentre trials (phases II and III) have been performed, but with unsatisfactory results [24]. Inefficient gene delivery leading to an insufficient transduction rate, with a technique of multiple depositions of vector-producing cells in the surrounding of the tumour cells, seems to have been the major cause of failure. Adenoviral vector transfection seems to be more efficient, but also more risky, and will be explored next [14]. Another method of gene therapy is the restoration of one or more of the genes that are deleted in the process of tumourigenesis. The most challenging candidate may be the TP53 gene, involved in several aspects of cell cycle control, and deleted in a significant percentage of GBM tumours. With the use of adenoviral vector-based TP53 gene transfer, successful tumour killing has been achieved in the laboratory [15], and clinically for, e.g., colorectal cancer. Clinical studies in GBM patients have been started, the results of which are yet to come. A third field in which gene technology plays a role is that of enhancing (natural) immune responses towards the tumour cells. This can be achieved for example by the elimination of immunosuppressors. Techniques consist of silencing the genes for the formation of insulin-like growth factor I (IGF I), transforming growth factor beta (TGFbeta) [19] and others. See also Sect.3.2.13.1.2. In the same way as has been done concerning the modulation of immunological factors by interference with relevant genes, manipulation of the genes pertinent for angiogenesis can be interfered with [4]. The highgrade gliomas have a high angiogenic activity, which is necessary for their growth and survival. The main factors involved in neo-angiogenesis belong to the VEGF family. Antisense techniques with retroviral or adenoviral vectors to silence the genes involved are almost at a

3.2.13 Novel Therapies

stage for clinical application (phase I studies). See also the Sect3.2.13.1.5. Viruses, besides their usefulness for gene transfection, can also be used for direct cell killing. With recombinant techniques, they can be made safe and effective. In particular, neurotrophic viruses like the herpes simplex virus and its family seem to be promising, once they have mutated into more specific forms that have direct cytopathic effects on tumour cells and not on normal brain tissue. Various clinical trials have been launched or have already led to interesting results. Also, the conditionally replicating adenovirus, modified to target p53-deficient cells, seems promising, as well as another type of virus, the reovirus [1, 5–7, 10, 19, 32, 35]. 3.2.13.1.2 Immunotherapy and Related Techniques

The limited immunogenicity of intrinsic brain tumours is not only due to the BBB, but also to immunosuppression by factors that hamper such immunogenicity. In particular, IGF and TGFbeta-2 are the factors involved. As already stated in Sect.3.2.13.1.1, elimination or minimalisation of their effect by downregulation of their production seems to raise immune responses, also to GBM. For example, local (intratumoural) application of a TGFbeta 2 antisense oligonucleotide (AP 12009) has now been tried in a clinical setting using microperfusion for several months, with an interesting response [30] Various other techniques exist and work in the laboratory environment, and some have already reached the clinical stage (reviewed in [31]). Among them are the transduction of IL2 and IL7 into tumour cells, in order to raise T cell responsiveness; the ex vivo activation of APCs and dendritic cells (passive and active immunisation, with risks of autoimmune reactions in the non-tumourous CNS), and various forms of autologous tumour cell immunisation. The latter method has been tried in a clinical multicentre study in which tumour cells are transfected ex vivo with IFN-γ and then used for repeated vaccination. Developments in the field of antigen targeting with specific (monoclonal) antibodies are dealt with in the next section. 3.2.12.1.3 Membrane Receptor Targets and Their Applications

As in many other tumours, high-grade brain tumours like GBM express specific receptors on their cell membrane, or have a specific amplification of such receptors. Among the most common receptors found on the surface of gliomas are EGF-R, PDGF-R, FGF-R, VEGF-R, transferrin, and the receptors for cytokines such as TGF-ß, IL-13 or IL-4. By coupling specific antibodies against these receptors with certain drugs or toxins, so-called immuno-

toxins (conjugates) are formed. Several of these products have been subjected to clinical trials to date. The most important are: • Transferrin with diphtheria toxin (TransMID) [17] • TGF (a ligand for EGF-R) with Pseudomonas exotoxin (TP-38) [29] • IL-4 ligand with Pseudomonas exotoxin (NBI-3001) [23] • IL-13 with Pseudomonas exotoxin (PRECISE) [22] Other receptors that have already been “targeted” are the PDGF-R and the VEGF-R, although these are mostly targeted by smaller molecules, the tyrosine kinase inhibitors [28]. It is noteworthy that the tumour cells overexpress all these receptors as well as their ligands, leading to autocrine loops that stimulate and support cell proliferation. A special group of ligands and receptors to be mentioned are the TNF-related apoptosis-inducing ligands (TRAIL) and the TRAIL receptors. Many tumours, including GBM, express TRAIL and TRAIL receptors. TRAIL can be given as a single drug, but can also be targeted by conjugation to a specific antibody, and thus become a specific targeting apoptotic drug too [18]. 3.2.13.1.4 Membrane Receptor-Related Intracellular Pathways as a Target

Most of the ligands and receptors mentioned are related with their intracellular domain to tyrosine kinase (TK) pathways. Activation results in cascades of intracellular processes, many of them leading to further cell proliferation and/or migration. Direct interference with these TK pathways can interrupt such events and subsequently lead to apoptotic cell death. Many (small) molecules have been developed, ATP mimetics, which have such an action, and are now tested in many cancer types, including GBM. Examples are erlotinib (Tarceva), which interferes with the EGF-R-related TK; gefitinib (Iressa, same pathway); imatinib (Glivec), which interferes with the PDGF-R-related TK. 3.2.13.1.5 Anti-Angiogenesis and Antimigration Therapy

Malignant tumours, and very markedly GBM too, induce neo-angiogenesis. Neovascularisation is necessary for further growth, and inhibition of angiogenesis may prevent that. Therefore, anti-angiogenesis seems to have become a strategy with high expectations for cancer therapy. The target cells in anti-angiogenic therapy may be the tumour cells that produce angiogenic factors, like VEGF and its corresponding VEGF-R, but also the endothelial cells themselves, which are more readily accessible, being outside the BBB.

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Closely connected to angiogenic activity of tumour cells is their migratory potential [16]. In order to proliferate, cells must invade the surrounding matrix, for which they produce matrix metalloproteinases (MMPs) [26]. Inhibition of MMPs prevents tumour cells from migrating, and indirectly from proliferating, bringing tumour growth to a halt. The close biochemical relationship between angiogenic factors and MMPs results in a double action of anti-angiogenic drugs against angiogenesis as well as migration. Since these drugs do not kill the tumour cells but only prevent further growth, they are often called cytostatic drugs. Examples of anti-angiogenic drugs that have been tested already in clinical studies are: thalidomide, angiostatin, endostatin, ZK222584/PTK787 and COX-2 inhibitors like celecoxib and cilengitide [3]. The most promising results are those of studies in which these drugs are combined with radiation therapy and/or cytotoxic chemotherapy. 3.2.13.2 Delivery In order to overcome the main obstacles to adequate delivery of therapeutic drugs or cells into the brain, various methods have been developed over recent years. 3.2.13.2.1 Local Injections

In the design for retroviral vector transfection it was necessary to use producer cells. These cells could only be placed in or around residual tumour or cavities by direct injections into the parenchyma. It has been shown in a variety of studies that this method of delivery did not do any harm to the patients in most cases, and produced only minimal changes on MRI. However, the efficiency of delivery, even with some 50 injections, was poor. Injection of cells or drugs by means of an Ommaya reservoir and an indwelling catheter results in a pooling of the injected material around the tip of the catheter. Drugs may dissolve into the tissue, by diffusion, but it is a prerequisite that they be lipophilic and of low molecular weight. 3.2.13.2.2 Slow-Release Systems

More promising seems the concept of slow-release systems, although with these, too, diffusion is the driving force of drug delivery, with the aforementioned limitations, especially when in brain oedema the interstitial pressure is high. Most experience has been obtained with biodegradable wafers containing (and releasing) BCNU, the Gliadel wafer [34]. This has had a significant but modest effect on survival, and is important, especially as a benchmark in comparison with other novel therapies.

Other slow-release systems, tested in the laboratory, and some already in patients, are liposomes, alginate spheres [2], and polymeric nanoparticles. Chip technology may also have a place in controlled local drug delivery, and has been tested on a limited scale. 3.2.13.2.3 Convection-Enhanced Delivery

In contrast to diffusion, where a concentration gradient is the driving force behind the dispersion of molecules/ drugs, convection is based on a pressure gradient. This makes it possible to deliver even large molecules over a longer distance [12]. This technique is especially feasible when immunotoxins are considered, which are indeed large molecules. The technique is rather consistent in smaller animals, whereas in humans it appears that the variation in brain tissue resistance and in that of the (residual) tumour tissue hampers a predictive distribution of solvents and drugs. Nevertheless, after a lot of lessons learned over the last few years, the feasibility of CED has now been proven in several of the afore-mentioned studies using this technique (e.g. TP 38, PRECISE). With a maximum of four catheters placed in the brain one can cover quite a large part of one hemisphere for the delivery of large molecules. All studies with drugs of large molecular weight are now using this CED technique. It has to be proven whether the combination of immunotoxins applied by the CED technique does indeed combine an ideal targeting drug with an optimal delivery technique. 3.2.13.3 Future Developments • In the near future another way of targeting may reach the clinical stage: neural stem cells and progenitor cells seem to have a tropism towards brain tumour cells. In the laboratory situation these cells, after having been loaded with a killing mechanism (transfection with specific genes) have been shown to be able to chase and kill brain tumour cells even far away from the injection site. • Surgical refinements may lead to a real and significant reduction of tumour load: intraoperative imaging, by intraoperative MRI, or by visualisation of residual tumour cells through vital staining (the ALA experience), may help to reach that goal. Selected Reading 1. Bischoff JR, Kirn DH, Williams A, Heise C, Horn S, Muna M, Ng L, Nye JA, Sampson-Johannes A, Fattaey A, McCormick F (1996) An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 274:373–376

3.2.13 Novel Therapies

2. Bjerkvig R, Read TA, Vajkoczy P, Aebischer P, Pralong W, Platt S, Melvik JE, Hagen A, Dornish M (2003) Cell therapy using encapsulated cells producing endostatin. Acta Neurochir Suppl 88:137–141 3. Bogler O, Mikkelsen T (2003) Angiogenesis in glioma: molecular mechanisms and roadblocks to translation. Cancer J 9:205–213 4. Bogler O, Mikkelsen T (2005) Angiogenesis and apoptosis in glioma: two arenas for promising new therapies. J Cell Biochem 96:16–24 5. Chiocca EA, Broaddus WC, Gillies GT, Visted T, Lamfers ML (2004) Neurosurgical delivery of chemotherapeutics, targeted toxins, genetic and viral therapies in neuro-oncology. J Neurooncol 69:101–117 6. Conrad C, Miller CR, Ji Y, Gomez-Manzano C, Bharara S, McMurray JS, Lang FF, Wong F, Sawaya R, Yung WK, Fueyo J (2005) Delta24-hyCD adenovirus suppresses glioma growth in vivo by combining oncolysis and chemosensitization. Cancer Gene Ther 12:284–294 7. Geoerger B, Grill J, Opolon P, Morizet J, Aubert G, Lecluse Y, van Beusechem VW, Gerritsen WR, Kirn DH, Vassal G (2003) Potentiation of radiation therapy by the oncolytic adenovirus dl1520 (ONYX-015) in human malignant glioma xenografts. Br J Cancer 89:577–584 8. Giese A, Bjerkvig R, Berens ME, Westphal M (2003) Cost of migration: invasion of malignant gliomas and implications for treatment. J Clin Oncol 21:1624–1636 9. Goetz C, Riva P, Poepperl G, Gildehaus FJ, Hischa A, Tatsch K, Reulen HJ (2003) Locoregional radioimmunotherapy in selected patients with malignant glioma: experiences, side effects and survival times. J Neurooncol 62:321–328 10. Gromeier M, Lachmann S, Rosenfeld MR, Gutin PH, Wimmer E (2000) Intergeneric poliovirus recombinants for the treatment of malignant glioma. Proc Natl Acad Sci USA 97:6803–6808 11. Guha A, Mukherjee J (2004) Advances in the biology of astrocytomas. Curr Opin Neurol 17:655–662 12. Hall WA, Rustamzadeh E, Asher AL (2003) Convectionenhanced delivery in clinical trials. Neurosurg Focus 14:e2 13. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003 14. Immonen A, Vapalahti M, Tyynela K, Hurskainen H, Sandmair A, Vanninen R, Langford G, Murray N, Yla-Herttuala S (2004) AdvHSV-tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: a randomised, controlled study. Mol Ther 10:967–972 15. Kock H, Harris MP, Anderson SC, Machemer T, Hanco*ck W, Sutjipto S, Wills KN, Gregory RJ, Shepard HM, Westphal M, Maneval DC (1996) Adenovirus-mediated p53 gene transfer suppresses growth of human glioblastoma cells in vitro and in vivo. Int J Cancer 67:808–815

16. Lamszus K, Kunkel P, Westphal M (2003) Invasion as limitation to anti-angiogenic glioma therapy. Acta Neurochir Suppl 88:169–177 17. Laske DW, Youle RJ, Oldfield EH (1997) Tumor regression with regional distribution of the targeted toxin TFCRM107 in patients with malignant brain tumors. Nat Med 3:1362–1368 18. Li L, Thomas RM, Suzuki H, De Brabander JK, Wang X, Harran PG (2004) A small molecule Smac mimic potentiates TRAIL- and TNFalpha-mediated cell death. Science 305:1471–1474 19. Lou E (2004) Oncolytic viral therapy and immunotherapy of malignant brain tumors: two potential new approaches of translational research. Ann Med 36:2–8 20. Menei P, Capelle L, Guyotat J, Fuentes S, Assaker R, Bataille B, Francois P, Dorwling-Carter D, Paquis P, Bauchet L, Parker F, Sabatier J, Faisant N, Benoit JP (2005) Local and sustained delivery of 5-fluorouracil from biodegradable microspheres for the radiosensitization of malignant glioma: a randomized phase II trial. Neurosurgery 56:242–248; discussion 242–248 21. Morokoff AP, Novak U (2004) Targeted therapy for malignant gliomas. J Clin Neurosci 11:807–818 22. Parney IF, Kunwar S, McDermott M, Berger M, Prados M, Cha S, Croteau D, Puri RK, Chang SM (2005) Neuroradiographic changes following convection-enhanced delivery of the recombinant cytotoxin interleukin 13-PE38QQR for recurrent malignant glioma. J Neurosurg 102:267–275 23. Puri RK (1999) Development of a recombinant interleukin4-Pseudomonas exotoxin for therapy of glioblastoma. Toxicol Pathol 27:53–57 24. Rainov NG (2000) A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Hum Gene Ther 11:2389–2401 25. Ram Z, Culver KW, Oshiro EM, Viola JJ, DeVroom HL, Otto E, Long Z, Chiang Y, McGarrity GJ, Muul LM, Katz D, Blaese RM, Oldfield EH (1997) Therapy of malignant brain tumors by intratumoral implantation of retroviral vectorproducing cells. Nat Med 3:1354–1361 26. Rao JS (2003) Molecular mechanisms of glioma invasiveness: the role of proteases. Nat Rev Cancer 3:489–501 27. Reifenberger G, Collins VP (2004) Pathology and molecular genetics of astrocytic gliomas. J Mol Med 82:656–670 28. Rich JN, Bigner DD (2004) Development of novel targeted therapies in the treatment of malignant glioma. Nat Rev Drug Discov 3:430–446 29. Sampson JH, Akabani G, Archer GE, Bigner DD, Berger MS, Friedman AH, Friedman HS, Herndon JE II, Kunwar S, Marcus S, McLendon RE, Paolino A, Penne K, Provenzale J, Quinn J, Reardon DA, Rich J, Stenzel T, Tourt-Uhlig S, Wikstrand C, Wong T, Williams R, Yuan F, Zalutsky MR, Pastan I (2003) Progress report of a Phase I study of the intracerebral microinfusion of a recombinant chimeric pro-

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tein composed of transforming growth factor (TGF)-alpha and a mutated form of the Pseudomonas exotoxin termed PE-38 (TP-38) for the treatment of malignant brain tumors. J Neurooncol 65:27–35 30. Schlingensiepen R, Goldbrunner M, Szyrach MN, Stauder G, Jachimczak P, Bogdahn U, Schulmeyer F, Hau P, Schlingensiepen KH (2005) Intracerebral and intrathecal infusion of the TGF-beta2-specific antisense phosphorothioate oligonucleotide AP 12009 in rabbits and primates: toxicology and safety. Oligonucleotides 15:94–104 31. Sikorski CW, Lesniak MS (2005) Immunotherapy for malignant glioma: current approaches and future directions. Neurol Res 27:703–716 32. Tyminski E, Leroy S, Terada K, Finkelstein DM, Hyatt JL, Danks MK, Potter PM, Saeki Y, Chiocca EA (2005) Brain tumor oncolysis with replication-conditional herpes simplex virus type 1 expressing the prodrug-activating genes,

CYP2B1 and secreted human intestinal carboxylesterase, in combination with cyclophosphamide and irinotecan. Cancer Res 65:6850–6857 33. Westphal M, Black PM (2004) Perspectives of cellular and molecular neurosurgery. J Neurooncol 70:257–271 34. Westphal M, Hilt DC, Bortey E, Delavault P, Olivares R, Warnke PC, Whittle IR, Jaaskelainen J, Ram Z (2003) A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neurooncology 5:79–88 35. Yang WQ, Senger D, Muzik H, Shi ZQ, Johnson D, Brasher PM, Rewcastle NB, Hamilton M, Rutka J, Wolff J, Wetmore C, Curran T, Lee PW, Forsyth PA (2003) Reovirus prolongs survival and reduces the frequency of spinal and leptomeningeal metastases from medulloblastoma. Cancer Res 63:3162–3172

3.3 Vascular Diseases

3.3.1 Aneurysms 3.3.1.1

Pathogenesis

Ken Lindsay Cerebral aneurysms arise at the bifurcation of blood vessels. They are primarily saccular in shape, but may have additional lobules or “nipples”. Far less commonly, fusiform dilatation or ectasia of intracranial vessels occurs and in some cases may be associated with connective tissue or atherosclerotic disease. Most saccular aneurysms occur in relation to the anterior cerebral artery (35%), followed by the internal carotid artery (30%), and the middle cerebral artery (25%). About 10% arise from the posterior circulation. The formation of cerebral aneurysms was originally attributed to the presence of developmental defects in the tunica media, but defects in this layer occur as frequently in extracranial vessels where saccular aneurysms are rare. Furthermore, cerebral aneurysms are rarely seen in children. Most now believe that the pathogenesis of intracranial aneurysm formation is multi-factorial and that acquired factors may combine with an underlying genetic susceptibility. Disruption of the internal elastic lamina appears to be most relevant. Those factors that contribute to atherosclerotic damage of blood vessel walls – hypertension and smoking – may produce local thickening in elastic regions within the intimal layer, i. e. “intimal pads”, leading to increased strain on the adjacent parts of the vessel wall. Degenerative change occurs predominantly at sites of haemodynamic stress – at vessel bifurcations – but particularly where developmental anomalies alter flow patterns. For example, with a hypoplastic anterior cerebral artery on one side, aneurysms tend to form on the wall that faces the brunt of the incoming flow from the dominant A1 vessel on the opposite side. Inflammatory processes similar to those seen in atherosclerotic plaques (not in themselves necessary for aneurysm formation) are found in the vessel wall and release matrix metalloproteinases (MMPs) and other proteolytic enzymes, and may play a role. The extracellular matrix provides strength and elasticity to intracranial arteries and is composed of collagen

and elastin fibres embedded in glycoproteins and proteoglycans. A balance normally exists between degradation by proteases (e. g. MMPs and elastase) and synthesis by protease inhibitors (e. g. MMP inhibitors, anti-trypsin), growth factors and cytokines. Over- or under-expression of such proteins may disturb this balance and result in remodelling of the extracellular matrix. Four genome-wide linkage studies have identified genetic loci for intracranial aneurysms, of which three include functional candidate genes coding for structural proteins of the extracellular matrix, including elastin and collagen type 1A2. This may in part explain how genetic factors could increase the tendency towards aneurysm formation. In a few patients, aneurysm formation has been associated with hereditary disorders of connective tissue such as polycystic kidney disease, Ehlers-Danlos disease type IV, fibromuscular dysplasia and Marfan’s syndrome. 3.3.1.2

Epidemiology

The prevalence of cerebral aneurysms depends on the method used for detection, how carefully this is applied and on the age of the patients undergoing investigation. Retrospective autopsy studies report an incidence of 0.4%, but this increases to 3.6% when aneurysms are sought prospectively. Angiographic studies detect cerebral aneurysms incidentally in 3.7–6% of patients, but this patient group may harbour a higher incidence of risk factors. For adults without risk factors, the prevalence lies between 2 and 3%. Cerebral aneurysms are rarely formed in patients under 20years of age and numbers peak between 60 and 80years. Female gender increases the likelihood of an incidental aneurysm (relative risk of 1.3) as does the presence of atherosclerosis. A family history of two or more affected first-degree relatives or a history of polycystic kidney disease increases the relative risk by a factor of 4. Those patients who have undergone repair of a ruptured aneurysm have an increased tendency to form other aneurysms. 3.3.1.2.1 Subarachnoid Haemorrhage

At least 75% of haemorrhage into the subarachnoid space results from a ruptured aneurysm. In about 20% of patients there is no identifiable cause; the remainder have

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various causes, including arteriovenous malformation, vasculitis and arterial dissection. The incidence of subarachnoid haemorrhage (SAH) varies from study to study and from country to country. In most western countries SAH occurs in about 8 patients per 100,000 per year, but this falls to 5.6 for SAH confirmed by CT. In Finland and Japan the figure increases to over 20 per 100,000 per year. Women have a 1.6-times greater risk of subarachnoid haemorrhage than men. In first-degree relatives the risk of SAH is increased 3–7 times. Other risk factors include excess alcohol intake (> 2 units per day), smoking, hypertension and the presence of inherited connective tissue disorders. 3.3.1.2.2 Incidental Aneurysms – Risk of Haemorrhage

Data from the International Study of Unruptured Intracranial Aneurysms (ISUIA), by far the largest study published on incidental aneurysms, has shown that for aneurysms < 7mm in diameter the risk of haemorrhage is extremely small. This risk increases with increasing size (Table3.3.1) and for those situated in the posterior circulation. Incidental aneurysms in patients with a previous history of SAH from a separate aneurysm are also at higher risk of rupture. The risk of treatment of incidental aneurysms (whether endovascular or surgical) must be weighed against the risk of rupture over the patient’s expected lifespan. Treatment risks increase with increasing age, with the location (highest risk in the posterior circulation) and with the size of the aneurysm. 3.3.1.3

Symptomatology – Subarachnoid Haemorrhage

Most cerebral aneurysms present acutely with SAH. A few present with symptoms and signs from pressure of the aneurysm sac on adjacent structures, either alone or in association with a subarachnoid haemorrhage. A third

nerve palsy is the most commonly encountered pressure effect – usually from a posterior communicating artery aneurysm, but occasionally from a superior cerebellar artery aneurysm. Carotid aneurysms within the cavernous sinus may compress the third, fourth, fifth and sixth cranial nerves. Rarely, visual field defects occur from pressure on the optic nerve or chiasm. More and more aneurysms are now discovered incidentally by the use of increasingly sensitive imaging techniques for investigation of unrelated symptoms. The classic description of SAH includes severe headache of instantaneous onset, often described as like a “blow to the back of the head” and accompanied by vomiting, neck stiffness and photophobia. About 50% of patients lose consciousness at the onset, in some due to a seizure. Coma may persist from an associated haematoma mass, acute hydrocephalus or global cerebral ischaemia. Reduced cerebral perfusion can occur from a sudden acute rise in intracranial pressure at the time of the bleed and should be differentiated from “delayed cerebral ischaemia” related to vasospasm, usually occurring 7–10days after the haemorrhage. About one third of patients develop focal signs (dysphasia and/or hemiparesis), often only lasting a few hours. In some patients the diagnosis is more difficult to establish from the clinical history since the headache is less pronounced and the onset more gradual. Neck stiffness may take hours to develop and does not always appear. On occasions, the patient fails to seek medical help. Many authors describe the occurrence of headache preceding SAH as a “sentinel bleed” or a “warning leak”. Such terms are misleading and although in some cases pain may result from expansion of the vessel wall, most probably represent a missed haemorrhage. Of those patients who present with sudden headache, only 1 in 4 will have had an SAH. Other causes include thunderclap headache, migraine and headache related to sexual activity and exertion. Only 1 in 10 of patients presenting with sudden headache alone are shown to have had a haemorrhage.

Table3.3.1 Data from the International Study of Unruptured Intracranial Aneurysms (ISUIA) showing the 5-year cumulative risk of bleeding according to aneurysm location. SAH subarachnoid haemorrhage Aneurysm location

< 7mm

7–12mm

13–24mm

> 24mm

No previous SAH (%)

Previous SAH (%)

(%)

Anterior circulation (excluding posterior communicating artery)

1.5

2.6

14.5

Posterior circulation (including posterior communicating artery)

2.5

3.4

14.5

18.4

3.3.1 Aneurysms

3.3.1.4

Diagnostic Procedures

None of the clinical features alone is sufficiently reliable to establish the diagnosis. When SAH is suspected, the inconvenience and cost of further investigations is offset by the importance of failing to establish the diagnosis of aneurysm rupture. An unenhanced axial CT scan will confirm the presence of SAH in 98% of patients if performed within 12h of the bleed, but this high detection rate falls off over time to 94% at 24h, 50% on day 7 and 20% on day 9 from the bleed. Hyperdense blood is usually most evident within the basal cisterns, in the interhemispheric and Sylvian fissures, in the cortical sulci and within the ventricles (Fig.3.3.1). Changes are often subtle depending on the time of the scan and severity of the haemorrhage, e. g. the normal hypodense fissure may be absent or an isodense fluid level may lie within the occipital horn of the lateral ventricle. The pattern of blood on the axial CT can provide a guide to the site of the ruptured aneurysm, which is important for determining the source of the bleed when multiple aneurysms are found.

In contrast, a “peri-mesencephalic” pattern of blood (Fig.3.3.1) indicates the likelihood of negative angiography, although it is still essential to exclude the possibility of an aneurysm around the distal basilar artery. The greater the amount of blood on the initial CT, the higher the risk of delayed cerebral ischaemia and the worse the outcome. In patients presenting with an impaired level of consciousness, a CT is essential, not only to establish the diagnosis, but to exclude the presence of hydrocephalus or a haematoma mass, either of which may require treatment in their own right. 3.3.1.4.1 Lumbar Puncture

Patients with a suspected SAH and normal CT require a lumbar puncture, but only after a delay of at least 6h and preferably 12h from the bleed to allow time for the red blood cells to break down and produce xanthochromic staining of the cerebrospinal fluid (CSF). The CSF should be centrifuged and the supernatant examined by spectro-

Fig.3.3.1 Computed tomography appearance – subarachnoid haemorrhage

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photometry for oxyhaemoglobin and bilirubin (the cause of the xanthochromia). The naked eye is insufficient to detect small amounts of pigment change. Red cells lyse in the CSF to produce oxyhaemoglobin either in vitro or in vivo, but conversion of oxyhaemoglobin to bilirubin requires the enzyme haemoxygenase, which is only present in macrophages, the arachnoid membrane and the choroid plexus. Thus, any delay in centrifuging RBCs from the CSF can lead to an erroneously high level of oxyhaemoglobin, but the presence of bilirubin (in the absence of jaundice) establishes a diagnosis of SAH and excludes a traumatic tap as a cause of the blood staining. Xanthochromia should persist for at least 2weeks after the bleed, but thereafter a negative result does not exclude SAH. 3.3.1.4.2 Further Investigation of SAH

Computed tomographic angiography will detect all but the smallest of aneurysms; 3D reconstruction allows detailed assessment of the neck and helps guide further treatment (see Sect.3.3.1.5). If a negative and an “aneurysmal” pattern of blood exist within the Sylvian or the interhemispheric fissure, digital angiography is still required to ensure that a small aneurysm is not missed. Until now digital angiography has been assumed to be the gold standard for aneurysm detection, but some now claim that CT angiography may replace this, particularly when blood within the fissure guides the neuroradiologist to the likely source of the bleed. The latest digital angio graphy equipment also allows three-dimensional rotation of the image to improve aneurysm detection and to help evaluate the aneurysm neck. This technique can detect even the smallest aneurysmal “bleb”. In patients with a peri-mesencephalic pattern of blood on CT, CT angio graphy is sufficient to exclude a posterior circulation aneurysm, but digital angiography may still be necessary to exclude a small arteriovenous malformation or fistula. 3.3.1.4.3 Subarachnoid Haemorrhage with Negative Digital Angiography

In about 20% of patients investigation fails to detect the cause of the SAH. A degree of vasospasm occurs in up to 50% of patients and may hinder aneurysm detection, particularly if severe. Patients with an “aneurysmal” pattern of blood on CT with negative angiography should undergo a repeat examination after 1 or 2weeks, or when the vasospasm has subsided. For those patients with a “peri-mesencephalic” pattern of blood and a negative angiogram, no further investigation is required and the outlook is excellent.

3.3.1.4.4 Transcranial Doppler

High-flow velocities in intracranial vessels (> 120 cm/s) suggest the presence of vasospasm. A sudden increase in flow velocity may precede the development of clinical signs of cerebral ischaemia and provide an opportunity to initiate early prophylactic measures. 3.3.1.4.5 Screening for Incidental Aneurysms

Screening (CT angiography) is considered in individuals aged between 25 and 70years with a family history of two or more first-degree relatives with SAH or with polycystic kidney disease. The clinician must inform the patient that a negative investigation does not exclude subsequent aneurysm development and rupture in future years and that the discovery of a small aneurysm left untreated may raise additional problems of anxiety or limitation of life insurance. The management of larger aneurysms requires careful discussion to ensure that the patient can compare the risk of treatment against the risk of conservative management. Any patient with a positive family history, whether or not they opt for investigation and/or treatment, should be advised to give up smoking and to undergo regular blood pressure checks. 3.3.1.4.6 Perioperative Management of Subarachnoid Haemorrhage 3.3.1.4.6.1 Clinical Assessment

The clinical condition of the patient, along with age and amount of blood seen on the CT, is an important guide to eventual outcome. The Glasgow Coma Score on admission, combined with the presence or absence of focal signs, makes up the WFNS grading scale (Table3.3.2). The WFNS scale correlates strongly with outcome (Table 3.3.3). An impaired conscious level indicates the need for an urgent CT scan to exclude concomitant hydrocephalus or a haematoma mass, either of which may require urgent treatment. 3.3.1.4.6.2 Re-Bleeding

About 40% of patients with an aneurysmal SAH will rebleed in the first 3weeks if left untreated. This risk is the highest in the first 24h after the ictus. After 6months the risk falls to 3.5% per year and this risk persists for at least 10 years. Only aneurysm repair prevents re-bleeding. Antifibrinolytic medication is of no benefit since the reduced risk of re-bleeding is offset by an increased risk of cerebral ischaemia. 3.3.1.4.6.3 Delayed Cerebral Ischaemia

The development of focal signs with or without deterioration in the level of consciousness occurs in about 25%

3.3.1 Aneurysms

Table 3.3.2 World Federation of Neurological Surgeons (WFNS) grading system for SAH WFNS grade

Glasgow Coma Scale

Motor deficit

Absent

13–14

Absent

III

13–14

Present

7–12

Absent or present

3–6

Absent or present

Table3.3.3 Data from the UK National Study of SAH, showing the relationship of WFNS grade to outcome WFNS grade on admission

Number of patients

Percentage with unfavourable outcome

1,214

24.7

378

37.6

III

48.9

164

64.0

118

71.2

1,962

34.4

Total

persist, induce hypertension with inotropes (but only if the aneurysm has been repaired, otherwise there is a high risk of re-bleeding). • If triple H therapy fails to reverse the neurological deficits, balloon angioplasty with or without infusion of papaverine may improve cerebral perfusion, but again no controlled trials have been published to confirm a beneficial effect. • Other treatments include the use of magnesium sulphate. Initial studies noted a possible benefit, but full evaluation is awaited. 3.3.1.4.7 Outcome

Outcome from the repair of incidental aneurysms, whether endovascular or surgical, depends on age, aneurysm site and size. Overall mortality, as reported in the International Study of Unruptured Intracranial Aneurysms, lies in the region of 1–2% with a morbidity of around 10%. After SAH, 10–15% of patients die before reaching hospital and a further 15% die within the first 24 h. Of those patients reaching a neurosurgical unit, the outcome relates to age, clinical grade (Table3.3.3), the amount of blood on the CT scan, the site and size of the aneurysm and the presence of associated medical conditions. 3.3.1.5 Surgical Therapy

of patients after SAH. The incidence peaks between the 7th and 10th day after the ictus, but may occur from days 4–20. The time course of blood vessel constriction on angiography (“vasospasm”) matches this and is the prime cause, but a fall in plasma volume occurs in association with a negative sodium balance in one third of patients after SAH, and this may also contribute to ischaemic damage. • The calcium antagonist nimodipine (60mg 4-hourly) reduces the incidence of delayed cerebral ischaemia by about one third and improves outcome. All patients should receive this from the outset. • To prevent hypovolaemia, give patients 3l per day of normal saline. • If hyponatraemia develops, do not restrict fluid as this can compound the fall in plasma volume. Treat with hypertonic saline or fludrocortisone. • Avoid antihypertensive medication unless the patient is already on this therapy. • If clinical signs of delayed cerebral ischaemia develop, the standard practice is to treat with hypervolaemia, haemodilution and induced hypertension (triple H therapy), but there is no evidence of benefit from randomised controlled trials. Initially, give plasma volume expanders, e. g. Gelofusine. If ischaemic signs

Ken Lindsay 3.3.1.5.1 Preoperative Considerations

Prior to operation the surgeon must assess the available imaging to determine: • The width of the aneurysm neck and the configuration of the surrounding vessels • The optimal side and route of approach • The ease of obtaining proximal control • The potential need for by-pass Rotation of a 3D digital or CT angiographic image provides the ideal method of preoperative assessment of the aneurysm neck. Try to envisage how the clip will be applied – preferably in the plane of the distal vessels to minimise kinking, and decide on the optimal route to achieve this. Aneurysms of the anterior communicating complex can be approached from either side or occasionally from an anterior inter-hemispheric approach. For such aneurysms points to consider include not only the configuration of the vessels, but also the side of the predominant filling (to aid proximal control) and whether or not a haematoma has already damaged the gyrus rectus on one side (if so, the preferred side of approach). Aneurysms arising at the origin of the ophthalmic artery often

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point medially and an approach from the contra-lateral side may provide an unobstructed route to the aneurysm neck.

before re-applying the temporary clip. When the proximal vessel is difficult to access (e. g. low basilar bifurcation or supraclinoid aneurysm), temporary occlusion can be provided with an endovascular balloon.

3.3.1.5.2 General Techniques of Operative Repair

3.3.1.5.2.6 Doppler Microprobe

3.3.1.5.2.1 Dissection

Dissection, if possible, should initially expose the proximal vessel, and then work towards the aneurysm neck. Use only sharp dissection for any resistant tissue in the vicinity of the aneurysm. 3.3.1.5.2.2 Direct Clipping

Direct clipping should aim to obliterate the aneurysm sac. Where possible, puncture the fundus to ensure complete occlusion of the aneurysm neck. Postoperative angiography shows that a residual neck remnant remains outside the clip in 2–10% of patients.

A Doppler microprobe applied to the distal vessels can provide some reassurance that flow persists. 3.3.1.5.2.7 CSF Drainage

After subarachnoid haemorrhage, about 50% of patients develop some obstruction to CSF flow. Of these, about half require CSF drainage either via an external ventricular drain, or where the blood clot does not obstruct the third or the fourth ventricles, by a lumbar drain. Lumbar drainage during any operative procedure helps improve access and minimises the effect of any brain retraction. Opening the lamina terminalis may reduce the need for a permanent CSF shunt.

3.3.1.5.2.3 Wrapping

Wrapping the aneurysm fundus with muslin provides some protection, but fails to eliminate the risk of rebleeding. Only use this technique if direct clipping and endovascular repair methods have failed. 3.3.1.5.2.4 Trapping/Extracranial– Intracranial Bypass

Trapping of the aneurysm, combined where necessary with extracranial–intracranial bypass, minimises the risk of ischaemic complications when size or shape (e. g. fusiform) prevents application of a clip or endovascular occlusion. 3.3.1.5.2.5 Temporary Clipping

Temporary clipping of the proximal vessel may facilitate dissection of the aneurysm neck and occlusion of the sac. If used, vessels should be occluded for no longer than 3–5min and a similar duration allowed for re-perfusion

3.3.1.5.3 Anterior Circulation Aneurysms – Operative Techniques – the Pterional Approach

The pterional route remains the standard approach for most anterior circulation aneurysms. The patient is positioned with the head slightly up, with the malar bone at the highest point and the head rotated to about 45° (more or less depending upon the intended direction of approach). Figure3.3.2a shows the line of the scalp flap (dotted line). Reflection must permit access to the angle between the zygoma and the frontal bone. The shaded area shows the extent of bone removal. A supra-orbital incision combined with a 2- × 3.5-cm “keyhole” bone flap (Fig. 3.3.2b) can provide access to most aneurysms approached through the standard pterional route, but the small flap limits the angle of approach and it is not clear whether any cosmetic benefit produced by such a small flap justifies the restricted access. The supra-orbital line

Fig.3.3.2 a Pterional approach – skin flap (dotted line) and area of bone removal. b Supraorbital approach – area of bone removal

3.3.1 Aneurysms

of approach gives good access to the Circle of Willis and I would always advise extending the pterional bone flap in this direction rather than limiting the craniotomy to the fronto-zygomatic angle. The outer sphenoid wing is removed with either rongeurs or a drill until flush with the floor of the anterior fossa. For supra-clinoid aneurysms, some prefer to drill the anterior clinoid process extradurally to permit access to the carotid cave, while others prefer to remove this intradurally. When the surgeon requires access from a low trajectory, removal of the zygomatic arch with or without removal of the superior orbital rim can improve access and minimise brain retraction (Fig. 3.3.3), although these techniques are rarely necessary. 3.3.1.5.3.1 Carotid Artery Aneurysms

For aneurysms arising at the origin of the posterior communicating artery, the direction of the fundus should determine the head position. When the aneurysm projects posteriorly, position the head almost laterally. When the aneurysm projects laterally, position the head about 45°. Open the arachnoid over the carotid artery without retracting the temporal lobe; retraction may cause rupture if the fundus of a laterally projecting aneurysm is adherent. Removal of the anterior clinoid may aid access to low-lying aneurysms. Try to identify both the posterior communicating and the anterior choroidal arteries before clipping. Occlusion or compromise of the posterior communicating artery, although best avoided, should not cause harm provided the posterior cerebral artery on that side fills from the posterior circulation, but occlusion of the anterior choroidal artery will cause a capsular infarct. For anterior choroidal and carotid bifurcation aneurysms, it is essential to ensure that no perforating vessels are compromised during clipping. Paraclinoid aneurysms (comprising ophthalmic, superior hypophyseal and posterior paraclinoid aneurysms) require extensive removal of the anterior clinoid process to provide access to the carotid cave and allow proximal

control. The transcavernous approach described by Dolenc provides excellent access to the intracavernous carotid artery. Alternatively, the carotid artery can be exposed in the neck. 3.3.1.5.3.2 Anterior Cerebral/Communicating Artery Aneurysms

Identify the carotid bifurcation and follow the anterior cerebral vessel anteriorly. Take care retracting the frontal lobe – an anterior communicating artery aneurysm pointing forwards and downwards could be adherent to the skull base. Removal of the gyrus rectus medial to the olfactory nerve on that side will improve access to the anterior communicating artery complex, particularly for aneurysms pointing posteriorly and superiorly between the distal vessels. Ensure that no damage occurs to the recurrent artery of Heubner; otherwise, a capsular infarct will result. Identify the proximal and distal vessels on each side before clipping and beware incorporating hypothalamic perforators within the clip. Opening the lamina terminalis may avoid the need for a shunt at a later stage. For some aneurysms of the anterior communicating artery complex, the surgeon may opt for an anterior interhemispheric approach, but this route tends to expose the fundus before gaining proximal control. Aneurysms arising at the origin of the pericallosal artery always require an interhemispheric approach. 3.3.1.5.3.3 Middle Cerebral Artery Aneurysm

For difficult aneurysms or for the less experienced surgeon, it is always wise to begin dissection at the proximal (medial) end of the fissure before working more distally. Take care not to damage the lenticulo-striate perforators on the superior surface of the middle cerebral artery. Alternatively, start by opening the fissure more laterally, either by direct dissection or by injecting saline through a small opening. Occasionally, the fissure does not split and it is necessary to enter the superior temporal gyrus to gain access to the middle cerebral vessels.

Fig. 3.3.3 a Zygomatic approach. b Orbito-zygomatic approach

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Ideally, any aneurysm clip should be applied in the plane of the distal vessels to minimise the risk of kinking and flow obstruction. For middle cerebral aneurysms, this usually entails dissection of the whole fundus, since this is often embedded within brain tissue. For larger aneurysms, application of a temporary clip should reduce tension within the aneurysm sac and make clip application easier. Some surgeons use temporary clipping during aneurysm dissection, but this introduces a time limit of about 5 min beyond which reperfusion for a similar period is required. Ensure the temporary clip does not incorporate perforating vessels arising from the obscured surface of the middle cerebral vessel. 3.3.1.5.4 Posterior Circulation Aneurysms – Operative Technique

The approach to posterior circulation aneurysms depends on where the aneurysm lies on the arterial tree (Fig.3.3.4). 3.3.1.5.4.1 Upper Basilar/Superior Cerebellar/ Posterior Cerebral Arteries 3.3.1.5.4.1.1 Basilar Bifurcation Aneurysms

The hazards of operative repair at this site lie primarily with the risk of damage to perforators supplying the midbrain and thalamus. These arise from P1, a few millimetres from the bifurcation, but some may arise directly from the basilar artery and adhere to the posterior surface of the fundus. The subtemporal approach is particularly suited for posteriorly projecting or low-lying basilar bifurcation aneurysms (Fig.3.3.5). A linear or curvilinear incision extends from the junction of the zygoma with the temporal bone. This provides a surface landmark for the basilar bifurcation. CSF drainage and mannitol aid retraction of the temporal lobe, but care is required to avoid

Internal carotid artery

damaging bridging veins, in particular, the vein of Labbé. Stitching back the edge of the tentorium (avoiding the 4th nerve) before opening the arachnoid layers over the interpeduncular fossa, improves the exposure. It is important to try to identify the left posterior cerebral artery before clipping and to separate any perforators from the posterior surface of the neck and fundus. Anteriorly projecting aneurysms tend to lie free from perforators and carry least risk during clipping. Superiorly and posteriorly projecting aneurysms usually require a fenestrated clip to encircle the right posterior cerebral artery and occasionally the III nerve. The clip length should only extend to the distal edge of the neck; otherwise, this may occlude perforators arising from the left P1. The transsylvian pterional approach was first described by Yasergil. The Sylvian fissure is widely opened and the frontal lobe, internal carotid artery and middle cerebral vessels retracted medially and the temporal lobe laterally. Following the posterior communicating artery posteriorly, the basilar artery and bifurcation are approached from an antero/lateral direction (Fig. 3.3.2, 3.3.5). Dissection continues either lateral to the posterior communicating artery or medially between the branches of its perfora-

Upper basilar / superior cerebellar / posterior cerebral arteries Basilar trunk / vertebro-basilar junction / low lying basilar bifurcation Vertebral artery

Fig. 3.3.4 approaches

Posterior circulation aneurysms – operative

Optic nerve

Transylvian pterional Transcavernous

III nerve V nerve VI nerve

Subtemporal

IV nerve

Temporo-polar

Fig.3.3.5 Approaches to basilar bifurcation. (Adapted from Lindsay & Bone, Neurology and Neurosurgery Illustrated, 2003, Churchill Livingstone)

3.3.1 Aneurysms

tors. Dividing the posterior communicating artery between liga clips may improve access; this carries little risk provided that this vessel is not the dominant source of filling of the right posterior cerebral artery. The transsylvian pterional approach provides good exposure of both posterior cerebral vessels, but has the disadvantage of preventing direct visualisation of the perforators behind the aneurysm fundus. This approach requires less temporal lobe retraction than the subtemporal route, but access may still be difficult for aneurysms > 10mm above the posterior clinoids. Such patients may benefit from a zygomatic or orbito-zygomatic approach (Fig.3.3.3), as these permit a higher trajectory with less retraction. Aneurysms lying below the level of the posterior clinoids preclude a transsylvian pterional approach, unless this is combined with the trans-cavernous route described by Dolenc. The temporo-polar approach (Fig. 3.3.5) provides a combination of both routes. By changing the direction of temporal lobe retraction, the surgeon can approach from a more anterior or lateral direction as required. Posteriorly projecting aneurysms carry a greater risk of operative complications because of the direct relationship with the perforating vessels; for these aneurysms a subtemporal approach aids identification of these perforators and should provide the safest approach. Basilar bifurcation aneurysms lying > 10 mm below the posterior clinoids require one of the approaches detailed in the next section. 3.3.1.5.4.1.2 Superior Cerebellar Artery Aneurysms

The subtemporal route demands an approach from the same side as the aneurysm, whereas the pterional route permits clipping of aneurysms on either side. With these aneurysms, perforators are less likely to involve the neck or the fundus, but the III nerve is often closely adherent and must be dissected off the neck before clipping. 3.3.1.5.4.1.3 Posterior Cerebral Artery Aneurysms

Aneurysms arising anterior to the midbrain (on either P1 or P2) can be approached via the subtemporal, the transsylvian pterional or the temporo-polar route. Those lying in the ambient cistern arising from the P2 segment require a subtemporal approach. Those in the most distal P3 segment may require an occipital interhemispheric approach. Occlusion of the distal posterior cerebral artery beyond the origin of the midbrain perforators or of the posterior choroidal artery seldom causes a permanent visual defect. 3.3.1.5.4.2 Basilar Trunk/Vertebro-Basilar Junction/Low-Lying Basilar Bifurcation

The subtemporal transtentorial approach permits access to aneurysms extending down to 18mm below the floor

of the sella turcica (i. e. to the level of the internal auditory meatus) – in some as low as the vertebro-basilar junction. The temporal craniotomy is sited more posteriorly, centred above the mastoid. Considerable caution is required during retraction to avoid damaging the vein of Labbé. The tentorium is incised from just behind the entry point of the IV nerve, and extended back to the transverse sinus. By stitching back the tentorial edge, the surgeon looks down the medial wall of the petrous bone. Aneurysms can be approached either medial or lateral to the trigeminal nerve (Fig.3.3.6, black and grey arrows), as required. Kawase et al. described an extradural transpetrosal approach where the petrous edge is drilled off between the internal auditory meatus inferiorly, the cochlea posteriorly and the trigeminal ganglion anteriorly; however, the operative field is restricted by the narrow bony opening (Fig.3.3.6, white arrow). The same technique can be adopted during an intradural transtentorial approach if a more anterior approach is required. Alternatively, aneurysms at the vertebro-basilar junction and on the basilar trunk can be approached from below. The standard lateral suboccipital route seldom affords sufficient exposure, but this approach can be improved by a variety of methods. Extending the area of bone removal to include a limited mastoidectomy exposes the sigmoid sinus. Opening the dura behind the sinus and either retracting the sinus anteriorly (retrosigmoid approach) or even dividing and reflecting the sinus anteriorly (transsigmoid approach; Fig.3.3.6) improve exposure of both the prepontine and cerebellopontine angle cisterns from a more anterior direction and reduce the distance to the midline. Alternatively, a combined supra- and infratentorial approach provides a wide view of the basilar trunk and vertebro-basilar junction. Al-Mefty et al. described this petrosal approach, in which in addition to a large temporo-occipital bone flap, a mastoidectomy provides a presigmoid retrolabyrinthine route to the posterior fossa (Fig. 3.3.6). Dividing the superior petrosal sinus and tentorium and retracting the transverse and sigmoid sinus medially gain extensive exposure, provide the shortest route to the aneurysm and minimise retraction of the pons and cerebellum. For the above-mentioned infratentorial approaches, the VII–XII cranial nerves lie between the surgeon and the vessels, and all are at risk of damage. The transclival approach (Fig.3.3.6), through either a transfacial route or a transoral route avoids brain stem and cranial nerve retraction. Such techniques present significant hazards – the operative corridor is long and narrow and the lateral exposure usually extends only 5mm from the midline. Anteriorly pointing aneurysms could rupture when opening the dura and the problems of postoperative CSF leaks persist, despite the availability of modern tissue glues.

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(Tentorium, dura and cerebellum omitted)

Fig.3.3.6 Approaches to the basilar artery and vertebrobasilar junction

Midbrain Optic tract

Posterior cerebral and superior cerebellar arteries

Orbital fissure Cavernous sinus V nerve

Petrous bone

Cerebellar peduncles

Superior petrosal sinus

VII-VIII- nerves

Transfacial transclival Transoral transclival

Lateral suboccipital

Retro- Trans- Presigmoid sigmoid sigmoid

Extreme lateral transcondylar

Retrolabyrinthine

Presigmoid

+ division of superior petrosal sinus

Transtentorial

= Petrosal

above V nerve below V nerve

Transpetrosal

3.3.1.5.4.3 Vertebral Artery

Most vertebral aneurysms arise at the origin of the PICA, but the height of this origin is variable, ranging from the level of the foramen magnum to the vertebro-basilar junction. Rarely, aneurysms lie extracranially – arising at the level of the anterior spinal artery or from a very low PICA origin. The standard lateral suboccipital approach usually provides sufficient access for most of these aneurysms. The craniectomy extends from the midline to the edge of the transverse/sigmoid sinus and includes a rim of foramen magnum. For low-lying aneurysms, to gain proximal control, the vertebral artery can be exposed extracranially in the sulcus arteriosis as it crosses the arch of C1 before penetrating the dura. The far lateral transcondylar approach, removing up to a third or even half of the occipital condyle, aids direct access to the hypoglossal and jugular region and provides a more caudal to rostral trajectory and a shorter route to the midline (Fig.3.3.7). In general, the larger the aneurysm and the nearer to the midline, the greater the need to extend bone removal in a lateral direction. With both the above approaches, it is often necessary to work between the branches of the lower cranial nerves to reach the aneurysm neck; this requires extreme care to avoid permanent nerve damage.

Fig. 3.3.7 Bone removal (dotted lines) for the far lateral transcondylar approach

3.3.1 Aneurysms

3.3.1.6

Endovascular Therapy

3.3.1.6.1 Techniques

Attempts at occluding the aneurysm sac with detachable balloons in the 1980s carried high risks and failed to prevent re-bleeding. The introduction of the Guglielmi detachable coil (GDC) in 1990 proved to be a far safer and more effective alternative (Fig. 3.3.8). Helical platinum coils are inserted through a tracker catheter into the aneurysm fundus and detached electrolytically when a satisfactory position is achieved. “Dense packing” of the aneurysm sac with multiple coils on screening (Fig.3.3.9) equates to the platinum occupying less than one-third of the actual volume, but this is sufficient to disrupt flow and prevent re-bleeding in most patients. In about one-third of cases, the radiologists intentionally leave a remnant of the aneurysm neck, rather than risk obstructing a distal vessel. In this instance, the risk of re-bleeding is higher. Approximately 5% of attempted coil procedures fail.

Aneurysms suitable for coil embolisation require a fundus: neck width of more than 2:1. The radiologists can select coils of different diameter and 3D shape. Usually, four to five coils are necessary, but the number required varies from a single coil for a 3-mm aneurysm to over 20coils for a giant aneurysm. 3.3.1.6.1.1 Balloon Remodelling

This technique, developed by Moret, permits coil embolisation in wide neck aneurysms. Periodically inflating a balloon on a separate catheter within the feeding vessel during coil insertion prevents the coils from falling back into the vessel lumen (Fig. 3.3.10). On completing the procedure, the coils adjacent to the vessel lumen retain the shape of the inflated balloon. Some centres use this technique in 30–40% of endovascular cases.

Fig.3.3.8 a Coil embolisation – insertion of first coil through the tracker catheter. b Insertion of further coils. Reproduced with permission Dr. J. Bhattacharya

Fig.3.3.9 a Digital angiogram showing anterior communicating artery aneurysm. b Final stage of coil embolisation showing fundus packed with coils

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Fig.3.3.10 First stage of coil embolisation with balloon remodelling, showing inflated balloon occluding the neck of a basilar trunk aneurysm. Reproduced with permission from Boston Scientific

3.3.1.6.1.2 Bio-Absorbable Polymer

More recent developments include the use of a bioabsorbable polymer coated around the coil (Matrix) or within the coil (Cerecyte). Experimental work in animals has shown that these polymers stimulate cell regeneration and repair, promote organisation of the thrombus within the aneurysm and encourage neo-intima formation. Whether these coils improve overall results remains uncertain and we await information from further trials. 3.3.1.6.1.3 Hydrogel and Fibre Coils

Hydrogel coils coated with a hydrophilic polymer expand on contact with blood to help fill adjacent space within the aneurysm lumen. Similarly, detachable fibre coils of Dacron or Nylon produce a more thrombogenic reaction than platinum; however, all these new technologies await full evaluation. 3.3.1.6.1.4 Intracranial Stents

The introduction of stents of suitable size and of sufficient flexibility to manoeuvre through intracranial vessels has provided another alternative for wide necked, giant or even fusiform aneurysms, particularly those arising from the internal carotid artery or basilar bifurcation. After placement of the stent, a microcatheter is manoeuvred through the mesh into the fundus to permit coil deposition without fear of occluding the vessel lumen (Fig.3.3.11). Distal thrombi may complicate stent usage and life-long anti-platelet therapy is essential in such patients.

Fig.3.3.11 After placement of the stent, a tracker catheter is manoeuvred through the mesh into the fundus to permit coil deposition without fear of occluding the vessel lumen. Reproduced with permission Boston Scientific

3.3.1.6.1.5 Onyx

Onyx, a liquid polymer that solidifies on contact with blood, can be injected in to an aneurysm sac with the neck protected by either an inflatable balloon or a stent. Although this technique sounds theoretically attractive, an initial series reported a high complication rate and prevented more widespread use. 3.3.1.6.1.6 Endovascular follow-up

All these interventional techniques require check angio graphy, usually 6months after treatment. Re-canalisation due to compaction or movement of the coils requires retreatment in about 10%. 3.3.1.6.2 Treatment Selection

In the 1990s, endovascular treatment was initially reserved for inoperable aneurysms. As techniques and results improved, coil treatment was increasingly used for aneurysms that were difficult to treat surgically, in particular those of the posterior circulation, despite any conclusive evidence of benefit. The International Subarachnoid Aneurysm Trial (ISAT) of clipping versus coiling began in 1994. The Data Monitoring Committee stopped data collection in 2001 after centres had entered 2,143 patients. At 1year follow-up endovascular coiling showed an absolute reduction in the risk of death or dependency of 7% (a relative risk reduction of 23%) compared with patients undergoing clipping. Significantly more re-bleeds and deaths from re-bleeding occurred within the first year in

3.3.1 Aneurysms

the coiled group, but despite this, analysis still favoured this treatment. Despite the absence of long-term followup and the fact that trial patients were a selected group of almost exclusively good grade patients with small anterior circulation aneurysms, an immediate shift in practice towards coil embolisation occurred in the UK, with the proportion of patients undergoing coil treatment increasing from 37 to 54%. In many units this figure now exceeds 80%. Subsequent follow-up of the ISAT patients for up to 7years has shown that the survival benefit is maintained for that period, despite a higher risk of late re-bleeding in the coiled group. Aneurysm treatment requires a neurovascular team composed of interventional radiologists and neurosurgeons. Even if there were no difference in outcome between the two treatments, most patients would opt for the least invasive approach. The ISAT results support the use of coil embolisation as the first-line approach. However, not all aneurysms are suitable for endovascular treatment. The following factors make coil embolisation more difficult or impossible: • Aneurysm in the middle cerebral artery territory • Aneurysms with a wide neck and a fundus/neck width ratio of less than 2:1 • Aneurysms < 3mm in size • Large or giant aneurysms, particularly if partially filled with thrombus Unfortunately, those aneurysms that are difficult to coil are often difficult to clip. The future vascular neurosurgeon (if not directly involved in endovascular techniques) will be required not only to deal with technically demanding aneurysms, but also aneurysms partially packed with coils in which re-embolisation has failed. The most complex aneurysms may require a joint approach combining endovascular occlusion with high- or low-flow bypass. Finally, those patients who deteriorate from a haematoma mass with an underlying aneurysm will require an operative approach to evacuate the haematoma and simultaneously repair the aneurysm. 3.3.1.6.3 Treatment Timing

Approximately 30% of re-bleeds occur within the first month, but the highest risk of re-bleeding occurs within the first 24h. Operative mortality falls the longer operation is delayed after the ictus, but the longer the delay, the greater the possibility of death from re-bleeding. Although there is no convincing evidence to support early operation a meta-analysis of non-randomised studies does suggest that there might be some benefit when the operation is performed within the first 3days of the ictus. Most surgeons follow a policy of early “operation, at least for Grade 1 to 3 patients”. Once the aneurysm is re-

paired, aggressive methods of treating cerebral ischaemia can be applied. Coil embolisation avoids the potentially harmful effects of brain retraction and vessel dissection, and some studies suggest that early coiling carries no additional risk. Whichever technique is planned, it makes sense to employ this whenever manpower and facilities permit – even within the first 12–24 h, if possible, to avoid the period of highest risk of re-bleeding. Selected Reading 1.

Al-Shahi R, White PM, Davenport RJ, Lindsay KW (2006) Subarachnoid haemorrhage. BMJ 333(7561):235–240 2. Bhattacharya JJ, Thammaroj J (2004) The current role of endovascular treatment for saccular cerebral aneurysms: consensus and controversy. Adv Clin Neurosci 14:301–322 3. De Gans K, Nieuwkamp DJ, Rinkel GJ, Algra A (2002) Timing of aneurysm surgery in subarachnoid hemorrhage: a systematic review of the literature. Neurosurgery 50:336–340 4. Fisher CM, Kistler JP, Davis JM (1980) Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery 6(1):1–9 5. Jane JA, Kassell NF, Torner JC, Winn HR (1985) The natural history of aneurysms and arteriovenous malformations. J Neurosurg 62(3):321–323 6. Lindsay KW (2003) The impact of the International Subarachnoid Aneurysm Treatment Trial (ISAT) on neurosurgical practice. Acta Neurochir (Wien) 145(2):97–99 7. Molyneux A, Kerr R, Stratton I, Sanderco*ck P, Clarke M, Shrimpton J, Holman R; International Subarachnoid Aneurysm Trial (ISAT) Collaborative Group (2002) International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet 360(9342):1267–1274 8. Molyneux AJ, Kerr RS, Yu LM, Clarke M, Sneade M, Yarnold JA et al. (2005) International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet 366:809–817 9. Murayama Y, Nien YL, Duckwiler G, Gobin YP, Jahan R, Frazee J, Martin N, Vinuela F (2003) Guglielmi detachable coil embolization of cerebral aneurysms: 11 years’ experience. J Neurosurg 98(5):959–966 10. Rhoton AL Jr (2002) Aneurysms. Neurosurgery 51(4 Suppl):S121–S158

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11. Rinkel GJ, Wijdicks EF, Hasan D, Kienstra GE, Franke CL, Hageman LM, Vermeulen M, van Gijn J (1991) Outcome in patients with subarachnoid haemorrhage and negative angiography according to pattern of haemorrhage on computed tomography. Lancet 338(8773):964–968 12. Rinkel GJE, Feigin VL, Algra A, van den Bergh WM, Vermeulen M, van Gijn J (2005) Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev (1):CD000277 13. Ruigrok YM, Rinkel GJ, Wijmenga C (2005) Genetics of intracranial aneurysms [review]. Lancet Neurol 4(3):179–189 14. Society of British Neurological Surgeons, the British Society of Neuroradiologists, and the Royal College of Surgeons of England, Clinical Effectiveness Unit (2006) National study of subarachnoid haemorrhage. Royal College of Surgeons of England, Clinical Effectiveness Unit, London 15. Van den Bergh WM, Algra A, van Kooten F, Dirven CM, van Gijn J, Vermeulen M, Rinkel GJ; MASH Study Group (2005) Magnesium sulfate in aneurysmal subarachnoid hemorrhage: a randomized controlled trial. Stroke 36(5):1011–1015 16. Van Gijn J, Rinkel GJ (2001) Subarachnoid haemorrhage: diagnosis, causes and management. Brain 124:249–278 17. Whitfield PC, Kirkpatrick PJ (2001) Timing of surgery for aneurysmal subarachnoid haemorrhage [review]. Cochrane Database Syst Rev (2):CD001697 18. Wiebers DO, Whisnant JP, Huston J 3rd, Meissner I, Brown RD Jr, Piepgras DG, Forbes GS, Thielen K, Nichols D, O’Fallon WM, Peaco*ck J, Jaeger L, Kassell NF, Kongable-Beckman GL, Torner JC; International Study of Unruptured Intracranial Aneurysms Investigators (2003) Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 362(9378):103–110

3.3.2 Arteriovenous Malformation 3.3.2.1

Pathogenesis

Hans-Jakob Steiger, Daniel Hänggi, R. Schmid-Elsaesser Arteriovenous malformations (AVM) of the brain are a complex tangle of abnormal blood vessels. They have three morphologic components: • The dysplastic vascular core (nidus) in which arterial blood flows directly into draining veins without the normal capillary beds interposed • The feeding arteries • The draining veins In most cases, the nidus appears well circ*mscribed with little intervening parenchyma and is considered to be

the source of haemorrhage. The vessels within the nidus usually have markedly attenuated walls due to a deficient muscularis. They are exposed to an increased intravascular pressure because of the absence of normal, highresistance arteriolar and capillary beds. Feeding arteries and draining veins are not exclusively devoted to the AVM. Therefore, the haemodynamic characteristics of the AVM may lead to physiologic changes in the normal vasculature adjacent to the malformation with dilatation of the feeding arteries and draining veins. AVM tend to enlarge with age and often progress from a low-flow lesion at birth to high-flow lesions in adulthood. Although the possibility exists that a pial AVM may develop as an acquired lesion, AVM are generally regarded as congenital lesions representing inborn errors of embryonic vascular morphogenesis caused by malfunction of the embryonic capillary maturation process. The lesions are thought to represent a perpetuation of a primitive arteriovenous communication, a shunt that normally would be replaced by an intervening capillary network. Capillary penetration of the cerebral hemisphere is a relatively late event in the development of the brain’s vascular system. This begins during the seventh week and continues almost until the end of the first trimester. It is generally believed that congenital vascular anomalies originate during the embryonic stage of vessel formation or at the foetal stage. However, there is some evidence that cerebral AVM may develop postnatally. The course of AVM cannot be easily predicted: they may remain static, grow, or even regress and recur. Little is known of the molecular mechanisms mediating the genesis and subsequent biological behaviour of CNS vascular malformations. Unlike cavernous malformations of the brain, it is unknown whether or not genetic mechanisms contribute to the pathogenesis and phenotype of cerebral AVM. Possible germline mutations affecting distinct angiogenetic pathways have been proposed to be the underlying cause of a variety of vascular malformations, including AVM. Familial clustering of AVM suggests the involvement of genetic factors. On the other hand, this could be coincidental considering the low incidence of a familial occurrence when specific congenital diseases, such as the Sturge–Weber syndrome (encephalotrigeminal angiomatosis), Rendu–Osler–Weber syndrome (hereditary haemorrhagic telangiectasia), Louis–Barr syndrome (ataxia teleangiectasia), or Wyburn–Mason syndrome (encephaloretinofacial angiomatosis), which are associated with vascular malformations, are ruled out. Hereditary haemorrhagic telangiectasia (HHT), or Rendu–Osler–Weber disease, is an autosomal dominant disorder of localised angiodysplasia. The vascular lesions that develop consist of direct arteriovenous connections without an intervening capillary bed. Germ line mutations in one of two different genes, endoglin or ALK-1, can cause HHT. Both are members of the transforming growth factor (TGF)-beta receptor family of

3.3.2 Arteriovenous Malformation

proteins, and are expressed primarily on the surface of endothelial cells. Considering factors of the surrounding parenchyma, ischaemia must be seen as a primary one. A number of case reports on the association between AVM and moyamoya disease are found in the literature.

identify other risk factors that predispose to haemorrhage. Several factors may increase the risk of haemorrhage: • High intranidal pressure due to high pressure in the feeding arteries or restrictions in venous outflow • Presence of an intranidal or feeder-related aneurysm • Deep location • Small size

3.3.2.2

In earlier investigations the incidence of aneurysm with AVM was reported to be around 10%. With the advent of superselective angiography and higher resolutions aneurysms are detected in up to 50% of patients with AVM. A uniform system is emerging in which it is proposed that aneurysms related to AVM can be divided into four groups: unrelated dysplastic or incidental, flow-related on proximal feeding vessels, flow-related on distal small feeding vessels, and intranidal. Flow-related distal feeder aneurysms appear to be the source of haemorrhage in up to 50% of the posterior fossa AVM, while intranidal aneurysms appear to be more important in supratentorial AVM. The relationship between the size of an AVM and its propensity to haemorrhage is unclear and a matter of continuing discussion. Some studies reported that small AVM present more often with haemorrhage than do large AVM. On the other hand it is conceivable that the impression that small AVM carry an increased bleeding risk is a misinterpretation, because small AVM are less likely to cause any other symptom and are therefore less likely to be diagnosed unless they bleed.

Epidemiology

The incidence of intracranial vascular malformations is not known with certainty. The prevalence data of cerebral AVM reported in the literature range between 0.02% and 0.5% and are probably influenced by geographical and racial factors. In Europe and the United States up to 0.1% of the population may have an AVM. There seems to be a modest male predominance among patients with an AVM, with a male/female ratio of about 1.4:1, and the majority of AVM become symptomatic before the age of 40. 3.3.2.3

Symptomatology

3.3.2.3.1 Haemorrhage

Intracranial haemorrhage is the most common clinical presentation with a reported frequency ranging from 30 to 80%. It is not unusual for old haemorrhagic areas and haemosiderin deposits to be detected on MR images, during open surgery or in autopsy series in patients in whom these events have not been recognised before. The reported risk of haemorrhage as the initial symptom is 2–4% per year. Ondra and collaborators followed 166 unoperated symptomatic patients with cerebral AVM (mean followup period 23.7years). The rate of major re-bleeding was 4.0% per year. There was no difference in the incidence of re-bleeding regardless of presentation with or without evidence of haemorrhage. In contrast, many other studies showed that patients initially presenting with haemorrhage are at higher risk of subsequent bleeding than those presenting with other symptoms. The Arteriovenous Malformation Study Group reported that on average the annual rate of re-haemorrhage was 18% among patients who had had haemorrhage at initial presentation, compared with a rate of 2% among those with no history of bleeding. The risk of re-bleeding appears to be higher in men than in women. Rates of repeated bleeding have been reported to be higher in the first year after initial haemorrhage and to decline rapidly thereafter. The mortality rate associated with the first haemorrhage has been estimated to be about 10–15%, and the overall morbidity about 50%. Nevertheless, since haemorrhage is the most common initial presentation and associated with a significant risk of death or permanent morbidity, it would be helpful to

3.3.2.3.2 Seizures

Seizures are the second most common presenting symptom and may also be a clinical manifestation of haemorrhage. Seizures that are not caused by haemorrhage are reported as the initial symptom in 20–70% of patients. As expected, seizures are usually associated with AVM that involve the motor/sensory cortex or the temporal lobe. The natural history of AVM presenting with seizures is less well known. Some studies have postulated a relationship between seizures and a history of haemorrhage. However, it is unclear whether AVM that present with a seizure without a history of haemorrhage are more likely to bleed than AVM that do not cause seizures. Anticonvulsant medication provides satisfactory control of the seizures, and further improvement is usually seen after treatment of the AVM. 3.3.2.3.3 Focal Neurological Deficits

Less common but more dramatic is the syndrome of progressive neurological deterioration. This syndrome is usually associated with large AVM and has been presumed to be caused by the vascular steal phenomenon, in which cerebral arterial hypotension leads to ischaemia in brain ar-

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eas adjacent to the lesion. This concept is supported by the fact that occlusion of the feeding arteries can ameliorate symptoms. Progressive neurological deficits have been reported in 1–40% of patients, and the wide range reflects the diversity of definitions of such deficits. Although it appears that steal is a logical haemodynamic consequence of AVM and may well be responsible for progressive neurological deficits, this concept has recently been challenged. Other non-haemorrhagic mechanisms that may explain the progression of deficits are venous hypertension due to arterialisation of the venous system, mass effect, perifocal oedema, and obstructive hydrocephalus from ventricular compression by dilated deep veins. 3.3.2.3.4 Other Manifestations

After haemorrhage and seizures, recurrent headaches are probably the next most common presenting symptom reported in 7–50% of patients, with no distinctive features such as frequency, duration, or severity. Not infrequently, imaging studies are performed because of severe headache and lead to the diagnosis of unruptured AVM. Several reports suggest a relationship between AVM in the occipital lobe and migraine-like symptoms with visual phenomena and headaches. Also, symptoms clinically indistinguishable from classic migraine were reported to immediately resolve after removal of the AVM. There is no doubt that headache is a symptom that can be related to AVM and may possibly be cured after treatment of the lesion. In particular, patients with new-onset headaches, headaches with a progressive course, headaches with a significant change in pattern, headaches that never alternate sides, and headaches associated with any neurological findings or seizures are substantially more likely to have a secondary cause, such as a tumour or AVM. Neuropsychiatric disturbances and progressive intellectual deterioration may also be caused by AVM. Interestingly, learning disorders have been documented in most adults with AVM. These patients were significantly more likely to report at least one skill difficulty during their school years than patients with a tumour or aneurysm despite the absence of other neurological symptoms of diseases not diagnosed for another 20years. 3.3.2.4

Diagnostic Procedures

3.3.2.4.1 Haemorrhagic Presentation

Standard diagnostic work-up in the case of intracranial haemorrhage includes CT and/or MRI and selective angiography. Angiography is not indicated in a patient with a typical hypertensive-type haemorrhage located in the basal ganglia, who has a known history of arterial hypertension and is of advanced age. These basic examinations are sufficient for emer-

gency management. If initial conservative management is planned for a small haematoma, additional functional diagnostics can be added after the acute phase. On the other hand, in the case of an acute mass haemorrhage with deteriorating neurological condition evacuation of the haematoma should be considered prior to selective angiography. Major vascular malformations can be identified on a CT angiography sequence, which can be added to the plain CT within a short time. 3.3.2.4.2 Epilepsy

Magnetic resonance imaging is the first step in the workup of epilepsy. This examination can reliably identify intraparenchymal AVM. Selective angiography can subsequently define the angio-architecture. If surgical therapy is considered, functional MRI has become more and more accepted for eloquent locations. 3.3.2.4.3 Other Manifestations

In the case of unspecific neurological deficits, the primary imaging parallels the procedure with epilepsy. If steal phenomena are suspected perfusion studies with SPECT, MRI etc. may be useful, although the impact on therapeutic strategy remains ill-defined. 3.3.2.5

Surgical Therapy

Although there are various kinds of modern treatment modalities for cerebral AVM, surgery is the best-known form of curative treatment, and should be the first choice whenever possible. Since the development of microsurgical techniques, both the operability and the success rates of complete excision have improved remarkably. Decision-making with cerebral AVM is one of the most difficult aspects of neurosurgical practice. The decision whether to recommend surgery should be based on an objective comparison of the long-term risks presented by the untreated AVM with the more immediate risk of operative treatment. In young patients, especially in the presence of neurological symptoms, attempts at surgical removal are justifiable since the surgical risk, albeit high, is still less than that of the natural history. In middle-aged and older patients with minimal symptoms, a conservative approach seems more reasonable as the risk of therapy may not be less than that of the natural history. The most popular system for estimating the risk of surgery is the five-point grading score developed by Spetzler and Martin. It incorporates three variables: • The size of the AVM • The pattern of venous drainage • Neurological eloquence of the brain regions adjacent to the AVM

3.3.2 Arteriovenous Malformation

Grade I malformations are small, superficial and located in the non-eloquent cortex, whereas Grade V lesions are large, deep and situated in neurologically critical areas. The size and pattern of venous drainage of an AVM as surgical risk factors are relatively easy to assess, but it is more difficult to assess the eloquence of brain regions. Alterations in gyral contour and translocation of function due to cortical reorganisation in patients with AVM can make it difficult to identify critical areas adjacent to the lesion. Preoperatively, functional MR imaging or positron emission tomography activation studies are helpful in determining eloquent areas of surrounding brain and in providing information on the location of speech, motor, sensory, and visual cortex for treatment-planning decisions. Intraoperatively, identification and preservation of eloquent brain tissue can be facilitated by electrophysiological monitoring, cortical mapping and neuronavigation systems. In general, small and medium-sized lesions of the convexity that do not involve critical areas should be surgically excised. Compared with radiosurgery or observation alone, surgical excision is highly cost-effective and very efficacious in prolonging quality of life expectancy. In our experience about one-third of AVM can be managed by surgery alone and in two-thirds of the cases embolisation and/or radiosurgery are required before, after or instead of surgery. Large AVM in critical areas with subcortical wedgeshaped extensions reaching the ventricular wall pose complex management problems. The deep portion usually recruits the choroidal arteries or small vessels that normally supply the basal ganglia, the internal capsule and the thalamus. Bleeding from these vessels during surgery may result in haematocephalus. Furthermore, difficulties in controlling deep feeding vessels, such as the lenticulostriate arterial supply, with the use of a cortical approach or via the ventricle, increases the risk of surgical complications. In these cases it is helpful when the deep arterial supply is obliterated by endovascular embolisation before surgery. Large high-flow AVM usually require preoperative staged embolisation and some authors recommend multiple-stage resections (Fig.3.3.12). The stepwise throttling of large AVM seems to minimise the risks of normal perfusion pressure breakthrough, which is hyperperfusion and haemorrhage of the surrounding brain after removal of the AVM. 3.3.2.6

Endovascular Therapy

J. Marc C. van Dijk An alternative to surgical resection of an AVM is endovascular embolisation. The principle of embolisation is to

permanently occlude the nidus of the AVM with either particles or with a liquid substance that quickly solidifies when deposited in a blood vessel. Since particles have failed to result in durable occlusion, nowadays embolics as NBCA (“glue”) and ONYX® are regularly used. Both agents have been demonstrated to be durable after longterm follow-up. The embolisation procedure is usually performed under general anaesthesia. Through a puncture of the femoral artery, using the Seldinger technique, a catheter is introduced and proceeds to the carotid artery. With a micro-catheter, superselective catheterisation of the feeding pedicle(s) of the AVM is performed, leading to a precise depiction of the nidus and its possible risk factors, e. g. intranidal aneurysms. Since most arterial pedicles not only feed the nidus, but also feed normal brain tissue (so-called “en-passage feeding” of the nidus), it is then attempted to put the tip of the micro-catheter in a position from where only the nidus is fed. In this ideal position the embolic agent is released and pushed forward into the nidus. As a rule, multiple sessions are necessary to achieve a favourable result. Although the technique of endovascular embolisation is elegant and is appealing to the patient because it obviates a craniotomy, the downside is that a cure is only obtained in about 15% of the cases and that the multiple embolisation sessions lead to cumulative complication rates. From this perspective, embolisation is mostly applied as a part of combination therapy with surgery or radiosurgery of Spetzler 3 or higher AVMs. Embolisation then serves, for example, as a tool to make the nidus smaller and therefore more amenable to radiosurgery, or to occlude deep feeders that are difficult to deal with in a surgical approach. In conclusion, endovascular embolisation is a well-established modality in the treatment of AVMs. Its associated significant risks must be weighed against its potential benefits in each patient. Therefore, it has earned its place mostly in a multimodal treatment setting. 3.3.2.7

Stereotactic Radiosurgery for Cerebral Arteriovenous Malformations

Andras Kemeny 3.3.2.7.1 Definition

Single-fraction, highly focused and stereotactically guided radiation to a small volume within the intracranial compartment. 3.3.2.7.2 Synonyms

Radiosurgery, SRS, STRS, and Gamma knife surgery.

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Fig.3.3.12 a,b Example of a large right parietal arteriovenous malformation supplied by the middle, c,d anterior and e posterior cerebral arteries as well as by f the external carotid artery. This

63-year old man presented with haemorrhage. Venous drainage takes places via the superior sagittal sinus. Treatment consisted of combined embolisation with microsurgery

3.3.2 Arteriovenous Malformation

3.3.2.7.3 Historical Notes

• 1951: the concept was introduced by Lars Leksell (1907–1986) • The first treatments were carried out in the 1950s with an X-ray tube attached to a stereotactic arc • 1954: cross-fired proton beam treatments were developed at the Lawrence and Berkeley laboratory • 1968: the first Gamma knife (GK) treatment was carried out • 1985: the modified linear accelerator was developed by Colombo • 2000: the automatic positioning system (APS) was developed for the GK 3.3.2.7.4 Principles of Radiosurgery

The treatment is usually carried out under local anaesthetic, as a day-patient, apart from children or claustrophobic individuals. The principle steps are: • Stereotactic imaging • Dose planning • Dose delivery 3.3.2.7.4.1 Stereotactic Imaging

First, a set of standard reference points, or a “fiducial system”, is established around the head using a stereotactic frame. The lesion is demonstrated by digital subtraction angiography (DSA), aided by an MRI and/or CT to provide axial information. In selected rare cases axial images alone may be sufficient. The contours of the target are delineated. 3.3.2.7.4.2 Dose Planning

The aim is to match the radiation treatment to the contour of the lesion with high conformity. Inclusion of adjacent normal tissue would lead to side effects and complications whereas omission of part of the lesion reduces efficacy. In addition to matching the shape, care is taken to avoid passing the radiation beams through eloquent structures adjacent to the lesion or even at a distance (e. g. the lens of the eye). This is achieved by plugging some

of the radiation sources in the Gamma knife or choosing the entry of the beams in linear accelerator (LINAC) techniques (see below). 3.3.2.7.4.3 Dose Delivery

The two basic technologies for dose delivery are the Gamma knife and LINAC. In terms of the number of patients and publications, the field is dominated by the Gamma knife and thus it is considered the “gold standard”. 3.3.2.7.4.3.1 Gamma Knife

A concentric array of 201 Co60 sources provides the output of gamma rays, highly focused to the target by a precision engineered shield (Fig.3.3.13). The combination of fixed sources and collimators results in 0.1-mm targeting precision. 3.3.2.7.4.3.2 LINAC

There are several LINAC techniques. Modified radiotherapy LINACs with a secondary collimator system or dedicated radiosurgery LINACs can be used. A singlefocus multiple non-coplanar arc and conformal block techniques are the most widely applied. The former means that the radiation source is moved along several arcs, while the latter involves manufacturing an irregularly shaped portal for each beam. The so-called micromultileaf collimator consists of a series of individually motorised tungsten leaves that can be positioned automatically to create any desired beam shape. In the intensity modulation technique (IMRT) the dose is delivered in different intensities across the lesion. The collimator leaves dynamically open and close under computer control to selectively expose or shield portions of the target. This technique is in its early stages of development and is still under clinical evaluation. 3.3.2.7.5 AVM Treatment

The target is the nidus of the AVM. The nidus is defined as a network of poorly differentiated and immature vessels to which feeding arteries converge and from which engorged veins drain.

Fig.3.3.13 The Leksell Gamma knife

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Mechanisms of action: • Predominant factor: endothelial proliferation and hyalinisation in the vessel wall. • Secondary factor: myofibroblast development in the adventitia. 3.3.2.7.6 Patient Selection Criteria

Management of AVM is multidisciplinary. For selection criteria see Table3.3.4.

3.3.2.7.9 Complications

• Swelling on MRI: mean onset at 11months, occurs in 2.5% of patients • Symptomatic focal neurological deficit (paresis, visual field, worsening seizures) or raised ICP, in 2–8% of patients • Risk factors: eloquent position (e. g. brain stem, thalamus), size > 3.5cm, peripheral dose > 25Gy, non-conformal dose plan is too simple

3.3.2.7.7 Suitable Targets

Most AVMs are suitable. The ideal lesion is small (<3cm), compact, and in a deep and eloquent position. Features of unsuitable AVMs include: • Pure fistula (endovascular treatment is usually successful) • Diffuse nidus (often untreatable by any method) • Wrapped around an eloquent structure (e. g. the optic nerve in Wyburn–Mason syndrome) • Most dural AVMs (large flat volume or no true nidus) • Maximum diameter > 4cm, unless very compact 3.3.2.7.8 Results

Outcome is dependent on lesion size and peripheral dose. In small (< 2cm) AVMs 85–95% obliteration rates are reported (Figs.3.3.14, 3.3.15). Table3.3.4 Selection criteria for AVM treatment

Fig.3.3.14 Arteriovenous malformation at radiosurgery

• Radiological factors – “Surgical” (Spetzler–Martin) – Size – Site (eloquence) – Draining veins (deep or superficial) – Radiosurgical – Diffuseness of the nidus – Shape of the nidus – Interventional radiology – Angio-architecture, nidal aneurysm • Patient factors – Clinical state (after haemorrhage) – Presentation – Bleed? Epilepsy? Steal phenomenon? – Age (lifetime risk) – Expectation and wishes • Departmental factors – Skills available (surgery, endovascular, radiosurgery)

Fig.3.3.15 Two-year follow-up angiography showing complete obliteration with radiosurgery

3.3.3 Cavernoma

3.3.2.7.10 Options for Large AVMs

• Expectant policy • Stereotactic radiosurgery – Lower dose – less effective – Partial volume – aiming at the fistulous point(s) – Staging (radiosurgery performed on different parts with some months between treatments) • Volume reduction – Surgery – Embolisation 3.3.2.8

Conservative Therapy

H.-J.Steiger, D. Hänggi, R. Schmid-Elsaesser Our data on the long-term spontaneous outcome in AVM patients are largely based on the follow-up of Ondra and colleagues. The rate of major re-bleeding was 4.0% per year, and the mortality rate was 1.0% per year. At followup review, 23% of the series were dead owing to AVM haemorrhage. The combined rate of major morbidity and mortality was 2.7% per year. These annual rates remained essentially constant over the entire period of the study. These numbers should be the reference for defining what is an acceptable surgical risk. The treatment risk of a highgrade AVM according to the Spetzler–Martin scale appears to be comparable to the natural risk over a 10-year period. Therefore, in the case of epilepsy or headache only, initial conservative management can be justified with the recommendation to reconsider in the case of haemorrhage. Selected Reading 1. Steiger HJ, Schmid-Elsaesser R, Muacevic A, Brückmann H, Wowra B (2002) Neurosurgery of arteriovenous malformations and fistulas. Springer, Vienna 2. Ondra SL, Troupp H, George ED, Schwab K (1990) The natural history of symptomatic arteriovenous malformations of the brain: a 24-year follow-up assessment. J Neurosurg 73(3):387–391 3. Mast H, Young WL, Koennecke HC, Sciacca RR, Osipov A, Pile-Spellman J, Hacein-Bey L, Duong H, Stein BM, Mohr JP (1997) Risk of spontaneous haemorrhage after diagnosis of cerebral arteriovenous malformation. Lancet 350(9084):1065–1068 4. Hartmann A, Stapf C, Hofmeister C, Mohr JP, Sciacca RR, Stein BM, Faulstich A, Mast H (2000) Determinants of neurological outcome after surgery for brain arteriovenous malformation. Stroke 31(10):2361–2364 5. Karlsson B, Lindquist C, Steiner L (1997) Prediction of obliteration after gamma knife surgery for cerebral arteriovenous malformations. Neurosurgery 40(3):425–430; discussion 430–431

3.3.3 Cavernoma

Ulrich Sure, Helmut Bertalanffy 3.3.3.1

Characteristics

• A well-defined mulberry-like vascular hamartoma usually consisting of a network of vessels with a single endothelial layer without intermingled brain parenchyma. • Cavernoma may develop de novo and have the potential to grow and cause hemorrhages • Treatment can be surgical or conservative 3.3.3.2

Pathogenesis

The biological behavior of cavernomas is not yet completely understood. They are thought to arise during the early stages of embryogenesis and grow according to malformative mechanisms. Blood flow changes may be the cause of the formation of dilated blood vessels. Cavernomas have been considered as static and non-growing lesions for decades; however, growth of these lesions has been frequently reported. Furthermore, de novo formation of cavernomas with and without prior radiotherapeutic induction has also been described. Consequently, the question arises whether these lesions are of a developmental or acquired nature and whether these lesions bear a proliferating or neo-angiogenetic capacity, or both. Immunohistochemical studies showed the expression of both proliferative and neo-angiogenetic factors. Therefore, cavernomas should not be considered as static, but rather as active lesions. Neo-angiogenesis seems to be more prominent in superficial cavernomas than in deep lesions and is not associated with prior hemorrhages. Cavernomas most often occur sporadically, but may also be inherited dominantly with incomplete penetrance. Patients may have single or multiple malformations. Autosomal dominantly inherited familial CCM has been estimated to occur with a frequency of 1:2,000–1:10,000. It is generally associated with the occurrence of multiple CCMs. In addition to a heterozygous germline mutation in one of three genes, CCM1, CCM2 or CCM3, a second somatic mutation appears to be required for lesion genesis. In familial cases, mutations in the gene CCM1 account for nearly all Hispanic and approximately 40% of non-Hispanic familial CCM cases. With very few exceptions, mutations in CCM genes are truncating or the result of large genomic rearrangements. which facilitates medical genetic counselling.

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3.3.3.3

Epidemiology

Studies based on large necropsy series estimated the incidence of cerebrovascular malformations in general to vary between 0.1 and 4%. Incidences of 0.02–0.9% of cavernous malformations were reported, showing a considerable range. Large studies show agreement that there is no difference in the sex incidence of cavernomas. The range in age varies between neonates and the ninth decade, with a median of 34years. The highest incidence seems to occur between the third and the fifth decade. The incidence of pediatric cases accounts for approximately one-fourth of the total cases. A major proportion of the lesions are located supratentorially. In a large series of cases, 67% of the lesions were located supratentorially, 26% were located infratentorially, and 6% of the lesions were found in the spinal cord respectively. 3.3.3.4

Symptomatology

Due to the heterogeneity in size, location and propensity of bleeding, cavernous angiomas may cause a wide spectrum of clinical symptoms with frequent changes over time such as repeated exacerbation of complaints and alternating periods of remission. In some instances cavernomas may simulate multiple sclerosis due to the fluctuating progressive neurological deficits. Classically, the clinical syndromes have been divided into the broad categories of seizures, focal neurological deficits and hemorrhages. Neurological disorders may occur at any site of the lesion, usually produced by intralesional or perilesional hemorrhage (see Table3.3.5). Neurological deficits may be transient, progressive, recurrent or fixed. Concerning the indication for surgery to treat epileptic seizures caused by cavernomas, it is generally agreed that the excision of the lesion improves seizure control most patients. 3.3.3.5

Diagnostics

Today, digital subtraction angiography (DSA) is considered rather an unnecessary diagnostic tool. The most sensitive and therefore the most important imaging study is magnetic resonance imaging (MRI), with particularly high sensitivity of gradient-echo sequences (Fig.3.3.18). However, since cavernomas are often associated with developmental venous anomalies (DVA), in rare instances (for example, for planning surgical approach) the angiography may complete a preoperative diagnostic work-up for a patient suffering from a cavernoma.

Table3.3.5 Symptomatology of cavernoma • Hemorrhage (rate per year: 0.4–10.6%) • Deep-seated (brain stem, thalamus, basal ganglia) and lesion with prior history of hemorrhage bear a higher risk compared with superficial cavernomas • Severe headache caused by hemorrhage • Often causes epilepsy (temporal) or • Cranial nerve palsies (brain stem)

In daily clinical practice, T1- and T2-weighted triplanar MRI studies constitute the most important diagnostic tool, not only to establish the diagnosis of cavernoma, but also to define the exact size, location and extent of the lesion, as well as other features such as multiplicity and associated hydrocephalus, or to estimate the condition of the adjacent brain parenchyma and the presence of an intra- or extralesional bleeding. Moreover, postoperative follow-up MRI is indicated in all surgical cases in order to confirm the completeness of cavernoma resection, and later, to assess a possible de novo formation (see Figs.3.3.16, 3.3.17). 3.3.3.6

Therapy

3.3.3.6.1 Stereotactic Radiosurgery

The use of radiosurgical treatment for cavernomas is controversial. Considering the high surgical risk in patients with deep-seated cavernomas, radiosurgery has been introduced in analogy with the successful radiosurgical treatment of arteriovenous malformations. The main goal of radiosurgical treatment must be a significant reduction in the risk of bleeding, especially after a latency period of 2years. This time delay derives from the experiences with radiosurgical treatment of AVMs, 2years being the time period over which radiosurgery exerts its effects on these high-flow malformations. Whether the same effect can also be achieved in low-flow malformations such as cavernomas is not yet proven. Different from AVMs, however, MRI or angiography cannot be used to follow the risk of bleeding and there is no obvious end point in evaluating the treatment results. In particular, Gamma knife treatment may result in a high incidence of neurological sequelae caused either by radiation necrosis or by post-treatment hemorrhage, and even fatal cases have been reported. In contrast to the optimistic view of few studies claiming that the stereotactic radiosurgery of small, deeply situated cavernomas may be superior to the results of microsurgical resection, recent publications have clearly shown that stereotactic radiosurgery appears to be an inappropriate treatment for the prevention of bleeding from a cavernoma.

3.3.3 Cavernoma

Fig.3.3.16 Imaging of cavernomas. a Upper left: female patient (aged 24) with severe headache and epilepsy, axial MRI (FLAIR) showing the intracapsular hemorrhage. Lower left: coronal T2weighted image. Upper right: CT shows the hemorrhage with intracapsular blood resulting from repeated hemorrhages. Lower right: immediate postoperative CT shows the complete removal of the cavernoma. b Upper left: MRI (T2- weighted)

male patient (aged 41) with multiple lesions including a clinical manifest large mulberry like cavernoma in the midbrain. The patient suffered from repeated history of hemorrhages. Upper right: Coronal MRI (T1-weighted MRI with contrast enhancement). Lower left: postop MRI after removal of the cavernoma via a subtemporal (transtentorial) approach. Lower right: Patient 7 days after surgery

3.3.3.6.2 Preoperative Considerations, Indication for Surgery

demonstrated that lesions within all such locations can also be removed safely and with acceptable morbidity. Brain stem cavernomas account for 9–35% of all cavernomas. This subgroup of lesions constitutes a special entity. The hemorrhage rate of these cavernomas is up to 30 times greater than that of other locations. Due to their anatomy hemorrhage is more likely to cause severe neurological deficits. Brain stem cavernomas represent a formidable treatment challenge because of their location within a parenchyma responsible for critical neurological function, rendering them much more difficult to remove than those in other locations.

The division of cavernous malformations into supratentorial (and cerebellar) and brain stem lesions is helpful in daily clinical practice as there are significant differences in the clinical presentation and management of these subgroups. Surgery for supratentorial (and cerebellar) cavernomas in young patients with mild or non-disabling symptoms might be questionable. However, in view of the cumulative risk of hemorrhage or neurological disability over time, an elective surgical resection might be indicated for some of these individuals. More problematic are the lesions located either within cortical or subcortical eloquent areas and within other functionally important regions such as basal ganglia and thalamus or those located within the third ventricle, the corpus callosum and cingulate gyrus, the paraventricular and paratrigonal region as well as the deep temporal area. However, recent publications have

3.3.3.6.3 Timing of Surgery, Goals of Surgery

For the timing of surgery, the following factors play an important role: the presence or absence of hemorrhage, the presence or absence or intractable seizures, the acuteness and the mass effect of hemorrhage, the patient’s

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Fig.3.3.17 Pre- and postoperative imaging and neuronavigation. Upper left: male patient (aged 41) with severe headache, axial MRI (T2-weighted) showing the cavernoma in the caput of the caudate nucleus. Lower left: axial T2-weighted image post-

operatively displays the complete removal. Rest of the images: intraoperative screen shot of a neuronavigation system showing the tip of the pointer when the cavernoma was identified during the surgery via a trans-Sylvian exposure

clinical condition, and the referral pattern. Owing to a considerable variability of these factors, no unanimous recommendations exist, and each clinical scenario requires a distinct management approach. The goals of surgery are summarized in Table3.3.6.

to aid the resection of cerebral cavernomas. Neuronavigation contributes to the definition of ideal vectors for the approach, an optimized positioning of craniotomy sites, subsequently a minimized cortical trauma, and it aids anatomical understanding, resulting in enhanced confidence and increased safety of surgery (see Fig.3.3.17).

3.3.3.6.4 Planning, Neuronavigation

The surgical technique includes precise preoperative planning of the surgical approach based on neuroimaging, and technical adjuncts such as image-guided localization and electrophysiological methods (see also below). Precise planning, intraoperative orientation, localization of anatomical landmarks, and avoidance of vital structures are important issues in surgery for cerebral cavernous malformations. With features like route planning, structure identification, and facilitation of anatomical understanding, navigation systems have the potential

Table3.3.6 Goals of surgery 1) To prevent re-bleeding, which implies total removal of the lesion 2) To minimize damage to the surrounding normal parenchyma, which implies designing a special and individually tailored approach in each patient 3) To preserve an associated venous anomaly (that is often associated and can be diagnosed by MRI and angiography, see above)

3.3.3 Cavernoma

Image-guided surgery provides genuinely useful feedback to the surgeon in preoperative the anatomical orientation, planning and simulation of the surgical approach, intraoperative navigation, avoidance of vital neurovascular structures and assessing the extent of possible resection. It provides warning of the proximity of important anatomical structures and identifies the possible location of the residual parts of any lesion. Current image guidance is dependent on preoperative digital images and the impact of brain shift on image guidance has been recognized. As it is well known that deep structures are remarkable for a small magnitude of

post-imaging brain distortion, intraoperative image updating might not be required for the surgical treatment of centrally located lesions. Intraoperative ultrasound can serve as an alternative or an addition to the standard neuronavigation based on preoperatively derived images. As well as intraoperative CT or MRI it is one of the modalities for image-updating that is currently in use. Features of sonography are its flexibility and its simple and independent application. However, intraoperative ultrasound images typically have a low signal-to-noise ratio (see Fig. 3.3.18). Its application, especially when integrated into a neuronavigation system, may be particularly help-

Fig. 3.3.18 Neurosonography and its integration into neuronavigation. Upper left: male patient (aged 32) with a high frequency of pharmaco-resistant epileptic seizures, axial gradientecho MRI displays the left frontal subcortical cavernoma. Lower left: intraoperative ultrasound image showing both the sulcal anatomy and the hyperechogenic cavernoma. Rest of the images (same patient): intraoperative screen shot of a neuronavigation system with integrated image-guided ultrasound showing the tip of the pointer at the sulcus where the access was planned (Left row: axial, coronal, and sagittal view). Note the black arrow indicating the planned sulcal approach. The right side of the screen shot illustrates (lower part) the ultrasound image with nice visualization of the sulcus. Furthermore, a MRI image corresponding to the same plane as seen in the ultrasound image is

shown (center). The upper part of the right side of the screenshot displays the fusion of both previously described images. In order to better understand the fused images, the ultrasound part of this composed image is transcribed into green, enabling the surgeon to gain a better understanding of which part of the information derives from which imaging modality (MRI or ultrasound). Note the white arrow within this image parallel to the sulcal approach to the cavernoma. Furthermore, this screenshot demonstrates the effect of brain shift, since the cavernoma is not seen in the MRI slice (center part of right side of the screen shot) as expected, which is an effect of the shift that was caused by CSF loss after opening of the dura in this case. Consequently, intraoperative ultrasound may help to overcome the problems of shifting after CSF release

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ful for both the sulcal approach planning after craniotomy and the deep cortical incision (see Fig.3.3.18). However, even with sophisticated equipment and high resolution, the spatial resolution is not superior to that of MRI. 3.3.3.6.5 Surgical Approach

A surgical approach that adequately exposes a cavernoma is essential for the success of the procedure. The majority of authors selected the surgical approach according to the relationship between the cavernoma and the pial or ependymal surface of the brain. For most supratentorial cavernomas, simple hemispheric craniotomies centered on the sulcus as the point of intended access offer sufficient visualization for microsurgical manipulation. For deep-seated lesions, standard approaches such as the pterional, suboccipital midline, retromastoid or subtemporal approaches may not be sufficient in many instances. Specially designed access routes and procedures may offer several advantages, particularly for complex and deepseated cavernomas. For example, a median suboccipital approach exposing the rhomboid fossa is one of the most frequently used routes for accessing brain stem cavernomas. Although an intertonsillar approach preserving the cerebellar vermis anatomically is advocated by the majority of neurosurgeons, some still split the vermis in order to expose the floor of the fourth ventricle. However, transection of the posterior inferior vermis may badly impair tandem gait. It is therefore advisable to use the intertonsillar approach, which yields sufficient exposure of the floor of the fourth ventricle in all cases. For ventrolaterally located lesions within the pons or the midbrain, a posterior, subtemporal, transtentorial approach with preservation of the trochlear nerve is often required for adequate exposure. 3.3.3.6.6 Intraoperative Electrophysiological Monitoring

Particularly for deep-seated cavernomas such as brain stem and basal ganglia lesions, intraoperative neuromonitoring has gained increasing importance. In these cases, monitoring of motor-evoked potentials (MEP) by high voltage vault stimulation, the continuous monitoring of somatosensory-evoked potentials (SSEP) as well as brain stem auditory-evoked potentials (BAEP) are used routinely in many centers. Critical SEP changes were defined as more than 50% amplitude reduction or latency delays of more than 10%, or an increase in the central conduction time of more than 1.0ms. Likewise, BAEP amplitude reductions in waves III, IV or V of more than 50% and/or increases in the latencies of the fifth peak of the interpeak latency difference (P5–P1) of more than 1ms were considered critical. Furthermore, the technique of phase reversal recording may be used to identify the central sulcus during sur-

gery for primary cortical cavernomas localized within the pre- or post-central gyrus. 3.3.3.6.7 Dissection Techniques

Apart from the exact localization and the optimal cortical incision, the dissection technique may significantly influence the outcome after surgery for removal of cavernomas. The identification of a hemosiderin-colored brain surface may guide the surgeon to the correct cortical incision; however, in subcortical or deep-seated lesions the brain surface might not be altered. In these cases, we use the image guidance techniques as well as intraoperative ultrasound image updates (in combination with the functional data from the electrophysiology) to make the decision where to incise the brain surface or where to open a sulcus in order to gain the closest access to a lesion in relation to the brain surface. Once the cavernoma is identified, it is mandatory to stay within the correct cleavage between the lesion and the healthy parenchyma. A cottonoid should be placed between the separated portions of the malformation and the parenchyma. Bipolar coagulation disconnecting tiny feeders and draining vessels with microscissors is necessary. A high-power magnification and the use of fine bipolar coagulation forceps with low power to limit the spread of current into the adjacent tissue should be used, particularly for deep-seated cavernomas. Associated developmental venous anomalies should be maintained. Piecemeal removal is required when the parenchymal opening is smaller than the lesion; however, small lesions may usually be shrunk into their cavity and removed in one piece. Once, the cavernoma is removed, it is mandatory to inspect the entire resection cavity in order to exclude any residual part of the lesion. The use of lasers for brain stem cavernoma surgery, as described more than a decade ago, has not gained general acceptance. Table 3.3.7 shows three aspects that have gained general acceptance in cavernoma surgery. 3.3.3.6.8 Postoperative Outcome, Complications, Morbidity and Mortality

Defining the outcome of surgery for cavernoma is a difficult matter. In spite of the clear goals of surgery mentioned above, there is no ultimate method to demonstrate the cure from a cavernous malformation that may even Table3.3.7 Recommendations for surgery 1) Complete removal of the lesion 2) Avoid injury to an associated venous malformation 3) Leave the surrounding hemosiderin-loaded gliotic parenchyma intact in case of brain stem cavernomas and remove this layer in subcortical epilepsy cases

3.3.4 Cranial Dural Arteriovenous Fistulas

show de novo appearance after apparently complete removal. Even high-resolution MRI techniques may not furnish 100% evidence of total resection of the lesion and thus elimination of the bleeding risk (see Fig.3.3.17). Moreover, the surgical procedure itself may cause various side effects that may persist or gradually disappear. Postoperatively, patients may be in the same condition as preoperatively, they may be improved or neurologically deteriorated. Some patients treated in the 1980s (when surgeons worldwide had little experience with cavernomas) suffered from severe complications, but with increasing surgical experience the outcome results have dramatically improved. Recently, the outcome of even deep-seated lesions (brain stem or basal ganglia) has usually been excellent, with minimal or virtually no surgical morbidity. In the few cases with deterioration, the operative morbidity is usually caused by an edema of critical (brain stem) parenchyma, and includes various degrees of internuclear ophthalmoplegia, worsening of hemiparesis, facial or abducens paresis, gaze palsy, facial, truncal and/or extremity numbness, dysphagia, dysarthria, gait ataxia, etc. In most of the cases the neurological dysfunction resolves completely within the first 6months of surgery. 3.3.3.7

Conservative Treatment

Patients with an established diagnosis of cerebral cavernous malformation who present without gross hemorrhage, seizures or other specific symptoms are candidates for clinical observation and repeated imaging. Non-operative management may be the best modality in patients with purely incidental lesions as well, particularly when the malformation is located deeply within functional areas of the brain, or in individuals harboring multiple lesions, even when accessible malformations have already been resected. Pharmacological treatment is indicated in patients suffering from epileptic seizures. We do not recommend the medication of aspirin for patients suffering from cavernoma.

discerns DAVFs from the pial arteriovenous malformations (AVMs). Furthermore, it is generally accepted that DAVFs are acquired, as opposed to the pial AVMs, which are thought to be congenital. For this reason, although in the literature in many instances DAVFs have also been referred to as “malformations,” in this chapter the term “fistulas” is preferred to avoid confusion. Dural arteriovenous fistulas were rarely identified before 1960; however, since then have emerged as a distinct entity owing to the advances in angiography, such as magnification and subtraction techniques and selective arterial catheterization. Although case reports had already appeared in the 1930s, the first concept of spontaneous DAVF was introduced in 1951 by Fincher. At first, the dural lesions were regarded as benign in comparison to pial AVMs. In the early 1970s, pioneers such as Aminoff, Newton, and Djindjian broadened the anatomical and clinical knowledge of DAVFs. In 1972, the concept arose that the pattern of venous drainage might relate to the clinical signs and symptoms; however, it was not until 1975 that the risks of particularly the cortical venous drainage (CVR) were recognized. Djindjian et al. made the first classification based on this concept, stating that DAVFs with a free outflow into a sinus were relatively harmless, while lesions with CVR could produce severe complications. The 1980s were dominated by three extensive reports in the literature. In 1984, Malik et al. published their review of 223 cases with the message that restriction of venous outflow was a key factor; however, they did not emphasize the importance of CVR. Lasjaunias et al. published a meta-analysis of 191 cases, spreading the message that focal neurological symptoms were dependent on the territory of draining veins and that CVR carries a high risk of intradural bleeding. The third report by Awad et al. reviewed 377 cases, mostly taken from the literature. The latter introduced the term “aggressive” for lesions presenting with a hemorrhage or a focal neurological deficit and emphasized the importance of CVR, venous ectasias, and galenic drainage. 3.3.4.2

3.3.4 Cranial Dural Arteriovenous Fistulas

J. Marc C. van Dijk 3.3.4.1

Introduction

Dural arteriovenous fistulas (DAVFs) are a unique neurovascular entity, representing 10–15% of all intracranial arteriovenous lesions. They consist of one or more true fistulas, direct arteriovenous connections without an intervening capillary bed, localized within the leaflets of the dura mater. This anatomical location clearly

Pathogenesis

The etiology of cranial DAVFs is unknown, although much speculation has been published. It has already been mentioned that these lesions are generally accepted to be acquired, described after surgery, after head trauma, and in relation to sinus thrombosis; however, the exact pathway has never been unequivocally proven. Two hypotheses of pathogenesis have been proposed. The first claims that cranial DAVFs arise from existing “dormant” channels between the external carotid circulation and the venous pathways within the dura mater. Histopathological and radio-anatomical studies have shown that these communications are normally present in the

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dura. These channels open owing to the venous hypertension associated with sinus thrombosis or sinus outflow obstruction. A variation on this theme is the reported existence of thin-walled venous pouches within the dura, close to small arteries. Rupture of these fragile pouches easily induces arteriovenous communications within the dura. The second hypothesis claims that DAVFs are the result of newly grown vascular channels due to provoked angiogenetic factors. These factors, such as VEGF and bFGF, originate either directly from the organization of a sinus thrombosis or indirectly induced by an increased intraluminal venous pressure through a mechanism of tissue hypoxia. Histopathologically, the true arteriovenous fistula has no intervening capillary bed and consists of small venules with a diameter of approximately 30 μm. These vessels have been called “crack-like vessels,” because they look like cracks in the dural sinus wall after histological staining. Furthermore, intimal thickening of both dural arteries and dural veins has been observed. Although the fistula has initially been described within a thrombosed sinus, the general acceptance is that the fistula is located within the wall of the sinus. This also explains the existence of the type of DAVF that drains directly into the pial venous network, without drainage into the venous sinus. 3.3.4.3

Classification

In concert with several authors the terms “benign” and “aggressive” are used throughout this section in relation to the different types of cranial DAVFs and their typical signs and symptoms. In this concept, clinical features such as non-hemorrhagic neurological deficits (NHND), hemorrhage, and death are considered aggressive, while complaints of chronic headache, pulsatile bruit, and orbital symptoms including cranial nerve deficits owing to cavernous sinus involvement are considered benign, even though the complaints might be regarded as intolerable by the patient. Several classification schemes for cranial DAVFs have been introduced, of which the classifications of Borden and Cognard are the most widely used (Tables3.3.8, 3.3.9). Although the three-step classification of Borden has the advantage of being relatively simple to apply, the Cognard classification (a revision of the Djindjian classification scheme) is theoretically superior, as it incorporates the additional effect of the flow-direction in the dural sinus. Both classifications have been validated in the literature. In this perspective, cranial DAVF categorized as Borden 1, Cognard I or Cognard IIa are to be considered benign, while all higher Borden and Cognard grades are to be categorized as aggressive DAVFs, with all their consequences.

Table3.3.8 Borden classification 1

Venous drainage directly into the dural venous sinus or meningeal vein

Venous drainage into the dural venous sinus with cortical venous reflux (CVR)

Venous drainage directly into the subarachnoid veins (CVR only)

Table3.3.9 Cognard classification I

Venous drainage into the dural venous sinus with antegrade flow

IIa

Venous drainage into the dural venous sinus with retrograde flow

IIb

Venous drainage into the dural venous sinus with antegrade flow and CVR

IIa+b

Venous drainage into the dural venous sinus with retrograde flow and CVR

III

Venous drainage directly into the subarachnoid veins (CVR only)

Type III with venous ectasias of the draining subarachnoid veins

3.3.4.3.1 Benign DAVFs

The absence of CVR can be considered as a predictor of both a benign presentation and an uneventful natural disease course. Regarding benign DAVFs, few publications with clinical and angiographic follow-up data have been published. Davies et al. reported their experience with a cohort of 54 cases without CVR over a mean follow-up period of 33months. Only one of the patients (2%) died after palliative endovascular treatment, without angiographic conversion into a lesion with CVR. This unusual course of a predicted benign disease was explained to be the result of venous hypertension owing to functional obstruction of the superior sagittal sinus. In the rest of their cohort Davies et al. found that the majority of cranial DAVFs without CVR behave in a benign fashion and that the focus of therapeutic efforts, if at all necessary, should be directed toward palliation rather than toward angiographic cure. Cognard et al. reported around 7 patients who initially had a DAVF without CVR, but following treatment experienced after a mean 7 years a worsening of the clinical symptoms. In a more recent study by Satomi et al., the chronological change in clinical symptoms and angiographic features of 117 patients with a benign cranial DAVF was evaluated. None of the cases presented with either intracranial hemorrhage or NHND; therefore, the preferred management of these lesions was observational. Palliative treatment, never aiming at cure,

3.3.4 Cranial Dural Arteriovenous Fistulas

was administered if the patient had intolerable symptoms or if there were pressing ophthalmologic indications. Using this conservative management 98% of the patients achieved a tolerable and often self-limiting disease. 3.3.4.3.2 Aggressive DAVFs

Cranial DAVFs with CVR are to be considered aggressive lesions (Fig.3.3.19). Their behavior includes the high likelihood of intracranial hemorrhage, NHND, and death at presentation. However, for a long time the natural disease course after the aggressive presentation was less well understood, with the publication during the 1990s of several reports with contradictory messages. These reports all had their limitations, varying from a very short follow-up to mixing up benign and aggressive lesions. In 2002, Van Dijk et al. reported a prospective study on DAVFs with persistent CVR, with a mean follow-up of 4.3years. It was found that the natural disease course of aggressive DAVFs had an annual mortality rate of 10.4%. In addition, the annual risks of subsequent intracranial hemorrhage or NHND after presentation were 8.1% and 6.9% respectively, adding up to a 15.0% annual event rate. These numbers mandate prompt diagnosis and treatment of these aggressive lesions. 3.3.4.4

Diagnostic Procedures

3.3.4.4.1 CT

Due to the absence of CVR, benign DAVFs are nearly always occult on CT imaging. In the case of an aggressive DAVF, unenhanced CT images may show hypodensities, representing areas of edema or venous ischemia. Abnormally enlarged pial veins can be depicted due to their increased density in comparison to the brain parenchyma. Contrast-enhanced CT shows enhancement of the refluxing cortical venous network. 3.3.4.4.2 MRI/MRA

On MRI, it is very challenging to detect a benign DAVF. MR angiography is more sensitive, although it still has its limitations in depicting the fistula. In the case of an aggressive DAVF, MRI is better able to visualize the abnormalities, characterized by flow voids on the cortex corresponding to dilated pial vessels. The brain parenchyma can show T2 hyperintensity in the white matter secondary to the venous hypertension leading to congestion of the brain, especially in the deep white matter. The venous hypertension will eventually lead to gliosis, which bears the same signal characteristics as edema on T2-weighted images. The differential diagnosis for T2 hyperintensity includes sinus thrombosis (with venous infarction or

Fig.3.3.19 Aggressive dural arteriovenous fistula (DAVF) with cortical venous reflux (CVR)

venous congestion), de/dysmyelination, and neoplasm. However, the combination of T2 hyperintensity and a surplus of pial vessels is highly suggestive of a vascular malformation and mandates prompt angiography. 3.3.4.4.3 Digital Subtraction Angiography

Angiography still is obligatory for confirming the diagnosis of DAVF and for planning treatment. Selective contrast medium injections into the different branches of the external carotid artery will reveal rapid arteriovenous shunting through the fistula into the cerebral venous system. The transit time of contrast medium injected selectively into the internal carotid artery is usually delayed, compatible with venous congestion. The main goal in the imaging of cranial DAVFs is definitely the scrutinizing of the venous phase when there is CVR. Other important findings are outflow obstruction owing to venous sinus occlusion, which can result in extracranial drainage via collateral routes, including the orbital system, and augments the risk of retrograde flow into the cortical and cerebellar veins. Finally, in diagnostic imaging, the existence of multiple DAVFs within one patient should be considered a possibility, since this scenario is reported to have a frequency of 7–8%. 3.3.4.5

Therapeutic Options

In general, treatment of a lesion is only to be performed if this treatment is expected to ameliorate the natural disease course. The natural history of cranial DAVFs is

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related to the venous drainage pattern, especially the existence of CVR. In benign cranial DAVFs, a 98% beneficial disease course without curative treatment has been reported, indicating that observation with timely angiographic reevaluation is the best available treatment. Therefore, only in those patients who suffer intolerable symptoms should treatment be limited to diminishing focal symptomatology with palliative arterial endovascular embolization. The sacrifice of a venous sinus is contra-indicated at all times. Aggressive cranial DAVFs demonstrate severe complications in their natural disease course, thus mandating aggressive treatment. Disconnection of CVR is obligatory to protect the patient from the sequelae of intracranial hemorrhage or NHND. Since partial treatment will not lead to risk reduction, the achievement of a cure by treating the CVR is essential. With both endovascular embolization and surgery it is possible to cure DAVFs. Surgery used to be the gold standard, but with the introduction of liquid adhesive embolics (NBCA) showing a durable result without recanalization, both techniques are regarded as equal. It is not necessary to achieve a complete resection or obliteration of the fistula; simple disconnection of the refluxing cortical veins to the brain parenchyma will yield the same result. Although reported occasionally, radiosurgery plays no role in the treatment of cranial DAVFs, with or without CVR. Benign cranial DAVFs need no treatment and any additional risk from radiosurgery is too great. Aggressive cranial DAVFs have a bad disease course after their presentation, with, untreated, an annual event rate of 15%, often leading to severe disability or death. Since the expected results of radiosurgery come only years after treatment, this delay is unacceptable. 3.3.4.6

Pearls

• Cranial DAVFs can be classified as benign or aggressive based on the presence of cortical venous reflux to the brain parenchyma (CVR). • DAVFs without CVR have a benign presentation and disease course; as a consequence they can be observed, with only palliative measures in patients with intolerable signs and symptoms. • Be aware of the small chance of a benign DAVF converting into an aggressive DAVF; timely clinical and angiographic re-evaluation is mandatory. • If untreated, an aggressive DAVF carries an annual event rate of 15%, with an annual mortality rate of 10.4%. • Selective disconnection of the CVR, either by endovascular embolization or surgery, is the treatment of choice in aggressive DAVFs.

3.3.5

Stenotic and Occlusive Vascular Disease

Vladimir Beneš 3.3.5.1

Pathogenesis

3.3.5.1.1

Physiology and Pathophysiology

The disease underlying 90–95% of ischemic strokes is atherosclerosis. Since atherosclerosis is a systemic disease, the majority of stroke patients suffer other atherosclerosis-related diseases as well – ischemic heart disease, diabetes mellitus, arterial hypertension, and ischemic disease of the lower extremities. Fat metabolism imbalance is frequent among these patients. The brain represents only 2% of the total body weight, but consumes 15% of the cardiac output (approximately 750 ml of blood/min) and utilizes 20% of oxygen. Cerebral blood flow (CBF) averages 50 ml/100 g brain tissue/min. Brain utilizes 90–100% of glucose supplied by oxidative phosphorylation. Glucose consumption under normal conditions is 4.5–5.5 ml/100 g brain tissue/min and oxygen consumption is 3.0–3.5 ml O2/100 g brain tissue/min. Most sensitive brain cells (hippocampal area CA1) survive some 3–5 min without oxygen. Brain–blood flow autoregulation is the ability to compensate for fluctuating levels of systemic arterial pressure. CBF remains stable within the range of systemic arterial pressure of 60–160 torr in healthy patients. The brain’s vascular supply consists of a system of collaterals: four major arteries (bilateral internal carotid arteries – ICAs – and bilateral vertebral arteries – VAs) constitute the circle of Willis, which is able to redistribute blood supply (in some cases even if only one of the main arteries is patent). This system is strengthened by collaterals between extra and intracranial vascular regions (ophthalmic artery, muscle branches of the VA, etc.). The most important part of the brain – the brainstem – is mainly supplied by the basilar artery (BA), which is supplied by both VAs and secured by both posterior communicating arteries (PcomA). Occlusion of one VA is almost always asymptomatic. On the other hand, untreated BA thrombosis is almost always fatal. Rapid thrombosis of the ICA usually causes a major stroke with ischemic lesions in the whole middle cerebral artery (MCA) territory. Slow progressive occlusion allows for enlargement and creation of collateral vessels, blood redistribution by the anterior communicating artery (AcomA) and PcomA, and thus may pass asymptomatically. Occlusion of the basal ganglia and brainstem perforators almost invariably causes permanent neurological lesions. The clinical picture depends on the rapidity of occlusion, and the depth and length of ischemia. Neurological deficit appears if the CBF decreases to < 30 ml/100 g brain tissue/min. EEG disappears with CBF < 18 ml/100g brain

3.3.5 Stenotic and Occlusive Vascular Disease

tissue/min (brain cells are still viable, but are non-functional = “electrical failure”); evoked potentials are suppressed with CBF < 15 ml/100 g brain tissue/min. CBF under 10–12ml/100g brain tissue/min causes significant concentration changes of ions (“ionic failure”). A penumbra, with CBF 12–15ml/100g brain tissue/ min, is a brain region of electrical silence, but without structural deficit, usually surrounding a central region of ischemia. When CBF < 10ml/100g brain tissue/min a cascade of processes is started that leads to cell death. Arteries and arterioles are resistant vessels due to their resistance to blood flow. Blood flow gradually decreases parallel to the ramification of the vessels and an increase in the total cross section of the vessels. Capillaries contain some 5% of the blood volume, and make up to 20% of vessel resistance. Perfusion pressure (the difference between mean intraluminal pressure on the arterial end and on the venous end of a capillary) has to exceed the level of “critical closing capillary pressure.” Otherwise, the capillary collapses. The pressure of inflowing blood has to exceed the interstitial pressure (approximately equal to ICP) and has to overcome the deformation resistance of red blood cells (capillary diameter is lower than that of red blood cells). Blood flow velocity decreases due to the greatest cross section of all capillaries (approximately to the level of 0.07cm/s). Veins generate the lowest resistance to blood flow, as they contain the largest volume of blood. Under physiological conditions blood flows laminary throughout the whole arterial blood circuit. The axial (central) flow is the fastest one; every other concentric fold is slower, the most excentric fold is the slowest one (due to fluid friction with the vessel wall). Below critical values, the laminar flow changes to a turbulent one. Such a flow can lead to thrombi formation.

anemia, MELAS syndrome, vasculitis) that are important in the differential diagnosis. According to “Stroke Data Bank NIH” up to 40% of strokes are of unknown origin; 27% are attributed to microangiopathy, 19% to embolization from the heart, and 14% to macroangiopathy (major extra- and intracranial vessels). It seems that a large proportion of strokes of unknown origin are actually embolic. The risk of ischemic stroke depends on the incidence of the risk factors. The best known risk factors are nonmodifiable (age, gender, genetic predisposition, weather influence, race) or modifiable (arterial hypertension – the single most important risk factor, hypotension, heart disease, atherosclerosis, diabetes mellitus, hypercholesterolemia, dyslipoproteinemia, smoking, alcohol consumption, obesity, polycythemia). 3.3.5.2

Epidemiology

The stroke incidence is 300–600/100,000 inhabitants/year, and is the third most common cause of death or severe disability. In the USA 700,000 inhabitants suffer a stroke every year (80% an ischemic one). In the USA every year 150,000 persons die of stroke, even though the mortality rate of stroke in the USA is the lowest in the world. At present, approximately 4.4 million stroke survivors live in the USA, and two-thirds of them are disabled to some extent. The total cost (direct and indirect) of treating these patients is estimated at $51 billion/year. Stroke incidence is somewhat higher in Europe. The worst epidemiological data are encountered in the satellites of the former USSR (stroke incidence up to 650/100,000 inhabitants/year, mortality 273/100,000 inhabitants/year) and in Finland. Switzerland and France are countries with a very low stroke incidence.

3.3.5.1.2 Specific Etiology

• Macroangiopathy (major vessels’ disease – both “arteryto-artery” embolization and hemodynamic strokes (in the vascular region of certain vessels or “watershed” strokes) • Atherosclerotic • Non-atherosclerotic (dissection, moya-moya disease, fibromuscular dysplasia, etc.) – Microangiopathy (perforating arterioles’ disease) – Embolization from the heart (mitral valve stenosis, atrial fibrillation, foramen ovale patens, etc.) – Stroke of unknown origin (non-lacunar ischemic lesions on CT of unknown origin – e. g., in the case of normal angiographic findings) There is another heterogeneous group of strokes of rare origin (migrainous strokes, resistance to APC, hyperhom*ocysteinemia, antiphospholipid syndrome, sickle-cell

3.3.5.3

Symptomatology

From the neurosurgical point of view, ischemic events can be divided into several groups. 3.3.5.3.1 Asymptomatic Patients

The finding is incidental (during investigation of some other disease) or targeted (e. g., investigation due to carotid bruit). 3.3.5.3.2 Transient Neurologic Deficit

There are clinical symptoms of amaurosis fugax, hemispheric transient ischemic attack (TIA), reversible ischemic deficit (RIND), and so-called vertebro-basilar insufficiency. Both singular and repeated events occur.

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“Crescendo” TIAs, cumulated transient attacks, represent the same type of reversible ischemia and repeated embolization. They are important from the point of view of intervention timing. Clinically, the most frequent symptoms of TIAs are: contralateral hemiparesis, hemihypesthesia, and hom*onymous hemianopia. Speech, gnostic, and practical disorders are caused by attacks in the dominant hemisphere. 3.3.5.3.3 Completed Stroke

Any permanent neurologic deficit following stroke (even if the only finding is abnormal reflexes, or minimal deficit) should be quoted as a completed stroke (CS). Completed strokes are divided into minor and major ones. In minor stroke the patient is fully ambulatory and he/she is able to care for him/herself; in major stroke the patient needs another person’s help with routine daily activities. 3.3.5.3.4 “Stroke in Evolution” or “Progressing Stroke”

The neurological deficit is fluctuating or changing in time. Deficit usually increases and leads to completed stroke, even if aggressive conservative treatment is applied. 3.3.5.3.5 Global Ischemia

Dementia and psychological changes are dominant in the clinical picture. Other causes of dementia have to be ruled out. 3.3.5.4

Clinical Picture

• Asymptomatic patient (with occluded or stenotic magistral or brain vessel) • Symptomatic patient – Transient deficit – Fixed deficit – Minor stroke – Major stroke – Dynamic deficit – Global deficit The source of embolization (from carotid artery stenosis – “artery-to-artery,” from the heart – “heart-to-artery,” and small vessel disease – “lacunar infarctions”) usually cannot be distinguished by clinical findings only. 3.3.5.5

Diagnostic Procedures

3.3.5.5.1 Doppler Ultrasonography

Doppler ultrasonography (DUS) is the most important screening procedure. Well-conducted and precise inves-

tigation is sufficient for an indication for intervention on cervical carotid arteries. Non-invasivity, simplicity, low price, and the ability to repeat the investigation frequently are the advantages of DUS. It is extremely useful in post-intervention check-ups and in the monitoring of the dynamic changes of atherosclerotic disease. The information about the structure of the atherosclerotic plaques is important. DUS (or TCD) does not provide sufficient data on intracranial circulation beyond the M2 and A1 segments. 3.3.5.5.2 CT Angiography

Computed tomographic angiography (CTA) is a noninvasive technique – stenosis is displayed on axial scans, and the shape of the plaque and calcifications is appreciated. 2D and 3D reconstructions are very useful. CTA can display intracranial vessels as well. The indication for intervention for both magistral and intracranial vessels can be based on CTA findings only. 3.3.5.5.3 MR Angiography

Magnetic resonance angiography (MRA) is a non-invasive technique; both intracranial and extracranial vessels can be shown. The treatment indications can be based on MRA findings only as well. MRA contraindications are placement of a pacemaker, a vascular clip of unknown origin, an artificial metallic heart valve, etc. 3.3.5.5.4 Digital Subtraction Angiography

Digital subtraction angiography (DSA) is still considered the golden standard. The disadvantages of DSA – invasivity, procedural complications – have to be added to the interventional complications. Morbidity/mortality of DSA is reported to be within the range 0.5–1.5%. The main advantages are obtaining precise information about both the aortic arch and the extracranial and intracranial vessels, and easy interpretation of the findings. The possibility of conversion into a therapeutic session is another major advantage. 3.3.5.5.5 Computed Tomography

Computed tomography is a mandatory investigation in all patients with cerebrovascular disease. The information about brain morphology, the extent and age of the ischemic changes are displayed, and other brain diseases are excluded (tumor, chronic subdural hematoma, etc.). CT provides information about small vessel disease as well (status lacunaris). CT is a must in the acute phase of stroke: normal brain or minimal/major changes can be shown (sulci smoothening, density changes, loss of gray/ white matter differentiation, expansive behavior of ischemic lesions, etc.). The sign of dense artery provides in-

3.3.5 Stenotic and Occlusive Vascular Disease

formation about thrombus in major vessels (in one-third of major strokes, usually MCA). 3.3.5.5.6 Magnetic Resonance Imaging

With magnetic resonance imaging (MRI) morphological information is even more precise. Perfusion/diffusion studies can be performed in the acute phase of stroke (tool to differentiate a penumbra – hypoperfused, but still viable brain from the necrotic regions). 3.3.5.5.7 Functional Diagnostic Studies

Perfusion parameters (CBF) under the basal condition and after stimulation (CO2 inhalation, i.v. acetazolamide, etc.) are appreciated. In specific cases, the utilization of certain metabolic substances and information about specific functional areas can be acquired. This is necessary when the revascularization procedure is considered (EC– IC bypass). 3.3.5.5.8 Transcranial Doppler

Transcranial Doppler (TCD) follows the changes in major brain vessels (vasodilatation does not appear during stimulation in these vessel’s segments). Any blood flow change is dependent on changes in the distal vascular territory. Blood flow velocity changes and their dynamics can be appreciated in real-time investigation. Hyperventilation can be used to evoke hypocapnia, which leads to distal vasculature vasoconstriction (if not, this can be a sign of complete vasoparalysis – important information if a high-flow bypass is considered). 3.3.5.5.9 Single Photon EmissionComputed Tomography

In single photon emission-computed tomography (SPECT) a 3D image is reconstructed from 2D (planar) images of local concentrations of radionuclide (99mTc – HMPAO – hexamethyl-propylenamino-oxime labeled by Technetium). The level of radionuclide agent concentration depends on the CBF.

stant velocity and every second new axial slice at the same brain level is acquired (usually lasting 40 s). The brain density is a marker of CBF. Time-to-start and time-topeak of maximal flow can be calculated (in semiquantitative fashion), as well as blood volume and cerebral blood flow. 3.3.5.5.12 Positron Emission Tomography

The presence or degree of hemodynamic impairment due to occlusive cerebrovascular disease is inferred from measurements of CBF, cerebral blood volume (CBV), oxygen extraction fraction (OEF), and the cerebral rate for oxygen metabolism (CMRO2). For studies 15O-labelled carbon monoxide and 15O-labelled water are used. There is a two-stage classification of chronic hemodynamic impairment for patients with atherosclerotic carotid artery disease – stage I (autoregulatory vasodilation), identified as an increase in CBV or mean vascular transit time (mathematically equivalent to the CBV/CBF ratio) in the hemisphere distal to the occlusive lesion, with normal CBF, OEF, CMRO2, and stage II (autoregulatory failure), characterized by reduced CBF and increased OEF with normal oxygen metabolism. 3.3.5.6

Surgical and Neurointerventional Treatment

3.3.5.6.1 Aortic Arch and Its Proximal Branches 3.3.5.6.1.1 Steal Phenomenon

Stenosis or occlusion of the brachial trunk (right) or subclavian artery (left) causes the blood-flow reversal in the opposite VA. The patients exhibit the signs of vertebrobasilar (VB) insufficiency – vertigo, dizziness – which is usually more pronounced during the increased physical exertion of the ipsilateral upper limb. 3.3.5.6.1.1.1 Diagnosis

Doppler ultrasonography and DSA can be used for diagnosis. The blood-flow reversal in the opposite VA is documented. 3.3.5.6.1.1.2 Indication

3.3.5.5.10 Xenon CT

Xe is a low-energy γ-emitter that is freely diffusible throughout the brain. Its washout or clearance is used to measure CBF. When small concentrations are used, the hazards of radiation to the patient and operating room personnel are minimized.

133

Empiric, individual.

3.3.5.6.1.1.3 Treatment

Stenting of the brachial trunk or subclavian artery is sometimes possible, even in patients with vessel occlusion. Carotido-subclavian bypass is the surgical option. 3.3.5.6.1.1.4 Complications

3.3.5.5.11 Per fusion CT

An axial brain slice at the level of all three vascular territories is performed. Contrast agent is applied under con-

In the case of endovascular treatment complications are minimal (dissection, arterial thrombosis with possible stroke); in the case of surgery complications include inju-

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ry to the surrounding structures (nerves, lymphatic duct) and vessel/graft occlusion. 3.3.5.6.1.2 Thoracic Outlet Syndrome

External pressure on the subclavian artery and/or brachial plexus causes diminished blood-flow in the upper limb, pain, and, rarely, symptoms of brachial plexus compression. The pressure is caused by cervical rib, scalenic muscles, etc. 3.3.5.6.1.2.1 Diagnosis

Plain X-ray, DSA, and electrophysiology are used. 3.3.5.6.1.2.2 Indication

Empiric, individual.

3.3.5.6.1.2.3 Treatment

Pressure release by rib resection, scalenic muscles section, etc. 3.3.5.6.1.2.4 Complications

Injury to the surrounding structures (nerves, lymphatic tract). 3.3.5.6.2 Carotid Bifurcation/Internal Carotid Artery Stenosis

The most typical site of atherosclerotic disease. Carotid endarterectomy (CEA) is the third most frequent surgical procedure. The atherosclerotic plaque causes stenosis but the clinical symptoms are caused by plaque fragmentation and/or blood aggregation on the plaque surface and distal embolization. Hemodynamic origin of symptoms is extremely rare. CEA is a tool of secondary prevention and surgery/intervention is considered in asymptomatic patients and in patients with transient deficits or minor stroke. Patients after a major stroke are less frequent surgical candidates.

dergoing surgery less than 2weeks after the last event), provided no large recent infarction is found on either CT or MR. If so, surgery should be postponed for 6weeks. The same criteria apply to carotid stenting (with distal protection). CEA is superior to stenting with regard to durability. Stenting should be considered as a treatment option in poor surgical candidates and in older patients. 3.3.5.6.2.4 Treatment

Endarterectomy could be performed under either general or regional anesthesia (cervical block). Neurological functions should be closely monitored (EEG, SSEPs). Stenting procedures are done under local anesthesia and/ or mild sedation. A skin incision runs along the anterior border of the sternocleidomastoid muscle, the carotid bifurcation is dissected free, the vessels closed by temporary clips and the vessel is incised from the common carotid artery (CCA) to the internal carotid artery (ICA). The use of an intraluminal shunt depends on institutional policy and varies from never to always. The plaque is removed. Extreme care is focused at the distal end of the CEA where the intima must be closely inspected and eventually sutured to the carotid wall to prevent dissection. Suture of the arteriotomy is performed either directly or with the use of a graft. 3.3.5.6.2.5 Restenosis

Restenosis occurs in 5% of patients. If necessary, restenosis is treated predominantly by stenting. 3.3.5.6.2.6 Complications

Stroke, carotid occlusion, dissection, postoperative hematoma, peripheral nerve (PN) injuries (VII, X, XII), and infection. 3.3.5.6.3 Carotid Pseudo-Occlusion

Doppler ultrasonography, CTA, MRA, and DSA are used.

In certain cases the ICA behind the plaque is not thrombosed, but has collapsed. The lumen remnants can often be detected on DSA. The stenosis is arbitrarily quoted as 95%.

3.3.5.6.2.2 Indication

3.3.5.6.3.1 Diagnosis

3.3.5.6.2.1 Diagnosis

Indications are evidence-based, on large multi-institutional randomized trials (NASCET, ECST, ACAS, ACST). 3.3.5.6.2.3 American Heart Association Recommendations

Surgery is indicated in symptomatic patients with stenosis above 50%, provided the institutional MM rate is below 6% and patients’ life expectancy is at least 5 years. In asymptomatic patients with stenosis above 60%, the MM rate is below 3% and life expectancy is 5years at least. In symptomatic patients the surgery should not be delayed (maximum benefit was observed in patients un-

Digital subtraction angiography. 3.3.5.6.3.2 Indication

Carotid endarterectomy can be attempted. 3.3.5.6.3.3 Treatment

Standard CEA.

3.3.5.6.3.4 Complications Stroke, carotid occlusion, dissection, wound hematoma, PN injuries (VII, X, XII), infection, and monocular blindness.

3.3.5 Stenotic and Occlusive Vascular Disease

3.3.5.6.4 Carotid Kinking and Coiling

Two types of carotid kinking are seen. The first type is probably based on hereditary elongation of the vessels; the second is seen in patients with atherosclerotic disease. Symptoms (usually TIAs) are caused either by embolization or by the hemodynamic effect of vessel occlusion during ipsilateral head rotation. Surgery is usually considered only in patients in whom best medical treatment (BMT) fails to prevent further TIAs. 3.3.5.6.4.1 Diagnosis

Doppler ultrasonography, CTA, MRA, and DSA (including forced positions) are used. 3.3.5.6.4.2 Indication

Empiric, individual.

3.3.5.6.4.3 Treatment

The carotid bifurcation is dissected free, mobilized, and in the case of minor kinking, the vessels are pushed downward and fixed to the surrounding structures. In more extensive kinks, the diseased part of the vessel is resected and the distal stump is either sutured end-to-end or replanted into the CCA. In the case of carotid coiling, the surgical approach is identical. Both procedures can follow routine CEA. 3.3.5.6.4.4 Complications

Stroke, carotid occlusion, dissection, wound hematoma, PN injuries (VII, X, XII), and infection. 3.3.5.6.5 Stump Syndrome

Emboli from the carotid stump can travel via natural or artificial (EC–IC bypass) collaterals and lodge either in the retina or cerebral vasculature, resulting in amaurosis fugax or TIAs. Only patients with repeated attacks who are not responding to BMT are considered for surgery. 3.3.5.6.5.1 Diagnosis

Doppler ultrasonography, CTA, MRA, and DSA are used. 3.3.5.6.5.2 Indication

Empiric, individual.

3.3.5.6.5.3 Treatment

The carotid bifurcation is dissected and an arteriotomy performed from the CCA to the ECA. Endarterectomy is performed and the orifice of the occluded ICA is closed by a running suture. The ICA flow can be restored in few cases, even if the vessel is thrombosed. In patients with retrograde flow reaching the carotid canal, an attempt at carotid recanalization can be performed. The Fogarty catheter is advanced to the region of the carotid canal and inflated. By gentle catheter withdrawal the thrombus is removed.

3.3.5.6.5.4 Complications

Peripheral nerve injuries (VII, X, XII), stroke, infection, and monocular blindness. 3.3.5.6.6 Extracranial Vertebral Artery 3.3.5.6.6.1 Vertebral Artery Origin

The origin of the VA is the typical location of VA stenosis. Patients usually exhibit symptoms of VB insufficiency (vertigo, dizziness, etc.). Alternatively, symptoms from the PCA territory can be seen (hom*onymous hemianopia). VA stenosis is also frequently found during the work-up for carotid territory ischemic symptoms. The symptoms are not only embolic. A hemodynamic origin can be suspected in some patients. It appears in patients with an aplastic or hypoplastic opposite VA and insufficient PCOM collaterals. 3.3.5.6.6.1.1 Diagnosis

Doppler ultrasonography, CTA, MRA, and DSA are used. 3.3.5.6.6.1.2 Indication

Empiric, individual, only higher degree stenoses are considered for treatment. 3.3.5.6.6.1.3 Treatment

An endovascular approach is the first-line treatment. Stenting may be performed, but simple percutaneous transluminal angioplasty is preferred at this location. Alternatively, VA–CCA transposition can be employed. The vessels are approached via the incision along the lower half of the anterior border of the sternocleidomastoid muscle. The VA is severed at its origin and sutured endto-side to the CCA. Extreme care is to be focused on the recurrent nerve and lymph tract (left side). 3.3.5.6.6.1.4 Complications

In the case of endovascular treatment, there are virtually no complications (dissection, arterial thrombosis); in the case of surgery injury to the surrounding structures (nerves, lymphatic tract), vessel/graft occlusion. 3.3.5.6.6.2 Middle Portion of the VA (C6–C2)

The presenting symptoms are as in Sect. 3.3.5.6.6.1. Only individual cases are encountered. Either the external pressure on the VA is caused by hypertrophic uncovertebral joints in patients with degenerative spine disease or VA kinking between the two foramens can be found. 3.3.5.6.6.2.1 Diagnosis

Doppler ultrasonography, CTA, MRA, and DSA are used.

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3.3.5.6.6.2.2 Indications

Individual.

3.3.5.6.6.2.3 Treatment

The VA can be decompressed via routine anterior diskec tomy in patients with uncovertebral osteophytes. The preferred approach is, however, lateral. The spine is approached either anterior or posterior to the sternocleidomastoid muscle, posterior to the carotid artery and jugular vein. Osteophytes can be selectively removed, the VA exposed to its desired length (removing the two adjacent foramina and allowing VA exposure to the length of some 45–50mm) for kinking resection or straightening. Atherosclerotic changes in this region are extremely rare. If necessary, these should be treated endovascularly. 3.3.5.6.6.2.4 Complications

Root injury, PN injury, thrombosis, and embolization. 3.3.5.6.6.3 Upper Segment (C2 to the VA Junction)

Sclerotic occlusive disease is more frequent in this region. Only symptomatic lesions can be considered for endovascular or surgical treatment. 3.3.5.6.6.3.1 Diagnosis

Doppler ultrasonography, CTA, MRA, and DSA. 3.3.5.6.6.3.2 Indication

Rare and strictly individual. 3.3.5.6.6.3.3 Treatment

Endarterectomies are not performed; bypass procedures (CCA–VA being the most frequent one) are now replaced by endovascular procedures (angioplasty, stenting). 3.3.5.6.6.3.4 Bow–Hunter Syndrome

In a maximal head rotation, the contralateral VA is stretched and thus stenosed or occluded. In a rare condition of hypoplastic or aplastic opposite VA and insufficient PCOM collaterals, VB–PCA ischemia can be encountered. The symptoms can be transient or permanent (hom*onymous hemianopia). Few fatal cases have been described. 3.3.5.6.6.3.4.1 Diagnosis Digital subtraction angiography in a neutral and maximal head rotation is used. 3.3.5.6.6.3.4.2 Indication Individual. 3.3.5.6.6.3.4.3 Treatment C1–C2 fixation or VA deliberation from the posterior approach is the treatment used. In the case of VA delib-

eration, the bone forming the C1 vertebral foramen is resected and the VA dissected free from the surrounding structures. 3.3.5.6.6.3.4.4 Complications Injury to the surrounding neural structures. 3.3.5.6.7 Direct Revascularization 3.3.5.6.7.1 ECIC Bypass

End-to-side anastomosis between the donor (superficial temporal artery – STA) and recipient (opercular branch of the MCA) provides some 18ml/min of blood. The International Cooperative ECIC Bypass Study Group failed to prove any beneficial role of bypass procedures in stroke prevention (particularly in patients with MCA stenosis). A new randomized study (COSS – Carotid Occlusion Surgery Study) has recently been running and the indication for ECIC bypass is studied in patients with impaired cerebrovascular reserve capacity (CVRC) according to PET. 3.3.5.6.7.1.1 Indication

Unavoidable ICA/MCA sacrifica for a tumor or aneurysm. 3.3.5.6.7.1.2 Uncertain Indication

Occlusion of the ICA/MCA in patients with impaired cerebrovascular reserve capacity (proven by SPECT, PET, perfusion CT studies) and no/small ischemic lesion (usually watershed infarction). 3.3.5.6.7.1.3 Diagnosis

Clinical, DSA, CT/MRI, and CVRC study are used. 3.3.5.6.7.1.4 Surgery

The STA branch is dissected free. A small craniotomy is centered 6 cm above the tragus and a dural incision in a “Y shape” is made. The recipient artery is identified, between two temporary clips linear arteriotomy is performed and the donor artery (with an ostium prepared in a “fish-mouth” shape) is sutured in an end-to-side manner using a 10/0 suture. Extreme care is to be focused on wound closure because of CSF leak, donor vessel distortion or occlusion by pressure of the bone flap. 3.3.5.6.7.2 Bypass Using Venous/Arterial Graft

In the case of insufficient STA, a graft is used to create a bypass between the CCA/ECA and the intracranial ICA or proximal MCA – a flow-through bypass > 100ml/min is rarely needed in occlusive disease patients as there is an extreme danger of hyperemic breakthrough. The alternative ICA petrous segment (C2 segment) graft inter-

3.3.5 Stenotic and Occlusive Vascular Disease

position is used in cases of intracavernous ICA stenosis, aneurysms, and ICA tumor involvement.

3.3.5.7

3.3.5.6.7.3 Posterior Circulation Bypasses

3.3.5.7.1 Moya-Moya Disease

Posterior circulation bypasses are performed in selected cases with posterior circulation ischemia of hemodynamic origin. They consist of the STA – superior cerebellar artery bypass, and the STA/occipital artery – posterior inferior cerebellar artery bypass. 3.3.5.6.7.3.1 Diagnosis

Clinical diagnosis, DSA, CT/MRI, and CVRC studies are used. 3.3.5.6.7.3.2 Indication

Rare and individual, recently often replaced by endovascular angioplasties and stenting procedures. 3.3.5.6.7.4 IC–IC Bypass

Mainly side-to-side anastomosis between both ACA arteries – in the case of, for example, an A2 segment fusiform aneurysm. 3.3.5.6.7.4.1 Indication

Indications are individual. In general, many variations of bypass procedures are described, with both low and high flow (e. g., the ELANA technique). Until now, no randomized trial has shown any proof of bypass procedure benefit in any subgroup of patients. 3.3.5.6.7.4.2 Complications

Stroke, hyperemic breakthrough, and wound healing problems.

Non-Atherosclerotic Occlusive Disease

Spontaneous stenosis/occlusion of intracranial carotid arteries (VB territory is rarely involved). Collateral flow develops through abnormal transdural anastomoses, known as rete mirabile. 3.3.5.7.1.1 Presentation

Ischemia occurs predominantly in children (mental retardation, IQ decrease, neurological deficit, seizures); intracerebral/intraventricular hematoma occurs predominantly in adults. 3.3.5.7.1.2 Diagnosis

Computed tomography, DSA – stenosis/occlusion of the distal ICA/proximal MCA+ACA, rete mirabile, and abnormal intraparenchymal anastomoses in the basal ganglia (moya vessels). 3.3.5.7.1.3 Treatment

Encephalo-duro-arterio-myo-synangiosis and its variations. 3.3.5.7.2 Fibromuscular Dysplasia

Fibromuscular dysplasia is the second most common cause of extracranial carotid stenosis (in 80% bilateral). 3.3.5.7.2.1 Presentation

Cerebral ischemia, mental distress, tinnitus, vertigo, and carotidynia. 3.3.5.7.2.2 Diagnosis

3.3.5.6.8 Indirect Revascularization 3.3.5.6.8.1 Encephalo-Duro-ArterioMyo-Synangiosis

Encephalo-duro-arterio-myo-synangiosis (EDAMS) and its variations (EMS, EDAS) – isolated temporalis muscle and uninterrupted STA branch are laid on the surface of the brain with exposed vessels. Neovascularization with the development of EC-IC collaterals can be proved angiographically in patients with moya-moya disease. 3.3.5.6.8.1.1 Indication

Individual, mainly moya-moya disease. 3.3.5.6.8.1.2 Complications

Infection and wound healing problems.

Doppler ultrasonography, CTA, MRA, and DSA – multiple concentric narrowings (“string of pearls”) are seen. 3.3.5.7.2.3 Treatment

Primarily medical, but in the case of medical treatment failure, endovascular procedures and bypass surgery can be considered as well. 3.3.5.7.3 Dissections and Dissecting Aneurysm

Dissection is the extravasation of blood between the intima and the media (most common intracranially); dissecting aneurysm is the extravasation of blood between the media and the adventitia (most frequently extracranially). Dissections are frequently associated with fibromuscular dysplasia, Marfan’s syndrome, Takayasu’s disease, etc. Dissection can be post-traumatic and iatrogenic (DSA) as well.

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3.3.5.7.3.1 Presentation

Ischemic events owing to embolization or compromised CBF and SAH. 3.3.5.7.3.2 Diagnosis

Computed tomography, MR, and CTA/MRA/DSA are used. 3.3.5.7.3.3 Treatment

Medical treatment, anticoagulation, endovascular stenting, vessel occlusion, and bypass procedure. 3.3.5.7.3.4 Complications

Ischemia and intracerebral hemorrhage.

3.3.5.8

Mass Effect-Producing Ischemic Lesions

Acute occlusion of the major cerebral artery results in ischemic changes leading to a breakdown of the blood– brain barrier, causing malignant cerebral edema in some cases. Neurological deterioration caused by herniation can be very rapid. • Infratentorial – the posterior inferior cerebellar artery (PICA) or superior cerebellar artery (SCA) territory is most frequently affected • Supratentorial – the MCA territory is typically affected 3.3.5.8.1 Diagnosis

3.3.5.7.4 Intracranial Arterial Stenoses (Including ICA Cavernous Segment, Intradural VA, BA)

Such lesions are rarely the source of emboli. In comparison with, for example, ICA stenosis at CCA bifurcation, the plaque surface is extremely small. Ulcers are not seen and lesions are harder. When symptomatic, the underlying pathophysiology is most likely hemodynamic. In the past patients with such lesions were considered candidates for bypass surgery. After the ECIC Bypass Study, however, the procedures were abandoned. Recently, patients with intracranial arterial stenoses are frequently treated by neurointerventional methods – angioplasty with possible stenting. 3.3.5.7.4.1 Diagnosis

Computed tomography angiography, MRA, DSA, and CVRC studies are used. 3.3.5.7.4.2 Indications

Empiric, individual. No evidence-based support is available and endovascular procedures should not be indicated outside the experimental protocol. The indication criteria should be similar to those of the ECIC bypass (CVRC evaluation). 3.3.5.7.4.3 Treatment

Angioplasty, stenting procedures with dedicated intracranial stents are employed, no distal protection is necessary. The neuroradiologist must be ready to use thrombolytic agents or mechanic means in the case of vessel thrombosis. 3.3.5.7.4.4 Complications

Vessel occlusion, vessel rupture, dissection, stent migration, etc.

Computed tomography or MRI is used. 3.3.5.8.2 Indication

The indication is absolute in cerebellar infarction with rapid neurological deterioration and an ischemic mass lesion on CT (similar to an epidural hematoma). Some of the recent studies support decompressive craniotomy in supratentorial MCA infarction (even in the dominant hemisphere), especially in young patients with rapidly deteriorating neurological status. 3.3.5.8.3 Treatment

• Infratentorial – ischemic lesion resection, decompressive craniectomy, and external ventricular drainage in the case of acute hydrocephalus • Supratentorial – large decompressive craniectomy with a dural patch 3.3.5.9

Acute Phase Treatment of Ischemic Stroke

3.3.5.9.1 Thrombolysis

Urgent neurological and CT examinations are mandatory in every case of cerebral stroke that does not last longer than 3h. If the ischemic stroke is confirmed and no contraindication for thrombolysis occurs, the patient should be transferred to the stroke ICU and thrombolytic therapy should be started immediately – rt-PA i.v. (dose of 0.9mg/kg, maximal dose of 90mg, with 10% of the dose as a bolus, followed by 60min of infusion of the remaining drug). Thrombolytic therapy contraindications (only the basic ones are mentioned): intracerebral hematoma, stroke history longer than 3h, unknown length of history, subarachnoid hemorrhage, NIHSS < 4, or rapidly improving neurological deficit, NIHSS > 25, or rapid progression of neurological symptoms, brain ischemia in more than

3.3.5 Stenotic and Occlusive Vascular Disease

one-third of the MCA region on CT, the seizure at the beginning of the stroke (suspected Todd’s paresis), pre-existing serious neurological deficit, repeated stroke within 3 months, history of intracerebral hemorrhage, brain disease in history (tumor, aneurysm, etc.), hemorrhagic retinopathy, hemorrhagic diathesis, liver failure, decompensated diabetes mellitus, major surgical procedure, or major trauma within 3months, international normalized ratio (INR) > 1.7, thrombocytes < 100000/mm3. The effect of intravenous thrombolysis is documented within 4.5 h after the stroke as well (the odds ratios are lower, but statistically significant). Intra-arterial thrombolyis may be a treatment alternative in patients with proximal MCA occlusion and a history shorter than 6h. Intra-arterial thrombolysis of acute BA thrombosis is a treatment option. The indication is not based on randomized study. This treatment should be performed within multi-institutional studies or within an experimental protocol. Mechanical embolectomy is a new treatment option of acute cerebral vessel occlusion (e. g., Merci Retriever). Randomized study is underway in patients with a stroke history shorter than 8 h, in whom intravenous thrombolysis is not indicated. The lower risk of intracerebral hemorrhage is the major advantage of this approach. The acceleration of occluded cerebral vessel recanalization by TCD is another new treatment option and constitutes the clinical phase of the investigation. Thrombolysis is performed in up to 15% of acute stroke patients in the USA, and in Europe this figure varies among different countries (0.5–3%). 3.3.5.9.2 Timing of Procedures 3.3.5.9.2.1 Emergency (Range of Dozens of Minutes)

Thrombolysis, posterior fossa decompression for mass effect ischemic cerebellar lesion. 3.3.5.9.2.2 Urgent (Range of Single Days)

Carotid endarterectomy or stenting for symptomatic ICA stenosis. Surgery/stenting should be delayed for approximately 6weeks in the case of larger ischemic lesions on CT (due to the risk of hemorrhagic conversion of ischemic lesions). 3.3.5.9.2.3 Elective (Range of Weeks)

Other vascular procedures.

3.3.5.10 Conservative Therapy The following treatment strategies can be applied for the acute stroke patients who are not candidates of throm-

bolysis: volume expansion with hemodilution (usually crystaloids in combination with volume expanders, glucose should not be administered within the first 2 days due to the risk of lactate acidosis in the region of the ischemic lesion). Venepunction can be considered in the case of hematocrit levels higher than 0.5 and if hemodilution therapy has failed. Either heparin (twice daily 5,000 IU subcutaneously) or low molecular weight heparins should be given. The effect of nootropic agents is not fully confirmed. 3.3.5.10.1 Primary Prevention 3.3.5.10.1.1 Arterial Hypertension

Arterial hypertension is the most important modifiable risk factor. Systolic pressure exceeding 160torr and diastolic pressure exceeding 90 torr increases significantly the risk of ischemic stroke. The relationship between increasing blood pressure and the risk of stroke is linear. Blood pressure should be kept under 140/90torr, in patients with diabetes mellitus under 130/85torr. 3.3.5.10.1.2 Smoking

The pathophysiological sequelae of smoking are multifactorial, the elasticity of red blood cells is decreased, the level of fibrinogen is increased, the aggregability of thrombocytes is increased, the HDL level is decreased, and the hematocrit level is increased. Smoking increases the risk of ischemic stroke 2-fold. 3.3.5.10.1.3 Other Risk Factors – Diabetes Mellitus, Hyperinsulinemia, and Insulin Resistance

The incidence of other atherogenic risk factors is high among insulin-dependent patients, especially hypertension, obesity, and dyslipidemia (syndrome X). Hyperinsulinemia with resistance to insulin is typical in these cases. Strict compensation of glucose levels is mandatory, and hypertension should be treated strictly (with the use of ACE inhibitors). 3.3.5.10.1.4 Atrial Fibrillation

Atrial fibrillation is a serious risk factor of stroke (approximately 3–5%). Stroke is caused by embolization from the heart in approximately 70% of patients with atrial fibrillation. There is a closed relationship among atrial fibrillation, the age of the patients, and the risk of stroke. Anticoagulation or anti-aggregation therapy should be applied in primary stroke prevention in patients with atrial fibrillation. Other heart diseases increasing the risk of stroke include mitral valve stenosis, mitral valve prolapse, artificial valves, dilatatory cardiomyopathy, patent foramen ovale, atrial septum defect, and atrial aneurysm.

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3.3.5.10.1.5 Hyperlipidemia

The dysbalance of blood fat levels are related to an increased risk of stroke; nevertheless, the relationship is weaker. Medication of statins reduces the risk of atherosclerotic disease of extracranial vessels. The dietary measures should be started in patients with hyperlipidemia, medication with statins is fully recommended in patients with ischemic heart disease and increased levels of LDL. 3.3.5.10.1.6 Other Risk Factors

Obesity, hyperhom*ocysteinemia, drug abuse, physical inactivity, the presence of antiphospholipid antibodies, hormone replacement therapy in climacterial women, and peroral contraception. 3.3.5.10.2 Secondary Prevention

The treatment of risk factors is mandatory. Anticoagulation is indicated in patients with cardio-embolic stroke (heart-to-artery) and atrial fibrillation (INR within the range 2 to 3). Anti-aggregation therapy by acetylsalicylic acid (ASA) is indicated (dose 50–325mg/day), if anticoagulation is contraindicated (Table3.3.10). Anti-aggregation therapy is indicated in patients with an atherothrombotic event from extracranial vessels or in the case of stroke of unknown origin. 3.3.5.10.2.1 Acetylsalicylic Acid

A dose of 50–325mg/day is accepted, as the ideal dose of ASA is unknown. The FDA (US Food and Drug Administration) recommends the above-mentioned range of doses; for secondary prevention the FDA prefers a full dose of 325mg/day. 3.3.5.10.2.2 Ticlopidine

Recently, ticlopidine has become a less accepted medication due to the incidence of side effects, especially neutropenia. The incidence of side effects is 10% lower among Afro-Americans, and serious neutropenia has not been observed at all.

3.3.5.10.2.3 Clopidogrel

Clopidogrel is chemically related to ticlopidine. The efficiency is equivalent to ticlopidine and ASA. The low incidence of side effects is the major advantage of this drug. 3.3.5.10.2.4 Combination of Dipyridamole, Phosphodiesterase Inhibitor and ASA, Cyclooxygenase Inhibitor

There is a theoretical advantage of this combination compared to single drug medication. 3.3.5.11 Anesthesia, Preoperative and Postoperative Management, Monitoring Surgeries are performed under either general or local anesthesia (e. g., extracranial carotid arteries – cervical block applied). If general anesthesia is used, neuroprotective anesthetics are recommended (barbiturates, thiopental or pentobarbital) – especially in intracranial reconstructive vascular surgery (for example, a high-flow bypass to the M1 segment of the MCA). Burst suppression on the EEG can be reached whenever necessary. Etomidate (ultrashort acting derivate of imidazole) is another neuroprotective anesthetic agent. The major advantage of etomidate is the less frequent incidence of intraoperative hemodynamic side effects. Isoflurane is an example of an inhalatory, neuroprotective anesthetic agent. Other drugs can be considered as well: a “Sendai co*cktail” (phenytoin, mannitol, dexamethasone, vitamin E), and nootropic agents. Hypothermia can be considered in complex arterial reconstructions. Continuous intra-arterial blood pressure monitoring is mandatory. Blood pressure should be raised by 10–30torr above the patient’s normal pressure. The monitoring of SSEPs, the spectral analysis of EEG, or TCD are considered as appropriate intraoperative adjuncts.

Table3.3.10 Anti-aggregation and anticoagulation therapy in patients after transient ischemic attack (TIA) or stroke. DP dipyridamole, ASA acetylsalicylic acid, INR international normalized ratio Type of event

Recommended therapy

Alternative treatment

Atherothrombotic

ASA 50–325mg/day

DP 200mg + ASA 25mg 2 × daily Clopidogrel 75mg/day Ticlopidine 250mg 2 × daily ASA 50–1,300mg/day

Atherothrombotic event in the event of intolerance or allergy to ASA, or repeated event on ASA medication

DP 200mg + ASA 25mg 2 × daily clopidogrel 75mg/day

Ticlopidine 250 mg 2 × daily Anti coagulation (INR 2–3) ASA 50–1,300mg/day

Cardio-embolic

Anticoagulation (INR 2–3)

ASA 50–325mg/day

3.3.6 Spontaneous Intracerebral and Intracerebellar Haemorrhage in Adults

Interventional procedures are usually performed under minimal sedation of the patient, and procedures under general anesthesia are less frequent. The anesthetist should be standing by in case of potential complications. Electrophysiological monitoring should be applied, if the interventional procedure is performed under general anesthesia. For postoperative care, continuous/frequent blood pressure measurement is important, the detection of post-intervention risk factors, and thorough preoperative medical investigation. Patients should be monitored at least 24h in an ICU bed, or semi-ICU after surgery/intervention. The parameters of the utmost importance are: GCS monitoring, neurological picture examination, direct blood pressure monitoring (which should be higher than a normal patient’s pressure), fluid balance, frequent surgical wound check-ups, etc.

3.3.6 Spontaneous Intracerebral and Intracerebellar Haemorrhage in Adults

Daniel Hänggi, Hans-Jakob Steiger 3.3.6.1

Pathogenesis

Depending on the underlying cause, it is useful to distinguish between primary (about 80%) and secondary intracerebral and intracerebellar haemorrhage [1]. Primary (spontaneous) haemorrhages usually occur intraparenchymally and can be subdivided into deep and lobar haemorrhages [2–4]. They are usually located in the basal ganglia, the thalamus, the brain stem (predominantly the pons), the cerebral lobes (lobar) and the cerebellum [5]. 3.3.6.2

Causes

The most important cause of spontaneous intracerebral haemorrhage seems to be a pathophysiological wall vessel change and in consequence the rupture of small penetrating arteries and arterioles 50–200 µm in diameter that originate from the major cerebral arteries [6–9]. Degenerative changes induced by chronic hypertension as a risk factor or cerebral amyloid angiopathy [10] increase the likelihood of rupture of these vessels [11]. The older theory of microaneurysms of Charcot– Bouchard [12] as an aetiology of spontaneous intracerebral haematomas seems to be debatable and has not been proven [7, 9]. Cerebral amyloid angiopathy plays another major role in the pathogenesis of intracerebral haemorrhage, even in

patients with more evident risk factors [10, 13, 14]. Other arteriopathies are rare, but as well documented as an aetiological factor for intracerebral haemorrhage. These include lipohyalinosis [6], fibrinoid necrosis [15] and cerebral arteritis [16]. Coagulopathies and induced clotting disorders must be ruled out as a potential aetiology for spontaneous bleeding. Particularly noteworthy is the iatrogenic pathway in patients on therapy with acetylsalicylic acid or other antiplatelet agents [17], the risk of anticoagulation [18, 19] and thrombolytic therapy with rt-PA [20, 21]. On the other hand, patients with leukaemia or thrombocytopaenia are also at risk of spontaneous cerebral bleeding. Other obvious and occasional causes of cerebral haemorrhage include vascular anomalies such as aneurysms, arteriovenous malformations and venous angiomas, central sinus thrombosis, hyperperfusion (locally and globally) [22], haemorrhagic brain tumours, trauma, cranial surgery and sepsis. 3.3.6.3

Epidemiology

3.3.6.3.1 Incidence

Spontaneous intracerebral haemorrhage accounts for 10–20% of all stroke-related sudden onset neurological deficits [23]. 3.3.6.3.2 Risk Factors

The risk factors can be divided into two major groups, epidemiological risk factors and non-epidemiological risk factors. 3.3.6.3.2.1 Race

The incidence of non-traumatic intracerebral haemorrhage worldwide ranges from 10 to 20 cases per 100,000 among whites [24, 25]. It is more common among certain populations including blacks and Japanese [26, 27]. For example, the incidence of intracerebral haemorrhage among blacks is more than twice that of the white population [26]. 3.3.6.3.2.2 Age

Five cohort studies have reported a significant relationship between age and the risk of intracerebral haemorrhage [28]. The incidence is expected to increase in the future because of the increasing age of the population. 3.3.6.3.2.3 Sex

Men have a higher incidence of spontaneous intracerebral haemorrhage than women, especially those over 55years of age [28, 29].

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3.3.6.3.2.4 Education

Another epidemiological risk factor seems to be the level of education [26], the lower the level, the higher the incidence of a spontaneous bleeding. An explanation of this correlation could be the lack of awareness of primary health care. 3.3.6.3.2.5 Hypertension

The most important non-epidemiological risk factor for spontaneous intracerebral haemorrhage is hypertension [11, 28]. Hypertension increases the risk of intracerebral haemorrhage, especially in the older population [30]; an antihypertensive treatment with blood pressure control showed a reduction in the incidence of spontaneous intracerebral haemorrhage [25]. Hypertension was defined in one study as diastolic blood pressure of at least 95mmHg [31], whereas another study defined hypertension as systolic blood pressure over 160mmHg [32]. 3.3.6.3.2.6 Alcohol

Alcohol consumption also increases the risk of spontaneous intracerebral haemorrhage [33, 34]. This was shown for recent moderate to heavy use and for chronic abuse [35, 36]. 3.3.6.3.2.7 Smoking

Cigarette smoking as a risk factor for intracerebral haemorrhage shows controversial results [28, 37–39]. 3.3.6.3.2.8 Hypercholesterolemia

Four case-control studies tended to show an association between low cholesterol and a higher risk of intracerebral haemorrhage [28, 40]. 3.3.6.3.2.9 Physical Activity

Two cohort studies comparing active versus inactive patients showed no significant relationship concerning the risk of intracerebral haemorrhage [28]. 3.3.6.4

Symptomatology

In general, the initial neurological findings at presentation of patients with supratentorial and infratentorial haemorrhages are dependent on the location and the size of the haematoma (see also Sect.3.3.6.1). It is useful for the classification to differentiate between specific and non-specific symptoms. Patients with intracerebral haemorrhage involving the putamen, caudate and thalamus have contralateral sensory motor deficits of varying severity. Patients with large haematomas usually suffer rapid deterioration with a decreased level of consciousness as a result of increased intracranial pressure and direct compression of the thalamic and brain stem reticular activating system [43, 44]. It is also known that small and deep haematomas can lead to altered levels of consciousness. One explanation postulates decreased central benzodiazepine receptor binding on cortical neurons [45]. Dysfunction or loss of higher cortical function like aphasia, dysphasia, contralateral hemisensory deficit or mild hemiparesis and hemi-anopia are typical of lobar haemorrhages [42]. Patients with cerebellar haematomas show a different clinical symptomatology. In general, local cerebellar symptoms and signs of a brain stem dysfunction are in the foreground. Ataxia, nystagmus and dysmetria show the involvement of the cerebellum [46]. Brain stem signs include abnormalities of gaze, cranial nerve abnormalities and contralateral motor deficits [46]. Headache, nausea, vomiting and neck stiffness are non-specific symptoms [43, 47]. 3.3.6.4.2 Secondary Deterioration

The risk of delayed or secondary deterioration concerns about one-third to one-half of all patients with intracerebral haematoma and the frequency of neurological deterioration was greatest within the first 24h [48]. The reason for secondary deterioration is any combination of re-bleeding, oedema, hydrocephalus and seizures. 3.3.6.4.2.1 Rebleeding

3.3.6.4.1 Primary Symptomatology

In cases in which the complete history was obtained, some patients described prodromal TIA-like symptoms with numbness and tingling or weakness [41]. The clinical features are in general different from ischaemic or embolic cerebrovascular accidents. In the Harvard Stroke Registry and the Michael Reese Stroke Registry 51–63% of patients reported a mild progressive onset over minutes to hours combined with headache, nausea and vomiting and additional alterations in the level of consciousness in contrast to a rapid onset in 34–38% patients with ischaemic or embolic cerebrovascular accidents [42].

The risk of rebleeding is well documented, is between 10 and 14% and decreases over time [49, 50]. Rebleeding is usually accompanied by clinical deterioration [50]. Worsening cerebral oedema is also implicated in delayed neurological deterioration [48]. Late deterioration during the second and third weeks is also observed and explained by oedema with unclear clinical significance [51]. 3.3.6.4.2.2 Hydrocephalus

The presence of ventricular blood and the development of obstructive hydrocephalus definitely increase the risk of secondary deterioration or death [48, 52].

3.3.6 Spontaneous Intracerebral and Intracerebellar Haemorrhage in Adults

3.3.6.4.2.3 Seizures

Patients with spontaneous intracerebral haematomas are at higher risk of developing seizures than ischaemic stroke patients [53]. Seizures may be non-convulsive and are associated with neurological worsening and an increased midline shift [54]. The risk of epilepsy is higher in the first year after the index event and overall corresponds to about 8 per 100 patient years. The risk is probably higher in those with lobar haemorrhage, which more commonly involves the cerebral cortex [53]. 3.3.6.4.3 Outcome

The functional outcome is similar to that of cerebral infarction [55]. Twelve community-based studies reporting a 1-month case fatality indicated a pooled estimate mortality of 42% [56]. A low score on the Glasgow Coma Scale, a large volume of the haematoma and the presence of ventricular blood on the initial CT are predictive factors of a high mortality rate [57–59]. 3.3.6.5

Diagnostic Procedures

Besides a clinical examination with control of the vital signs and a check of the coagulation status, a conclusive distinction between cerebral infarction and intracerebral haemorrhage requires some sort of brain imaging [60]. 3.3.6.5.1 CT

Computed tomography easily and immediately demonstrates blood as high density and the tendency towards a mass effect is also shown. In addition, a rapid manual method of measuring the haematoma volume on CT has been developed and validated. The volume is half the product of the diameters A, B and C (for each dimension) [57]. 3.3.6.5.2 MRI

Magnetic resonance imaging also demonstrates intracerebral haemorrhage excellently. There is a time-dependent variation in MRI appearance and it may be difficult to detect an intracerebral haemorrhage within the first few hours [61, 62]. Further investigations are sometimes necessary to differentiate between primary and secondary intracerebral haemorrhage. One study reported abnormalities on angiography in 49% of patients with lobar haemorrhage and in 65% of patients with isolated intraventricular haemorrhage [63]. In addition, it reported abnormalities on angiography in

48% of patients younger than 45years who did not have hypertension. Therefore, additional diagnostics may be recommended in all patients with isolated intraventricular haemorrhage and lobar haemorrhage, independent of their age. On the other hand normotensive patients under 45years with putaminal, thalamic or cerebellar haemorrhage should undergo conventional angiography. Computed tomographic angiography should be reserved for emergency situations with mass effect; MRA can also be used the sensitivity is not well established [64]. 3.3.6.6

Treatment

3.3.6.6.1 Initial Management and Conservative Therapy

The initial work-up should concentrate on a basic examination including the evaluation of airways and breathing, circulation and a focused neurological status. 3.3.6.6.1.1 Oxygenation

The evaluation of adequate ventilation and the observation of a decreasing level of consciousness or airway protecting reflexes due to brain stem dysfunction are important clinical markers. Intubation is indicated for all patients with respiratory insufficiency as indicated by hypoxia (pO2 < 60mmHg or pCO2 > 50mmHg) or an obvious risk of aspiration (level of evidence A; Table3.3.11) [65]. 3.3.6.6.1.2 Blood Pressure

There is still considerable controversy regarding the initial treatment of blood pressure after intracerebral haemorrhage. One rationale is that hypertension in patients with intracerebral haemorrhage increases the risk of ongoing bleeding, which is associated with a poor outcome [66]. The data for this relation remains unclear with regard to the question whether hypertension predisposes to haematoma expansion or is a consequence of this event [67]. The opposite rationale is that elevated blood pres-

Table3.3.11 Levels of evidence Level of evidence Grade A

Data from randomised trials

Level of evidence Grade B

Data from non-randomised concurrent cohort studies

Level of evidence Grade C

Data from non-randomised cohort studies using historical controls

Level of evidence Grade D

Data from anecdotal case series

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sure has protective properties as it preserves cerebral perfusion (Cushing–Kocher response), especially in the case of elevated intracranial pressure [68]. To reconcile these rationales, our recommendation for patients with a history of hypertension is a moderate control of mean arterial blood pressure below 130mmHg (systolic arterial blood pressure below 170mmHg; level of evidence D; Table3.3.11) [69]. If intracranial pressure is available, cerebral perfusion pressure should be maintained over 70mmHg (level of evidence D; Table3.3.11) [23]. 3.3.6.6.1.3 Fluid Management

Normovolemia with a central venous pressure between 5 and 12mmHg is the aim of the treatment. Electrolytes (sodium, potassium, calcium) should be controlled and substituted into a normal range. 3.3.6.6.1.4 Seizures

Most seizures develop at the onset of intracerebral haemorrhage or within the first 24h [70]. There is a trend towards increased poor outcome in patients with posthaemorrhagic seizures [54]. Therefore, our recommendation is the treatment of seizures with anticonvulsants and discontinuing the antiepileptic therapy if no seizure activity occurs after 1 month (level of evidence D; Table3.3.11) [71]. 3.3.6.6.1.5 Medical Therapy: Randomized Trials

Two small randomized trials comparing steroids versus placebo treatment showed no significant benefit [72, 73]. In fact, one of these studies demonstrated that the patient group treated with steroids developed more infectious complications than the placebo group. Likewise, one randomized trial using glycerol versus placebo [74] and another using haemodilution versus best medical therapy [75] ended without demonstration of a significant beneficial effect. Ultra-early haemostatic therapy to minimise the increase in haemorrhage volume is currently thought to improve the outcome [76]. Several agents including fresh frozen plasma, prothrombin concentrate, factor IX concentrate, human and recombinant factors VIII and IX, cryoprecipitate, aminocaproic acid, aprotinin and activated recombinant factor VII theoretically influence the rebleeding rate [76]. Activated recombinant factor VII with probably the highest potential was investigated in patients with spontaneous intracerebral haemorrhage and published in February 2005 [77]. In the course of a multicentre, prospective and randomized study in patients with intracerebral haematoma, the investigators compared one group treated with recombinant activated factor VIIa (rFVIIa) and another group treated with placebo. The results in 399 patients documented that treatment with rFVIIa,

within 4h after the onset of intracerebral haemorrhage, limits the growth of the haematoma, reduces mortality and improves functional outcomes after 90days, despite a small increase in thromboembolic adverse effects (level of evidence A; Table3.3.11). 3.3.6.6.1.6 Intracranial Pressure Management

Elevated intracranial pressure is considered to be a major contributor to mortality after intracerebral haemorrhage [23]. Elevated intracranial pressure for adults is defined as intracranial pressure more than 20 mmHg over 5 min. The therapeutic target is intra cranial pressure below 20mmHg and cerebral perfusion pressure over 70mmHg [69]. Initial treatment for intracranial hypertension should include an optimised head position, moderate hyperventilation and osmotic agents (level of evidence D; Table3.3.11) [78]. Few data are available on mannitol. There are no randomised trials documented in literature; however, mannitol 0.25–0.5g/kg every 4h is often used in patients with large haematomas in combination with increased intracranial pressure for up to 5 days [23]. Corticosteroids should be avoided as mentioned before (level of evidence A; Table3.3.11) [72, 73]. Experience with high doses of barbiturates to induce a barbiturate coma is limited. They can be chosen as a last resort to control intracranial hypertension, provided there is tolerance, but further investigation is needed [79]. 3.3.6.6.2 Surgical Therapy

The surgical therapy of intracerebral haemorrhage is one of the most debated and controversial areas of neurosurgery. Theoretically, haematoma evacuation should be beneficial due to volume reduction and lowering of intracranial pressure [80–82]. Therefore, perfusion in the surrounding areas should be improved by evacuation of the haematoma [83–85]. Additionally, secondary enlargement of the haematoma and the results of toxic products could be avoided [51]. However, clinical results in a number of different trials have not established a generally accepted treatment strategy so far [86, 87]. The major questions are whether, on whom, when and how should we operate? 3.3.6.6.2.1 Removal of Intracerebral Haemorrhage

In 1961, McKissock and Taylor reported the first prospective randomised trial that showed that operative treatment was associated with worse patient outcome [88]. More than 25years later the second prospective random-

3.3.6 Spontaneous Intracerebral and Intracerebellar Haemorrhage in Adults

ized controlled trial documented the opposite result for endoscopic clot removal [89] and was disproven by another group in the same year [90]. These initial trials were followed by studies of Batjer and colleagues [91], Morgenstern and colleagues [92], Zuccarello and colleagues [93] as well as smaller trials and meta-analyses. Congruent results with clear treatment guidelines are not available [94], even the results of the latest prospective randomised study, the STICH trial, published in January 2005, have been obtained [95]. In this international trial, early surgery and initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas were compared. A total of 1,033 patients were included and randomized for conservative management (530) or early surgery (503). The authors concluded that there was no overall benefit from early surgery when compared with initial conservative therapy [95]. However, going into the study in more detail there was a subgroup of patients clearly profiting from early surgery. These were patients with superficial large lobar haematomas in a better neurological condition. As known from earlier trials, prognosis was additionally related to age. Therefore, our recommendation to operate on intra cerebral haematomas is dependent on age, neurological condition and trend, haematoma location and volume as well as radiological tentorial herniation and coagulation disorders. Compose a cross sum of these above-mentioned factors is important in the decision process. An age of over approximately 65years inclines more to initial conservative management (level of evidence A–D; Table3.3.11). Patients with a GCS score below 4 should be treated with supportive care because of a high chance of poor functional outcome that cannot be improved by surgery (level of evidence A–D; Table3.3.11). Secondary neurological deterioration in patients after intracerebral haematoma is an indicator surgery (level of evidence B–D; Table3.3.11). Patients with large haematomas measuring more than 50ml are potential surgical candidates (level of evidence A–D; Table3.3.11) particularly in case of superficial or lobar haemorrhages (level of evidence A–D; Table3.3.11). Patients with coagulation disorders should first be treated with conservative therapy.

For this reason, we recommend surgical removal as soon as possible in patients with a cerebellar haemorrhage larger than 20–30ml or 3cm in diameter who are neurologically deteriorating, or patients with brain stem dysfunction or with obstructive hydrocephalus [98] (level of evidence B–D; Table3.3.11).

3.3.6.6.2.2 Cerebellar Haemorrhage

There has been up to now no documented randomised trial on the treatment of intracerebellar haemorrhage. Non-randomised trials reported in patients with cerebellar haemorrhage larger than 3cm in diameter or signs of brain stem compression or hydrocephalus have reported good outcomes [46, 96–98]. In these patients, medical treatment alone resulted in poor outcome [99].

3.3.6.6.2.3 Minimally Invasive Surgery

There is evidence that classical craniotomy for intracerebral haematoma additionally traumatises brain tissue and influences the functional outcome negatively [100, 101]. Therefore, minimally invasive surgery was developed to achieve clot removal with minimal side effects. One of the first documented studies to use ultrasoundguided endoscopic clot removal was published by Auer and colleagues [102]. The following randomised trial resulted in the improved outcome of a surgically treated group [89]. An even less invasive technique was introduced by using plasminogen activator for clot lysis in combination with minimally invasive surgery. So far, to investigate the efficacy of stereotactic treatment for primary intracerebral haematoma, case reports, a couple of small trials [93, 103–105] as well as the randomised SICHPA trial [106] have been published and documented an improved functional outcome. Therefore, particularly for deep haematomas, the stereotactic approach is favoured, while a small focused craniotomy allows complete and immediate removal of the haematoma in superficial haemorrhages (level of evidence B–D; Table3.3.11). References 1.

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70. Berger AR, Lipton RB, Lesser ML, Lantos G, Portenoy RK (1988) Early seizures following intracerebral hemorrhage: implications for therapy. Neurology 38(9):1363–1365 71. Cervoni L, Artico M, Salvati M, Bristot R, Franco C, Delfini R (1994) Epileptic seizures in intracerebral hemorrhage: a clinical and prognostic study of 55 cases. Neurosurg Rev 17(3):185–188 72. Poungvarin N, Bhoopat W, Viriyavejakul A et al. (1987) Effects of dexamethasone in primary supratentorial intra cerebral hemorrhage. N Engl J Med 316(20):1229–1233 73. Tellez H, Bauer RB (1973) Dexamethasone as treatment in cerebrovascular disease. I. A controlled study in intracerebral hemorrhage. Stroke 4(4):541–546 74. Yu YL, Kumana CR, Lauder IJ et al. (1992) Treatment of acute cerebral hemorrhage with intravenous glycerol. A double-blind, placebo-controlled, randomized trial. Stroke 23(7):967–971 75. Italian Acute Stroke Study Group (1988) Haemodilution in acute stroke: results of the Italian haemodilution trial. Italian Acute Stroke Study Group. Lancet 1(8581):318–321 76. Mayer SA (2003) Ultra-early hemostatic therapy for intracerebral hemorrhage. Stroke 34(1):224–229 77. Mayer SA, Brun NC, Begtrup K et al. (2005) Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 352(8):777–785 78. Qureshi AI, Geocadin RG, Suarez JI, Ulatowski JA (2000) Long-term outcome after medical reversal of transtentorial herniation in patients with supratentorial mass lesions. Crit Care Med 28(5):1556–1564 79. Woodco*ck J, Ropper AH, Kennedy SK (1982) High dose barbiturates in non-traumatic brain swelling: ICP reduction and effect on outcome. Stroke 13(6):785–787 80. Kingman TA, Mendelow AD, Graham DI, Teasdale GM (1988) Experimental intracerebral mass: description of model, intracranial pressure changes and neuropathology. J Neuropathol Exp Neurol 47(2):128–137 81. Nehls DG, Mendelow DA, Graham DI, Teasdale GM (1990) Experimental intracerebral hemorrhage: early removal of a spontaneous mass lesion improves late outcome. Neurosurgery 27(5):674–682; discussion 682 82. Chambers IR, Banister K, Mendelow AD (2001) Intracranial pressure within a developing intracerebral haemorrhage. Br J Neurosurg 15(2):140–141 83. Nath FP, Kelly PT, Jenkins A, Mendelow AD, Graham DI, Teasdale GM (1987) Effects of experimental intracerebral hemorrhage on blood flow, capillary permeability, and histochemistry. J Neurosurg 66(4):555–562 84. Mendelow AD (1993) Mechanisms of ischemic brain damage with intracerebral hemorrhage. Stroke 24 [12 Suppl]:I115–117; discussion I118–119 85. Siddique MS, Fernandes HM, Arene NU, Wooldridge TD, Fenwick JD, Mendelow AD (2000) Changes in cerebral blood flow as measured by HMPAO SPECT in patients following spontaneous intracerebral haemorrhage. Acta Neurochir Suppl 76:517–520

86. Hankey GJ ( Evacuation of intracerebral hematoma is likely to be beneficial – against. Stroke 34(6):1568–1569 87. Minematsu K (2003) Evacuation of intracerebral hematoma is likely to be beneficial. Stroke 34(6):1567–1568 88. Mckissock WRA, Taylor J (1961) Primary intracerebral haemorrhage: a controlled trial of surgical and conservative treatment in 180 unselected cases. Lancet 1961(278):221–226 89. Auer LM, Deinsberger W, Niederkorn K et al. (1989) Endoscopic surgery versus medical treatment for spontaneous intracerebral hematoma: a randomized study. J Neurosurg 70(4):530–535 90. Juvela S, Heiskanen O, Poranen A et al. (1989) The treatment of spontaneous intracerebral hemorrhage. A prospective randomized trial of surgical and conservative treatment. J Neurosurg 70(5):755–758 91. Batjer HH, Reisch JS, Allen BC, Plaizier LJ, Su CJ (1990) Failure of surgery to improve outcome in hypertensive putaminal hemorrhage. A prospective randomized trial. Arch Neurol 47(10):1103–1106 92. Morgenstern LB, Frankowski RF, Shedden P, Pasteur W, Grotta JC (1998) Surgical treatment for intracerebral hemorrhage (STICH): a single-center, randomized clinical trial. Neurology 51(5):1359–1363 93. Zuccarello M, Brott T, Derex L et al. (1999) Early surgical treatment for supratentorial intracerebral hemorrhage: a randomized feasibility study. Stroke 30(9):1833–1839 94. Donnan GA, Davis SM (2003) Surgery for intracerebral hemorrhage: an evidence-poor zone. Stroke 34(6): 1569–1570 95. Mendelow AD, Gregson BA, Fernandes HM et al. (2005) Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet 365(9457):387–397 96. Van Loon J, Van Calenbergh F, Goffin J, Plets C (1993) Controversies in the management of spontaneous cerebellar haemorrhage. A consecutive series of 49 cases and review of the literature. Acta Neurochir (Wien) 122(3–4):187–193 97. Firsching R, Huber M, Frowein RA (1991) Cerebellar haemorrhage: management and prognosis. Neurosurg Rev 14(3):191–194 98. Kobayashi S, Sato A, Kageyama Y, Nakamura H, Watanabe Y, Yamaura A (1994) Treatment of hypertensive cerebellar hemorrhage – surgical or conservative management? Neurosurgery 34(2):246–250; discussion 250–251 99. Da Pian R, Bazzan A, Pasqualin A (1984) Surgical versus medical treatment of spontaneous posterior fossa haematomas: a cooperative study on 205 cases. Neurol Res 6(3):145–151 100. Prasad K, Shrivastava A (2000) Surgery for primary supratentorial intracerebral haemorrhage. Cochrane Database Syst Rev (2):CD000200

3.3.7 Pediatric Vascular Lesions

101. Zuccarello M, Andaluz N, Wagner KR (2002) Minimally invasive therapy for intracerebral hematomas. Neurosurg Clin N Am 13(3):349–354 102. Auer LM, Ascher PW, Heppner F et al. (1985) Does acute endoscopic evacuation improve the outcome of patients with spontaneous intracerebral hemorrhage? Eur Neurol 24(4):254–261 103. Montes JM, Wong JH, Fayad PB, Awad IA (2000) Stereotactic computed tomographic-guided aspiration and thrombolysis of intracerebral hematoma: protocol and preliminary experience. Stroke 31(4):834–840 104. Rohde V, Rohde I, Reinges MH, Mayfrank L, Gilsbach JM (2000) Frameless stereotactically guided catheter placement and fibrinolytic therapy for spontaneous intracerebral hematomas: technical aspects and initial clinical results. Minim Invasive Neurosurg 43(1):9–17 105. Marquardt G, Wolff R, Janzen RW, Seifert V (2005) Basal ganglia haematomas in non-comatose patients: subacute stereotactic aspiration improves long-term outcome in comparison to purely medical treatment. Neurosurg Rev 28(1):64–69 106. Teernstra OP, Evers SM, Lodder J, Leffers P, Franke CL, Blaauw G (2003) Stereotactic treatment of intracerebral hematoma by means of a plasminogen activator: a multicenter randomized controlled trial (SICHPA). Stroke 34(4):968–974

3.3.7 Pediatric Vascular Lesions* *reprinted in part from Surgical Neuroangiography vol3 2nd edition, neurovascular diseases in neonates, infants and children.

P. LASJAUNIAS, K. ter BRUGGE, A. BERENSTEIN Springer Verlag 2006

Pierre Lasjaunias 3.3.7.1

Pediatric Intracranial Arteriovenous Shunts

3.3.7.1.1 From Adults to Children

Cerebral arteriovenous (AV) shunts have different characteristics in children from those in adults. Children can have multifocal lesions, induced remote AV shunts, large venous ectasias, high-flow lesions and single-hole arteriovenous fistulas (AVF), venous thrombosis, brain atrophy, and systemic phenomena. Conversely, high-flow angiopathic changes are rare in children as are flow-related arterial aneurysms, while proximal occlusive arteriopathy is more frequent. For this reason, management protocols

derived from experience in adults should not be applied to the pediatric population. In particular, adult-based classifications and AVM grading according to the expected surgical outcome is particularly inappropriate in children, in whom: • Cerebral eloquence is difficult to assess, particularly in the first few years of life. • Most lesions are fistulas or multifocal. • Drainage usually affects the entire venous system. • The potential for recovery is different. In addition to the conventional objectives, the decisionmaking process in children must take into consideration additional specific details pertaining to the veins and the myelinization process. Neurocognitive evaluation is the key follow-up criterion in children even without deficits, hemorrhage or seizures, as it helps in the assessment of treatment quality and success. Failure to obtain a normal maturation process may constitute a therapeutic failure if the optimal moment for intervention has been missed (therapeutic window). Lesions in children are divided into non-proliferative and proliferative lesions. The former group comprises vascular malformations, the latter hemangiomatous lesions. In fact such a distinction, which has been helpful during the past 20years, has also greatly benefited from recent biological contributions as well as the recognition of shear stress mechanisms in vascular modeling and remodeling. 3.3.7.1.2 Types and Disease Groups of Vascular Lesions

Even in an apparently single disease category such as CAVMs, several entities must be distinguished, as their predictable presentation or evolution requires different management at different times. The generic name regrouping of artificially different situations expresses the use of a single key (the arteriovenous shunt, for example), where two or three would reveal the differences (familial disorder for hereditary hemorrhagic telangiectasia [HHT], metameric disease for CAMS, proliferative activity for proliferative angiopathy, PHACE [posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities] syndrome, etc.) (Fig. 3.3.20). 3.3.7.1.2.1 Non-Proliferative Lesions 3.3.7.1.2.1.1 AV Lesions

The AV lesions that can be encountered depend on the meningeal space from which they primarily develop: dural, pial, “subarachnoid” or choroidal. These locations give rise to several subtypes and may be unifocal, multifocal, hereditary, etc.

229

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3.3 Vascular Diseases

Arteries Art Aneur., dissections (Ch 2, 4,16,17, …) associated art.variations

Fig. 3.3.20 Vascular Diseases according to the arterio-veno-lymphatic tree

PHACE (prolif.,meningeal malf.,art Aneur., associated art.variations CAMS (metameric syndrome intra dural AVMs, facial an.) HHT1/ CAVF, CAVM, (Ch 9,12) VGAM (ass. art. & venous maturation delay) BRBN (Ch 9,1) CVMS DSM (associated DVAs, cavernomas)) Cavernomas (Ch 7) (associated DVAs) Arteries and veins exist as such before vascular lumen exist

Max.Fac. VLM (associated DVAs)

Veins and lymphatics

3.3.7.1.2.1.2 Isolated Brain AVMs

3.3.7.1.2.1.5 Dural Lesions

3.3.7.1.2.1.3 Vein of Galen Aneurysmal Malformations

3.3.7.1.2.1.6 Telangiectasias

Isolated brain AVMs can be small (micro-AVM) or large (macro-AVM), and this distinction is of nosological interest as the passage from one type to the other cannot be demonstrated. Of interest is the distinction between the nidus type (with an arteriolar network) and the fistulous type (single or multiple large, direct AV communication). Finally, there is no gender dominance in CAVM in children.

Vein of Galen aneurysmal malformations (VGAM) constitute a unique, well-defined group of malformations that occur at the end of the embryonic period. They make up a separate group from other lesions such as CAVMs, which are often called non-Galen vein AV malformations, particularly in neonates and infants. In the VGAM group, there is a 2–3:1 male predominance. 3.3.7.1.2.1.4 Cerebrofacial Arteriovenous Metameric Syndrome

Features of the cerebrofacial arteriovenous metameric syndromes (CAMS), as originally described and common to all, include arteriovenous malformations of the brain and orbit (with retinal and/or retrobulbar lesions) (Bonnet–Dechaume–Blanc or Wyburn–Mason syndrome) and maxillo-facial lesions. We have suggested segmental patterns of involvement in what is likely to be a disease of the neural crest and/or adjacent cephalic mesoderm. A newly proposed rational classification reflects the putative, underlying disorder and calls for a new acronym: CAMS.

Dural lesions can be encountered at any age in children, but represent different disease entities (Fig. 3.3.21). They can present as true malformations in very young children or as secondary AV shunts in older children. The former are encountered in neonates and infants and can be diagnosed in utero. The latter are usually multifocal and contain large sinuses and high-velocity flow phenomenon, but are originally associated with low pressure in the dural sinuses. Telangiectasias are usually included in the malformation group and they are occasionally described in children at autopsy. They are likely to represent improper capillary remodeling. 3.3.7.1.2.1.7 Blue Rubber Bled Nevus Syndrome

The blue rubber bled nevus (BRBN) or Bean syndrome can produce multiple types of CNS (central nervous system) involvement. These features consist of multiple VMs (venous malformations similar to large telangiectasias), DVAs (developmental venous anomalies) in supratentorial brain, the cerebellum, and the tectum mesencephali. Although BRBN can be sporadic, its familial transmission is frequent and the link with HHT1 unlikely, despite the involvement of the same chromosome (Chr9p). 3.3.7.1.2.1.8 Venous Malformations (Cavernomas)

Venous malformations (cavernomas) are located outside the nervous tissue and therefore do not contain nervous or glial elements. They are referred to as being cavernous and can be isolated or multiple. In the latter case, they

3.3.7 Pediatric Vascular Lesions

Brain damage

Severe Neurol. Outcome

Ante natal diagnosis

DSM at the Torcular

No Brain damage

No Cavernous capture Cavernous capture

DSM away from the Torcular

No Jugular bulb dysmaturation

Jugular bulb dysmaturation

No Pial, Straight S. or Sup.Sag.S reflux

Pial, Straight S. or Sup.Sag.S reflux

Thrombosis (spontaneous or induced)

Severe Neurol. Outcome

Thrombosis (spontaneous or induced)

Good Neurol. Outcome*

Thrombosis (spontaneous or induced)

Good Neurol. Outcome*

Thrombosis (spontaneous or induced)

Good Neurol. Outcome*

Thrombosis (spontaneous or induced)

Good Neurol. Outcome*

No Thrombosis (spontaneous or induced)

Severe Neurol. Outcome

Fig. 3.3.21 Dural sinus malformation prognostic features

are often familial with autosomal dominant transmission. These lesions are malformations and can be found in autopsy series in any location within the intradural space (subarachnoid, subpial). They increase in size following intralesional hemorrhage. They occasionally have the appearance of a tumor (particularly in children) or a cyst, through confluence of recurrent hematomas. They can be associated with venous anomalies or other malformations such as dural sinus AV malformations (DSM) and can be induced by radiation therapy.

of cutaneous, facial, port-wine stain (venular malformation), subcutaneous lymphatic malformations (with secondary maxillo-facial bone and soft tissue hypertrophy), and cerebral, cortical vein thrombosis with cortical atrophy, secondary angiogenesis and transhemispheric venous drainage, with or without choroid plexus hypertrophy. The facial involvement represents the distal destination of the migrating neural crest cells, contributing to the vascular network rather than the “trigeminal dermatome.”

3.3.7.1.2.1.9 Developmental Venous Anomalies

Induced pial shunts are unique in juvenile dural arteriovenous lesions and occur only in children. They develop with the sump effect from the abnormal dural sinus, retrograde to the cerebral vein, with subsequent pial AV shunt formation.

So-called venous angiomas or developmental venous anomalies (DVA) are anatomic variations that can involve one or both hemispheres and be located infratentorially. They do not exist at the spinal cord level or where no secondary germinal matrix migration has occurred. DVAs should therefore never be a target for treatment. 3.3.7.1.2.1.10 Cerebrofacial Venous Metameric Syndrome

Cerebrofacial venous metameric syndrome (CVMS, formerly Sturge–Weber syndrome). The syndrome consists

3.3.7.1.2.1.11 Induced Pial Shunts

3.3.7.1.2.1.12 Spinal Cord AVM

Spinal cord AVM and spinal cord cavernous malformations present the same characteristics as those mentioned in the brain. Similar to the cranial region, SAMS are recognized, enriching the historical description of Cobb’s syndrome.

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3.3 Vascular Diseases

3.3.7.1.2.2 Proliferative Lesions

Proliferative vascular lesions in children form a distinct group of disorders; the name angioma is often given indiscriminately to all apparently congenital, non-ischemic vascular lesions. 3.3.7.1.2.2.1 Hemangiomas

The name angioma (vascular growth) should be abandoned or reserved for hemangiomas, which are benign tumors of blood vessel origin in infants. Some hemangiomas can be seen intracranially, but such localization is rare and usually associated with superficial hemangiomas. Yet some of them keep a capillary angioarchitecture and are named NICH (non-involuting capillary hemangiomas). 3.3.7.1.2.2.2 PHACE Syndrome

PHACE or PHACES are acronyms for a syndrome of variable phenotypic expression comprising posterior fossa malformations, facial hemangiomas, arterial anomalies, coarctation and other cardiac disorders, eye abnormalities, and stenotic artery disease; many of the elements of this disorder may reflect an underlying abnormality of cell proliferation and apoptosis. 3.3.7.1.2.2.3 Proliferative Angiopathy

Moya-moya disease, moya-moya-like syndromes, and proliferative angiopathy in children are the most typical disorders in this group. They combine neoangiogenesis (production of the lumen) and angioectasia (production of the vessel wall), which may be difficult to differentiate; however, in such instances there is a discrepancy between the apparent size of the “nidus-like” network of vessels and the draining veins that are often normal or slightly enlarged. In proliferative angiopathy, while seizures are the most common clinical symptom at presentation, headaches and progressive deficits are also possible, whereas hemorrhage is exceptional. In our experience, the risk of hemorrhage being low at presentation, the risk of recurrence once a hemorrhagic episode has occurred is significantly higher than in CAVM. Transdural supply in remote locations (supra- and infratentorial, bilateral) confirms the diffuse character of the angiogenetic activity of the disease, suggesting an unrepressed response to cerebral subischemic manifestations. Proliferative angiopathy is still often confused with CAVMs and thought to represent a diffuse nidus. Treatment should therefore not be embolization (or surgery or radiation therapy) unless areas of the angio-architecture suggest zones of weakness or demonstrate obvious constraints to the eloquent brain. Today, perfusion MRI has reinforced the suspicion of chronic ischemic disease with angiogenetic activity, as in moyamoya, and similar treatment with burr holes has already been performed in a handful cases with immediate good

clinical results on both the headaches and the seizure response to medical treatment. 3.3.7.1.2.2.4 Moya-Moya Disease

Moya-moya disease is a primary vascular disease characterized by progressive stenosis and eventual occlusion of the supra-clinoid portion of the internal carotid artery and the adjacent segments of the middle and anterior cerebral arteries. In response, an abnormal vascular network of small collateral vessels develops to bypass the area of occlusion. The most frequent symptoms in childhood are multiple transient ischemic attacks, with permanent residual following some episodes. Seizures occur in 33% of children under the age of 6years. Moya-moya represents 10–20% of strokes in children, and is grouped into primary and secondary moya-moya. Many pseudo-moyamoya patterns can be seen, with slowly progressing largevessel vasculopathy with collateralization in childhood. Moya-moya syndrome or the moya-moya phenomenon can be considered to be responses to different triggers of different weaknesses, rather than true diseases. Specific vulnerability includes a familial occurrence noted in 10% of cases with linkage to Chr17q25, and 3p24.2–26. 3.3.7.1.2.2.5 Hemorrhagic Angiopathy

Hemorrhagic angiopathy is another entity that we encounter in some rare cases of intracerebral hematomas in children. Often, after the age of 5, they correspond to a network of intracerebral subcortical arterioles with normal morphological and sequential venous drainage. They may re-hemorrhage and can therefore be partially embolized when the area of weakness in the angioarchitecture can be identified. The response to radiation therapy is amazingly rapid and efficient. 3.3.7.1.3 Classification of CAVMs by Age Group 3.3.7.1.3.1 Fetal Age

Intrauterine antenatal ultrasound or MRI diagnosis of a large fetal intracranial mass as a pseudocystic, non-echogenic or poorly echogenic spherical image, depending on its topography, either represents a VGAM or a dural sinus malformation (DSM). With regard to the fetal brain, macrocrania can be seen in both VGAM and DSM, but the two types differ with regard to prognostic value. In VGAM, macrocrania (in the absence of ventricular enlargement) is usually a benign observation without a negative impact on the prognostic neonatal score. In contrast, macrocrania in DSM indicates an already active sinus dysfunction with water and venous effect; if present, the prognosis, which is already not good, would become even worse. The only finding that has the same importance at the fetal stage, regardless of the type of AV shunt, is the presence of encephalomalacia. The presence

3.3.7 Pediatric Vascular Lesions

of isolated cardiomegaly has no impact on prognosis. On the other hand, cardiac failure in fetuses with VGAM is known to be pejorative (Fig. 3.3.22). 3.3.7.1.3.2 Neonatal Age

At the neonatal stage there is a fundamental difference between VGAM and non-Galenic AV malformations (pial). Early neurological symptoms in VGAM are of major negative prognostic value, to the extent that treatment may be withheld. On the other hand, similar symptoms are an indication for emergency management in nonGalenic AVMs (Table 3.3.12). The systemic symptoms in neonatally diagnosed CAVM are usually better tolerated than in VGAM, probably because the veno-dural junction is relatively well preserved and protects the cardiac function. Hemorrhage in VGAM does not occur in this age group. A hemorrhagic episode or convulsion in a neonate should steer one away from the diagnosis of VGAM. 3.3.7.1.3.3 Infancy

Infancy is dominated by hydrovenous disorders. The granulations are not yet functional, and their maturation is likely to be delayed if increased pressure is present in the dural sinuses. The signs of water retention start with macrocrania without ventriculomegaly. Clinical consequences are almost consistently neurocognitive delay without any Neonate

direct relationship to the degree of the increase in the head circumference. If left untreated, this water dysfunction progressively leads to ventriculomegaly. Ventricular shunting at that time is associated with significant morbidity. Venous changes have a direct impact at this age. In non-Galenic AVMs, local congestion rapidly leads to focal ischemia, as revealed by convulsions and later hemorrhage. In VGAM, pial congestion is absent for a long time and depends on whether maturation of the venous drainage at the skull base occurs (cavernous sinus capture). The dysmaturation and subsequent closure of the jugular foramen in VGAMs, in some CAVMs and in DSM patients are unlikely to be related to high-flow venous angiopathy, and more likely to lead to impaired postnatal development. The slowly developing end result of hydrovenous dysfunction at the posterior fossa level will be progressive tonsillar prolapse. This prolapse is reversible for a long time with adequate treatment of the AV shunt. This supports the concept of a therapeutic window during which to intervene at the optimal moment, permitting treatment to result in a normally developing child. 3.3.7.1.3.4 After the Age of 2Years

Children who have not presented with systemic and hydrovenous disorders will reveal their vascular lesions with neurological symptoms. Venous thrombosis may start to

Infant

Child < 5 years

Child > 5 years

Congestive cardiac failure

Macrocrania hydrocephalus

Multiorgan failure

Hydrodynamic disorders

Encephalomalacia

Dural venous thrombosis (sigmoid s., jugular bulb) Fall off in head circumference

Neurocognitive delay

Dural venous congestion and supra tentorial pial reflux bone hypertrophy Infratentorial pial reflux and congestion Tonsillar prolapse

Facial venous collateral circulation epistaxis

Optimal therapeutic window Hydromyelia or syringomyelia

Fig. 3.3.22 Natural history of vein of Galen aneurysmal malformations

S/ependymal atrophy (pseudo ventriculomegaly) calcifications (chronic venous ischemia)

Convulsions neurological deficits cerebro-meningeal haemorrhages

Epilepsy neurological deficits

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3.3 Vascular Diseases

Table 3.3.12 Bicêtre Neonatal Evaluation Score Point s

Cardiac function

Cerebral function

Respiratory function

Normal

Overload, no med tt.

Subclinical isolated EEG Abn’s

Failure – stable with med tt.

Non convulsive inter- Tachypnea does not mittent neurologic finishe bottle

No hepatomegaly, normal function

Normal

Failure – not stable with med tt.

Isolated convulsion

Assisted ventilation, normal saturation FIO2 < 25%

Hepatomegaly, normal function

Transient anuria

Ventilation necessary Seizures

Assisted ventilation, normal saturation FIO2 < 25%

Moderate or transient hepatic insufficiency

Unstable diuresis with treatment

Resistant to med tt.

Assisted ventilation, desaturation

Abn coagulation, elevated enzymes

Anuria

Permanent neurological signs

Hepatic function

Renal function

Normal

–

Tachypnea, finishes bottle

Maximal score = 5 (cardiac) + 5 (cerebral) + 5 (respiratory) + 3 (hepatic) + 3 (renal) = 21

occur as part of the high-flow angiopathy phenomenon. The clinical interaction with young children and adolescents will be particularly challenging and entirely different from that in adults; information for parents also requires thorough knowledge of the consequences of the diseases involved rather than the techniques available (Table 3.3.13).

Table 3.3.13 Bicêtre Admission and Outcome Score* score

Condition

Normal (N)

Minimal non-neurological symptoms, not treated (MS) and/or asymptomatic enlargement of the cardiac silhouette

Transient neurological symptoms, not treated (TNS) and/ or asymptomatic Cardiac overload under treatment

Permanent minor neurological symptoms, mental retardation of up to 20%; Non-permanent neurological symptoms under treatment (MNS) Normal School with Support and/ or Cardiac failure stabilised with treatment

Severe neurological symptoms, mental retardation of more than 20% (SNS); Specialised School and/or Cardiac failure unstable despite treatment

Death (D)

3.3.7.1.4 Melting Brain Syndrome

Melting brain syndrome consists of the rapid destruction of the brain, usually the white matter, with secondary ventricular enlargement. This phenomenon is associated with severe neurological manifestations and no signs of increased intracranial pressure, although they are usually present before the morphological damage is seen. When the brain suffering leads to trophic changes these are usually bilateral and symmetrical; they correspond to a regional decrease in the cerebral blood flow caused by retrograde venous hyperpressure, leading to hydrovenous dysfunction. Arterial steal is not present or an accessory in this syndrome. The local atrophy around a PAVM can represent focal expression of this phenomenon. These findings are never encountered in adults. This mechanism is progressive and once it starts, develops fairly rapidly, although it is slow enough to result in a loss of substance rather than a hemorrhagic infarct, which supports the role played by water in the maintenance of brain tissue. In contrast, the subarachnoid veins travel directly into the peri-cerebral spaces with little impact on the intrinsic water physiology as long as the dural sinuses are sufficiently

* Does not apply to neonates

patent. Thus, two high-flow lesions, both apparently located on the surface of the brain, may have different effects on the underlying cerebral tissue depending on whether they open directly into subpial or subarachnoid outlets, almost independently of the flow they carry.

3.3.7 Pediatric Vascular Lesions

3.3.7.2

Intracranial Aneurysms in Children

3.3.7.2.1 Introduction

Aneurysms are not congenital, in the respect that they are not present at birth. Yet, they reflect various types of structural or functional weaknesses already present in utero and expressed at a later age. Aneurysm is therefore a generic name encompassing various disorders involving the vessel wall. Aneurysm formation is likely to require both a local target (vessel wall structure or function) and systemic triggers that are more or less specific for that arterial segment. Aneurysmal vasculopathies in the pediatric age group are significantly different from those in adults: • There is a male dominance of 2–3:1. • There is a higher incidence of unusual sites (posterior circulation > 30%. • There is a predilection for a carotid bifurcation location (31–54%). • There are a greater number of large and giant aneurysms (20%). • There is a lower incidence of multiple aneurysms (< 10%). • The morbidity rate is lower. • There is a higher incidence of traumatic, dissecting, and infectious etiologies. • There is a higher incidence of spontaneous thrombosis. • Aneurysms are 1.6 times more frequently responsible for intracranial hemorrhage (ICH) than CAVMs in white populations. • Aneurysms are four times less frequently responsible for ICH than CAVMs in some Asian populations. These differences are more pronounced in early childhood and become less obvious toward adolescence. 3.3.7.2.2 Incidence

Intracranial aneurysms in the pediatric age group represent less than 5% (0.6–4.6%) of the total number of intracranial aneurysms in the general population The higher incidence of intracranial aneurysms in women in the adult population is reversed in the pediatric population, in which the male to female ratio varies from 2:1 in infants up to 8years of age, to a nearly equal ratio of 1.2:1 in the 10–20 age group. 3.3.7.2.3 Presentation

When assessing the entire pediatric age group, about 70% of patients with intracranial aneurysms present with subarachnoid hemorrhage. The incidence of hemorrhage, however, is reported to be as high as 82% if only infants

and children below 5years of age are considered The incidence appears to progressively decrease and to be as low as 45% if only children over 5years of age are considered. Other clinical presentations, such as seizures and stroke, are uncommon and occur in less than 10% of cases. Many of the children in our studies presented with a neurological deficit or headaches. The type of presentation with subarachnoid hemorrhage (SAH) or intracerebral hematoma varied depending upon the age of the child and was increased below 2years of age and between 6 and 15years of age, which coincided with the peak incidences of dissections and saccular aneurysms (Fig. 3.3.23). 3.3.7.2.4 Etiology

In our patient groups, clear known causes were found in less than 50% of the aneurysms. However, various subgroups of aneurysms can be identified: traumatic (5–10%), infectious (15%), saccular (30%), and dissections (about 50%). Such numbers must be adjusted to the age at the time of referral as dissection will be dominant during the first 5years of life and saccular ones occurring between the ages of 6 and 15 (Fig. 3.3.24). 3.3.7.2.4.1 Traumatic Aneurysms 3.3.7.2.4.1.1 Traumatic

The majority of children with traumatic aneurysms present with a hemorrhagic episode about 3–4weeks after the original injury. Twenty percent healed spontaneously. A mortality rate of 31% has been reported in children with traumatic intracranial aneurysms that were not operated upon. 3.3.7.2.4.1.2 False or Pseudo-Aneurysm

In this group of post-traumatic AA, a false or pseudoaneurysm from a ruptured vessel can occur, which corresponds to an extravascular space, usually within a hematoma. Evolution of such lesions can sometimes be favorable, with spontaneous healing of the leakage point. 3.3.7.2.4.2 Infectious Aneurysms

Today the term “infectious arterial aneurysm” (IAA) seems more appropriate. While they can be caused by fungal infections, they are most often bacterial. They account for 1.5–9% of all intracranial aneurysms (pediatric and adult), but represent less than 1–2% of our interventional practice. The most common organism has been Staphylococcus, followed by Streptococcus and other Gram-negative organisms. They often complicate bacterial endocarditis in infants with congenital or rheumatic heart disease. IAAs may involve the intracavernous ICA by contiguity, following severe sphenoid sinus infections with osteomyelitis and cavernous sinus thrombophlebitis.

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Fig. 3.3.23 Age at presentation and etoliology of intracranial aneurysms in children (Bicêtre hospital series)

Age at presentation (92 children<18 years) <2y 16%

11-18y 36%

2-5y 15%

6-10y 33%

Etiology (92 patients <18 years) trauma 8%

infectious 17%

dissection 40%

saccular 35%

Fig. 3.3.24 Etiology distribution of intracranial pediatric aneurysms according to age (Bicêtre hospital series)

18 16 14 12 10 8

Dissecting saccular infectious Trauma

6 4 2 0 Dissecting saccular infectious Trauma

<2 years 9 3 1 2

2-5 years 11 1 1 1

6-10 years 10 11 7 3

Yet, the concept of “infectious” is too narrow to account for the complexity of the disorders encountered under this heading. In fact “infectious and immune” indicates the agent and the host, describing the two components of the same disorder. Several reports of aneurysms associated with the human immunodeficiency virus (HIV) can be found in the literature.

11-18 years 10 18 7 1

We observed similar features in chronic mucocutaneous candidiasis (CMCC). CMCC is a familial disease with a primary immunodeficiency disorder that should be distinguished from the opportunistic candidiosis seen in globally immunocompromised patients (steroid therapies, chemotherapies).

3.3.7 Pediatric Vascular Lesions

3.3.7.2.4.3 Saccular Aneurysms

The saccular type of aneurysm remains as controversial in the pediatric age group as they are in adults. Between 50 and 70% of aneurysms in the pediatric population are believed to be of this type. Despite their location at the bifurcation of various vessels, intrinsic hemodynamic factors almost certainly play less of a role than in adults. Mural or systemic factors are considered to be more important. Ehlers–Danlos syndrome, Klippel–Trenaunay syndrome, polycystic kidney disease, tuberous sclerosis, moya-moya syndrome, co-arctation of the aorta, and fibromuscular hyperplasia have all been documented to occur in association with aneurysms in children. 3.3.7.2.4.3.1 Familial Occurrence

Familial occurrence has been reported in children, but appears to be less frequent than in adults. The association of autosomal dominant polycystic kidney disease (PKD) with intracranial aneurysms (IA) is a well-known occurrence in the adult age group, but is rare in children. The combination of the recessive form and AA is exceptional. No data exist regarding the outcome of non-operated children presenting with saccular AA. Most of the familial diseases associated with AA do not occur during childhood, as though additional triggers with subsequent alteration of the disease or loss of compensation (“second hit”), is needed for the AA to develop. 3.3.7.2.4.3.2 Multiple Saccular Aneurysms

The incidence of multiplicity is higher in children with aneurysms of infectious origin. In fact, the multiplicity is low in saccular aneurysms in comparison to adult groups, but is high if the dissection etiology group is considered and is even higher among the infectious and immunocompromised ones. 3.3.7.2.4.3.3 Flow-Related Aneurysms

Flow-related aneurysms associated with CAVMs are not seen in the pediatric population. 3.3.7.2.4.3.4 Additional Aneurysms

Additional aneurysms seen in children and likely to correspond to an underlying specific dysplastic disease are those associated with PHACE and CAMS. These two syndromes illustrate the angiogenetic nature of some aneurysmal vasculopathies. 3.3.7.2.4.4 Dissecting Aneurysms

The dissecting aneurysm group is related to a specific type of mural damage, non-infectious and non-immune in this section, which may actually ignore the fact that spontaneous dissections in babies may result from an unrecognized immune type of segmental aggression or

segmental vascular failure. The frequency of dissecting aneurysms in the pediatric age group is four times that of the adults. The mean age of the child with dissecting aneurysm is 6years. Focal arterial stenotic segments are often observed proximal or distal to the dissecting aneurysm, suggesting mural damage. Impaired vessel wall with stenosis can induce spontaneous thrombosis. Some of the dissecting aneurysms heal spontaneously, leading to associated occlusion of the parent artery. This is often well tolerated in the child owing to good collateral circulation via the circle of Willis or pial collateral anastomoses. Dissecting aneurysms of the MCA (M1), or ACA (A1) are the most difficult cases to manage because of the absence of a neck and the involvement of perforating arteries arising from the dissected aneurysmal wall. These tend to be unstable and rebleed rapidly. Dissecting aneurysms presenting with deep-seated ischemic infarcts should therefore be analyzed with great care. Schematically, two types of dissections can be encountered: • Extensive vessel wall damage (fusiform or wide neck “saccular” aneurysms) without evidence of mural hematoma; they may present with a deep-seated stroke or an SAH. Early recurrence of rupture often occurs during the first few days. Aggressive treatment is recommended. • Focal lesions that can be of large size (giant or large “saccular” aneurysms), with evidence of recent mural hematoma on CT or MRI. Presentation is often ischemic and spontaneous healing with completion of the lumen thrombosis is frequently observed and medical treatment with aspirin or even anticoagulation is recommended; anti-inflammatory treatment may have to be discussed. 3.3.7.2.4.5 Giant Aneurysms

Giant aneurysms, as seen in adults, should not only be distinguished because of their size, but also as a group within the dissection category. They seem to constitute a specific type of mural failure (perhaps disease). Their frequency is higher in children. Giant-sized aneurysms are about four times more common in children than in adults. 3.3.7.2.5 Location

Recent reviews demonstrate that depending on the type of referral the most frequent location will in fact vary. This observation accounts for the wide range of numbers quoted in the literature and which did not discriminate amongst the various etiologies. In particular among infectious, immune and saccular aneurysms there is a clear preference for involvement of the anterior circulation, whereas the posterior circulation is predominantly in-

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volved by the dissections. The age profile of the referred children will also have an impact on the type of etiology faced and consequently the location of the aneurysms. The likelihood of the multiplicity of the lesions in a given child will also depend on the etiology of the aneurysm (Fig. 3.3.25). 3.3.7.3

Location of 112 aneurysms

other ICA 29%

ACA/AcoA 27%

Pearls intradural ICA 19%

3.3.7.3.1 Pial AV Shunt in Children

• • • • • • • •

Micro/Macro AVM Micro/macro AVF Multifocal CAMS Familial Proliferative angiopathy Hemorrhagic angiopathy False and induced AV shunts

3.3.7.3.2 Galenic Vascular Lesions in Children

• • • • •

Choroidal VGAM Mural VGAM VGAD Dural VGAV shunt Venous dilatation

3.3.7.3.3 Dural AV Shunt in Children

• • • • •

Sinus malformation High-flow lesions Multifocal “Adult” types Post-traumatic

3.3.7.3.5.2 Hydrodynamic Manifestations

• • • • • •

3.3.7.3.5 Intracranial AV Shunt in Children

Cardiac failure Pulmonary hypertension Renal dysfunction Hepatic insufficiency Coagulation disorders

Venous congestion Venous ischemia Hemorrhagic infarct Melting brain syndrome Arterial steal

3.3.7.3.5.4 Neurological Symptoms

• • • • •

3.3.7.3.5.1 Systemic Manifestations

Macrocrania Ventriculomegaly Hydrocephaly Tonsillar prolapse Melting brain syndrome Hydromyelia

3.3.7.3.5.3 Cerebral Manifestations

• • • • •

3.3.7.3.4 Intracranial AV Shunt in Children: In Utero Manifestations

• Congestive cardiac failure (CP > 200/min, ventricular extrasystoles, tricuspid insufficiency) • Macrocrania • Ventriculomegaly • Brain loss

VB system 12%

Fig. 3.3.25 Location of 112 intracranial pediatric aneurysms (Bicêtre hospital series)

• • • • •

MCA 13%

Mental retardation Epilepsy Deficit Hypertony Headaches

3.3.7.3.6 Familial Diseases

Seldom symptomatic in the pediatric age Arterial aneurysm (PKD, Chr16, Chr4, etc.) Pial arteriovenous shunts (HHT, Chr12, Chr9) Usually high-flow multifocal AVFs ED Chr2, NF1 Chr17: “spontaneous” AVFs, parachordal AVFs • Cavernomas Chr7: often multiple in the brain and the cord • BRBN Chr1, Chr9

3.3.7 Pediatric Vascular Lesions

3.3.7.3.7 Sporadic or “Primitive” Diseases

• Vein of Galen aneurysmal malformations (30% diagnosed in utero) • Dural sinus malformation (50% diagnosed in utero) • Pial arteriovenous shunts (cerebral or cord; 1.3% diagnosed in utero) • CAMS/SAMS (Bonnet–Dechaume–Blanc, Wyburn– Mason, Cobb)

• Single cavernoma • CVMS (Sturge–Weber) 3.3.7.3.8 Acquired or Secondary

• Dural arteriovenous shunt (juvenile and adult types)

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3.4 Infectious Disease M. Necmettin Pamir

3.4.1 Infection of the Scalp 3.4.1.1

Basics

• The layers of scalp are the Skin, Subcutaneous tissue, Galea aponeurotica, Loose connective tissue and the periosteum. 3.4.1.2

Aetiology/Epidemiology

• These lesions are mostly a complication of craniotomy incisions. Other factors are trauma, pin placements (halo or stereotactic frame), or cosmetic surgery for hair loss. • The scalp infection rate after craniotomy is 1–5%. Predisposing factors are long operating times, very tight closure of the skin, remnant of the necrotic tissues, penetration of the paranasal sinuses and decreased blood supply to the skin flap. • The responsible organisms are usually Staphylococcus aureus, Staphylococcus epidermidis, streptococci and Gram-negative bacilli. Anaerobic microorganisms can be found in traumatic lacerations. 3.4.1.3

Symptoms

• The main signs are tissue swelling, erythema, tenderness and local heat. • Systemic signs of infection such as fever and fatigue can be seen. If the infection spreads into the deep tissues such as bone and the intracranial space the clinical picture can be more serious. 3.4.1.4

Diagnostic Procedures

• The diagnosis mainly relies on physical examination. • Elevated white blood cell count and erythrocyte sedimentation rate can be found. • Plain radiographic films may show swollen tissue and additional osteomyelitis (Fig. 3.4.1). CT and MR are

Fig.3.4.1 Surgical wound infection complicated by osteomyelitis of the skull

seldomly used for diagnosis. They aid in ascertaining whether there is any intracranial component of the infection. 3.4.1.5

Therapy

• The superficial infections can be treated with anti biotics. • If there is a subcutaneous abcess, reopen the wound, drain the pus, take a culture of the pus, remove the necrotic tissues, clean the area with antiseptic solutions, place a drain and close the wound with monofilament nylon or wire. Close inspection of the infected area and antibiotherapy are mandatory. • Analgesics, antipiretics

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3.4.2 Osteomyelitis of the Skull 3.4.2.1

Aetiology/Epidemiology

• The infection of the calvarium is mainly due to craniotomy, trauma (compound depression fractures) or the spread of scalp infection. • Basal skull infections may develop due to infection of the paranasal air sinuses. • The most common pathogens are Staphylococcus and Streptococcus. Fungal infections, anaerobic micro-organisms, Gram-negative bacilli are rarely reported. • The rate of osteomyelitis in clean surgery is less than 1%. 3.4.2.2

Symptoms

• Pain, erythema and local increased heat over the infected bone. If there is an accompanying scalp abscess, pus may drain from the wound. • The systemic signs of infection can be found. 3.4.2.3

Diagnostic Procedures

• Postsurgical or post-traumatic acute osteomyelitis should be suspected in a patient with the abovementioned symptoms. Chronic osteomyelitis may only demonstrate slight swelling and pain. Osteomyelitis of the skull base may cause cranial nerve palsies.

Fig.3.4.2a,b Osteomyelitis of the skull

• Plain films: spotty areas of demineralisation, resorption of the bone flap. In chronic cases, oedema and swelling may become detectable on X-rays and this is called “Pott’s puffy tumor” (Fig.3.4.2). • CT: may show bony changes at an earlier stage. • MR: helpful in showing additional soft tissue changes. • Bone scintigrams: gallium-67 citrate accumulates in inflammatory tissues, and shows osteomyelitis. Technetium-99m methylene diphosphonate also detects osteomyelitis. 3.4.2.4

Therapy

• Removal of all infected and necrotic bone is mandatory. Cultures should be taken. • Antibiotic therapy should be given for at least 6weeks. • Hyperbaric oxygen therapy can be used. • Cranioplasty for the bone defect is performed 6–12months after completing antibiotic treatment. • Response to the treatment can be monitored with bone scintigraphy.

3.4.3 Epidural Abscess 3.4.3.1

Definition

• An abscess between the bone and the dura mater. The dura is a strong barrier to the spread of the abscess. These lesions are mostly well localised.

3.4.4 Subdural Empyema

3.4.3.2

Aetiology/Epidemiology

• This condition mostly accompanies osteomyelitis of the skull. • Aetiological factors are: craniotomy, trauma and paranasal air sinus infections. • Incidence in clean craniotomies is less than 1%. • The organisms responsible are Staphylococcus and Streptococcus. Gram-negative micro-organisms and anaerobics are rare. 3.4.3.3

Symptoms

• Systemic signs of infection, signs of the additional infections such as scalp infection and osteomyelitis. • Because of the strong barrier feature of the dura, symptoms and signs are mostly related to the mass effect of the abscess. 3.4.3.4

Diagnostic Procedures

• CT: hypodense epidural mass, may demonstrate contrast enhancement at the rim of the purulent mass. Small abcesses are sometimes not be visible on CT. • MR: demonstrates more anatomical details. Additional subdural empyema and cerebral infection can easily be detected.

3.4.4.2

• Subdural empyema constitutes 13–23% of the localised intracranial bacterial infections. • The most common predisposing factor for SDE is paranasal air sinus infections. In infants, SDE usually follows meningitis. SDE secondary to craniotomy or trauma is rare. Evacuation of chronic subdural haematoma may predispose to SDE. • Aerobic and anaerobic micro-organisms may be responsible for the infection. In SDE following meningitis in infants, the most common organisms have been Haemophilus influenzae and Streptococcus pneumoniae. 3.4.4.3

Therapy

• Remove the infected and devitalised bone, and drain the abscess. Place a drain and close the skin with nonabsorbable nylon suture. Do not open the dura unless there is an existing subdural empyema. • Culture for aerobic and aneorobic micro-organisms. Begin antibiotics and analgesics. • Subgaleal and epidural antibiotic irrigation and suction drain system may preserve the bone flap in some cases.

3.4.4.1

Definition

• A subdural empyema (SDE) is an infectious condition between the dura and the arachnoid membrane. Empyema refers to an infection within a pre-existing normal space.

Diagnostic Procedures

• Skull films may help to demonstrate predisposing factors such as paranasal air sinus infections (Fig.3.4.3). • CT may not show the thin collections at the subdural space. • MR is the preferable screening method. It shows the detailed spread of the pus and additional cerebral and cerebellar infection. • Lumbar puncture may be dangerous and adds little critical information. 3.4.4.5

3.4.4 Subdural Empyema

Symptoms

• Patients with SDE may have a more dramatic clinical picture. They are seriously ill and febrile. Headache and nuchal rigidity can be seen. Seizures can be seen in up to 60% of the patients. Hemiparesis, sensory deficits, hom*onymous hemianopsia and alterations in the mental state can be seen. • The reasons for this septic condition in these patients are cerebral venous thrombosis, oedema, cerebral venous infarct and small subcortical abscesses. SDE is more fulminant and fatal than epidural abscess. 3.4.4.4

3.4.3.5

Aetiology/Epidemiology

Therapy

• Acute SDE is treated with systemic antibiotics and burr holes. In the early stage of SDE, the purulent material flows freely and burr holes usually suffice. • If loculations are encountered and drainage is inadequate, then a craniotomy will be required. Drains can be used 24–48h postoperatively.

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Fig.3.4.3a–c Subdural empyema

3.4.5 Meningitis 3.4.5.1

Definition

• Meningitis is an acute, fulminating febrile illness caused by infection of the subarachnoid space. May be caused by bacteria, viruses or fungi. 3.4.5.2

Aetiology/Epidemiology

• Micro-organisms may reach the meninges and CSF by dissemination through the bloodstream, by retrograde propagation from the nasopharynx, or by direct spread from contiguous foci of infection. • The most common causative agents are: – In normal adults 15–50years: Neisseria meningitidis, Streptococcus pneumoniae – In normal adults >50years: Streptococcus pneumoniae, Neisseria meningiditis, Listeria monocytogenes and aerobic Gram-negative bacilli. – In old, debilitated or alcoholic patients: S. pneumoniae, enterococci, Listeria. – In immunocompromised patients fungi, tuberculosis and aseptic HIV meningitis may be seen in addition to those conditions found in adults. • In a post-neurosurgical setting or after craniospinal trauma: Staphylococcus aureus, enterobactericae, Pseudomonas and S. pneumoniae. • Shunt infection: foreign body provides microbes with a favorable site for colonisation while at the same time hampering host defences. Almost one-fourth of the shunt patients develop infection. Most shunt infections are caused by S. epidermidis and diphtheroids.

Other micro-organisms such as S. aureus, Pneumococcus, Haemophilus and Gram-negative bacilli can be the causative organisms. 3.4.5.3

Symptoms

• The classic triad is fever, headache and nuchal rigidity. • Photophobia, anorexia, nausea, vomiting, back pain and myalgias are frequently present and may be severe. • Focal neurological signs or altered mental status will indicate meningoencephalitis and is seen in 75% of the cases. Coma occurs in about 5–10% of cases, seizures in 20% and cranial nerve palsies in 5%. • Increased ICP is common: 90% have an opening pressure of >180mmH2O, and 20% have opening pressures of >400mmH2O. Herniation occurs in 1–8%. 3.4.5.4

Diagnostic Procedures and Treatment

• Blood cultures are drawn and antibiotic treatment started immediately. Antibiotics do not alter CSF examination within the first few hours. • Immediate CT to rule out mass effect is followed by emergency lumbar puncture. • Lumbar puncture will indicate a high progressive multifocal leukoencephalopathy (PML) count, increased protein (>45mg/dL) and decreased glucose (<40mg/ dL and/or CSF/serum glucose ratio of <0.4). Gram stain demonstrates micro-organisms in >60%, and CSF cultures are positive in >80%.

3.4.7 Encephalitis

3.4.6 Brain Abscess 3.4.6.1

Aetiology/Epidemiology

• Brain abscess may be caused by haematogenous spread (cardiac, pulmonary or dental foci, which are common in IV drug abusers), direct extension (from the temporal bone or paranasal sinus infections) or by penetrating injury (may also be post-surgical).

3.4.6.4

• Wide-spectrum antibiotics are the first line treatment. • Unresponsive cases are treated with aspiration + biopsy or surgical resection when necessary (open debridement is indicated when foreign material is present).

3.4.7 Encephalitis 3.4.7.1

3.4.6.2

Symptoms

Therapy

Definition

• Generalised signs of elevated intracranial pressure and focal neurological deficit. Rapid onset and progression.

• Parenchymal infection of the brain. May be acute or chronic • Commonly associated with meningitis (meningoencephalitis)

3.4.6.3

3.4.7.2

Diagnostic Procedures

• Pathology and CT imaging evolves through four phases. Early cerebritis (0–4days), late cerebritis (4– 10days), abscess (early capsule stage) and abscess (late capsule stage; Figs.3.4.4, 3.4.5). • Leukocytosis. • Lumbar puncture is rarely conclusive and carries the risk of herniation.

Aetiology/Epidemiology

• Acute cases are commonly caused by viral or toxic agents. • Acute encephalitis in immunocompetent adults is most commonly due to herpes simplex, which causes a fulminant, necrotising, haemorrhagic meningiencephalitis. It has a preference for the temporal lobe. • Other non-infectous acute causes include Reye’s syndrome and scute disseminated encephalomyelitis. • Various forms of chronic encephalitis may be encountered including progressive multifocal leukoencephalopathy (PML) in immunosuppressed adults or subacute sclerosing pan-encephalitis (SSPE) in children aged 5–12years. • It is a complication of the measles infection with long latent periods. 3.4.7.3

Symptoms

• Focal or diffuse neurological symptomatology occurs in addition to the febrile illness and meningeal involvement. The most common signs are aphasia, ataxia, hemiparesis, seizures and cranial nerve deficits. 3.4.7.4

Fig.3.4.4 Brain abscess

Diagnostic Procedures

• If not contraindicated because of elevated ICP, lumbar puncture reveals lymphocytic pleocytosis, slightly elevated protein and normal glucose. Steroids may blur the picture. PML strongly indicates a non-viral cause. Erythrocytes in the absence of a traumatic tap will indicate herpes simplex virus (HSV) encephalitis.

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Fig.3.4.5a–d Brain abscess

• PCR has 98% sensitivity and 94% specifity for HSV. Remains positive despite 1week of antiviral therapy. • MRI reveals focal changes in 90% of cases. • Brain biopsy is reserved for patients who have focal abnormality, a negative PCR study and continue to deteriorate despite antivial therapy. 3.4.7.5

Therapy

• Intravenous acyclovir is empirically started in suspected cases of viral encephalitis. • Supportive treatment with suppression of seizures and fever is initiated.

Selected Reading 1. Blomstedt GC (1992) Craniotomy infections. Neurosurg Clin N Am 3(2):375–385 2. Bernardini GL (2004) Diagnosis and management of brain abscess and subdural empyema. Curr Neurol Neurosci Rep 4(6):448–456 3. Levy RM (1994) Brain abscess and subdural empyema.Curr Opin Neurol 7(3):223–228 4. Van de Beek D, de Gans J, Tunkel AR, Wijdicks EF (2006) Community-acquired bacterial meningitis in adults. N Engl J Med 354(1):44–53 5. Morris A, Low DE (1999) Nosocomial bacterial meningitis, including central nervous system shunt infections. Infect Dis Clin North Am 13(3):735–750

3.4.7 Encephalitis

6. Tabas JA, Chambers HF (2002) Dexamethasone in adults with bacterial meningitis. N Engl J Med 347(20):1613–1615 7. BSAC Working Party Report (2000) The management of neurosurgical patients with postoperative bacterial or aseptic meningitis or external ventricular drain-associated ventriculitis. Br J Neurosurg 14 [Suppl 1]:7–12 8. BSAC Working Party Report (1994) Antimicrobial prophylaxis in neurosurgery and after head injury. Lancet 344:1547–1551 9. Barker FG (1994) Efficacy of prophylactic antibiotics for craniotomy: a meta-analysis. Neurosurgery 35 [Suppl 3]:484–490 10. Logan SA, MacMahon E (2008) Viral meningitis. BMJ 336(7634):36–40 11. BSAC Working Party Report (2000) The rational use of antibiotics in the treatment of brain abscess. Br J Neurosurg 14 [Suppl 6]:525–530

12. Bayston R, de Louvois J, Brown EM, Johnston RA, Lees P, Pople IK (2000) Use of antibiotics in penetrating craniocerebral injuries. Lancet 355:1813–1817 13. Adamo MA, Deshaies EM (2008) Emergency decompressive craniectomy for fulminating infectious encephalitis. J Neurosurg 108(1):174–176 14. Kimberlin DW (2007) Management of HSV encephalitis in adults and neonates: diagnosis, prognosis and treatment. Herpes 14(1):11–16 15. Steiner I, Budka H, Chaudhuri A, Koskiniemi M, Sainio K, Salonen O, Kennedy PG (2005) Viral encephalitis: a review of diagnostic methods and guidelines for management. Eur J Neurol 12(5):331–343 16. Von Stuckrad-Barre S, Klippel E, Foerch C, Lang JM, du Mesnil de Rochemont R, Sitzer M (2003) Hemicraniectomy as a successful treatment of mass effect in acute disseminated encephalomyelitis. Neurology 61(3):420–421

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3.5 Trauma

3.5.1 General Principles and Pathophysiology of Head Injuries

Jürgen Piek 3.5.1.1

Historical Perspective and Introduction

Neurosurgery began with the treatment of head injuries. Around the world we find skulls with healed trephinations, some of them several thousand years old (Fig.3.5.1). The treatment of patients with head injuries consisted mostly of war surgery performed by general surgeons until the end of World War II. Industrialisation and in particular the increase in motor-driven vehicles after World War II were accompanied by a rapid increase in head injuries. The neurosurgical community met that need. Shortly after World War II neurosurgeons specialised in trauma care and developed the first Intensive Care Units in the 1950s and early 1960s in various countries. They started to perform tracheostomies, recommended drugs to treat spasticity, and also started to cool patients with an acute midbrain syndrome and increased body temperature. Mechanical ventilators became more and more readily available in the 1960s in most hospitals and also central i. v. lines and gastric tubes to apply parenteral and enteral nutrition. This brought anaesthesiologists onto the scene as major players in the treatment and management of head trauma victims. Together with neurosurgeons they developed regimens for treatment. With the increasing number of patients and the spreading of ICUs in developed countries in conjunction with the limited neurosurgical resources, it was evident that neurosurgeons could not handle these patients alone. Figures for Germany indicate that neurosurgeons care for approximately 30% of all patients with severe head injuries, whereas patients with minor injuries are mainly looked after by staff from other disciplines. Computed tomography (which was introduced in the mid-1970s) has dramatically changed the treatment of traumatic brain injury (TBI). When this method became available it rendered defunct echosonography (Fig.3.5.2) and angiography (Fig.3.5.3) as well as woodpecker surgery with exploratory burr holes to detect an intracranial hae-

matoma. It also enabled neurosurgeons to detect intracranial haematomas before patients developed clinical signs of herniation and as such further improved outcome. Systematic research (both clinical and laboratory) has improved our knowledge and understanding of the dynamic processes within the brain that are initiated by the primary trauma. Laboratory research has led to the invention of devices and new drugs to monitor and treat our patients. Clinical research in conjunction with the increasing use of computers has resulted in large so-called Coma Data Banks, which help to identify patients at risk, to improve prognosis and to compare different treatment strategies. As a result of these developments, nowadays, unfortunately, novices (and sometimes even experienced neurosurgeons) tend to rely mainly on pictures and data instead of on clinical examination and judgement when treating patients with head injuries. They often forget that careful history-taking and clinical examination is still the basis for treatment. Using the fundamental rule “patient first – pictures second”, careful study of Fred Plum’s and Jerome Posner’s wonderful textbook Coma and Impaired Consciousness and assuming the personal attitude of the late J. Douglas

Fig. 3.5.1 Neolithic skull found in Mecklenburg-Vorpommern (Germany) with a parietal trephination performed approximately 2,400 years BC

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Fig. 3.5.2a,b Detection of a midline shift by echoencephalography in the 1960s (courtesy of Professor Collmann, Department of Neurosurgery, University of Würzburg, Germany). a Siemens electroencephalograph. b Displacement of the midline (M) due to a developing epidural haematoma

Fig. 3.5.3a,b Detection of an epidural vertex haematoma by cerebral angiography (single-shot, direct puncture of the carotid artery) in the 1970s. Note the displacement of the cerebral ves-

sels (red arrow) caused by the haematoma. No vessels are visible in the region of the haematoma. a Antero-posterior view. b Lateral view

3.5.1 General Principles and Pathophysiology of Head Injuries

Miller (1937–1995) to neurotrauma comprise the personal advice I would give to them! 3.5.1.2

Definitions, General Principles and Pathophysiology

3.5.1.2.1 Definitions

If a force from outside hits the head this force may result in various injuries possibly involving scalp, skull, dura, brain and their supplying vessels. This explains why in various papers different terms are used for such injuries. While some authors exclusively focus on “brain injuries” (i. e. trauma to the central nervous system), others use the term “head injury (HI)” to include injuries to the soft tissue, the skull, as well as to the facial fractures. If a patient has sustained a traumatic brain injury, this fact will alter his level of consciousness in some way. Level of consciousness is usually examined by applying the Glasgow Coma Scale (see later). As TBI is a dynamic process, definition of its severity is problematic. In accordance with most authors, a head injury is called “severe” if the worst GCS score within the first 48 h is between 3 and 8 points. Head injuries are called “moderate” with the worst GCS score of 9–12 points, and “mild” if the worst score is 13 or better. Together with the anatomical description of the structures involved (e. g. “moderate TBI with a left temporal epidural hematoma and a right zygomatic fracture”) this definition is usually sufficient to describe the injury.

Primary

Damage

Secondary

3.5.1.2.2 General Principles and Pathophysiology

Traumatic brain injury (TBI) is a very common disease in all countries with long-term, often life-long consequences for the patient involved. It is essential to understand that TBI is a dynamic process that is initiated by the initial trauma. This means that individual situations, particularly in the early period, can vary from minute to minute. The so-called “primary” damage happens at the scene of the accident and determines outcome in a large proportion of the patients. It is estimated that even in countries with a sophisticated rescue and emergency system like Germany, 30–50% of all patients with TBIs die at the scene of the accident or during transport to the hospital as a result of their primary damage. Primary brain damage cannot be treated, it can only be prevented. Therefore, neurosurgeons involved in neurotrauma care should also feel responsible for the prevention of TBI. “Secondary” injuries to the brain may have intracranial as well as extracranial causes (Fig.3.5.4). Avoidance and treatment of these secondary insults is the core of neurotrauma care. As a chapter like this cannot cover all aspects of treatment, it mainly focuses on the clinical examination, operative treatment and on some general aspects. For detailed information (in particular on pre-hospital treatment, treatment of brain oedema and raised intracranial pressure, general ICU treatment, as well as on rehabilitation) the reader should refer to the different textbooks mentioned in the suggested literature.

Damage

• Hemorrhagic contusion • Disruption of vessels • Disruption of nerve fibers

• Intracranial complications –Hematomas –Brain edema –ICP increase • Systemic insults –Hypoxia –Hypotension –Pneumonia –Septicemia –Coagulopathy

Not preventable/ Not treatable

Avoidable Treatable

Fig. 3.5.4 Pathophysiology of traumatic brain injuries: Primary damage vs secondary insults

251

3.5 Trauma

192

others/unknown 9

Suicide

936

Assault

3460

Fall 455

Sport/Recreation 44

Traffic unknown

778

Car/Truck 9

Motorbike - helmet

Motorbike + helmet

520

Bicycle - helmet 83

Bicycle + helmet

211

Pedestrian 0

500

1000

1500

2000

2500

3000

3500

4000

N= Fig. 3.5.5 Mechanism of head injuries in Germany (according to Rickels etal.) > 65

3.5.2 Epidemiology

17,7

27-64

Age

252

35,8

17-26

16,8

6-16

0-5

12,7

50 Percent

Fig. 3.5.6 Age distribution of head injuries in Germany (according to Rickels etal.)

none

26,9

Pelvis

3,4

Abdomen

2,6

Chest

7,2

Spine other

2,6

Cervical Spine

8,8

Maxillofacial

58,7

100

Percent

Fig. 3.5.7 Accompanying injuries in patients with head injuries (according to Rickels etal.)

There are no world-wide data on the epidemiology of head injuries as the incidence, the types of injury, and their causes vary widely from society to society and also over time. For the United States and European countries it is estimated that approximately 2% of the whole population are affected by TBI per year. Between 200 and 300 patients per 100,000 inhabitants are hospitalised every year for a traumatic brain injury. From a large population-based study on 6,783 patients with head injuries performed 2000 by Rickels etal. it can be calculated that in Germany 331 patients per 100,000 inhabitants per year suffer a head injury severe enough to be admitted to a hospital. (Patients dead at the scene of an accident are not included). According to these data, 90.9% of the injuries are mild, 3.9% moderate and 5.2% severe. Of the patients, 58.4% were male and 41.6% were female. In patients aged 16–35 years, however, men constituted two-thirds of all victims. Detailed data on age and mechanism are shown in Figs.3.5.5 and 3.5.6. Data on accompanying injuries are shown in Fig.3.5.7. From the data above and from a comparison with the older literature it is obvious that the epidemiology of the “typical” patient with a head injury has totally changed over the last few years, at least in central Europe, because of the introduction of various protective vehicle-related advice (use of helmets in motor-bikers, introduction of airbags, anti-lock braking systems, electronic stability programs). Falls account for more than 50% of our patients, shifting the age group to older patients, with all their accompanying internal diseases and problems for which the neurosurgeon has to be prepared.

3.5.3 Initial Assessment and Early Management

3.5.3 Initial Assessment and Early Management 3.5.3.1

Introduction

Care for patients with head injuries is a dynamic process starting at the scene of the accident. During the early stages of hospital care, the patient may require management in a variety of locations, including the emergency room (ER), the operating room (OR), the radiology department and the intensive care unit (ICU). In the later course of the disease transfer of the patient to a rehabilitation facility has to be organised. Additionally, the patient may require further neurosurgical operations (e. g. for the treatment of post-traumatic hydrocephalus, closure of skull defects), even decades after the trauma (e. g. to treat late infectious complications). This continuum of care has to be ensured by the neurosurgeon responsible for the trauma patient. 3.5.3.2

Initial Assessment of the Head Injured Patient

The main aim of patient care in the early stages of management should be to prevent or minimise the risk of secondary brain injuries and to assess the full extent of the injury. 3.5.3.2.1 Clinical History

The importance of ascertaining a complete history in a patient with acute head injury is extremely important, but is often overlooked. Eye-witness reports of the mechanism of injury and the initial level of consciousness are of critical importance. The same is true of reports from the ambulance crew and emergency doctors. The following items should be checked in a standardised fashion: • Past medical history (concomitant diseases, current medication) • Suspected influence of drugs/alcohol • Possible medical reason for the accident (e. g. seizure, heart attack, stroke) • Time, place, mechanism and speed of the accident • Use of airbags, seat-belts, crash-helmets etc. • Vital parameters at the scene and during transport • Neurological state (level of consciousness, pupillary response) at the scene and during transport • Treatment at the scene and during transport 3.5.3.2.2 Physical Examination

It is well known that secondary insults to the already injured brain dramatically increase mortality and morbid-

ity in head trauma victims. Therefore, the initial examination starts with checking and stabilising vital functions. Blood pressure should be kept normal and sufficient oxygenation has to be secured either by O2 insufflation in minor injuries or by intubation and ventilation in unconscious patients (GCS < 9 points). A careful head-to-toe examination should address the following points: • Inspection of the entire scalp (as scalp wounds may be hidden by blood-clotted hair) • Peri-orbital or retro-auricular bruising or haematomas (indicating the possibility of a basal skull fracture) • Rhinorrhoea or otorrhoea • Open injuries of the cranial vault with CSF leakage or cerebral debris • Gunshot wounds, stabbing, presence of foreign bodies (glass or metal splinters) • Maxillofacial injuries • Injuries to the eyes • General examination of the whole body (front and back!) to identify extra-cranial injuries • Breathing pattern (e. g. abnormal respiratory pattern indicating cerebral damage, diaphragmatic breathing indicating lower cervical spinal cord injury • Priapism in males may indicate lesions to the cervical spinal cord Due to the fact that up to 10% of all patients with severe head injuries may also have a spinal fracture all patients should be managed and treated accordingly during the whole examination until such a fracture has been ruled out by radiographic studies. Dangerous mechanisms are road-traffic accidents and falls from heights. 3.5.3.2.3 Neurological Examination

A detailed neurological examination is not necessary during the initial examination. A neurological “mini-exam” is carried out focussing on the level of consciousness and to note the presence or absence of focal or lateralising neurological signs. The level of consciousness is determined by applying the Glasgow Coma Scale Score (Table3.5.1). Cranial nerve deficits are examined by checking the pupils for symmetry, size and reaction to light (directly and indirectly) separately and in comparison to the opposite side, testing the corneal reflex and the brain-stem reflexes. Lateralising motor signs are tested by observing and testing the motor function independently for each limb and comparing it with that of the opposite side. The main cervical and lumbar deep tendon reflexes should be tested and compared, in order not to overlook peripheral nerve root injuries. A positive Babinski’s sign is caused by lesions of the pyramidal tract.

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Table 3.5.1 Glasgow Coma Scale score Eye opening (E)

Spontaneous To voice To pain None

4 points 3 points 2 points 1 point

Verbal response (V)

Oriented Confused Inappropriate words Incomprehensible sounds None

5 points 4 points 3 points 2 points 1 point

Best motor response (M)

Follows commands Localises pain Withdraws from pain Abnormal flexion Abnormal extension None

6 points 5 points 4 points 3 points 2 points 1 point

3.5.3.3

Early Management

3.5.3.3.1 Monitoring

Basic monitoring is indicated in all patients admitted to the hospital for a significant head injury. It includes: • 3-lead ECG in all patients • Pulse rate and arterial blood pressure (non-invasive) • Pulse oximetry • Capnography (ventilated patients) 3.5.3.3.2 Neurological Monitoring

Repeated neurological examinations have to be performed for clinical monitoring in all patients admitted. Additional technical monitoring includes measurement of intracranial pressure (ICP), mean arterial pressure (MAP) and cerebral perfusion pressure (CPP) in more severe head injuries (usually GCS < 9 points). In specialised units this basic monitoring can be complemented by advanced methods of intracranial monitoring, which may give further insights into cerebral perfusion, oxygenation and biochemistry (local CBF, transcranial Doppler, brain-tissue PO2, jugular venous oxygenation, microdialysis) and electrophysiology (evoked potentials, transcranial Doppler). For details, refer to specialist neurosurgical ICU textbooks.

patients a central venous catheter should be inserted after the first CT together with an arterial line. A nasogastric tube (oro-gastric tube in the presence of facial or fronto-basal injuries) is also inserted. Patients with severe injuries or multiple trauma also require a bladder catheter for the monitoring of urine excretion and temperature. 3.5.3.3.4 Laboratory Investigations

In all patients who are going to be admitted to the hospital for further treatment/observation, the following laboratory values should be obtained during the initial resuscitation phase: • Haemoglobin, haematocrit, leucocytes, platelets • Sodium, potassium, blood glucose • Coagulation parameters • Blood urea, creatinine • Liver enzymes • Pregnancy test (if appropriate) • Drug screening (if appropriate) Patients with moderate or severe injuries also require determination of arterial blood gases and cross-matching of at least 4 units of blood. 3.5.3.4

Imaging

3.5.3.3.3 Catheters and More

Two peripheral i. v. cannulae are usually appropriate during initial evaluation and resuscitation. In patients with moderate or severe injuries and in multiple trauma

3.5.3.4.1 Computed Tomography

Details of the scanning procedure and the various types of intracranial pathology that might be detected after head

3.5.4 Diagnostic Procedures

3.5.3.5

Fig. 3.5.8 Typical example of an anisocoria caused by an ipsilateral intracranial expanding haematoma

injuries are described in detail in Sect.3.5.4. In general, cranial CT should be obtained in: • All patients with a GCS of 12 and lower on admission (i. e. moderate or severe head injuries) • Patients with a GCS of 13–15 on admission (mild head injuries) if they present at least with one of the following risk factors: – Focal neurological symptoms and signs (hemiparesis, seizure, pupil inequality, other cranial nerve deficits) – Neurological deterioration – Alcohol or drug abuse/intoxication – Disturbances of blood coagulation (e. g. coumarins, aspirin) – Suspected penetrating injury – CSF leak – Age > 65years – High-speed accidents – Amnesia > 30min As it is well known that a large of number patients may develop delayed intracranial haematomas (Fig.3.5.8), the initial CT should routinely be repeated after 4–6h.

Classification

As a head injury is a dynamic process, from a practical point of view, the initial evaluation should guide further treatment and allow patients with head injuries to be classified according to: • Severity of the brain injury – Severe head injury (GCS score 3–8 points) – Moderate head injury (GCS score 9–12 points) – Minor head injury (GCS score 13–15 points) • Type of brain injury – Focal or diffuse – CT classification (refer to Sect.3.5.4) • Open or closed injury • Structures involved (skin, skull, brain, vessels, cranial nerves) 3.5.3.6

Treatment

3.5.3.6.1 Severe and Moderate Injuries

Every patient with a severe or moderate head injury and every patient requiring an intracranial operation should be observed and treated in an ICU (preferably in a specialised neurosurgical intensive care unit). For detailed information about the broad and complex subject of ICU treatment in head injuries the reader should refer to specialised ICU textbooks, as this section can only cover the more general aspects of head injury treatment. 3.5.3.6.2 Minor Head Injuries

There is a continuing debate as to which patient with a minor injury can be safely discharged and treated as an outpatient. Table3.5.2 describes the current algorithm at the author’s institution.

3.5.4 Diagnostic Procedures 3.5.3.4.2 Other Investigations

In order “to clear the spine”, the following radiographies should be obtained in any patient at risk (moderate/severe injuries; minor head injury if high-speed accident or clinically suspect): • C-Spine: antero-posterior; lateral; odontoid; oblique • T-Spine: antero-posterior; lateral • L-Spine: antero-posterior; lateral Multi-slice CT may be a substitute for these radiographs. In suspected multiple trauma, additional examinations are necessary, such as X-rays of the chest and pelvis (or multi-slice CT), and of the extremities, and abdominal ultrasound.

3.5.4.1

Computed Tomography

Computed tomography (CT) is the type of imaging that is the first choice in any head-injured patients in whom an intracranial lesion is clinically suspected. In Europe, CT scanners are available in all major trauma centres around the clock. The main advantages are their rapid imaging time, especially with the new generations of multi-slice CT scanners that allow scanning of the whole body of a multiple trauma victim in 1- to 3-mm slices within minutes. The other advantage over MRI scanners is that they can produce valuable images even in moving patients, which diminishes the need for sedation. It has also been

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Table 3.5.2 Algorithm for the treatment of patients with minor head injuries (GCS 13–15 on admission) GCS (admission)

History

CT findings

Procedure

3–8

Does not apply

Admit to ICU

9–12

Does not apply

Admit to ICU

13 and 14

Risk factors not present

Negative

Admit and observe on regular ward; repeat CT if clinical deterioration

13 and 14

Risk factors not present

Positive

Admit and observe on intermediate care unit; repeat CT after 4–6 hours or if clinical deterioration

13–15

Risk factor present

Negative

Admit and observe on intermediate care unit; repeat CT after 4–6 hours or if clinical deterioration

13–15

Risk factor present

Positive

Admit and observe on ICU; repeat CT after 4–6 hours or if clinical deterioration

15 Risk factors not present Loss of consciousness

Does not apply

Admit and observe on regular ward; do CT, if clinical deterioration

15 No loss of consciousness

Does not apply

Discharge, if observed homea

Risk factors not present

Patients with minor injuries who cannot be scanned (e. g. for technical reasons) should also be admitted and observed. Patients without sufficient supervision at home should also be admitted and observed. In patients who are discharged, a detailed instruction should be given to the patient’s relatives, together with an emergency telephone number

Table 3.5.3 Computed tomography classification of head injuries (Marshall etal., 1991, reproduced with permission) Category

Definition

Diffuse injury I

No visible intra-cranial pathology on CT scan

Diffuse injury II

Cisterns are present with midline shift 0–5mm, and/or lesion densities present No high or mixed density lesion > 25cc May include bone fragments/foreign bodies

Diffuse injury III (swelling)

Cisterns compressed or absent with midline shift 0–5mm No high or mixed density lesion > 25cc

Diffuse injury IV (shift)

Midline shift > 5mm No high or mixed density lesion > 25cc

Evacuated mass lesion

Any lesion surgically evacuated

Non-evacuated mass lesion

High or mixed density lesion > 25cc, not surgically evacuated

3.5.4 Diagnostic Procedures

demonstrated that the results obtained correlate closely with the clinical outcome of the patient. A practical CT classification of such injuries was given by Marshall in 1991 (Table3.5.3). Thus, CT has replaced skull radiography in most institutions as it does not only show skull fractures, intracranial air and foreign bodies (as plain radiographs do), but also show the parenchymal lesions of the brain itself, especially space-occupying haematomas requiring urgent evacuation. A special scanning protocol should be instituted in every individual centre and should be strictly adhered to in all cases without exception in order not to miss any clinically important lesions. At our institution we obtain 0.5mm axial slices from the foramen magnum up to the vertex angled parallel to the orbit-meatal line. The images are reconstructed and printed in various window algorithms for bone, soft tissue and blood. Intravenous contrast medium infusion is usually not indicated, but may be necessary if underlying diseases (example: head injury owing to a seizure caused by an intracranial tumour) or vascular lesions are suspected. Sometimes contrast enhancement may also be indicated to detect an isodense subacute or chronic subdural haematoma. It should also be kept in mind that a marked number of patients with head injuries may have additional injuries to their spine that should be ruled out with a standardised protocol.

The following sections describe the most common findings in patient with acute head injuries.

Fig. 3.5.9 Typical frontal and temporal location of cerebral contusions (arrowheads)

Fig. 3.5.10 Haemorrhagic contusion of the right temporal lobe (double arrowheads) with marked surrounding oedema (single arrowheads)

3.5.4.1.1 Parenchymal Injuries

Parenchymal brain injuries result from laceration of smaller intracranial vessels owing to shearing forces. From a clinical point of view they are classified as present vs not present, single vs multiple, and are described with regard to their size, their location and their mass effect. 3.5.4.1.1.1 Contusions

Cortical contusions are found if the accelerated–decelerated brain hits the inner side of the skull. As most patients sustain their injury while moving in forwards, most of these contusions are located within the brain parenchyma at the floor of the anterior or the middle skull-base, resulting in contusional lesions of the frontal and the temporal lobe surface. In some cases additional contusions can be detected on the opposite side to that of the original impact (coup–contre coup lesions). Contusions are often bilateral and multiple (Fig. 3.5.9). They present as focal cortical hyperdense lesions. In some (older) cases they are accompanied by surrounding local oedema (Fig.3.5.10). Usually, initial CT does not show the complete extent of the injury, as these contusions may “grow” (Figs. 3.5.11) within the few next hours or days (in up to 30% of all cases). Growing contusions are particularly

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Fig.3.5.11a–c “Growing” bifrontal contusions in a 47-year-old heavy drinker. The date of the examinations is indicated on the images

observed in patients with disturbances of blood coagulation. If a patient shows such a contusion on the first CT, it is therefore advisable to repeat this imaging procedure within the next 4–8h or whenever clinical deterioration (drop in GCS score, new papillary abnormalities, ICP rise) occurs. 3.5.4.1.1.2 Diffuse Axonal Injuries

Diffuse axonal injuries (DAI; synonym – diffuse white matter shearing injuries) result from severe shear-strain forces during high-speed accidents. Clinically, the patients present in deep coma with midbrain or brain-stem symp-

toms. Most injuries occur along the midline with small punctual lesions in the deep lobar white matter, the corpus callosum, and the dorso-lateral brain stem (Fig. 3.5.12). In some cases, only small amounts of sedimented blood in one of the lateral ventricles caused by rupture of its ependyma will be visible on the CT, although without therapeutic consequences an additional MRI procedure (see later) will reveal the full extent of the injury. 3.5.4.1.1.3 Subcortical Grey Matter Injuries

Subcortical grey matter injuries (Fig.3.5.13) are occasionally (3–5%) found in the basal ganglia and the thalami.

3.5.4 Diagnostic Procedures

Fig. 3.5.12 Computed tomography examination in diffuse axonal injury. Numerous haemorrhagic shearing injuries (arrowheads) are found along the midline as well as a right frontotemporal epidural haematoma (EDH)

Fig. 3.5.13 Typical thalamic haemorrhage (arrowhead) in a younger patient admitted in a deep coma (GCS 4)

They are usually associated with a poor prognosis. The postulated mechanism is a disruption of small arteries in this region by shearing forces. 3.5.4.1.1.4 Brain-Stem Injuries

Brain-stem injuries are best detected on MRI as CT will only show approximately 10% of these lesions. These severe injuries are usually observed in conjunction with severe diffuse axonal injuries. Isolated brain-stem injuries are found in less than 1% of all cases of severe head injuries (Fig. 3.5.14). They must be differentiated from secondary brain-stem haemorrhages due to prolonged transtentorial herniation. 3.5.4.1.2 Extra-Axial Haematomas 3.5.4.1.2.1 Epidural Haematoma

See Sect.3.5.9.1. Fig. 3.5.14 Isolated brain-stem haemorrhage (arrowhead) in a 12-year-old girl admitted with a GCS 3. Note: brain-stem injuries are best diagnosed by MRI

3.5.4.1.2.2 Acute Subdural Haematoma

See Sect.3.5.9.2.

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Fig. 3.5.15 Marked pneumoencephalus in an older patient with a fronto-basal injury

Fig. 3.5.16 Subfalcine herniation (single arrowhead) causing hydrocephalic dilatation of the contralateral ventricle (double arrowheads) caused by a large acute subdural haematoma (ASDH)

3.5.4.1.2.3 Traumatic Intracerebral Haematoma

Expanding supratentorial mass lesions initially cause obliteration of the ipsilateral cortical sulci followed by compression of the ipsilateral ventricle and subfalcine herniation. As the mass effect continues transtentorial herniation occurs followed by herniation of the cerebellar tonsils resulting in brain death. All these mass effects can be demonstrated on CT.

See Sect.3.5.9.3.

3.5.4.1.3 Traumatic Pneumoencephalus

The normal intracranial compartment does not contain air. The presence of air on the initial CT within the brain, the ventricles or the subdural/epidural space, therefore, indicates communication of the intracranial compartment with the paranasal sinuses, the mastoid, or direct communication with the external environment (Fig. 3.5.15). CSF fistulas are frequently found as a result of this type of injury. Small amounts of intracranial air will usually be resorbed and will disappear on the follow-up CT. Acute tension pneumoencephalus, however, is an emergency situation resulting from a valve gear mechanism where more and more endonasal air is entrapped via a fronto-basal lesion with every breath of the patient. 3.5.4.1.4 Secondary Effects of Head Injuries 3.5.4.1.4.1 Brain Herniations

Displacement of the brain caused by an expanding mass results in typical CT findings that should be known to every neurosurgeon involved in neurotrauma care.

3.5.4.1.4.1.1 Subfalcine Herniation

Subfalcine herniation (Fig.3.5.16) is caused by a supratentorial mass displacing the cingulated gyrus beneath the falx cerebri. In severe cases, subfalcine herniation may lead to contralateral entrapment of the lateral ventricle and subsequent hydrocephalus on this side. If the subfalcine herniation persists, ipsilateral entrapment of the anterior cerebral artery may result in infarction. 3.5.4.1.4.1.2 Descending Transtentorial or Uncal Herniation

Descending transtentorial or uncal herniation (Fig. 3.5.17) results from displacement of the mediobasal temporal lobe (uncus, parahippocampal gyrus) in the medial and inferior direction. Typical CT findings are obliteration of the ipsilateral perimesencephalic cistern and compression of the midbrain. In severe cases, haemorrhagic infarctions of the midbrain itself may result from this type of herniation.

3.5.4 Diagnostic Procedures

3.5.4.1.4.1.3 Tonsillar Herniation

Tonsillar herniation (Fig. 3.5.18) results either from an expanding infratentorial mass or from prolonged transtentorial herniation. The cerebellar tonsils are displaced downwards into the foramen magnum. Obstructive hydrocephalus may accompany these findings. 3.5.4.1.4.2 Diffuse Supratentorial Brain Swelling

Diffuse supratentorial brain swelling (Fig. 3.5.19) can quite often be found in patients with severe injuries, especially in younger patients. Loss of the contour of the cerebral sulci, compression of the Sylvian fissures and the third ventricle, and obliteration of the basal cistern indicate high intracranial pressure. The whole supratentorial brain appears hypodense compared with the tentorium and the cerebellar hemispheres. The white–gray matter interface is usually lost. This finding may result either from diffuse injuries, accompanying hypoxia, or a combination of both. 3.5.4.1.4.3 Hydrocephalus

Fig. 3.5.17 Transtentorial herniation of the medio-basal temporal lobe caused by a large acute subdural haematoma (ASDH)

Communicating hydrocephalus is a frequent finding in severe head injuries. Acute, obstructive hydrocephalus (Fig.3.5.20), however, is a very rare finding and is usually observed if a mass (e. g. intraventricular blood clot) blocks CSF outflow from the ventricles above.

Fig. 3.5.18 Typical CT of a patient with tonsillar herniation (single arrowhead) and brain-stem compression (double arrowheads)

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Fig. 3.5.19 Diffuse supratentorial brain swelling in a young child. Note especially the hypodense aspect of the supratentorial parts of the brain compared with the tentorium and the infratentorial space

Fig. 3.5.20 Acute obstructive hydrocephalus in a young child (same case as in Fig.3.5.4.11). The patient had developed this complication within 6h of the first CT (Fig.3.5.4.11)

3.5.4.2

3.5.4.3

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) has several disadvantages and advantages compared with CT in the acute trauma setting. On the one hand, it is more sensitive in detecting small extra-axial and non-haemorrhagic lesions, especially in the deeper parts of the brain. On the other hand, factors like the need for non-magnetic monitoring equipment, its sensitivity to the patient’s motion and its longer scanning time limit its use in the acute care of a head trauma victim. At our institution we use additional MRI if the clinical picture is not fully explained by the CT obtained and in all cases in which diffuse axonal injuries are suspected. With the rapid development of high magnetic field scanners, the introduction of new scanning techniques and the shortening of the examination time it is certain that its role in neurotrauma will have to be re-defined during the coming years. The examples in Figs.3.5.21–3.5.26 show typical indications and examinations of patients with various posttraumatic pathological conditions.

Cerebral Angiography

Cerebral angiography is rarely indicated in the acute examination of a head injury patient. It should, however, be kept in mind that in the absence of a CT scanner or in an emergency situation percutaneous injection of a contrast medium into the common carotid artery followed by single-shot antero-posterior radiography will usually show larger space-occupying extracranial haematomas in typical locations. Injuries to cerebral vessels (dissections, carotid-cavernosus fistulas; Fig.3.5.27) may also be demonstrated by cerebral angiography, although CT or MRI angiography has already replaced it in most cases. 3.5.4.4

Skull Radiography

There is a continuing debate – particularly in patients with minor trauma – whether skull radiography should be obtained as the first diagnostic tool in head injuries. Although it is well known that the presence of a skull

3.5.4 Diagnostic Procedures

Fig. 3.5.21 Magnetic resonance imaging in a patient with subacute epidural haematoma (arrowhead)

Fig. 3.5.22 Magnetic resonance imaging in a patient with chronic subdural haematoma (arrowheads)

Fig. 3.5.23 a CT and b MRI images of a patient with a hypodense right temporal contusion (arrowheads)

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Fig. 3.5.24 a CT and b MRI images of a patient with a post-traumatic basal ganglia haemorrhage (arrowhead)

3.5.4 Diagnostic Procedures

Fig. 3.5.25 a CT and b see next page

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3.5 Trauma

Fig. 3.5.25 (continued) b MRI images in a case of diffuse axonal injury. The initial CT only demonstrates some blood within the third ventricle and on the tentorium. The full extent of the cerebral damage is revealed by the corresponding MRI. These images show shearing lesions to the frontoparietal cortex (1), the dorsal corpus callosum (2), the dorsal right thalamus (3), both temporo-mesial lobes (4), the vermis (5), and the left dorso-lateral brain-stem (6)

3.5.4 Diagnostic Procedures

Fig. 3.5.26 a Follow-up CT of a young boy with an initial GCS score of 15 on admission who deteriorated 2days after the trauma. Marked infarcts to both cerebellar hemispheres explain the

clinical picture. b MRI angiography demonstrates the absence of the left vertebral artery with some irregularities in the upper basilar artery (dissection of the vertebral artery)

Fig. 3.5.27a,b Cerebral angiography in a patient with a carotid-cavernosus fistula (arrowhead) a pre- and b post-embolisation (radiologist: Dr. Jens Kröger)

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fracture dramatically increases the risk of harbouring an intracranial haematoma, we have abandoned plain radiographs and perform CT instead. The indication for CT as the initial examination follows generally accepted rules in neurotrauma care and is shown in Table3.5.4.

3.5.5 General Principles of Treatment 3.5.5.1

Minor and Moderate Injuries

The main aim of treating patients with minor and moderate injuries is to prevent secondary insults to the injured brain. Anticipation of such insults and careful observation by experienced staff are the key-points during the early course. The current policy at our department is to follow patients with minor injuries and normal CT on the regular ward. Patients with moderate injuries or patients with minor injuries and abnormal CT are best observed on an intermediate care unit for at least 8–12 h. Vital signs, pupils and GCS score should be checked regularly (at our institution: patients with minor injuries and normal CT every 2h; patients with moderate injuries or patients with abnormal CT at least every hour). Any abnormal CT scan should be repeated within 4–6h in order not to overlook a developing intracranial haematoma. Any drop in the GCS score of 2 or more points or any change in pupil reaction should also prompt follow-up CT. 3.5.5.2

Severe Injuries

3.5.5.2.1 General Remarks

Patients with severe injuries should be treated on a specialised neuro-intensive care unit. As the general principles of ICU treatment of patients with severe injuries are extensively discussed in Sect.3.5.1, only some aspects should be mentioned in this section. Virtually any medical complication can occur during the post-traumatic course of a patient with a severe head injury. The most frequent medical complications include disturbances of serum electrolytes with an estimated rate of 60%, pneumonia (40%), disturbances of blood coagulation (18%) and septicaemia (10%). Hypotension can occur during the pre-hospital phase (29%) and in hospital (21%). However, only some of these events are independent predictors of a negative outcome in this patient group. It has been estimated that the elimination of hypotension only can reduce the unfavourable outcome in patients with severe head injuries by 9.3%. The corresponding figures for pneumonia are 2.9%, for coagulopathy 3.1% and for septicaemia 1.5%.

Table 3.5.4 Indications for CT in patients with minor head injuries (GCS 13–15) at our institution All patients with a GCS of 12 and lower on admission (i. e. moderate or severe head injuries) Patients with a GCS of 13–15 on admission (mild head injuries) if they present with at least one of the following risk factors: – Focal neurological symptoms and signs (hemiparesis, seizure, pupil inequality, other cranial nerve deficits) – Neurological deterioration – Alcohol or drug abuse/intoxication – Disturbances of blood coagulation (e. g. coumarins, aspirin) – Suspected penetrating injury – CSF leak – Age > 65years – High-speed accidents – Amnesia > 30min

Therefore, ICU treatment needs to focus on the prevention and aggressive treatment of these extracranial events. 3.5.5.2.2 Circulation and Oxygenation

Adequate oxygenation needs to be ensured by early intubation and ventilation. Peripheral oxygenation of the patient should be monitored continuously and blood gases should be checked regularly. Although the exact threshold for arterial oxygenation is not known, SaO2 should be maintained at > 90%. Blood pressure should be measured via an arterial line. Any hypotension (defined as systolic blood pressure < 90 mmHg) must be avoided if possible or corrected. If intracranial pressure (ICP) is monitored, the cerebral perfusion pressure (CPP) calculated should not be lower than 60mmHg. 3.5.5.2.3 Prevention of Infection

Prophylactic administration of antibiotics can be used in order to reduce the risk of pneumonia. This does not, however, change the length of stay or mortality. Early tracheostomy should be performed to reduce the number of ventilation days. Routine exchange of intraventricular catheters will not reduce the incidence of meningitis. Whether special catheters covered with silver or antibiotics will do so has to be proven yet.

3.5.6 Skull Fractures and Open Injuries

3.5.5.2.4 Prophylaxis of Deep Vein Thrombosis

Graduated compression stockings combined with regular physical therapy are highly recommended. The administration of low molecular weight heparin or low unfractionated heparin (higher incidence of heparin-induced thrombocytopaenia compared with low molecular weight heparin) may lower the incidence of deep vein thrombosis, but increase the incidence of intracranial haemorrhage. Therefore, the risks and benefits of this prophylaxis have to be calculated. 3.5.5.2.5 Nutrition

Even sedated patients with severe head injuries will have a resting energy expenditure of 120–160% compared with the normal level. Caused by severe catabolism, even patients with isolated injuries will lose up to 20–30 g of nitrogen per day during the first week. This must be matched by artificial nutrition. Full nutritional replacement should therefore be achieved within the first week after trauma. As these patients tend to develop hyperglycaemia with nutritional support one has to be extremely cautious not to overload patients with glucose calories. Blood glucose levels should therefore be kept normal as hyperglycaemia may worsen outcome in this patient group. Until now it has not been proven which kind of nutritional support (enteral vs parenteral) is superior. 3.5.5.2.6 Intracranial Pressure Monitoring: Indications, Monitoring Technique, Thresholds for Intervention

Intracranial pressure should be monitored in all salvageable patients with severe head injuries. This is especially true of patients in whom the initial CT shows any sign of raised intracranial pressure (absent or compressed subarachnoid spaces, compressed ventricles and basal cisterns) and in patients in whom the CT shows a midline shift or contusions. Ventricular catheters connected to an external transducer are still the gold standard for monitoring ICP. They are cheap, reliable, can be re-calibrated in situ, and allow withdrawal of CSF to lower increased ICP. The risks of intracranial haemorrhages caused by puncture and their higher infection rate compared with other devices have to be taken into account. Parenchymal devices are as accurate, but more expensive and do not allow re-calibration in situ. Epidural, subdural and subarachnoid devices are less accurate. There is no generally accepted upper threshold for any therapeutic intervention to lower increased ICP. Most studies, however, suggest that an ICP of higher than 20– 25mmHg should be treated. If CPP is calculated it should be maintained at at least 50–60 mmHg. The attempt to

Table 3.5.5 Algorithm for treatment of raised intracranial pressure Basic therapy – Keep normal milieu interieur • Glucose • Electrolytes • Osmolarity • Body temperature – Mild hyperventilation (paCO2 32–35mmHg) CSF drainage (if ventricular drain) Mannitol (0.3–1.25g/kg body weight) Second tier therapies – Decompressive (hemi)craniectomy – Forced hyperventilation (paCO2 28–32mmHg) – Tris-hydroxymethyl aminomethane (THAM) – Barbiturates – Hypothermia

increase CPP to > 70 mmHg may adversely influence outcome owing to a higher rate of patients with acquired respiratory distress syndrome. As a textbook like this cannot extensively cover all aspects of the conservative treatment of raised ICP, advanced neurological monitoring and general ICU treatment, the reader should refer to specialist ICU textbooks and published guidelines (see Selected Reading). A useful algorithm for the treatment of raised ICP is shown in Table3.5.5. The different treatment techniques should be performed in a stepwise fashion after having excluded an operable mass as the underlying cause by CT. Treatment thresholds at our institution are ICP > 25mmHg and CPP < 60 mmHg (for further details refer to specialist ICU textbooks).

3.5.6 Skull Fractures and Open Injuries 3.5.6.1

Linear Fractures

Less than 1% of all patients admitted with a minor head injury and a GCS score of 15, but 75% of all patients dying from a head injury have a skull fracture. Most of these fractures are linear (Fig.3.5.28). It must, however,