Neurology: A Queen Square Textbook

Neurology A Queen Square Textbook Neurology: A Queen Square Textbook Edited by Charles Clarke, Robin Howard, Martin Ro...

Author: Charles Clarke | Robin Howard | Martin Rossor | Simon D. Shorvon (Editors)

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Neurology A Queen Square Textbook

Neurology: A Queen Square Textbook Edited by Charles Clarke, Robin Howard, Martin Rossor and Simon Shorvon © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-13443-9

Whilst every effort has been made in the preparation of this book to ensure that the details given are correct, it is possible that errors have been overlooked (for instance in pharmaceutical or pharmacokinetic data). The reader is advised to refer to published information from the pharmaceutical companies and other reference works to check accuracy. For figures, tables and other previously published data, every effort has also been made to contact relevant copyright holders but if any have been inadvertently overlooked, the publishers will be pleased to make the necessary arrangements at the earliest opportunity.

Neurology A Queen Square Textbook E D I TE D B Y

CHARLES CLARKE RO B I N HOWA RD National Hospital for Neurology & Neurosurgery University College London Hospitals NHS Foundation Trust Queen Square, London WC1

MART IN ROSS OR SI MO N S HORVON Institute of Neurology, University College London Queen Square, London WC1

FOREWORD BY PROFESSOR RO GER LEMON Institute of Neurology, University College London

A John Wiley & Sons, Ltd., Publication

This edition first published 2009, © 2009 by Blackwell Publishing Ltd Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing program has been merged with Wiley’s global Scientific, Technical and Medical business to form Wiley-Blackwell. Registered office: John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 111 River Street, Hoboken, NJ 07030-5774, USA For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley. com/wiley-blackwell The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by physicians for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data Neurology : a Queen Square textbook / edited by Charles Clarke . . . [et al.]. – 1st ed. p. ; cm. Includes bibliographical references and index. ISBN 978-1-4051-3443-9 (alk. paper) 1. Nervous system–Diseases–Textbooks. 2. Neurology–Textbooks. I. Clarke, Charles (Charles R. A.) II. National Hospital for Neurology and Neurosurgery (London, England) III. Institute of Neurology, Queen Square. [DNLM: 1. Nervous System Diseases. 2. Neurology. WL 140 N492687 2009] RC346.N44 2009 616.8–dc22 2008015538 ISBN: 978-1-4051-3443-9 A catalogue record for this book is available from the British Library. Set in 9.25/12pt Minion by SNP Best-set Typesetter Ltd., Hong Kong Printed and bound in Singapore by COS Printers Pte Ltd First published 2009 1 2009

Contents

Editorial Team, vii Beginnings, xi Foreword, xiii Preface, xv Acknowledgements, xvi 1 Neurology Worldwide: the Burden of Neurological Disease, 1 Simon Shorvon 2 Nervous System Structure and Function, 13 Charles Clarke, Roger Lemon 3 The Language of Neurology: Symptoms, Signs and Basic Investigations, 75 Charles Clarke, Richard Frackowiak, Robin Howard, Martin Rossor, Simon Shorvon 4 Stroke and Cerebrovascular Diseases, 109 Nicholas Losseff, Martin Brown, Joan Grieve 5 Movement Disorders, 155 Niall Quinn, Kailash Bhatia, Peter Brown, Carla Cordivari, Marwan Hariz, Andrew Lees, Patricia Limousin, Mary Robertson, Anette Schrag, Sarah Tabrizi 6 Epilepsy and Related Disorders, 189 Simon Shorvon, John Duncan, Matthias Koepp, Josemir Sander, Shelagh Smith, Matthew Walker 7 Cognitive Impairment and Dementia, 245 Martin Rossor, John Collinge, Nick Fox, Robin Howard, Giovanna Mallucci, Catherine Mummery, Jason Warren 8 Infection in the Nervous System, 289 Robin Howard, Hadi Manji 9 Nerve and Muscle Disease, 337 Michael Lunn, Michael Hanna, Robin Howard, Matthew Parton, Mary Reilly

10 Multiple Sclerosis and Demyelinating Diseases, 411 Siobhan Leary, Gavin Giovannoni, Robin Howard, David Miller, Alan Thompson 11 Headache, 449 Peter Goadsby 12 Cranial Nerve Disorders, 465 Paul Jarman, Jeremy Chataway, Charles Clarke, Robin Howard 13 Neuro-Ophthalmology, 489 Gordon Plant, James Acheson, Charles Clarke, Elizabeth Graham, Robin Howard, Simon Shorvon 14 Neuro-Otology: Problems of Dizziness, Balance and Hearing, 533 Rosalyn Davies, Linda Luxon, Doris-Eva Bamiou, Simon Shorvon 15 Spinal Cord Disorders, 585 Simon Farmer, Adrian Casey, David Choi, Robin Howard, Geoffrey Raisman 16 Cerebellar Ataxias and Related Conditions, 629 Nicholas Wood 17 Restorative and Rehabilitation Neurology, 645 Richard Greenwood, Jon Marsden, Diane Playford, Valerie Stevenson, Nick Ward 18 Toxic, Metabolic and Physical Insults to the Nervous System and Inborn Errors of Metabolism, 675 Robin Howard, Robin Lachmann, Philip Lee, Alexander Leff 19 Disorders of Consciousness, Intensive Care Neurology and Sleep, 723 Robin Howard, Nicholas Hirsch, Neil Kitchen, Dimitri Kullmann, Matthew Walker 20 Neuro-Oncology, 771 Jeremy Rees, Sebastian Brandner, Robin Howard, Rolf Jäger, Susan Short, David Thomas, Emma Townsley, Gelareh Zadeh

v

Contents 21 Psychiatry and Neurology, 823 Michael Trimble 22 Pain, 847 Geoffrey Schott 23 Autonomic Dysfunction, 871 Christopher Mathias 24 Uro-Neurology, 893 Clare Fowler, Sohier Elneil

vi

25 Systemic Conditions and Neurology, 913 David Werring, Robin Howard, Alexander Leff, Simon Shorvon Index, 945 The colour plate section can be found facing p. 464

Editorial Team

Principal editors Dr Charles Clarke

International regional editors FRCP

Consultant Neurologist National Hospital for Neurology & Neurosurgery

Dr Robin Howard

PhD FRCP


Professor Martin Rossor

MD FRCP

FMedSci

Professor of Clinical Neurology Head, Division of Clinical Neurology Director, Dementia Research Centre Institute of Neurology

Professor Frederick Andermann

Professor Sebastian Brandner

OC MD FRCP(C)

FRCPath

Professor of Neurology & Paediatrics McGill University Montreal Canada

Professor of Neuropathology Head, Division of Neuropathology Institute of Neurology

Mr Neil Kitchen Dr Nadir Bharucha

MD FRCP FRCP(C)

Professor of Neurology Bombay Hospital Institute of Medical Sciences Head, Department of Neuro-Epidemiology Medical Research Centre Bombay Hospital, India

Professor Raymond Cheung Professor Simon Shorvon

MD FRCP

Professor of Clinical Neurology Institute of Neurology & Clinical Subdean University College London

Specialist advisory editors MD

MD FRCS (SN)

Consultant Neurosurgeon Head, Division of Neurosurgery Institute of Neurology

Professor Martin Koltzenburg

PhD

MD

Professor of Neurophysiology Head, Division of Neurophysiology Institute of Neurology

MD

PhD FRCP FAAN

Dr Nicholas Murray

Professor of Neuroscience & Neurology Director, Acute Stroke Services Department of Medicine University of Hong Kong, China

Consultant in Clinical Neurophysiology National Hospital for Neurology & Neurosurgery

FRCP

Professor Tarek Yousry Professor Peter Kaplan

FRCP

Professor of Neurology Johns Hopkins University School of Medicine Baltimore, USA

Professor Jürg Kesselring

Dr. med.

Habil FRCR

Professor of Neuroradiology Head, Division of Neuroradiology & Neurophysics Institute of Neurology

MD

Head, Department of Neurology & Neuro-Rehabilitation The Rehabilitation Centre Valens, Switzerland

Professor Philip Thompson

PhD

FRACP

Professor of Neurology University Department of Medicine University of Adelaide & Department of Neurology Royal Adelaide Hospital, Australia

vii

Editorial Team

Professor John Collinge

Authors Mr James Acheson

MRCP(UK) FRCS

FRCOphth

Consultant Neuro-Ophthalmologist National Hospital for Neurology & Neurosurgery

Dr Doris-Eva Bamiou

MD PhD

Consultant Audiovestibular Physician National Hospital for Neurology & Neurosurgery

Professor of Clinical Neurology Institute of Neurology

Professor Sebastian Brandner

MD

Professor of Clinical Neurology Head, Department of Neurodegenerative Disease & Director, MRC Prion Unit Institute of Neurology

Reader in Clinical Neuroimmunology Institute of Neurology & Professor of Neurology Barts & The London School of Medicine & Dentistry

Dr Carla Cordivari

Professor Peter Goadsby

MD FRCP

Consultant in Clinical Neurophysiology National Hospital for Neurology & Neurosurgery PhD FRCP

Consultant Audiovestibular Physician National Hospital for Neurology & Neurosurgery

Professor John Duncan FMedSci

Professor of Neuropathology Head, Division of Neuropathology Institute of Neurology

Professor of Clinical Neurology Institute of Neurology & Medical Director, National Society for Epilepsy, Chalfont

MD FRCP

Professor of Stroke Medicine Institute of Neurology

Professor Peter Brown

MD FRCP

Professor of Clinical Neurology Head, Sobell Department of Motor Neuroscience & Movement Disorders Institute of Neurology

Mr Adrian Casey

Miss Sohier Elneil

MD PhD

FRACP FRCP

Professor of Clinical Neurology Institute of Neurology & Professor of Neurology University of California, San Francisco

Dr Elizabeth Graham

FRCOphth FRCP

DO

Consultant Medical Ophthalmologist National Hospital for Neurology & Neurosurgery

DM FRCP

FRCPath

Professor Martin Brown

PhD FRCP

FRCPath

Dr Rosalyn Davies Professor Kailash Bhatia MD DM FRCP

Dr Gavin Giovannoni

CBE MD

FRCP FRS

Dr Richard Greenwood

MD FRCP


PhD MRCOG

Consultant in Urogynaecology & Uro-Neurology National Hospital for Neurology & Neurosurgery

Miss Joan Grieve

Dr Simon Farmer

Professor Michael Hanna

MD FRCS (SN)

Consultant Neurosurgeon National Hospital for Neurology & Neurosurgery

PhD FRCP


MD FRCP

Professor of Clinical Neurology Director, MRC Centre for Neuromuscular Disease Institute of Neurology

FRCS(SN)

Consultant Spinal Neurosurgeon National Hospital for Neurology & Neurosurgery

Professor Clare Fowler

Dr Jeremy Chataway

PhD FRCP

Professor Nick Fox MD FRCP

Professor of Functional Neurosurgery Institute of Neurology



Dr Nicholas Hirsch

FRCP

Professor Richard Frackowiak Mr David Choi PhD

FRCS (SN)


Dr Charles Clarke

FRCP


viii

Professor Marwan Hariz

Professor of Uro-Neurology Institute of Neurology

DSc FRCP FMedSci

Professor of Cognitive Neurology Institute of Neurology & Vice-Provost (Special Projects) University College London

MD PhD

FRCS(Ed)

MD

FRCA FRCP

Consultant Neuroanaesthetist National Hospital for Neurology & Neurosurgery

Dr Robin Howard

PhD FRCP


Editorial Team

Dr Rolf Jäger

Dr Patricia Limousin

MD FRCR

MD PhD

Reader in Neuroradiology Institute of Neurology

Reader in Clinical Neurology Institute of Neurology

Dr Paul Jarman

Dr Nicholas Losseff

PhD FRCP

MD FRCP


Mr Neil Kitchen

Dr Michael Lunn

MD FRCS (SN)

Professor Matthias Koepp

MD PhD


Professor Dimitri Kullmann

DPhil

FRCP FMedSci

Professor of Clinical Neurology Head, Department of Clinical & Experimental Epilepsy Institute of Neurology

Dr Robin Lachmann

Dr Siobhan Leary

MD FRCP FRCOphth


PhD MRCP(UK)

Dr Diane Playford

Professor Linda Luxon

Professor Niall Quinn

FRCP

MD FRCP

Senior Lecturer in Clinical Neurology Institute of Neurology MD FRCP

Consultant Audiovestibular Physician National Hospital for Neurology & Neurosurgery Professor of Audiovestibular Medicine University College London

DPhil FRS

Dr Giovanna Mallucci

Chair of Neural Regeneration Institute of Neurology

PhD MRCP(UK)

Honorary Clinical Senior Lecturer in Neurology Institute of Neurology

Dr Hadi Manji

MD FRCP


MD MRCP(UK)


Dr Gordon Plant


PhD MRCP(UK)

Consultant in Metabolic Medicine National Hospital for Neurology & Neurosurgery

PhD MRCP(UK)



Consultant Neurosurgeon Head, Division of Neurosurgery Institute of Neurology

Dr Matthew Parton

Dr Jon Marsden

PhD MCSP

Clinician Scientist Fellow Institute of Neurology


Professor Geoffrey Raisman

Dr Jeremy Rees

DM

PhD FRCP


Dr Mary Reilly

MD FRCP FRCPI


Professor Mary Robertson

MD DSc

FRCP FRCPsych

Dr Philip Lee

Professor Christopher Mathias

DM FRCP

Consultant in Metabolic Medicine National Hospital for Neurology & Neurosurgery

DPhil DSc FRCP FMedSci

Professor of Neurovascular Medicine Institute of Neurology

Emeritus Professor of Neuropsychiatry University College London

Professor Martin Rossor

MD FRCP

FMedSci

Professor Andrew Lees

MD FRCP

Professor of Clinical Neurology Director, Reta Lila Weston Institute Institute of Neurology

Dr Alexander Leff

PhD MRCP(UK)


Professor Roger Lemon

PhD FMedSci

Sobell Chair of Neurophysiology & Director, Institute of Neurology (2002–2008)

Professor David Miller

MD FRACP

FRCP

Professor of Clinical Neurology Head, Department of Neuroinflammation Institute of Neurology

Professor of Clinical Neurology Head, Division of Clinical Neurology Director, Dementia Research Centre Institute of Neurology

Professor Josemir Sander

MD PhD

FRCP

Dr Catherine Mummery

PhD FRCP


Professor of Clinical Epilepsy Institute of Neurology

Dr Geoffrey Schott

MD FRCP


ix

Editorial Team

Dr Anette Schrag

Professor David Thomas

MD PhD


Dr Susan Short

FRCP

Professor Simon Shorvon

Miss Emma Townsley

MD FRCP

Professor of Clinical Neurology Institute of Neurology & Clinical Subdean University College London FRCP

MD FRCPI

Professor of Clinical Neurology & Director, Institute of Neurology (2008–) RGN BSc(Hons)

Clinical Nurse Specialist in Neuro-Oncology National Hospital for Neurology & Neurosurgery

Professor Michael Trimble

MD FRCP

Consultant in Clinical Neurophysiology National Hospital for Neurology & Neurosurgery

FRCPsych

Dr Valerie Stevenson

Professor Matthew Walker

MD MRCP(UK)

Professor of Behavioural Neurology Institute of Neurology



Dr Sarah Tabrizi

Dr Nick Ward

PhD FRCP


x

Dr Jason Warren

PhD FRACP

Clinical Senior Lecturer in Neurology Institute of Neurology

Professor Alan Thompson

PhD FRCR

Consultant Clinical Oncologist National Hospital for Neurology & Neurosurgery

Dr Shelagh Smith

FRCS FRCP

Professor of Neurosurgery Institute of Neurology

PhD

FRCP

MD FRCP

Clinical Senior Lecturer in Neurology Institute of Neurology

Dr David Werring

PhD MRCP(UK)


Professor Nicholas Wood

PhD FRCP

FMedSci

Professor of Clinical Neurology & Neurogenetics Head, Department of Molecular Neuroscience Institute of Neurology

Dr Gelareh Zadeh

MD PhD FRCS (C)


Beginnings

A conversation with Professor Ian McDonald Ian McDonald1 kindly agreed to write the foreword for this book. Sadly, he died shortly before it was completed. We had met in Queen Square in 2004 to discuss what I had in mind, an integrated, practical textbook from the National Hospital and the Institute of Neurology. ‘That is quite splendid’, Ian had replied when I explained the nature of our project. ‘Of course’, he continued: ‘a book like this has never been produced previously, and I think no one has been able to draw together the different personalities here – and that will not be at all easy . . .’. Ian went on: ‘Charlie Symonds2 once told me that he had suggested a similar project to the National Hospital Medical Committee in the late 1930s’. Dr Charles Symonds’ proposal had received an immediate veto from his senior colleague Dr Samuel Kinnier Wilson3: ‘Dr Symonds there is no place for that. I have already written the definitive book, there is no need for another’, Kinnier Wilson is said to have responded, acidly. True, this present book came to fruition slowly. The authors are busy people, distinguished in specialist fields, but they have

come together to produce this volume. The editors are most grateful to them all. During the last five decades, neurology has progressed immeasurably and Queen Square has become a truly international centre. The editors have tried to integrate this international dimension, drawing on clinical experience and perspectives from Australia, Canada, China, Europe, India and USA. We thank our international editors for their comments and guidance. We hope Neurology: A Queen Square Textbook achieves its object – to reflect the clinical practice of neurology as we know it and to illustrate the approach we teach and follow at the National Hospital for Neurology & Neurosurgery and the Institute of Neurology, Queen Square. We all have valued Ian McDonald’s encouragement and hope that if he were still with us, he would feel the finished product was worthy of the institutions and teachers that have guided our thoughts and practice over the years. Charles Clarke Queen Square London WC1

1. Professor Ian McDonald (1933–2006) was Professor of Neurology from 1978 to 1998. One of his great legacies remains his research into multiple sclerosis; his humanity, warmth and civility provide enduring memories for his students, colleagues and friends throughout the world. 2. Sir Charles Symonds, KBE, CB (1890–1978) was appointed physician to The National in 1926. A selection of his many papers entitled Studies in Neurology was published in 1970. 3. Dr Samuel Kinnier Wilson (1878–1937) was appointed physician to The National in 1912. He had written the seminal paper on Progressive Hepato-Lenticular Degeneration shortly before this. Neurology, his famous textbook, was published posthumously in 1940.

xi

Foreword

Queen Square in Bloomsbury, London, is known the world over as a centre for neurology and clinical neuroscience. Like many institutions, The National, initially The National Hospital for the Relief and Cure of the Paralysed and Epileptic, was founded through the hard work and generosity of people with a broad sense of charitable intent, especially the Chandler family – Johanna Chandler, her sister Louisa and their brother Edward. The doors of the original building opened in Queen Square in 1860. Dr Jabez Spence Ramskill was the first physician appointed, followed shortly by Dr Charles Brown-Séquard. Since 1860 there has been an unbroken record of progress across the clinical neurosciences. The names of all those who contributed in those early years are too numerous to mention, but amongst those who stand out today in an historical perspective are Dr Charles BrownSéquard, Dr John Hughlings Jackson, Sir William Gowers, Sir David Ferrier, Sir Victor Horsley, Sir Gordon Holmes, Dr Samuel Kinnier Wilson, Sir Francis Walshe, Sir Charles Symonds and Dr Macdonald Critchley. The National Hospital has undergone many changes and revolutionised its approach, for example towards neurological rehabilitation and brain injury, and has developed close and inseparable links with the Institute of Neurology, which has helped to promote research at Queen Square in both basic and clinical sciences. Both Hospital and Institute are now involved in advancing an extensive range of developments in translational medicine that are transforming the treatment of neurological diseases. These developments are reflected in this book.

The Institute of Neurology The Institute of Neurology was established in 1950 and has been part of University College London since 1997. The Institute provides research and teaching of the highest quality in neurosciences, and professional training for clinical careers in neurology, neurosurgery, neuropsychiatry, neuroradiology, neuropathology and clinical neurophysiology. With its concentration of clinical and applied scientific activity, the Institute provides a unique national resource for both postgraduate training and research in

the basic neurosciences and its associated clinical disciplines. The Institute currently holds active grants for research into the causes and treatment of a wide range of neurological diseases, including movement disorders, multiple sclerosis, epilepsy, brain cancer, stroke and brain injury, muscle and nerve disorders, cognitive dysfunction and dementia; the work of the Institute’s clinical academic staff remains closely integrated with the Hospital.

The National Hospital for Neurology & Neurosurgery today The National, now part of University College London Hospitals NHS Foundation Trust, is a thriving hospital, largely refurbished behind the 1890 façade. The hospital receives over 1000 new outpatient referrals each month and has over 200 beds, a dedicated ITU, extensive rehabilitation services and all ancillary departments in the most substantial specialist neurological hospital within the UK. The hospital provides the surrounding district general hospitals with specialist services. Many of the consultant staff continue to hold appointments that are linked to both general hospitals, the Institute of Neurology and The National itself. This maintains unique contact between the disciplines of research and clinical practice.

Neurology: A Queen Square Textbook This book, the first of its kind to come from these two institutions, has a distinctly clinical flavour. It has been written very largely by clinicians, each in the forefront of their field, and focuses on the practical aspects of diagnosis, treatment and patient care. The book also provides an introduction to the basic sciences of neurology, of increasing importance in medical practice. It has been a pleasure to be one of the contributing authors. Professor Roger Lemon PhD FMedSci Sobell Chair of Neurophysiology & Director, Institute of Neurology (2002–2008)

xiii

Preface

All Editors, Authors and Specialist Advisory Editors of Neurology: A Queen Square Textbook hold or recently held consultant or equivalent posts at the National Hospital for Neurology & Neurosurgery and/or the Institute of Neurology, Queen Square. The National Hospital is part of University College London Hospitals NHS Foundation Trust, and the Institute of Neurology part of University College London. The twenty Co-ordinating Authors organised individual chapters, encouraged and liaised with over 70 contributors and with them wrote this book. The Specialist Advisory Editors gave invaluable advice and guidance in their respective fields. To ensure a worldwide perspective, the six International Regional Editors, all of whom have had close connections with Queen Square, provided advice and comment. This book is an attempt to provide a fresh and up-to-date approach to the fascinating subject of neurology. We encouraged each author to relate their own clinical experience but, in order to achieve a degree of consistency, we took a robust overview of

the important specialities within neurology and their relevance. Each chapter has been coordinated by an expert in the field, to give the reader an overall grasp of each major subject, indicating where developments within neurosciences fit into a broader picture. The limited size of this book means that it has not been possible to provide references for all material. With the growth of information technology, a wealth of detailed sources are readily available. We are most grateful to all those who have helped in this joint venture. Charles Clarke Robin Howard Martin Rossor Simon Shorvon Queen Square London WC1

xv

Acknowledgements

We know that the skills of clinical practice are handed down, both by teachers and role models. The editors wish to thank all those who have taught, advised and inspired them – in many aspects of neurology and its related disciplines, in neuroscience and in research. When we came to list these many individuals, we soon realised we would be unable to mention each by name. Instead, we trust that those who read this book will understand how much the editors and authors owe to others. We hope we can pass on some of that knowledge and experience. We thank our publishers, Wiley-Blackwell, and especially Helen Harvey (Project Manager), Rob Blundell (Development Editor), Martin Sugden (Publisher), who, having accepted that the project was viable, have waited for and worked on the draft manuscripts with unstinting patience. David Gardner, in Cyprus and Best-set,

xvi

Hong Kong have transformed the draft illustrations into a coherent sequence, to make the finished product one that has truly crossed national boundaries. The authors have worked hard, for no personal reward and, despite numerous requests for text, diagrams and amendments, have remained firmly behind this project. Secretarial help has also been invaluable, and amongst those who have contributed over and above their normal duties, we thank especially Claire Bloomfield, Wyn Jagger and Mary Wright. The Rockefeller Library has provided its valuable resources, both historical and current. The Audio Visual Services Unit has been most helpful with the sourcing of some of the figures and photographs.

Plate 2.2 Cortical and cerebellar fMRI with voluntary activity of left hand (button press). Task-related activation can be seen in the contralateral hand region of primary sensorimotor cortex on the axial image and in the ipsilateral contralteral lobule VI of the cerebellum on the coronal image (Courtesy Dr Alex Leff, Wellcome Trust Centre for Neuroimaging, Institute of Neurology).

Plate 2.1 Astrocytes.

1

1

Cingulate cortex executive area

2 2

3

4

Dorso-lateral prefrontal cortex

3

Area 22 (a)

4

(b)

Plate 2.3 Functional MRI (a) and diagram (b) indicating cortical eye fields. 1. Supplementary eye field. 2. Frontal eye field. 3. Parietal eye field. 4. Occipital cortex.


(a)

(b)

(c)

(d)

(e) Plate 5.1 MRI findings in Parkinson’s disease (PD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). (a) Putaminal atrophy, hyperintense rim (arrow) and putaminal hypointensity (relative to globus pallidus) on T2-weighted images (1.5 T) in a patient with MSA. (b) T2-weighted images (0.5 T) showing ‘hot cross bun’ sign (inset shows a real hot cross bun) in a patient with MSA. (c) Infratentorial atrophy and signal change in pons, middle cerebellar peduncles (arrow) and cerebellum on T2-weighted images (0.5 T) in a

patient with MSA. (d) Sagittal images in patients with (left to right) PD, MSA and PSP, showing atrophy of pons and cerebellum (arrows) in MSA and atrophy of midbrain (arrow – the ‘hummingbird sign’). (e) Tractography (3 T) of the middle cerebellar peduncle (MCP, yellow) and superior cerebellar peduncle (SCP, purple) in patients with (left to right) PD, MSA and PSP, showing selective atrophy of MCP in MSA and of SCP in PSP. (Figure 5.1(a–c) from Schrag et al. 1998 and (d,e) from Nilsson et al. 2007 with permission.)

Plate 7.1 (a) Neuropil spongiosis occurring in superficial cortical laminae is seen in FLTD (Haematoxylin and eosin preparation, frontal cortex). (b) Tau-positive Pick body is a characteristic feature of Pick’s disease (AT8 immunohistochemistry, temporal cortex). (c) A combination of tau-positive neuronal (arrowhead) and glial pathology is found in FLTD due to intronic mutations located close to the alternatively spliced exon 10 (this case: exon 10 +16 mutation). Insert showing tau-positive oligodendroglial coiled bodies (AT8 immunohistochemistry, temporal cortex). Tau-positive neurofibrillary tangles and pretangles (arrowhead) occur both in progressive supranuclear palsy and corticobasal degeneration (d and e arrowhead). However, tufted astrocytes are the characteristic glial pathology in progressive supranuclear palsy (d arrow) and the so called astrocytic plaques are found in corticobasal degeneration (f arrow) (AT8 immunohistochemistry, frontal cortex). Neuronal intracytoplasmic inclusions (arrow) and neurites (arrowhead) are ubiquitinpositive (g) and are immunoreactive for TDP-43 (h) in FTLD-U (g: ubiquitin immunohistochemistry; h: TDP-43 immunohistochemistry, temporal cortex). Figures courtesy of Professor Tamas Revesz, Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology.

Plate 9.1 Charcot–Marie–Tooth type 1a with formation of onion bulbs. (a) Paraffin section (transverse) shows concentric formations (arrows) with a reduction of fibre density. The interstitial space is widened, indicating oedema with a mucoid component. (b) Semi-thin resin section (toluidine blue) confirms the abundant presence of onion bulbs (arrows). (c) Electron microscopy of the same nerve with concentric arrangement of Schwann cells around myelinated axons. The Schwann cells appear as plump, elongated and rounded stacks, separated by longitudinally oriented collagen fibres (light grey).

(a)

(b)

(c)

(d)

(e)

(f)

(g)

(h)

(a)

(b)

(c)

(a) (a)

(b)

(c)

(d)

(e)

(b) (f)

(g)

(h)

(c) Plate 9.2 Amyloid neuropathy. (a) Haematoxylin and eosin stained paraffin section with a large amyloid deposition in the endoneurium, displacing normal structures. The nerve is severely depleted of large myelinated axons. (b) Electron microscopy of the same nerve, visualizing amyloid fibrils. (c) The amyloid is composed of transthyretin (determined by immunohistochemistry).

(i)

Plate 9.3 Chronic inflammatory demyelinating polyradiculoneuropathy. (a) Patchy loss of myelinated fibres in a fascicle of the sural nerve (semi-thin resin section, toluidine blue). The left lower rectangle is shown in higher magnification in (b). (b) Close-up of the area with a significant loss of large myelinated fibres (arrowhead indicates a thinly myelinated fibre). There are several other thinly myelinated and entirely demyelinated fibres. (c) More densely populated area corresponding to the right upper rectangle in (a). (d) Endoneurial T cells (CD8 immunohistochemical staining). (e) Most CIDPs are also characterized by a variable peri-vascular infiltrate as shown here (CD8 immunohistochemistry). (f) Teased fibre preparation which shows a segmental demyelination. To unequivocally identify segmental demyelination, myelinated fibres have to be identified on either end of the demyelinated stretch. (g) Closeup of demyelination, which shows a myelinated segment on the left, the end of which is indicated by the left arrowhead. This is followed by an expanded internode length, the end of which is indicated by the right arrowhead. The subsequent stretch of the axon is very thinly myelinated. (h) Electron microscopy of a demyelinated and thinly remyelinated axon. (i) Axon with almost regular myelin thickness, surrounded by concentric formations of Schwann cell laminae, also designated onion bulbs.

Plate 9.4 Widely spaced myelin. The normal myelin lamellae are tightly compacted and have a periodicity in electron microscope preparations of 12–15 nm. In the demyelinating neuropathy associated with immunoglobulin M (IgM) paraprotein that has activity against MAG (anti-Mag PDPN) the intraperiod line becomes split giving an overall periodicity of 30–40 nm. There is a suggestion of material within the widened spaces, possibly IgM.

Plate 9.5 Vasculitis and severe axonal neuropathy in a peripheral nerve. (a) Fibrinoid necrosis (black arrow) of a medium-sized vessel. The vessel wall is densely infiltrated by inflammatory cells (white arrows). (b) Van Gieson elastica staining to visualize the distended and infiltrated vessel walls (red, black arrows) and interdispersed lymphocytes (white arrows). (c) CD8 immunohistochemical staining to visualize T cells in the vessel walls. (d) Semi-thin resin sections on a transverse section of the adjacent nerve. Black arrows show acutely degenerating axons. White arrows indicate macrophages with the characteristic fine granular bright cytoplasm and peripheral small dark nucleus. (e) CD68 immunohistochemical staining to visualize digestion chambers and macrophage in the acutely degenerating nerve. (f) Accompanying occasional T-cell infiltrates in the affected nerve. This is regarded as a bystander effect to the overall inflammatory disease and should not be regarded as primary inflammation.

(a)

(b)

(c)

(d)

(e)

(f)

Plate 9.6 Charcot joint in a foot secondary to recurrent severe vasculitic neuropathy. The second phalanx has been amputated and a new vasculitic ulcer is present on the sole of the foot.

Plate 9.7 Typical clinical appearance of a patient with myotonic dystrophy. Note ptosis, frontal balding, typical facies and distal wasting.

Plate 9.8 Typical facial, hand and foot appearances in Anderson–Tawil syndrome. Note hypertension, micrognathism, low-set ears, downturned mouth, short digits, clinodactyly of the fifth digits and syndactyly of the toes.

(a)

Plate 9.9 (a) Mitochondrial myopathy. Note not only the ptosis but hearing aid indicating deafness. (b) MRI T2W showing occipito-parietal, not respecting usual anotomical vascular territories, following a stroke-like episode in a case of mitochondrial disease. (c) Ragged red fibres stained with Gomori Trichrome stain – muscle fibres with peripheral accumulations of abnormal mitochondria.

(b)

(c)

* * (a)

(b)

(c)

(d)

(e)

(f)

(g)

(h)

Plate 9.10 In dermatomyositis, atrophic fibres often display a peri-fascicular arrangement (a, double arrow). Lymphocytic infiltrates are frequently peri-vascular (b, * indicate small arterioles) and peri-mysial but may extend into the endomysium. There is fibre necrosis (c, arrows) and regeneration (c, double arrow). MHC Class I is expressed at the sarcolemma (d, arrow). The features of inclusion body myositis include endomysial lymphocytic infiltration with infiltration into intact muscle fibres (e, arrow) and rimmed vacuoles that occur in fibres without lymphocytic infiltration (f, arrow). The inflammatory infiltrate is composed predominantly of CD8-positive T lymphocytes (g). In polymyositis, the inflammation is largely endomysial in location (h, arrow). In this example, necrotic fibres infiltrated by macrophages are prominent (h, double arrow). a–c, e, f, h, haematoxylin and eosin; d, immunohistochemical staining for MHC Class I; g, immunohistochemical staining for CD8.

Plate 9.11 Inclusion body myositis may present with focal weakness of the quadriceps muscles, identified easily in this case by the focal thigh wasting – when compared to the lower leg muscle compartments.

(a)

(b)

(c)

(d)

(e)

(f)

(g)

(h)

Plate 10.1 Macroscopic and microscopic findings in multiple sclerosis. (a,b) Macroscopic pathology of demyelination (coronal sections of formalin fixed brains). (a) Arrow pointing at a small circumscribed demyelination in the frontal white matter. Loss of myelin appears grey, similar to cerebral cortex. (b) Coronal section of the occipital lobe with extensive multi-focal and confluent demyelinations (arrowhead). (c–e) Two foci of demyelination, one with partial remyelination (red box) stained for myelin or axons. (c) Luxol fast blue stains myelinated structures dark blue and the punched-out well-demarkated defects indicates loss of myelin. (d) Myelin basic product (MBP) immunohistochemistry labels myelinated fibres, and shows the same punched-out demyelination with a smaller rim of remyelination fibres in the lowest lesion. (e) Immunohistochemical staining of phosphorylated neurofilament demonstrates the prescence of axons

within the demyelinating lesions, which appear of slightly increased density than the surrounding intact white matter. (f) CD68 immunohistochemistry labels microglia and macrophage activity. The area corresponds to the red rectangle in (c–e), it clearly shows a demarcation between demyelinated and remyelinated regions. (g) High power magnification of the boxed area in (d) (MBP) on the left with loss of the myelin (demyelinated white matter [dWM]), a myelinated area in the centre (WM) and normal cortex (Cx) with myelinated on the right, all indicated by arrows. (h) High magnification of the labelled area in (e) shows the axons in the lesion on the left (dWM) and outside the lesion (nWM), the border is indicated by arrows. (Images and macroscopic specimens courtesy of Sebastian Brandner; histological specimens courtesy of Klaus Schierer, UCL Institute of Neurology.)

(a)

CSF−/Serum−

(b)

CSF+/Serum−

(c)

CSF++>Serum+ (d) CSF+/Serum+

Plate 10.2 Isoelectric focusing of paired cerebrospinal fluid (CSF) and serum. (a) CSF−/ serum−. (b) CSF+/serum−. (c) CSF++/serum+. (d) CSF+/serum+. The oligoclonal band patterns in (b) and (c) indicate intrathecal antibody synthesis.

Plate 10.3 Abdominally placed baclofen pump and intrathecal catheter. Medtronic™.

(a)

(a)

(b)

(b)

(c) Plate 11.1 Activation on positron emission tomography (PET) in a patient with cluster headache and migraine (a) who experienced a migraine without aura during the scan after nitrate triggering, and demonstrated activation in the rostral ventral pons. Similarly activation in the same region with spontaneous attacks of episodic migraine (b) and in chronic migraine (c).

Plate 11.2 Activation on positron emission tomography (PET) in the posterior hypothalamic grey matter in patients with acute cluster headache (a). The activation demonstrated is lateralized to the side of the pain (May et al. 1998). When comparing the brains of patients with cluster headache with a control population using an automatic anatomical technique known as voxel-based morphometry (VBM) that employs high-resolution T1-weighted MRI, a similar region is shown (b) with increased grey matter signal activation (May et al. 1999).

Plate 13.1 Mild optic disc swelling in acute demyelinating optic neuritis. The absence of haemorrhages or exudates is characteristic.

Plate 13.2 Optic neuritis in secondary syphilis. Typically, slit lamp examination shows vitreous cells.

Plate 13.3 Acute neuroretinitis. Note the hard exudates, swollen disc and perivenous infiltrates (arrow).

Plate 13.4 Branch retinal artery occlusion. Note the cloudy retinal swelling superiorly.

Plate 13.5 Central retinal artery occlusion with cherry red spot.

Plate 13.6 Cholesterol emboli (arrows).

Plate 13.7 Left optic disc swelling and crowded right disc with absent physiological cup in non-arteritic ischaemic optic neuropathy.

Plate 13.10 Temporal arteritis with superficial scalp necrosis.

Plate 13.8 Pseudo-Foster Kennedy syndrome. Left optic disc swelling caused by non-arteritic AION; right optic disc atrophy resulting from previous episode.

Plate 13.9 Vasculitic anterior ischaemic optic neuropathy (AION) – note left disc swelling with pallor and flame-shaped haemorrhages.

Plate 13.11 Temporal arteritis histology. Note massive intimal thickening to obliterate vascular lumen and multinucleate giant cells (arrows).

Plate 13.12 Optic disc swelling plus cherry red spot in neoplastic infiltration.

Plate 13.13 Bilateral optic atrophy caused by dominant optic atrophy.

Plate 13.16 Disc drusen. Note anomalous vessel branching and absent physiological cup.

Plate 13.14 Temporal optic disc pallor in established Leber’s hereditary optic neuropathy.

Plate 13.17 Myelinated retinal nerve fibres.

Plate 13.15 Traumatic optic neuropathy.

Plate 13.18 Acute haemorrhagic papilloedema.

Plate 13.19 Early papilloedema. Note nerve fibre layer swelling starting to obscure right supero-temporal branch retinal artery (arrow).

Plate 13.20 Asymmetrical bilateral papilloedema.

Plate 13.21 Chronic compensated papilloedema.

Plate 13.22 Vintage papilloedema with corpora amylacea (arrowed).

Plate 13.23 Atrophic papilloedema.

Plate 13.24 Subtle right proptosis due to orbital mass is best observed from above.

Plate 13.25 Colour Doppler flow mapping showing flow reversal (red) in superior ophthalmic vein due to carotid-cavernous fistula.

(a)

(b)

Plate 13.26 (a) Arterialized conjunctival vessels in carotid-cavernous fistula. (b) Bilateral chemosis in carotid-cavernous fistula.

Plate 13.27 Band atrophy in bitemporal hemianopia due to chiasmal transection.

Plate 13.28 Visual phenomena recorded by four patients with occipital epilepsy. (Reproduced from Panyiotopoulos, 1999 with permission.)

Plate 13.29 Geometric hallucinations within a hemianopic field defect recorded by the patient. (Reproduced from Kölmel, 1985 with permission.)

Plate 13.30 Metamorphopsia recorded by a patient following occipital lobe surgery. (From Mooney et al. 1965, with permission.)

(a)

(d)

(b)

(e)

(c)

Plate 15.1 Electronmicrograph of olfactory ensheathing cells (OECs). Each colour represents the cytoplasm of a different OEC.

Plate 15.2 Photomicrograph of longitudinal section of rat spinal cord showing regeneration of neurones (green) through an area of transplanted olfactory ensheathing cells (OECs; red).

Plate 15.3 Operative photograph of intradural microscopic exploration of spinal meningioma with overlying arachnoid intact. Stay sutures hold dura opening, tumour arises from anterolateral dura mater.

Plate 15.4 Operative photograph showing TOMITA™ spinal fixation.

Plate 16.1 Conjuctival telangiectasia in a case of ataxia telengiectasia. (Courtesy of The Audio Visual Services Unit, National Hospital for Neurology & Neursurgery.)

(a)

(b)

Plate 18.1 Fatal high-altitude cerebral oedema. (a) Brainstem showing haemorrhagic infarction; (b) ring haemorrhages in cerebral white matter. (From Clarke 2006, with permission.)

Plate 18.2 Abrupt cerebral oedema at extreme altitude – papilloedema, retinal oedema and venous congestion; Mount Everest SW Face, 1975. (From Clarke 2006, with permission).

Plate 18.3 Symptomless retinal haemorrhages at 5500 m; Mount Everest, 1975. (From Clarke 2006, with permission.)

Plate 18.4 High altitude retinopathy with permanent visual loss. Retina showing extensive haemorrhagic change. (From Clarke 2006, with permission.)

Sagittal

Coronal

Transverse

Z value

3

3

1

0 Plate 18.5 FDG-PET scan showing hypometabolism in Korsakoff patients with significant reduction of signal in thalamus, ventromedial cortex and retrosplenium. (From Reed et al. 2003. Courtesy of Professor M. Kopelman, St. Thomas’ Hospital.)

Pilocytic astrocytoma (WHO Grade I)

Rosenthal fibres Eosinophilic granular bodies Vascular proliferation can occur, no evidence of malignancy (no mitoses) Elongated ‘piloid’ cells

Diffuse astrocytoma (WHO Grade II)

Fibrillary matrix

Diffuse infiltration of normal brain tissue Normal vessels Reactive astrocytes Tumour astrocytes Abnormal, hyperchromatic nuclei

Anaplastic astrocytoma (WHO Grade III)

Infiltration of normal brain

Normal tumour vessels No endothelial hyperplasia Frequent mitoses Nuclear pleomorphism No necrosis

Glioblastoma (WHO Grade IV)

Infiltration of normal brain Thrombotic occlusion of tumour vessels Abnormal proliferation of vessels with endothelial hyperplasia Atypical mitosis and bizarre nuclei Necrosis with palisading tumour cells Abnormal vessels

Necrosis

Astrocyte

Neurone

Tumour astrocyte

Tumour cells with neuronal phenotype

Astrocyte; mitosis Increasing de-differentiation Plate 20.1 Histological features of WHO Grade I–IV astrocytomas.

Vessel Tumour vessel with abnormal endothelial profliferaiton

Calcification

Oligodendroglioma (WHO Grade I)

Satellitosis and brain infiltration

Small astrocytic tumour cells Branching capillaries Reactive and neoplastic astrocytes

Ependymoma (WHO Grade II)

Pseudorosettes around vessels with thickened walls Glial processes radiating to vessels Monomorphic cells Pepper and salt structured nucleus

Classic medulloblastoma Neuroblastic rosettes Medulloblastoma (WHO Grade IV)

High nucleus : cytoplasm ratio Poorly differentiated areas Desmoplastic medulloblastoma Islands of neuronal differentiation Surrounded by collagen and poorly differentiated tumour cells Astrocyte

Neurone

Tumour astrocyte

Tumour cells with neuronal phenotype

Oligodendroglioma tumour cell

Increasing de-differentiation

Plate 20.2 Histological features of three common intrinsic brain tumours.

Vessel

Schwannoma (a)

(b) Reticulin silver

S-100 (IHC)

Chordoma

Haematoxylin–eosin

(c)

(d)

(e) Cytokeratin (IHC)

S-100 (IHC)

Lymphoma


(f)

(g)

(h) B cells (CD20 IHC)

Proliferation (Ki67 IHC)

Pineoblastoma


(i)

(j)

(k) Haematoxylin–eosin

(l) Toluidine blue (smear)

Plate 20.3 Histological features of schwannoma, chordoma, lymphoma and pineoblastoma.

Synaptophysin (IHC)

Glioblastoma

Anaplastic astrocytoma

Diffuse astrocytoma

Pilocytic astrocytoma

Magnetic resonance imaging

Plate 20.4 Imaging and macroscopic appearance of gliomas.

Macroscopic appearance

Macroscopic pathology

Meningioma

Medulloblastoma

Ependymoma

Oligodendroglioma

Imaging

Plate 20.5 Imaging and macroscopic appearance of common brain tumours.

(a)

(b)

(c)

Plate 20.6 (a) Selection of magnetic resonance (MR) perfusion source images from a frontal parasagittal meningioma, showing marked decrease of signal intensity within the tumour during the first pass of contrast medium bolus, indicating increased tumour vascularity. (b) Corresponding colour map of relative cerebral blood volume (rCBV). Red areas indicate regions of most markedly elevated rCBV within the tumour and over brain surface vessels. (c) External carotid artery angiogram shows tumour blush and confirms increased vascularity of the meningioma.

Plate 20.7 (a) Coronal functional magnetic resonance imaging (fMRI) during opening and closing of hand in a patient with right superior frontal gyrus low-grade tumour. (b) Sagittal fMRI during picture naming task in a patient with a periinsular tumour showing activity in Broca’s area and in the visual cortex remote from the tumour.

(a)

Plate 20.8 Relative cerebral blood flow (rCBV) colour overlay map in a low-grade oligodendroglioma showing area of increased rCBV in the anterior part of the tumour.

(b)

(a)

(b)

(c)

Plate 20.9 (a) T2 images of a high-grade oligodendroglioma showing a heterogeneous mass with a necrotic centre. (b) The contrast-enhanced T1 image demonstrates irregular ring enhancement within the mass. (c) On rCBV map large intra-tumoural areas of increased blood volume (in red) indicate areas of neovascularity.

(a)

(b)

Plate 20.10 (a) Radiation necrosis following radiotherapy for a high-grade glioma. Contrast-enhanced T1 images show a brightly enhancing left parietal mass, indistinguishable from recurrent glioma. (b) rCBV shows mass has a decreased blood volume compared to normal white matter and appears dark, in keeping with radiation necrosis. A recurrent glioma is likely to have shown an elevated rCBV.

Plate 23.1 Segmental hyperhidrosis as a presenting feature in a patient in whom there were large areas without sweating. He had the Holmes–Adie syndrome with Ross’s variant. (From Mathias 1998, with permission.)

Plates 23.2 (left) and Plate 23.3 (right) Pupillary dilatation in Holmes–Adie syndrome and its response to pilocarpine. In Plate 23.2, the left pupil is clearly the larger – there is a diminished response to light. In Plate 23.3, the pupillary response to dilute pilocarpine (constriction) is greater on the left than in the normal right eye. (From Mathias 1998, with permission.)

1

Neurology Worldwide: the Burden of Neurological Disease Simon Shorvon

Neurological disease casts a heavy shadow on the lives of the patient, their family and friends and on society. The aim of all neurological services should be to alleviate the suffering associated with the disease, and to realize this aim the rational planning of such health services requires knowledge in four broad areas. First, information is required about the epidemiology of the condition – its frequency and distribution within a population, its causation, mortality and co-morbidity. Second, it is important to know the broad impact of the disease (the ‘burden of illness’) on individuals, families and on health services and societies and also its financial cost. Third, data are needed on the effectiveness (and cost-effectiveness) of diagnostic, investigatory and treatment interventions. Finally, knowledge is required of the existing health care resources and their distribution and priorities. The last two areas are outside the scope of this chapter, and here a necessarily extremely brief overview of selected issues related to the epidemiology and burden of illness is given, where possible using figures derived from studies from the National Hospital in London. These set the scene for the more detailed consideration of neurological disease contained in the rest of the volume.

Epidemiology of neurological disease It is self-evident that knowledge of epidemiology will be important to underpin any decision about the provision of health care resources. It is also clear that epidemiological data (on frequency, distribution, mortality, etc.) are of little value unless related to an intervention or therapeutic advance. Epidemiclogical data is particularly valuable for resource provision. Sadly, however, in practice, even where reliable data exist, these are used only inconsistently in planning health care. It is for this reason that in many, indeed perhaps most, health care settings, the provision of facilities for neurological care is often surprisingly fragmented and inappropriately targeted. Neurology: A Queen Square Textbook Edited by Charles Clarke, Robin Howard, Martin Rossor and Simon Shorvon © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-13443-9

Frequency and distribution of neurological disease Incidence and prevalence are the most common measures of frequency used in medicine. Incidence is defined as the rate at which new cases occur in a specified population during a specified period. The incidence rate is usually calculated as the number of new cases occurring per 100,000 of the general population per year. Prevalence is defined as proportion of a population that are cases at a point in time. The prevalence rate is usually calculated as the number of existing cases per 1000 of the general population. Point prevalence is calculated as the number on a particular day (prevalence day) and period prevalence is calculated as the number in a population over a specified period of time. Lifetime prevalence is defined as the risk of acquiring the condition at any time during life and is another important figure. For many neurological diseases, information on even these basic measures is incomplete. Furthermore, the frequency of many neurological disorders varies markedly in different geographical regions, differs in urban when compared with rural settings, may differ with ethnicity, and is of often linked to lifestyle and socio-economic factors. In most neurological illnesses there are also striking differences in frequency at different ages, and so the age distribution of the population will affect the frequency, and some diseases have marked gender differences. For these reasons, age-specific or sexspecific rates, or frequency estimates in restricted age ranges, are generally more informative than crude rates. For instance, the annual incidence of stroke in a population is about 190/100,000/ year, but in the population over 65 years the rate is 1100/100,000/ year. Similarly, the incidence and prevalence of Parkinson’s disease in the general population is 20/100,000/year and 2/1000, and in those over 65 years is 160/100,000/year and 10/1000. Changes in age structure in populations will impact heavily on the number of patients with diseases that have age-specificity. In most developing countries, the population has a far greater proportion of children and young adults than in developed countries (Figure 1.1 shows age structures in a typical developed [Sweden]

1

Chapter 1

and developing country [Costa Rica]). It is also important to recognize that although worldwide human populations are growing in an exponential fashion, growth rates vary widely among different countries and regions and the concept of ‘doubling time’ is a useful way of quantifying this. Doubling time – the time it is predicted to take for a population to double in size – depends not only on population size and mortality rates, but also on the number of children per woman (Table 1.1) and various other social and health parameters. The approximate non-standardized figures for the prevalence and incidence of neurological disorders in a developed country are shown in Table 1.2. This table illustrates one other important point – that for chronic diseases, as for many neurological diseases, the incidence rates may be low but prevalence rates are high. This is important for health service planning, as the facilities required for incident cases are very different from prevalent cases. The former require provision for investigation and acute therapy and the latter largely for follow-up, social care, long-term therapy and rehabilitation.

Males

Females

1900

Males

80

Females

COSTA RICA 60

SWEDEN

1920

40

1940

20

1960 10

0

10

20

10

0

10

20

Age (years)

Year of birth

1880

0

Percent of population in age class Figure 1.1 Age structure in developed (Sweden) and developing (Costa Rica) countries. (From Worldwatch Database (1996), with permission.)

The results of age-adjusted incidence and prevalence figures in a population of 100,230 persons in a selection of general practices served by the National Hospital for Neurology and Neurosurgery in London from a research project published in 2000 are shown in Tables 1.3–1.5. Here, the rates are adjusted for age to reflect the general UK population and are given alongside comparative results from other studies. Overall, the onset of 625 neurological disorders was observed per 100,000 population during the year of observation. Six per cent of the population in whom lifetime prevalence was surveyed had had a neurological disorder. In the UK, diseases of the nervous system accounted for 7.6% of all GP consultations between 1981 and 1982. The frequency of disability in private households amongst those over 16 years of age in the UK in 1971 was comprehensively delineated in the Harris Report. Disabilities relevant to neurology – CNS disorders, muscular dystrophies, congenital malformations of the spine and hydrocephalus, cerebral birth injury, senility as a cause of cognitive disability – occurred with a prevalence of 78/1000. The UK Office for Population Censuses and Surveys (OPCS) survey of disability 16 years later graded disability according to severity as well as overall frequency. The prevalence of complaints relevant to neurology was 13% for ‘CNS disorders’, 2% each for dementia and mental retardation, and 6% for back complaints. In a later study, ‘CNS complaints’ accounted for 7% of disability overall but for 16% of conditions with a high severity score. Roughly similar figures are found elsewhere. Population-based estimates from the USA, for instance, report point prevalence rates of neurological conditions (excluding headache, back pain and discs, mental retardation, psychosis, non-neurological visual and hearing loss and nervous system trauma) of 3.6/100. It is therefore clear that neurological diseases are common and cause significant degrees of disability. Furthermore, the existing figures are probably underestimates, as there are many difficulties associated with the collection of statistics in neurology, leading mainly to under-ascertainment. Such issues apply to epidemiological studies in all areas, but in addition to the varied general issues there is one particular problem for neurology that requires

Country

Approximate population size (millions)

Fertility (mean number of children per woman)

Doubling time* (years)

Germany Japan USA China Mexico Philippines Iran Nigeria

81 125 258 1178 90 65 63 95

1.40 1.50 2.00 1.90 3.40 4.10 6.60 6.60

−654 217 92 60 30 28 20 23

* Doubling time is the predicted time it will take for the population to double in size. The doubling time depends on population size, age structure, number of children per women and mortality rates. These figures were taken from the WorldWatch database, and predate improvements in child health, reductions in mortality rates amongst children and young adults and the HIV epidemic. A negative number implies a shrinking population.

2

Table 1.1 Population size in selected developing and developed countries – doubling time.

Neurology Worldwide Table 1.2 Annual incidence and point prevalence figures of common neurological disorders (1984). Data derived from Kurtzke 1982; Hopkins 1993; Hughes 2002; Zakrzewska & Hamlyn 1999; Hirtz et al. 2007 and other sources. The table includes only those conditions with an incidence above 1/100,000/year; whole populations considered, without age standardization, and excludes shingles.

Disorder

Incidence (per 100,000 persons/year)

Point prevalence (per 100,000 persons)

Migraine Acute stroke Epilepsy Febrile convulsions Dementia Chronic polyneuropathy (all types) Transient ischaemic attacks Bell’s palsy Parkinson’s disease Meningitis Subarachnoid haemorrhage Metastatic brain tumour Primary brain tumour Trigeminal neuralgia Multiple sclerosis Motor neurone disease Acute post infectious polyneuropathy All muscular dystrophies

370 190 50 50 50 40 30 25 20 15 15 15 5 4 4 2 2 1

12,100 900 710 250 24

200

6 1 90 4 1 6

Table 1.3 The National Hospital for Neurology and Neurosurgery (NHNN) record linkage study: age- and sex-adjusted incidence rates for neurological conditions, compared with previously reported rates. Conditions

Stroke First cerebrovascular episode Second cerebrovascular episode Intracranial haemorrhage Seizure disorders Epilepsy Single seizures Tumours Primary CNS tumours (benign and malignant) Parkinson’s disease Compressive mononeuropathies – all except carpal tunnel syndrome (CTS) Arm – all excluding CTS Leg – all

NHNN linkage age- and sex-adjusted rate (95% CI)/100,000/year

Previously reported incidence rates/100,000/year

205 (183–230) 42 (33–55) 10 (5–17)

200 28–35 5% of stroke, i.e. 10

46 (36–60) 11 (7–18)

24–53 20

10 (5–18) 19 (12–27) 49 (39–61)

7; 15 12–18 40

24 (17–33) 20 (14–29)

Polyneuropathies Diabetic polyneuropathy All excluding diabetic and alcoholic Shingles Post herpetic neuralgia Bacterial CNS infection (overall) Essential tremor

54 (33–83) 15 (9–23) 140 (104–184) 11 (6, 17) 7 (4–13) 8 (4–14)

40 11 71; 131; 400; 480 13; 34; 9% of shingles 10; 11 24 Continued on p. 4

3

Chapter 1

Table 1.3 Continued Conditions

NHNN linkage age- and sex-adjusted rate (95% CI)/100,000/year

Previously reported incidence rates/100,000/year

Trigeminal neuralgia Benign CNS tumour Multiple sclerosis Severe head injury Subarachnoid haemorrhage Subdural haematoma Cluster headache Cranial nerve disorder (excluding II, III, IV, VI, Bell’s palsy or trigeminal neuralgia) Disorders of II, III, IV, VI, including pupillary abnormalities but not optic neuritis Aseptic meningitis Metastatic CNS tumour Presenile dementia Cerebral palsy Neonatal encephalopathy or stroke Other congenital CNS abnormalities Brachial neuritis Guillain–Barré syndrome Myasthenia gravis Primary malignant CNS tumour Transient global amnesia Spinal cord injury Acute cervical myelopathy related to disc Cranial nerve injury Demyelination disorders not limited to optic nerve and not fulfilling criteria for MS HIV encephalopathy Idiopathic myelopathy Motor neurone disease Spondylitic myelopathy (chronic) Truncal mononeuropathy Diabetic amyotrophy Focal dystonia Non-cervical disc-related cord or cauda equine damage (i.e. other disc or anatomical anomalies) Optic neuritis Spinal malformation

8 (4–13) 7 (3–13) 7 (4–11) 7 (3–12) 7 (3–12) 6 (3–12) 6 (3–10) 6 (2, 12)

2; 4 10 2–8 4–6 10–15 10 (6–14)

6 (3–11) 5 (2–9) 4 (1–9) 4 (2–9) 3 (1–8) 3 (1–8) 3 (1–8) 3 (1–7) 3 (1–6) 3 (0.8–7) 3 (0.7–7) 3 (0.5–7) 3 (0.9–7) 2 (0.2–6) 2 (0.5–5) 2 (0.4–5)

1; 11 (10–12) 14 (12, 16); 15 1.5; 2.7; 9 7 2 1–2 0.25–0.8; 1 5 (F) 6 (M); 5 1.3–4; 5

1.2

2 (0.8–5) 2 (0.4–6) 2 (0.3–5) 2 (0.5–6) 2 (0.6–6) 1 (0.1–4) 1 (0.1–4) 1 (0.1–3)

2.2 1.6; 3

1 (0.2–3) 1 (0.1–2)

3.3

1–2

A small number of cases of the following diseases were also found in this study: cerebellar degeneration, dementia of uncertain cause, frontal dementia with anterior horn cell disease, neurosarcoid with cord involvement, neurofibromatosis, tuberous sclerosis, communicating hydrocephalus, aqueduct stenosis, cerebral cyst, tonsillar herniation with Chiari malformation, syringomyelia, myotonic dystrophy, myositis, idiopathic neurogenic bladder, tubercular meningitis, meningococcal meningitis, syphilis, streptococcal meningitis, Streptococcus pneumoniae brain abscess, Listeria meningitis, cryptococcal meningitis, and an unidentified ventriculitis in a man dying of a reticulosis).

4

Neurology Worldwide Table 1.4 The National Hospital for Neurology and Neurosurgery record linkage study: lifetime prevalence of neurological conditions, and previously reported rates. Conditions

Lifetime prevalence/1000 population (95% CI)

Previously reported point prevalence (PP) rates or estimated lifetime prevalence/1000

Stroke Transient ischaemia Epilepsy Congenital neurological deficit Parkinson’s disease Multiple sclerosis Diabetic polyneuropathy Compressive mononeuropathies (except CTS) Subarachnoid haemorrhage Polyneuropathy (excluding diabetic and alcoholic) Single seizures Bacterial meningitis Other meningitis or encephalitis Aseptic meningitis Essential tremor Polio Severe head injury Optic neuritis Benign CNS tumours Intracranial haemorrhage Other movement disorders Viral encephalitis Spondylitic and compressive myelopathy Cluster headache Subdural haemorrhage Malignant CNS tumours PN or plexus injury Demyelinating conditions not fulfilling the criteria for MS Cauda equina lesion Dystonia primary/secondary

9 (8–11) 5 (4–6) 4 (4–5) 3 (3–4) 2 (1–3) 2 (2–3) 2 (1–3) 2 (2–3) 1 (0.8–2) 1 (0.8–2) 1 (0.9–2) 1 (0.8–2) 1 (1–1) 0.9 (0.6–1) 0.8 (0.5–1) 0.7 (0.4–1) 0.6 (0.4–1) 0.6 (0.3–1) 0.5 (0.3–1) 0.5 (0.2–0.8) 0.4 (0.2–0.7) 0.4 (0.2–0.7) 0.4 (0.2–0.7) 0.3 (0.2–0.6) 0.3 (0.2–0.6) 0.2 (0.06–0.4) 0.2 (0.05–0.4) 0.1 (0.04–0.3)

5 2; 6 5 3, 2/1000 between 7 and 10 years; CNS malformation 0.7, Down’s syndrome 0.5 1 (PP); 2 (1); 2 1; 2 3 0.4 (PP) 0.5 0.4 (PP)

Benign intracranial hypertension Intrinsic myelopathy Spinal cord injury Narcolepsy Motor neurone disease Aqueduct stenosis and hydrocephalus in adults HTLV 1 myelopathy Transient global amnesia Leg mononeuropathy – all Arm mononeuropathy – all excluding CTS Trigeminal neuralgia Post-herpetic neuralgia Muscular dystrophies Myasthenia gravis Eye movement disorders Brachial neuritis Guillain–Barré syndrome Horner’s syndrome

0.1 (0.02–0.4) 0.1 (0.02–0.4) 0.1 (0.03–0.3) 0.1 (0.02–0.3) 0.1 (0.02–0.3) 0.1 (0.02–0.3) 0.1 (0.02–0.3) 0.1 (0.01–0.3) 0.1 (0.01–0.3) 0.04 (0–0.2) 0.04 (0–0.2) 1 (0.8–2) 0.7 (0.5–1) 0.7 (0.4–1) 0.7 (0.4–1) 0.4 (0.2–0.7) 0.4 (0.2–0.7) 0.3 (0.2–0.7) 0.3 (0.1–0.6) 0.2 (0.08–0.5) 0.2 (0.04–0.4)

abscess 0.02 (PP), meningitis 0.05 (PP)

3 (1) 1 0.1 0.6 in brain, 0.1 in cord Hereditary ataxia 0.08 0.1 0.3 (F), 1 (M, M + F) Primary malignant 0.05; metastatic in brain 0.15, 0.05 in cord 0.3

0.3

Syrinx 0.07, 0.06 0.5, 0.8 0.04–0.1; 0.06

0.4 0.02–0.05; 0.6 0.04–0.1; 0.08, 0.1 (0.08–0.2); 0.4

0.08 Continued on p. 6

5

Chapter 1

Table 1.4 Continued Conditions

Lifetime prevalence/1000 population (95% CI)

Other mononeuropathy Pupillary abnormalities Sacral plexitis/plexopathy

0.1 (0.04–0.3) 0.08 (0.01–0.3) 0.04 (0–0.2)

Previously reported point prevalence (PP) rates or estimated lifetime prevalence/1000

CTS, carpal tunnel syndrome; HTLV 1, human T-lymphotrophic virus type 1; MS, multiple sclerosis; PN, peripheral nerve. Shingles was excluded from this survey of lifetime prevalence.

Age band

Incidence rates /100,000/year by age band adjusted to the UK population First stroke Men

0–4 5–9 10–14 15–19 20–24 25–29 30–34 35–39 40–44 45–49 50–54 55–59 60–64 65–69 70–74 75–79 80–84 85–89 >90 >40

Epilepsy M + F

Single seizures M + F

86 46 94 52 33 19 24 54 18 50 50 31 34 37 142 50 32 29

32 12

Women

35 194 240 560 1051 817 850 972 806 299

82 167 203 629 940 926 1271 890 757

467

446

16 19 5 14 9 10 15 34

20

25

50 37 222 100

29

116

mention. This is the difficulty of ‘case definition’ (and thus case ascertainment). Many neurological disorders are defined on clinical criteria, with the inevitable subjectivity this entails. Thus, boundaries exist in which symptoms are occurring without formal diagnosis – for instance, the boundaries between ageing and Alzheimer’s disease and between chronic headache and migraine. Similarly, in epilepsy, the inclusion of febrile seizures, single seizures and acute symptomatic seizures within a definition of epilepsy will more than double frequency figures. In some neurological disorders, only ‘the tip of the iceberg’ cases are known to health care professionals, a common effect in condi-

6

Parkinson M + F

Table 1.5 The National Hospital for Neurology and Neurosurgery record linkage study: age-specific incidence rates for stroke, epilepsy and Parkinson’s disease.

tions that are only mildly symptomatic in their early stages, such as migraine, some neuropathies, some dementing illnesses and Parkinson’s disease. Severity also varies markedly, and the inclusion of mild cases will greatly inflate frequency figures but with relative reduction in burden of illness. Studies of epilepsy from the National Hospital provide examples of this – with over 60% of patients with epilepsy entering long-term remission and incurring only a minor impact on health services (see below). Case finding methods also need to be tailored to the disease’s spectrum of severity and frequency, and any method using hospital statistics will greatly underestimate the true number of cases as many

–8 4 ≥8 5

–7

4

80

4

4

–6

70

60

4

–5 50

–4 40

–3

4

4 –2

4 –1

0–

10

30

9 8 7 6 5 4 3 2 1 0

20

220 200 180 160 140 120 100 80 60 40 20 0

4

Incidence per 100,000 people

minor or static neurological conditions are cared for outside the hospital setting. Ethnic differences in disease were shown by the study of Stewart et al. from a multi-ethnic region of London in stroke. A stroke register was used with 12 sources of case ascertainment. The population size was 234,533 with 72% Caucasian, 21% Black (11% Afro-Caribbean, 7.5% West African and 2.5% mixed) and 3% South Asian. Incidence rates were standardized for age and sex. The crude annual incidence rate of stroke was 130 (120– 141/100,000/year and the age-adjusted rate figure (to a standard European population) is 125 (115–135). The rate in the Black population was significantly higher with an incidence rate of 221 (177–276 per 100,000). The rate, not surprisingly, increased with age. The study also looked at social class and found higher rates in those less than 64 years in lower social classes. This sort of study generates hypotheses about causation (as yet not explained) and provides data for rational health care planning (partially implemented). Similar considerations apply when considering rarer conditions, especially those requiring complex medical care where a sound estimate of frequency is important. A study of the prevalence and causation of dementia in those under 65 years, carried out by Harvey et al. in West London, is one example. In this population of 567,500 people, the prevalence of dementia in those aged 30–64 years was 0.54/1000 (0.45–0.64). For those aged 45–64 years, the prevalence was 0.98/1000 (0.81–1.18). From the age of 35 onwards, the prevalence of dementia was found to approximately double with each 5 year increase in age. On the basis of these figures, it was estimated that in 2003, there were 18,319 (15,296–21,758) people with dementia under the age of 65 in the UK. Using diagnostic algorithms, 34% had Alzheimer’s disease, 18% vascular dementia, 12% fronto-temporal dementia, 7% dementia with Lewy bodies and 19% had other causes which included Huntington’s disease, multiple sclerosis, corticobasal dementia, prion disease, Down’s syndrome (probably underestimated), Parkinson’s disease and others. From the perspective of health services, figures of prevalence and incidence of the cases receiving treatment are important, as it is these cases that consume resources, not untreated (usually mild) or cases before diagnosis. In 1998, a large study of epilepsy was published by the author and colleagues amongst a population of 2,052,922 in England and Wales of persons with epilepsy receiving anti-epileptic drug treatment (Wallace, Shorvon & Tallis 1998). This provided accurate age-specific rates (Figure 1.2) and both the period prevalence and incidence of treated epilepsy was lower in children and higher in the elderly. Neurology is also distinguished from other areas of medicine by the large number of uncommon conditions within its purview (neurology has the highest number of conditions listed in the International Classification of Diseases), and therefore large populations must be studied to obtain accurate population-based data with appropriate statistical reliability. Sampling error increases with rarer events and for many diseases there are few reliable data.

Prevalence per 1000 people

Neurology Worldwide

Age (years) Figure 1.2 Standardized prevalence and incidence rates of treated epilepsy in a population of 2,052,922 persons in England and Wales in 1995. (Bars indicate 95% CI.) Prevalence of treated epilepsy: overall 5.15/1000 people (95% confidence interval [CI] 5.05–5.25); age 5–9 years 3.16 [2.86–3.48]; 10–14 years 4.05 [3.70–4.42], 65–69 years 6.01 [5.50–6.57]; 70–74 years 6.53 [5.97–7.14]; 75–79 years 7.39 [6.73–8.11]; 80–84 years 7.54 [6.78–8.39]; 85 years and older 7.73 [6.98–8.66]). Incidence of treated epilepsy: overall 80.8/100,000 people (76.9–84.7); 5–9 years 63.2 [50.5–79.1]; 10–14 years 53.8 [42.4–68.3]),` 65–69 years 85.9 [68.5–107.3]; 70–74 years 82.8 [65.0–105.2]; 75–79 years 114.5 [116.9–179.2]; 80–84 years 159 [125.2– 202.6]; 85 years and older 135.4 [100.4–178.7]). (From Wallace, Shorvon & Tallis (1998), with permission.)

Causation The attribution of causation to neurological disease is not always a simple matter. Most neurological diseases are multifactorial in nature, being the result of complex interactions between genetic and environmental influences. The balance between the two varies. The genetic influences can be very strong – for instance, in single gene disorders with high penetrance (e.g. Huntington’s disease). In others the genetic influence is the result of more complex interactions between presumed susceptibility genes of which there may be many (e.g. epilepsy), and in other diseases identifiable Mendelian genetic influences do exist but are seen in some families cases only (Alzheimer’s disease for instance is familial in about 10% of cases). The environmental influences are predominant in many diseases, for instance head injury or cerebrovascular disease. An interaction between genetic and environmental factors occurs in other diseases, for instance the interaction of smoking and genetic susceptibility in Parkinson’s disease, or geographic location and genetic susceptibility in multiple

7

Chapter 1

sclerosis. The latter is an interesting example as there are often unexplained geographical variations which may reflect either environmental or genetic influences or both. In most neurological diseases, even the common diseases, the primary causes are not clearly understood (see Chapter 10). In multifactorial disease, it is often helpful to define ‘risk factors’. The study of the epidemiology of a disease, in particular using case–control methodologies, can give important clues as to relative importance of different risk factors. The use of risk factor, hazard ratio and odds ratio calculations allows meaningful comparative statistics to be drawn up. This is demonstrated by the example of epilepsy resulting from cerebrovascular disease. In one study, a history of stroke has been found to be associated with an increased lifetime occurrence of epilepsy (OR 3.3; 95% CI 1.3–8.5). Among the other vascular determinants, only a history of hypertension was associated with the occurrence of unprovoked seizures (OR 1.6; 95% CI 1.0–2.4). The risk of unprovoked seizures rises to 4.1 (95% CI 1.5–11.0) in subjects having a history of both stroke and hypertension. Haemorrhagic stroke (subarachnoid haemorrhage and, to a lesser extent, primary intracerebral haemorrhage) are followed by a higher risk of seizures. The cumulative probability of developing seizures after a first stroke is about 6% after 1 year and rises to 11% at 5 years, with significant differences across stroke subtypes (cerebral infarction 4 and 10%; primary cerebral haemorrhage 20 and 26%; subarachnoid haemorrhage 22 and 34%). The risk of epilepsy among survivors of subarachnoid haemorrhage caused by ruptured cerebral aneurysm is highest in patients with acute symptomatic seizures (RR 7.0; 95% CI 2.3–21.6) and those with severe neurological sequelae (RR 2.5; 95% CI 0.9–6.3). Another study by Wallace and colleagues compared the frequency of stroke after the development of late-onset seizures in 4709 individuals who had seizures beginning at or after the age of 60 years, with 4709 randomly selected, matched controls with no history of seizures. Log-rank testing, adjusted for matching, showed a highly significant difference in stroke-free survival between the two groups (P < 0.0001) and the relative hazard of stroke at any point for people with seizures compared with the control group was 2.89 (95% CI 2.45–3.41).

Mortality The mortality rate of any condition is defined as the number of persons with that condition dying during a specified period divided by the number of persons in the same population. This information is of limited value, particularly in chronic neurological disease, without a knowledge of the underlying rate of death in patients without the condition or of age distribution. Therefore, mortality is often expressed as the ratio between the observed and expected numbers of death – this measure is known as the standardized mortality ratio (SMR). Expected deaths are calculated by measuring the death rates of a reference population with an age distribution that is similar to the study population. When there is no difference in mortality between the study and reference population the SMR is 1. The 95%

8

CI provides an estimate of the significance of the calculated SMR. Another useful measure is the proportional mortality ratio which is the percentage of deaths that are due to any one cause. Life expectancy, defined as the median survival, is linked to age and is often lowered in neurological disease when compared with a healthy population, but statistics are complex to derive and there are few studies of this in neurological disease. Taking epilepsy as an example, in a UK cohort study we followed a cohort of 564 newly diagnosed cases of epilepsy for 11–14 years and found an overall SMR of 2.1 (95% CI 1.8–2.4). Patients with acute symptomatic epilepsy (SMR 3.0; 95% CI 2.0–4.3), remote symptomatic epilepsy (SMR 3.7; 95% CI 2.9– 4.6) and epilepsy due to congenital neurological deficits (SMR 25; 95% CI 5.1, 73.1) had significantly increased long-term mortality rates. In idiopathic epilepsy the SMR was 1.3 (0.9–1.9) – in other words not significantly different from the national population. The study also calculated the hazard ratio (HR), or risk of mortality in a particular group with a particular risk factor compared to another group without that particular risk factor. For epilepsy overall , it was 6.2 (95% CI 1.4–27.7; P = 0.049). Rates varied with the cause of epilepsy: cerebrovascular disease (HR 2.4; 95% CI 1.7–3.4; P < 0.0001), CNS tumour (HR 12.0; 95% CI 7.9–18.2; P < 0.0001), alcohol (HR 2.9; 95% CI 1.5–5.7; P = 0.004) and congenital neurological deficits (HR 10.9; 95% CI 3.2–36.1; P = 0.003). An older age at the time of diagnosis was also associated with significantly increased mortality rates (HR 1.9; 95% CI 1.7– 2.0; P < 0.0001). Life expectancy has also been calculated in the same population based on the Weibull distribution. This depends on age at time of diagnosis and aetiological group, and of course reductions in life expectancy diminish over time. In our study of epilepsy, overall reduction in life expectancy, at the time of diagnosis, was found to be up to 2 years for people with a diagnosis of idiopathic or cryptogenic epilepsy, and up to 10 years in people with symptomatic epilepsy. Mortality rates can be a useful way of quantifying treatment, but it is equally important in some neurological conditions to consider quality of life. This was well shown in a study of survival after radiotherapy in malignant glioma by Clarke and colleagues in 1996. Radiotherapy is known to prolong life (in one trial to 38 weeks after radiotherapy compared to 14 weeks with steroids alone). However, the side effects of radiotherapy can be severe, and the trade off between survival and quality of life is important to consider. It was found that the clinical status before radiotherapy was a good indicator of the duration of disability-free life after radiotherapy. The authors concluded that for those already disabled by the tumour, radiotherapy offered little physical gain and even if not severely disabled the treatment could cause severe adverse effects.

Other measures and rates Other epidemiological measures and rates can be derived, for instance related to childbirth or co-morbidity, and are of importance in certain health care areas:

Neurology Worldwide • Birth rate is usually defined as the number of live births per mid-year population; • Fertility rate is usually defined as the number of live births per number of women aged 15–44 years; • Infant mortality rate is defined as the number of infant (100 billion within the human brain) is the functional unit of the nervous system. Neuronal specificity, size and cell type vary greatly. One α-motor neurone of the lumbar cord has an axon over 1 m in length and innervates between several hundred and 2000 muscle fibres – to form a motor unit. By comparison, some spinal or intracerebral interneurones have axons under 100 μm long which terminate on a single neuronal cell body. A summary of neuronal ultrastructure follows. The neurone is constituted by its nucleus, cytoplasm, neuronal membrane and cytoskeleton (Figure 2.3). Neurotransmission and intrinsic modification of the neurone itself are its functions – to facilitate transfer of information, to adapt to and record change. The combination of axonal electrical activity and synaptic neurotransmitter release provides the basis for most interneuronal transmission, with an important role also for the release of neuromodulators. The integrity of intraneuronal and glial structure and function is also essential; glia are now known to play a part in synaptic transmission, re-uptake of neurotransmitters and the general control of the extracellular environment in which the neurones are located. Neuronal plasticity indicates the ability of neurones to adapt, to change, singly, in sequence and/or in groups and is a particularly well-developed aspect of the mammalian nervous system. Plasticity has a pivotal role in both learning and recovery from injury, and can involve changes in all or any part of the neurone. From the neurone cell body (soma, perikaryon) extend neurites, i.e. axons (up to 1 m long) and dendrites (rarely longer than a few millimetres). Most axons branch repeatedly to establish synaptic connections with other neuronal cell bodies. In this way neurones are able to make divergent connections with many other neurones within the CNS.

13

Chapter 2

Figure 2.1 Santiago Ramón y Cajal (1852–1934) with his light microscope in 1915. (With kind permission of the Instituto Cajal, Madrid.)

The dendritic and soma membrane represents the main region through which the neurone receives its synaptic input. Some neurones receive many thousands or even hundreds of thousands of such inputs. The neuronal membrane is the 5 nm thick barrier enclosing cytoplasm, excluding substances bathing the neurone. This membrane bilayer of phospholipid has typically a polar hydrophilic head and an insoluble non-polar hydrophobic tail. Neuronal membrane proteins are responsible for the interaction between the neurone and its environment. These proteins are: • Ion channels, usually either ligand-gated or transmitter-gated; • Receptors; and • Cell adhesion molecules. The cytoskeleton consists of microtubules, neurofilaments and microfilaments. Microtubules are some 20 nm diameter, hollowwalled strands of α and β tubulin – polymers of globular microtubule associated proteins (MAPs). Tau is an axonal MAP. Dynein and kinesin are motor proteins (aka molecular motor or motor molecules) that convert chemical energy in ATP into mechanical energy (movement). Neurofilaments are 10 nm thick (intermediate filaments of all other cells), braided, tight, physically strong protein strands. They form a peri-nuclear network and provide structural integrity. Microfilaments are 5 nm thick, braided duplexes of actin (42– 44 kDa). They are critically involved in neurone shape, where they have a role analogous to those in muscle. Neuronal replication is the exception, although neurogenesis has been clearly shown to take place in the olfactory neuroepithelium, hippocampus and hypothalamus. Neuronal dynamics imply that intraneuronal contents are continually being reformed and degraded. The cofactor ubiquitin molecule interacts with degraded proteins via hydrophobic residues – complexes of more than five ubiquitin molecules are broken down by an ATPdependent multi-enzyme system, the 26S proteasome. Failure to remove degraded proteins is of signal importance in many neu-

14

Figure 2.2 Fine detail of cortical neuronal networks (Cajal). First, second and third layers of precentral gyrus of the cerebrum. A, B, C, small pyramidal cells; D, E, medium pyramidal cells; F, G, H, bitufted cells and dendritic shafts. (With kind permission of the Instituto Cajal, Madrid.)

rodegenerative diseases (e.g. Alzheimer’s disease; Chapter 7), and myopathies such as inclusion body myopathy (Chapter 9).

Amyloid and tau in degenerative brain diseases Any detailed account of normal and pathological neurochemistry is far outside the scope of this chapter. However, it is relevant to include here a synopsis of some neurochemical findings in common degenerative neuronal diseases, especially Alzheimer’s (Chapter 7). In Alzheimer’s disease, neurofibrillary tangles develop – filamentous inclusions within the soma and dendrites adjacent to it. Paired helical and 15 nm straight insoluble protein filaments become visible. These are isoforms of tau, the microtubule binding protein that in health is soluble. This structural change in the cytoskeleton is likely to impair axonal transport, neurotransmission and eventually viability of the neurone. In the second pathological hallmark of Alzheimer’s, the extracellular senile plaque, deposits of amyloid are surrounded by dystrophic neuronal elements. Amyloid is the name given to

Nervous System Structure and Function

Dendrite

Perikaryon Soma Nucleus

Axon Collateral

Tubulin molecule

Schwann cell

Actin molecule 20 nm

(c)

(a)

10 nm

Microtubule

5 nm

Microfilament Neurofilament

Dendrite

Lysosome Axosomatic synapse

Microfilaments and microtubules Golgi complex

Nissl body

Mitochondrion Neuroglial matrix Axodendritic synapse Axoaxonic synapse

Axon Myelin sheath Smooth endoplasmic reticulum

(b)

Extracellular Enzyme-linked receptor

Phospholipids, e.g. phosphatidyl chlorine

G-protein-linked receptor NH2

Cadherin cell adhesion molecule

Voltage or ligand activated ion channel

α β γ G-protein Intracellular (d)

Protein molecule

Enzymes of secondary messenger cascade

COOH

Attached to cytoskeleton fibres

Figure 2.3 Motor neurone. (a) Soma, axon and Schwann cell; (b) ultrastructure; (c) cytoskeleton; (d) neuronal membrane.

β-pleated sheets of aggregates of fibrillar peptides that stain with Congo red and are doubly refractive in polarized light. Aβ amyloid, a 4 kDa peptide cleaved from amyloid precursor protein (APP) is the main constituent of histological amyloid.

APP is one member of a larger family of amyloid precursor-like proteins, APLP1 and APLP2. APP is encoded by a gene in the long arm of chromosome 21; it exists in three main isoforms of 695–770 aminoacids. Neuronal APP is the source of most

15

Chapter 2

extracellular Aβ amyloid in Alzheimer’s disease. APP synthesis takes place in the rough endoplasmic reticulum. It is glycosylated in the Golgi apparatus and offered to the surface of the neurone as an integrated membrane protein. A fraction of APP within the plasmalemma remains within the neurone from which are generated various forms of Aβ (Aβ1–40, Aβ1–42, truncated Aβ17–40 peptides). Putative mechanisms of neurotoxicity of Aβ fragments and the genetics of Alzheimer–APP gene mutations (chromosome 21), presenilin 1 and 2 (chromosomes 14 and 1), and allelic forms of ApoE (chromosome 19) are discussed in Chapter 7.

Asymmetrical membrane differentiation (a)

Symmetrical membrane differentiation (b)

Neurotransmission Electrical synapses Between mammalian neurones, electrical synapses, found, for example, in the giant squid, have largely been replaced by chemical transmission systems. Evolutionarily distant electrical synapses still occur at gap junctions, where the synaptic cleft is some 3 nm wide. Connexin protein complexes (see Myelin below) span these narrow gaps, coupling adjacent cells electrotonically with pores some 2 nm in diameter. These pores are large enough for the passage of all major cellular ions and many organic molecules. Electrical transmission is bi-directional, and slow. Gap junctions are seen in mammalian glial cells, epithelial cells, smooth and cardiac muscle cells, and in some nuclei in the brain, e.g. the inferior olivary nucleus. There is evidence that during brain development, transmission via gap junctions between neighbouring neurones coordinates growth and maturation.

Chemical synapses In a chemical synapse, the synaptic cleft is some 20–50 nm wide and filled with an adherent matrix, ensuring its stability. The presynaptic element, usually an axon terminal, houses mitochondria, synaptic vesicles and larger secretory granules – the densecore vesicles seen on electron microscopy (EM). Either side of the synaptic cleft specialized areas of accumulated protein comprise membrane differentiations, with an active zone on the presynaptic side opposite the post-synaptic density. The post-synaptic density houses receptors. Receptors make possible intracellular events, a change in membrane potential or secondary chemical events. Receptors are specially sensitive to interaction with neurotransmitters and neuromodulatory agents released by the presynaptic neurone.

Types of CNS synapse CNS synapses are classified as axodendritic (axon → dendrite), axosomatic (axon → cell body), axo-axonic and dendrodendritic. The terms Gray’s Type I and II synapses are also used (Figure 2.4): • Gray’s Type I: asymmetrical, post-synaptic membrane differentiation thicker and more complex than presynaptic, usually excitatory;

16

Figure 2.4 Types of synapse. (a) Gray’s Type I: asymmetrical, typically excitatory; (b) Gray’s Type II: symmetrical, typically inhibitory.

•

Gray’s Type II: symmetrical membrane differentiation, similar thickness, usually inhibitory.

Peripheral nervous system synapses Synaptic transmission is involved in communication throughout the peripheral nervous system (PNS), including transmission from motor nerves to striated skeletal muscle fibres and from autonomic fibres to smooth and cardiac muscle. The skeletal neuromuscular junction is a specialized cholinergic synapse facilitating fast reliable neuromuscular transmission. Its peripheral site and accessible micro-anatomy has made possible a detailed study of its function in health and disease.

Neuromuscular junction At the motor end-plate presynaptic active zones are closely aligned to the post-synaptic membrane densely packed with acetylcholine receptor sites (Figure 2.5). Acetylcholine, liberated by an action potential leads to acetylcholine release from synaptic vesicles into the synaptic cleft. Depolarization of the motor endplate follows.

Neurotransmitters Effective chemically mediated synaptic transmission requires transmitters to be synthesized, transported, liberated appropriately and metabolized or recycled. Neurotransmitters fall into one of four categories (Table 2.1). Neurotransmitters are synthesized in several ways. Glutamate and glycine are ubiquitous amino acids, abundant in all cells including neurones. GABA and amine neurotransmitters are made only by neurones that release them, via specific enzymes and precursors. Synthesizing enzymes for both amino acid and amine neurotransmitters are transported to the axon terminal where they direct transmitter synthesis, locally and promptly.

Nervous System Structure and Function

Myelinated axon of motor neurone

Axon terminal Sarcolemma of muscle fibre Nucleus of muscle fibre Ca2+

Axonal terminal of motor neurone Mitochondrion Synaptic vesicle with acetyl choline Active zone Synaptic cleft Acetylcholine receptors Junctional fold

M SF SV PSM SC Na + K+

Ion channels

(b)

(a)

Figure 2.5 Neuromuscular junction. (a) General arrangement and detail. (b) Electron micrograph of a neuromuscular junction from mouse flexor digitorum brevis muscle. M, mitochondrion; PSM, postsynaptic membrane; SC, synaptic cleft; SF, synaptic fold; SV, synaptic vesicle. Courtesy of Dr Tom Gillingwater, Centre for Integrative Physiology, University of Edinburgh. From Gillingwater TH, Ribchester RR. Compartmental neurodegeneration and synaptic plasticity in the Wlds mutant mouse. J Physiol 2001; 534: 627–39 with permission.

Table 2.1 Principal neurotransmitters. Amino acids

Amines

Peptides (many others)

Gases

γ-Amino-butyric acid (GABA) Glutamate (Glu) Glycine (Gly)

Acetylcholine (ACh) Dopamine (DA) Adrenaline (epinephrine) Noradrenaline (norepinephrine) Histamine Serotonin (5-HT)

Cholecystikinin (CCK) Dynorphin Enkephalins (Enk) N-acetyl-aspartyl-glutamate (NAAG) Neuropeptide Y Somatostatin Substance P Thyrotropin-releasing hormone (TRH) Vasoactive intestinal peptide (VIP)

Nitric oxide (NO) Carbon monoxide [?] (CO)

Purines, ATP and adenosine are also neurotransmitters.

17

Chapter 2

Once synthesized, transporter proteins concentrate amino acid and amine transmitters within synaptic vesicles. Peptide neurotransmitters are strung together by ribosomes within the rough endoplasmic reticulum (ER) and cleaved to form active molecules in the Golgi apparatus (GA). Secretory granules bud off the GA and are carried to the axon terminal by axoplasmic transport. Amine and amino acid transmitters are stored in and released from synaptic vesicles. Peptide neurotransmitters are stored in and released from secretory granules. These may coexist in the same neurone, to be released under different conditions.

Transmitter release Neurotransmitter release into the synaptic cleft is triggered by the arrival of an action potential at the axon terminal, where depolarization of the terminal membrane causes voltage-gated calcium channels to open. Vesicles release transmitters by exocytosis at an active zone into the synaptic cleft; the vesicle membrane is recovered by endocytosis. Secretory granules (dense core vesicles) also release neurotransmitters by exocytosis, but typically not at active zones. Peptide neurotransmitters are not released by every action potential, but typically by high frequency trains of action potentials. Peptide release is typically slow (50 ms), while amino acid and amine release is rapid.

Transmitter-gated ion channels and G-protein-coupled receptors Neurotransmitter–receptor binding – a key–lock analogy is simple but valuable – alters the shape of receptor protein and hence its function. There are two distinct types of receptor. Transmitter-gated ion channels consist of protein subunits that open an ion pore, and change shape in response to neurotransmitter. For example, the ACh-gated ion channel at the neuromuscular junction, permeable to both Na+ and K+, is triggered to produce an excitatory post-synaptic potential (EPSP) in response to ACh. Both ACh and glutamate-gated channels trigger EPSPs when activated, i.e. are excitatory. Glycine-gated and GABAgated channels, permeable to Cl− ions and tending to hyperpolarize the resting membrane potential, are inhibitory, triggering inhibitory post-synaptic potentials (IPSPs). Amino-acid and amine neurotransmitters deliver fast synaptic transmission via transmitter-gated ion channels. G-protein-coupled receptors are involved in a more diverse, slower and longer lasting mechanism of chemical synaptic transmission in response to amino-acid, amine and peptide neurotransmitters. Receptor proteins activate G-proteins that travel along the intracellular face of the post-synaptic membrane. These in turn activate effector proteins – membrane-located G-protein-gated ion channels or enzymes that synthesize second messengers.

Glia Within the CNS, four types of glial cells support neuronal activity: astrocytes, oligodendrocytes, microglia and ependymal cells.

18

Schwann cells are the neuroglia of the PNS, investing certain peripheral axons with myelin. Neurones are biologically dependent upon glia.

Astrocytes These are microscopically star-shaped shaggy cells from which protrude several dozen, fine astroglial processes that make intimate contact with neurones (Plate 2.1). Intermediate filaments within astrocyte cytoplasm lend tensile strength to the brain and cord. Glycogen granules within astrocyte cytoplasm provide intermediate energy (glucose) to surrounding neurones. Astrocytes are engaged in recycling glutamate and GABA and scavenging K+ ions following neurotransmission; they have an essential role in controlling the composition of the extracellular fluid. Glial limiting membranes – from astrocytic processes – cover the pial surface of the brain and with ependyma line the ventricles. Vascular processes of astrocytes are in intimate contact with CNS capillaries. Astrocytes retain a capacity to multiply throughout life, and do so following neuronal injury to form glial scars (gliosis). Neoplastic proliferation leads to astrocytomas (Chapter 20).

Oligodendrocytes (oligodendroglia) One oligodendrocyte lays the myelin sheaths of 30–40 CNS axons, the inner and outer surfaces forming the spiral sheaths seen as minor and major dense lines on microscopy. The axon is exposed between oligodendroglial segments at each node of Ranvier. Paranodal pockets – collections of cytoplasm – are visible at each end of each myelin lamination (see Schwann cells below). CNS myelination commences in utero and continues for some 20 years in humans. The effect of the ensheathing myelin lamellar spiral is to facilitate both saltatory conduction and axonal integrity. The nature of CNS demyelination, i.e. the breakdown of normal rapid axonal saltatory conduction, seen typically in multiple sclerosis, is discussed in Chapter 10. Neoplastic proliferation leads to oligodendrogliomas (Chapter 20). Within grey matter, modified oligodendroglia are seen as satellite cells – involved in interneuronal ion transfer. Many CNS axons remain unmyelinated – typically small 4 mm, and is demonstrated by flexion/extension X-rays of cervical spine or sagittal CT reconstruction. Three-dimensional CT allows assessment of any rotational component. Instability may occur spontaneously or develop secondarily to inflammation or trauma. It is a recognized feature of the complex developmental cranio-facial and craniovertebral anomalies, particularly if there is atlas assimilation and segmentation failure as in the Klippel–Feil syndrome. Syndromes that are also associated with ligamentous laxity carry a particular risk of dislocation, e.g. the mucopolysaccharidoses and Down’s syndrome. The surgical treatment of cranio-cervical junction anomoly is complex and complete description is beyond the scope of this

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Horizontal atlantoaxial instability is commonly treated by posterior C1–2 fixation and bone graft, whereas vertical instability or ‘cranial settling’, analogous to a toffee apple on a stick, requires posterior occipito-cervical fusion.

Down’s syndrome Trisomy 21 occurs in around 1/650 live births and is the single most common cause of severe learning difficulties. It initially presents with characteristic dysmorphic features and hypotonia, often with associated cardiac and gastrointestinal anomalies. It is estimated that up to 25% of patients with Down’s syndrome have asymptomatic atlanto-axial instability. Only around 1% are symptomatic. Recognized presentations include mild pyramidal tract signs with gait disturbance or the precipitous onset of cord compression. In the absence of signs or symptoms, screening of the atlanto-dens interval is no longer routine.

Chiari malformations

Figure 15.4 Congenital basal impression. Odontoid peg compression at cranio-cervical junction (MRI T2W).

Figure 15.5 Transoral surgical approach to the cranio-cervical junction.

chapter. If neurological symptoms and signs of brainstem compression occur, or abnormal movement at C1–2 generates significant pain, then surgery is usually indicated. The aim of surgery is twofold: first to decompress and secondly to stabilize the craniocervical junction when necessary. Anterior decompressive surgery is commonly performed by the transoral approach, e.g. for tumours, rheumatoid pannus, os odontoideum and non-united odontoid fractures (Figure 15.5). Posterior decompression may be performed for Chiari malformations.

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Professor Hans Chiari, an Austrian pathologist (1851–1916) described four types of hindbrain malformation. The Chiari I malformation is demonstrated on neuroimaging by the dorsal extension of the cerebellar tonsils below the level of the foramen magnum. The prevalence of Chiari I in asymptomatic individuals is probably less than 1%, although it rises if tonsillar descent on sagittal MRI is associated with appropriate symptoms or other hind brain anomalies and in around 50% of cases of true cerebellar ectopia there is elongation of the medulla. Approximately 50% of Chiari I malformations are associated with cranio-cervical anomalies and syringomyelia. The development of Chiari I is likely to be multifactorial. It has been postulated on the basis of familial aggregation that Chiari I is a disorder of para-axial mesoderm. Chiari I is present in renalcoloboma syndrome in which mutations in the PAX-2 gene have been identified. However, unlike Chiari II-IV there are clear examples of acquired Chiari I in which serial MRI has demonstrated postnatal development of the anomaly. Furthermore, lowering of CSF pressure following lumbar puncture or lumbar peritoneal shunting may be a risk factor for cerebellar tonsil descent. Chiari I has occurred during baclofen-pump insertion. There are well-documented examples of ‘Chiari’ or ‘pseudoChiari’ malformations improving following treatment of abnormally low CSF pressure caused by CSF leakage (Figures 15.6 and 15.7). The symptoms and signs resulting from Chiari I overlap with those associated with other cranio-cervical anomlies (see above). These include headache, especially cough headache, nystagmus and quadriplegia. Additional symptoms and signs may result from associated hydrocephalus or syringomyelia. The condition is rarely symptomatic in childhood. Unusual presentations of Chiari I have been described: sudden death, syncope, ventricular fibrillation resulting from head movement, lingual myoclonus, pulsatile tinnitus, Ménière-type symptoms, acquired esotropia, central apnoea and paroxysmal rage.

Spinal Cord Disorders

Figure 15.6 Chiari I malformation. MRI showing pre-operative appearances.

often accompanied by partial herniation of the fourth ventricle and distortion of midbrain tectum. Associated abnormalities of supratentorial and midbrain structures are common. Chiari III is analogous to type II but describes downward displacement of the cerebellum into a posterior encephalocoele, again with elongation and herniation of the fourth ventricle. Clinical features are severe and often life-threatening, particularly where there is cranial nerve dysfunction. The Chiari IV malformation describes cerebellar hypoplasia and on current understanding is not part of the Chiari spectrum. Asymptomatic Chiari I malformations may be treated conservatively. There have been case reports of sudden death in some patients with untreated malformations, but majority of these were not truly asymptomatic. Pregnancy in patients with significant Chiari I needs to be monitored and managed with care. Pushing during the second stage of labour causing further tonsillar descent and inadvertent dural puncture during epidural anaesthesia producing coning are two risks that need to be carefully considered. Some neurologists and neurosurgeons recommend that the baby be delivered by caesarean section and under general anaesthetic. Planned pregnancy is not an indication for prophylactic foramen magnum decompression. Surgical treatment involves decompression of the foramen magnum and should be offered on the basis of significant and relevant symptoms, e.g. severe cough headache, or the presence of physical signs indicating neurological compromise. Posterior suboccipital decompression is the standard surgical management for symptomatic malformations, although there is much debate over how much bone to remove, whether the dura should be opened, scored or left intact, whether to use a dural patch graft or leave the dura widely open, and whether to resect the cerebellar tonsils to encourage good CSF flow. Surgery aims to prevent progression of symptoms, and improvement is seen in more than 80% of patients. Coexistent hydrocephalus usually improves after decompression of the foramen magnum, but if persistent, ventriculo-peritoneal shunting may be performed. Persistent syringomyelia may be treated by syringostomy, or by syringosubarachnoid, syringopleural or syringoperitoneal shunting. After foramen magnum decompression it may take several weeks for a patient to become accustomed to their altered CSF dynamics, and the patient may feel unsteady or experience low-pressure headaches. Aseptic meningitis occurs in a minority, and usually responds to a tapered course of steroids over a few weeks, after a diagnostic lumbar puncture has been performed to exclude infection.

Figure 15.7 Chiari I malformation. Post foramen magnum decompression of patient whose scan is shown in Figure 15.6 (MRI T2W).

Syringomyelia Chiari II malformation is a congenital anomaly that is associated with myelomeningocoele and hydrocephalus in >90% of cases and generally manifests in the neonatal period. It consists of caudal displacement of the medulla and cerebellum (particularly vermis) into the cervical canal over-riding the spinal cord

A syrinx is a cystic cavity in the spinal cord (syringomyelia) or brainstem (syringobulbia) which is lined by spinal cord parenchyma, as distinct from a cystic cavity which is in continuity with the central canal and lined by ependymal cells (hydromyelia). It is caused by abnormal transmission of raised CSF pressure through the spinal cord parenchyma during coughing and raised

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Figure 15.8 Syringomyelia. Post-traumatic cervico-thoracic syrinx (note T2–3 trauma and artefact resulting from pedicle screws) (MRI T2W).

Figure 15.9 Syringomyelia. Imaging of patient whose scan is shown in Figure 15.8 following insertion of syringopleural shunt resulting in successful syrinx decompression (MRI T2W).

intra-abdominal or thoracic pressure, as a result of pathologically altered CSF dynamics. Syringomyelia may be caused by several conditions: 1 Trauma, with or without spinal cord injury, often with spinal deformity. Around 2–8% of patients with spinal cord injury develop a syrinx over time, usually several years after the injury. 2 Congenital conditions such as Chiari malformations, basilar invagination and Dandy–Walker syndrome. 3 Tumours, especially intramedullary tumours such as astrocytomas and ependymomas. Investigation of syringomyelia should always include a gadolinium-enhanced MRI to exclude a tumour as the cause. 4 Arachnoiditis, particularly when affecting thoracic and cervical spine. 5 Spinal infections. The symptoms and signs of syringomyelia typically progress gradually over time, and are discussed in the section above. Diagnosis is usually made from the clinical features and typical appearance on MR imaging of the spine (Figure 15.8). A cause for the syrinx, e.g. Chiari malformation, spinal tumour or arachnoiditis, should be actively sought.

possible, the cause of the syrinx should be treated first, e.g. posterior fossa decompression for Chiari malformation. If the syrinx progresses and is symptomatic, treatment may include percutaneous drainage or open syringotomy. However, these techniques are associated with a high rate of syrinx recurrence, and a more permanent measure is to shunt the syrinx to the subarachnoid space, pleural or peritoneal cavities (Figure 15.9). Seventy-five per cent of patients were stabilized or improved in one surgical series, but because of the rarity of the condition and the variability in the surgical techniques available it is difficult to compare the outcomes of specific surgical options.

Treatment of syringomyelia Non-progressive post-traumatic syringomyelia or hydromyelia causing mild clinical features is best managed conservatively. Progressive symptoms of syringomyelia need to be treated. As far as

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Congenital basilar invagination Congenital basilar invagination results from a defect in the development of the cartilaginous skull base, producing elevation of the foramen magnum in relation to the occipital bone, with invagination of the lip of the foramen, along with flattening of the angle between the clivus and anterior fossa floor. This may be associated with other anomalies including occipitalization of the atlas, Klippel–Feil segmentation defects, Chiari malformation and syringomyelia. Basilar invagination should be distinguished from basilar impression, which is an acquired vertical translocation of the odontoid process into the foramen magnum occurring in conditions such as rheumatoid disease. Basilar impression is not usually associated with moulding of the skull base.


Os odontoideum Congenital atlanto-axial instability is sometimes caused by aplasia or hypoplasia of the odontoid process, but is more commonly the result of an os odontoideum. This is an independent ossicle located above the centrum of the axis vertebra in the position of the odontoid process, which may be associated with a hypoplastic or completely absent dens. The abnormality is more common in Down’s syndrome, spondylo-epiphyseal dysplasias and Morquio’s syndrome. The cause is thought to be in utero, neonatal or childhood fracture of the odontoid process with subsequent non-union and remodelling. If there is significant instability in a physically active patient, surgical fusion of C1 and C2 is recommended to minimize the risk of damage to the spinal cord in the future. Radiological instability is seen in 15–30% of people with Down’s syndrome, but instability is symptomatic in only 1–2% of patients. The current recommendation for patients with Down’s syndrome and atlanto-axial instability is to restrict sporting activities if asymptomatic and to fuse patients who develop symptoms.

Spinal dysraphism Spinal dysraphic states are caused by localized failure of neural tube closure during fetal development. Myelomeningocoele is the most common form, with an incidence of 0.8/1000 live births. Neural tube defects are caused by a variety of mechanisms: chromosomal abnormalities, single gene defects and teratogens. There are marked regional variations in its incidence and the condition is heterogeneous. There are strong genetic components and recurrence risks rise from 1–2% after one affected child to 10% with two affected children. Certain polymorphisms in genes involved in gene repair and folic acid metabolic pathways are associated with an increased risk of neural tube defect. The process of neuralation may be disrupted by teratogenic agents and in particular by maternal and/or fetal folate deficiency. Early folic acid supplementation reduces the incidence of neural tube defects, so that all women are recommended to take supplemental folate prior to conception and during the first trimester. It is estimated that approximately 70% of neural tube defects are preventable through maternal folic acid supplementation (400 μgm/ day). This advice is especially important for women with a previously affected pregnancy or those taking anticonvulsants in whom the incidence of neural tube defects is around 1% of pregnancies; larger amounts of folic acid are recommended for these women (5 mg/day). Folic acid supplementation should be started preconception. Routine antenatal screening provides a prenatal diagnosis in many cases; raised maternal serum α fetoprotein is associated with open neural tube defects and fetal ultrasonography allows cranial and vertebral structures to be visualized directly. Prenatal counselling and pregnancy termination can then be offered. Myelomeningocoele and myeloscisis comprise 95% of cases of spinal dysraphism, with exposed neural tissue a common feature.

In a meningocoele and in spina bifida occulta neural elements are covered by skin. The clinical features are determined by the extent of the myelocoele and the presence of associated abnormalities, which may include both neural and extraneural anomalies. Progressive hydrocephalus requiring surgical treatment is present in 90% of cases and around 70% have a Chiari II malformation. Learning difficulties are common, one-third have an IQ < 80. Syringomyelia is present in up to 75% of cases and is often associated with severe scoliosis. Approximately one-third of patients have diastematomyelia. Approximately 80% of open spina bifida defects are located in the lumbosacral area. The sensory level indicates the upper level of the lesion. Lesions above L3 result in complete paraplegia, but motor deficits may otherwise be patchy with a mixed pattern of upper and lower motor neurone signs. Sphincter and detrussor function is always compromised and careful urological assessment is required. Surgical closure is undertaken within 48–72 hours of delivery to reduce the risk of ascending infection and protect viable neural tissue within the placode. Following closure delayed hydrocephalus is likely. Patients generally require ongoing medical care by a multi-disciplinary team. Spina bifida occulta describes occult dysraphism, where neural structures have not herniated through the mesenchymal defect. It includes diastematomyelia, terminal myelocystocele and tight filum terminale. Lipomyelomeningocoele and dermal sinuses are often included in this classification as they also result from abnormal secondary neurulation. Spina bifida occulta is often neurologically asymptomatic. The majority of patients have associated cutaneous abnormalities such as a tuft of hair or a dimple over the region, and plain X-rays show underlying vertebral anomalies. MRI scan then confirms the diagnosis. Two neurological presentations are recognized. First, a congenital asymmetric weakness and atrophy of the lower limbs and second the ‘tethered cord syndrome’ with progressive and sometimes precipitous onset of weakness and spasticity. The latter often presents in childhood or during the adolescent growth spurt and is an important cause of toe walking in childhood. Both presentations may be associated with sphincter disturbance. Treatment is primarily neurosurgical, with release of the spinal cord from the tethering lesion, with full preoperative neurological and urological assessment. Orthopaedic, othortic and physiotherapy management of lower limb deformity is also important.

Klippel–Feil syndrome Described by Maurice Klippel and André Feil (Paris, 1912), the disorder is characterized by a short neck, impaired neck mobility and a low hairline. The incidence is approximately 1/42,000 births. Three types of Klippel–Feil syndrome are described. Skeletal abnormalities include fusion of two or more cervical or cervico-thoracic vertebrae (Figure 15.10). The syndrome is heterogeneous; differing numbers and positions of fused vertebrae

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Figure 15.11 Split cervical spinal cord in patient with Klippel–Feil syndrome (MR axial).

Figure 15.10 Lateral X-ray of patient wih Klippel–Feil syndrome showing vertebral segmentation anomaly.

are described and the associated anomalies are highly variable. The condition may be familial: dominant, recessive and X-linked inheritance patterns have been proposed; mutations in the PAX1 gene may be associated with the condition. Despite the sometimes dramatic spinal abnormalities, a follow-up study over a 10-year period has indicated that only 20% of patients experienced significant cervical spine symptoms; only 6% required surgical intervention. Extravertebral anomolies associated with Klippel–Feil syndrome affect multiple systems. Skeletal and systemic abnormalities include: scoliosis, scapula elevation, rib anomalies, cranio-facial dysmorphology, pulmonary, cardiac, gastrointestinal and urogenital anomalies. Neurological problems include syringomyelia, cranial nerve abnormalities, Duane’s retraction syndrome, deafness, acquired myelopathy resulting from the spinal abnormality, thin corpus callosum, split cervical spinal cord (Figure 15.11) and failure of pyramidal tract decussation. The latter anomaly is particularly interesting as it may underlie the intense congenital mirror movements that affect a number of these patients.

Congenital mirror movements These are intense involuntary movements, primarily of distal upper limb muscles, which mirror the voluntary unilateral movement. They cannot be suppressed and typically do not occur during passive movement. Mirror movements occur normally during a child’s motor development, however, they are rarely

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intense and disappear by the age of 6 years. Pathological mirror movements are rarely disabling and patients learn adaptive proximal movements so as to avoid inappropriate finger movements, e.g. wrong key strikes while typing. Neurophysiological study of mirror movements has provided new insights into central motor control and plasticity. A single subject with Klippel–Feil syndrome and mirror movements has been studied in detail. Unilateral focal electrical or magnetic brain stimulation (TMS) of either left or right primary motor cortex at threshold in non-mirroring subjects evokes contralateral short latency electromyographic (EMG) responses because of rapid conduction through pyramidal tract pathways. In contrast, mirroring individuals show simultaneous bilateral short latency EMG responses following unilateral motor cortex stimulation. Abnormal bilateral EMG responses indicate that in subjects with mirror movements the cortico-spinal tract is aberrant and bilaterally represented. In mirroring subjects the short latency (N20) component of the somato-sensory evoked potential is confined to the contralateral sensory cortex. Spinal (short) latency cutaneo-muscular (CMR) and stretch reflexes are confined, as in normal subjects, to the stimulated side. However, in mirroring subjects the long-latency components of the CMR and stretch reflexes are simultaneously present in both the stimulated and non-stimulated limbs. Cross-correlation analysis of EMG activity recorded simultaneously from homologous muscles of left and right hands reveals, in contrast to healthy subjects, the presence of a short duration peak at time zero indicating that during normal muscle contraction both hands receive abnormal common presynaptic drive. This abnormal drive can be shown to be highly muscle specific, indicating that abnormal bilateral cor-

Spinal Cord Disorders X-Linked Kallmann’s syndrome: coherence

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Figure 15.12 Abnormal brain–muscle coherence and cumulant in subject with aberrant corticospinal tract. (a,c) Data from control subject with coherence and cumulant between right motor cortex electroencephalogram (EEG) and left hand muscle electromyogram (EMG). (b,d) Data from X-linked Kallmann’s syndrome subject in whom transcutaneous magnetic brain stimulation showed abnormal ipsilateral fast conduction corticospinal pathways. In this subject there is abnormal coherence and cumulant between left motor cortex EEG and left hand EMG.

ticospinal axons innervate the equivalent motor neurone pools, e.g. those of first dorsal interosseous muscle on left and right sides of the spinal cord. This suggests that the abnormality is at the level of the pyramidal decussation with normal neuronal guidance mechanisms to the spinal motor neurone pools thereafter. Recent studies using EMG–EMG coherence analysis and EEG–EMG coherence analysis in subjects with X-linked Kallmann’s syndrome with mirror movements have shown that aberrant corticospinal pathways provide abnormal oscillatory drive from cortex to muscle (Figure 15.12). Taken together, these findings indicate that voluntary and long-loop reflex activity in abnormal central motor pathways produces the mirror movements seen in Klippel–Feil syndrome and other neurodevelopmental conditions. Intense mirror movements are a recognized feature of childhood hemiplegia and have been proposed to represent a physical sign of corticospinal tract rewiring following early brain damage. Children with hemiplegia and mirror movements have been studied using the approach outlined above for Klippel–Feil syndrome. The findings are similar except that the cortico-spinal axons reach both sides of the spinal cord from the undamaged motor cortex. The presence of mirror movements with character-

istic neurophysiological findings is associated with MR imaging in which there is no gliosis in response to the cerebral injury, suggesting that antenatal insults before gestational age 28 weeks causing hemiplegia are associated with very significant pyramidal tract reorganization and mirror movements. This remarkable central nervous reorganization may help to sustain function of the child’s hemiplegic hand, albeit at the expense of mirror movements. Recently, a patient with left hemisphere hydranencephaly (probably caused by a vascular insult at 20–27 weeks’ gestation, i.e. after neural migration but before synaptogenesis) in which the entire left hemisphere was missing has been reported to be living a healthy, minimally affected life with a mild hemiparesis but otherwise excellent cognitive, motor and language function. This individual had strong mirror movements suggesting corticospinal reorganization and only on detailed testing could subtle prehension deficits be detected in the right hand.

Malformations of the pyramidal tracts Consideration of the details of Klippel–Feil syndrome, X-linked Kallmann’s syndrome and congenital hemiplegia pathophysiology has led to a wider appreciation of corticospinal tract development. While there are many tracts within the spinal cord, the

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Chapter 15 Table 15.3 Pyramidal tract malformations. (After ten Donkelaar et al. 2004.) Induction defect

Cell proliferation

Neural migration

Guidance

Acquired

Anencephaly Encephaloceles Meckel–Gruber Apert ?Klippel–Feil

?X-linked Kallmann’s syndrome Hemimegalencephaly

Lissencephaly Walker–Warburg Polymicrogyria Schizencephaly Zellweger’s syndrome

X-linked hydrocephalus and other phenotypes associated with L1CAM mutations HGPPS (ROBO3 mutations)

Hypoxic-ischaemic damage (e.g. hemihydranencephaly) Peri-venticular leucomalacia (PVL) Congenital infections

HGPPS, horizontal gaze palsy with progressive scoliosis.

normal development of which is crucial to function, much is known about the development and maldevelopment of the pyramidal tract and thus work in this area has led our understanding of developmental anomalies. The pyramidal tract develops late in humans: in the embryo, fibres have reached the pyramidal decussation by the eighth week post-fertilization. Subsequent development is slow with tract myelination continuing into the third year of life. Our understanding of human pyramidal tract development is highly dependent on data from rodents and primates. In rat, the corticospinal growth cone must navigate through the internal capsule, cerebral peduncle, pons and medulla to reach the spinal grey matter. At a number of points in that journey there are ‘choice points’ at which chemoattractants and repellents can influence the journey. Mutations in genes coding for these molecules lead to gross developmental anomalies. The corticospinal tract reaches the cervical cord shortly after birth and then gradually extends to the lumbar-sacral regions. Initially, there are exuberant collaterals such that most parts of the cortex, including the occipital cortex, innervate the cord. There is then a rapid withdrawal of collaterals and loss of fibres from the corticospinal tract. This process is activity-dependent; a functional lesion of one or other corticospinal tract will lead to persistence of ipsilateral projections from the intact corticospinal tract. Failure of pyramidal decussation occurs in a number of conditions including Klippel–Feil and X-linked Kallmann’s syndromes. In animal models, mutations in oligodendrite membrane-bound neurite growth inhibitors appear to lead to loss of normal channelling of myelinated fibres leading to abnormalities of growth; furthermore, a midline anchored repellent (ephrin-B3) prevents the corticospinal tract from recrossing into the ipsilateral spine. In humans, malformations of the corticospinal tract may be caused by: 1 Induction failure, i.e. disruption during early spinal development (see Klippel–Feil syndrome above); 2 Abnormal cell proliferation; 3 Abnormal neural migration; 4 Abnormal guidance mechanisms; 5 Acquired injury. In all of these cases there are abnormalities of the pyramidal tract, the pyramids and the pyramidal decussation with abnormal ipsilateral cortico-spinal pathways. Mirror movements are a

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common feature of a number of these conditions and have been described in all the categories of pyramidal tract malformation set out below. The characteristic neurophysiology described in detail above for Klippel–Feil syndrome has been discovered also for X-linked Kallmann’s syndrome, disorders of neural migration and prenatally acquired hemiplegia. In addition, ipsilateral TMS responses indicating an abnormal ipsilateral corticospinal tract have been described in patients with familial horizontal gaze palsy with progressive scoliosis (HGPPS). In these subjects, deletions in the ROBO3 gene cause failure of pyramidal decussation. L1CAM disorders associated with a variety of phenotypes including X-linked hydrocephalus, have also been studied using TMS and, surprisingly, given that in animal models a misdirected pyramidal tract is usually the result of L1CAM mutations, no TMS evidence of an abnormal ipsilateral pathway was detected in humans. However, in the only neurophysiological study carried out, subjects with L1CAM mutations were not studied in the ways set out above, instead the focus of the investigation was on proximal rather than distal upper limb muscles. Table 15.3 shows examples of pyramidal tract malformation and misdirection.

Rheumatological disorders affecting the spine and spinal cord Paget’s disease The disorder is rare before the age of 40 but becomes increasingly common with time, affecting 10% of 90-year-olds. The clinical features are those of bone pain, local deformity, bone enlargement, pathological fracture and a predisposition to sarcomatous change. The disorder often affects the skull and spine and as a result neurological involvement is common. Typical radiological appearances and the finding of an elevated serum alkaline phosphatase make the diagnosis of Paget’s disease. The disease is one of excessive bone resorption with excessive osteoblastic and osteolytic activity. A genetic predisposition is described and some familial cases have been linked to chromosome 18q. A syndrome of Paget’s disease with inclusion body myositis and dementia has been described. Pagetic osteoclasts contain nuclear inclusions and osteoclastic infection is one proposed mechanism

Spinal Cord Disorders although firm evidence for a causative paramyxovirus infection is lacking. There are numerous potential neurological sequelae of Paget’s disease. Direct compression by pagetic bone may lead to headache, dementia, brainstem and cerebellar dysfunction, cranial neuropathies, myelopathy, cauda equina syndrome and radiculopathies. The most common cranial neuropathy is sensorineural deafness. Optic atrophy, trigeminal neuralgia and hemifacial spasm may occur also. Pagetic softening of the skull may lead to basilar invagination resulting in brainstem and high cervical compression syndromes and occasionally hydrocephalus. The brain and spinal cord can become acutely compressed from epidural haematoma. The vascularity of pagetic bone may lead to cerebral ischaemia as part of a steal syndrome (compared to normal bone, blood flow in pagetic bone is increased threefold). Neurological syndromes may also develop because of compression of blood vessels. Paget’s disease generally responds to treatment with bisphosphonates although a relative resistance to these drugs is described. First line treatment is with potent oral bisphosphonates. Second line treatment regimes include calcitonin, etidronate and intravenous bisphonsphonates. Bone pain in particular can resolve within 1–2 weeks of commencement of treatment. Treatment efficacy may be monitored by serum alkaline phosphatase levels and a therapeutic response may be expected in approximately 80% of patients treated. Neurological syndromes often improve with medical treatment. Rapidly progressive neurological syndromes require high-dose intravenous bisphosphonate therapy and/or treatment with calcitonin. However, hydrocephalus generally requires shunting. Surgical decompression for basilar invagination, cranial nerve lesions, spinal cord and root compression is indicated if neurological symptoms and signs progress rapidly or despite best medical treatment. Medical treatment prior to surgical intervention may reduce bone vascularity and thus the risk of peri-operative haemorrhage.

Rheumatoid disease Rheumatoid disease is a chronic inflammatory immune-mediated symmetrical polyarthritis with a predilection for the distal joints. Females are affected twice as commonly as males and the prevalance ranges from 0.2–2% of the population in Europe and North America. The inflamed synovium is termed the pannus; it is characterized by T- and B-cell activation, cytokine release, immune complex deposition, angiogenesis and cellular proliferation. This inflammatory process leads to damage and destruction of bone, cartilage and ligaments. Aggressive immunosuppressive therapy with disease-modifying drugs (in particular sulfasalazine and methotrexate) improves the prognosis of rheumatoid arthritis. The newer immune-modifying drugs, such as antitumour necrosis factor and anti-interleukin 1 agents, have improved the prognosis of the disease: compared to past decades, fewer rheumatoid patients are now presenting for surgery to the cervical spine and large joints.

Neurological manifestations of rheumatoid arthritis include entrapment neuropathy, vasculitic neuropathy, myopathy and ischaemic syndromes caused by vasculitis; these are discussed further in Chapter 25. The spinal cord manifestations result from ligamentous disruption, bone destruction and secondary osteoporosis. A rare syndrome of diffuse dural infiltration with inflammatory cells producing a pachymeningitis has been described. Patients with rheumatoid arthritis of the cervical spine frequently experience headache and neck pain; however, the most feared neurological complication of rheumatoid arthritis is upper cervical cord and brainstem compression. Neurological symptoms usually result from one of three ways: atlanto-axial subluxation, basilar impression (vertical translocation) or subaxial subluxation. Involvement of the atlanto-axial ligament often combined with local pannus formation and bone destruction produces subluxation. Atlanto-axial subluxation affects 25% of rheumatoid patients of whom 25% have neurological signs. Atlanto-axial subluxation may occur in lateral, rotational, anterior, posterior and vertical directions; the latter three directions being the most neurologically significant. Rheumatoid arthritis may affect the spinal cord caudal to the C1–2 level independently or in association with a high cord lesion. Postmortem studies of myelopathy show necrosis, gliosis and Wallerian degeneration within ascending and descending white matter. Cervical myelopathy is caused by repetitive minor trauma to the spinal cord because of excessive movement of the unstable level. The degree of atlanto-axial subluxation is well characterized by plain flexion– extension radiography; however, because a large part of the compression is caused by inflammatory soft tissue proper assessment requires detailed MR imaging.

Natural history In a series of 235 rheumatoid patients referred for neurosurgical assessment of cranio-cervical junction instability, 60% had myelopathy, the majority of these either had motor or mixed motor and sensory long-tract signs; in approximately 10% the predominant deficits were loss of joint position and Rombergism, indicating a mainly posterior compression. Cranial nerve signs and nystagmus were rare and in this series were associated with other pathologies, especially Chiari malformation. Rheumatoid arthritis initially involves the hands and feet, and large joints usually require surgery before the neck. Wolfe found that in the USA one in four patients had a large joint arthroplasty in the first 6 years of the disease and Casey et al. (1996) discovered that in their population, cervical disease required surgical treatment in patients who had had between two and four previous arthroplasties. This implies that greater degrees of mobility in rheumatoid joints leads to accelerated degeneration and instability. Hence, the cervical spine is affected commonly, particularly the atlanto-axial joint and the cranio-cervical junction, and the lower spine is usually spared. The percentage of rheumatoid patients who develop atlanto-axial subluxation varies between

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series, and is largely biased by the source of data collection. There are few large population-based cohort studies in the literature, but from non-surgical studies over the past few decades the percentage of rheumatoid patients with atlanto-axial subluxation varies from 14% to 73%, with an average incidence of 35% (21% horizontal and 14% vertical subluxation). More than 30% will have symptomatic atlanto-axial subluxation 5–7 years after the onset of the disease. Five per cent then become myelopathic a decade later, 14–17 years after onset. Once myelopathy has developed the outlook is poor, with up to 50% mortality within a year.

Indications for surgical management of the rheumatoid spine A study of surgical outcome comparing the 1970s with the 1990s found an improvement in mortality from 9% to 0%, a decrease in complication rate from 50% to 22%, and improvement of symptoms in 89% of patients who had surgery. Improved outcomes have been a result of better instrumentation and the trend towards earlier surgery; it is now accepted that operations for non-ambulant myelopathic patients are associated with an unacceptably high complication rate, and poor functional improvement. Atlanto-axial fusion is now more commonly performed for instability causing pain, early neurological symptoms and signs, occipital neuralgia or progressive radiological appearances (Figure 15.13). Selection of appropriate patients for surgical intervention presents a major clinical problem. The policy of waiting until

Flexion–extension cervical spine X-ray

>3 mm instability or translocation Scan No myelopathy

Myelopathy

Fit for surgery

OBSERVE

DISCUSSION: Elective fixation? • to control pain • to prevent injury Or observe?

FUSION

Fixation of the occiput to cervical spine should be considered for Vertical translocation Excessive degeneration or instability of the occipito-atlantal joints When C1 or C2 bone quality does not allow adequate screw purchase or fixation of a short segment Disruption of the ring of C1 by fracture or after transoral odontoidectomy When there is a significant ‘stair-case’ deformity or instability in the subaxial spine, requiring a longer construct to simultaneously fuse lower levels

Unfit OBSERVE

Figure 15.13 Algorithm for assessment and treatment of rheumatoid atlantoaxial disease.

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Table 15.4 Indications for different types of surgical stabilization in rheumatoid disease. C1–2 fixation should be considered for Instability and intractable pain Clinical myelopathy Occipital neuralgia Progressive radiological subluxation Antero-posterior spinal cord diameter less than 6 mm on flexion MRI PADI less than 10 mm on CT Patients with instability who are unable to wear a hard collar or brace

Rheumatoid arthritis and neck pain

No instability

rheumatoid patients with atlanto-axial subluxation develop signs of serious myelopathy has been strongly challenged on the basis that once spinal cord damage has been sustained it is rarely reversible. In a prospective trial it has been shown that following surgical stabilization, with or without transoral anterior decompression, approximately 60% of ambulant patients will show stabilization or improvement of their functional status; in contrast only 20% of non-ambulant patients will show any recovery. Furthermore, surgical morbidity and mortality was found to be significantly higher in the non-ambulant (12.7%) compared to the ambulant group (8.9%). In the past, major surgery was often performed for patients with end-stage myelopathy, often with poor results. Now surgical stabilization is generally performed at an earlier stage once instability has been demonstrated. Early surgery is associated with a better outcome, lower risk and prevents further deterioration in the diseased joint. It should be noted that the combination of mild neurological impairment and rheumatological/orthopaedic problems puts rheumatoid patients at increased risk of falls and even minor cervical injury can produce catastrophic neurological deterioration. Atlanto-axial subluxation increases the anaesthetic risk because of neck extension during artificial ventilation (Table 15.4).

Transoral decompression and posterior fixation should be considered When there is irreducible atlanto-axial subluxation causing ventral compression of the neuraxis When there is marked vertical translocation (>5 mm) causing brainstem compression When an anterior soft tissue mass causes compression around the cranio-cervical junction MRI, magnetic resonance imaging; PADI, posterior atlanto-dental interval.


Spondyloarthropathies The inflammatory spondyloarthropathies include ankylosing spondylitis, psoriatic arthritis; arthritis associated with inflammatory bowel disease and reactive arthritis, e.g. Reiter’s disease. Low back pain is common to all conditions. The primary neurological manifestations are best represented through consideration of ankylosing spondylitis, although they may also occur in association with the other spondyloarthritides. Ankylosing spondylitis is the most prevalent of the seronegative spondyloarthritides, affecting up to 2% of the population in the West. It usually presents with gradual onset low back pain and stiffness of the large joints. The condition can affect other organ systems. Men are affected more than women. Disease onset is typically before age 40. HLA B27 is strongly associated with >90% of patients expressing the antigen. Unlike rheumatoid disease, it commonly affects the spine and sacroiliac joints, rather than the peripheral joints, and the disease progresses in a caudal–rostral direction, resulting in flexion deformities in posture. The pathological hallmark is the development of enthesopathy, that is inflammation around sites of tendinous insertion. Syndesmophytes form in the spinal column points where spinal ligaments attach to the vertebral bodies. The neurological manifestations of ankylosing spondylitis are usually a late stage complication. Loss of spinal movement is associated with vertebral body squaring and extensive loss of ligamentous laxity because of syndesmophyte formation. This process produces a rigid spine with kyphosis. Spinal involvement may produce atlanto-axial subluxation, pathological vertebral fracture, disco-vertebral destruction, spinal canal especially lumbar canal stenosis and a cauda equina syndrome. Atlantoaxial subluxation occurs more rarely than in rheumatoid arthritis; however, the management issues are similar. Spinal rigidity and disco-vertebral problems predispose to cord compression. Acute spinal cord compression resulting from epidural haematoma is a recognized problem. Spinal fractures are more common because of the rigidity of the spine, and the use of a rigid collar in the emergency department is often prevented by the degree of kyphotic deformity. Forcing the neck into a collar can itself result in a cervical fracture. Despite the tendency to ankylosis in these patients, conservative management often results in a pseudoarthrosis, and anterior or posterior fusion with surgical fixation is required. The cauda equina syndrome is a rare late stage complication of ankylosing spondylitis. It presents gradually with leg pain, leg weakness, sensory disturbance and sphinteric dysfunction. On imaging studies posterior lumbar-sacral diverticulae are present. An arachnoiditis may also contribute to the development of the cauda equina syndrome; however, the presence of the diverticulae indicates that ankylosing spondylitis is the likely cause rather than some other form of arachnoiditis (Figure 15.14). It is important to remember that spinal irradiation was used to treat ankylosing spondylitis and late radiation neurological damage and bone sarcoma may result.

Figure 15.14 Lateral X-ray of thorocolumbar spine in a patient with ankylosing spondylitis.

Miscellaneous conditions affecting the spine and spinal cord Superficial siderosis This is a condition in which there is abnormal subarachnoid haemosiderin deposition (Chapter 16). The condition affects many neurological systems and when taken together the symptoms and signs form a coherent and recognizable clinical picture. A literature review of 87 cases revealed the following clinical features: sensorineural deafness (95%), cerebellar ataxia (88%), pyramidal signs (76%), dementia (24%), bladder disturbance (24%), anosmia (at least 17%), aniscoria (at least 10%) and sensory signs (13%). Less frequent features included extraocular motor palsies, movement disorders and lower motor neurone signs secondary to anterior horn cell damage (5–10% each). Neck pain, low back pain and sciatic type pain are recognized clinical features. T2-weighted MRI studies of these patients reveal a dark rim, representing the paramagnetic affects of iron deposition, particularly around posterior fossa structures, the spinal cord and occasionally the cerebral hemispheres. Previous spinal surgery is a recognized cause of superficial siderosis with chronic subarachnoid bleeding resulting from small

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Table 15.5 Causes of superficial siderosis. Neurosurgery SAH

Tumours

Nerve root trauma Miscellaneous causes

Including late effects following CNS tumour removal in childhood Caused by aneurysm, AVM or angiogram negative; SAH due to Transthyretin (Asp18Gly TTR mutation) leptomeningeal amyloidosis; intracerebral and spinal cavernomas Pituitary, cerebellar, spinal astrocytomas, spinal teratoma, ependymoma, filum terminale preganglionomas, spinal meningeal melanocytoma Avulsion, pseudomeningocoele Neurofibromatosis Type 1, CNS vasculitis, anticoagulation

AVM, arteriovenous malformation; SAH, subarachnoid haemorrhage. Figure 15.15 Arachnoiditis deforming thoracic cord (axial MRI). Table 15.6 Causes of arachnoiditis. Iatrogenic: spinal surgery, multiple lumbar punctures and spinal anaesthesia Trauma Subarachnoid haemorrhage (SAH) including spinal SAH Spinal infection, especially tuberculosis and suppurative pyogenic meningitis Myodil (Pantopaque) radiological contrast agent (this has not been used in the UK since 1984)

blood vessel anomaly. Local spinal pathology affecting the dura such as a root lesion/avulsion or vascular anomaly are also recognized causes of the condition. The remainder of cases in which a cause may be identified usually result from subarachnoid haemorrhage or the late consequences of a major neurosurgical procedure such as hemispherectomy. However, as shown in Table 15.5, there are a number of case reports implicating a variety of conditions in the development of superficial siderosis. The serious long-term prognosis of the disorder means an exhaustive search for a bleeding source should be undertaken. This may involve exploratory surgery of a region from which chronic bleeding might possibly occur, e.g. the site of previous surgery. Successful surgical ablation of a bleeding source may arrest the condition. The role of medical treatment with chelation therapy (trientene) is not established. However, anecdotal accounts suggest such treatment may have a role in slowing disease progression. Cochlear transplants have been successfully performed for the hearing loss associated with siderosis.

The diagnosis involves the exclusion of other causes of radicular pain or myelopathy, and the demonstration of arachnoiditis on MRI. The differential diagnosis includes intrinsic tumours and carcinomatous meningitis. Radiological arachnoiditis is seen in many asymptomatic patients who have had spinal surgery or myelography, and there is no clear evidence to associate radiological findings directly with symptoms. In postoperative patients therefore, arachnoiditis should not necessarily be assumed to be the cause of new symptoms. In the lumbar region, nerve roots adhere to form bundles, or lie centrifugally in contact with the thecal sac, producing the appearance of an empty sac. In the thoracic spine, arachnoiditis produces intra-medullary cystic changes with syrinx and cavity formation. The MRI appearances can be confusing (Figure 15.15). When arachnoiditis occurs in the thoracic regions, the cord may be tethered to the theca, e.g. at the point of surgical durotomy, or may produce arachnoid cysts as a result of poor communication of the CSF spaces. Surgical de-tethering may treat a tethered cord in a patient with progressive neurological symptoms. Arachnoid cysts producing cord compression may be marsupialized or shunted but the problem is often recurrent. Lumbar arachnoiditis producing radicular pain is usually best treated by symptomatic control, including epidural injections of local anaesthetic and steroid, pain management techniques and analgesics. Despite attempts to inhibit fibrosis as yet no successful medical therapies capable of reversing arachnoiditis have been developed.

Arachnoiditis Fibrosis and adhesions of the intradural space may occur after trauma, infection, surgery or subarachnoid bleeding, and usually involve the pia and theca as well as the arachnoid layers around the cord (Table 15.6). Radicular symptoms may arise because of involvement of the lumbar nerve roots, or myelopathy if the cord becomes tethered by these adhesions at any point.

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Spinal cord injury ‘The person dies instantly when the spinal cord is pierced . . . and therefore it would seem lies the foundation of movement and life.’ Leonardo da Vinci (1425–1579) Quaderni d’Anatomica, Vol. V

Spinal Cord Disorders Few survivable injuries have as much impact on a patient’s life as acute spinal cord trauma, and its associated human and social cost. The most common cause is vehicle accidents, followed by violent assault, falls and sports injury, especially high board diving. Severity of injury may be classified using the American Spinal Injury Association Score (ASIA) for quantitative assessment of motor and sensory function, or the ASIA/Frankel grading system, A–E for clinical grading: • A: the most severe with no motor or sensory function below the level of the lesion with no preservation of sensation in sacral dermatomes S4–S5; • B: ‘incomplete’ in which there is no motor function below the lesion but there is preservation of sensory function (in this group sacral preservation of pin prick indicates a better prognosis for functional recovery); • C: ‘incomplete’ motor function is preserved below level of lesion (MRC 4–6 mm in any direction), in older age groups when spontaneous fusion is less likely, or with chronic non-union of the fracture. Within 6 weeks of the accident, a type II peg fracture may be fixed with anterior odontoid peg screws (Figure 15.16), but after longer intervals soft tissue becomes interposed between the bone fragments and posterior C1–2 fixation and bone grafting is required (Figure 15.17). This latter operation will limit cervical rotation by 30%. Injuries associated with hyperflexion and rotation of the neck can result in a unilateral facet joint dislocation in the subaxial cervical spine. Such patients are usually neurologically intact and do not exhibit instability on flexion–extension X-rays. However, extreme hyperflexion injuries may result in bilateral dislocation of the facet joints, usually associated with more extensive disruption of joint capsules, discs and posterior ligaments. CT scanning should be performed to inspect the integrity of the facets, and traction is used to reduce bilateral dislocations. If traction is unsuccessful, then open reduction is required, either by an anterior or posterior approach, followed by fixation and bone graft fusion.

Thoracolumbar fractures The stability of thoracolumbar fractures is well described by the Denis three-column model. The spine may be considered as three columns of stability: the anterior, middle and posterior columns. The anterior column consists of the anterior half of the vertebral bodies, discs and the anterior longitudinal ligament. The middle column includes the posterior half of the vertebral bodies, discs and the posterior longitudinal ligament. The posterior column is made up of the facet joints, joint capsules, laminae, spinous processes and adjoining ligaments. Disruption of two of the three columns is considered to be mechanically unstable and probably


Figure 15.17 Lateral cervical X-ray showing C1–2 fixation for chronic odontoid peg fracture. Figure 15.16 Lateral cervical X-ray showing a screw inserted to stabilize an acutely fractured odontoid peg.

requires operative fixation, whereas disruption of a single column is likely to be stable and can be treated with bed rest. If surgery is required, posterior instrumentation with pedicle screws is the most common fixation technique, although thoracotomy or retroperitoneal approaches are sometimes required for stabilization of the thoracic and lumbar spines, respectively.

Non-surgical management of spinal trauma Whiplash injury Whiplash is a traumatic injury to the cervical soft tissues (including joint capsules, ligaments and muscles) resulting from hyperflexion or hyperextension, in the absence of fractures or instability. Symptoms of pain usually start several hours after the injury, and may be associated with tension headache and poor concentration. Diagnosis is by exclusion of instability, disc herniation or spinal cord injury. It is interesting to note the findings of a Lithuanian study, where few drivers have insurance and disability compensation is unlikely. In this survey there was no significant difference in the incidence of chronic neck pain in people who were involved in a road traffic accident and the general population.

Rehabilitation Rehabilitation is covered in detail in Chapter 17. The primary goal of rehabilitation should be to increase functional capability, especially in walking and standing. Weight-supported treadmill training has shown promise in partial spinal cord lesions. In contrast to studies on the cat, at present there is little evidence in humans for a spinal central pattern generator that in the absence of descending control will drive limb movements and posture capable of supporting functional gait. Spinal pattern generators are favourably influenced by afferent feed back from the limbs and centrally by neurotransmitters, especially adrenergic transmitters. This raises the possibility that functional gains in spinal cord injured humans can be achieved through use of treadmill training supplemented by afferent stimulation and adrenergic drugs. Long-term care of spinal cord injured patients This is considered in more detail in Chapter 17. Complications of long-term management include pressure sores, autonomic dysreflexia, spasticity, syringomyelia, deep vein thrombosis and respiratory problems. Regular turning and good standards of nursing care, physiotherapy, compression stockings, subcutaneous low molecular weight heparin and antispasmodic

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medications minimize these risks. Autonomic dysreflexia is an exaggerated response to normally innocuous stimuli, occurring in patients with spinal cord injury above T6, and resulting in tachycardia, hypertensive surges, sweating, anxiety and headache. The most common causes are bladder distension, faecal impaction, urinary tract and other infections, tight clothing and mild pain (pressure sores or ulcers). Treatment involves identifying and eliminating the stimulus, and pharmacological control of blood pressure and anxiety if required.

Prospects for repair of spinal cord injuries When nerve fibres are severed, as in spinal cord injury, there is an immediate loss of function. Over time, the patient generally recovers some of the loss by re-assigning functions within the surviving undamaged parts of the nervous network, and also by establishing new connections among the surviving parts. However, the nerve fibres that have been severed do not regenerate so the original pattern of connections is never restored. To the extent that the severed fibres carry unique information, the patient endures a permanent and currently incurable functional deficit that cannot be compensated for by reassignments and rearrangements within the surviving network. The purpose of basic research in this field is to provide a basis for clinical procedures that will overturn this grim prognosis and lead to restoration of lost functions. There are a number of approaches to repairing severed nerve fibres in the brain and spinal cord. They include diminishing the effects of putative inhibitory molecules, providing additional neurotrophic support for damaged nerve fibres, providing antiinflammatory and/or neuroprotective interventions, or transplantation of stem cells, and these may be referred to in the cited articles and are discussed in brief in this section. Some have reached or nearly reached the level of clinical trials, but none is yet part of accepted practice. This section discusses the approaches that are a major subject of research and clinical effort in brief before focusing on an approach based on repairing the nervous pathway by transplantation of adult cells derived from the olfactory system. Broadly, research strategies for spinal repair in humans fall into two interrelated categories. 1 Neurone based. The first category is directed towards the neurones. It comprises anti-inflammatory and neuroprotective approaches as well as addition of neurotrophic molecules, which could enhance the growth status of axotomized neurones. Included in the category of neurone-orientated repair is the parallel idea of encouraging the formation of new connections (‘sprouting’) that could produce new circuitry to enhance the functional value of surviving undamaged neurones. Another approach to the neuronal defect is the transplantation either of neurones themselves or neural stem cells.

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2 Glia based. The second category of approaches is directed towards the glia. Attempts to reconstruct damaged glial pathways by transplantation are dealt with later. Another glial-orientated approach is to neutralize the effects of proposed inhibitory molecules present in the glial environment of the spinal cord, thus making the milieu more permissive to axon growth. There are two classes of putative inhibitory molecules. The first includes molecules associated with oligodendrocytic myelin, their receptors and the downstream signalling mechanisms to which they are linked. The second comprises various classes of proteoglycan molecules up-regulated in astrocytic scars and associated with the peri-neuronal net. Certain general caveats must be borne in mind. The principal symptoms of spinal cord injury are caused by disconnection of ascending and descending tracts of nerve fibres, a large number of whose cells of origin survive. Local destruction of segmental nerve cells at the level of the spinal injury contributes very little to the functional deficits. Therefore, measures to enhance local neuronal survival can only have limited benefit. The same consideration applies to the transplantation either of neurones or of neural stem cells. A number of experiments from different groups have shown that embryonic neurones can be transplanted into adult spinal cord where they survive and establish synaptic connections with the host tissue. However, these transplants have not been found to convey functional improvement. Proposals for the use of neurotrophic factors are based on the observation that the sprouts of axotomized neurones cease to advance, and that growth-associated molecules become downregulated. While the principle of adding further neurotrophins could obviously be of value, it has not often been recorded to what extent neurotrophins are in fact absent from the damaged spinal cord. There is also a possibility that further induction of sprouting may also enhance undesirable effects, such as neuropathic pain often associated with spinal cord injury. In evaluation of the anti-inflammatory measures, it should be borne in mind that the inflammatory response to physical injury is a protective measure whose purpose is not to cause more damage but to enhance tissue healing by encouraging the removal of debris and pathogens and stimulating vascularization. Suppression of the inflammatory response could also impair these processes. The view that inflammation is in itself harmful and increases the size of the original damage is not fully substantiated. In considering the principle of a molecular approach to the repair of spinal cord injury it is important not to lose sight of the fact that nervous function depends on a complex and accurate pattern of neural connections. Without the restoration of connections the major defects of spinal cord injury cannot be improved. A purely molecular intervention, which does not lead to the reconstruction of pathways, may only be of limited value. It must also be borne in mind that antagonizing molecules that are an intrinsic element of central nervous tissue may have unde-

Spinal Cord Disorders sirable consequences because of the disturbance of their normal function. The fact that there are so many different approaches to the repair of injuries to the spinal cord is encouraging, showing the widespread interest in this area, and suggesting many potential candidates for a future therapy. The different approaches are not mutually exclusive, and indeed the idea of combination therapy is becoming current. The remainder of this chapter deals with the concept of repair of glial pathways and its experimental and clinical implications.

Neural plasticity There are two important observations on the damaged nervous system. The first is that after injury the severed ends of cut nerve fibres, like the stumps of felled trees, send out vigorous, everincreasing and persistent sprouts (the neuroma). The second is that nerve cells that have been denervated – i.e. deprived of input from one set of fibres – rapidly refill the vacant space (reinnervation) by acquiring new adventitious connections formed opportunistically by adjacent undamaged nerve fibres. These observations indicate that damaged nerve cells retain a persistent vitality, and that they can and do respond positively to injury. This function is referred to as plasticity; it is a function that science is only at the early stages of understanding. For the patient with brain or spinal cord injuries the existence of plasticity provides a paradox. If severed nerve fibres are able to sprout, and if denervated nerve cells are spontaneously reinnervated by newly formed connections, two important questions arise: first, why do the brain and spinal cord not repair themselves in the same manner, as do other adult tissues such as skin and bone, and, secondly, why are the sprouts produced by the cut nerve fibres unable to cross the gap separating them from their original target destinations, even though those targets are both willing and able to receive new connections to fill the vacant space? These questions focus attention on the nature of the tissue that separates the cut fibre sprouts from their original targets, and how that tissue differs from the original tissue along which those nerve fibres grew during their normal embryonic development. The pathway hypothesis of repair proposes that the failure of regeneration of nerve fibres is because of loss of a suitable pathway.

The pathway hypothesis The pathway along which nerve fibres travel is made up of at least four types of glial cells arranged in a repeating lattice. Much current interest focuses on the adult glia, astrocytes, whose cell bodies are prolonged into elongated thread-like structures aligned like railway tracks and forming the pathways along which nerve fibres travel. The astroglial cells, which it is thought are key to the events preventing nerve fibres regenerating, react to injury by forming a scar. This scar has the vital function of closing off the injury and restoring the blood–brain barrier needed to

protect the nervous system and preserve the sequestered ionic environment that the nervous system requires for its function. At the same time, however, the scarring astrocytic structures set up a massive barrier to the advance of the nerve fibre sprouts produced by the severed nerve fibres. One of the first approaches to restoring a pathway for severed nerve fibres in the brain and spinal cord was the idea of transplanting a segment of a pathway tissue taken from a part of the body where severed nerve fibres are able to elongate, i.e. the peripheral nerves. Transplanted into areas of damage in the central nervous system, pieces of peripheral nerve ‘picked up’ the sprouts of cut central nerve fibres, whose progress would otherwise be blocked in the astrocytic scar, and provided a conduit that allowed them to elongate for great distances. This effect depends on the presence of living cells in the peripheral nerve grafts, and the same effect could be produced by transplantation of cultured Schwann cells, the unique type of glial cells present in peripheral nerve tissue and absent from the normal brain and spinal cord. Unfortunately, Schwann cell transplants suffered a serious limitation. Although they allowed the growth of nerve fibres out of the damaged brain or spinal cord and into the graft, the fibres remained trapped in the graft and very few were able to leave it and re-enter their original pathways. The astrocytic barrier had been opened for entry but not for exit. It has been discovered that olfactory ensheathing cells, when transplanted, can allow regenerating fibres to leave the astrocytic environment but also allow them to cross back into the astrocytic territory of the damaged spinal cord.

The olfactory system Until the 1970s it had been thought that no new nerve cells are formed in the adult brain, but with new labelling techniques it was found that in one part of the nervous system – the olfactory system – new nerve cells are being continually generated by division of an adult stem cell located in the nasal mucosa. Throughout normal life, and also at a much accelerated rate after injury to the olfactory nerves, the adult olfactory nerve cells die and are completely replaced by the progeny of adult stem cells lying in the olfactory mucosa. The nerve fibres belonging to the new nerve cells grow through the cribriform plate of the base of the skull and enter the brain. Thus, the glial pathway cells in the olfactory nerves – now called olfactory ensheathing cells (OECs; Plate 15.1 and Figure 15.18) – are capable not only of sustaining long growth of nerve fibres, but they are also able to negotiate an entry through the astrocytic coverings of the surface of the brain even after injury. Can transplantation of OECs provide the glial bridge to allow regeneration?

Animal models In a rat model of spinal cord injury it was observed that transplantation of cultured adult OECs into complete unilateral lesions of the corticospinal tract resulted in the formation of a

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(a)

(b)

(c)

(d)

Figure 15.18 Steps in olfactory ensheathing cell (OEC) facilitated spinal regeneration. (a) Intact spinal cord. (b) Sectioned spinal cord. (c) Glial scar formation in sectioned spinal cord. (d) Pathway re-opened following OEC transplantation.

cellular bridge across the defect. The profuse sprouting of the cut ends of the severed nerve fibres was repressed and in their place the cut fibres extended rapidly (at around 1–2 mm/day) as a single long straight process which passed through the transplants and across the astrocytic scar back into the spinal cord (Plate 15.2). Once back in the spinal cord, the regenerating fibres travelled through the distal part of the corticospinal tract to reach an area of their normal target tissue where they regenerated a terminal arborization similar to that of normal corticospinal fibres. The OEC grafts had thus restored a connection that had been severed by the original damage. This repair could be produced by transplantation several months after the original injury, a time when a dense astrocytic scar would already have been formed, thus indicating a powerful reorganizing effect of OECs on astrocytes which had already organized themselves into a scar. When the OECs were transplanted into complete lesions in animals, which showed permanent loss of function, the anatomical reconstruction of the severed corticospinal pathway was accompanied by return of the ability to learn the directed forepaw reaching task. The putative role of OECs in spinal repair is summarized in Figure 15.18.

Future for clinical application of OEC transplantation The encouraging reparative results in animal experiments have led to a clinical safety trial in Brisbane, Australia, which has shown no adverse side effects following transplantation of OECs cultured from biopsy samples from the patient’s own olfactory mucosa and injected as a suspension at multiple sites in spinal cord injuries. So far, however, functional improvements have not been observed. One possible explanation for this lies in the early stage in development of the cell technology, and the experience serves to illustrate the further work that still needs to be carried out at the research level. Even with autografts of OECs cultured from biopsy samples of the patient’s own nasal mucosa, there remains an urgent need to characterize the human cells and establish a standard culture technology. Although typically located posteriorly on

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the superior turbinate bone and adjacent lining of the sphenoethmoidal recess and nasal septum, considerable variability has been reported in the distribution of the human olfactory area and its histology, probably as a result of the inevitable accumulation throughout life of the effects of periodic infectious and allergenic insults, as well as continuous exposure to damaging agents in the environment we have to breathe. It would be helpful to have further characterization of the map of the topographical distribution and the degree of variability that will be encountered in obtaining OECs from small nasal mucosal samples.

Evaluation of OEC transplantation The problems in evaluating the possible clinical benefits of transplantation of OECs are exacerbated by the natural history of spinal cord injury. The majority of spinal injured patients show a degree of spontaneous recovery, extending over a period of at least 1–2 years, and even of those who on admission have no movement and severe sensory loss, around 40% will recover at least aided walking at the time of discharge. This makes it difficult to be certain of the extent that any intervention, especially in the acute phase, has contributed either positively or negatively to any observed recovery. Claims for the potential contribution of OEC transplants will also have to control for the known major improvements produced by physiotherapy and relearning, as well as any benefits resulting from the other aspects of the surgical interventions. Minimally, a long-term and preferably blind quantitative follow-up of the pre-operative and postoperative symptom history of the spinally injured patient will be needed to provide assurance that benefits are brought about by transplantation of OECs. To identify a situation that may give a more convincing and rapid answer, we are planning to examine the effects of OEC transplantation in traumatic injuries resulting in avulsion of spinal roots. There have been a number of experimental studies of transplantation of OECs into the dorsal root entry zone of avulsed dorsal roots. Experiments in a repaired lumbar dorsal root in rats show an ingrowth of up to 10% of fibres. Clinically, avulsion of dorsal roots leads to an immediate and permanent loss of sensation, for which there is no known method of repair. Unlike the spinal cord itself, where transplantation would involve developing novel surgical approaches, surgical access to the spinal roots is already in practice. This, and the ability to bridge large gaps with peripheral nerve grafts, means that the small numbers of OECs that can be obtained, combined with the use of endogenous matrix to retain them, should be sufficient to bridge the gap to the denervated spinal cord. Combined with the positive animal data, a predictable natural history, the availability of a routine surgical approach and the availability of sufficient cells to bridge the gap, make the repair of brachial plexus avulsion an attractive first situation for evaluating the benefits of clinical transplantation of OECs. The first trials of this approach are underway.


Spinal tumours Spinal tumours may be benign or malignant, primary or secondary. Consideration should always be given to the tissue of origin. Most spinal tumours are metastatic malignant tumours. Breast, bronchus, kidney, prostate, thyroid, multiple myeloma and malignant melanoma are the most common tumours. Tumours can also be categorized by their anatomical location, i.e. extradural or intradural. Intradural tumours may be extramedullary or intramedullary (Tables 15.7 and 15.8). Intramedullary spinal cord tumours account for approximately 2% of adult and 10% of pediatric central nervous system neoplasms. In adults, 85–90% of intramedullary tumours are astrocytomas or ependymomas. Ependymomas account for approximately 60–70% of all primary spinal cord tumours found in adults, while in children 55–65% of intramedullary spinal cord tumours are astrocytomas. Haemangioblastomas account for 5% of tumours, whereas paragangliomas, oligodendrogliomas and gangliogliomas account for the remainder. Astrocytomas and ependymomas are more common in patients with neurofibromatosis Type 2, which is associated with an abnormality on chromosome 22. Spinal haemangioblastomas occur in 30% of patients with von Hippel–Lindau syndrome, which is associated with an abnormality on chromosome 3. Clinical presentation is typically with pain and neurological dysfunction. Night pain or pain at rest is typical. Nocturnal pain

is related to disturbances in CSF venous outflow causing engorgement and swelling of the spinal cord. Axial spinal pain not located in the lumbosacral region should be regarded as a red flag and warrants further investigation, particularly if it is associated with weight loss, decreased appetite or previous medical history of malignancy. Investigations include blood tests, urine analysis for BenceJones protein, and other tumour markers. Radiologically, plain X-rays, CT, MRI, isotope bone scan, positron emission tomography (PET) scan are all potential imaging technologies. For primary bone tumours it is desirable to have maximal information prior to treatment. A biopsy (Tru Cut or fine needle aspiration under CT scan guidance) can be very helpful in treatment decisions. For example, the prognosis from Ewing’s tumour (see below) is better if chemotherapy is given pre-operatively. Similar treatment protocols should be for treatment of osteosarcoma. Other tumours are best dealt with by an en bloc dissection. Identification of tumour type at an early stage is of vital importance in planning definitive treatment. Pre-operative MRI imaging in many cases allows a preoperative diagnosis to be made. It is now an essential part of tumour localization and characterization necessary for preoperative planning. MRI features helpful for diagnosis are shown in Table 15.9.

Spinal manifestations of neurofibromatosis Type 1 Neurofibromatosis is dealt with elsewhere in this book but its spinal manifestations are especially important. These include various tumour types but also varied and complex spinal deformities (kyphoscoliosis) and dural ectasia.

Table 15.7 Classification of intradural intramedullary spinal tumours. Tumour type

Incidence in adults

Ependymoma Astrocytoma (pilocytic/fibrillary, WHO I/II) Glioblastoma multiforme (WHO IV) Haemangioblastoma (25% of patients have von Hippel–Lindau) Other glial tumours (oligodendroglioma, ganglioglioma) Metastases Cavernomas

65% 30–35% 1.5% 1–3%

Table 15.9 Magnetic resonance imaging characteristics of intradural spinal tumours.

Very rare Rare Rare

Ependymoma T1-weighted images – isointense signal with spinal cord T2-weighted images – hyperintense signal Strong homogeneous enhancement with contrast

Table 15.8 Classsification of intradural extramedullary tumours. Meningioma Neurofibroma/schwannoma including dumb-bell tumours Paraganglioma Metastatic including lepromeningeal disease Arachnoid cyst Perineural cysts including Tarlov cysts Epidermoid

Astrocytoma T1-weighted images – isointense or hypointense signal with spinal cord T2-weighted images – hyperintense signal Cyst formation Heterogeneous enhancement with contrast Haemangioblastoma T1-weighted images – isointense signal to spinal cord T2-weighted images – hyperintense signal Cystic with tumour nodule (50–70%) Enhances strongly with contrast Extramedullary extension in 15%

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Neurofibromas The typical spinal nerve sheath tumours seen in neurofibromatosis Type 1 (NF1) patients are benign neurofibromas. They consist of fibroblasts, nerve sheaths and nerve cells. The nerve cells are incorporated into the tumour mass, which complicates surgical removal of the tumour. The spinal nerve root neurofibromas in NF1 are often asymptomatic. A rapid increase in size may be a sign of malignant change, albeit a rare complication; less than 5% of NF1 patients develop neurofibrosarcomas. In most instances, malignant progression of the fibroblast component appears to be responsible for the development of malignancy, and molecular genetic studies suggest that inactivation of the p53 tumour suppressor gene is an important factor in the sarcomatous progression of neurofibromas. Fusiform neurofibromas of spinal nerves are usually bilateral, extend to the branch fibres of the nerve and exceed 30 cm in length. They are seen on CT scans as tumours of low attenuation with areas of higher density, which enhance with intravenous contrast medium. MRI shows nerve sheath tumours to be iso- or slightly hyper-intense with respect to muscle on T1, enhanced T1 and T2 sequences. In approximately 50% of cases, a target pattern with a peripheral hyperintense rim and central low intensity may be seen. This pattern corresponds histologically to peripheral myxomatous tissue and central fibrocollagenous tissue. This pattern is absent in lesions with cystic, haemorrhagic or necrotic changes. Benign nerve sheath tumours usually have intradural extramedullary location. They extend extradurally and have a dumb-bell configuration through the intervertebral foramen in as many as half of cases. Solitary tumours may involve individual nerves, or multiple nerves may be involved in a plexiform fashion. The tumours are usually multiple, appear at different levels and show different stages of growth. Plexiform neurofibromas involve long segments of the spinal nerves and extend into the spinal cord. They appear more frequently in the second and third decades of life, and the cervical and thoracic segments are primarily affected. Thakkar et al. (1999) studied 54 patients with NF1 aged 5–56 years and found spinal tumours in 65%. A tumour was discovered in almost all symptomatic patients and in 40% of asymptomatic patients. The site of the tumour was intramedullary in 6%, intraspinal extramedullary in 33% and intraforaminal in 57%.

Abnormal spinal curvature is detected in up to 40% of NF1 patients. The majority of cases develop problems between 11 and 16 years of age. A short segment of angular scoliosis with five or fewer vertebrae primarily involved, usually located in the lower thoracic region, may be diagnostic of NF1. Kyphosis of varying degrees is usually associated with NF1scoliosis. Kyphosis has been considered a poor prognostic sign because of its tendency to rapid progression and resistance to all types of treatment. Localized or multi-level dural ectasia with enlargement of the spinal canal is also a relatively common finding in neurofibromatosis and is strongly associated with kyphoscoliosis. On X-ray, dural ectasia is associated with vertebral scalloping or concavity of vertebral bodies. The cause of dural ectasia may be a congenital weakness of the dura, in which case the constant pulsation of CSF causes progressive enlargement of the dural sac with resultant scalloping of the posterior portions of the vertebral bodies and erosion of the pedicles. Scalloping of bone may also result from NF1-related primary bone dysplasia. The damaged vertebrae result in disorders of spinal alignment and are interestingly not necessarily directly related to an underlying neurofibroma.

Lesions of the bony spine in NF1 Spinal and skeletal changes are observed in up to 71% of NF1 patients. They can be classified as: 1 Bony erosions caused by a tumour; 2 Pressure damage from intradural, extradural and paravertebral nerve sheath tumours affecting mainly the intervertebral foramen and the spinal canal; 3 Osteomalacia from a genetic tubular defect; 4 Congenital abnormalities, such as macrocranium; and 5 Mesodermal dysplasias, such as pseudoarthrosis of the extremities, local gigantism and scoliosis.

Treatment of spinal tumours In 1887, Sir Victor Horsley performed the first successful resection of an intradural neoplasm, the diagnosis of which was initially secured by the neurologist Sir William Gowers. This lesion was an intradural extramedullary tumour located outside the spinal cord parenchyma causing compression of the spinal cord. Intradural tumours are now dealt with by microsurgical excision. This is aided in certain cases by the use of an ultrasonic aspirator where an en bloc excision is not feasible. Spinal cord monitoring using somato-sensory evoked potentials and motor evoked potentials improves the operative safety margin.

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Primary bone tumours These are comparatively rare. They may be benign, e.g. aneurysmal bone cyst, osteoid osteoma, osteoblastoma or malignant. Some tumours occur much more commonly in younger age groups, e.g. aneurysmal bone cyst or Ewing’s tumour. Osteosarcoma has a bimodal age distribution affecting young children and older patients, the latter being associated with malignant changes in Paget’s disease. The most common tumours are those arising from the bone marrow, particularly multiple myeloma. A more detailed description of these tumours is outside the remit of this book chapter and the reader is referred to Chapter 20 and more dedicated oncology, haematology or orthopaedic textbooks. A working classification is based on tissue origin with tumour types differentiated into bone forming, cartilage forming, giant cell tumours, bone marrow tumours, vascular tumours, other connective tissue tumours, other tumours and tumour-like lesions. The simplified list in Table 15.10 contains examples of each tumour type and is based on the World Health Organization (WHO) classification.

Spinal Cord Disorders Table 15.10 Modified World Health Organization classification of primary skeletal tumours. Tissue type

Tumour types

Bone

Osteoma (B) Osteoid osteoma (B) Osteosarcoma – central and peripheral (M) Chondroma (B) Osteochondroma (B) Chondrosarcoma (different types) (M) Osteoblastoma (B) Ewing’s sarcoma (M) Lymphoma (M) Myeloma (M) Haemangioma (B) Lymphangioma (B) Glomus tumour (B) Angiosarcoma (M) Fibroma (B) Lipoma (B) Fibrosarcoma (M) Liposarcoma (M) Leiomyosarcoma (M) Neurofibroma (B) Neurilemmoma (B) Adamantimoma (M) Chordoma (M) Simple + aneurysmal cysts Fibrous dysplasia Eosinophilic granuloma

Cartilage

Giant cell Bone marrow

Vascular

Other connective

Other tumours

Tumour-like

B, benign; M, malignant.

Ependymomas are usually resectable. Primary astrocytomas can occasionally be completely resected. Surgical excision is easier in children than adults. Complications for intramedullary tumours are common with most patients experiencing short-term neurological deterioration. The role of radiotherapy for intramedullary tumours is controversial (Chapter 20). Repeat surgery should probably be considered first for tumour progression. Many of these tumours are slow growing so treatment effects are difficult to judge. In Brotchi’s series of 239 patients with low-grade spinal tumours, 5% worsened, 50% stabilized and 40% improved. A patient’s neurological function after surgical intervention depends on his or her pre-operative neurological condition. The goal of surgery is to prevent further neurologic dysfunction and to cure the neoplastic condition with complete resection. Neurofibromas (schwannomas) are relatively easy to remove, with very low morbidity. This is because schwannomas usually arise from the sensory nerve root and the resulting spinal compression is slowly progressive. Meningiomas arise from the meninges (Plate 15.3), are more common in women and most often affect the thoracic region. Surgical results are generally very good. Operative morbidity

Figure 15.19 Clival chordoma (MRI T1W).

most commonly arises from dural defects producing leakage of CSF. Radical excision of the dural origin of the tumour will give the best chance of cure, minimizing the risk of tumour recurrence. With the exception of Ewing’s tumour, primary spine tumours are usually treated by excisional surgery. En bloc resection is useful for chordoma but is often not technically possible. Chordomas arise from the notochord remnants. The majority arise from the most rostral and caudal notochord remnants (craniocervical/clivus and sacral; Figure 15.19). With the development of more reliable spinal fixation and reconstruction techniques, removal of the whole vertebra is now technically feasible either piecemeal or en bloc. However, in the cervical spine the vertebral artery prevents such an aggressive approach. In the thoracic and lumbar spine posterior en bloc resection is a favoured approach. Titanium mesh expandable cages or stackable carbon fibres cages allow reconstruction of the vertebral body. Spinal stability is also assisted by pedicle screw fixation (Plate 15.4).

Management of metastatic tumours These are the most common type of spinal tumour (Chapter 20). Historically, surgery involved laminectomy for resection of posterior elements and extradural tumours. While this approach decompressed the spinal cord it further destabilized the spinal column. Most tumours metastasize to the vertebral body and therefore resection of the posterior elements removes the only sound bone in the vertebral complex therefore leading to instability, and deformity with ensuing neurological deterioration and pain. Findlay (1984) found that surgery (laminectomy) provided no better results than

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radiotherapy alone, and was associated with more complications. However, Patchell et al., in a multi-centre randomized controlled series, have recently demonstrated that surgery and radiotherapy are superior to radiotherapy alone. This study was stopped after planned interim analysis showed superiority of the surgical treatment arm. Outcome measures included pain, ambulation, neurological recovery and bladder control. All outcomes were better with surgical treatment. Other studies have shown surgery should precede radiotherapy. Radiotherapy followed by surgery is associated with a doubling of wound complications such as breakdown or infection.

Degenerative disease of the spine Cervical spine Age-related degenerative disease in the cervical spine most commonly affects the mid cervical levels, reflecting the distribution of stress in the neck with upright posture and loading. In younger people, more movement occurs at C5–6 and C6–7 and these levels are the most commonly affected, whereas in older age groups C4–5 and C3–4 become affected in addition. Occasionally, involvement of the atlanto-axial joints and ligaments can produce instability and a soft tissue mass, or ‘pseudotumour’, in the position of the degenerate odontoid process. Cervical disc degeneration is associated with the formation of osteophytes around the annular attachments to the end-plates, with reciprocal degeneration and hypertrophy of the facet joints. Dehydration of the discs may result in reversal of the normal lordosis to produce a straight neck or even kyphotic deformity. Vertebral subluxations may occur. Atlanto-axial instability may occur because of degenerative changes in the joints and ligaments at the cranio-cervical junction producing a pseudotumour around the degenerate odontoid process. Treatment involves fusion of C1 and C2, with surveillance MRI to ensure the size of the odontoid mass does not increase. If the diagnosis is in doubt then a transoral biopsy should be taken. In the subaxial spine, osteophytosis can cause radiculopathy if stenosis of nerve root canals develops, or myelopathy if the spinal canal is sufficiently compromised. Radicular pain usually follows a waxing and waning course, with intermittent exacerbations but, like lumbar radiculopathy, most symptoms of brachalgia settle down with time and surgery is often not required. Surgery may be performed if symptoms fail to improve after 2–3 months, or if neurological signs progress. Surgery to decompress cervical roots may be performed by anterior or posterior approaches. Anterior cervical discectomy with decompression of the nerve roots is performed if there is any coexistent cord compression, or if the majority of root compression is caused by disc prolapse. Posterior foraminotomy is a simpler operation that may be used if there is no cord compression. This approach avoids the small risk of recurrent laryngeal nerve palsy that may occur with anterior operations, and does not require fusion of a motion segment,

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but is associated with more postoperative neck pain in the short term. Myelopathy may occur because of disc herniation and osteophytic compression of the cervical cord. Furthermore, the anterior horn cells of the cervical expansion are affected by direct compression, arterial insufficiency, venous congestion, repetitive minor trauma or a combination of these events. In general, 25% of patients with spondylotic cervical cord compression remain static, but 75% progressively deteriorate. It is common to observe an initial deterioration followed by a period of stabilization, but most patients will later progress further if untreated. The main aim of surgery is to prevent deterioration; however, improvement can occur. Surgical treatment may be performed anteriorly, by cervical discectomy and sometimes corpectomy, or posteriorly by laminectomy or laminoplasty. The method of decompression depends on the degree of lordosis or kyphosis of the spine, the main cause of the cord compression and surgeon’s preference. If the cord compression is mainly caused by a disc prolapse in a kyphotic neck, then anterior decompression is preferable. Compression from hypertrophy of the ligamentum flavum in a lordotic neck is best treated by posterior decompression. After laminectomy there is a risk of progressive kyphosis because of removal of the posterior tension-band elements of the cervical spine, leading many surgeons to adopt the technique of spinal canal augmentation by laminoplasty which was originally developed in Japan for treatment of patients with ossification of the posterior longitudinal ligament. The overall results of anterior and posterior decompressive surgery for myelopathy are similar, although it should be remembered that the indications for each approach are different and therefore not directly comparable. After laminectomy in one series, 56% of patients improved, 25% were unchanged and 19% slightly worse, and with anterior decompression 75% of patients improved. The Smith–Robinson and Cloward techniques for anterior cervical discectomy were originally described with the insertion of an iliac crest bone graft to produce fusion. Some surgeons have since advocated discectomy without fusion, although there is an increased incidence of kyphotic deformity and transient radicular pain after the operation if no graft or spacer is used, because of partial subsidence of the adjacent vertebral bodies and consequent narrowing of the intervertebral foramina. More recently, artificial titanium, plastic or carbon fibre cages have been developed which can be filled with bone and inserted in place of iliac bone graft. The use of cages can decrease the length of operations and avoid complications associated with iliac crest harvest, including pain, infection, haematoma, and even pelvic fracture. Fusion after cervical discectomy has been the standard treatment for a number of years, but there is an increased incidence of accelerated degenerative disease in adjacent discs, because of the added mechanical stresses placed on adjacent discs after fusion of a previously mobile segment. Within 10 years of fusion, around 29% of adjacent discs will degenerate and require surgery. To avoid this complication, a number of different artificial disc


(a)

younger age groups (third to fifth decades) at T8–12 levels. Patients often present with a history of chronic pain with only subtle sensory or motor changes. In symptomatic patients, discectomy is performed by an anterolateral approach, most commonly by thoracotomy. Direct posterior approaches are associated with a high risk of mechanical cord damage and should be avoided, although in some cases a postero-lateral approach (transpedicular or costotransversectomy) may be appropriate. The spinal fusion is achieved in a similar way to cervical spine surgery.

Lumbar spine

(b) Figure 15.20 (a) Photograph of artificial cervical disc implant. (b) Lateral cervical spine X-ray showing artificial disc implants at two levels.

implants have been developed that do not restrict movement after anterior decompression, and thereby minimize the development of adjacent segment disease (Figure 15.20). The short-term results of artificial disc implants have been favourable, but in the longer term it is unclear whether they will require replacement within a lifetime.

Thoracic spine Degenerative disease in the thoracic spine is less common than in the cervical and lumbar spine because of the decreased movement that occurs at thoracic levels. Thoracic disc prolapses account for only 0.5% of all disc prolapses and usually occur in

Lumbar canal stenosis may occur because of acquired degenerative changes such as hypertrophy of facet joints, ligamentum flavum, disc prolapse or spondylolisthesis, or congenital causes such as achondroplasia. If the spinal canal cross-sectional area diminishes below a critical value then radicular symptoms or neurogenic claudication may occur, either because of direct compression or ischaemia of nerve roots. Neurological examination may be normal, including straight-leg raising. The natural history if untreated is a slowly progressive course with most symptoms remaining the same, or gradually worsening over the next few years after diagnosis. Treatment is by laminectomy with or without discectomy; 60–80% of claudication improves after surgery. Lumbar disc prolapse is a common cause of radicular leg pain, and is present in 1–3% of people with lower back pain. Approximately 80–90% of patients with radicular leg pain improve over the following few months without surgery. Long periods of immobilization should be discouraged and gentle mobilization and exercise can aid recovery. ‘Red flags’ of urinary incontinence, urinary retention, faecal incontinence, peri-anal numbness and leg weakness should prompt urgent referral for MR imaging to exclude a central disc prolapse and cauda equina compression. Otherwise, unless the pain is refractory to medical treatment, 2–3 months of pain management is recommended before consideration of surgery. The L4–5 and L5–S1 vertebral discs are the most common levels of disc prolapse. They produce L5 and S1 radiculopathies, respectively. A disc prolapse more commonly involves the nerve root of the level below. For example, at L4–5, although the L4 nerve root exits at that level, it has already exited lateral to the common position of a disc bulge and will not be caught by it unless the bulge is more laterally placed. Instead, the L4–5 disc bulge will usually catch the L5 nerve root en passant. Lumbar microdiscectomy is the standard surgical technique for removing disc prolapses, although percutaneous techniques (using laser, thermocoagulation, chymopapain or mechanical disruption with a nucleotome) and minimally invasive techniques are now sometimes used with varying efficacy. In a randomized controlled trial of microdiscectomy versus non-surgical therapies, surgically treated patients had better outcomes at 1 year, but the difference was not significant by 4 and 10 years.

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Low back pain Low back pain affects 70–85% of population at some point in their lives, with an incidence of 15% and point prevalence of 30%. The primary risk factor is age-related degenerative change in the lumbar spine. The intervertebral discs in particular show degeneration which can be appreciated as loss of hydration on MRI. By the age of 50 years 90% of the population show loss of hydration of the nucleus pulposus. The disc comprises the nucleus pulposus, a gelatinous structure surrounded by the annulus fibrosus. With ageing there are changes in the collagen matrix, loss of hydration, apoptosis and loss of the blood supply. The hydrostatic mechanisms for dissipation of force are lost. This, coupled with weakening of the annulus, leads to an increased risk of rupture of the nucleus pulposus through the annulus fibrosus. This is most likely to occur during loading of the spine in flexion and torsion. Importantly, the nucleus pulposus is likely to be an immune privileged site like the testis. The evidence for this is that like other immune privileged tissues it expresses the FAS ligand, which induces apoptosis of FAS-positive invading T cells. The annulus fibrosus and notochord elements do not express FAS ligand. Extrusion of the disc into the epidural space sets up an intense inflammatory process with autoimmune reaction and inflammatory cell infiltration. There is a resulting increase in inflammatory cytokines especially interleukin 1, tumour necrosis factor α (TNFα), interleukin 6 along with increased levels of prostaglandin E2. In degenerate discs there is an increase in matrix metalloproteinases (MMPs). MMPs are zinc-dependent enzymes that are involved in modelling of connective tissue. Experimental data implicates MMPs 1 and 2 in the pathogenesis of disc herniation. Ultimately, spontaneous resorption of herniated disc material may occur as the result of action of MMPs and cytokines. The pain in degenerative spinal disease results from a variety of interacting mechanisms. A major contributor to the pain is the inflammatory response evoked by the disc herniation. There are important nociceptive contributions from the facet joints, vertebrae, muscles, ligaments and fascia. Nociceptive pathways involve the sinovertebral nerve, which arises from the ventral root and grey rami near the dorsal root ganglion to innervate a number of structures, particularly the posterior longitudinal ligament. There is also a noiceptive contribution from the dorsal root ganglion.

Management of lower back pain Pain may be managed by conservative and surgical methods. If radicular pain is very severe, then bed rest may be advised to minimize loading of the lumbar spine and nerve root foramina, with analgesia (including paracetamol and non-steroid antiinflammatory drugs), and sometimes benzodiazepine muscle relaxants. However, prolonged bed rest beyond 3–4 days should be discouraged because it is usually associated with a worse outcome than a gradual return to normal activities and work. Heavy lifting, prolonged sitting and abnormal postures should be discouraged, and a program of gentle exercise and education

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established, often supplemented with physiotherapy. Correct posture, sleeping position and lifting techniques are important. Chiropractic and osteopathy, acupuncture, epidural steroid and facet joint injections may help in the short term, but there is little evidence of long-term benefits. Spinal manipulation should not be performed in the presence of severe or progressive neurological deficit. Surgical lumbar fusion is accepted practice in the presence of instability resulting from tumour, trauma, infection or degenerative disease, but its use for mechanical back pain alone is controversial. A randomized controlled trial comparing surgical fusion with an intensive rehabilitation programme revealed improvements in both groups after treatment, but no significant difference between surgery and rehabilitation. Whereas surgical fixation was associated with an improved outcome, there is limited evidence to support the use of surgery in the absence of instability. In fact, surgical fusion of a mobile segment is associated with exaggerated adjacent disc disease in 20% of patients over the next 10 years after surgery. This has stimulated interest in artificial disc replacements, such as the ‘ProDisc’ and ‘Charite’ prosthetic lumbar discs, which have been associated with good outcomes in back pain and patient satisfaction after 2 years from operation. However, recent reports may suggest that some of these disc replacements actually result in a fusion anyway, without changing the patient outcome.

Spinal infections All components of the spine are vulnerable to attack by bacterial, fungal, viral and parasitical infections. The structures involved include the vertebral column, most commonly the intervertebral disc (discitis) and the vertebra (osteomyelitis). Infection can spread to the extradural space with abscess formation and the intradural contents can also be affected. Intramedullary infection is very rare. Further detailed discussion of infectious disease of the nervous system and spine can be found in Chapter 8.

Bacterial infections In adults, lumbar bacterial infections often originate from urinary tract infections which drain via the Batson venous plexus. The respiratory system is a common source of blood-borne infection with spinal infection usually following the initial infection by some 1–8 weeks. Purulent material may break out of cortex of the bone anteriorly to form a paravertebral abscess or posteriorly to form an epidural abscess. Infection-related weakening of the bone may cause vertebral body collapse. Haematogenous osteomyelitis is seen more often in children than adults. This is believed to be because the epiphyseal plate site present in the growing skeleton of a child and absent in adults is more vulnerable than mature bone to blood-borne infection. Risk factors for bacterial spinal infection include an immunocompromised state, including diabetes, TB, HIV, malnutrition and intravenous drug use.

Spinal Cord Disorders The risk factors for bacterial discitis are the same as those for osteomyelitis. Iatrogenic cases occur after disc surgery, therapeutic injections, lumbar puncture and epidural anaesthesia. The most common organism is Staphylococcus aureus, particularly Staphylococcus epidermidis. Methicillin-resistant Staphylococcus aureus (MRSA) can occur. Streptococcus viridans is the next most common infecting organism. Blood cultures sometimes identify the infecting organism and guide appropriate antibiotics use. Because of difficulty in obtaining a culture from blood, CT-guided biopsy of the infected area should always be considered prior to antibiotics. Epidural abscesses are usually considered to be a surgical problem but in a debilitated patient with a small thin abscess and a bacteriological diagnosis, appropriate antibiotic therapy alone is a reasonable approach. Antibiotics are given for variable lengths of time and 2–3 months of parenteral antibiotic therapy may be required. Before parenteral antibiotics are discontinued, the erythrocyte sedimentation rate (ESR) should have fallen to at least two-thirds of the pre-treatment level. In addition, the patient should be afebrile, without pain on mobilization, and ideally improving from disease-related neurological complications. A persistently high ESR or C-reactive protein implies continuing infection, and additional intravenous antibiotics are indicated. In such an instance, additional biopsies for microbial culture may need to be taken. Bracing or other forms of orthosis is strongly recommended to provide stability for the spine while the infection is being treated and the tissues are healing. The goal of spinal immobilization is to provide opportunity for the affected spinal level(s) to fuse in an anatomically aligned position. Bracing is usually continued for 6–12 weeks, until either a bony fusion is seen on radiography or until the patient’s pain subsides. A rigid brace is optimal and only need be worn when the patient is upright or mobile.

Spinal tuberculosis Mycobacterium tuberculosis of the spine is an uncommon form of tuberculosis occurring in less than 1% of patients with tuberculosis. TB typically first affects the intervertebral discs. The primary risk factors for TB infection in the UK include membership of an ethnic group in which the disease is endemic and/or being in an immunocompromised state. TB infection typically presents with local pain, fever, night sweats and general ill health including weight loss. If the disease spreads from the disc into the vertebral body osteomyelitis will occur with epidural abscess formation and/or vertebral body collapse. Pathological fractures will cause pain, deformity (kyphosis) and in some cases spinal cord compression. The diagnosis is difficult in patients with no evidence of extraspinal TB. The clinical presentation together with the radiological appearances (plain X-ray, CT and MRI) of spinal TB and a positive tuberculin test usually suggest a diagnosis of spinal tuberculosis (Figure 15.21).

In Pott’s disease, the spinal cord may become involved either because of compression by disrupted bone and/or disc and ligaments, expansion of a TB abscess or by direct invasion of cord and leptomeninges by granulation tissue. Primary tuberculoma of the spinal cord is rare. Neurological deficits when present usually develop gradually. A positive diagnosis is made from detection and culture of acid-fast bacilli from the bone or body fluids. Polymerase chain reaction (PCR) detection of mycobacterium DNA may speed the diagnosis but initiation of effective treatment should not be delayed if the clinical index of suspicion is high. With the advent of effective combination chemotherapy in the early 1950s, the mortality rate among patients with spinal TB decreased from nearly 100% to 3%. It is important to note that while triple and quadruple therapy drug regimens remain highly effective for most cases of spinal TB, in immuno-compromised patients, especially those with HIV/AIDs, drug-resistant TB is an increasing problem. Management of spinal TB and the role of surgery The initial procedure introduced for the surgical treatment of spinal infections was laminectomy. However, this procedure did not allow access to anterior abscesses and contributed to spinal instability, which often resulted in progressive deformity. Hodgson and Stock (1960) extensively reported this procedure in the treatment of TB of the spine. Late spinal deformity was prevented with spinal fusion and instrumentation. The need for an anterior approach (by thoracotomy) was stimulated by the failures of posterior fusion in some of their patients, many of whom had TB involving four to eight vertebrae and such pronounced kyphosis as to make posterior fusion mechanically unsound. The current surgical management of spinal TB requires of radical debridement and anterior fusion. The anterior approach gives a wide access to the disease. The removal of all avascular bone is essential to ensure rapid sound bone fusion. Anterior fusion by bone transplantation after a thorough excision of the disease focus is successful in a very high proportion of cases. The Medical Research Council (MRC) examined the role of surgery for spinal TB with antibiotic chemotherapy versus antibiotic chemotherapy alone. The first MRC trial of the treatment of spinal TB revealed equivocal results at 5 years when chemotherapy alone was compared with radical surgical treatment combined with chemotherapy (MRC working party on TB of the spine, 1974). The primary advantage of anterior spinal arthrodesis was a decreased tendency for progression of deformity. The role of surgery for spinal TB has been re-examined in a recent Cochrane review. This concluded that the data were insufficient to be clear whether surgery with chemotherapy is better than chemotherapy alone. However, it is very important to note that very few patients in the MRC trial were neurologically affected. Furthermore, it is important to appreciate that the surgical approach analysed by the original MRC trials is not comparable to modern spinal surgery performed by specialist spinal surgeons with high-quality spinal instrumentation, modern

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(a)

(b)

anaesthesia, intra-operative neurophysiological monitoring with decisions informed by neurologists and infectious diseases specialists and by modern radiology (MRI and CT). Surgery may be indicated in certain subgroups of patients, particularly those presenting with a significant neurological deficit, with progressive neurological deficits, those who develop neurological deficits on appropriate antibiotic therapy and those with an initial kyphosis angle greater than 30°, especially if a child with further skeletal growth potential.

Fungal infections Fungal infections of the spine are rare. Fungi such as Cryptococcus, Candida and Aspergillus are found worldwide, whereas Coccidioides immitis and Blastomyces dermatitidis are limited to specific geographical areas. Aspergillus and many Candida species are normal commensals of the body and produce disease in susceptible individuals when they gain access to the vascular system through intravenous lines, during implantation of prosthetic devices or during surgery. Other fungi produce spinal involvement usually as a result of haematogenous or direct spread of organisms from an initial pulmonary source of infection. Involvement of the vertebral bodies can lead to vertebral compression fractures and gross deformity of the spine. Spread of infection along the anterior longitudinal ligament can lead to psoas or paravertebral abscesses, similar to tuberculosis. Recognition of the disease requires a high index of suspicion, proper travel history and a detailed physical examination. Treatment relies on the early and effective pharmacotherapy and constant monitoring of clinical progress. Resistance to medical therapy,

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Figure 15.21 Spinal TB. (a) Pathological collapse C3/4 disc space and C6 vertebra with retropharyngeal swelling (lateral X-ray). (b) Pre-vertebral swelling, kyphosis and cord compression (MRI T2W).

spinal instability and neurologic deficits are indications for spinal debridement and stabilization with spinal fusion. Prognosis depends on the premorbid state of the patient, the type of fungal organism and the timing of treatment. Immuno-compromised patients fare badly.

Viral infections Tropical spastic paraparesis (TSP) is an incurable viral infection of the spinal cord that causes weakness in the legs. It is caused by the human T-cell lymphotropic virus-1 (HTLV-1) retrovirus. Symptoms may begin years after infection. In response to the infection, the body’s immune response may injure nerve tissue, causing symptoms that include neurogenic bladder problems, leg pain and loss of feeling in the feet, tingling sensations and unpleasant sensations when the skin is touched. Patients with TSP may also exhibit uveitis, arthritis, pulmonary lymphocytic alveolitis, polymyositis, keratoconjunctivitis sicca and infectious dermatitis. Factors that may have a role in transmitting the disorder include being a recipient of transfusion blood products (especially before 1989), breast milk feeding from a seropositive mother, intravenous drug use or being the sexual partner of a seropositive individual for several years. Not every HTLV-1 seropositive carrier will develop TSP; fewer than 5% will exhibit neurological dysfunction or, eventually, haematological malignancy such as adult T-cell leukaemia/lymphoma.

Treatment of tropical spastic paraparesis Initial trials of treatment using antiretroviral drugs have not produced neurological improvement nor have they convincingly

Spinal Cord Disorders shown a slowing of disease progression. Essentially there are two approaches. The first is to try to inhibit viral replication. This has been attempted with antiviral drugs: the reverse transcriptase inhibitor zidovudine (AZT) and the cytosine analogue lamivudine alone and in combination. Problematically for this approach, in contrast to HIV, the virus replicates without the need for reverse transcription. These drugs can produce a reduction in HTLV1 pro-viral load. However, little clinical response was seen in a randomized double-blind placebo controlled trial of Combivir (zidovudine + lamivudine). The second approach has been to suppress the immune response both with steroids and steroidsparing drugs and interferon-1α. Although short-term improvements have been noted no sustained clinical improvement or measurable reduction in disease progression is yet reported in rigorous analysis of the effects of these approaches. Future trials are in progress and are planned to assess the affects of ciclosporin, anti-TNFα and Campath 1H. There are numerous viral causes of transverse myelitis which are discussed in the following section and in Chapters 8 and 10.

Devic-like picture of spinal and optic nerve inflammation. Devic’s disease is in the differential diagnosis of paraneoplastic syndromes and spinal cord infections. In these conditions there is a myelitis sometimes associated with optic neuropathy. Often an extensive investigation is required to look for evidence of SLE, sarcoid and neoplasia. The differential diagnosis of transverse myelitis is very extensive (Table 15.11). However, if the NMO-IgG serum test proves to be clinically useful then such extensive investigation to search for diseases driving Devic-like myelitis and optic neuritis may be unnecessary.

Spinal cord inflammation Devic’s disease (neuromyelitis optica) The evidence is now strongly that this disease is a separate entity from multiple sclerosis (MS). It is characterized by episodes of myelopathy (Figure 15.22) and optic neuropathy which are often severe. It is more common amongst the Japanese. The involvement of optic nerve and spinal cord is selective. The condition is also discussed in Chapter 10. A Devic-like syndrome is also described in association with other autoimmune diseases including systemic lupus erythematosus (SLE). Neurological sarcoidosis may also present with a

Table 15.11 Causes of transverse myelitis.

Infections

Figure 15.22 Devic’s disease: extensive intrinsic cord lesion with cavitation (MRI T1W).

Bacterial

Viral

Parasitic

Especially staphylococcus, including epidural abscess Mycoplasma TB Borrelia Rickettsia Syphilis Tetanus Enterovirus – coxsackie, poliovius, enterovirus 71 Flavivirus – West Nile HZV, HSV 1, 2 HIV, HTLV-1 CMV, EBV Influenza Schistosomiasis Toxoplasma Malaria Cysticercosis

Fungal

Continued on p. 620

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Post-infectious Post-vaccination Primary demyelination Inflammatory disorders

Primary neoplasia Secondary neoplasia Paraneoplastic Drugs Vitamin deficiency/ toxins; see also Chapter 18

Radiation Miscellaneous

Acute disseminated encephalomyelitis Especially rabies vaccine, (numerous other case reports) Multiple sclerosis Devic’s disease Systemic lupus erythematosus Mixed connective tissue disease Sjögren’s disease Scleroderma Rheumatoid disease Antiphospholipid syndrome Sarcoidosis Vasculitides Ulcerative colitis Behçet’s disease Serum sickness Post-haematopoietic stem cell infusion Graft versus host disease Immune dysregulation and immune reconstitution in AIDS Gliomas Ependymomas (see above) Especially lymphomas, metastases Especially associated with small cell carcinoma of lung, and lymphoma Heroin Subacute combined degeneration of the cord ( typically B12 deficiency; exceptionally copper deficiency) Snake and spider bite Arsenic Diethylene glycol Nitrous oxide Cynanide Intrathecal chemotherapy Dose-dependent, acute, early- and late-delayed Decompression sickness Electrical injury

Vascular disorders of the spine Clinical features Vascular diseases including those of the spinal cord are discussed further in Chapters 4 and 25. Like vascular disease of the brain the syndromes can be thought of in terms of infarction, haemorrhage, transient loss of vascular supply and vascular malformations. The clinical manifestations differ between each of the above categories. Spinal cord infarction usually presents acutely, often with pain followed by paralysis and sensory loss. The most common arterial territory involved is the anterior spinal artery. In anterior spinal artery occlusion the anterior two-thirds of the spinal cord is affected. The spinal level is determined by where in its course the supply from the anterior spinal artery is interrupted. The patient presents with an acute flaccid paraparesis with loss of sphincter control and anaesthesia to temperature and

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Table 15.11 Continued

pain but classically with preservation of posterior column functions of joint position and vibration sense. The most typical level is the upper thoracic cord but involvement of the cervical spine and even the caudal brainstem can occur. Anterior spinal artery infarction can be partial. The syndromes of posterior spinal artery infarction, watershed infarction, venous infection, transverse infarction, central cord infarction and lacunar infarction are far more rare. Watershed infarcts and spinal artery hypoperfusion causing spinal TIA and ‘claudication’ may occur because of atheromatous disease of the aorta and its branches. The most common site of hypoperfusion syndromes is the mid thoracic area T4–9 where perfusion is relatively poor. The artery of Adamkiewicz (approximately T6 level) supplies blood to the spinal cord in this region. Common causes of spinal cord infarction are listed in Table 15.12. Haemorrhage in the spine is classified according to the spinal level and anatomical site. Haemorrhages may be intramedullary, subarachnoid, epidural and subdural. The presentation is usually

Spinal Cord Disorders Table 15.12 Causes of spinal cord infarction.

Atherosclerosis Inflammatory Infective Vasculitis Aortic disease Arteriopathy Embolic disease Hypoperfusion states Vertebral artery disease Hypercoagulable states Drug abuse Miscellaneous medical Iatrogenic

Diabetes, hypertension, hyperlipidaemia Sarcoidosis, arachnoiditis Syphillis, TB, herpes zoster, HIV, bacterial meningitis SLE, giant cell arteritis, polyarteritis Dissecting aortic aneurysm, aortic occlusion, trauma, Takayasu’s disease Connective tissue disease, Marfan’s syndrome, fibromuscular dysplasia Cardiac embolism, decompression sickness Cardiac arrest, hypovolemia, cardiopulmonary bypass Dissections, trauma Clotting factor disorders, antiphospholipid antibodies, blood transfusion Cocaine, heroin, ecstasy Anaemia, sickle cell, Moyamoya, CADASIL, Paget’s disease Vascular surgery, cardiac surgery, spinal surgery, diagnostic catheter radiology, interventional radiology, spinal/epidural anaesthesia; intrathecal drugs

CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy; SLE, systemic lupus erythematosus; TB, tuberculosis.

acute with severe spinal pain and myelopathy with a motor and sensory level and sphincter loss. Spinal subarachnoid haemorrhage presents with severe back pain, radicular pain followed by the classic signs and symptoms of subarachnoid bleeding, i.e. obtundation, neck stiffness and photophobia. Myelopathy may be present but unlike other causes of spinal haemorrhage not necessarily severe.

Vascular malformations Spinal vascular malformations usually present subacutely unless there is acute haemorrhage (this does not happen with dural AVMs or fistulae). Dural fistulae present as a myelopathy with progressive motor sensory and sphincteric loss. There may be radicular involvement and lower motor neurone signs because of impairment of dorsal and ventral root blood supply as well as anterior horn cell loss. Intradural fistulae more typically present acutely with the affects of intramedullary or subarachnoid bleeding. Adhesive arachnoiditis of the spine may be a late complication of spinal haemorrhage but rarely is a presenting feature leading to the diagnosis of a vascular malformation that has bled previously. Cavernous malformations may present acutely with large intramedullary haemorrhage or with a subacute myelopathy resulting from venous bleeding and consequent spinal damage. The presentation of cavernomas is often with stepwise neurological deterioration.

Neoplastic vascular lesions Cavernous angiomas (also known as cavernomas, cavernous haemangiomas or malformations) consist of a mass of endothelial cells which form sinusoidal spaces filled with blood, without intervening parenchyma, surrounded by haemosiderin-stained spinal parenchyma. They may present with focal haemorrhage or with mass effect and spinal cord syndromes. Symptomatic cavernous angiomas should be treated by surgical excision to prevent further haemorrhage and progression of deficits, whereas

asymptomatic lesions should be observed because the natural history of these lesions is unclear. Definitive treatment should take into account the accessibility of the lesion, age of the patient and degree of neurological deficit. Haemangioblastomas are neoplastic masses consisting of endothelial cells, pericytes and stromal cells. They may occur sporadically, or as part of von Hippel–Lindau syndrome. They usually are intramedullary, but have contact with the pial surface, and may have an associated cystic component or syrinx. Prior to surgery it is important to localize angiographically the large feeding vessels supplying the tumour, to minimize bleeding during resection. Treatment is by surgical resection, staying on the tumour capsule and dividing feeding vessels as they are exposed, similar to the technique of AVM resection.

Arteriovenous malformations AVMs account for about 4% of primary intraspinal masses, and may be classified into the following four types. 1 Type I. Dural arteriovenous fistulas (AVFs) are the most common type of AVM. AVFs do not have a nidus of abnormal vessels like classic AVMs. Instead, there is a direct connection between an artery and vein, with either single or multiple feeders. The dural fistula is in the root sleeve at an intervertebral foramen, feeding directly into spinal draining veins which may be intradural or extradural (Figures 15.23 and 15.24). They usually present with progressive myelopathy in middle-aged adults, resulting from venous congestion and hypoperfusion of the spinal cord, and are more common in the thoracic spine. Treatment of AVFs involves occlusion of the fistula by surgery or embolization by interventional radiology. 2 Type II. Glomus AVMs consist of a nidus of compacted abnormal arteries and veins within the spinal cord which may be fed by multiple normal vessels, such as the anterior and posterior spinal arteries (Figure 15.25). The abnormal vessels are intramedullary, and are similar to the vessels seen in intracranial AVMs,

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Fistula

Figure 15.23 Extradural spinal arteriovenous fistula, Type I.

Figure 15.25 Glomus or nidus spinal arteriovenous malformation, Type II.

Fistula

Figure 15.24 Intradural spinal arteriovenous fistula, Type I.

Figure 15.26 Juvenile-type arteriovenous malformation, Type III.

either in a compact mass or diffusely arranged. The vessels in the nidus are usually high flow, resulting in myelopathy from the mass effect or steal phenomena. Treatment is by surgical excision of the nidus, embolization, or both. 3 Type III. Juvenile or metameric AVMs are large AVMs that are intradural and extradural, fed by multiple vessels, often involving neighbouring bone and soft tissues (Figure 15.26). They are very difficult to treat and require a multi-modal approach. 4 Type IV. These are AVFs on the surface of the cord that are intradural but extramedullary.

Most AVMs present with a progressive neurological deficit over months to years as a result of venous congestion or arterial steal, but may also present with sudden parenchymal haemorrhage, subarachnoid haemorrhage, mass effect or cord infarction. A spinal AVM is an important differential diagnosis for patients with apparent intracranial subarachnoid haemorrhage and normal intracranial angiography, especially when neck stiffness and pain is more of a feature than headache. MRI and spinal angiography are the investigations of choice for diagnosis and treatment planning.

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Diagnosis of spinal vascular disease The differential diagnosis of spinal cord vascular diseases is influenced primarily by the rapidity of symptom presentation. Severe infectious, para-infectious and inflammatory myelitis including Devic’s disease may present acutely. However, hyperacute presentations are more suggestive of vascular disease. Subacute and chronic presentations, either without haemorrhage as in dural AVMs or with small venous haemorrhage as with cavernomas, need to be differentiated from the causes of progressive myelopathy, particularly structural causes and spinal demyelination. MRI is the primary diagnostic investigation. Spinal MRI will detect over 90% of acute spinal cord ischaemic lesions. Diffusionweighted and contrast-enhanced MRI may increase the yield further. MRI usually excludes compressive lesions and often will find evidence of demyelination especially if cranial MRI is also performed. Imaging of the aorta with abdominal CT, and with CT or MR angiography is important. Subdural and epidural haematomas are detectable but need to be distinguished from abscesses and other causes of fluid collection. AVMs and dural fistulae are usually detectable with expert neuroradiological interpretation of T1.5 MRI. The vessels of the malformation are seen as serpiginous flow voids. In addition, there is usually T2-weighted signal change within the spinal cord substance. However, AVMs and dural fistulae can be missed on MRI. Spinal myelography has detected the vessels of AVMs and dural fistulae that are not visible on MRI. Finally, spinal angiography may be required both for definitive diagnosis and to plan treatment with interventional radiological occlusion either through embolization or gluing techniques. In suspected spinal subarachnoid haemorrhage cranial CT often detects subarachnoid blood and a lumbar puncture will provide definitive evidence of subarachnoid haemorrhage. Other investigations are directed towards detection of the cause or contributing factors of the infarct or haemorrhage (e.g. looking for infections such as syphilis, hypercoagulant and hypocoagulant states and vasculitis). Management of spinal vascular disease There is no curative treatment for acute spinal cord infarction. During high-risk vascular procedures pre-treatment with steroids and opiate antagonists has been advocated and neuroprotective agents have been examined in the basic science setting. However, there is no clinical evidence for effectiveness of any of these approaches. Some vascular surgeons advocate spinal fluid drainage during surgery believing that through the lowering of CSF pressure spinal perfusion may be maintained during critical moments such as placing of the aortic cross-clamp during aortic aneurysm repair. The best safe guard against iatrogenic spinal cord infarction, however, is highly skilled surgical and anaesthetic practice. Spinal epidural and subdural haematomas should be decompressed acutely by a spinal surgeon or neurosurgeon. Spinal AVMs and cavernomas can be excised. However, the majority are not amenable to this approach. Interventional radiology is the treatment of choice for dural fistulae and intradural AVMs.

The prognosis for functional recovery in established spinal infarction is poor with significant functional recovery leading to ambulation in well under 50% of those affected. The prognosis for spinal haemorrhage is more variable. In the case of compressive epidural and subdural haematomas it is dependent on the rapidity of decompression. In intradural bleeding it depends greatly on the site and source of bleeding. Haematomas caused by high-flow intradural AVMs are often catastrophic. The effects of bleeding from cavernomas may be milder and disability often progresses over many years. The natural history of cavernomas is still poorly understood and therefore the decision when and whether or not to intervene remains problematic.

Hereditary spastic paraplegia Hereditary spastic paraplegia (HSP) denotes a heterogeneous group of inherited disorders characterised by progressive spasticity and weakness predominantly affecting the lower limbs. The transmission may be X-linked, autosomal dominant or recessive and they may be divided into pure (uncomplicated) and complicated forms. In the former there is only spinal involvement but the latter are associated with other neurological abnormalities. In pure HSP patients present with steadily progressive gait disturbance or, in childhood, with delayed motor milestones. There is usually progressive spasticity of the lower limbs with hyper-reflexia and extensor plantars. However there may be little or no pyramidal limb weakness and examination tends to be characterized by dissociation between the severity of the spasticity and relatively mild weakness. Rarely, there may be wasting of intrinsic muscles of the feet, urinary disturbance with urgency, frequency and hesitancy, anal sphincter disturbance, sexual dysfunction, pes cavus or mild proprioceptive impairment. Spasticity predominantly affects the lower limbs; there may be mild signs in the upper limbs. In complicated HSP, spastic paraparesis is associated with other neurological manifestations in a variable phenotype. These may include optic atrophy, retinopathy, extrapyramidal involvement (choreoathetosis, dystonia and rigidity), cerebellar signs (ataxia, dysarthria and nystagmus), cognitive impairment, sensorineural deafness and epilepsy. Peripheral neuropathy, amyotrophy, icthyosis and cardiomyopathy may also be associated (Tables 15.13, 15.14 and 15.15).

Investigation and mangement Spinal and cranial MR imaging are typically normal but there may be cord atrophy in some forms (e.g. SPG6 and 8). In complicated forms, imaging may show cerebral and cerebellar atrophy or hypoplasia of the corpus callosum. The age of onset varies from infancy to the eighth decade but is usually between the second and fourth. Prognosis is variable between families and to a lesser extent within families. Early onset HSP (>35 years) tends to be slower in progression and most

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Table 15.13 X-linked forms of HSP. SPG1

Xq28

Mutations in L1CAM, one of a sub-group of integral transmembrane glycoproteins that mediate cell adhesions at cell surfaces Mutation in proteolipid protein (PLP) which is a major myelin protein affecting oligodendrocyte function

SPG2

Xq22

SPG16

Xq11.2

Different mutations give rise to syndromes of MASA (mental retardation, aphasia, shuffling gait and adducted thumbs) Gives rise to both pure and complicated forms. Same locus as Perlizaeus-Merzbacher disease. Complicated forms include cerebellar syndromes and mental retardation Both pure and complicated forms associated with motor aphasia, impaired visual acuity, mild mental retardation, bowel and bladder involvement

Table 15.14 Common autosomal dominant forms of HSP. SPG4

SPG3A

2p22-p21(multiple SPG4 mutations including point mutations, small insertions and deletions) 14q11–21

SPG6

15q11.1

SPG10

12q–13

SPG13

2q24–34

SPG17 (Silver’s syndrome) SPG31

11q12–q14

Spastin (an AAA protein which acts as a protein chaperone in assembly and function of protein complexes. Involved in motor axonal regulation in corticospinal tracts) Atlastin involved in axonal development and trafficking NIPA 1 (may encode a membrane protein) KIF5A (defect in microtubule mediated trafficking leads to axonal degeneration) Heat shock protein 60 (part of mitochondrial complex, regulates correct protein folding) Aggregate formation leading to neurodegeneration Receptor expression enhancing protein 1 (REEP1)

SPG33

25%. Treatment is initially supportive and involves eliminating the continuing source. Chelation therapy is used to remove lead before it can be incorporated into the CNS or soft tissues. This involves treatment with EDTA, dimercaprol (2,3-dimercaptopropanol) or D-penicillamine. Early treatment usually leads to improvement in the neuropathy but the prognosis of the encephalopathy is less certain.

Mercury Mercury exists in an elemental inorganic or organic form. The inorganic form is absorbed rapidly following inhalation during industrial exposure in the production of thermometers, barometers or batteries and traditionally was also ingested during hatmaking. The organic form, methyl mercury, is far more toxic and occasionally poisons water supplies, notably in the Minimata outbreak in Japan. Methylmercury is bio-amplified by aquatic species and causes paraesthesiae, tremor, ataxia, spasticity, progressive visual field and hearing loss with encephalopathy, progressing to stupor, coma and death. Chronic industrial exposure to elemental or inorganic mercury causes systemic manifestations with renal, skin, pulmonary and gastrointestinal involvement including cutaneous erythema, anaemia and proteinuria. Patients develop progressive rest and intention tremor (‘hatter’s shakes’), ataxia and myopathy; there is memory and cognitive impairment, social withdrawal, personality change with anxiety, excitability, emotional lability and insomnia. Eventually, drowsiness, confusion and stupor supervene. Diagnosis is confirmed by demonstrating elevated blood and urine mercury. Treatment is by facilitating the elimination of mercury with prompt chelation using penicillamine and providing supportive care. The role of chelation therapy with dimercaprol is controversial. Arsenic Arsenic has been used as a poison because it is odourless, tasteless and highly toxic. It has been extensively employed in herbicides and pesticides and as a timber preserver in the past, although current use is mainly restricted to the production of glass, electronics and computer microchips. Exposure occurs by drinking contaminated well water, especially in the Indian subcontinent, or as a consequence of mining lead or copper smelting; arsenic is sometimes found in herbal medications. The mode of action is to inhibit mitochondrial function and oxidative metabolism. Acute or subacute exposure is associated with nausea, vomiting, abdominal pain and bloody diarrhoea, followed by progressive encephalopathy. Autonomic features including hypotension, tachycardia and vasomotor collapse develop culminating in arrhythmia, myoglobinuria, acute renal failure, obtundation, acute confusional state, coma and death. Low dose chronic exposure causes weight loss, severe alopecia and white horizontal striations on the nails (Mees’ lines). There is usually severe gastrointestinal disturbance and skin changes include melanosis,

Toxic, Metabolic and Physical Insults keratosis and malignancy. There may be personality disturbances with confusion, irritability, delusions and visual hallucinations; optic nerve and spinal cord involvement can also occur. Arsenic neuropathy is predominantly axonal although demyelinating features occur soon after exposure. It usually develops within several weeks of the acute exposure and is characterized by distal pain and progressive weakness initially in the lower limbs, subsequently spreading to the upper limbs with areflexia and distal sensory loss. The neuropathy is associated with respiratory muscle weakness. Investigations may show myoglobinuria, elevated liver enzymes and CSF protein. Arsenic binds to keratin and therefore can be detected in hair, nail or urine. Nerve conduction studies show motor and sensory axonal neuropathy with occasional demyelinating features and nerve biopsy confirms axonal degeneration. Treatment involves removal of exposure, decontamination of the gastrointestinal tract and aggressive support. Chelation therapy may be undertaken with derivatives of dimercaprol such as 2,3dimercapto-1-propanesulfonic acid (Unithiol) or d-penicillamine but there is little evidence to suggest this helps in the later stages of arsenic neuropathy.

Manganese Manganese is present in all living organisms and functions as an enzyme cofactor. It is widely used as a fuel additive and also in fertilizers and fireworks. Toxicity occurs as a consequence of its industrial use in iron and steel manufacturing and in welding but exposure may also be iatrogenic as a consequence of poorly balanced total parenteral nutrition. Acute exposure may lead to a progressive encephalopathy (‘manganese madness’) characterized by fatigue, apathy, insomnia, auditory and visual hallucinations, personality change, compulsive behaviour, irritability and aggression culminating in progressive memory disturbance. More chronic exposure leads to a characteristic pattern of extrapyramidal abnormalities characterized by parkinsonian facies, hypersalivation, micrographia, bradykinesis, rigidity and severe dystonia with occasional myoclonic jerking. There is often an associated encephalopathic component including emotional lability and progressive cognitive impairment. The diagnosis is confirmed by the presence of elevated serum manganese and urine levels may also be helpful. MRI scan may show abnormal signal intensities in the globus pallidus and subthalamic nucleus. Management necessitates removal of the toxic sources and chelation with EDTA is occasionally helpful. The response to levodopa is variable. Dialysis may be necessary. Aluminium Aluminium is abundant and is extensively used in packaging, food containers and cooking utensils and in water treatment. Industrial exposure may occasionally occur after smelting or inhalation of aluminium dust but this is rare. Acute intoxication leads to progressive agitation, confusion and myoclonic jerking. There may be development of generalized tonic–clonic seizures progressing to coma and death. More chronic exposure causes a

progressive tremor, incoordination and ataxia with the development of focal epilepsy. Dialysis dementia (Chapter 19) is at least partly brought about by the toxic effects of aluminium in the dialysis fluid and in phosphate binders. Aluminium retention occurs in the uraemic state and progressive cognitive impairment, dysarthria and encephalopathy may develop after several years’ dialysis. The treatment includes de-ionization of the dialysate and avoidance of aluminium-containing phosphate binders. However, aluminium intoxication can occur as a consequence of chelation therapy that actually displaces sequested aluminium from bone and this should therefore be avoided.

Thallium Exposure to thallium is now relatively rare as its use has been banned in pesticides. There is still an occasional incidence of deliberate exposure by attempted murder or suicide. Acute exposure may lead to an encephalopathy characterized by hallucinations, paranoia and cognitive impairment. Systemic involvement is similar to arsenic in causing abdominal cramps, vomiting and diarrhoea. Alopecia develops after several weeks and Mees’ lines are seen in the nails. There may be a progressive encephalopathy with ataxia, chorea and confusion culminating in cardiac and respiratory failure and coma. Chronic exposure leads to a progressive predominantly sensory axonal neuropathy which is painful and associated with distal sensory loss, weakness and areflexia. Neurophysiology confirms progressive axonal loss. High thallium levels can be detected in blood, urine and hair samples. The treatment is with gastric lavage, laxatives and haemodialysis. Absorption from the gastrointestinal tract can also be reduced by Prussian blue or activated charcoal, both of which bind thallium. Tin Tin is extensively used in the manufacture of electronics and in soldering. The inorganic form is not associated with any abnormal neurological features but the organic forms (in particular triethyl tin), which may be inhaled, lead to progressive neurological dysfunction characterized by raised intracranial pressure with headache, apathy, cognitive impairment and hallucinosis culminating in seizures and coma. There may also be behavioural disturbances including emotional lability and cognitive impairment with confusion and disorientation. Abnormal eye movements, papilloedema and a cerebellar syndrome also occur. Blood levels are a poor guide; urine levels may be more reliable. Treatment is by use of chelating agents, plasma exchange and d-penicillamine. Bismuth Bismuth is contained in some surgical dressings and is sometimes used in the treatement of peptic ulcers and to bulk stools after colostomy. Excessive intake can lead to a progressive behavioural disturbance including depression, apathy and irritability, culminating in a florid encephalopathy with hallucinosis, tremor,

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myoclonus, ataxia and dysarthria leading to convulsions and coma. The myoclonus is characteristically stimulus-sensitive and may be multi-focal or generalized. Chelation treatment with dimercaprol is often effective.

Solvents and toxins CNS dysfunction can occur as a consequence of an accidental exposure to a high dose of industrial solvents or to more prolonged chronic exposure to moderate levels in the workplace or as a drug of abuse. The long-term symptoms of prolonged exposure to solvent vapour include progressive cognitive deficits affecting attention, memory and executive function and causing visuo-spatial disturbance with subsequent cerebellar or motor involvement.

Toluene Toluene (methyl benzene) is a volatile hydrocarbon solvent used in the manufacture of paints, glues and petrol. Exposure occurs relatively commonly during manufacture or industrial processes and the condition may be unrecognized. However, much of toluene poisoning is attributable to deliberate inhalation, such as in glue sniffing. Toluene is highly lipid-soluble and so crosses the blood–brain barrier readily. It causes CNS demyelination, with secondary neuronal damage (Figure 18.1). It also causes a mixed axonal–demyelinating neuropathy. Acute exposure leads to progressive headache, nausea, vomiting and dizziness. There may be cardiorespiratory symptoms secondary to pulmonary hypertension before the development of cognitive impairment including euphoria, disorientation, memory loss and focal neurological signs such as dysarthria, ataxia and intention tremor with progression to stupor and coma. Long-term exposure is associated with toxic encephalopathy, progressive intention tremor and stimulus-sensitive myoclonus and there may be a progressive optic neuropathy with opsoclonus. MRI scan may show cerebral atrophy or diffuse symmetrical abnormalities in the basal ganglia, thalamus or cingulate gyrus or extensive white

matter high signal change. There are elevated urinary hippuric acid levels and blood toluene can also be a valuable guide. Treatment is by removal of the source of the exposure and supportive care.

Trichloroethylene and tetrachlorethylene Trichloroethylene (TCE) and tetrachlorethylene (perchlorethylene; PCE) are industrial solvents particularly used as degreasers but also in dry-cleaning fluids. Exposure occurs by inhalation, contamination of drinking water or in recreational abuse because of their euphoric effects. Acute toxicity causes encephalopathy characterized by progressive nausea, dizziness and headache leading to disorientation, stupor and coma. Chronic exposure is associated with trigeminal neuropathy causing progressive sensory impairment spreading from the nose in a trigeminal distribution leading to facial and buccal numbness. Weakness of the muscles of mastication and facial expression may then develop with progressive ptosis, ophthalmoplegia, retrobulbar neuritis, optic atrophy and vocal cord involvement. Further exposure leads to a chronic sensorimotor neuropathy with mixed axonal and demyelinating features and progressive impairment of attention, memory and orientation. The level of TCE metabolite tricholorethanol can be measured to monitor exposure. Treatment is by removal from exposure. Patients who have been acutely exposed should have oxygen administered and be treated with gastric lavage and haemodialysis. Improvement in trigeminal and other cranial nerve involvement is usually incomplete. Ethylene oxide Ethylene oxide is used to sterilize heat-sensitive medical equipment and as an alkylating agent in industrial synthesis. It is highly toxic causing a severe progressive reversible encephalopathy. Long-term exposure leads to a sensorimotor axonal neuropathy and mild cognitive change. Improvement generally follows discontinuation of exposure.

Figure 18.1 Toluene exposure. MRI T1W showing extensive white matter change.

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Hexacarbon solvents Hexacarbon solvents, and in particular n-hexane and methyl nbutyl ketone (MnBK), are neurotoxic and are liberated during petrol production and refining. They are also present in most glues and solvents and are widely abused for recreational reasons. A reversible acute encephalopathy is common in those who take solvents for recreational reasons, leading to euphoria, dizziness, ataxia and progressive cognitive impairments. However, chronic exposure causes a progressive distal sensorimotor axonal peripheral neuropathy associated with autonomic involvement and parkinsonism. Xylene and styrene Xylene and styrene are structurally similar to toluene and found in solvents, paints and varnishes. Acute exposure occurs by inhalation or absorption from the skin and may lead to acute encephalopathy with disturbances of cognition, attention and behaviour. Chronic exposure to lower levels can cause mild but progressive disturbance of behaviour, psychomotor performance and visual function. Carbon disulphide Carbon disulphide is used as a solvent in varnishes and insecticides, in the manufacture of plastics including rayon and cellophane as well as the vulcanization of rubber. It is a potent neurotoxin with exposure caused by inhalation and oral ingestion rather than by transdermal exposure. Acute exposure to high levels leads to encephalopathy with progressive drowsiness and disruption of behaviour, personality and memory with mood swings, mania, hallucination, depression, psychotic disturbances and memory loss. A similar encephalopathy occurs with chronic exposure but a distal demyelinating sensori-motor peripheral neuropathy may occur and there may also be parkinsonism, retinopathy, optic neuropathy and a small vessel vasculopathy. Blood and urine carbon disulphide levels give a guide to exposure. The treatment is removal from the source of toxicity but no agent is available to neutralize the effects of carbon disulphide which may be present for many years. Cyanide Cyanide blocks trivalent iron in cellular respiration enzymes and inactivates cytochrome oxidase. This leads to an immediate cessation of cell respiration with hypoxia and respiratory arrest. Exposure usually occurs as a consequence of deliberate poisoning. However, cyanide poisoning can also occur during accidental smoke inhalation or from ingestion of incorrectly prepared cassava flour (Konzo, see below). Acute exposure affects structures with high oxygen requirements leading to haemorrhage necrosis. Presentation is with dizziness, headache, vertigo and agitation, culminating in seizures, respiratory arrest and death. Chronic ingestion can cause progressive cognitive impairment, parkinsonism and delayed dystonia. MRI shows bilateral areas of hyperintensity in the lentiform and caudate nuclei also the striatum and globus pallidus. Treatment involves immediate admin-

istration of 100% O2 followed by hydroxycobalamin and sodium thiosulphate.

Acrylamide Acrylamide is used as an adhesive and grouting agent. Inhalation or cutaneous exposure may occur during manufacture or in the polymerization process. Acute high-dose exposure can cause an encephalopathy characterized by confusion hallucinations and drowsiness. More commonly, however, chronic exposure leads to a characteristic progressive sensorimotor axonal neuropathy which initially develops in the lower limbs before affecting the upper limbs. Autonomic involvement is common with hyperhidrosis and dermatitis. There may be a progressive cerebellar ataxia and occasionally pyramidal signs occur. Nerve conduction studies confirm the presence of an axonal sensorimotor polyneuropathy initially affecting large myelinated fibres and biopsy shows distal axonal degeneration. Allyl chloride Allyl chloride is used in the preparation of epoxy resins and insecticides. It can cause a mixed motor and sensory distal axonal neuropathy which only recovers after prolonged discontinuation. Methyl bromide Methyl bromide is widely used as a refrigerant, in fire extinguishers and as a soil fumigant. Acute exposure causes encephalopathy with progressive convulsion and delirium leading to hyperpyrexia, coma and death. Chronic exposure to lower levels causes systemic features including nausea, vomiting, headache and mucosal irritation before CNS deficits develop which may include progressive speech disturbance and cerebellar ataxia, incoordination and myoclonus. Long-term exposure leads to a distal sensorimotor polyneuropathy, occasionally upper motor neurone signs, and visual disturbance including optic atrophy. Management is supportive but dialysis may be necessary to remove bromide. Methyl chloride Methyl chloride is a methylating agent used in the production of lead, rubber or polystyrene foam. Toxicity is associated with inhalation or absorption through the skin. There is CNS depression which may cause headache, dizziness, confusion, speech abnormalities and diplopia with incoordination. Severe prolonged exposure may lead to seizures or stimulus-sensitive myoclonus. Nitrous oxide Exposure to nitrous oxide (N2O) occurs in patients receiving prolonged general anaesthesia or by intentional inhalational abuse. N2O disrupts B12-dependent pathways and the clinical pattern of toxicity is therefore identical to subacute combined degeneration with extensive spinal cord, brain and peripheral

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nerve demyelination. Nitrous oxide oxidizes cobalamin and therefore disrupts methionine synthase reduction, necessary for methylation reactions, which are in turn important for production of myelin. N2O causes a progressive distal sensory neuropathy beginning in the hands with proprioceptive loss secondary to involvement of large sensory nerves and dorsal columns. Progressive spasticity and hyper-reflexia reflecting myelopathy then develops. Nerve conduction confirms slowing of motor and sensory conduction velocities with secondary axonal loss. Vitamin B12 replacement may help in the management but this does not always reverse the neuropathy.

Organophosphates Forty per cent of pesticides contain organophosphates; they are also found in herbicides, as a petroleum additive and a flame retardant. Exposure usually occurs in agricultural settings although ingestion may occur in children or in suicide attempts. Organophosphates inhibit acetylcholinesterase leading to cholinergic toxicity. In acute exposure this is typically manifest within 4 days and resolves over 3–4 weeks. Presentation is with salivation, lacrimation, diarrhoea, urinary frequency, mydriasis, bradycardia, bronchoconstriction and diffuse muscle weakness involving respiratory, bulbar and proximal limb musculature leading to respiratory failure. Acute central effects are also seen causing confusion, dizziness, ataxia, blurred vision and impaired memory culminating in seizures and coma. Chronic exposure (‘sheep dipper flu’) is characterized by transient symptoms including headache, rhinitis, pharyngitis and myalgia. However, a longer term mild impairment of cognitive and memory functions occasionally occurs. Prolonged exposures may also lead to a late onset sensorimotor axonal peripheral neuropathy and occasionally ataxia and upper motor neurone involvement with spasiticity. Organophosphates are easily absorbed through the skin and therefore it is important that those with potential exposures use protective masks, gloves and appropriate clothing. The skin should be carefully washed following exposures and it is essential to maintain the airway because of the risk of aspiration. Prolonged treatment with atropine, pralidoxime or obidoxime and benzodiazepines may be necessary. Carbon monoxide Carbon monoxide (CO) is clear, colourless and odourless. It is commonly used in attempted suicide but exposure also occurs from leaking car exhausts or incorrectly installed domestic gaspowered boilers. Occasional exposure may occur in miners and gas workers. CO has a greater affinity for haemoglobin than does oxygen itself and therefore binds preferentially to oxygen-binding sites to form carboxyhaemoglobin. This limits dissociation of oxygen in the tissues resulting in relative tissue hypoxia. Carboxyhaemoglobin also inhibits oxygen binding and oxidative phosphorylation in the mitochondria further exacerbating functional hypoxia in tissues with a high metabolic demand. Acute exposure causes headache, dizziness, confusion, disturbance of conscious-

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ness and behavioural change. Visual disturbance and progressive shortness of breath develop rapidly with subsequent loss of consciousness, seizures, coma and cardiac arrest. Exposed individuals can have pink/red skin, or may be cyanosed. Prolonged acute intoxication is fatal in 2–25% of exposed individuals. A high proportion of survivors have residual neurological features including extrapyramidal signs. Patients with initial transient choreiform movements may develop progressive parkinsonian features, progressive dystonia and urinary incontinence. A delayed onset encephalopathy may develop after a period of apparent partial or complete recovery with cognitive and personality impairment with memory dysfunction, apathy, mutism and the progressive development of vegetative features. There may be elevated levels of carboxyhaemoglobin and MRI shows diffuse symmetrical high intensity white matter change involving caudate and bilateral pallidal necrosis. Treatment of acute exposure is by removal from the source and the provision of 100% oxygen. Hyperbaric oxygen may enhance recovery from acute symptoms. However, the prognosis for neurological recovery after CO exposure is poor. Insidious chronic low-grade exposure to CO may be associated with industrial exposure or badly ventilated and faulty household heating appliances. The syndrome of chronic occult CO poisoning is manifest as headache, fatigue, dizziness, paraesthesiae, visual disturbance with chest pain and palpitation associated with ventricular arrhythmias. The diagnosis of low-grade exposure depends on recognition of the syndrome and demonstration of elevated levels of carboxyhaemoglobin. Management depends on identifying the source of CO and prompt removal. Oxygen therapy, as discussed above, may be necessary.

Marine toxins Marine toxins are difficult to detect as they are often without colour, taste or odour. Furthermore, most are unaffected by cooking, freezing or salting.

Ciguatera Ciguatera toxin (ciguatoxin) occurs in reef fish (e.g. snapper or barracuda) who consume an apophytic dinoflagellate which elaborates the toxin. The toxin causes voltage gated sodium channels to open. Poisoning leads to the rapid development of acute abdominal cramp, nausea, vomiting and diarrhoea. Peri-oral, limb and trunk paraesthesiae develop 12–48 hours after ingestion of contaminated fish. In the most severe cases there is a characteristic cold allodynia (‘temperature reversal’). Cranial nerve palsies, polymyositis or a rapidly progressive sensorimotor and autonomic polyneuropathy affecting bulbar and respiratory muscles can occur. This progresses to limb weakness, flaccid quadriplegia and respiratory muscle impairment. Although the condition generally resolves spontaneously within a few days, fatalities are caused by respiratory insufficiency and cardiac dysfunction may occur. Bioassay of the toxin is possible. Treatment is supportive.


Tetrodotoxin Tetrodotoxin (TTX) occurs in the liver and ovaries of puffer fish and toad fish from the family Tetraodontidae and also occurs in some types of crabs. TTX blocks voltage-gated sodium channels at nanomolar concentrations. Onset is with numbness of the lips and tongue followed by worsening paraesthesiae in the face and limbs with a sense of floating or light-headedness and systemic features including gastrointestinal disturbance. With ingestion of large amounts of TTX there is worsening neuromuscular paralysis involving the limbs, trunk, cranial nerves and respiratory muscles leading to death if artificial ventilation is not instituted. Supportive treatment is successful in most cases because the condition is fully reversible, although it is important to note that patients can be fully conscious in spite of total paralysis. Atropine treatment may be necessary to treat bradycardia. Scombroid Scombroid poisoning is common as it is caused by poor storage of tuna and similar fish. Toxicity differs from the other marine toxins as it has a histamine-like effect. The onset is rapid and resembles an acute anaphylactic response with pruritus, throbbing headache, erythema, urticaria, paraesthesiae and palpitation; poisoning tends to be self-limiting. Treatment is with intravenous histamine receptor blockers and supportive care. Shellfish Shellfish toxicity may be caused by secondary infectious agents such as Vibrio cholerae and hepatitis A and occurs with bi-valve molluscs including clams, mussels, scallops and oysters. Saxitoxin is a heat-stable water-soluble toxin that is concentrated in shellfish which also acts by blocking voltage gated sodium channels. There is a rapid onset of paraesthesiae, particularly peri-orbital, and subjective limb weakness. There may be severe respiratory involvement including the diaphragm with significant mortality. Neurotoxic shellfish poisoning is caused by brevetoxins which cause depolarization of excitable membranes with persistent activation and repetitive firing of nerve and muscle. There is simultaneous onset of gastrointestinal and neurological symptoms including tremor, dysphagia, pupillary paralysis and hyporeflexia. Amnestic shellfish poisoning is caused by the toxin domoic acid which stimulates kainate-type glutamate receptors and has a toxic action on the limbic system leading to antegrade and retrograde amnesia, seizures, myoclonus and coma. Systemic symptoms include labile blood pressure, cardiac dysrhythmia and myoglobinuria. The syndrome may improve gradually over 3 months but residual amnestic deficits occur.

Other biological toxins Snake venom Snake venom from many members of the Elapidae family, which includes the banded krait and sea snakes, contains toxins that cause neuromuscular junction (NMJ) blockade resulting in a myasthenia-like syndrome, particularly affecting the muscles of

neck flexion and the ocular, bulbar and proximal limb muscles, occasionally leading to respiratory paralysis. Onset is often with local pain, swelling and erythema in the region of the bite with local lymph node involvement. The onset of systemic symptoms depends upon the site of the bite and the species, but over 1–12 hours muscle fasciculation, weakness and hypotension can develop with eventual shock. Presynaptic NMJ dysfunction occurs with β-bungarotoxin envenomation by banded kraits while α-bungarotoxin causes an additional post-synaptic NMJ blockade. Snake bites generally cause death not because of the paralysis but because of the systemic effects of proteolytic toxins acting on blood constituents and tissues. Nevertheless, the neurological features can aid diagnosis and choice of appropriate anti-venom.

Spiders The female black widow spider produces a neurotoxin (α-latrotoxin) which triggers massive spontaneous neurotransmitter release, from the NMJ as well as other synapses. There may be intense pain in the region of the bite with a characteristic erythematous target lesion. This is followed by the development of involuntary spasms in the abdominal muscles which spreads to involve the limbs. The funnel-web spider, indigenous to parts of Australia, produces a toxin that affects sodium channels and causes a severe dysautonomia, piloerection, sweating and diaphragm involvement culminating in respiratory arrest. Treatment is by supportive care in intensive care with anti-venom if available. Muscle spasm is treated with benzodiazepines. Scorpions Scorpions elaborate a toxin that has both presynaptic and postsynaptic effects. These may lead to local symptoms followed by the development of progressive severe autonomic impairment with muscle fasciculation and progressive bulbar, respiratory and cardiac involvement. Occasionally, encephalopathy may occur secondary to CNS involvement. Ticks Ticks cause a rapidly developing, progressive flaccid motor weakness affecting ocular, bulbar, respiratory and limb musculature because of presynaptic inhibition of acetylcholine. It is essential for the tick to be removed immediately. Fungal poisons Fungal poisons are highly diverse, and neurotoxic compounds occur in several of the most toxic species. Some members of the Amanitae family such as the fly agaric (Amanita muscaria) contain molecules that act at GABA, glutamate and acetylcholine receptors (muscimol, ibotenic acid and muscarine). However, the high fatality associated with death cap (Amanita phalloides) ingestion is mainly associated with amatoxin, which inhibits mRNA synthesis and leads to hepatic and nephrotic toxicity. Some members of the Psycilocybe family are used recreationally because of their

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psychoactive effects. Psilocybins are structural analogues of serotonin and produce LSD-like effects with euphoria, hallucination, tachycardia and eventually seizures.

Lathyrism Lathyrism occurs in countries where the chickling pea (grass pea) Lathyrus sativus is grown, and generally only under conditions of food deprivation. It is may be caused by the neurotoxic amino acid β-N-oxalylamino-L-alanine (BOAA), which acts as an agonist at the AMPA subclass of glutamate receptors. There is prominent degeneration in Betz cells of the motor cortex and pyramidal tracts. The condition develops with an insidious onset of gait unsteadiness and development of a spastic paraparesis with normal sensory examination. There is no involvement of cognition or cerebellar function. A peripheral sensory neuropathy, which is predominantly demyelinating, may occur in a minority of patients. A related toxin, beta-methylamino-L-alanine (BMAA) is present in the fruit of the cycad palm, and has been implicated in the amyotrophic lateral sclerosis–parkinsonism– dementia complex amongst the Chamorro population. However, it remains unclear whether consumption of this toxin can account for the epidemiological evidence. Konzo Konzo occurs in epidemics in East and Central Africa. It affects children above the age of 3 years and women of childbearing age, causing sudden-onset symmetrical non-progressive permanent spastic paralysis, predominantly affecting the lower limbs but spreading to involve the upper limbs and the cranial nerves. The pathology resembles lathyrism with involvement of cortical Betz cells directed towards the lower extremities and their corresponding corticospinal tracts. It is believed to be associated with high dietary levels of cyanide caused by the intake of poorly prepared bitter cassava, particularly if there is protein malnutrition, but the aetiology of Konzo continues to be debated. Methanol and ethanol Methanol and ethanol are considered below. Botulism Botulism is considered in Chapter 8.

Radiation-induced neurological disease Exposure to radiation occurs naturally but this is usually low intensity and carries few risks. Increased levels are associated with exposure to occupational or therapeutic radiation and, rarely, to nuclear weapons. Radiation can be divided to non-ionizing and ionizing. Non-ionizing radiation (e.g. ultraviolet, infra-red, microwaves, radio waves, laser radiation and visible light) has low energy and is therefore unable to break chemical bonds and cause ionization; thus, injury is caused by local heat production and is generally mild, although damage to retinal and optic nerve fibres

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may occur. However, ionizing radiation is considerably more serious. This radiation is caused by high energy particles or electromagnetic waves (X-rays and gamma rays) which can break chemical bonds and therefore produce ionization within tissues leading to DNA damage and mutation. Ionizing particulate radiation is caused by α particles, electrons, neutrons or protons. Alpha particles (composed of two protons and two neutrons) are produced by uranium, radium and polonium. They lead to high levels of ionizing radiation but are usually blocked by paper or clothing and are therefore only toxic if ingested or inhaled. Beta particles are high energy electrons emitted from decaying isotopes of strontium 90 which are commonly used to generate X-rays and radiotherapy. Toxicity also occurs with ingestion. High energy neutrons are only produced with nuclear fission but are a serious radiation risk following detonation of a nuclear reaction or if a reactor becomes critical. Proton exposure also occurs naturally from cosmic radiation. The early effects of radiation, seen after exposure to large doses delivered over a short period of time (>1 Gy), affect rapidly dividing tissues including skin, bone marrow and gut epithelium. The onset is with prodromal gastrointestinal symptoms before the condition manifests with bone marrow suppression, loss of intestinal mucosal cells leading to bowel disturbance and sepsis, and finally cerebrovascular involvement. Management involves meticulous decontamination at the site of exposure and supportive care with transfusion and treatment of sepsis. Late toxicity following accidental or therapeutic exposure to radiation is usually seen in organs with slowly dividing cells such as the CNS, kidney and liver, causing radiation necrosis. The characteristic delayed complication is malignancy, particularly of the thyroid gland, breast or leukaemia.

Therapeutic radiation Therapeutic radiotherapy creates ionized oxygen which reacts with cellular DNA. Healthy cells have a greater ability than tumour cells for DNA repair and therefore the cumulative effects of unrepaired DNA result in cell death (apoptosis of tumour cells while healthy cells are more able to repair themselves). Acute complications of therapeutic radiotherapy include encephalopathy which can occur during or up to 1 month after radiotherapy has been commenced. It is associated with headaches, nausea, changes in mental state and symptoms suggestive of increased intracranial pressure because of breakdown of the blood–brain barrier and secondary cerebral oedema. The more acute effects of therapeutic radiotherapy also include hypersomnolence, encephalopathy, memory disturbance and there may also be gastrointestinal symptoms. The MRI shows increased oedema with contrast enhancement which may resolve over several months. The condition is caused by damage of the blood–brain barrier and is steroid responsive. (See Chapter 20.)

Early-delayed radiation encephalopathy Early-delayed radiation encephalopathy develops 1–4 months after radiotherapy and is caused by injury to oligodendroglia

Toxic, Metabolic and Physical Insults producing demyelination and vasogenic oedema. This may present with somnolence, decline in long-term memory and encephalopathy. There may also be brainstem involvement with diplopia, nystagmus, dysarthria and ataxia. This form of radiation encephalopathy resolves over several weeks but occasionally may progress to profound encephalopathy, coma and death. Subacute encephalopathy may also be associated with a myelopathy and a transient brachial plexopathy.

Late-delayed radiation encephalopathy Late-delayed radiation encephalopathy develops several months or years after cranial irradiation and is associated with diffuse cerebral atrophy, focal radiation necrosis or secondary vascular change. The pathological findings are of demyelination. There may also be signs of raised intracranial pressure. The patient presents with cognitive decline, personality change and gait disturbance developing 6–18 months or more after total brain irradiation. There may be a more indolent intellectual impairment leading to dementia. Delayed effects of radiotherapy also include endocrine dysfunction because of hypothalamic impairment, optic neuropathy, progressive cranial neuropathy or chronic progressive myelopathy. The incidence of delayed radiotherapy effects is related to total radiation dosage and the size of fractionated doses. A total dose of 1 year after radiotherapy or tumours in the head and neck, cervical or mediastinal region. Focal neurological deficits related to spinal cord involvement include progressive sensory impairment in the lower limbs followed by progressive myelopathy. There may be a transverse myelitis or Brown-Séquard syndrome with sphincter disturbance. Treatment is with corticosteroids but this only leads to a temporary improvement and there is generally secondary necrosis and atrophy of the cord because of vasculopathy.

Radiation plexopathy Plexopathy can affect the brachial or lumbar plexus and follows radiotherapy in these regions. It is important to distinguish the development of progressive plexopathy from direct neoplastic involvement of the plexus. The onset is characterized by paraesthesiae and dysaesthesiae with pain and progressive atrophy and weakness developing over several months. It develops 1–3 years or longer after radiotherapy and is particularly associated with high doses of radiotherapy (>6000 Gy), large daily fractionations, lymphoedema, induration of the supraclavicular fossa and myokymia on electromyography (EMG). The condition seems to be due to small vessel damage and fibrosis; it responds poorly to steroids. Positron emission tomography (PET) imaging of the brachial plexus may distinguish malignant infiltration from radiotherapy induced plexopathy. Radiation administered to the neck can also accelerate the development of carotid artery atherosclerosis. This may develop as early as 1 year after treatment but is often delayed by 10 years or more. It is associated with a high treating dose and daily fractionated dose. Cerebral ischaemia may be caused by atherosclerotic embolization to the brain or haemodynamically significant arterial stenosis. Histologically arterial damage cannot be distinguished from typical atherosclerosis but it occurs in the radiotherapy field.

Lightning and electrical damage to the nervous system Fifty people are struck by lightning in the UK each year, usually with some three fatalities. This compares with 100 fatalities in the USA. For injuries related to technical electricity (at work and at home), the UK annual estimate is approximately 3000 incidents with 30 fatalities. There are some 1500 deaths from electrocution annually in the USA.

Mechanisms of lightning and other electrical damage Lightning: initiation and pattern of contact Intra-cloud lightning is the most common form of lightning, but it is cloud-to-ground lightning that causes human injury. Usually, a highly branched discharge, known as the stepped leader, appears below the cloud base and heads toward the ground at a speed of 106 m/s. When the tip of the leader approaches within 30 m of the ground, the induced electric field produces an upward connecting discharge, usually from the nearest tallest object(s). When the two discharges meet, the first return stroke begins; this is an intense wave of ionization that propagates up the leader into the cloud at close to the speed of light. This is followed by a series of further ionizing strokes between the cloud and the ground each lasting some 500 ms with 40–80 ms gaps. These gaps are long enough to allow for retinal resolution of the individual strokes – which is why lightning is seen to flicker. The repeated earthbound strokes do not always follow the path of the initial leader, which

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is why lightning can appear forked. The large current of the return stroke causes the air in the surrounding channel to heat up to about 30,000°K in a microsecond, the channel pressure rises to 20 atmospheres or more; the decay of this pressure wave is heard as thunder. Although the electrical forces associated with lightning strike are enormous (106 V, 30,000 amps), the damage caused to a person struck is limited by the very short duration of the passage of current. In contrast, in accidental electrical injury, the power sources are much less, but contact can last for seconds or even minutes leading to severe thermal injury of tissues in and around the current path. The prelude to a strike, familiar to many mountaineers, is the build-up of atmospheric charge with buzzing of metallic equipment, skin tingling and hair standing on end. This is signal for immediate evacuation from prominent features such as a summit or crest of a ridge, if this is feasible. It is unusual for lightning strikes to occur in aircraft, cars or ships at sea because these vehicles act as ‘faradic cages’; that is, containers made from a conductor that shields its contents from external electric fields. Because the conductor is an equipotential there is no potential difference within the container. A major factor that determines injury in lightning strikes is whether the heart or CNS is involved in the current path (either can result in cardiorespiratory arrest), this in turn depends on the way the strike reaches the subject. 1 Direct strikes are the most damaging as the head is usually involved. 2 Side flash occurs when lightning strikes a nearby object such as a tree, and the current arcs to flow through the subject. 3 Ground current injuries are caused by lightning striking the ground near the subject; as the current dissipates, it reaches the subject and passes through them, usually via the legs if they are standing. 4 Most indoor injuries are minor and occur when the subject is shocked by current dissipating along telephone or other wiring. Many people can be injured at the same time as all of the above mechanisms of current transfer can occur in a single strike; at Ascot racecourse, UK, in 1956, 46 people were injured, two of them fatally.

Electrical injuries: high and low-voltage Electrical injuries are usually categorized on the basis of the voltage exposure: high (≥1000 V) or low. Low-voltage injuries usually result from exposure in the home, are relatively common but rarely severe (although death can occur from contact with as little as 25 V). High-voltage injuries usually affect those whose occupations bring them into contact with high-tension power lines or electrified rails. Members of the public may be involved in accidents that bring them into contact with these sources – children, anglers carrying their rods, those erecting or using aerials, parachutists and those attempting deliberate self-harm. High-voltage exposure is the cause of some 70% of electrical

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injuries and death. The voltages and currents associated with electrical exposure are much less than with lightning; however, the period of exposure is longer which magnifies the heating effects of current passage through the body leading to deep tissue necrosis, a complication rarely encountered in lightning strikes. Alternating current can increase this effect if tetanic contraction is induced in flexor muscles of the grasping hand, with periods of exposure approaching a minute or beyond in some cases.

Nervous system complications of lightning and electrical injury Neurological sequelae can be split into four categories: immediate and transient (IT), immediate and prolonged/permanent (IP), delayed and progressive (DP), and secondary trauma caused by lightning or electrical exposure (e.g. head or spinal injury caused by falls, usually secondary to a loss of consciousness). Complications are generally shared by both types of exposure. Transient loss of consciousness is the most common symptom associated with both types of electrical exposure, occurring in 70–80% of patients. Confusion, amnesia, paraesthesiae and limb weakness are also common IT symptoms. A specific IT syndrome said to be pathognomic of lightning strike is known as keraunoparalysis (kerauno, Greek for thunderbolt; literally, ‘smasher’). This is sometimes known as Charcot paralysis; he provided the first description – of short-lived complete lower limb paralysis with spared sphincter function and marked vasoconstriction with limb coolness, lividity and peripheral cyanosis. The symptoms abate over hours or, rarely, days. The pathophysiology is poorly understood. This syndrome should be differentiated from the much rarer true spinal cord syndromes that complicate lightning or electrical injury, which are usually of the IP or DP type. The neuropathological mechanisms that result in IP or DP symptoms are not fully understood, but probably comprise a mixture of thermal and non-thermal effects of current passage through affected tissues culminating in cell membrane breakdown. Thermally driven cell membrane damage occurs at temperatures as low as 43°C, although exposure needs to be for 4 hours or more to cause thermal disruption of the bilipid layer. Non-thermal mechanisms include electroporation, a process driven by supraphysiological rises in transmembrane electric potential that causes permanent holes in the cell membrane leading to fatal loss of the ionic gradient. Micropathological CNS lesions vary and include haemorrhage (both gross and petechial), neuronal cell death, myelin breakdown and glial proliferation. Cerebral oedema is seen in cases complicated by hypoxic brain injury secondary to cardiopulmonary arrest. The three most reported DP syndromes affect motor neurones, basal ganglia and the cord. Stroke-like syndromes (particularly venous sinus thrombosis), seizures, extrapyramidal syndromes, isolated cerebellar dysfunction (rare) and spinal cord syndromes at any level (also rare) are all described. Delayed syndromes are the least common. There is often doubt over any causative link, especially as the time since exposure can

Toxic, Metabolic and Physical Insults be many years. This is well illustrated by a study of psychological morbidity in a series of 165 patients with chronic sequelae of lightning and electrical injury. The mean symptom lag from time of exposure was 4.5 years; the majority of the symptoms reported were suggestive of depression. There is even less evidence for IP or DP syndromes affecting the peripheral nervous system causing a mononeuropathy or polyneuropathy, with the exception of direct thermal damage causing full-thickness burns through individual nerves. Complex regional pain syndromes are also described and are hard to evaluate.

Non-nervous system complications of lightning and electrical injury Cardiac Cardiopulmonary arrest is the most common cause of death in lightning and electrical injuries. Although this can be neurogenic it is usually caused by the direct effect of current passing through the heart leading to asystole or ventricular fibrillation. Cardiopulmonary resuscitation in these circumstances is often much more successful than out-of-hospital arrests from other causes. Skin and muscle damage Fern-shaped superficial cutaneous burns are sometimes seen following lightning strikes; these heal, but discoloration can persist for some years, or even permanently. Lightning rarely causes major skin or deep tissue burns; however, electrical injury, especially of high-voltage type, can be devastating to deep tissues. It is not possible to predict the amount of deep tissue injury from the overlying skin involvement. Striated muscle is particularly sensitive to AC current and high-voltage exposure is often complicated by rhabdomyolysis, subsequent renal failure, compartment syndromes and surgical amputation following overwhelming limb damage. Cataracts complicate lightning and electrical injuries that involve the head and neck in the current path, including lightning strikes that dissipate along telephone wires.

Management Initial management includes basic resuscitation and CPR. All patients suffering lightning strike or high-voltage electric injury require transfer to hospital for appropriate therapy and, in some cases, ECG monitoring. Asymptomatic patients with lowvoltage injuries in the absence of nervous system, cardiac or skin involvement need not be admitted. The neurologist, like members of other specialist teams, is most likely to be called upon to help with patients with moderate to severe injuries following lightning or electrical injury. There is no good evidence base for particular treatment of neurological symptoms caused by electrical current exposure; symptoms should be treated on their own merits.

Heat stroke Heat stroke is present if the core body temperature exceeds 40°C (104°F). It may occur either as a result of vigorous and prolonged exertion or during excessively hot weather, when it affects those who have difficulty with heat regulation including children, the elderly or those with chronic medical problems causing impairment of the mechanisms of heat loss (e.g. dermatological disease or following ingestion of anticholinergic drugs). In non-exertional heat stroke, presentation is usually with progressive impairment of consciousness manifest as irritability, confusion, delusions and hallucinations culminating in coma. There is usually anhidrosis and patients may develop hallucinations, cranial nerve abnormalities, early cerebellar dysfunction (ataxia, tremor and dysarthria), seizures and opisthotonus or the development of cerebral oedema with decerebrate posturing and status epilepticus. Systemic involvement leads to a hyperdynamic circulation with tachycardia and postural hypotension (caused by vasodilatation of cutaneous vessels and venous pooling), dehydration, congestive cardiac failure, systemic inflammatory response syndrome, multi-organ failure, myocardial damage and rhabdomyolysis. Following exertional heat stroke, non-specific symptoms of heat exhaustion are often unrecognized before impairment of consciousness develops – these include fatigue, weakness, nausea, vomiting, abdominal pain, muscular cramp, headache and syncope. Predisposing factors include exercise in inappropriate clothing, e.g. wet-suits, viral illness, obesity, dehydration, poor physical fitness, excessive alcohol and illicit drugs, e.g. cocaine and amphetamines. When heat stroke becomes established the clinical features are identical to those patients with non-exertional causes. Treatment is with rest, removal from the hot environment and correction of dehydration and electrolyte disturbances. Gentle cooling and oral rehydration is adequate in mild cases but in more severe cases ventilatory support, intravenous fluids and intensive monitoring of fluid, electrolyte balance and cardiac and neurological function is necessary. Cold gastric or peritoneal lavage or the use of cooling devices or controlled hypothermia may be of value. Iced water immersion is an efficient form of reducing the core temperature rapidly but is usually impracticable in patients with impaired consciousness and highly uncomfortable for those patients who are awake. Evaporation techniques are safer and as effective as immersion. A poor prognosis is suggested by the development of lactic acidosis, acute renal failure, hypercalcaemia, coagulopathy or prolonged coma (>4 hours). Muscle necrosis may lead to a grossly elevated creatine kinase (CK) level. Death occurs as a consequence of cerebral oedema and herniation. It is essential to recognize persons at risk of heat stroke and to ensure they are not exposed to excessive heat and maintain adequate fluid replacement.

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Hypothermia and non-freezing cold injury Accidental hypothermia is the unintentional decline in core temperature below 35°C (95°F). Primary hypothermia is caused by exposure to cold; secondary hypothermia occurs when a disease causes failure of thermoregulation (e.g. CNS tumour leading to hypothalamic impairment, exposure to toxins or neurodegenerative disorders). Hypothermia causes bradycardia because of decreased depolarization of cardiac pacemaker cells which is not mediated by the vagus and is resistant to therapies such as atropine. Hypothermia progressively depresses the CNS. With mild hypothermia there is confusion, lethargy, loss of fine motor coordination with ataxia, dysarthria and slowed reflexes. Severe hypothermia (5000 m but rarely cause visual loss and usually resolve spontaneously. They are not a manifestation of high altitude cerebral oedema. Cerebral infarction manifest as stroke or transient ischaemic attack (TIA) occurs more commonly than expected and is probably related to dehydration and polycythaemia secondary to hypoxia. High altitude pulmonary oedema High altitude pulmonary oedema is also caused by hypoxia but is often less obvious than cerebral oedema. It is manifest as breathlessness at rest, dry cough, dyspnoea, crackles in the lung bases and the production of copious pink frothy sputum. Once again the patient must be evacuated immediately to a lower altitude and rapidly provided with oxygen inhalation at a minimum of 2 L/min. Acetazolamide 250 mg 6-hourly may also be valuable and nifedipine and prophylactic salmeterol have also been used (Figure 18.3).

Figure 18.3 Chest X-ray showing high altitude pulmonary oedema. (From Clarke 2006, with permission from the publishers.)

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Table 18.2 Treatments for severe forms of altitude illness. (From Clarke 2006, with permission.) Manoeuvre/drug

Regimen

Comment

Descent Dexamethasone Nifedipine Oxygen Portable chamber (Plate 18.4)

250 m descent often helpful 8 mg + 4 mg every 6 h (iv, im, oral) 10 mg + 20 mg sustained release every 12 hours 2–6 L/min by mask or cannula 2–4 psi for 2–3 hours

Essential, if possible Often helpful in minutes, used primarily for brain oedema Mainly for pulmonary oedema Always helpful, calming Never truly portable/claustrophobia

im, intramuscular; iv, intravenous.

Table 18.3 Potential biological agents of terrorism.

Neurobiological weapons Biological weapons, although simple to produce, may be highly potent and difficult to detect. Indeed, recognition that a chemical or biological attack has occurred may be extremely difficult because of the delay before clinical manifestations become apparent. Diagnosis may depend on recognizing a pattern of clustering or atypical illness in animals or humans, possibly occurring at an unusual age. Potential biological agents of terrorism are listed in Table 18.3.

Modes of release Aerosol release of infectious particles is the most efficient form of dissemination and can be accomplished relatively easily. Particles remain suspended in the air for many hours increasing the infective capabilities. In contrast, contamination of food and water is more difficult to undertake as large amounts of infective agents are required and dissemination using bombs or missiles would be of limited value because much of the infective agent is lost at impact or explosion. Contamination of mail items or direct injection can only be undertaken on a small scale and is unreliable. Finally, dissemination of infectious diseases could theoretically be undertaken by infiltrating a contagious person.

Nerve agents Organophosphates Organophosphates (see above) act as cholinesterase inhibitors to precipitate the rapid onset of cholinergic crisis by hyperstimulation of muscarinic and nicotinic receptors. Unless a specific reactivator (an oxime) is administered recovery will not occur for several months until acetylcholinesterases can be resynthesized. Organophosphates have been used in attacks in Japan and Iraq. Sabin, tabun, soman, cyclosarin, VX These nerve agents are all liquids at room temperature and are tasteless and odourless. However, most are spontaneously

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Bacteria Bacillus anthracis Brucella suis Francisella tularensis Rickettsia Salmonella typhi Shigella Vibrio cholerae Yersinia pestis Viruses Encephalomyelitis Engineered viruses Smallpox Viral haemorrhagic fever

Chemical agents Hydrogen cyanide Chlorine Mustard gas Nerve agents Tabun Sarin Soman VX VR Ricin Toxin Aflatoxin Botulinum Mycotoxins Tetrodoxine Saxitoxin

volatile and evaporate rapidly and spontaneously apart from VX, which is an oily liquid that evaporates more slowly. All are toxic via inhalation or skin absorption. The most likely agent to be used is sarin, which is usually absorbed by inhalation. The onset of symptoms is with headache, pupillary constriction leading to blurred vision and cholinergic symptoms of rhinorrhoea, sialorrhoea and bronchorrhoea with secondary bronchoconstriction and respiratory distress. There may be nausea, vomiting, abdominal cramps and diarrhoea, bradyarrythmias and tachyarrhythmias and hypertensive crisis. Progressive cholinergic muscle involvement leads to fasciculation, weakness and respiratory muscle impairment causing apnoea and respiratory arrest. VX is a viscous liquid that degrades rapidly on exposure to the

Toxic, Metabolic and Physical Insults atmosphere but is easily absorbed through the skin and is extremely toxic causing rapid involvement of the NMJ leading to irreversible muscle contraction and a complete paralysis of all musculature. VR, a structural isomer of VX, also leads to cholinergic crisis with profound irreversible cholinergic weakness, seizures and cardiorespiratory arrest. The management of nerve agents involves decontamination, supportive care and the administration of specific antidotes. Decontamination is undertaken by immediate removal of all clothing to prevent continuing exposure and careful scrubbing with water and antiseptic. Supportive care may require intubation and ventilatory support. Atropine is recommended as a first line treatment, this competes with acetylcholine at the postsynaptic muscarinic receptors and may prevent cholinergic crisis, thus drying secretions and resolving bronchoconstriction. It may be necessary to administer repeated doses of atropine every 5–10 minutes and extremely high doses may be required. Oximes (pralidoxime, obidoxime) cleave the nerve agent into harmless and rapidly metabolized fragments, thus restoring normal catalytic activity, they also react directly with acetylcholinesterases and therefore work equally at mixed cholinergic sites. Pralidoxime chloride is the drug of choice but its use is limited because binding leads to a chemical change in the nerve agent which blocks the ability of the oxime to reactivate the complexes. Prior to exposure pyridostigmine may be of value as it reversibly binds a proportion of acetylcholinesterase allowing it to become gradually available to counteract the effects of the permanent blockade caused by the nerve agent. This may be of use for rescue workers. The long-term effects of nerve agents remain unclear.

Other toxins and poisons Antitoxin A Antitoxin A is elaborated by a freshwater bacterium and is an acetylcholine agonist that causes cholinergic crisis with fixed permanent muscle contraction as it is not released from the receptor. Furthermore, the toxin inhibits acetylcholinesterase leading to a further cholinergic stimulation. A severe flaccid paralysis with respiratory muscle involvement leads to apnoea. Management is with supportive care as there is no specific antidote although oximes may have some value. Mycotoxin Mycotoxins are produced by fungi and may be used as biological agents as they are resistant to destruction and rapidly absorbed through the skin. The mechanism of action involves the blocking of protein synthesis leading to inhibition of mitochondrial metabolism. There may be rapid cutaneous, respiratory and CNS toxicity. Management requires decontamination and supportive care. Ricin Ricin is extracted from the bean of the castor plant. It inhibits DNA replication leading to cellular necrosis when internalized in

cells. Historically, it has been used to assassinate individuals rather than as a weapon of mass destruction. It can be administered as an aerosol, droplet or by injection and leads to rapid tissue necrosis in the gastrointestinal tract, kidney and heart. Convulsions may occur. Management is supportive.

Marine toxins Marine toxins are discussed above. Dioxin and Agent Orange These were particularly used during the Vietnam war as defoliants and herbicides. The long-term consequences are now recognized and there may be cognitive and neuropsychiatric impairment as well as a distal sensory peripheral neuropathy particularly affecting the lower limbs. Biological botulism Botulism has been discussed in Chapter 8. The toxin is highly potent and can be readily aerosolized and absorped by inhalation or ingestion into the gastointestinal tract, persisting in this state for many weeks. The toxin is relatively easily degraded by exposure to heat, acidity or sunlight for >12 hours. Recovery follows only after there is regeneration of new axons which can take many months. Presynaptic inhibition of both cholinergic and autonomic (muscarinic) and motor (nicotinic) receptors leads to an extensive flaccid paralysis. Anthrax Spores of the Gram-positive organism Bacillus anthracis can be inhaled, ingested or absorbed through the skin and cause a severe haemorrhagic bacterial meningitis in addition to primarily pulmonary, cutaneous and gastrointestinal toxicity. The diagnosis is made difficult by the prolonged interval from exposure to presentation. Involvement of the CNS greatly increases the risk of mortality. Ciprofloxacin is the treatment of choice but doxycycline, clindamycin or rifampicin are also effective. Pre-exposure vaccination may have some protective effect. B. anthracis is easy to produce, the spores are hardy, highly infectious and remain in the environment for many years. They can be stored almost indefinitely and can only be removed by filtration with small pores or by formaldehyde. Aerosol deployment of dry spores risks secondary infection and spores could be effective in water or food supplies. Smallpox Smallpox is a potentially devastating infection caused by variola, which is a DNA virus, infectious in droplet form. The last known case was in 1977 but intact virus remains in a number of laboratories. The Variola virus invades mucosal cells of the respiratory system before viraemic dissemination to bone marrow, spleen and other lymph nodes. Immediate vaccination following exposure is essential and the subject should be isolated as soon as possible.

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Other viruses Arboviruses might be used as biological weapons because of high infectivity, low infectious dose and the absence of any specific treatment. However, most forms of arbovirus encephalitis are self-limiting. With supportive care patients recover well from these forms of infection although fatal encephalitis can occur. Vaccines are of limited benefit and treatment is with supportive care. Tularemia This is caused by Francisella tularensis, a non-motile aerobic Gram-positive coccobacillus that is highly infective and may cause a meningitis or encephalitis although an atypical pneumonia is more frequent. First line treatment is an aminoglycoside antibiotic (streptomycin or gentamycin); alternatives include doxycycline, chloramphenicol and ciprofloxacin.

Vitamin deficiencies and toxicity Vitamin A Vitamin A deficiency occurs in fat malabsorption syndromes and leads to a variety of ophthalmic disorders. Retinol is required for the synthesis of rhodopsin, a visual pigment necessary for normal rod function in the retina; its deficiency leads to night blindness. There may also be corneal ulceration and carotenization of the conjunctiva. ‘Bitot spots’ are white foam-like lesions, which appear on the side of the cornea and are characteristic of vitamin A deficiency. Vitamin A toxicity is associated with ingestion of carotene-rich liver and proprietary treatments and may cause idiopathic intracranial hypertension. The skin is often dry and pruritic and generalized joint and bone pains occur. Serum retinol levels may be helpful to establish the diagnosis.

Vitamin B1 (thiamine) Thiamine is found in most food and cereals but reduced intestinal absorption occurs in alcoholism and malabsorption syndromes. Deficiency is also associated with malnutrition, inadequate parentral nutrition, haemodialysis, uraemia or repeated vomiting. Thiamine depeletion may develop acutely and is a medical emergency because of the development of congestive cardiac failure and peripheral oedema (wet beri-beri), a sensory axonal neuropathy (dry beri-beri) or Wernicke–Korsakoff syndrome (cerebral beri-beri). The effects of thiamine deficiency are discussed below.

Vitamin B3 (niacin, nicotinic acid) Niacin deficiency leads to the syndrome of pellagra. The condition occurs in populations that are dependent on corn but has decreased in frequency as white bread now is now enriched with niacin. Clinically pellagra is characterized by the development of dermatitis, diarrhoea and dementia (the three d’s). The

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onset is usually with gastrointestinal symptoms including anorexia, diarrhoea and stomatitis. Skin changes are also frequently seen and erythema particularly affects the face, chest and dorsal surfaces of the hands and the feet. There may be mood changes, fatigue, malaise, lethargy and confusion with progression to neuropsychiatric disturbances including apathy, inattentiveness and memory loss or the development of spastic paraparesis with startle myoclonus. The cognitive impairment, which occurs in chronic alcoholics even with adequate thiamine replacement, is probably caused by niacin deficiency and is characterized by a defect in recent memory, visuospatial ability, abstract reasoning and speed of information processing. Treatment is with oral niacin replacement, often provided in food supplements.

Vitamin B6 (pyridoxine) This is important in the metabolism of many amino acids. Deficiency often occurs in infancy because of feeds containing inadequate levels of B6. In children there may be hyperirritability, exaggerated auditory startle and recurrent convulsions leading to status epilepticus. In adults, pyridoxine deficiency is usually secondary to medication including isoniazid, hydralazine and penicillamine. There may be peripheral neuropathy with distal weakness and painful sensory loss, absent tendon reflexes and Romberg’s sign. High dose pyridoxine also causes a distal sensory axonal neuropathy with sensory ataxia.

Vitamin B12 deficiency Vitamin B12 is abundant in meat, fish and animal by-products. Approximately 90% of total body B12 is stored in the liver. Because of the large body stores, even with severe impairment of B12 absorption, the symptoms and signs of B12 deficiency may take many years to evolve. Daily requirements are small and only rarely can B12 deficiency arise because of dietary insufficiency. It is associated with pernicious anaemia caused by defective intrinsic factor production by the gastric parietal cells but may also follow gastrectomy or small intestine disorder including surgical resection of the terminal ileum and blind loop syndrome. The elderly, vegetarians and patients taking H2 blockers for ulcers are at particularly high risk. Systemic manifestations of vitamin B12 deficiency include gastrointestinal involvement, characterized by the development of glossitis and a pan-enteropathy with diarrhoea and malabsorption of nutrients. Neurological features occur in up to 40% of patients with B12 deficiency but these evolve over several months or longer. Symptoms develop insidiously with progressive paraesthesiae in the hands and feet with weakness and unsteadiness of gait culminating in peripheral neuropathy and myelopathy. Central manifestations include confusion, depression, progressive hallucination and mental slowing. Patients occasionally present with isolated cognitive or psychiatric disturbances and direct relationship between B12 and dementia remains unclear. There may also be optic neuropathy.


Subacute combined degeneration of the cord This effect of B12 deficiency is characterized by a sensorimotor axonal neuropathy and myelopathy. Neuropathic manifestations include distal paraesthesiae, numbness, gait ataxia and diminished proprioception in the lower limbs, while the myelopathic component leads to variable motor impairment because of pyramidal tract dysfunction; the reflexes are variable depending on the extent of cord and peripheral nerve involvement with extensor plantar responses. Incontinence of bowel, bladder with impotence and postural hypotension occur as part of the myelopathy. Visual impairment is also associated with B12 deficiency with the development of optic atrophy, impaired acuity and centro-caecal scotoma. Brainstem cerebellar signs are occasionally present. Progressive cognitive impairment is characterized by memory loss, behavioural affective changes and occasionally stupor and coma. The blood film shows the development of a macrocytic anaemia with hypersegmented neutrophil nuclei and megaloblastic change in the bone marrow. Serum cobalamin levels may be used as a screening test and the Schilling test is valuable in demonstrating impaired absorption of vitamin B12 even if serum levels are normal. MRI scan may show extensive white matter change which can become confluent with disease progression culminating in leucoencephalopathy. The spinal cord shows abnormalities in the lateral and posterior columns with enhancement and residual changes may persist after treatment (Figure 18.4). Visual and somatosensory evoked potentials are delayed. Nerve conduction studies reveal small or absent sensory action potentials reflecting an axonal neuropathy in approximately 80% of patients. The clinical features of nitrous oxide intoxication and the vacuolar myopathy of AIDS are identical to those of subacute combined degeneration. The pathological changes of subacute combined degeneration of the spinal cord include spongy change with focal loss of myelin and axonal destruction in the white matter of the spinal cord particularly affecting posterior and lateral columns of the cervical and upper thoracic spinal cord. The peripheral nerves show axonal degeneration without significant demyelination. There may also be involvement of the optic nerves and cerebral white matter. Treatment of B12 deficiency With adequate treatment, some of the deficits of B12 deficiency may be reversible with most improvement occurring within the first 6 months of treatment. The myelopathy is least likely to make a complete recovery. B12 replacement should be given twice weekly for 2 weeks followed by monthly injections. If there is malabsorption of B12 then injections should be continued life-long. With full treatment at least partial improvement occurs in most patients but daily oral supplementation with large amounts of cobalamine may be necessary.

Folate deficiency Absorption of folate takes place in the jejunum and ileum and levels are reduced in chronic alcoholism and following small

(a)

(b)

Figure 18.4 Subacute combined degeneration of the cord. On admission (a) and after initiation of cobalamin treatment (b). The hyper-intense lesions of the posterior column disappeared after treatment. (MRI T2W.) (From Hemmer et al. 1998, with permission.)

bowel resection or disease. A number of drugs interfere with folate metabolism including sulfasalazine, methotrexate and azathioprine. Overt neurological deficit is unusual in folate deficiency but there may be mild cognitive impairment, depression and an increased risk of stroke or neural tube deficit in pregnancy. Folate deficiency may rarely produce a syndrome resembling subacute combined degeneration of B12 deficiency. Folate deficiency leads to elevated homocysteine levels, a risk factor for the development of cerebrovascular, cardiovascular and peripheral vascular disease. Folate is administered orally but may be given parenterally in acutely ill patients.

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Vitamin D Vitamin D deficiency is associated with hypoparathyroidism, hypophosphataemia, chronic renal failure, malabsorption, dietary deficiency or inadequate exposure to sunlight. Neurological presentation is as a proximal myopathy which may be associated with osteomalacia. There is proximal weakness with a characteristic waddling gait but no involvement of bulbar or ocular musculature. CK is elevated, electromyography (EMG) shows myopathic change and biopsy will confirm evidence of type II muscle fibre atrophy. Treatment is vitamin D replacement which leads to a slow recovery of the weakness.

of acetaldehyde in alcohol toxicity is uncertain but it is highly cytotoxic and is also readily metabolized to acetate by the mitochondrial enzyme acetaldehyde dehydrogenase. Tolerance to alcohol is the acquired resistance to its effects. Intoxication occurs because alcohol crosses the blood–brain barrier. The clinical manifestations of alcohol may be divided into: 1 Effects of acute intoxication; 2 Effects of alcohol substitutes; 3 Withdrawal syndrome occurring after sudden abstinence; and 4 Chronic disorders associated with prolonged alcohol abuse.

Vitamin E

Effects of acute intoxication

Vitamin E is fat-soluble and acts as a free radical scavenger and antioxidant. It is normally stored in large amounts so that clinical symptoms only become apparent after many years of deficiency, usually secondary to malabsorption in cystic fibrosis, adult coeliac disease or because of abnormalities of specific vitamin E receptors, e.g. abetalipoproteinaemia. There is progressive spinocerebellar degeneration with limb ataxia, because of involvement of the posterior columns, and an axonal, predominantly sensory, peripheral neuropathy with prominent involvement of proprioception. Rarely, pyramidal features may develop with extensor plantar responses and ocular signs including ptosis, nystagmus, external opthalmoplegia and optic neuritis. Investigation shows evidence of spiky red blood cells (acanthocytes) as well as retinal pigment change. Low serum vitamin E can be shown on assay but CSF is normal. Nerve conduction studies confirm a mild axonal neuropathy and occasionally the MRI scan shows high signal in the posterior columns. Treatment is with the recommended daily requirement of vitamin E of 10 mg/day. If the vitamin is deficient then the therapy should be given with the water-soluble tocopherol 200–600 mg/day.

The effects of acute alcohol intoxication are widely accepted by many societies, particularly amongst young people. The initial behavioural effects of euphoria, social disinhibition, loss of restraint and reduced psychomotor capacity are well-recognized but progression to behaviour disturbance, irritability, slurred speech, ataxic gait, aggression and loss of control may have serious consequences with high levels of intoxication. Depressant effects including drowsiness, stupor and coma may supervene with the risk of vomiting, aspiration and respiratory impairment. Acute intoxication is associated with psychotic disturbances including an acute paranoid state with auditory hallucinations, anxiety, agitation, outbursts of aggression and inappropriate violent or even destructive social behaviour of which the patient may have no recollection. These periods of amnesia, in which there is no ability to retain short-term memories, increase in duration and persist into periods when sober and fully conscious. Symptoms occur with serum levels as low as 50–150 mg/dL (10–31 mmol/L) but in those with previous alcohol intake and induction of the hepatic enzymes, symptoms develop at a higher concentrations of blood alcohol. Extreme intoxication (>300 mg/dL or 65 mmol/L) results in cerebellar impairment (ataxic dysarthria and nystagmus) and coma associated with hypotension, respiratory depression and hypothermia, with death occurring from brainstem depression if the blood alcohol level exceeds 400 mg/100 mL. Because alcohol is rapidly absorbed acute intoxication may require sedation and treatment of agitation with haloperidol or chlorpromazine, or ventilatory support and haemodialysis, especially if there is a suggestion of methanol intake in addition.

Alcohol abuse Alcohol abuse is extremely common and is associated with important cultural, economic and environmental factors; there is also a strong genetic component. It affects all socio-economic strata of society. Primary alcoholism may be defined as addiction to alcohol in the absence of an underlying cause. Physical dependence may become such a strong compulsion that psychopathology develops with neglect of self and family. This may culminate in severe disruption of general health, behaviour and cognitive function leading to loss of personal relationships and occupation. Secondary alcoholism occurs when excessive drinking is the consequence of other major psychiatric illness, e.g drug addiction, schizo-affective disorder or manic depression.

Metabolism of alcohol Alcohol is rapidly absorped from the gastrointestinal tract and is metabolized in the liver where it is oxidized to acetaldehyde by the action of alcohol dehydrogenase and other enzymes. The role

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Effects of alcohol substitutes Methyl alcohol (methanol) This is commonly used as a solvent and in antifreeze. It may be abused as a substitute for ethyl alcohol in ‘meths’. It is directly toxic to the CNS as a depressant and is oxidized to formaldehyde and formic acid, which inhibit cytochrome oxidase and have a direct toxic effect on the putamen and optic nerves. Acute intoxication may be delayed for many hours. Delirium may develop at the onset but a rapid progression occurs to cause visual field loss, blindness secondary to retinal oedema, pseudobulbar palsy and cognitive impairment. Severe toxicity culminates in metabolic acidosis and cerebral oedema leading to respiratory failure, coma

Toxic, Metabolic and Physical Insults and death. In patients who recover from acute intoxication there may be residual blindness and parkinsonian features. Treatment involves reversing the acidosis with large doses of sodium bicarbonate, retarding the mechanism of methanol with ethyl alcohol or fomepizole and, where necessary, haemodialysis.

Ethylene glycol This is also commonly used as a solvent, in antifreeze, air conditioners and fire extinguishers. It may contaminate proprietary alcoholic drinks or be ingested in suicide attempts. Intoxication is associated with lethargy and progressive hypersomnolence, hyperventilation with seizures and hypotension. There is a metabolic acidosis with an anion gap. Anuric renal failure develops which is also associated with seizures. With high levels there may be the delayed onset of a cranial neuropathy, which resolves slowly. Treatment is by haemodialysis with intravenous sodium bicarbonate and, if necessary, ethanol. Fomepizole (4methylpyrazole) is also used as a competitive inhibitor of alcohol dehydrogenase.

Withdrawal syndromes The severity of withdrawal symptoms is proportional to the level of previous alcohol intake and the abruptness of cessation. Withdrawal of alcohol in the chronic abuser may lead to the development of delirium tremens with CNS hyperexcitability, initially characterized by tremulousness with anxiety, insomnia, confusion, hyperactivity, hallucinations and seizures. The symptoms progressively worsen over several hours before settling, up to 72 hours after the last intake of alcohol. The tremor is generalized, present at rest and on action and may involve the face and tongue. It is associated with irritability and is usually present in the morning, but progressively worsens and increases in duration with prolonged withdrawal. There is usually an associated gastrointestinal disturbance with nausea, vomiting and autonomic hyperactivity with tachycardia, hypertension and sweating. Disturbing vivid auditory and visual hallucinations develop and these may persist for several days after the physical symptoms have settled. The patient frequently awakes lucid with no recollection of the acute delirious phase. Recurrence is common and, in severe cases, death may supervene. It is essential to consider the possibility of alcohol withdrawal in patients who develop confusion, tremor or seizures after being admitted to hospital for more than 12 hours. Severe withdrawal delirium tremens occurs in about 5% of patients withdrawing from alcohol and is associated with hyperpyrexia, ketoacidosis and circulatory collapse. Isolated hallucinations may occur in up to one-quarter of patients following withdrawal. They are often visual but occasionally auditory. Patients often lack insight into their hallucinations and their development indicates a poor prognosis with significant mortality.

Withdrawal seizures (rum fits) These typically occur within the first 24–48 hours of withdrawal. They are generalized, tonic–clonic convulsive seizures, which

usually occur singly or in brief clusters although status may develop. The EEG shows mild changes and generally reverts to normality within a few days. Even if status develops, the condition is usually self-limiting and patients often do not require antiepileptic medication although acute treatment with lorazepam or diazepam may be necessary.

Management of alcohol withdrawal Minor symptoms can be managed with simple reassurance and nursing in a calm quiet well-lit environment although benzodiazepines may be helpful. Moderate symptoms, including autonomic hyperactivity and irritability, necessitate an incremental dose of benzodiazepines. Severe symptoms associated with confusion, poor cooperation, restlessness and aggressive behaviour may require intravenous Diazemuls given by slow injection and, if further treatment is necessary, haloperidol 5–10 mg i.m. or 5 mg twice daily up to 20 mg/day is the treatment of choice. Chlordiazepoxide, clomethiazole or clonidine are also effective.

Chronic disorders associated with prolonged alcohol abuse Wernicke–Korsakoff syndrome This is a complex of symptoms and signs resulting from an acquired nutritional deficiency of thiamine (vitamin B1) rather than any direct toxic effect of alcohol. Thiamine (and other B vitamins) is a co-enzyme in glucose and lipid metabolism, amino acid production and neurotransmitter synthesis. Because thiamine stores are relatively small and there is a large daily turnover, deficiency may occur within 2–3 weeks of low intake. The brain is particularly sensitive to disturbance of complex B vitamindependent metabolism of glucose. Wernicke’s encephalopathy may present as an acute or slowly evolving disorder, often precipitated by an intercurrent medical event or metabolic stress such as trauma or infection. In addition to alcohol, it is caused by other conditions in which a depletion of thiamine may occur: hyperemesis of pregnancy, systemic malignancy, haemo- or peritoneal dialysis, gastrointestinal surgery, prolonged intravenous feeding, anorexia and AIDS. The acute syndrome is characterized by apathy, confusion, impairment of ocular motility and cerebellar ataxia lapsing into an encephalopathy with progressive disturbance of behaviour, personality, orientation and cognitive function developing over days or weeks leading to stupor, coma and ultimately death. There may be hallucinations, perceptual disorder and agitation. Ocular signs are characteristic and include ophthalmoplegia, nystagmus and conjugate gaze palsy. The ophthalmoplegia is initially caused by paresis of the lateral recti with subsequent involvement of other ocular muscles leading to total ophthalmoplegia. Nystagmus may be both horizontal and vertical and there is also sluggish pupillary response to light with light-near dissociation. Fundal examination shows small retinal haemorrhages and occasionally optic neuropathy develops. Progressive truncal and gait ataxia is common but the limbs are rarely involved.

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Figure 18.5 Wernicke’s syndrome. T2-weighted MRI showing high intensity lesions in the medial thalami and peri-aqueductal grey matter of the midbrain.

MRI shows high T2 signal in the peri-aqueductal and the paraventricular region of the medial thalamus and hypothalamus while the mamillary bodies appear shrunken (Figure 18.5). CSF is characterized by elevated protein, serum thiamine; erythrocyte transketolase activity is reduced. The pathology in Wernicke’s syndrome shows symmetrical haemorrhagic and necrotic change predominantly affecting the mamillary bodies, dorsal medial nucleus of the thalamus and peri-aqueductal region as well as the tegmentum of the pons. Treatment is by thiamine given immediately commencing at 50–100 mg parenterally in the acute stages. Untreated Wernicke’s encephalopathy is associated with a significant mortality but with adequate treatment the signs resolve rapidly.

Korsakoff ’s syndrome This is a progressive and severe amnestic syndrome which is incompletely reversible. Memory is preferentially involved in comparison to other cognitive function with a profound impairment of both retrograde and antegrade memory. The memory of recent past is usually more severely affected than distant past while language and calculation abilities are well preserved. There may also be perceptual difficulties and loss of insight although this is often less marked. Patients show striking loss of working memory with disorientation in person and place but retain reference memory, alertness, attention, calculation and, at onset, normal social behaviour. The condition is characterized by confabulation, the deliberate attempt to hide the memory defect by fabricating events. Pathologically, the memory impairment of Korsakoff ’s syndrome is associated with selective necrosis of the basal septal nuclei of the frontal lobes, the temporal lobes and diencephalon. In alcoholism Korsakoff ’s syndrome is caused by thiamine deficiency but it may also occur following infarction, anoxia, trauma, tumours involving the frontotemporal regions, temporal lobe epilepsy and herpes simplex encephalitis (Figure 18.6; Plate 18.5). Treatment requires urgent and high doses of thiamine replacement and should be continued until a noticeable improvement

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Figure 18.6 Korsakoff’s syndrome. T2-weighted axial MRI showing thalamic infarction. (Courtesy of Professor M. Kopelman, St. Thomas’ Hospital.)

has occurred and for as long as clinical improvement continues. Improvement in memory function is slow and usually incomplete. Up to one-quarter of patients show no recovery while only slight improvement occurs in the remaining patients. Significant or complete recovery is rare. Wernicke–Korsakoff syndrome may be difficult to detect and a high index of suspicion is necessary in all patients who abuse alcohol and those with poor diet or gastrointestinal disturbance including diarrhoea and vomiting.


Cerebellar ataxia Chronic alcohol abuse is the most common cause of acquired cerebellar atrophy and is often associated with alcohol polyneuropathy. The ataxia usually affects men and may be so severe that the patient is unable to stand without support. Patients walk with a broad-based gait with slow short steps but limb ataxia and speech disturbance are minimal although cerebellar abnormalities of ocular movement are often present. Progressive unsteadiness evolves over several months with truncal ataxia and mild gait disturbance. Abstinence from alcohol leads to a slow and incomplete improvement. Pathological examination shows selective atrophy of the anterior and superior part of the cerebellar vermis with cell loss particularly involving the Purkinje cells. Cerebellar ataxia may be associated with Wernicke’s encephalopathy or occur in isolation. Confusional state and dementia Cortical atrophy and ventricular dilatation occur with prolonged alcohol intake. This is associated with a global confusion characterized by progressive indifference to surroundings and abulia may occur. Patients are easily aroused but are disorientated with cognitive deficits which may worsen and become fixed, interfering with activities of daily living, before evolving into frank dementia which may persist even after discontinuation of alcohol. Alcoholic peripheral neuropathy Sensorimotor axonal peripheral neuropathy is a characteristic feature of alcohol abuse, occurring as a consequence of thiamine deficiency in Wernicke’s encephalopathy or because of direct alcohol toxicity. The neuropathy is usually insidious in onset, often mild and predominantly sensory. However, rapid progression may occur with motor impairment severe enough to affect gait. Painful symmetrical sensory loss occurs to all modalities, particularly affecting the lower limbs; it is characterized by distal tingling, burning and lancinating pain. Autonomic involvement is manifest as impotence, sweating, pupillary abnormalities and postural hypotension. Investigation shows a macrocytosis and elevation of hepatic enzymes. There may be an elevated CSF protein and nerve conduction studies show an axonal polyneuropathy predominantly affecting sensory and motor action potential with slowing of conduction velocity. Management is discontinuation of alcohol consumption and ensuring adequate nutritional intake with thiamine and vitamin B supplements. Alcoholic myopathy Acute myopathy can occur with chronic alcohol abuse but may also follow binge intake. It is secondary to the direct toxic effects of alcohol although other factors including muscle crush, seizures and electrolyte disturbances may contribute. The onset is with acute and severe muscle pain, cramp, swelling and a rise in the CK, evolving rapidly into focal or generalized myopathic weakness often with selective involvement of the calves. A cardiomyopathy may coexist. Although recovery usually occurs within

days or weeks, rhabdomyolysis and myoglobunuria may occur, leading to hyperkalaemia and renal failure. A more chronic myopathy is associated with prolonged consistent alcohol abuse, characterized by slowly developing, painful proximal myopathy particularly affecting the shoulder and hip girdle muscles. This myopathy may be asymptomatic and noted because of an isolated elevation in CK. EMG shows myopathic features and there may also be a coexisting neuropathy. Biopsy of chronic alcohol myopathy shows no significant muscle fibre necrosis but atrophy affecting type II (especially type IIB) fibres. In the acute form there is scattered muscle fibre necrosis with regeneration. The myopathy may be reversible with many months of abstinence and good nutrition.

Other neurological complications of alcohol abuse Marchiafava–Bignami syndrome This is a condition associated with strong red wine, usually chianti, that affects severe and chronic alcoholics in middle or late life. The aetiology is unknown and presentation is variable with a slowly progressive disturbance of cognitive function, personality and behaviour. There is progressive motor slowing with incontinence, frontal release signs and a broad-based gait. There may be cognitive impairment, dysarthria, hemiparesis, apraxia, aphasia and seizures and occasionally a patient may present in stupor or coma. There is selective demyelination of the central portion of the corpus callosum with sparing of the anterior and posterior portions, other white matter tracts are also affected. Treatment is with nutritional support and rehabilitation but recovery is variable. Imaging shows high signal lesions on T2 MRI in the corpus callosum and anterior commissure. Fetal alcohol syndrome Prenatal exposure to ethanol impairs fetal growth and neurodevelopment. There may be dysmorphic facial features and microcephaly, mental retardation and learning difficulties including speech delay and hyperactivity. Psychiatric sequelae In chronic alcohol abuse depressive illness is common, particularly on withdrawal, and up to one-quarter of patients fulfil the criteria for a major depressive disorder; however, it often remits after several months and rarely requires antidepressant medication. Some patients also have an anxiety disorder which may develop into frank psychotic symptoms during withdrawal. Traumatic injury Traumatic injuries to the head may occur during intoxication causing parenchymal contusions, subdural or extradural haematoma, subarachnoid haemorrhage and lead to post-traumatic epilepsy. Compressive neuropathies The most common neuropathies occurring in alcohol abuse include compression of the radial nerve at the spiral groove

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causing ‘Saturday night palsy’. The peroneal nerve may be trapped at the fibula head leading to a foot drop and the sciatic nerve may be compressed in the gluteal region.

Drugs of abuse Epidemiology

Amblyopia Amblyopia occurs as a consequence of chronic alcoholism and is associated with poor dietary and heavy tobacco intake and weight loss. Progressive optic nerve involvement leads to painless visual loss affecting both eyes with diminished visual acuity with centro-caecal scotoma and mild disc pallor. The treatment is with adequate diet and B vitamins which generally leads to visual recovery. Alcoholic cirrhosis It must be emphasized that neurological effects of alcohol abuse run in parallel with systemic factors. Alcohol-related cirrhosis is the most common and serious manifestation. Patients may develop porto-systemic encephalopathy, tremor, myoclonus and asterixis. Strachan’s syndrome This is a severe painful ataxic sensorimotor neuropathy associated with visual loss resulting from amblyopia, tinnitus, gastritis and stomatitis. The condition is related to nutritional deficits. There have been outbreaks of the condition in Cuba associated with retrobulbar optic neuropathy, peripheral neuropathy, sensory neural hearing loss and myelopathy with spastic paraparesis and dysphonia. The aetiology remains unclear but a relationship to poor nutrition and heavy alcohol and tobacco exposure has been noted.

Other deficiency states associated with neurological manifestations Copper deficiency This occurs following gastrointestinal disturbance, in particular after gastrectomy. Copper is essential to the nervous system and bone marrow and functions as a prosthetic group in key enzymes involved in catecholamine synthesis, the respiratory chain, folate metabolism and antioxidant function. The most common neurological manifestation of acquired copper deficiency is a myeloneuropathy with sensory ataxia. The MRI shows increased T2 signal in the dorsal spinal cord. The condition appears clinically and radiologically identical to subacute combined degeneration of the cord associated with B12 deficiency.

Magnesium deficiency This may also occur after gastrointestinal surgery or with chronic use of diuretics. It is an essential co-enzyme involved in the metabolism of thiamine and its deficiency may lead to an impaired response to thiamine in Wernicke’s encephalopathy resulting from alcohol or hyperemesis gravidum.

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The clinical assessment of drug abuse is extremely difficult because addicts may use several drugs at one time, or abuse alcohol concurrently. Furthermore, the drug may be contaminated either at source or at the time of administration and the metabolism of drugs of abuse is unpredictable depending on dosage, mode of administration and the ability of the body to metabolize the drug. Drug dependence is both psychological when drug use is compulsive because of pleasurable or dysphoric effects and physical if discontinuation of the drug will lead to serious and painful symptoms. Drug users develop tolerance and require larger doses to maintain the effects of the drug and to prevent the development of withdrawal symptoms. There are five major groups of drugs of abuse: 1 Stimulants; 2 Sedatives; 3 Hallucinogens; 4 Organic solvents; and 5 Drugs used to enhance athletic performance.

Stimulants Stimulants (Table 18.4) share the ability to enhance transmission at the catecholaminergic synapse and therefore have common pharmacological and toxic effects and also develop crosstolerance. Stimulants are abused because they cause elation, increased alertness and motor activity as a consequence of their central effects. Prolonged excessive use is associated with motor manifestations including tics, tremor, myoclonus and an acute dystonic reaction.

Amphetamines Dexamphetamine, the dextro-isomer of amphetamine, is used in clinical practice. Metamphetamine (‘crystal meths’ or ‘ice’) is widely abused. Acute intoxication is characterized by increased alertness, a sense of self-confidence and well-being, euphoria and extrovert behaviour, loss of appetitie and the desire to sleep, tremor, dilated pupils, tachycardia and hypertension. In extreme cases there may be paranoid delusions, hallucinations and violence. Prolonged intoxication may lead to convulsions,

Table 18.4 Stimulants commonly used as drugs of abuse. Cocaine/crack Amphetamines 3,4-Methylene dioxymethyl amphetamine (MDMA, Ecstasy) Ephedrine Phenylpropanolamine methylphenidate Khat

Toxic, Metabolic and Physical Insults hyperthermia, rhabdomyolysis and intracerebral haemorrhage. Stroke resulting from stimulant abuse is discussed below.

Designer drugs Designer drugs are synthetic derivatives, usually amphetamine analogues. Ecstasy (MDMA) is a derivative of methamphetamine that is widely used as a stimulant, euphoric and hallucinogen. In high doses it has an amphetamine-like stimulant effect and unpredictable toxicity, exacerbated by dehydration. It may cause an acute toxic reaction with headache, hypertension, hyperpyrexia, seizures, rhabdomyolysis and the development of a hypertonic state with hepatic failure, coagulopathy, coma and death. Cerebral infarction or haemorrhage is rare. MDMA causes a massive central serotoninergic discharge which accounts for its psychic effects. There may be permanent impairment of memory. Several other amphetamine-derived drugs are widely used; all have similar effects following acute and prolonged intoxication. Methylphenidate (Ritalin) This can rarely cause an amphetamine-like syndrome with central disturbance seizures and intracerebral haemorrhage. Khat Khat is a flowering plant native to East Africa and the Arabian Peninsula. The leaves contain the alkaloid cathinone, an amphetamine-like stimulant. The leaves have been chewed for many years as a recreational drug within the region where it naturally grows because only fresh leaves are strongly psycho-active. Its stimulatory effects include a feeling of euphoria, excitement, increased alertness and sexual arousal. Toxic effects include anorexia, tremor, tachycardia, arrhythmia, hypotension and respiratory arrest. Improved air transport has led to extensive smuggling of the drug with a global distribution. Cathinone breaks down to cathine and norephedrine. This occurs after khat has been ingested or if the leaves are left to dry for more than 48 hours. Methcathinone (‘cat’) is a derivative of cathinone. It is inexpensively and easily manufactured as a designer drug from its precursor ephedrine. It has a similar amphetamine-like stimulant effect when snorted, ingested or injected. MPTP Methylphenyltetrahydropyridine (MPTP) was developed in the USA as a designer drug with close clinical similarities to amphetamine. The effects of abuse were similar but some abusers developed a moderate to severe parkinsonian syndrome with bradykinesis, freezing, rigidity, instability, dysarthria and a symmetrical parkinsonian tremor. There was a variable response to levodopa with the development of typical motor fluctuations and dyskinesiae. Pathological features include moderate to severe neuronal loss and gliosis in the substantia nigra without Lewy bodies. Cocaine Cocaine is the most commonly abused psychomotor stimulant and is administered intranasally, parenterally or smoked as crack.

Moderate doses are associated with mood elevation, increased alertness, reduced fatigue and enhanced performance but psychiatric effects develop rapidly including paranoia, delusions, hallucinations, choreo-athetoid movements and agitation. Chronic abuse may lead to progressive neuropsychiatric features including restlessness, irritability and psychotic aggressive paranoid states. These are associated with visual and auditory hallucinations with amphetamine abuse and violent behaviour with the cocaine alkaloid, crack. Long-term abuse of stimulants may lead to toxic encephalopathy or a fixed cognitive dysfunction with cerebral atrophy.

Conditions caused by stimulant abuse Stroke This may occur as a consequence of stimulant abuse for several reasons. It is associated with vasoconstriction, dissection and vasculitis occurring with amphetamine and cocaine. Furthermore, cardiac thrombus may embolize to the brain in patients with infective endocarditis or cardiomyopathy caused by arrhythmias or because foreign body material may be injected with the drug. Stroke may also be a consequence of endocarditis causing mycotic aneurysms or haemorrhagic transformation in cerebral infarction. Crack cocaine is the most important cause of drug-related stroke accounting for about 50% of all cases and being much more common than amphetamine-related stroke. Haemorrhagic stroke This is particularly associated with cocaine and seems to occur with intranasal or intravenous usage or smoking crack. Intracerebral haemorrhage is usually in basal ganglia but is occasionally lobar, intraventricular or subarachnoid. A pre-existing aneurysm or arteriovenous malformation may rupture. Cerebral infarction This is also associated with smoking crack cocaine. Infarction often affects the cortical or deep penetrating arteries, but anterior spinal artery occlusion also occurs. The onset of stroke following use of amphetamine or crack cocaine is rapid because of blood pressure surges. Approximately 50% occur in the middle cerebral artery territory. Imaging shows asymptomatic subcortical white matter lesions are common in crack and cocaine users. Vasculitis This is seen more commonly with amphetamine than cocaine. It usually evolves rapidly with headache, progressive encephalopathy and raised ESR. Diffuse vasospasm is associated with bleeding or focal narrowing; there may also be a vasculitis involving small calibre vessels and necrosis. Treatment is with high dose steroids. Other effects of stimulant abuse In addition to stroke and epilepsy, systemic complications of stimulants include the development of hyperthermia, dehydration and rhabdomyolysis with an increased risk of myocardial

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infarction and cardiac arrhythmia. Cocaine and amphetamine may also give rise to movement disorders including vocal and motor tics, chorea, dystonia and acute dystonic reaction of the head and neck. There may also be an oromandibular dyskinesia. Treatment is supportive with attempts to cool the patient, reduce blood pressure and maintain oxygenation. Neuroleptics, anxiolytics and sedatives may be necessary and seizures should be treated appropriately. Withdrawal of cocaine can be difficult as the tolerance develops to the euphoric and anorexic effects of the drug and the psychiatric manifestations may worsen.

Sedatives Opiates Heroin and morphine are highly addictive drugs which are usually administered intravenously but can be sniffed, smoked or injected subcutaneously (skin popping). Intravenous administration is often non-sterile and may lead to infective complications (Table 18.5). The effects of heroin are the same as morphine but more powerful. There is an initial analgesic effect and then a sense of ‘rush’ with euphoria or dysphoria before drowsiness and hallucinations. Systemic features include pruritus, dry mouth, nausea, vomiting, constipation and urinary retention. There may be severe pupillary constriction before the development of respiratory depression, cerebral anoxia and post-anoxic encephalopathy. The immediate effects can be reversed with naloxone, a safe and effective antidote which should be given to anyone with a suspected opiate overdose. If the patient has not been discovered for a prolonged period of time there may be extensive compression and stretching of peripheral nerves and damage to the brachial plexus, common

peroneal, ulnar or sciatic nerves with secondary ischaemia. Rhabdomyolysis may be caused by a compartment syndrome as a consequence of trauma, hypotension, fever and seizures or brought about by direct opiate toxicity. It occurs after prolonged periods of unconsciousness and may lead to myoglobinuria and renal failure. Repeated intramuscular injections can also lead to focal fibrosis and weakness in injected muscles with contractures. Stroke may occur secondary to an infective arteritis or to the development of mycotic aneurysms but infarction may also be a consequence of paradoxical embolism or contaminants. An acute myelopathy may occur with excessive heroin abuse with paraparesis, urinary retention and segmental sensory level, and urinary retention. A distal sensory or sensorimotor neuropathy may also occur. Inhalation of heroin pyrolate, particularly if contaminated by heating the drug on aluminium foil, may cause toxic encephalopathy with extensive white matter change on MRI (Figure 18.7).

Table 18.5 Infective complications of non-sterile intravenous drug administration. Local abscess Cellulitis Infective endocarditis Botulism Tetanus Embolic infarction Meningitis Pyogenic arthritis

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Figure 18.7 Toxic encephalopathy caused by inhalation of heroin pyrolate. MRI T2W scan showing extensive white matter change.

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Infectious hepatitis Liver abscess Cerebral abscess Septic arthritis Mycotic aneurysms Osteomyelitis Discitis HIV Septicaemia

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Toxic, Metabolic and Physical Insults The symptoms and signs of withdrawal from opioids may appear within hours and include the characteristic syndrome of drug craving, restlessness and irritability, followed by the development of autonomic flu-like symptoms, sweating, lacrimation and rhinorrhoea. There may be piloerection, abdominal cramps, diarrhoea and coughing. The symptoms may develop rapidly following administration of naloxone but controlled withdrawal ought not to be dangerous and treatment of symptoms with oral methadone, a long-acting opiate, may ameliorate the symptoms. Clonidine and α2-adrenergic agonists suppress the autonomic disturbances of opioid withdrawal.

Barbiturates Barbiturates are abused because of their euphoric and sedative actions which are similar to alcohol. Acute intoxication leads to slurred speech, gait ataxia, coma, hypotension and eventually respiratory depression with apnoea. Treatment is supportive and involves the use of gastric lavage. When barbiturates are withdrawn acutely there may be irritability, tremor, tachycardia and a reduced seizure threshold; it may be necessary to reinstitute the barbiturate before reducing with gradual tapering dosage. Benzodiazepines Benzodiazepines, when used acutely, induce a comfortable sensation of lassitude, but in excessive doses there is progressive drowsiness, confusion, euphoria and impairment of psychomotor function leading to stupor and coma. The effects of acute overdoses can be reversed by flumazenil which is a specific antagonist, but this is short-lived. Chronic use of benzodiazepines leads to tolerance and physical dependence. Withdrawal symptoms develop within 24 hours of cessation of the use of shortacting benzodiazepines leading to irritability, increased sensitivity to light and sound and autonomic disturbance including tremor and tachycardia which may develop into delirium and hallucinosis; seizures may be provoked.

Hallucinogens Hallucinogens are abused because of the heightened sensory perception with eventual hallucinogenic effects (Table 18.6). The subject experiences perceptual change, decreased pain sensation and autonomic effects which may include flushing, sweating, hypertension and tachycardia. Abuse is associated with an acute

Table 18.6 Hallucinogens commonly used as drugs of abuse. Phencyclidine Lysergic acid diethylamide (LSD) Ketamine Marijuana GABA hydroxybutyrate (GHB) Solvents Psilocybin (magic mushrooms)

confusional state, ataxia, dysarthria and nystagmus. Numbness and perceptual change develop with features of self-mutilation, convulsions, dystonia and coma.

Phencyclidine (angel dust) This is taken orally, nasally or by inhalation and has a mixture of effects including a euphoric or dysphoric state, which may lead to catatonia and psychosis with chronic abuse. Lysergic acid diethylamide (LSD) This is a hallucinogen that alters perception, mood and thought. Acute effects are associated with dizziness, blurred vision, nausea and weakness. There is often euphoria, depersonalization, distortion of time and bizarre behavioural effects, including arousal and depression, which may lead to accidents or suicide. Chronic abuse has been associated with cerebral infarction and cognitive deficits. Marijuana Marijuana can be smoked, eaten or taken intravenously. It is widely abused because of its effects on memory, mood, judgement and sense of time. It induces a sense of relaxation with a subjective slowing of time with euphoria and depersonalization. In high doses there may be a toxic psychosis with hallucination, paranoia and a variable degree of anxiety, aggressiveness or sedation and sleepiness. The long-term consequences of abuse remain uncertain but paranoia and panic reaction may occur. Tolerance leads to a degree of irritability, restlessness and insomnia. Ketamine Ketamine is primarily used as an anaesthetic but has hallucinogenic properties. It is a drug of abuse and in large doses may lead to coma in humans while moderate doses can cause euphoria, relaxation and paranoia. Prolonged use leads to a long-term syndrome of psychosis, agitation, bizarre behaviour and catatonia. GABA hydroxybutyrate GABA hydroxybutyrate (GHB) induces euphoria, disinhibition and loss of short-term memory but its use is associated with sedation, disorientation and vomiting. In higher doses, seizures may develop. Anticholinergics These may also be used as recreational drugs because they can cause hallucinations and delirium. Excessive anticholinergic stimulation is associated with mydriasis, dry flushed skin, tachycardia, urinary retention and fever. In severe overdoses there may be myoclonus, seizures, coma and death.

Solvents Lighter fluids, varnishes and paint thinners are frequently abused as inhalants because they are based on organic solvents including toluene, hexane and benzene. Their use is associated with a characteristic rash with inflammation around the mouth and the

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nose. Inhalation of low doses leads to a feeling of exhilaration, light-headedness and giddiness with auditory and visual hallucinations. With more prolonged or severe usage there may be vomiting, tinnitus, headache and eventually the development of seizures. Long-term exposure causes toxic encephalopathy with progressive impairment of coordination, cognition and the development of diplopia and ataxia with increasing disorientation, confusion, respiratory depression and coma. Toluene particularly can give rise to dementia, ataxia, oculomotor and brainstem dysfunction, and pyramidal features. Long-term complications include cardiac arrhythmias, suffocation from the use of plastic bags during inhalation, vomiting, aspiration and peripheral neuropathy. Sudden death can occur. MRI may show widespread white matter abnormalities.

Athletic performance-enhancing drugs The neurotoxicity of some of these drugs is uncertain. Anabolic steroids including corticosteroids, insulin and growth hormone have direct physiological effect in building muscle. Stimulants, including amphetamine and cocaine, are also used to heighten alertness, reduce fatigue and prolong endurance. Erythropoietin (EPO) increases haemoglobin and oxygen delivery in endurance sports and β2-agonists have a fat burning effect. Control of these drugs is variable and their effects may be unpredictable.

Seizures Many drugs induce seizures in healthy individuals or, more commonly, provoke seizures in patients with pre-existing epilepsy or a low seizure threshold (Table 18.7). Iatrogenic seizures may also occur as a consequence of withdrawal of antiepileptic medication or be provoked by other medical procedures such as surgery, electroconvulsive therapy, labour and delivery or intrathecal chemotherapy. Other predisposing factors include metabolic abnormalities, organ failure, water intoxication or electrolyte abnormalities, particularly hyponatraemia.

Headache Headache may occur either as a direct consequence of medication or because the medication has acted as a trigger in a predisposed individual (Table 18.8). Acute exposure may cause a primary headache often brought about by vasodilatation. The most common drugs causing headaches are non-steroidal anti-inflammatory drugs (indometacin, diclofenac), nifedipine, cimetidine, ranitidine, β-blockers (atenolol, metoprolol, propranolol) and vasodilatator drugs (including glyceryltrinitrate). A number of drugs also cause or exacerbate a tendency to migraine including cimetidine, the oral contraceptive pill, atenolol, indomethacin and nifedipine. Chronic headache is associated with the overuse of medication or

Table 18.7 Drugs that may provoke seizures.

Investigation of suspected substance abuse The first line of investigation is a urine toxicology screen, which may become positive within hours of ingestion. The toxicology screen remains positive for variable periods depending on the drug used and the presence of coincidental alcohol use. Positivity for amphetamine, cocaine, barbiturates and morphine is relatively short but benzodiazepines and heroin remain detectable for up to 8 weeks. Imaging and angiography may show the presence of abscesses, an incidental arteriovenous malformation, aneurysm or mycotic aneurysm. Serology for syphilis and HIV is necessary and an echocardiogram is undertaken to exclude endocarditis. CSF examination may indicate infective CNS. Ultimately, cerebral and meningeal biopsy may be indicated.

Adverse reactions to drugs Adverse reactions to drugs are a common cause of neurological morbidity and mortality. Drug reactions commonly lead to a variety of manifestations which may mimic naturally occurring neurological disease. There are many individual anecdotal case reports suggesting drugs are relevant to the aetiology of individual conditions but a clear causal relationship is much more difficult to establish. Throughout this section only the most important or most common forms of neurological drug toxicity are discussed.

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Respiratory agents – theophylline, aminophylline, terbutaline Psychotropic medication – phenothiazines, clozapine, butyrophenones, lithium Antimicrobial agents – antibiotics (isoniazid, nalidixic acid), antifungal, antituberculous, antihelminthics CNS stimulants – caffeine, cocaine, amphetamines, methylphenidate Antineoplastic agents Opiates and narcotic agents – pethidine, morphine Vaccines Radiological contrast agents Local anaesthetics, e.g. lidocaine

Table 18.8 Drugs that may cause headache. Non-steroidal anti-inflammatory drugs Analgesics Antimicrobial medication Antiviral agents Cytotoxic medication Corticosteroids Carbamazepine Intravenous immunoglobulin Intrathecal injection Others

Ibuprofen, diclofenac, celecoxib Overuse Sulphonamides, cephalosporins, ciprofloxacin, isoniazid, penicillin Valaciclovir Cytosine arabinoside

Cytotoxics e.g. methotrexate and contrast Antimicrobials, baclofen, spinal anaesthesia

Toxic, Metabolic and Physical Insults by drug withdrawal. Headaches resulting from transient hypertension occur with monoamine oxidase inhibitors (MAOIs), as a reaction to treatment or when sympathomimetic agents are given concurrently. Intravenous immunoglobulin (IVIG) commonly gives rise to headache particularly in known migraine sufferers. Idiopathic intracranial hypertension occurs predominantly in young women who are overweight and is particularly associated with use of the oral contraceptive drug, vitamin A intoxication or a variety of other medications including antibiotics (tetracycline, ampicillin, nitrofurantoin), non-steroidal anti-inflammatory drugs (naproxen, ibuprofen), retinoids, danazole, amiodarone, perhexiline and thyroxine. Headache may also occur as a consequence of drug-induced aseptic meningitis (e.g. NSAIDs).

Memory disturbance Cognitive impairment is commonly associated with the use of medication. This may cause temporary impairment of antegrade and retrograde memory, a transient global amnesia, fugue-like state or, much less commonly, a fixed and irreversible amnesia (Table 18.11).

Neuropsychiatric effects

Confusional states Drugs are a common cause of a confusional state, manifest as a fluctuating level of consciousness, diminished awareness, impairment of intention and memory, disorientation, hallucination and paranoid delusions. The primary drugs that may be responsible are summarized in Table 18.9.

Encephalopathy Clouding of consciousness or delirium is commonly caused by multiple general medical factors but is particularly related to the effects of medication. It may be manifest as a disturbance of

Table 18.9 Drugs associated with confusional states. Tranquillizers and hypnotics – barbiturates, benzodiazepines Antiparkinsonian medication Antidepressants including SSRIs Abrupt withdrawal of drugs SSRI, selective serotonin re-uptake inhibitor.

Table 18.10 Drugs associated with encephalopathy.

consciousness but there may also be changes in cognition or perception. The disturbances develop over a relatively short period of time and fluctuate during the course of the day. A large number of drugs may cause delirium but most reports are anecdotal. The most important medications may have multiple effects (Table 18.10).

The behavioural effects of medication may be difficult to assess and be non-specific. The development of listlessness, insomnia, drowsiness, restlessness, anxiety, euphoria or depression may be a manifestation of underlying disease or other metabolic or infective complications but a variety of medication does contribute; these include tricyclic antidepressants, amphetamines, phenothiazines, barbiturates, hypnotic, anticholinergics, antiepileptic medication and antihistamines. Similar features may be precipitated by acute withdrawal of medication. Affective disorders are less common but may be severe. A depressive reaction may occur during drug treatment. In the past, reserpine and methyldopa were recognized to cause depression. More commonly now depression occurs with other antihypertensive medication (clonidine, propranolol and calcium channel blocking drugs) but is also seen with corticosteroids, hypnotic agents, non-steroidal anti-inflammatory drugs, antituberculous medication, H2 antagonists, digoxin, baclofen, anabolic steroids, barbiturates and benzodiazepines. Acute manic or hypomanic psychosis is unusual but may be associated with corticosteroids, thyroid replacement or, rarely, captopril, chloroquine and dopaminergic drugs.

Lithium

Psychotropic medication

Anticholinergic medication Drugs of abuse Histamine (H2) receptor antagonists Non-steroidal anti-inflammatory drugs Opioid analgesics Others

Diffuse disturbance of cerebral function associated with tremor, myoclonus, seizures, ataxia and confusion. Cerebellar dysfunction may persist Impairment of consciousness and memory with psychomotor activity is common, particularly with neuroleptics (e.g. haloperidol), tricyclic drugs, fluoxetine, venlafaxine e.g. antiparkinsonian, antipsychotics, antihistamines, antiemetics, benzodiazepines e.g. cocaine, opiates e.g. cimetidine Morphine and heroin Penicillins, cephalosporins, vigabatrin, valproic acid

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Table 18.11 Drugs that may be associated with memory disturbance.

Table 18.12 Drugs that may be associated with toxic leucoencephaolopathy.

Chemotherapy Anticholinergic medication Antidepressants Antiepileptic drugs Analgesics drugs of abuse

Antineoplastic treatments Immunosuppressant Antimicrobial Drugs of abuse Environmental toxins

Cranial irradiation, methotrexate, cisplastin, cytarabine, levamisole, IL-2, interferon Tacrolimus, ciclosporin Amphotericin B Toluene, ethanol, cocaine, amphetamine, ecstasy, heroin (iv, inhaled), psilocybin Carbon monoxide, arsenic, carbon tetrachloride

Coma This usually results from an inadvertent or deliberate overdose with hypnotic sedatives, antidepressants, analgesics or drug combinations. An overdose of insulin will also produce an acute hypoglycaemic coma and other drugs that may be implicated include phenothiazines, salicylates and valproic acid.

Sleep disorders Sleep disorders resulting from medication may be manifest by excessive sleepiness, insomnia, sleep-related breathing disorders or parasomnias. Excessive drowsiness is associated with sedative, hypnotic or antidepressive medication and may also occur with antiepileptic drugs. Paradoxically, the same medication may also be associated with insomnia as may respiratory drugs including bronchodilators, cardiovascular drugs (antihypertensive medication, calcium channel blockers, beta-blockers and CNS stimulants). Vivid dreams and nightmares are often associated with drugs affecting noradrenaline, serotonin and dopamine neurotransmitters; these include the CNS stimulants, antipsychotic drugs and antiparkinsonian medication. Parasomnias may be related to the introduction of antipsychotic medication, sedative, hypnotics or antidepressants.

Toxic leucoencephalopthy This is a disorder caused by a structural alteration of white matter caused by a variety of toxic insults usually related to therapeutic agents, illicit drug use and occupational exposure to toxins. The condition involves white matter tracts serving higher cerebral function and therefore presents with neurobehavioural disturbances including inattention, forgetfulness and changes in personality leading to somnolence, apathy, cognitive impairment and ultimately dementia, coma and death. MRI initially shows hyperintensity in the periventricular white matter but this progresses to a severe hyperintensity involving widespread white matter with necrotic areas. These changes are reflected in the pathology of patchy oedema within myelin which becomes widespread, leading to the destruction of oligodendrocytes, axonal loss and necrosis. The condition is associated with a variety of toxins listed in Table 18.12.

Cerebrovascular disease Cerebrovascular disease may be associated with the use of drugs by a large number of potential mechanisms. There is a clear risk of haemorrhage as a complication of anticoagulant and throm-

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bolytic therapies. Cerebral blood flow may be reduced particularly in elderly patients in the presence of cerebrovascular disease by any antihypertensive medication that reduces blood pressure below perfusion pressure. This may predispose to cerebral infarction in watershed territories. Cerebrovascular disease may be caused by direct neurotoxicity or indirect mechanisms such as involvement of other systems including cardiovascular, haematological, respiratory, renal, hepatic and metabolic or the presence of predisposing or coexisting general medical risk factors. A variety of medications may cause transiently elevated blood pressure including sildenafil, amphetamines, ephedrine, heroin and other drugs of abuse. Vasospasm may occur with sympathomimetics, triptans and cerebral vasculitis is particularly associated with amphetamines, ecstasy, penicillin, tacrolimus and occasionally allopurinol. There is a small increased risk of thrombo-embolism, ischaemic arterial or cerebral venous occlusion in women taking the oral contraceptive pill; chemotherapeutic agents including cisplatinum may also cause cerebral venous or arterial thrombosis or haemorrhage.

Impairment of taste and small Disturbances of taste (dysgeusia) and smell (dysosmia) are extremely common manifestations of drug toxicity. They are particularly associated with antidiabetic therapy (oral hypoglycaemics), phosphodiesterase inhibitors, theophylline, caffeine, ethambutol, other antibiotics including penicillin, antirheumatic medication (gold, D-penicillamine), angiotensin converting enzyme inhibitors and many cytotoxic agents.

Drug-induced movement disorders Several movement disorders are caused by commonly prescribed medication (Table 18.13). Acute dystonic and dyskinetic reactions often develop immediately following treatment and may be manifest as oromandibular dystonia, oculogyric crisis and opisthotonus. Dystonia may be more generalized with slow writhing movements of the limbs or prolonged contractions of the axial and limb musculature. The acute dystonias are usually self-limiting once the drug is discontinued. Akathisia is a state of motor restlessness characterized by an inability to keep the legs still and an urge to constantly move, pace or run. Akathisia usually remits within days or weeks following withdrawal

Toxic, Metabolic and Physical Insults Table 18.13 Drug-induced movement disorders.

Acute dystonia

Akathisia

Choreoathetosis

Parkinsonism

Tremor – essential and action

Tardive dyskinesia

of the neuroleptic drug but may occasionally persist or be permanent. Choreoathetosis is manifest as irregular multifocal non-stereotyped semi-purposeful jerky movements often associated with slower dystonic movements. Drug-induced tics are associated with amphetamine-like drugs, methylphenidate, haloperidol and other antipsychotic medication. Drug-induced parkinsonism is the most common form of iatrogenic movement disorder and may be extremely difficult to distinguish from idiopathic Parkinson’s disease. The onset tends to be slow, with bradykinesis being the most prominent feature with variable rigidity, tremor and gait disturbance. The condition is usually reversible after drug withdrawal or dosage reduction over the course of several weeks but drugs may unmask latent idiopathic Parkinson’s disease. A number of drugs may aggravate an essential or physiological tremor. Tardive dyskinesia usually develops after more than 12 months of continuous therapy but may evolve over a much shorter period, occasionally developing after cessation of therapy. It is characterized by orofaciobuccal dyskinesia

Neuroleptics (phenothiazines and butyrophenones) Tricyclic antidepressants Metoclopramide Antiepileptic drugs (phenytoin, carbamazepine) Others (propranolol, ondansitron and fluoxetine) Phenothiazines, butyrophenones Benzodiazepines Antidepressants, SSRI (particularly fluoxetine) Antiepileptic medication Oral contraceptives Drugs of abuse e.g. crack cocaine Lithium Dopamine receptor blocking drugs (e.g. phenothiazines and butyrophenones) SSRIs may induce or exacerbate parkinsonian syndromes Sympathomimetics Tricyclic antidepressants, e.g. amitriptyline Other antidepressants Lithium Levodopa Caffeine, theophylline, aminophylline Hypoglycaemic drugs Antiepileptic drugs (valproate, phenytoin, carbamazepine, primidone) Sedatives, e.g. barbiturates, benzodiazepines Dopamine antagonists (especially antipsychotics) Metoclopramide Promethazine Prochlorperazine Antihistamines Tricyclic antidepressants Levodopa Monoamine oxidase inhibitors

with lip-smacking and pursing, jaw opening, closing and protrusion of the face with writhing movements of the tongue and facial grimacing. The movements tend to be stereotyped and may interfere with speech or swallowing. There may be associated choreoathetotic movements of the limbs and trunk with repetitive foot tapping. Tardive forms of tic, myoclonus and tremor are also described. A variety of dopamine receptor blocking drugs can cause tardive dyskinesiae; the newer atypical dopamine receptor blocking drugs, including clozapine, appear to carry less risk. All the major classes of conventional neuroleptic drugs (phenothiazines, butyrophenones, thioxanthenes) and the atypical antipsychotic drugs including clozapine, olanzapine, quetiapine and risperidone have been described as causing extrapyramidal syndromes. All these side effects are idiosyncratic and patients vary greatly in their susceptibility and in the dose necessary to precipitate the side effects; patients with dementia with Lewy bodies are particularly susceptible.

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Ototoxicity Drug-induced damage to the cochlear and vestibular function is common. The former is manifest as tinnitus and hearing loss and the latter as vertigo, oscillopsia and imbalance. Both are characteristically associated with aminoglycoside antibiotics, gentamicin and streptomicin. Balance is usually preferentially affected. Loop diuretics, salicylates, antimalarials (quinine, chloroquine) and cytotoxic agents including cisplatin and vincristine may be associated with hearing loss (Chapter 14).

intrathecal injection of steroids, cytotoxic medication or contrast material leading to an infective or asceptic meningitis, adhesive arachnoiditis or direct toxic effects on the spinal cord or nerve roots. Epidural injection is not associated with these problems unless there is penetration of the dura.

Neuromuscular drug effects There are many drugs that may cause non-specific fatigability but peripheral neuropathy is an extremely common manifestation of drug toxicity (Chapter 9).

Cerebellar disorders Cerebellar disorders are usually dose-related and reversible but may become fixed deficits after antiepileptic drugs, phenothiazides, lithium or ciclosporin.

Visual disorders Drug-induced visual disorders may be brought about by a variety of different mechanisms and visual disorders. • Pupillary: miosis is produced by parasympathetic drugs which include cholinergic agents (neostigmine, pyridostigmine) and opiates (morphine) but mydriasis, which may occur with anticholinergic agents (atropine, hyoscine), tricyclic antidepressants and phenothiazines (MAIOs, tricyclics), is a more serious drug effect because of the risk of precipitating closed angle glaucoma. • Distortion of the lens may cause refractory changes because of fluid shifts with diuretics and antidiabetic therapy (insulin, oral hypoglycaemics) and corticosteroids. • Drug-induced retinopathy may be caused by the development of pigmentary change (as occurs with chloroquine-like drugs and cardiac glycosides). • Macular oedema (oral contraceptive) or visual field loss (e.g. ethambutol, indometacin, vigabatrin) may occur and optic neuropathy has been associated with some antibiotics (e.g. chloramphenicol, isoniazide, ethambutol, cytotoxic medication, opiates and non-steroidal anti-inflammatory drugs). • Nystagmus is the most common drug-related eye movement disorder and is caused by antiepileptic drugs, tricyclic antidepressants, ototoxic medication, salicylates and MAOIs.

Autonomic effects Disturbances of autonomic function are commonly caused by drug toxicity. Drug-induced syncope may occur as a consequence of vasovagal disturbances, postural hypotension or cardiac disease. Postural hypotension occurs with a variety of antihypertensive medication (particularly β-blockers, vasodilatators and diuretics), antidepressants and levodopa. In the elderly, syncope is particulary associated with fluoxetine, haloperidol and levodopa. Bladder disturbance occurs with anticholinergic medication (atropine, hyoscine), particularly with pre-existing prostatic outflow tract obstruction. Medication may cause sexual dysfunction at any level of function. Antihypertensive medication (β-blockers) is particularly associated with impotence or impairment of ejaculation, while antidepressant medication may affect libido or cause orgasmic dysfunction. Spinal toxicity may follow

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Peripheral neuropathy Most drug-related neuropathies are predominantly axonal (A) although demyelination (D) and conduction block may occur. Both motor and sensory patterns are seen. The major categories of drug-induced peripheral neuropathy are summarized in Table 18.14.

Table 18.14 Drugs causing peripheral neuropathy. Antibiotics Metronidazole Nitrofurantoin Isoniazide Ethambutol Dapsone Antiviral nucleoside analogues

A/D A A A A A

Neuropathy Sensory Sensorimotor or motor Sensorimotor or sensory Sensorimotor or motor Motor Sensory

Chemotherapeutic agents Cisplatin Vinca alkaloids Cytarabin (high dose) Thalidomide

A A D A

Sensory Sensorimotor ± autonomic Sensory Sensory

Cardiovascular drugs Statins Amiodarone Enalapril Hydralazine Streptokinase

A A/D A A A

Sensory > sensory motor Sensorimotor > motor Sensorimotor > sensory Sensorimotor > sensory GBS-like syndrome

Antirheumatic drugs Gold Chloroquine Colchicine Allopurinol

A/D D A A/D

Motor > GBS-like Sensorimotor Sensorimotor Sensorimotor

Others Tacrolimus Ciclosporin Disulfiram Lithium overdose Phenytoin

D A A A A

GBS-like Sensory Sensorimotor GBS-like Sensory and motor

A, axonal; D, demyelinating.

Toxic, Metabolic and Physical Insults Table 18.15 Drugs that interfere with neuromuscular junction transmission. Antibiotics – aminoglycosides, tetracycline, ciprofloxacin Anti-arrhythmics – quinidine, procainamide Antimalarials – chloroquine Antirheumatics – pencillamine D β-Blockers – propranolol, atenolol, metoprolol, sotalol Antiepileptics – phenytoin Neuroleptics – chlorpromazine, clozapine, flupenthixol, lithium, MAOIs Muscle relaxants MAOIs, monoaminase oxidase inhibitors.

Drugs interfering with neuromuscular transmission These may cause a myasthenic-like syndrome, uncover latent myasthenia or exacerbate the existing disease (Table 18.15). These are discussed in Chapter 9; only the most important drugs are listed in Table 18.15. Muscle disease A large variety of muscle diseases may be caused by drugs (Chapter 9). Myalgia, stiffness and cramp Many drugs cause myalgia, stiffness and cramp, often in association with a transiently elevated CK. Drug-induced myopathy may be associated with myotonia, pain or myokymia and may be focal or generalized. The most important drugs causing the different forms of myopathy are listed in Table 18.16.

Malignant hyperthermia This condition occurs in susceptible individuals following anaesthesia using a halogenated inhaled anaesthetic (including halothane, enflurane and isoflurane) and/or a depolarizing muscle relaxant such as succinylcholine. The condition is characterized by the sudden onset of fever and rigidity associated with a high CK level with metabolic acidosis and myoglobinuria. Liability to malignant hyperthermia is transmitted in an autosomal dominant fashion and occurs in genetically predisposed individuals who have an intrinsic abnormality of the excitation–contraction coupling mechanism in skeletal muscle. This leads to an excessive release of Ca2+ from the sarcoplasmic reticulum resulting in myofibrillar contraction. The condition seems to be caused by a defect in the calcium release channel (RYR1) and the genetic basis is a mutation in the RYR1 gene on chromosome 19q or in other calcium channel genes. The onset of the condition is variable. In the most florid forms acidosis, rigidity and hyperpyrexia may develop within 30 minutes of anaesthesia but in some patients the onset is slower with the condition developing over several hours with only mild signs. The initial features are tachycardia, raised end tidal CO2, metabolic acidosis and progressive muscular rigidity. The hyper-

thermia develops later but may be severe. In its most severe form the condition progresses to rhabdomyolysis and myoglobinuria, disseminated intravascular coagulation (DIC), cardiovascular collapse or hyperpyrexia leading to multi-system failure. There seems to be similar sensitivity to anaesthetic agents in patients with other neuromuscular diseases, in particular Duchenne muscular dystrophy, myotonia congenita, myotonic dystrophy, central core disease, congenital myopathy and osteogenesis imperfecta. Vulnerability to this syndrome is suggested by a positive family history or previous difficulties during anaesthesia. It can be tested in vitro using biopsied muscle and observing a hypercontractile response to caffeine or halothane. Management involves the immediate discontinuation of the triggering anaesthesia and hyperventilation with 100% O2 at high flow. Dantrolene is recommended as specific therapy in a dose of 2.5 mg/kg i.v. repeated as necessary. Supportive care of heart rate, temperature and oxygenation are essential. Core temperature can be reduced by ice lavage. Hyperkalaemia is managed by the use of bicarbonate, glucose, insulin and calcium but it is essential to be aware of rebound hypokalaemia which may precipitate further episodes. Myoglobinuria is treated with diuretics, fluid support and bicarbonate as necessary. With rapid and appropriate management the prognosis in an acute episode is good and the syndrome resolves rapidly. It is clearly essential to be aware of any susceptibility to this condition in planning anaesthesia. Complete recovery occurs in general but weakness may last for months after an acute episode.

Neuroleptic malignant syndrome This is a serious and potentially fatal complication of treatment with antipsychotic agents. The condition is characterized by onset within 2 weeks of initiating or increasing neuroleptic therapy although, less commonly, it may develop after months or years of stable treatment. The signs evolve over up to 72 hours although the onset may be more acute and the condition usually resolves within 2 weeks. The onset is usually with progressive and severe pyrexia (>40°C in 40% of patients) although a more insidious onset with a modest pyrexia may occur. There is progressive encephalopathy and impairment of conscious state ranging from lethargy to delirium, confusion, agitation and coma. Severe ‘lead pipe’ rigidity with other extrapyramidal features including bradykinesis, rest tremor and dystonia develop. There is autonomic instability including tachycardia, tachypnoea, diaphoresis, labile blood pressure, skin pallor or flushing, sialorrhoea and urinary disturbance including incontinence. The condition is characterized by grossly elevated CK level and there is also usually a leucocytosis, metabolic acidosis and elevated CSF protein but muscle biopsy is non-specific. The most common drugs causing this condition are haloperidol, fluphenazine and chlorpromazine but other phenathiazines, lithium, metoclopramide, tricyclic antidepressants or atypical antidepressants (clozapine, olanzapine) may also be responsible. Other risk factors seem to include the use of depot injections, high potency neuroleptics, rapid dose increase and the presence

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Table 18.16 Drugs that cause muscle disease.

Subacute necrotizing myopathy – symmetrical proximal weakness with myalgia and elevated CK Amiodarone Chloroquine Lipid-lowering medication – simvastatin, pravastatin, atorvastatin Colchicine Corticosteroids Zidovudine Heroin Myositis – inflammatory myopathy indistinguishable from polymyositis with elevated CK Chloroquine Corticosteroids D-penicillamine Lipid-lowering drugs – simvastatin, pravastin Others – phenyton, levodopa, cimetidine Myotonia – drug either causing the myotonia or unmasking latent myotonic disorders Proprofol Depolarizing muscle relaxants – suxamethonium Diuretics – frusemide, acetazolomide Vincristine Lipid-lowering drugs – simvastatin, pravastatin β-Blockers – propranolol, pindolol Focal fibrous myopathy following intramuscular drug injection – caused by needle trauma and local effects of agent injected leading to severe muscle fibrosis and contractures Antibiotics Chloroquine Drug abuse Myopathy caused by hypokalaemia Diuretics Purgative abuse Licorice Amphotericin B Mitochondrial myopathy – characterized by myalgia, proximal weakness and elevated CK Zidovudine Rhabdomyolysis – acute and severe necrotizing myopathy characterized by severe muscle pain, swelling and weakness leading to myoglobinuria and renal failure Anaesthetics Lipid-lowering drugs – simvastatin, pravastatin Diuretics Barbiturates Opiates – morphine, heroin Alcohol Other drugs of abuse – amphetamines, LSD CK, creatine kinase; LSD, lysergic acid diethylamide.

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Toxic, Metabolic and Physical Insults of dehydration or agitation. There may also be a genetic predisposition to the condition. Despite treatment, neuroleptic malignant syndrome (NMS) may progress to the development of rhabdomyolysis leading to myoglobinuria and renal failure, coagulation defects from DIC, respiratory failure, shock, seizures and coma. In some series mortality has been up to 20%, with persisting neurological sequelae in 10% of survivors. The management is both supportive and specific. The neuroleptic must be immediately discontinued and the core temperature normalized. There must be close attention to hydration, cardiac, respiratory and renal function with adequate anticoagulation. Specific management remains controversial. Dantrolene is a muscle relaxant that inhibits excitation contraction mechanisms and may influence central dopaminergic mechanisms in the active phase of NMS. It has been reported to be effective but there is a risk of hepatic toxicity. Bromocriptine is a dopamine agonist that works by acting centrally to counter the neuroleptic effects. It has been given in divided doses for up to 10 days after resolution of symptoms but its use is limited by side effects of nausea, hypertension and worsening mental state. NMS probably results from a sudden decrease in central dopaminergic function resulting from profound dopamine receptor blockade at multiple sites including the corpus striatum and thermoregulatory and vasomotor centres in the hypothalamus. However, while the condition usually occurs with dopamine receptor blocking drugs it may also be seen with dopamine depleting drugs or even without exposure to neuroleptics.

Serotonin syndrome Serotonin syndrome is a variable but potentially life-threatening drug reaction caused by excessive serotonin stimulation of the central and peripheral nervous systems. It results from therapeutic use, intentional self-poisoning or inadvertent interaction between drugs. Clinical manifestations are variable. There is a characteristic triad of mental state change, neuromuscular abnormalities and autonomic hyper-reactivity. The condition is probably more common than was previously thought particularly with increasing use of selective serotonin re-uptake inhibitors (SSRIs). Presentation may be with mild tachycardia and minor autonomic features including shivering, diaphoresis and mydriasis. These may be considered to be simple drug reactions and the medication is often discontinued. However, in more severe forms the condition may progress to an intermittent tremor or myoclonus with hyper-reflexia. There may be severe hyperthermia, tachycardia and hypertension. Progressive encephalopathy with clouding of consciousness, confusion and hypomania may develop. Autonomic features that may evolve include mydriasis, hyperactive bowel sounds, diaphoresis and neurological involvement including the development of lead pipe rigidity, myoclonus, tremor, incoordination, clonus and hyper-reflexia. The condition usually develops within 24 hours of the initiation of causative medication but the onset may be within minutes or come on after several weeks at stable dosage.

Laboratory investigation may show metabolic acidosis, rhabdomyolysis, abnormalities of liver function and there may be features of DIC or renal failure but most cases are relatively minor and resolve over 12–24 hours. The condition occurs with monotherapy using SSRIs or when there is an interaction between two drugs from this class. These include SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline) or other antidepressant drugs which inhibit the re-uptake of serotonin by other mechanisms including duloxetine, olanzapine, mirtazapine and venlafaxine. Serotonin syndrome may also be associated with other drugs that inhibit the re-uptake of serotonin and these are listed below. The condition has been reported to follow administration of a serotoninergic agent up to 5 weeks after discontinuation of fluoxetine. Drugs that may cause serotonin syndrome either in isolation or when combined include: • SSRIs; • Atypical antidepressants; • MAOIs – phenelzine and selegiline; • Tricyclic antidepressants; • Dopaminergic agents; • Antiepileptic drugs – sodium valproate, carbamazepine; • Lithium; • Anaesthetics; • Opiate analgesics – tramadol, meperidine, pentazocine; • Risperidone; • Over-the-counter cold remedies containing ephedrine and dextromethorphan; • Antiemetics – ondansetron, metoclopramide; • Antimigraine – sumatriptan and other triptans; • Drugs of abuse – Ecstasy, opioids, LSD; • Herbal products – St John’s Wort; • Withdrawal of medication. The condition may be transient and not require treatment other than the discontinuation of the relevant medication. However, if the symptoms are severe, management is both supportive and specific. Following discontinuation of the serotoninergic medication it is necessary to control agitation, monitor the level of consciousness, respiratory and cardiac function and to control hyperthermia and autonomic instability. Sedation, neuromuscular paralysis and orotrachial intubation with ventilation may be necessary. There remains controversy about specific treatment using 5-HT antagonists. A variety of treatments have been used but none is proven. The present recommendations are for the administration of cyproheptadine as it binds to 5-HT receptors. Chlorpromazine has also been used but there is no benefit from other 5-HT antagonists including lorazepam, methysergide and propranolol. It is important to distinguish this condition from neuroleptic malignant syndrome, malignant hyperthermia, anticholinergic syndrome and the tyramine cheese reaction and this differential diagnosis is summarized in Table 18.17.

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Table 18.17 Comparison of clinical features of serotonin syndrome, neuroleptic malignant syndrome (NMS), malignant hyperpyrexia, tyramine, anticholinergic syndrome.

Medication Onset Vital signs

Systemic

Neurology

Temperature Blood pressure Pulse (tachycardia) Diaphoresis/skin Bowel sounds Headache Flushing Mental state Mydriasis Rigidity Reflexes Myoclonus/tremor

Serotonin syndrome

NMS

Malignant hyperpyrexia

Tyramine

Anticholinergic

Serotoninergic drugs

Dopamine agonists

MAOI

Anticholinergic

20 or PaCO2 12,000 or 10 minutes) and early onset REM (>20 minutes). The Multiple Sleep Latency Test (MSLT) is used to confirm the diagnosis. In this test the patient is allowed to fall asleep 4–5 times at 2-hourly intervals throughout the day and the latency to onset of sleep and REM sleep is measured. In narcolepsy, about 70% of patients will have a mean sleep latency of 3% or arousal on

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EEG. OSAHS is considered moderate if there are more than 15 apnoeas/hypopnoeas per hour. Obstruction of the upper airway usually occurs between the caudal soft palate and epiglottis. It is worsened during sleep when reduced upper airway muscle tone leads to collapse of the upper airway and obstruction. This is exacerbated by obesity (body mass index >28 kg/m2), a narrow palate, crowding of the oropharynx and jaw or facial structural anomalies. Patients have difficulty falling asleep, loud snoring, stridor, coughing spells during sleep and restless sleep with frequent wakenings. There may be snoring and irregular breathing patterns and prolonged apnoea. Severe obstructive sleep apnoea is associated with morning headache, impaired memory, anxiety and the development of Pickwickian features with cor pulmonale.

Management The first line management is weight loss, establishing regular sleep patterns and avoidance of alcohol, nicotine, caffeine and sedatives in the evening. Investigation and appropriate treatment of co-morbidity, particularly hypothyroidism, is mandatory. CPAP by nasal or face mask is effective in OSAHS, improving sleep architecture, nocturnal oxygenation and the symptoms of sleepiness, impaired cognition, mood and driving ability and cardiovascular function. However, its use requires considerable educational support and technical back-up. Compliance may be variable in the less severe forms of the condition because of poor mask fitting, dryness of the mouth and airways, claustrophobia, aerophagia and social difficulties. Oral appliances such as mandibular repositioning splints may be valuable in improving EDS and the cardiovascular complications of mild OSAHS. They work by holding the mandible forward, thus increasing the upper airway space by advancing the tongue and possibly changing genioglossus activity. Surgical treatment (uvulopalato-pharyngoplasty) does not have a role. Tracheostomy may be necessary in patients with incipient cor pulmonale.

Restless legs syndrome Restless legs syndrome (RLS) affects 2–5% of the population but is more frequent in the older age group. It is characterized by uncomfortable dysaesthesiae, in the calves and feet leading to an urge to move the limbs and motor restlessness which, transiently, relieves the symptoms. The discomfort is worse at rest, especially in the evening or at night, and may lead to difficulty getting to sleep, frequent awakenings, reduced sleep efficiency and severe insomnia. Leg jerking may also occur during wakefulness and be independent of the dysaesthesiae. RLS usually follows a chronic and often progressive course with intermittent fluctuations, but there may be prolonged periods of remission. Periodic limb movements of sleep are commonly associated with RLS. The condition is usually isolated but may occur in association with pregnancy, iron deficiency anaemia, chronic renal failure, small fibre neuropathies, polymyalgia rheumatica, intermittent claudication and nocturnal leg cramps; there is a significant familial incidence.

Disorders of Consciousness and Sleep RLS may be difficult to relieve completely. Any underlying cause should be sought and treated and there should be careful explanation and attention to any psychological or social factors that may be exacerbating the situation. Levodopa preparations lead to substantial relief in >50% and short-term benefits in 85% with improved sleep efficiency and less arousals or periodic limb movements; however, the benefits are often poorly sustained and repeated dosage adjustment and medication changes are often necessary. Bromocriptine, pergolide and ropinirole are also effective in controlled trials. Symptomatic relief can also be achieved with benzodiazepines, gabapentin and opioids.

Periodic limb movement disorder Periodic limb movement disorder (PLMD) is extremely common, with more than 30% of individuals over 65 years having a significant number of periodic limb movements. They are characterized by jerking and kicking of the limbs occurring with varying frequency and localization during sleep. They occur in bouts of dozens or more lasting for many minutes and recurring every 20–30 minutes. Although PLMD may be asymptomatic, patients may have complaints of difficulty falling asleep, frequent awakenings, daytime sleepiness or because bed partners may actually complain more about movements. The sensory symptoms and waking dyskinesiae characteristic of RLS do not occur. They can be associated with other sleep disorders including RLS, sleep apnoea, narcolepsy or REM behaviour disorders or, most commonly, as an isolated phenomenon. The movements are most frequent during stage 1 and 2 sleep, less frequent during SWS and generally absent during REM sleep except in associated with narcolepsy or sleep apnoea. Treatment is only justified if periodic limb movements are symptomatic and follows the same principles as RLS.

Circadian rhythm disorders Intrinsic circadian rhythms maintain a sleep–wake cycle of approximately 24 hours. They are set by environmental day length and are influenced by social activity, which can adjust timings. A mismatch between the internal circadian cycle and the external environment leads to insomnia, EDS and disruptive sleep function and activities of daily living. These may occur because of alterations in the internal circadian cycle (i.e. delayed or advanced sleep phase syndrome) or to changes in the environment (e.g. jet lag).

Delayed or advanced sleep phase syndrome These conditions are characterized by an inability to fall asleep or remain asleep at a conventional time. The persistence of the pattern distinguishes the condition from alterations in sleep rhythms, change in work timetables or travel across time zones. These conditions may be difficult to manage as attempts to regularize rhythms can lead to prolonged sleep latency and chronic insomnia, resulting in the excessive use of stimulants,

hypnotics or alcohol. These conditions can be helped by cognitive– behavioural therapy, and a regimen of planned advancement of bedtime. Bright light therapy and melatonin may also be of some benefit.

Shift work and jet lag These conditions occur when the physical environment is altered and there is a mismatch with the internal circadian cycle. Many social factors influence the ability to acclimatize to a change in routine or travel including age, community, work responsibility and stress. They may lead to EDS or insomnia and a deterioration in the performance at work and a dependence on medication. Melatonin has been shown to have a benefit in these conditions.

Parasomnias Parasomnias are undesirable motor, verbal or experiential phenomena that occur during the sleep period and may be considered disorders of sleep state transition, partial arousal or arousal. They are categorized as primary (disorders of sleep state) and secondary (disorders of other organ systems manifest themselves during sleep). The primary sleep parasomnias can be classified according to sleep state of origin (Table 19.24).

Table 19.24 A classification of parasomnias. Primary parasomnias Normal sleep–wake transition phenomena Sleep starts Hypnic jerks Motor, visual, auditory & somatosensory phenomena Hypnagogic imagery Arousal disorders (typically arising in NREM sleep) Sleep walking Sleep terrors Confusional arousals REM-related REM-related behaviour disorder (RBD) Nightmares Sleep paralysis Others Rhythmic movement disorders Fragmentary myoclonus Bruxism Enuresis Nocturnal paroxysmal dystonia Snoring Sleep talking Secondary parasomnias Headaches – vascular, exploding head, hypnic headache Cardiorespiratory, e.g. cardiac failure, angina, respiratory dyskinesias Gastrointestinal, e.g. gastro-oesophageal reflux Functional disorders

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Non-REM parasomnias Sleep–wake transition disorders are non-REM phenomena that occur in the transition between waking and sleeping. Hypnic jerks (sleep starts), sleep talking and nocturnal leg cramps all commonly occur in otherwise healthy individuals and are regarded as physiological alterations rather than pathological conditions. Hypnic jerks are brief body jerks at sleep onset, which may involve limbs, trunk or head. The jerks may be single or repetitive and may be spontaneous or provoked by stimuli. Visual, auditory or somatosensory sleep starts may also occur. In non-REM sleep, small flickering movements called sleep myoclonus are associated with very brief, highly localized EMG potentials. In some cases, the amplitude and frequency of these movements increase, at which points they are called fragmentary myoclonus. The exploding head syndrome is also a form of parasomnia and may represent a form of sleep start in which there is a sudden arousal during transition into sleep with a sensation of a loud noise ‘bursting’ the head. They can also occur during REM. Hypnic headache is rare, occurring in older patients, regularly at constant times at night. The headache is diffuse, protracted and relatively mild. The arousal disorders are also abnormal non-REM sleep phenomena and consist of confusional arousal, sleep walking and sleep terrors. The conditions are characterized by a family history, a tendency for the disorder to arise from slow wave sleep (stage 3 and 4) and a higher incidence in childhood. They represent incomplete awakenings from sleep, most commonly deep slow wave sleep. Sleep walking is common in children, but also occurs in adults. It arises from a deep sleep, typically in the first third of the night, and may be either calm or agitated, with varying degrees of complexity and duration. Repetitive behaviours may occur and occasionally eating may be a feature. The episodes usually last 1– 2 minutes but prolonged complex behaviours including driving have been reported. It is often very difficult to awaken the patient who is then confused with variable amnesia for the event. The most important consideration is protection from injury. Treatment is often unnecessary but precipitating factors such as sleep deprivation and alcohol should be avoided; drug treatment with benzodiazepines or tricyclic medication may be valuable. Sleep terrors are the most disturbing disorder of arousal for the patient and family. They are often characterized by a loud scream associated with extreme panic and prominent, occasionally violent, motor activity, resulting in bodily injury or property damage. The patient is inconsolable during the terror and amnesic for the event, which may be complete. Often, people report dream-like episodes in which they are being attacked or chased. The patient appears to be in a state of acute terror with tachycardia, tachypnoea, mydriasis and increased muscle tone. They last between 30 seconds and 3 minutes and can occur from early childhood. Treatment is rarely necessary but diazepam and tricyclic medication are helpful. Sleep terrors characteristically begin during the deep sleep of the first third of the night; however, when episodes are very frequent they may be diffusely distributed across

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the sleep period and occur in any non-REM stage. Sleep terrors are sometimes familial and are associated with increased incidence of sleep walking and confusional arousals. Confusional arousals usually occur in children and are characterized by partial awakening movements in bed, occasional thrashing about or inconsolable crying and associated with confusion and impaired mentation, disorientation in time and place, and perceptual impairment. Behaviour is often inappropriate and aggressive behaviour may be observed, indeed murder has been committed immediately on sudden arousals from deep sleep. Confusional episodes are usually brief but may last up to 30 minutes. Confusional arousals can be associated with disorders causing deep or disturbed sleep, including metabolic, toxic and other encephalopathies; idiopathic hypersomnia; symptomatic hypersomnia and sleep apnoea syndrome. Episodic nocturnal wanderings are nocturnal episodes in adults, characterized by abrupt arousal followed by motor activities such as kicking, leaping, head banging and violent ambulation associated with screaming, yelling and unintelligible speech. The patient seems afraid, completely unresponsive to the environment and at risk of injury. The attacks usually occur in clusters during nonREM sleep stage 2 and all respond well to carbamazepine. Disorders of arousal may be triggered by pyrexia, alcohol, prior sleep deprivation, emotional stress or a variety of medications including sedatives and hypnotics, neuroleptics, minor tranquillizers, stimulants and antihistamines. They are also exacerbated by pregnancy and menstruation. Treatment is usually unnecessary with adequate reassurance. However, tricyclic antidepressants and benzodiazepines may be effective if the behaviours are dangerous to persons or property or are disruptive to the family. Cognitive behavioural therapy may be particularly helpful. Bruxism is intermittent repeated grinding or clenching teeth during sleep which is common in children and also in the severely disabled and may appear to any sleep stage. It may be associated with other movement disorders during sleep. Sleep bruxism may be a manifestation of mild REM sleep behaviour disorder. There is no satisfactory treatment although attempts are made at occlusal adjustment and splints.

REM sleep disorders REM-related parasomnias with movement disorders include nightmares, sleep paralysis and REM sleep behaviour disorder. Nightmares are dreams with progressive content that become frightening. They usually last only a few minutes and are associated with movements, mumbling and vocalization before awakening. They occur in the second half of the night during REM sleep and may be related to REM rebound during a period of recuperation after REM sleep deprivation from either stress, drugs or surgery. Terrifying hypnagogic hallucinations (sleep onset nightmares) are part of the narcoleptic tetrad but may also occur in isolation. They are nightmares occurring at sleep onset in association with sleep onset REM. The usual treatment is tricyclic antidepressants especially clomipramine which appears effective both for episodes in non-REM and in REM sleep onsets.

Disorders of Consciousness and Sleep REM sleep behaviour disorder (RBD) is a rare condition that occurs predominantly in older men. It is characterized by ‘dream enactment’ causing abnormal behaviour during REM sleep, including generalized limb or truncal jerking which may progress to prominent, violent or more complex disruptive sleep behaviours, which are often aggressive, confrontational and may be violent with patients enacting intense dreams occasionally leading to self-injury. The duration is 2–10 minutes, recurring a few times a week. Twenty-five per cent have a prodrome involving subclinical behavioural release during sleep characterized by talking, yelling or vigorous sleep-related movements which precede the full-blown episode by a number of years. REM sleep disorder is characterized by loss of intermittent REM sleep atonia, and by the appearance of elaborate motor activity associated with dreams. The condition may be idiopathic or associated with neurodegenerative disorders (parkinsonism, multi-system atrophy, Lewy body dementia), narcolepsy, cerebrovascular disease, MS or Guillain–Barré syndrome. RBD may develop months or years before the onset of any underlying neurological disorder. RBD may also emerge during withdrawal from ethanol or sedative-hypnotic abuse and with anticholinergic and other drug intoxication states leading to loss of REM atonia. Clonazepam is an effective treatment in RBD in suppressing both the violent behaviour and the intense subjective dream recall by suppression of phasic EMG activity during REM sleep rather than by restoration of REM atonia. Adjunctive or alternative medication may involve imipramine, carbamazepine, levodopa or gabapentin. It may be necessary for the patient or partner to take selfprotective measures.

Other forms of parasomnia Rhythmic movement disorders Rhythmic movement disorders (jactatio capitis nocturna) are a group of behaviours characterized by stereotyped movements (rhythmic oscillation of the head or limbs, head banging or body rocking) which typically occur just before sleep onset and persist into light sleep. They most commonly occur in infants and young children often associated with autism and mental retardation, but have been described in adults with normal IQ. Significant complications include scalp and body wounds, subdural haematoma, retinal petechiae, skull callus formation and significant family and psychosocial problems. There are no EEG signs of arousal during the rocking movements. Nocturnal paroxysmal dystonia Nocturnal paroxysmal dystonia (NPD) are sleep-related attacks in which intense stereotypical choreoathetotic, dystonic and ballismic movements occur and can cause severe sleep disruption with EDS or injury to the sleeping partner. Two varieties exist: a short-lived form lasting 15–60 seconds (resembling paroxysmal kinesogenic dystonia of wakefulness) and a prolonged form that lasts up to an hour. The nature of the movements is similar in both varieties. The attacks arise from light sleep with the eyes remaining open and may recur several times a night for many

years. The nature of NPD remains uncertain but the present evidence indicates that NPD with short-lasting attacks represents a peculiar nocturnal epileptic seizure, probably of frontal lobe origin, characterized by their occurrence during non-REM sleep, negative EEG and good response to carbamazepine.

Other sleep disturbances in extrapyramidal disease In extrapyramidal disorders, particularly idiopathic Parkinson’s disease (PD), Huntington’s, Tourette’s syndrome and torsion dystonia, involuntary movements may persist during sleep. These usually occur during stage 1, 2 and REM sleep and are less common in stage 3 and 4 sleep. Sleep difficulties are particularly frequent in patients with PD and these include difficulty getting to sleep, inadequate time asleep, disrupted sleep and daytime sleepiness which may occur as a result of nocturia, inability to turn over during the nights or on waking, inability to get out of bed unaided, leg cramps and jerks, dystonic spasms of the limbs or face and back pain during the night. There may be an increased prevalence of PLMD, RLS and RBD in association with PD. The treatment of PD itself may alleviate abnormal motor activity during sleep but separate treatment may be necessary and clonazepam is particularly valuable. Respiratory disturbances, characterized by involuntary movements of laryngeal or respiratory muscles and impaired volitional control, are common in PD, progressive supranuclear palsy (PSP) and multiple-system atrophy. There are also sleep-fragmenting respiratory disorders, such as sleep apnoea or upper airway resistance syndrome, a restrictive type of lung defect caused by an intrinsic defect in breathing control, impaired respiratory muscle function caused by rigidity and faulty autonomic control of the lungs. PD patients may also have obstructive respiratory defect, stridor or laryngeal spasm associated with off states or dystonic episodes, diaphragmatic dyskinesiae, drug-induced respiratory arrhythmias and dyspnoea and upper airway dysfunction with tremor-like oscillations. Dystonic movements and tics may persist during sleep at a reduced frequency and amplitude but are maximally active during stage 1 and 2 and REM sleep episodes. Epilepsy syndromes associated with sleep It is essential to distinguish the sleep-related paroxysmal events described above from nocturnal epilepsy and it may be difficult on history alone to distinguish epilepsy from cataplexy, confusional arousals, night terrors and RBD. Epilepsy has a complex association with sleep. Certain seizures are more common during sleep such as frontal lobe seizures that occur during non-REM sleep. Rarely, nocturnal seizures may be the only manifestation of an epileptic disorder and these can be confused with a parasomnia – this has been especially true for autosomal dominant nocturnal frontal lobe epilepsy, the seizures of which were thought originally to represent an NPD. Nocturnal frontal lobe seizures are brief, stereotypical, cluster and occur at any time of night.

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Many cases of episodic nocturnal wanderings are possibly seizures or post-ictal confusion. Rarely, non-convulsive status epilepticus can occur during slow wave sleep; the clinical manifestation of this is usually intellectual regression and autism. Lack of sleep can precipitate seizures especially in the idiopathic generalized epilepsies, and sleep apnoea has been reported to worsen seizure control. Sleep disturbances also commonly occur in people with epilepsy in whom there is a higher incidence of sleep apnoea, fragmented sleep and insomnia as well as daytime somnolence (often drug-related).

Acknowledgement The authors are grateful to BMJ Publications for permission to reproduce sections from Howard R. et al. Admission to neurological intensive care: who, when and why? J Neurol Neurosurg Psychiatry 2003; 74: 2–16.

References Bacon D, Williams MA, Gordon J. Position statement on laws and regulations concerning life-sustaining treatment, including artificial respiration and hydration, for patients lacking decision-making capacity. Neurology 2007; 68: 1097–1100. Bassetti C, Aldrich MS. Idiopathic hypersomnia. A series of 42 patients. Brain 1997; 120: 1423–1435. Bleck TP, Smith MC, Pierre-Louis SJ, et al. Neurologic complications of critical medical illnesses. Crit Care Med 1993; 21: 98–103. Bolton CF, Young GB, Zochodne DW. The neurological complications of sepsis. Ann Neurol 1993; 33: 94–100. Bolton CF. Sepsis and the systemic inflammatory response syndrome: neuromuscular manifestations. Crit Care Med 1996; 24: 1408–1416. Campellone JV, Lacomis D, Kramer DJ, et al. Acute myopathy after liver transplantation. Neurology 1998; 50: 46–53. Case Records of the Massachusetts General Hospital. Case 11–1997: A 51-year-old man with chronic obstructive pulmonary disease and generalized muscle weakness. N Engl J Med 1997; 15: 1079–1088. Czosnyka MJ, Pickard JD. Monitoring and interpretation of intracranial pressure. J Neurol Neurosurg Psychiatry 2004; 75: 813–821. Diringer MN, Zazulia AR. Hyponatraemia in neurologic patients: consequences and approaches to treatment. The Neurologist 2006; 12: 117–126. Evans TW. Hemodynamic and metabolic therapy in critically ill patients. N Engl J Med 2001; 345: 1417–1418. Guidelines for the management of severe traumatic brain injury. J Neurotrauma 2007; 24 (Suppl 1): S1–S108. Howard RS, Kullmann DM, Hirsch NP. Admission to neurological intensive care: who, when and why? J Neurol Neurosurg Psychiatry 2003; 74 (Suppl. 3): 2–9. Howard RS, Radcliffe J, Hirsch NP. General medical care on the neuromedical intensive care unit. J Neurol Neurosurg Psychiatry 2003; 74 (Suppl. 3): 10–16. Hudson LD, Lee CM. Neuromuscular sequelae of critical illness. N Engl J Med 2003; 8: 745–747.

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Hughes RA, Cornblath DR. Guillain–Barré syndromes. Lancet 2005; 366: 1653–1666. Hund E. Critical illness polyneuropathy. Curr Opin Neurol 2001; 14: 649–653. Hurford WE. Sedation and paralysis during mechanical ventilation. Respir Care 2002; 47: 334–346. Jacobi J, Fraser GL, Coursin DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med 2002; 30: 119–141. Lacomis D, Giuliani MJ, Van Cott A, et al. Acute myopathy of intensive care: clinical, electromyographic, and pathological aspects. Ann Neurol 1996; 40: 645–654. Lacomis D, Petrella JT, Giuliani MJ. Causes of neuromuscular weakness in the intensive care unit: a study of ninety-two patients. Muscle Nerve 1998; 21: 610–617. Lacomis D, Zochodne D, Bird SJ. Critical illness myopathy. Muscle Nerve 2000; 23: 2785–1788. Leijten FS, Harinck-de Weerd JE, Poortvliet DC, et al. The role of polyneuropathy in motor convalescence after prolonged mechanical ventilation. JAMA 1995; 274: 1221–1225. Lesage S, Hening WA. The restless legs syndrome and periodic limb movement disorder: a review of management. Semin Neurol 2004; 24: 249–260. Lorin S, Nierman DM. Critical illness neuromuscular abnormalities. Crit Care Clin 2002; 18: 553–568. Mahowald MW, Bornemann MC, Schenk CH. Parasomnias. Semin Neurol 2004; 24: 283–292. Morris HR, Howard R, Brown P. Early myoclonic status and outcome following cardio-respiratory arrest. J Neurol Neurosurg Psychiatry 1998; 64: 267–268. Olson EJ, Boeve BF, Silber MH. Rapid eye movement sleep behaviour disorder: demographic, clinical and laboratory findings in 93 cases. Brain 2000; 123: 331–339. Rabinstein AA, Wijdicks, EFM. Hyponatraemia in critically ill neurological patients. Neurologist 2003; 9: 290–300. Razvi SSM, Bone I. Neurological consultations in the medical intensive care unit. J Neurol Neurosurg Psychiatry 2003; 74 (Suppl. 3): 16–23. Shorvon S. The management of status epilepticus. J Neurol Neurosurg Psychiatry 2001; 70 (Suppl. 2): 22–27. Towne AR, Waterhouse EJ, Boggs JG, et al. Prevalence of nonconvulsive status epilepticus in comatose patients. Neurology 2000; 54: 340–345. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345: 1359–1367. Wijdicks EEF, Litchy WI, Weisner RH, Krom RAF. Neuromuscular complications associated with liver transplantation. Muscle Nerve 1996; 19: 696–700. Wijdicks EF. Determining brain death in adults. Neurology 1995; 45: 1003–1011. Available online at the American Academy of Neurology: www.aan.com/professionals/practice/pdfs/g10065.pdf[Medline] Wijdicks EF. Brain death worldwide: accepted fact but no global consensus in diagnostic criteria. Neurology 2002; 58: 20–25. Wijdicks EFM, Bamlet WR, Maramattom BV, Manno EM, McClelland RL. Validation of a new coma scale: the FOUR score. Ann Neurol 2005; 58: 585–593. Wijdicks EF, Young GB. Myoclonus status in comatose patients after cardiac arrest. Lancet 1994; 343: 1642–1643.

Disorders of Consciousness and Sleep Wiles CM. Neurological complications of severe illness and prolonged mechanical ventilation. Thorax 1996: 51 (Suppl. 2): S40–44. Working Party of the Royal College of Physicians, UK. A code of practice for the diagnosis of brainstem death including guidelines for the identification and management of potential organ and tissue donors. Department of Health, UK: 1998. Available online at: www.doh.gov.uk/pdfs/brainstemdeath.pdf Yentis SM, Hirsch NP, Smith GB. A to Z of Anaesthesia and Intensive Care, 4rd edn. Oxford: Butterworth, Heinemann. 2008 Young GB, Bolton CF, Austin TW, et al. The encephalopathy associated with septic illness. Clin Invest Med 1990; 13: 297–304.

Zaman A, Britton T, Douglas N, et al. Narcolepsy and excessive daytime sleepiness. Br Med J 2004; 329: 724–728. Zandbergen EG, de Haan RJ, Stoutenbeek CP, et al. Systematic review of early prediction of poor outcome in anoxic-ischaemic coma. Lancet 1998; 352: 1808–1812. Zochodne DW, Bolton CF, Wells GA, et al. Critical illness polyneuropathy: a complication of sepsis and multiple organ failure. Brain 1987; 110: 819–841. Zochodne DW, Rarnsay DA, Saly V, Shelley S, Moffatt S. Acute necrotizing myopathy of intensive care: electrophysiological studies. Muscle Nerve 1994; 17: 285–292.

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Neuro-Oncology Jeremy Rees, Sebastian Brandner, Robin Howard, Rolf Jäger, Susan Short, David Thomas, Emma Townsley, Gelareh Zadeh

Neuro-oncology covers the scientific and clinical basis of CNS tumours and neurological complications of cancer. In common with many other areas of medicine, a multi-disciplinary approach provides optimal standards of care. The emergence of new therapies throughout neurology has changed the role of neurologists from diagnostic to therapeutic clinicians. This is especially relevant in neuro-oncology. Improvements in diagnosis and surgical technique, new biological agents and increasing use of combined radiotherapy and chemotherapy for tumours such as gliomas have led to small but definite improvements in survival. There is increasing awareness amongst neurological trainees of the large array of CNS tumour types, the spectrum of neurological complications of cancer, particularly paraneoplasia, and the neurotoxicity of chemotherapy and radiotherapy, making it essential to have up-to-date knowledge. This chapter provides a clinically dominated guide to the key issues in neuro-oncology. The initial sections reflect the highly specialized nature of disciplines within neuro-oncology. The multi-disciplinary aspects of care are outlined in the sections on clinical management.

Epidemiology of common primary intracranial tumours Incidence Brain tumours include primary tumours arising from intracranial structures and metastases from outside the CNS. Primary CNS tumours account for approximately 8% of all cancers in adults and 2% of all cancer deaths; broadly, there is a 25% chance of any adult patient who has a brain tumour dying from it. Some 20% of malignancies in childhood are within the CNS. In adults


they are second only to stroke as a cause of neurological death. They place a considerable burden of suffering on patients, their families and carers. Incidence figures for brain tumours depend much on methods of case ascertainment. Incidence of specific tumour types is believed to be much the same worldwide. The crude UK annual incidence for primary tumours is 15.3/100,000 and for secondary tumours 14.3/100,000 patients. It is likely that the true incidence is considerably higher. One study from the south-west of England ascertaining data mainly from radiology records found the crude annual incidence for primary tumours to be 21/100,000. There are some suggestions that the incidence of glioma and CNS lymphoma is increasing, particularly in elderly patients. This may simply be because of better case ascertainment and the increasing use of imaging, e.g. for patients presenting with stroke. Different tumour types present in different age groups. Supratentorial gliomas are uncommon below the age of 30 years but become increasingly prevalent thereafter. They account for over 60% of primary tumours. The most frequent tumours of adolescence are germ cell tumours and astrocytomas, those in middle life astrocytomas, meningiomas and pituitary adenomas and in later life, highly malignant astrocytomas and metastases. Infratentorial tumours are more common in childhood. Seventy per cent of paediatric primary intracranial tumours arise in the cerebellum and brainstem, specifically astrocytomas, ependymomas and medulloblastomas. Meningiomas and schwannomas occur more frequently in women; the reverse is true for astrocytomas.

Survival The survival of a patient with a brain tumour is related to age, performance status, histological type, grade and location. Intraaxial tumours are associated with poorer survival than extraaxial. Although there has been some improvement over the last 30 years, only about 30% of adults with malignant brain tumours in the UK survive 1 year and 15% survive 5 years. This compares

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to a 5-year survival rate of 17–20% in Europe and 25% in the USA. These discrepancies may be partly because of inclusion of benign brain tumours, certainly in US registries. As a general rule, young patients fare better than older with the same histological types. Patients with benign tumours, e.g. meningiomas, may survive many decades or be cured permanently. Children with brain tumours survive for longer than adults: 5-year survival in children is around 60%. Histological grading has particular prognostic implications and is an essential part of the neuropathological assessment. This is especially so because brain tumours rarely spread outside the nervous system. They are therefore not classified with the familiar TNM (tumour, node, metastasis) system. Prognosis is usually expressed in terms of percentage survival at 5 years. For astrocytomas, 5-year survival is over 85% for WHO Grade I tumours, around 50% for WHO Grade II tumours, 20% for WHO Grade III tumours and less than 5% for WHO Grade IV tumours.

Risk factors The cause of most brain tumours remains unknown. The only definite environmental risk factor is ionizing radiation, either following nuclear explosions or therapeutic radiation. Cranial radiotherapy (RT) even at low doses has been shown to increase the relative risk of meningiomas by a factor of 10 and of gliomas by a factor of 3. Other RT-induced tumours include sarcomas and schwannomas. They have been described following RT for tinea capitis, craniopharyngioma, pituitary adenomas and prophylactic cranial irradiation for acute lymphoblastic leukaemia. Secondary tumours tend to lie within the radiation field, usually within lower dose regions, and develop from a few years to many decades after RT. The median time to the development of gliomas is 7 years. Sarcomas develop with a longer lag time and meningiomas may be seen 30–40 years later. The histology is identical to spontaneous tumours although meningiomas are more likely to have atypical histology. No other environmental risk factor has been clearly identified. There has been widespread concern about cellular phones. Case– control studies have shown no increased risk of any brain tumour related to type of phone, duration and frequency of use and cumulative hours of use. However, with the exponential increase in the ownership and duration of use of cellular phones, particularly in children, it is vital that brain tumour trends continue to be surveyed to detect a latent interval, which might be several decades. Genetic causes of brain tumours are rare but important. Occasionally, brain tumours occur in successive generations without any other tumour predisposition. Typically, they are associated with neurocutaneous syndromes such as neurofibromatosis (optic nerve glioma, meningioma, vestibular schwannoma), tuberous sclerosis (subependymal giant cell astrocytoma) and von Hippel–Lindau syndrome (haemangioblastoma). There are also rare familial tumour syndromes, e.g. Li–Fraumeni syndrome (glioma) and Cowden’s disease (dysplastic cerebellar gangliocytoma or Lhermitte–Duclos disease).

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Clinical features The clinical presentation of a brain tumour depends on location, rate of growth and pathology. Any tumour has the potential to produce a focal deficit and raised intracranial pressure although this is most commonly seen with high-grade tumours because of rapid growth and brain tissue necrosis and with posterior fossa mass lesions. In contrast, low-grade tumours are infiltrative, less destructive than their high-grade counterparts and present more frequently with a seizure disorder. Several hospital-based studies have examined the clinical features of brain tumours. One study of over 300 brain mass lesions showed that headache and seizures were the most frequent symptoms followed by neurological deficit and cognitive behavioural changes. Patients with cognitive decline tended to be diagnosed late and had developed focal or multiple symptoms by the time they were seen. Asymptomatic papilloedema and hemianopia was noted in particular, pointing to the need for careful fundoscopy and visual field testing.

Headache Tumours can produce raised intracranial pressure either by the mass effect of a rapidly growing lesion with associated vasogenic oedema or by blockage of CSF pathways, typically seen with posterior fossa tumours and with intraventricular tumours. Stretching or distortion of the meninges can give rise to headache without raised pressure. Intra-tumoural haemorrhage can produce an acute rise in pressure leading to severe headache with coma or reduced consciousness. This clinical picture is also sometimes seen with large tumours without any evidence for a bleed, particularly in periventricular locations where encystment of a horn of the lateral ventricles can occur. Severity of headache is not a helpful diagnostic pointer – indeed, the most severe headaches encountered in practice are almost invariably caused by primary headache syndromes such as migraine or cluster headache. One study of over 100 patients with brain tumours revealed that headaches were present in nearly half, equally for primary and metastatic tumours, and that they were similar to tension-type headaches or migraine in over 80%. The typical tumour headache was bi-frontal, worse on one side but it was the worst symptom in under half of the patients. Brain tumour headaches were worse with bending in around one-third, unlike true tension-type headaches. Nausea or vomiting was present in 40%. Early morning headache was uncommon. Nausea and vomiting, abnormal physical signs or a significant change in prior headache pattern were particular risk factors for a tumour. What usually distinguishes headaches of a brain tumour from benign headaches is the gradual evolution of associated symptoms, i.e. focal deficit, seizures, ataxia and vomiting, the latter being seen particularly with posterior fossa tumours. It is quite exceptional for a patient with a brain tumour to present with headache alone.

Neuro-Oncology

Seizures Tumour-associated seizures may be partial and/or generalized. There is an inverse relationship between tumour grade and occurrence of seizures and certain low-grade tumours, e.g. oligodendrogliomas and gangliogliomas are associated with seizures in over 90% of cases. The type of seizure is dependent on tumour location and there are no distinguishing features of focal seizures to distinguish a tumour from a non-neoplastic process. In a recent retrospective study of over 80 adults with supratentorial low-grade gliomas, seizures occurred in all but one and only 30% of patients became seizure-free on anticonvulsants. There was no clear association between severity of the seizure disorder and behaviour of the underlying tumour, in particular the return of seizures after a period of seizure freedom did not invariably indicate tumour recurrence.

Focal deficits Focal deficits depend on the location of the tumour and are usually subacutely progressive. However, stroke-like presentations, and even TIAs, are well recognized. These are sometimes caused by intra-tumoural haemorrhage and sometimes by presumed vascular changes associated with the tumour. Progressive focal deficits occur typically in patients with high-grade tumours, e.g. glioblastoma multiforme and brain metastases, rather than with low-grade tumours, presumably because of the ability of the latter to infiltrate normal tissue without interfering with function.

Cognitive and behavioural symptoms A minority of patients with tumours present with cognitive symptoms and/or a behavioural disorder, e.g. abulia caused by a subfrontal meningioma. Specific focal cognitive deficits e.g. alexia, acalculia may be seen in tumours affecting the dominant parietal lobe particularly around the angular gyrus. Psychiatric symptoms such as depression, paranoid delusions and personality changes are all well recognized and stress the need for imaging in patients with atypical affective disorders.

Endocrine symptoms Pituitary and hypothalamic tumours may present with endocrine disturbances brought about by anterior or posterior pituitary failure or oversecretion, e.g. acromegaly. They may also cause visual failure typically commencing with bitemporal quadrantanopia or hemianopia as the optic chiasm is further compressed. Pituitary tumours are discussed below.

Unusual symptoms Other presentations of tumours include: • Anosmia: orbital plate tumours (Chapter 12); • Cranial nerve lesions: skull base and cerebellopontine angle tumours; • Cachexia: hypothalamic tumours; and • Precocious or delayed puberty: craniopharyngiomas.

Pathology of common primary brain and spinal tumours Histogenesis The nomenclature of brain tumours has relied on the resemblance of tumour cell shape, morphology and localization to those of differentiated cells of the brain or expression of glial or neuronal proteins, identified by immunohistochemical techniques. Thus, gliomas are thought to arise from neoplastic transformation of astrocytes, oligodendrocytes or their precursors. Currently, it is impossible to demonstrate directly which cell of origin gives rise to which specific glioma in humans. This remains a fundamental question in glioma biology. Possibilities include differentiated astrocytes, oligodendrocytes, glial progenitor cells or even cells originating from the stem cell compartment of the adult brain. It may be that the initial genetic mutation determines the final tumour phenotype independent of the original cell type, in which case the identity of a differentiated cell may alter during the process of transformation, as more genetic mutations arise resulting in progressively more undifferentiated tumours. There is increasing interest in the role of stem cells in the origins of brain tumours. These are defined as cells that have the ability to perpetuate themselves through self-renewal and to generate mature cells of a particular tissue through differentiation. There are numerous parallels between somatic stem cells and cancer cells. Both show self-renewal, differentiation and capacity for histogenesis. Somatic stem cells self-renew in a highly controlled manner and differentiate into mature cells which go on to form normal tissues, whereas cancer cells show poorly controlled self-renewal, often abortive differentiation and go on to form abnormal tissues. The observation that only a small minority of tumour cells show an indefinite potential for self-renewal in vitro or in vivo gave rise to the hypothesis that tumours are composed of both cancer stem cells and more differentiated cells. The existence of a cancer stem cell has been proven for acute myeloid leukaemia, breast cancer (CD44+/CD24− cells), glioblastoma and medulloblastoma (CD133+ cells). Implications of the cancer stem cell hypothesis are: • Cancer cells can be hierarchically organized in that they range from poorly differentiated, highly proliferative cells to more mature, less proliferative forms; • Cancer cells share cell cycle pathways that are relevant to normal human development and control of growth.

Molecular pathways involved in tumour formation An intrinsic difficulty in the study of signalling pathways involved in oncogenesis is the abundance of mutations that accumulate during the multi-step process of malignant transformation of normal cells into tumour cells. An additional obstacle is the heterogeneity of mutations within a single tumour which suggests separate subpopulations of cells are capable of promoting growth in the same malignancy.

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Three types of genes are involved in tumorigenesis: 1 Oncogenes; 2 Tumour suppressor genes; and 3 Repair/stability genes. Oncogenes and tumour suppressor genes regulate cell division, control apoptosis or cell cycle arrest, while repair/stability genes become tumorigenic by loss of their DNA repair function. Oncogenes are genes that under normal conditions, i.e. development and cell self-renewal, promote cell birth and growth but when unleashed become autonomously active. For example, a point mutation in c-kit, which codes for a tyrosine kinase, leads to constitutive activation in the kinase domain and is causally implicated in the pathogenesis of gastrointestinal stroma tumours which arise from Cajal cells. In contrast, tumour suppressor genes are gatekeepers of cell cycle function and under physiological conditions exert a negative regulation on processes promoting the cell cycle. They may also control apoptosis and therefore mutations in these genes can lead to a failure of apoptosis. Typical examples are: • p53: the ‘guardian of the genome’ which causes induction of apoptosis in response to cell damage; • Retinoblastoma (Rb): the prototypic tumour suppressor gene which controls the cell cycle at G1; and • PTEN (phosphatase and tensin homologue): mutations are associated with Cowden syndrome and other hamartomatous disorders. All of these are abnormally expressed in gliomas. Repair/stability genes normally function by repairing DNA damage–mismatch repair, nucleotide excision repair and base excision repair. Under normal conditions, DNA damage is kept to a minimum, but loss of function results in accumulation of DNA mutations and eventually tumour formation. Mutations in oncogenes, tumour suppressors and repair/stability genes can occur in the germ line, resulting in hereditary tumour syndromes or in somatic cells, causing sporadic tumours. The initial event in the neoplastic process is a single somatic mutation resulting in a growth advantage of a clonally expanding cell population. Additional mutations then accrue and cause further series of clonal expansions, eventually resulting in a tumour. The cell cycle is controlled by a cascade of genes, which may either promote or suppress it: for example, mutations of cdk4 and cyclin D1 in the Rb pathway are oncogenic, i.e. activating, while mutations of Rb and p16, both tumour suppressor genes, lead to inactivation. Hence, the combinations of these mutations result in activation of the same pathway. However, despite the detailed knowledge of pathway function, it still remains unclear what eventually determines the phenotype of a brain tumour – is it the initial mutation, the sequence of subsequent mutations or the differentiation state of the cell in which the initial genetic event occurs? As a corollary of this complexity and multiplicity of mutations in an advanced tumour, it is impossible to track back to the primary event. Hence, in vivo models are needed in which

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specific pathways in stem cells can be altered to study the genotype–phenotype correlation of brain tumours.

WHO classification of CNS tumours Most brain tumour classifications are based on the work of Bailey and Cushing (1926) who named tumours after the cell type in the developing embryo, fetus or adult that most resembled the tumour histologically. The classification system most widely accepted is that of the World Health Organization (WHO 2007) which recognizes more than 120 different tumour types, and is shown in Table 20.1.

Neuroepithelial tumours Neuroepithelial tumours form the vast majority of intrinsic brain tumours and encompass a broad spectrum of neoplasms that arise from or share morphological properties of neuro-epithelial cells. Accordingly, they are further subgrouped into: • Glial neoplasms, which include astrocytic, oligodendroglial and ependymal tumours; • Tumours with predominant neuronal phenotype, such as ganglioglioma, dysembryoplastic neuro-epithelial tumour and neurocytoma; • Neuroblastic tumours; • Pineal tumours; • Embryonal tumours such as medulloblastoma; and • Choroid plexus tumours. The grading of gliomas and other tumours in the WHO scheme is based on the presence of certain morphological characteristics within the tumour: cellular and nuclear atypia, mitotic activity, vascular endothelial proliferation and necrosis. These features reflect the malignant potential of the tumour in terms of invasion and growth rate. Tumours without any of these features are WHO Grade I; those with atypia alone are WHO Grade II. Those tumours with atypia and mitosis are WHO Grade III and those with vascular proliferation or necrosis or both are WHO Grade IV. Grade I and II tumours are termed low grade and Grade III and IV tumours high grade. In one subset of astrocytomas the usual four-featured grading system is not used, because of their distinctive cell appearance. Tumours in this subset may have endothelial proliferation and marked atypia; nevertheless, they are slow growing, well circumscribed and thus low grade: • Juvenile pilocytic astrocytoma; • Pleomorphic xantho-astrocytoma; and • Subependymal giant-cell astrocytoma. Plates 20.1 and 20.2 illustrate the histological features of some common tumours. Astrocytomas Astrocytic tumours comprise a wide range of neoplasms differing in their location, age distribution, biology and clinical course. The most common are the astrocytomas, subdivided into WHO Grades I–IV:

Neuro-Oncology Table 20.1 WHO 2007 classification of nervous system tumours (grades I, II, III, IV). TUMOURS OF NEUROEPITHELIAL TISSUE A. Astrocytic tumours i. Pilocytic astrocytoma (I) pilomyxoid astrocytoma (II) ii. Subependymal giant cell astrocytoma (I) iii. Pleomorphic xanthoastrocytoma (II) iv. Diffuse astrocytoma (II) fibrillary astrocytoma, gemistocytic astrocytoma protoplasmic astrocytoma v. Anaplastic astrocytoma (III) vi. Glioblastoma (glioblastoma multiforme, grade IV) giant cell glioblastoma, gliosarcoma vii. Gliomatosis cerebri B. Oligodendroglial tumours i. Oligodendroglioma (II) ii. Anaplastic oligodendroglioma (III) C. Mixed gliomas (oligoastrocytic tumours) i. Oligoastrocytoma (II) ii. Anaplastic oligoastrocytoma (III) D. i. ii. iii. iv.

Ependymal tumours Subependymoma (I) Myxopapillary ependymoma (I) Ependymoma (II) cellular, papillary, clear cell, tanycytic Anaplastic ependymoma (III)

E. Choroid plexus tumours i. Choroid plexus papilloma (I) ii. Atypical choroid plexus papilloma (II) iii. Choroid plexus carcinoma (III) F. Other neuroepithelial tumours i. Astroblastoma ii. Chordoid glioma of 3rd ventricle (II) iii. Angiocentric glioma (I) G. Neuronal and mixed neuronal–glial tumours i. Dysplastic gangliocytoma of cerebellum (Lhermitte–Duclos disease, grade I) ii. Desmoplastic infantile astrocytoma/ ganglioglioma (I) iii. Dysembryoplastic neuroepithelial tumour (I) iv. Gangliocytoma (I) v. Ganglioglioma (I, II) vi. Anaplastic ganglioglioma (III) vii. Central neurocytoma (II) viii. Extraventricular neurocytoma (II)

ix. x. xi. xii.

Cerebellar liponeurocytoma (I, II) Papillary glioneuronal tumour (I) Rosette-forming glioneuronal tumour of 4th ventricle (I) Paraganglioma (I)

H. Tumours of the pineal region i. Pineocytoma (I) ii. Pineal parenchymal tumour of intermediate differentiation (II, III) iii. Pineoblastoma (IV) iv. Papillary tumour of the pineal region (II, III) I. Embryonal tumours i. Medulloblastoma (IV) desmoplastic/nodular medulloblastoma, medulloblastoma with extensive nodularity, anaplastic medulloblastoma, large cell medulloblastoma ii. CNS primitive neuroectodermal tumour (IV) CNS neuroblastoma, CNS ganglioneuroblastoma, medulloepithelioma, ependymoblastoma iii. Atypical teratoid/rhabdoid tumour (IV) TUMOURS OF CRANIAL & PARASPINAL NERVES Schwannoma (I) cellular, plexiform, melanotic Neurofibroma (I) plexiform Perineurioma perineurioma (NOS, I–III), malignant perineurioma (II-IV) Malignant peripheral nerve sheath tumour (MPNST, II–IV) epithelioid MPNST, MPNST with mesenchymal differentiation, melanotic MPNST, MPNST with glandular differentiation TUMOURS OF MENINGES A. Tumours of meningothelial cells i. Meningioma meningothelial (I), fibrous (fibroblastic, I), transitional (mixed, I), psammomatous (I), angiomatous (I), microcystic (I), secretory (I), lymphoplasmacyte-rich (I), metaplastic (I), chordoid (II), clear cell (II), atypical (II), papillary (III), rhabdoid (III), anaplastic (malignant, III) B. Mesenchymal tumours (I–IV) i. Lipoma ii. Angiolipoma

iii. iv. v. vi. vii. viii. ix. x. xi. xii. xiii. xiv. xv. xvi. xvii. xviii. xix. xx. xxi. xxii. xxiii.

Hibernoma Liposarcoma Solitary fibrous tumour Fibrosarcoma Malignant fibrous histiocytoma Leiomyoma Leiomyosarcoma Rhabdomyoma Rhabdomyosarcoma Chondroma Chondrosarcoma Osteoma Osteosarcoma Osteochondroma Haemangioma Epithelioid haemangioendothelioma (II) Haemangiopericytoma Anaplastic haemangiopericytoma (III) Angiosarcoma Kaposi’s sarcoma Ewing’s sarcoma – PNET

C. Primary melanocytic lesions Diffuse melanocytosis, melanocytoma, malignant melanoma, meningeal melanomatosis D. Other neoplasms related to the meninges Haemangioblastoma (I) LYMPHOMAS AND HAEMATOPOIETIC NEOPLASMS Malignant lymphomas, plasmacytoma, granulocytic sarcoma GERM CELL TUMOURS Germinoma Embryonal carcinoma Yolk sac tumour Choriocarcinoma Teratoma mature, immature, teratoma with malignant transformation Mixed germ cell tumour TUMOURS OF THE SELLAR REGION Craniopharyngioma (I) adamantinomatous, papillary Granular cell tumour (I) Pituicytoma (I) Spindle cell oncocytoma of adenohypophysis (I) METASTATIC TUMOURS (IV)

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Pilocytic astrocytoma (WHO Grade I); Diffuse astrocytoma (WHO Grade II); • Anaplastic astrocytoma (WHO Grade III); and • Glioblastoma multiforme (GBM; WHO Grade IV). Diffuse astrocytomas (WHO Grade II) tend to develop within the cerebral hemispheres, especially in the frontal and temporal lobes. This tumour with its subtypes fibrillary, gemistocytic, i.e. large swollen cytoplasm and the very rare protoplasmic variant, is a slowly growing tumour that typically affects young adults and has an intrinsic tendency to progress into higher grades (WHO Grades III and IV). This process, known as malignant transformation, distinguishes WHO Grade II tumours from WHO Grade I tumours with more stable histology which have a considerably better prognosis. The characteristic morphology of the cells of WHO Grade II astrocytomas resembles well-differentiated astrocytes, embedded in a fibrillary or microcystic matrix. Mitotic activity is typically absent and there is no microvascular proliferation or necrosis. The gemistocytic subtype is particularly prone to progress to high-grade glioma. The high-grade anaplastic astrocytoma (WHO Grade III) shows an infiltrative behaviour with focal or generalized increase in proliferative potential. These tumours may progress from a low-grade astrocytoma but they are also seen at first biopsy without evidence for an underlying low-grade lesion. Compared with WHO Grade II astrocytomas, anaplastic astrocytomas are characterized by increased cellularity, higher mitotic activity, more distinct nuclear atypia but no necrosis or vascular proliferation. They also have an intrinsic propensity to progress to GBM. GBM is the most frequent malignant primary CNS tumour, accounting for about 30% of all primary brain tumours and 60% of all gliomas. This highly malignant astrocytic tumour preferentially affects older adults (peak incidence 60–70 years) and arises in the cerebral hemispheres, most commonly temporal, parietal and frontal lobes. Typical histological features include poorly differentiated, often highly pleomorphic glial tumour cells with marked nuclear atypia and brisk mitotic activity. Necrosis and/or microvascular proliferation are essential for diagnosis and in most cases both are present. GBM can vary considerably in their histological appearance, ranging from highly cellular and monotonous to very variable and heterogeneous. This may present a challenge when histological diagnosis is based on small needle biopsies. Genetic studies suggest that primary (de novo) and secondary (evolving from low-grade gliomas by multi-step progression) GBM are different entities. Primary GBMs arise in older patients and are strongly associated with amplification and overexpression of the epidermal growth factor receptor gene (EGFR), and show increased murine double minute 2 promoter (MDM2) oncogene activity, while secondary GBMs arise from previous low-grade gliomas, occur in younger individuals and are associated with early p53 loss and over-expression of platelet-derived growth factor gene (PDGF). Both primary and secondary GBMs •

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show frequent loss of the phosphatase and tensin homologue (PTEN) gene.

Other astrocytic tumours Pilocytic astrocytomas (WHO Grade I) are most common in children but also occur in young adults. They have a predilection for the cerebellum. They also occur in locations close to the midline such as the hypothalamus, thalamus, optic chiasm and brainstem. In adults they may be also found in the cerebral hemispheres. Pleomorphic xantho-astrocytomas are found most commonly in the cerebral hemispheres, particularly within the temporal lobes. Subependymal giant cell astrocytomas occur most commonly in the lateral wall of the third ventricle, almost exclusively in patients with tuberous sclerosis. Brainstem gliomas are rare, usually occur in children and are associated with a dismal prognosis with a median survival of less than 1 year. In adults they behave typically as low-grade gliomas with median survival measured in years rather than months but occasionally present as high-grade gliomas. Optic nerve gliomas are usually pilocytic astrocytomas presenting in children. These behave indolently. In adults, however, these are highly aggressive tumours associated with a survival of a few weeks.

Oligodendrogliomas These account for 10–15% of all gliomas and occur predominantly in adults. Despite their name, their origin from oligodendrocytes or their precursors has not been proven. They comprise a continuous spectrum ranging from well-differentiated tumours to highly malignant neoplasms. The WHO grading system distinguishes two malignancy grades: Grade II oligodendrogliomas are slowly growing, well-defined hemispheric tumours composed of rounded homogenous nuclei. Paraffin embedding results in a reproducible artefact, the formation of clear cytoplasm around the nuclear giving rise to a perinuclear halo, often referred to as ‘fried egg’ or ‘honeycomb’ cells. Further typical features are branching capillaries and calcification. High-grade features are increased tumour cell density, mitotic activity, presence of microvascular proliferation and necrosis. These are graded WHO Grade III rather than IV. Some gliomas have intermixtures of astrocytic and oligodendroglial cellular elements and are appropriately called oligoastrocytomas or mixed gliomas. Like astrocytomas and oligodendrogliomas they have a propensity to transform into high-grade gliomas.

Molecular genetics of oligodendroglioma The discovery that loss of heterozygosity (LOH) of chromosomal arms 1p and 19q in anaplastic oligodendroglioma was associated with a prolonged and durable response to chemotherapy marked

Neuro-Oncology an important step forward in the treatment of brain tumours. Numerous studies on this genotype–phenotype correlation have subsequently shown that: 1 LOH of 1p/19q occurs in about 70% of oligodendrogliomas but is rare in astrocytomas (4 mitoses per 10 high power field (HPF)), patternless growth and necrosis

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corresponding to WHO Grade II (atypical) or WHO Grade III (anaplastic meningioma), when there are greater than 20 mitoses per 10 HPF. The higher grade meningiomas have a propensity for recurrence, as one might expect. In rare cases they behave almost as aggressively as malignant gliomas. Histology of less common tumours The histological features of four less common tumours are illustrated in Plate 20.3. Clinical details are described below. The schwannoma shown in Plate 20.3 has typical arrangements of pallisading nuclei against a fibrillary background, forming socalled Verocay bodies. Around those structures are loosely textured tumour areas, so-called Antoni B areas (a). Reticulin silver stain visualize the dense pericellular basement membranes (b). S100 immunohistochemistry typically shows nuclear and cytoplasmic staining in schwannoma (c). Chordomas are characterized by chords of cells arranged against a background of myxoid stroma (d). Typical immunohistochemical profile includes positive labelling of the tumour cells with cytokeratin (e) and S100 protein (f). Lymphomas are arranged in dense patternless sheets and infiltrate adjacent brain tissue diffusely and also in characteristic peri-vascular arrangements, shown in (g). Most primary intracerebral lymphomas are of B-cell type and are positive for the B-cell marker CD20, as shown here (h). These tumours are highly malignant and exhibit a very high mitotic index; Ki67 proliferation can be as high as 90%. The lymphoma shown here has a proliferation index of approximately 50% (i). Pineoblastomas belong to the group of primitive neuroectodermal tumours and arise in the pineal region. Histological features include the formation of neuroblastic rosettes as shown in (j). In intra-operative smear preparations, these tumours typically spread out to monolayers with fine synaptic networks (k). They almost invariably express the neuronal marker synaptophysin, as shown in (l).

Imaging of common brain tumours Structural brain imaging Magnetic resonance imaging (MRI) is the preferred modality for structural imaging of brain tumours and provides better soft tissue differentiation and tumour delineation than computed tomography (CT). CT demonstrates tumour calcification better than MRI: on MRI the signal may be difficult to distinguish from intra-tumoural haemorrhage. Structural MRI of brain tumours should include T2-weighted (T2) fluid-attenuated inversion recovery (FLAIR) and T1-weighted (T1) images before and after injection of gadolinium. The general imaging and macroscopic appearance of common intracranial tumours are shown in Plates 20.4 and 20.5.

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Most tumours appear hypodense on CT, hypointense on T1 and hyperintense on FLAIR and T2 MRI. Highly cellular tumours such as lymphomas and primitive neuro-ectodermal tumours have a decreased water content and therefore appear hyperdense on CT and relatively hypointense on T2 MRI. Intra-tumoural haemorrhage and tumour calcification appear usually hypointense on T2 images and become more conspicuous on T2* gradient echo images. Hyperintensities on T1 images can be because of haemorrhage, calcification, melanin or fat. Contrast enhancement on CT or MRI is either seen in highly vascular extra-axial tumours such as meningiomas (Figure 20.1) or in intra-axial tumours disrupting the blood–brain barrier such as cerebral lymphomas (Figure 20.2). Enhancement is generally a feature of high-grade tumours such as high-grade gliomas and metastases but can also be present in certain low-grade tumours, such as pilocytic astrocytomas and WHO Grade II oligodendrogliomas. The visibility of contrast enhancement on MRI can be improved by magnetization transfer imaging, by doubling or tripling the gadolinium dose or by using high relaxivity gadolinium compounds.

Physiological imaging Diffusion-weighted imaging (DWI), perfusion-weighted imaging (PWI), MR spectroscopy (MRS) and functional MRI (fMRI) provide information about physiological and metabolic processes not seen with standard MRI. Much of the recent progress in tumour imaging is based on these physiological methods, which are now being increasingly implemented in clinical practice. More recently, CT perfusion imaging has emerged as another technique to assess the relative cerebral blood volume (rCBV) and permeability changes in brain tumours. Compared with MR perfusion techniques it brings limited diagnostic focus to the region of interest despite progress in multi-detector technology.

MR perfusion imaging Dynamic susceptibility-weighted contrast-enhanced (DSC) MRI is the most widely used technique of PWI in brain tumours and analyses a series of images acquired during the first pass of an intravenously injected bolus of gadolinium (Plate 20.6). rCBV measurement provides an indirect measure of tumour neovascularity. This correlates closely with angiographic and histological markers of tumour vascularity and the expression of vascular endothelial growth factor (VEGF). High-grade glial tumours tend to have higher rCBV values than low-grade tumours and PWI significantly increases the specificity and sensitivity of conventional MRI in the classification of gliomas. Maps of rCBV can also be a useful adjunct for stereotactic tumour biopsies, directing tissue sampling towards areas of maximal angiogenesis.

Neuro-Oncology

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(b) Figure 20.1 (a) Sagittal contrast-enhanced T1 images of a meningioma showing typical appearances of an enhancing durally based mass associated with bony hyperostosis and a dural tail sign. (b) Corresponding axial T2 images demonstrating a grey matter iso-intense mass displacing the frontal lobe with hyperostosis but no associated oedema.

Permeability imaging (Ktrans) Microvascular permeability of brain tumours can be quantified by measuring the transfer coefficient Ktrans which is influenced by endothelial permeability, vascular surface area and flow. This can be measured using a T1 steady state or a first pass T2* gradient echo technique. The former has a higher spatial resolution and is more accurate but requires longer acquisition times and more complicated post-processing; the latter can be combined with DSC perfusion imaging. Ktrans correlates with tumour grade and is probably more sensitive than rCBV measurements for glioma grading. MR diffusion imaging DWI measures Brownian motion of water molecules within tissue. Images are obtained by measuring the signal loss typically on MR T2 images following the application of diffusion gradients (Figure 20.3). The signal loss depends on several factors including the gradient strength and apparent diffusion coefficient (ADC) which describes water diffusion within tissue. The more mobile

the water molecules, the higher the ADC and the greater the signal loss on DWI. DWI are still influenced by T2 effects, which can lead to artefacts known as T2 shinethrough, whereas ADC maps provide a quantitative representation of water movement. Therefore, highly cellular tumours, e.g. lymphoma, which are associated with limited water mobility, show up as dark on ADC and bright on DWI. Visual inspection of DWI has a limited role in the diagnosis of brain tumours. However, it may be valuable to identify lesions with severely restricted diffusion, such as acute infarcts or abscesses that can occasionally mimic brain tumours on standard MRI but which appear as high-intensity lesions on DWI (Figure 20.4). ADC measurements provide more detailed information about brain tumours and have been shown to correlate with the histological cell count and with the presence of hydrophilic substances in the tumour matrix. Diffusion tensor imaging (DTI) provides additional information about the direction of water diffusion. The tendency of water to move in some directions more than others is called anisotropy and can be quantified using parameters

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such as fractional anisotropy (FA). Compact white matter tracts normally show a high degree of anisotropy which can be lost if they are infiltrated by tumour cells destroying ultrastructural boundaries. Another application of DTI is tractography, which depicts white matter tracts and their connections on

direction-encoded colour images. Tractography is useful in the pre-operative assessment of brain tumours and can differentiate between displacement and infiltration of white matter tracts.

MR spectroscopy Proton MR spectroscopy (MRS) analyses aspects of the biochemical make-up of a brain tumour and provides semi-quantitative information about major metabolites. A common pattern in brain tumours is a decrease in N-acetyl-aspartate (NAA), a neurone-specific marker, with an increase in choline (Cho), lactate and lipids. The concentration of Cho is a reflection of the turnover of cell membranes and is more elevated in regions with a high neoplastic activity (Figure 20.5). Lactate is the end product of nonoxidative glycolysis and a marker of hypoxia in tumour tissue, now recognized as a major promoter of tumour angiogenesis and invasion. Lactate probably indicates viable but hypoxic tissue, whereas mobile lipids reflect tissue necrosis and breakdown of cell membranes. MRS with a short echo times (20–40 ms) can demonstrate additional metabolites, such as myoinositol, glutamate and/or glutamine and mobile lipids but is hampered by baseline distortion and artefactual NAA peaks. Chemical shift imaging (CSI) or MRS provides spectral information across a whole tumour region and has been used to inform surgical biopsy targets.

Figure 20.2 Contrast-enhanced computed tomography (CT) of a patient with cerebral lymphoma demonstrating an enhancing mass infiltrating the genu and splenium of the corpus callosum.

Functional MRI Blood oxygen level-dependent (BOLD) imaging detects changes in regional cerebral blood flow during various forms of brain activity (Chapter 3). Paradigms using motor tasks, language and speech production and memory are able to show recruitment of activation within relevant cortical areas. The main use of fMRI in tumour imaging is the pre-operative localization of eloquent cortical regions Plate 20.7 which may have been displaced,

Figure 20.3 Diffusion-weighted images of a frontal low-grade glioma. With increasing diffusion weighting (higher b values) progressive signal loss occurs, first in areas of high water mobility, such as cerebrospinal fluid (CSF) and subsequently also in the tumour.

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Figure 20.4 (a) T2 image of a cystic high-grade glioma with a hyperintense centre, irregularly thickened rim and vasogenic oedema. (b) The diffusion-weighted image shows loss of signal in the central portion, typical of a necrotic centre in a cystic neoplasm. (c) T2 image of another, undiagnosed cystic frontal lobe mass lesion with a hyperintense centre and surrounding vasogenic oedema. (d) Diffusion-weighted image shows markedly restricted diffusion in this case, typical of an abscess confirmed at biopsy. (e) On the corresponding ADC map the abscess cavity appears dark and vasogenic oedema appears bright.

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matter and have less well-defined borders than pilocytic astrocytomas. Mass effect is variable and contrast enhancement usually absent. They appear isodense or hypodense on CT which shows areas of calcification in up to 20%. On MRI, diffuse astrocytomas are hypointense or isointense on T1 images and hyperintense on T2 and FLAIR images, which provide the best contrast between tumour and normal brain tissue (Figure 20.7). WHO Grade II astrocytomas show a low mitotic activity but have a propensity to progress to a higher histological grade, as suggested by the development of new gadolinium enhancement (Figure 20.7d).

Anaplastic astrocytomas Anaplastic astrocytomas (WHO Grade III) are high-grade gliomas which usually show contrast enhancement and more extensive infiltration of the peri-tumoral tissues than WHO Grade II lesions. They may also be accompanied by vasogenic oedema. In many cases, however, it is not possible to distinguish radiologically between Grade II and Grade III tumours, i.e. the absence of enhancement does not rule out a high-grade tumour.

(e) Figure 20.4 Continued

distorted or compressed by the tumour. This can both improve the safety of surgery and allow for a more radical resection. Ideally, fMRI should be combined with MR tractography in order to minimize intra-operative injury to white matter tracts connected to eloquent cortical areas.

Imaging of neuroepithelial tumours The focus here is on the imaging appearances of the more common brain tumours.

Pilocytic astrocytomas Pilocytic astrocytomas, the most common WHO Grade I astrocytomas, are well-circumscribed, potentially resectable lesions with a low proliferative potential and a predilection for the posterior fossa, optic nerves and hypothalamus. Pilocytic atrocytomas usually have a significant cystic component and show mural enhancement which can be nodular or ring-like (Figure 20.6). Infratentorial pilocytic astrocytomas in adults may be mistaken for haemangioblastomas. Diffuse astrocytomas Diffuse astrocytomas (WHO Grade II) typically occur in the cerebral hemispheres of young adults, involve cortex and white

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Pleomorphic xanthoastrocytomas Pleomorphic xanthoastrocytoma (WHO Grade II or III) is an astrocytic tumour that arises near the surface of a cerebral hemisphere and is frequently cystic. The tumour may enhance strongly and is usually associated with little or no oedema. Despite its fat content, it is T1-hypointense and T2-hyperintense on MRI. Glioblastoma multiforme Glioblastoma multiforme (GBM; WHO Grade IV) is a poorly differentiated, highly pleomorphic tumour with vascular proliferation and necrosis. Vasogenic oedema and contrast enhancement are more extensive than in anaplastic (WHO Grade III) astrocytomas. Tumour necrosis appears as intra-tumoural areas of approximately CSF signal intensity, frequently surrounded by irregularly enhancing regions of active mitosis (Figure 20.8). Intra-tumoural haemorrhage with T1 hyperintense and T2 hypointense areas contributes to the heterogeneous MR appearance of GBMs. Oligodendrogliomas Oligodendrogliomas (WHO Grades II and III) are diffusely infiltrating neoplasms found almost exclusively in the cerebral hemispheres, most commonly in the frontal lobes and typically involving subcortical white matter and cortex. Both low- and high-grade oligodendroglial tumours express pro-angiogenic mitogens and may contain regions of increased vascular density with finely branching capillaries which have a chickenwire appearance seen on contrast-enhanced MRI and PWI. Up to 90% of oligodendrogliomas contain calcification visible on CT, central, peripheral or ribbon-like. Contrast enhancement is variable and often heterogeneous. It is a much less reliable indicator of tumour grade than in astrocytic tumours.

Neuro-Oncology

Choline

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(c) Figure 20.5 (a) Single voxel MR spectroscopy of a temporal lobe tumour demonstrating region of interest. (b) Initial MR spectrum of a low-grade primary tumour showing a high choline : creatine ratio. (c) MR spectrum 6 months later, following transformation into a high-grade tumour shows a further increase in the choline peak compared to the baseline study (from 1.6 to 3.1 mmol/L).

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values. Measurement of the ADC, using a whole tumour histogram analysis, appears promising for the differentiating between astrocytomas and oligodendrogliomas. The latter have significantly lower ADC values than astrocytomas (Plate 20.8 and Figure 20.9), reflecting a higher cellular density and differences in tumour matrix composition. Distinguishing between low-grade and high-grade gliomas Advanced MRI can help distinguish between low-grade and highgrade gliomas. Formation of new blood vessel (angiogenesis) represents an important aspect of glial tumour progression and mean maximum rCBV values correlates closely with histological grades. PWI is also valuable (Plate 20.9) DWI can be disappointing in helping to differentiate high-grade from low-grade gliomas (Figures 20.10 and 20.11).

Figure 20.6 Contrast-enhanced T1 image of an adult patient with a pilocytic astrocytoma showing a cystic lesion with a small enhancing mural nodule anteromedially.

Oligodendrogliomas with intact 1p/19q (see above) tend to have a more homogenous signal on T1 and T2 images with sharper borders than tumours with 1p/19q deletions.

Ependymomas Ependymomas (WHO Grades II and III) in the brain are usually intraventricular, although extraventricular rests of ependymal cells may also give rise to hemisphere tumours. They are welldemarcated lobulated mass lesions with calcification on CT in over 50% and mixed signal intensity on MRI (predominantly hyperintense on T2 and isointense to hypointense on T1 images). Enhancement is mild to moderate and often heterogeneous. Physiological imaging and grading of glial tumours Distinguishing between astrocytomas and oligodendrogliomas PWI and DWI can help to differentiate between low-grade astrocytic and oligodendroglial tumours. WHO Grade II oligodendrogliomas have significantly higher rCBV than WHO Grade II astrocytomas with median values of 3.68 versus 0.92, respectively, which concurs with the histological findings of increased vascular density in oligodendrogliomas (Plate 20.8). In addition, rCBV of oligodendrogliomas appears dependent on their genotype, the loss of 1p/19q being associated with significantly higher rCBV

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Physiology-based MRI of peri-tumoural tissue Investigation of peri-tumoural regions with physiology-based MR techniques may be of similar importance to the radiological assessment of the tumour itself. Differences in the peri-tumoural tissues of low-grade and high-grade gliomas have been demonstrated with DWI, PWI and MRS. The peri-tumoural regions of high-grade gliomas show a more marked decrease in ADC, FA and NAA and increase in rCBV compared to low-grade tumours. This is a reflection of the more invasive nature of these tumours which infiltrate the adjacent brain tissue along vascular channels leading to an increase in rCBV, destroy ultrastructural boundaries to produce a decrease both in ADC and FA and replace normal brain tissue with a corresponding fall in NAA. Metastases, on the other hand, are surrounded by pure vasogenic oedema that contains no infiltrating tumour cells. Peri-tumoural regions in metastases typically show neither increase in rCBV nor decrease in FA.

Tumours of predominantly neuronal cell origin Gangiogliomas and gangliocytomas Gangiogliomas and gangliocytomas (WHO Grade I) are slowgrowing tumours that grow preferentially within the temporal lobes of children and young adults. CT and MRI show peripherally located mixed solid and/or cystic lesions that commonly calcify. Enhancement can be variable and is often peripheral. Central neurocytomas Central neurocytomas (WHO Grade I) occur predominantly in the second and third decades of life and are the most common masses within the lateral ventricles in this age group. They typically arise from the septum pellucidum and occupy the frontal horns and bodies of the ventricles and sometimes extend through the foramen of Monro. Obstructive hydrocephalus is common. CT frequently demonstrates calcification and small cysts. MRI shows a heterogeneously enhancing mass with septated cysts and isointense grey matter nodules with susceptibility artefact from calcification.

Neuro-Oncology

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Figure 20.7 (a) FLAIR image of a WHO Grade II astrocytoma presenting as well-demarcated hyperintense temporal lobe mass containing small cysts. (b) Corresponding contrast-enhanced T1 image does not demonstrate any pathological enhancement. (c) 12 months’ follow-up FLAIR image demonstrates tumour enlargement with disappearance of cystic elements. (d) 12 months’ follow-up contrast-enhanced T1 image: pathological enhancement at the inferior aspect of tumour. Repeat biopsy confirmed progression to WHO Grade III astrocytoma.

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0.4 Astrocytoma Oligodendroglioma Normal appearing white matter

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Figure 20.9 Whole tumour ADC histograms of a low-grade astrocytoma and a low-grade oligodendroglioma. Both have higher ADC values than normal white matter. Histogram of the oligodendroglial tumour is shifted to the left compared to histogram of the astrocytic tumour, indicating overall lower ADC values in the former.

Figure 20.8 Right, deep temporal glioblastoma multiforme (MR T1W).

Dysembryoplastic neuroepithelial tumours Dysembryoplastic neuroepithelial tumours (DNET) are WHO Grade I and usually located in the cerebral cortex. Intractable complex partial seizures are common. On CT, DNET are usually hypodense. On MRI they are T1-hypointense and T2hyperintense. Small intra-tumoural cysts may cause a bubbly appearance; calcification is seen in about 25% and enhancement is uncommon. Thinning of the overlying bone is present in approximately half of the cases, reflecting the extremely slow growth of these tumours which allows bone remodelling to occur (Figure 20.12). Choroid plexus tumours Choroid plexus tumours are either WHO Grade I or III, i.e. papillomas or carcinomas. Choroid plexus papillomas are much more common than carcinomas. The location and incidence of choroid plexus papillomas varies with age. They are more common in childhood, presenting as a cauliflower-like mass in the trigone of the lateral ventricle. In adults, papillomas occur predominantly in the fourth ventricle. CT shows an isodense to hyperdense mass with punctate calcification and homogenous enhancement. On MRI the papillomas appear as lobulated, intraventricular masses of heterogeneous, predominantly intermediate signal intensity on T1 and T2 images with intense contrast enhancement. Medulloblastomas and other primitive neuro-ectodermal tumours WHO Grade IV tumours of neuro-ectodermal origin include medulloblastomas and other primitive neuro-ectodermal tumours

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(PNETs). Medulloblastomas usually arise in the cerebellar midline in children and the cerebellar hemispheres in adults. In contrast, PNETs are usually supratentorial. The high nuclear : cytoplasmic ratio of both these tumours is responsible for their hyperdense appearance on CT and hyperintense appearance on DW images. A three- to fourfold elevation of Cho and lipid on MRS is caused by their intense cellularity and cell turnover. PNETs enhance and have a propensity for dissemination in the subarachnoid space with leptomeningeal deposits. Staging of these tumours requires contrast-enhanced MRI of the entire neuraxis.

Primary CNS lymphomas PCNSL usually presents as a single, lobulated enhancing mass, often abutting an ependymal (Figure 20.2) or meningeal surface. Occasionally, PCNSL are multiple. Enhancement is uniform in immunocompetent patients but tends to be ring-like in immunocompromised patients because of areas of central necrosis. The high cellular density of PCNSL accounts for its hyperdensity on CT and hypointensity on T2 MRI. The ADC of PCNSL is lower than in gliomas or toxoplasmosis which is an important differential diagnosis in immunocompromised patients (Figure 20.13). PCNSL grows in an angiocentric fashion around existing blood vessels without extensive new vessel formation. PWI therefore shows only a modest increase in rCBV, much less marked than in high-grade gliomas where angiogenesis is a prominent feature. Metastases Brain metastases most commonly arise from carcinoma of the lung, breast and malignant melanoma. Most metastases enhance strongly with contrast media, either uniformly or they are seen as ring-like structures if the metastasis has outgrown its blood supply. Metastases are frequently associated with vasogenic oedema, often disproportionate to the size of the tumour.

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(c) Figure 20.10 (a) T2 image of a homogeneously appearing right frontal low-grade astrocytoma. (b) The tumour is not very conspicuous on diffusion-weighted images as diffusion and T2 effects cancel each other out (T2 masking). (c) Tumour becomes very conspicuous on the ADC map because of its relatively increased water diffusivity. Overall appearance on the ADC map is also homogeneous.

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(c) Figure 20.11 (a) T2 image of a high-grade anaplastic astrocytoma with a heterogeneous appearance. Note enlarged vessels at posterior aspect of mass. (b) Diffusionweighted image shows a peripheral hyperintense rim, confirmed to be of restricted diffusion on the ADC map with a cystic necrotic centre. (c) ADC map confirms a centre of increased diffusivity (bright) and rim of decreased diffusivity (dark) as well as surrounding oedema (bright).

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(a) Figure 20.12 (a) T2 image of right parietal hyperintense mass that proved to be a dysembryoblastic neuroepithelial tumour (DNET). (b) Coronal FLAIR image shows cystic components within DNET with scalloping of inner table of the skull, indicating slow growth of this neoplasm.

Haemorrhage occurs in about 10% of metastases, resulting in high signal on T1 images and low signal on T2 images. Similar signal characteristics can also occur in non-haemorrhagic metastases from melanoma, because of the paramagnetic properties of melanin. Increasing the dose or relaxivity of gadolinium compounds can improve the sensitivity for detection of metastases on MRI. DWI may help to predict the histology of brain metastases. Small cell lung cancer metastases and neuro-endocrine metastases have a lower ADC than adenocarcinoma metastases and appear bright on DWI (Figures 20.14 and 20.15). PWI and MRS of the peri-tumoural rather than intra-tumoural region help to differentiate a single metastasis from a high-grade glioma. DWI is helpful in distinguishing cystic metastases from cerebral abscesses. The latter contain more viscous fluid and pus; they show a more marked restriction of water diffusion than necrotic tumours.

Extra-axial tumours Meningiomas Meningiomas (WHO Grades I–III) can be spherical and wellcircumscribed, craggy and irregular or flat, infiltrating en plaque lesions. They arise within the parasagittal area, convexities, sphenoid wing, tuberculum sellae, olfactory groove, tentorium and foramen magnum. Spinal meningiomas usually arise dorsally in the thoracic spine almost exclusively in women. On CT 60% of

meningiomas are hyperdense without contrast and some 20% contain calcification. Hyperostosis, best seen on bone window settings indicates the site of the tumour attachment to the meninges. On MRI, meningiomas appear frequently isointense to cerebral cortex on both T1 and T2 images and may occasionally be difficult to detect without IV contrast. They can have capping cysts of CSF signal intensity. Associated vasogenic oedema is not infrequent and often disproportionate to tumour size. Meningiomas enhance vividly and homogeneously. Linear enhancement can extend along the adjacent dura mater (Figure 20.1). This sign, known as the dural tail, was once thought to be pathognomonic for meningioma but can also be seen with other tumours such as schwannomas or even metastases. DWI helps to distinguish between typical (WHO Grade I) and atypical (WHO Grade II) meningiomas; the latter having lower ADC values. MRS may show an alanine peak, characteristic for meningioma but seen in less than 50% of cases. PWI of meningiomas shows typically a markedly elevated rCBV, which can be of help in differentiating these benign tumours from dural metastases which tend to have a lower rCBV.

Epidermoid and dermoid tumours (WHO Grade I) Intracranial dermoid cysts lie usually near the midline and contain all skin elements, including fat, which appears as very low density on CT and high signal intensity on MR T1 images.

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(c) Figure 20.13 (a) Axial T2 image in a patient with cerebral lymphoma: hypointense mass lesions and extensive temporal lobe peri-ventricular oedema. (b) Contrastenhanced T1 image shows enhancing masses and irregular subependymal enhancement. (c) Enhancing lesions appear dark on ADC map, in keeping with a highly cellular neoplasm and typical of lymphoma. Surrounding oedema appears bright.

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(c) Figure 20.14 (a) Contrast-enhanced T1 image of a left frontal metastasis from a squamous cell bronchial carcinoma. (b) Diffusion-weighted image shows a relatively hypointense mass. (c) ADC map confirms increase water diffusivity within the tumour (bright), a feature of squamous cell carcinoma.

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(c) Figure 20.15 (a) Contrast-enhanced T1 image of a right parietal metastasis from a small cell lung carcinoma. (b) Mass appears markedly hyperintense on diffusionweighted image. (c) ADC map confirms decreased water diffusivity within the tumour (dark), consistent with a highly cellular metastasis.

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Figure 20.16 (a) T2 image of an extensive epidermoid tumour spreading through the basal cisterns and invading the temporal lobes. (b) Diffusion-weighted image of the epidermoid tumour: characteristically bright and well delineated from surrounding CSF and brain parenchyma.

Epidermoid cysts, formerly known as pearly tumours, grow slowly over many years by accumulating desquamated epithelium. They conform to the contour of the subarachnoid space they occupy, sometimes invaginating into the brain parenchyma. On CT and standard T1 and T2 MRI, epidermoid cysts are nonenhancing lesions of signal intensity to cerebrospinal fluid (CSF), a reason why they can be confused with arachnoid cysts. DWI easily distinguishes epidermoid tumours from arachnoid cysts, as water diffusion is markedly restricted in the former but not in the latter (Figure 20.16).

Monitoring tumour growth and response to treatment Change in tumour size has in the past been the most important imaging criterion for the evaluation of treatment response. Many treatment protocols for solid tumours recommend unidimensional or bi-dimensional measurements of tumour size. Volumetric (three-dimensional) tumour measurements are better predictors of patient survival than linear or two-dimensional tumour measurements. Volumetric contrast-enhanced T1 images are valuable in any serial imaging protocol that aims to assess tumour progression or treatment response. Parameters detectable with physiological MRI have an increasing role in monitoring disease progression and early effects of treatment. This pertains particularly to measurements of rCBV

and Ktrans. The strength of these perfusion techniques lies in their ability to detect changes within internal tumour architecture in the absence of or prior to an overall change in tumour size. Serial PWI of conservatively treated low-grade gliomas show an increase in rCBV 12 months before visible tumour enhancement, the conventional marker of tumour progression. PWI and permeability measurements have also been used to monitor antiangiogenic therapy. A significant fall in rCBV was observed in one study some 2 months after combination antiangiogenic and carboplatin therapy but not after carboplatin alone. Measurements of rCBV also correlate better with clinical status than conventional MRI. PWI has also demonstrated a significant reduction of rCBV in enhancing cerebral mass lesions treated with dexamethasone, an important fact to consider when comparing different treatment regimens. Surgical treatment can be rendered more efficient with intraoperative MR brain imaging. The technique can be used to check for residual tumour following initial resection. This has been shown to increase the extent of complete tumour removal compared with neuro-navigation alone.

Imaging appearances of complications of treatment Radiotherapy The effect of radiation on the brain has a time-dependent course, with a distinction between acute, early-delayed and late-delayed

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(c) Figure 20.17 (a) T2 MR in a 6-week-old child following intrathecal methotrexate for acute lymphoblastic leukaemia (ALL) shows very subtle signal increase in parietal white matter. (b) Diffusion-weighted images show much more conspicuous increase of signal intensity in the posterior part of the centrum semiovale. (c) ADC map confirms restricted diffusion in the posterior white matter, a feature of methotrexate toxicity, potentially reversible.

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Neuro-Oncology radiation injury (Chapter 18). Severity depends on the total radiation dose, individual fraction size and volume of brain irradiated. Imaging is especially helpful in the diagnosis of late-delayed radiation-induced leucoencephalopathy and radiation necrosis. Radiation-induced leucoencephalopathy Radiation-induced leucoencephalopathy is a late-delayed demyelinating process that involves the peri-ventricular region and can extend into the juxtacortical region in more severe cases. On MRI it appears as non-enhancing, confluent, usually symmetrical areas of T2 hyperintensity, typically 6 months or more following radiotherapy. Radiation necrosis Radiation necrosis is also a late-delayed complication of radiotherapy and radiosurgery, which can appear similar to an enhancing mass lesion and thus be difficult to distinguish from recurrent tumour on conventional imaging. PWI and DWI may help to distinguish between radiation necrosis and tumour recurrence (Plate 20.10). In radiation necrosis the enhancing lesion has a low rCBV, whereas this tends to be high in tumour recurrence as a consequence of increased new vessel formation. ADC measurements of the enhancing components in recurrent tumour are significantly lower than in radiation necrosis, mirroring the higher cellular density in recurrent neoplasm. Other complications Optic neuropathy is most commonly seen following radiotherapy of sellar and parasellar lesions and is a late-delayed complication of radiotherapy, with T2 hyperintense signal change typically in the intracranial portion of the optic nerve. Meningiomas are the most commonly encountered radiationinduced tumours, with typical latency periods over 10 years. Gliomas and schwannomas are also seen, developing many years after radiotherapy. Radiation-induced cavernomas are more common than previously assumed; their detection rate is significantly increased with the use of haemorrhage-sensitive gradient echo MR sequences.

Chemotherapy A large number of chemotherapeutic agents are neurotoxic. Combining chemotherapy and radiotherapy can result in additive and synergistic effects. The most frequent imaging findings are posterior leucoencephalopathy (Chapters 18 and 19), with bilateral, typically symmetrical white matter lesions of low density on CT but T2-hyperintense on MRI. These are most commonly seen following methotrexate, even when given alone. In the acute stage abnormalities may be undetectable on T2 images and only become apparent on DWI and ADC maps (Figure 20.17).

oncology, specialist nursing, general practice and palliative care. Within the last decade a further dimension has been clearly defined – an approach that unites these disciplines into therapy that is focused on improving the quality of life, with greater involvement of both patient and carers in the therapeutic process. There are decisions to be made about diagnoses of the utmost gravity. One significant advance, sometimes painful to all, is to discuss frankly the probable prognosis, the limited choice of therapy available and the uncertainty of outlook in an individual case.

Improving outcomes and quality of life The impact of a diagnosis of a brain tumour upon a person’s life is profound and multi-faceted. Patients experience both physical effects of the tumour and side effects of treatment. They and their carers have to cope with the emotional impact and psychological effects of living with a life-threatening illness. The diagnosis is likely to be the major life event to date and to colour every aspect of the remaining months or years. Cognitive deficits, of memory, speech and language, behavioural changes and physical decline combine to produce a formidable burden. When cognitive problems are prominent, recovery from or preservation of cognitive function has been shown to be, in the main, more important to patients than loss of physical function. To plan treatment and gain consent from patients with cognitive impairment is difficult. Progressive cognitive decline presents a continuing challenge for patients, carers and all involved in providing care. Multi-disciplinary working is essential to improving outcomes for these patients, providing access to specialist services though collaboration between neurosurgery, radiotherapy, oncology and community teams. The ideal model of service provision promotes a unified care pathway, incorporating physical, psychological, supportive and palliative care for patients and carers. There is no doubt that quality of life can be enhanced by skilled key workers, good communication with patients and carers, access to high-quality information, specialist rehabilitation, supportive and palliative care. Above all, patient and carer need a central point of contact and a scheme for action in emergencies and for intercurrent problems. The development of charitable support networks has helped towards providing nonhospital based support for patients, families and carers. It is often the neuro-oncology clinical nurse specialist who has a primary role in providing information, advice and support to patients and carers at the time of diagnosis, during treatment and disease progression and facilitates continuity of care across the disciplines involved.

Management in a multi-disciplinary setting

Surgical management of brain and spinal tumours

The management of benign or malignant brain tumours has long been known to require the disciplines of clinical neurology, neuroradiology, neuropathology, neurosurgery, radiotherapy,

Surgery remains the mainstay of treatment for brain tumours, ranging from stereotactic biopsy to open craniotomy and resection of tumour. The overall goals of surgery are to obtain

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a histological diagnosis, relieve mass effect and improve focal neurological deficit, and the ultimate goal to allow for cure of the tumour. More often than not however, surgery only offers theoretical improvement in response to adjuvant therapy. Over the last decade neurosurgery, in particular for brain tumours, has benefited significantly from technological advances. Neuro-navigation guided biopsy and surgical resection, awake craniotomies using neurophysiological monitoring together with cortical mapping, microsurgical techniques combined with minimally invasive neuro-endoscopy and intra-operative real-time neuroimaging have made a significant impact on the outcome of surgery and patient morbidity and mortality.

General principles The neurosurgical techniques used for brain tumours include image-directed biopsy, either by frame-based, stereotactic methods or by frameless methods using neuro-navigation techniques, with craniotomy for partial or gross total tumour resection. In addition, specific subspecialty tumour surgery include skull base, pituitary and sellar tumours, which have all benefited from use of neuro-endoscopy and allowed for extensive operative techniques to be converted to minimally invasive surgery, with significantly lower morbidity and mortality. With all tumours, total macroscopic excision is the surgical aim, but this is only realistic in a limited proportion, given the high eloquence of brain structure. Tumours frequently either infiltrate eloquent brain anatomy or are intimately involved with very sensitive anatomical structures such as the optic nerve, cavernous sinus or the petro-clival region. Complete resection is commonly possible with extra-axial tumours, in particular meningiomas or sometimes metastatic tumours, but rarely possible with intrinsic tumours. The most difficult of this category are the low-grade gliomas, given the extensive invasive nature often into eloquent cortical structures. Tumours of the middle and posterior skull base require highly specialized surgical avenues such as trans-oral, maxillotomy, retro- or trans-labrynthine routes to make access possible, while avoiding injury to critical neural structures, e.g. specific cranial nerves and sensitive vascular anatomy.

Surgical instrumentation and methods Stereotactic frames A large variety of CT and MRI compatible stereotactic frames are available which can be rigidly applied to the patient’s head for surgical biopsy by pins affixed to the outer table of the skull. Frame-based stereotactic biopsy renders an accuracy of about 1–2 mm, with the most accuracy achieved for deep-seated lesions versus more superficial lesions. Frame-based stereotactic biopsy can be used to obtain a histopathological diagnosis of all regions of the brain, including deep structures such as the thalamus, basal ganglia or brainstem. The complication rate associated with stereotactic biopsy is low; the most major complications are a consequence of bleeding. Overall risks include a 80% tumour resection provides oncological advantage by providing cytoreduction and improving response to adjuvant chemo- and radiation therapy. A few centres suggest that resection of >98% is an independent variable associated with longer survival, with an approximate 3-month survival advantage compared to patients

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with 80% resection. In a small proportion of patients with recurrent disease, a second resection (11%) or a third resection (4%) is performed, again in younger patients with high performance status who have responded well to first line treatment.

Low-grade gliomas Low-grade (WHO Grade II) glioma typically presents with epilepsy in young adults; investigation with CT or MRI reveals a low-density or high-signal non-enhancing lesion. The timing of neurosurgical intervention, either in the form of image-directed biopsy or tumour resection, depends on many factors. However, with technical advances in pre-operative structural and functional imaging, there is a trend towards more extensive tumour resection, particularly as research has shown that all low-grade gliomas grow steadily and that the vast majority transform into high-grade gliomas at some point in their natural history. Recent data from a single centre suggests that larger, safer resections can be carried out by direct intra-operative electrical stimulation and may be associated with an improvement in long-term prognosis. However, even in the hands of a dedicated low-grade glioma neurosurgeon, only 25% of tumours are completely resectable. Awake craniotomy with cortical mapping provides the opportunity to maximize tumour resection, while minimizing neurological deficits and overall morbidity to the patient compared to standard craniotomy performed under general anesthesia. In the case of low-grade gliomas, in particular for tumours that are located primarily subcortically with minimal to no abnormality evident on surface cortical structures, identification of eloquent cortex is of paramount importance, hence use of awake craniotomy is advocated, largely in cases where on pre-operative highresolution MRI tumour infiltrates are found within or adjacent to anatomical eloquent cortical landmarks. A battery of diagnostic tests can be performed pre-operatively to aid in characterizing the relationship of tumour to eloquent cortex. MRI is helpful in defining the anatomical sulcal and gyral patterns correlating tumour location to motor, sensory and speech cortex. In addition, MRA may be helpful in defining critical vascular structures surrounding and often involving tumour boundaries. Functional MRI (fMRI) provides more accurate localization of motor and sensory cortex in addition to expressive speech centres, with receptive speech or comprehension being less accurately identified on fMRI. DTI can identify white matter tracts adjacent to or infiltrated by tumour, which can help planning surgery pre-

operatively. Neuropsychological testing is used to establish dominance for speech and memory, in addition whether any functional compromise has occurred from mass effect or infiltration by tumour into the mesial temporal structures. Information gathered from pre-operative diagnostic tests is combined with data obtained during intra-operative neurophysiological testing to identify areas of critical function, the area of pathology and safe corridors of entry into the cortex. Therefore, the surgeon is given greater confidence, because great variability exists in the morphology of cortical structures and their landmarks, and recognition of sulcal and gyral patterns intra-operatively is rarely straightforward. During cortical stimulation, the patient is asked to perform tasks testing motor and sensory function. Language testing is more accurately carried out using specific language paradigms and visual cards than counting or naming of objects, days or the alphabet. Therefore, a dedicated team is required in order to carry out complex awake craniotomies together with cortical mapping. If the patient is under general anaesthesia, although the extent of cortical mapping will not be to the same accuracy as in awake craniotomy, somatosensory evoked potentials (SSEPs) can be used to identify motor and/or sensory cortex. Surgeon comfort, patient preference, availability of pre-operative and intra-operative tests along with a dedicated neuro-anaesthesia team are key factors for performing awake craniotomies; few centres that offer neurosurgery have such capabilities. Management of low-grade gliomas is best carried out in centres that support awake craniotomies and cortical mapping.

Meningiomas Completeness of surgical removal of tumour is the single most important prognostic factor for patients with meningiomas. Various characteristics of meningiomas have been used to predict tumour recurrence, such as anatomical location, extent of tumour resection and histopathological features, with the single most important prognostic factor being the completeness of surgical resection. Simpson introduced a classification system that can predict recurrence rates based on extent of tumour resection, (Table 20.2). This classification system has been modified to include extent of microscopic resection; however, the Simpson classification remains the most widely used system. Tumour histology is also an important factor in predicting recurrence, if the tumour exhibits anaplastic and malignant features (WHO Grade

Recurrence

Grade

Description

10% 20% 30%

I II III

40%

IV V

Macroscopically complete removal, excision of dural attachment Macroscopically complete removal, coagulation of dural attachment Macroscopically complete removal, without resection or coagulation of dural attachment Partial removal Decompression/biopsy

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Table 20.2 Prediction of recurrence rates for meningiomas.

Neuro-Oncology II–III), the rate of recurrence is significantly higher, with 3% recurrence predicted for benign meningiomas, versus 40% for atypical and 80% for malignant meningiomas over a 5-year period. The introduction of new surgical approaches has improved operability of meningiomas at some previously relatively inaccessible sites. Radiosurgery and focused fractionated radiotherapy has also provided improved control of residual and/or recurrent meningioma. Pre-operative embolization in very vascular meningiomas is sometimes advocated to reduce peri-operative blood loss.

Brain metastases Patients with brain metastases are an increasing population, as improvements in systemic chemotherapy have led to more patients surviving and developing brain metastases. As a result treatment options and paradigms for patients with brain metastases are evolving. Available options for brain metastases currently include focal treatment, in the form of brain surgery and radiosurgery, and non-focal treatment using the standard and previously accepted treatments, whole-brain radiotherapy and chemotherapy. Novel treatment paradigms should combine these various treatment modalities in order to provide the most comprehensive and tailored therapeutic option for individual patients. General indications for surgery on brain metastases include de novo presentation in the brain, without a known primary tumour being diagnosed; in this case resection of the brain lesion will provide diagnosis in addition to excision. Surgery should also be considered if a metastatic tumour has associated oedema, mass effect and focal deficits or seizures that are not controlled on antiepileptic therapy; tumours larger than 3 cm in diameter should be considered, because this size excludes consideration of radiosurgery. Surgical resection of solitary metastases followed by whole brain radiotherapy (WBRT) results in a longer median survival (10 months versus 3.75 months) and extended functional independence compared to WBRT alone; this is recommended when the general condition of the patient is satisfactory and when the underlying primary disease is stable. Stereotactic radiosurgery (SRS) with either a cobalt source (gamma knife) or linear accelerator (LINAC based) may be used as an alternative to surgery, particularly for metastases in eloquent regions of the brain, although no head-to-head comparison with surgery has been carried out. In a large randomized Radiation Therapy Oncology Group (RTOG) trial the value of adding a radiosurgery boost to WBRT has been demonstrated by improving overall survival and performance status, together with the benefits of tapering off steroids faster. The same RTOG study showed that for patients with multiple metastases, radiosurgery boost is beneficial if the patient has stable systemic disease and good performance status. There are no studies demonstrating benefits of surgery for multiple metastases; common practice does not advocate surgery for multiple lesions, but only considers surgical resection for the lesion that generates mass effect, oedema and focal neurological deficits, in order to help improve quality of life and decrease need for steroids.

Primary spinal tumours Primary tumours of the spinal cord are relatively rare and are chiefly astrocytomas or ependymomas, usually low-grade, affecting commonly the cervical cord or, in the case of ependymomas, the conus. Other, less rare, primary spinal tumours are meningiomas arising from the dura, schwannomas arising from the spinal nerve roots and lipomas, either intramedullary or extramedullary. The symptoms and signs at presentation are a combination of the effects of nerve root involvement at the level of the tumour, e.g. girdle pain, and the effects of long tract involvement at that level, e.g. paraparesis or tetraparesis. MRI is usually diagnostic. Surgical treatment is indicated for extramedullary tumours via laminectomy at the appropriate level(s). Occasionally, more extensive approaches are required, e.g. with dumb-bell schwannomas, where thoracotomy or abdominal surgery may be required. In the case of intramedullary astrocytoma, it is sometimes possible to enter the spinal cord posteriorly in the midline, between the posterior columns, or alternatively through the dorsal root zone. Tumours associated with a cyst can occasionally be dissected free from the normal structures with little morbidity, with an apparently total macroscopic removal. In the case of ependymoma, it is frequently possible to obtain a macroscopic total removal of the tumour. However, with this type of tumour there may be local and more distant seeding of tumours through the CSF pathways, requiring adjuvant treatment. With spinal meningiomas, excision is usually curative and recurrence is uncommon, even when it has not been feasible to excise the dura widely. Similarly, most but not all schwannomas affecting spinal nerve roots can be cured by total excision. However, in some cases these tumours may have an aggressive course and not be surgically curable. Metastatic spinal tumours The spine is a common site for metastatic disease, commonly with bony involvement, but sometimes with extradural deposits and, rarely, with intramedullary spread. These tumours usually spread haematogenously into the vertebral bodies and cause epidural spinal cord compression. Typically, the clinical history is much shorter than with primary spinal tumours. Thus, patients may present as an emergency, with rapidly progressing paraparesis and urinary incontinence and/or retention. Referral may be delayed when there is no previous history of cancer, unless the true nature of the problem is identified. Oncologists are well aware of syndromes caused by spinal metastases, and in patients with a previous known history of malignancy, the diagnosis tends to be made promptly. Speed of diagnosis followed by urgent imaging is of the essence in preventing or minimizing permanent neurological deficit. Where there has been a short clinical history and the patient has a severe paraparesis with sphincter function lost for more than 12 hours, the results of surgical decompression are poor. A recent randomized trial of surgery followed by radiotherapy against radiotherapy alone for metastatic spinal cord compression

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showed that significantly more patients in the surgery group were able to walk after treatment and retained the ability to walk significantly longer than in the radiotherapy group. The benefits of this trial cannot be applied to patients with multiple metastases and in this group urgent radiotherapy is usually offered, particularly where the tumour is likely to be radio-sensitive and the patient is deemed sufficiently well to survive for a number of months. Patients with more rapidly advancing neurological deficits and with severe cord compression by tumour, as well as spinal disease, generally need urgent surgery if stabilization of their deficits is to be achieved. There has been a clear trend towards adjusting the surgical approach to the exact site of the metastatic tumour in order to obtain maximum decompression, coupled with fixation to stabilize the diseased spine. Major anterior or lateral approaches are suitable for anteriorly or laterally placed spinal metastases, but these often require a neurosurgeon to have assistance from a thoracic or abdominal surgeon. Single or multiple level corpectomy of the vertebral body with subsequent repair by bone cement, titanium-based cages or bone graft and concomitant posterior spinal fixation with metal instrumentation are performed more frequently than in the past. Posterior decompression should not be performed for anteriorly placed tumours as the resulting laminectomy can lead to spinal instability and rapid neurological deterioration when the patient is mobilised.

Radiotherapy and chemotherapy for common CNS tumours The benefits of surgical treatment for the majority of intrinsic malignant tumours are limited by their aggressive biological behaviour together with considerations surrounding neurological deficits following removal of tumour tissue from infiltrated normal brain or spinal cord. Many CNS tumours, even benign WHO Grade I meningiomas, may recur many years after removal particularly if initial resection is incomplete. For these reasons, radiotherapy and chemotherapy play an important part of the overall management of primary intracranial and spinal tumours.

Brain radiotherapy: planning Radiotherapy planning based on CT and MRI is now the standard approach to glioma treatment. CT-based planning allows accurate tumour dose localization and relative sparing of normal brain. The patient is immobilized in a plastic mask. CT slices (0.5–1 cm) are obtained in the treatment position. MRI data from diagnostic studies are then fused with CT data, to define the precise volumes to be treated to high dose. The patient is usually treated in the supine position unless the tumour volume lies very posteriorly. This position is most easily reproducible and the most comfortable. The field arrangement is chosen to encompass the tumour volume with maximal sparing of surrounding brain, usually utilizing 2–3 fixed fields. Using modern conformal

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radiotherapy techniques, scanning and planning software permits reconstruction of three-dimensional anatomy. The tumour and target volumes are visualized from the plane of the incoming radiation beams. Using these data the radiotherapist can then design shielding that conforms closely to the tumour volume, giving a steep dose gradient between tumour and normal brain. Total radiation doses given are usually in the range 45–60 Gy, with typical daily fractions of 2 Gy.

Stereotactic brain radiotherapy A refinement of conventional brain radiotherapy is to combine conformal planning with stereotactic techniques for both immobilization and tumour localization. This enables a further reduction in the treatment volume because of increased accuracy of tumour localization; relocation error is often reduced to below 1 mm. Relocatable stereotactic frames permit the dose to be given in a conventionally fractionated regime. Currently, these techniques are being explored in the treatment of gliomas, particularly in the paediatric population and for treatment of recurrent disease. Unfortunately, with gliomas, because the size of the treated volume is influenced most by the large clinical target volume necessary to include likely tumour infiltration, these techniques do not usually reduce the irradiated volumes by significant amounts. A further development is Intensity Modulated Radiotherapy (IMRT). This enables the radiation dose to be modified throughout the treatment volume. This permits treatment of concave volumes, sparing organs at risk lying within concavities such as the pituitary.

Spinal radiotherapy: planning Developments in radiotherapy planning technology have improved accurate delineation of spinal tumour masses using MRI data superimposed on CT scans in the treatment position. In most cases, MRI will be used to define the target lesion and fields designed to encompass this volume with 3–5 cm margins. Attention should be paid to anatomical influences on tumour spread, e.g. when treating disease in the conus medullaris the anatomical boundary to spread is at S3. Treating below this level will only add toxicity. In most cases, treatment fields do not need to extend further laterally than the lateral processes of the vertebral bodies, i.e. some 2 cm lateral to the border of the vertebral body. Patient positioning and immobilization for treatment are important to prevent dose inaccuracies or inhomogeneity. Radiotherapy doses for young female patients need to be reduced as far as possible. Planning systems that use three-dimensional imaging of the target conformal shielding can be a great advantage in these situations. It is generally safe to irradiate limited volumes of spinal cord to doses of 50–55 Gy. Animal data suggest a relatively small effect of volume once treatment lengths of 8 mm are exceeded. Estimates of the total dose to give 5% toxicity rate at 5 years (TD 5/5) using 2 Gy fractions are between 57 and 61 Gy: previously damaged spinal cord probably has a lower radiation tolerance.

Neuro-Oncology

Brain and spinal cord irradiation: toxicity issues Radiotherapy-induced neurotoxicity is seen commonly following treatment of even relatively benign CNS tumours both in children and adults. Radiation damage to the brain and spinal cord is categorized according to the time at which the clinical features develop. Acute, early-delayed and late-delayed radiation effects must be considered. As a general rule, acute and early-delayed toxicity are reversible and improve spontaneously and/or with steroids. Late-delayed toxicity is irreversible.

Secondary tumours and vascular disease In addition to direct neurotoxic effects, radiotherapy can cause second brain and exceptionally spinal tumours. Meningiomas, gliomas, schwannomas and cavernomas can develop years after treatment. Radiotherapy can also cause accelerated large vessel arterial disease, most commonly seen in young adults presenting with internal carotid artery occlusion after treatment in childhood for optic nerve or hypothalamic gliomas.

Spinal cord irradiation Brain irradiation Acute toxicity Common acute effects include alopecia, scalp erythema, fatigue, headache, nausea and sometimes vomiting; neuronal toxicity is thought to underlie the feelings of intense lethargy seen commonly within 2 weeks of starting treatment. Acute encephalopathy may occur in patients with raised intracranial pressure fractions of brain radiation above 3 Gy. The usual daily radiation dose is 1.8–2 Gy. Encephalopathy is now seldom seen since these low-dose radiation fractions have been given and almost always patients are pre-treated with steroids. Early-delayed toxicity Acute toxicity can be followed by a longer period of lethargy and exhaustion lasting up to 3 months after treatment, known as early-delayed toxicity. Worsening of pre-existing deficits and seizures can occur. This condition is usually reversible with steroids but improvement is sometimes slow, over many weeks. Late-delayed toxicity Late-delayed effects include cognitive decline resulting from leucoencephalopathy, vascular damage and radiation necrosis (see above), the latter clinically and radiologically similar to recurrent tumour. These late-delayed effects become apparent between 6 months and even up to 20 years following treatment. Other late effects include changes in taste, hearing and vestibular function. Radiation necrosis, usually apparent between 6 and 24 months after radiation, can mimic tumour recurrence both clinically and radiologically. The estimated risk of necrosis is 5% following 64 Gy; some data suggest a lower threshold dose of 50–58 Gy. PWI and DWI can help distinguish between necrosis and tumour recurrence. ADC and rCBV measurements are also of some value (see above). Other complications of cranial radiotherapy Other late toxicity may become relevant if other normal structures are included in the high radiation dose volume, e.g. the optic chiasm, pituitary and skin. The lens is commonly treated to near-tolerance in frontal tumours, with a substantial risk of cataract. These toxicities can be avoided to some extent by planning and accurate shielding of normal structures. In some instances moderate dose irradiation will be unavoidable and patients must be warned of possible consequences.

Myelopathy, radiculopathy and plexopathy Radiotherapy to the spinal cord is rarely associated with acute toxicity: however, a myelopathy may ensue in the months following treatment. Radiation myelopathy is usually late-delayed and presents either as a progressive myelopathy or as a lower motor neurone syndrome. This is most commonly seen in patients with Hodgkin’s disease given mantle radiotherapy. Some patients seem especially susceptible to myelotoxic effects of radiotherapy and develop a severe cord syndrome after radiation doses well below usual tolerance. Patients treated with axillary radiotherapy for breast cancer may develop a late-delayed radiation brachial plexopathy, distinguished from tumour recurrence by the absence of pain and sometimes the presence of fasciculation on electromyography. Diagnosis of radiotherapy-induced toxicity The development of neurological symptoms and signs should only be ascribed to the damaging effects of radiotherapy if the following conditions are met: • The anatomy of the clinical signs corresponds to the radiation portals. • The dosage and fractionation are sufficient to damage that particular area of the nervous system. • The time elapsed between radiotherapy and development of the neurological syndrome is compatible with known effects of radiotherapy on the nervous system. • Tumour recurrence has been excluded, particularly in the brain where clinical and radiological features of radiotherapy necrosis can be hard to differentiate. • Other differential diagnoses, e.g. spinal intramedullary metastasis, paraneoplastic syndromes, CNS infection and malignant meningitis, have been excluded.

Radiotherapy and chemotherapy for high-grade gliomas Radiotherapy for high-grade gliomas The addition of radiotherapy to surgery is standard palliative management for patients with high-grade gliomas (WHO Grades III and IV). The degree of benefit varies between different prognostic groups; it is typically modest and measured in months. Several studies have demonstrated a dose response to radiation, with improved median survival when fractionated doses of around 60 Gy in 30 daily fractions are given compared to lower doses in the 45 Gy range. No convincing further improvement is apparent when doses are increased above 60 Gy, using either

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external beam or brachytherapy boost doses. This may be because a potential increase in tumour control is obscured by an increase in early radiation toxicity or because high doses given to a very localized field do not encompass the whole area at risk for recurrence. For patients in the best prognostic groups with WHO Grade IV gliomas, i.e. those with little deficit, addition of radiotherapy improves survival by 5–6 months but only to a median figure of 9–12 months. In patients with lower than median expected survival the impact of radiotherapy is even more modest and may be only a matter of weeks. Overall, functional deficit improves in one-third of patients and stabilizes the situation, if briefly, in half. In the poorest prognostic groups an alternative approach using shortened course, high-dose palliative radiotherapy regimes is sometimes advocated on the basis that this impinges less on quality of life in the remaining months. When discussing relative risks and benefits of radiotherapy, it is important to take into consideration the limited symptomatic improvement that can be anticipated, the rarity of a prolonged response and the lethargy, hair loss and risks of neurological deterioration resulting from radiation.

Chemotherapy for high-grade gliomas The place of chemotherapy in first line treatment of high-grade gliomas has been assessed in many studies since the 1960s. These have included regimes in which chemotherapy is administered adjuvantly (following surgery and radiotherapy) or neoadjuvantly (prior to radiotherapy). Few have demonstrated a significant benefit in terms of survival compared with surgery and radiotherapy alone. The MRC Glioma Meta-analysis Group concluded that adjuvant chemotherapy given at or around the time of surgery and radiotherapy had a marginal benefit of 6% absolute improved survival at 1 year. The chemotherapy regimes were most commonly procarbazine, CCNU (lomustine) with vincristine (PCV), the most active combination of traditional chemotherapy in this disease. Common UK practice has been to give chemotherapy at first relapse rather than around the time of initial radiotherapy. The oral alkylating agent temozolomide has been used as an alternative to PCV and is currently being compared head-to-head with the older regime in recurrent highgrade gliomas. This approach – to save chemotherapy for recurrent disease – has been challenged recently both by new data and recognition of specific tumour subgroups that may be especially chemosensitive. Concomitant chemotherapy for high-grade gliomas Despite lack of evidence in favour of traditional adjuvant PCV chemotherapy overall in high-grade gliomas, recent data suggest a significant benefit for patients with WHO Grade IV astrocytomas (GBM) when temozolomide chemotherapy is given both concurrently with radiotherapy and subsequently adjuvantly for a further 6 months. These data support use of daily low-dose temozolomide throughout a 6-week course of radiotherapy followed by monthly 5-day courses for 6 months. Overall median survival, although modest, increased from 12.1 to 14.6 months;

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2-year survival increased from 10% to 26%. The addition of chemotherapy produced some increased toxicity, although mild with no measurable impact on quality of life. An important issue was a high incidence of Pneumocystis carinii pneumonia during concomitant treatment necessitating prophylaxis with cotrimoxazole or pentamidine. This regime has rapidly become standard treatment for patients with GBM with good performance and who are considered to be able to tolerate combined treatment. The situation for patients with WHO Grade III tumours is uncertain. Grade III cases have in any event a better prognosis than WHO Grade IV and therefore may experience late-delayed toxicity from combined chemo-radiation that offsets any potential survival benefits. An additional question is whether molecular analysis will enable identification of glioma patients who are more likely to respond to temozolomide. The mechanism of cytotoxicity of temozolomide relies on DNA base damage that can be repaired by a specific enzyme, O6-methylguanine-DNA methyltransferase (MGMT). MGMT is responsible for removal of O6-alkylguanine from DNA induced by alkylating mutagens/carcinogens. Levels of MGMT within tumour cells vary between GBM patients. Initial data suggest that patients with high levels of MGMT repair enzymes are less likely to benefit from the addition of temozolomide chemotherapy. Molecular and chromosomal analysis of all high-grade gliomas is likely to become a standard part of management. Chemotherapy for relapsed disease in high-grade gliomas Chemotherapy was until recently in the UK used almost exclusively at the time of relapse of high-grade gliomas. The standard approach in the UK has been the PCV combination regime in 6weekly cycles. Response rates (temporary symptomatic benefit) are 20–30%. Radiological improvement and clinical response are associated with increased time to further progression. However, there are no data that suggest significant improvement in overall survival for the majority of patients. Toxicities from this regime include bone marrow suppression, liver function test abnormalities, neuropathy, skin rash and gastrointestinal upset. In most patients the regime is well tolerated; if it is not, it is rarely appropriate to continue in view of the poor response rates. Whether this regime represents the optimal approach to treating relapsed disease, or whether temozolomide is substantially better remains unresolved. Optimal chemotherapy for patients who have previously received adjuvant treatment with temozolomide is also not resolved. This situation is difficult because of the relative paucity of agents with well-documented response rates in this situation. An alternative approach if the recurrence is operable is to insert carmustine (Gliadel) wafers into the resection cavity. This tends to avoid systemic side-effects but may cause cerebral oedema and poor wound healing. Other potentially useful agents include carboplatin and taxol. Novel agents are being assessed, including the c-kit tyrosine kinase inhibitor imatinib (Gleevec), epidermal growth factor receptor (EGFR) signalling antagonists and anti-angiogenic agents. Of the latter, the monoclonal antibody

Neuro-Oncology bevacizumab has shown some promise in Phase II studies when combined with irinotecan and Phase III trials are currently underway.

Radiotherapy for low-grade gliomas Several trials have examined dose response and timing of radiotherapy for WHO Grade II gliomas. WHO Grade I tumours are rarely treated with radiotherapy. Contrary to the situation in high-grade gliomas there is little evidence with WHO Grade II tumours for a dose response beyond 50 Gy. The timing of radiotherapy for these patients has also been contentious. Some centres have always advocated early postoperative radiotherapy on the basis that it is likely to be radio-biologically most effective when tumour volume is small and that the incidence of malignant transformation will be reduced. Others have felt that the long natural history of the disease means that such early intervention is unwarranted. This issue has been addressed in a randomized trial. The results suggest that while early irradiation to 54 Gy does not improve overall survival, time to progression is improved from 3.4 to 4.8 years in the treated group. Thus, many would now advocate early treatment in those patients at highest risk of progression, such as those with tumours in eloquent areas or for whom surveillance is inappropriate. Radiotherapy is also used in patients with intractable seizures in the absence of tumour progression. There is an approximately 75% chance of seizure improvement. In one trial comparing radiotherapy with no radiotherapy for low-grade gliomas, 25% of patients who had been irradiated had seizures at 1 year, while nearly 50% who had not been irradiated had seizures. The role of chemotherapy in low-grade glial tumours is not yet established so it is generally reserved for treatment of oligodendrogliomas particularly large volume tumours where the radiation field would be extensive or when radiotherapy has been given and there is transformation to a high grade. Chemotherapy for anaplastic oligodendrogliomas Oligodendroglial tumours are known to carry improved prognosis compared to high-grade astrocytic tumours. Recently, it has been found that an association with abnormalities of chromosomes 1p and 19q (see above) seems to define a group of oligodendroglial tumours that respond well to either chemotherapy or radiotherapy. Because many older studies did not distinguish this subgroup, these treatment-sensitive patients were probably an important source of heterogeneity. Current data suggest that response rates to nitrosurea-based chemotherapy in these anaplastic oligodendrogliomas (AO) is 60–70%. This is compared to figures of 20–30% for other high-grade gliomas and reflects the fact that about 70% of AOs have LOH at chromosomes 1p/19q associated with 100% chemosensitivity. The exact relationship between each of these chromosomal losses and the mechanisms underlying the chemo-sensitivity is unclear. However, despite this relative chemo-sensitivity, large clinical studies have not demonstrated a survival benefit for either neoadjuvant or adjuvant chemotherapy in this patient group when compared with

patients given their first chemotherapy at relapse. Current practice for anaplastic oligodendroglioma is therefore to assess chromosome loss as a prognostic rather than a predictive factor. Surgery and radiotherapy remain the primary treatments. Chemotherapy tends to be reserved for relapsed disease.

Radiotherapy for meningiomas The majority of meningiomas are benign, with recurrence rates frequently less than 10% after total excision. Radical surgery remains the mainstay of treatment. A minority of meningiomas present management problems if they cannot be fully excised or if there are aggressive histological features suggesting a risk of recurrence. In these circumstances recurrence rates may be as high as 80% over 10 years. The role and timing of radiotherapy as adjuvant treatment in these circumstances is debated. Several retrospective series have suggested that radiotherapy improves local control of these aggressive tumours, but no randomized series are available. In one retrospective series of WHO Grade I meningiomas, local recurrence rates following presumed total resection and subtotal resection were 52% and 77%, respectively, at 7 years median follow-up. Subtotal resection with radiotherapy achieved local control rates of 91% compared to 38% with subtotal resection alone. There was no influence on survival with adjuvant radiotherapy treatment. Although these data argue in favour of radiotherapy as adjuvant treatment after subtotal resection, they do not address its long-term side effects, particularly in younger age groups. Long-term risks include induction of a second tumour, pituitary failure and cognitive decline. Radiotherapy is therefore not offered routinely after subtotal resection of meningiomas because of these concerns. A common approach is to reserve radiotherapy for adjuvant treatment at first or subsequent relapse or in subgroups with higher risks of local relapse, including Grade II meningiomas or other atypical histology. Whether or not radiotherapy is effective as primary treatment in circumstances where surgery is either impossible or associated with significant risks has not been clearly addressed. Retrospective series suggest that local radiotherapy as primary treatment may produce local control rates >90% in Grade I tumours. In individual patients this must be balanced against the likelihood of long-term sequelae of radiotherapy, especially relevant in patients with life expectancies beyond 10 years. Newer radiotherapy planning techniques and radiosurgery can be used to reduce the volumes of normal brain irradiated in these patients, as these tumours can often be treated with a very small margin (5–7 mm) beyond visible tumour on MRI. However, there are no data that show the reduction in late toxicity by this approach.

Brain metastases: radiotherapy and chemotherapy Treatment for most brain metastases is purely palliative. Chemosensitive tumours such as germ cell neoplasms and trophoblastic disease are rare examples in which cure may be achieved with

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aggressive treatment. In other cases the management of these patients must be carefully considered in the context of their overall disease burden and prognosis. Several groups have attempted to categorize these patients into prognostic groups with the aim of predicting those most likely to benefit from treatment. Clearly, these decisions depend on having accurate and up-to-date information about disease status within and outside the brain and a careful assessment of the patient’s performance status. Broadly, treatment options in this group lie between surgical resection and radiotherapy for almost all patients. In some groups with no previous malignant history or in whom there is diagnostic doubt, biopsy may be necessary to confirm the diagnosis even if no other surgical intervention is planned. The most difficult group in this respect are elderly patients with concurrent medical conditions and no obvious primary site. In these cases even biopsy may not be appropriate. However, caution in diagnosis is essential: about 10% of patients with suspected brain metastases harbour unsuspected histology including abscesses, inflammatory/infective lesions (such as neurocysticercosis) or gliomas. Resection of brain metastases is the only treatment that can offer rapid relief of symptoms from mass effect. It is indicated particularly for single lesions in the posterior fossa causing obstructive symptoms and solitary hemisphere lesions with controlled systemic disease. It is usually contraindicated in cases with several brain lesions, as surgical results are so poor, a reflection that many patients will die in any event from uncontrolled disease outside the brain within a few months of surgery. A further question is WBRT following resection. Available data suggest that WBRT improves local (brain) control but not overall survival. The standard approach is to add a short course of palliative radiotherapy, e.g. 20 Gy given in five daily fractions of 4 Gy in 1 week. Radiotherapy alone to the whole brain has also been standard treatment for patients with unresectable metastatic brain lesions and/or with uncontrolled systemic disease. However, the palliative value of short course radiotherapy has been questioned. It is hard to know whether improvements are a result of the radiation or concomitant use of steroids.

Radiosurgery for brain metastases Radiosurgery can be appropriate in patients with one to three lesions that are not accessible surgically. Most practitioners limit the size of lesions to be treated to those less than 4 cm diameter because of the high radiation doses administered. Chemotherapy for brain metastases In all CNS malignancies the blood–brain barrier is at least a theoretical limitation to drug penetration, but the exact contribution that this makes to the poor response to chemotherapy is unclear. A distinct minority of tumour types presenting as brain metastases are known to demonstrate clinically useful chemo-sensitivity. These metastases include small cell lung cancer (SCLC), germ cell

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tumours and breast cancer. Response rates up to 66% at first treatment in SCLC have been documented. Some studies have shown that breast cancer brain metastases can respond to agents used for systemic disease in over 50% of cases. Median survivals after chemotherapy are similar to those after WBRT. Therefore, chemotherapy is probably most appropriate for those who are relatively chemo-naïve, as many patients will have been exposed to multiple chemotherapy agents prior to presenting with brain metastases. New approaches are clearly needed in the treatment of brain metastases. Combinations of conventional chemotherapy agents with molecularly targeted drugs such as gefitinib (Iressa), a tyrosine kinase inhibitor, have been shown to produce responses at primary tumour sites such as lung tumours and may help metastases. Temozolomide has also been studied alone or in combination with radiotherapy. New approaches to radiosensitization with agents such as COX2 inhibitors are being investigated. The use of dexamethasone to improve symptoms of raised intracranial pressure and focal deficits is part of standard treatment of brain metastases and brain malignancies generally. The optimal dose has not been defined but some data suggest that low-dose dexamethasone (4 mg/day) is as effective as high dose (16 mg/day) in the majority.

Radiotherapy and chemotherapy for spinal tumours Ependymomas The most common primary spinal intramedullary tumour in adults is ependymoma, which makes up 50–60% of diagnoses and occurs most commonly in mid adult life. It is common for the diagnosis to be made after months or years of slowly progressing symptoms. Surgery is usually the first treatment, to make a histological diagnosis and attempt gross removal. A postoperative MRI at 2–3 months is often recommended to record residual disease and serve as a baseline for follow-up. In low-grade fully resected tumours, recurrence rates are low, in the region of 5–10%. However, this does not fully take in to account the problems of defining grade and extent of resection in these tumours. A recent series suggests that local relapse rates may be higher than generally appreciated at long-term follow-up: there is a significant recurrence rate beyond 5 years, with only 50% of patients progression free at 10 years. Local postoperative radiotherapy is usually recommended in all patients. There are not enough data available to be able to assess whether there is a dose response to radiation in these circumstances. Most studies reporting outcome after radiotherapy are small series that use a narrow range of doses. It is clear though that recurrences distant from the original ependymoma site are very rare, therefore extended field or cranio-spinal treatments are not recommended unless there is evidence of distant spread. The maximum radiation dose that can be administered is limited by the tolerance of the spinal cord. Current practice is to treat low-grade ependymomas to a dose of 50 Gy in 1.8 Gy fractions and higher grade tumours to 54 Gy.

Neuro-Oncology

Astrocytomas of the cord The only other primary intrinsic cord tumours that occur with any frequency are astrocytomas. They are most often fibrillary, low-grade subtypes. Clinically and radiologically these tumours often present in a very similar way to ependymomas although they may be less well defined than a typical ependymoma. Surgery is often not appropriate in patients with significant neurological deficit or with high-grade lesions for whom extensive resection does not improve survival. Prognosis is less good than in ependymoma. High-grade tumour cases have a median survival around 20 months. No large studies have addressed the role of radiotherapy in spinal glioma patients. Small series suggest that less extensive surgery plus postoperative radiotherapy can produce local control in around 50% of patients with low-grade tumours, with 5-year survival rates around 60%. Chemotherapy for intrinsic cord tumours Overall there are few data on the chemo-sensitivity of intrinsic cord tumours. The literature addressing responses to chemotherapy in intracranial ependymoma suggests a low response rate to combination chemotherapy regimes and no evidence that it improves survival. Low chemo-sensitivity has been attributed to over-expression of MDR1 (multi-drug resistance gene) in ependymoma tissue. Paediatric literature suggests a modest response to chemotherapy in high-grade spinal astrocytomas. However, these small studies do not allow firm conclusions to be drawn about responses in adult patients.

Radiotherapy and chemotherapy for spinal metastases Following decompressive spinal surgery, local radiotherapy is often used as palliative treatment. Chemotherapy, depending upon the nature of the primary, is sometimes appropriate.

Non-gliomatous tumours This section summarizes features of various tumours of the brain and cord referred to in Table 20.1.

Pituitary tumours The pituitary is a tiny organ, uniquely supplied by two separate circulations: the systemic and portal systems. The sellar region is the site of many disease processes (Table 20.3) of which pituitary tumours account for the majority. Pituitary tumours represent 10–15% of all intracranial neoplasms. They can be classified by biological behaviour, size or histological and functional criteria (Tables 20.4 and 20.5).

Biological behaviour Tumours may be either benign, invasive adenomas or carcinomas. Benign forms are most common but up to 50% show evidence of capsule invasion and about one-third invade the dura or the sphenoid sinus. Pituitary carcinomas are exceedingly rare.

Table 20.3 Lesions of the sellar region. 1 Tumours Primary pituitary tumours Craniopharyngioma Meningioma Germ cell tumours Glioma – hypothalamic, optic nerve Granular cell tumours Lymphoma Ependymoma Metastases 2 Others Cysts – Rathke’s pouch, epidermoid, dermoid Empty sella syndrome Carotid and anterior communicating artery aneurysm Lymphocytic hypophysitis 3 Granulomatous disease Sarcoidosis Wegener’s granulomatosis Histiocytosis X 4 Infections Pituitary abscess – bacterial or fungal infection Tuberculosis Syphilis

Size Microadenomas are less than 10 mm and macroadenomas greater than 10 mm in diameter. Microadenomas are the more common and typically lie within the sella but can extend into the suprasellar space. Macroadenomas as they enlarge erode the sellar floor and eventually cause its destruction. The anatomy of adenomas is defined most accurately by MRI which clearly displays anterior and posterior lobes of the pituitary and its relation to the paranasal air and venous sinuses. Histology Cells forming a pituitary adenoma are defined by histological, hormonal and immunological characteristics. Acidophilic and chromophobe cells usually produce prolactin (Prl), growth hormone (GH) or thyroid-stimulating hormone (TSH). Basophilic cells produce adrenocorticotrophic hormone (ACTH), βlipotrophin, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Functional criteria Radioimmunoassay allows precise measurement of pituitary hormones. The most common type of pituitary adenoma (approximately 30%) are functionally inactive and typically chromophobe adenomas. Of those adenomas that secrete hormones, 60–70% produce prolactin, 10–15% secrete growth hormone and some

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Table 20.4 Classification of pituitary tumours. Cell of origin

Hormone

Clinical features

Non-functioning

None

Lactotroph

Prolactin

Corticotroph

ACTH

Somatotroph

GH

Thyrotroph

TSH (also occasionally GH & Prl)

Gonadotrophin

FSH or LH

Plurihormonal Carcinoma

More than one hormone

Cause symptoms only when they extend beyond the sella Most common type of macro-adenoma (30–35%) Typically intrasellar but may enlarge The most common hormone producing pituitary adenoma (40% of cases) Secretion of ACTH leading to Cushing syndrome (approx. 10% of cases) Usually confined to sella. May enlarge and become invasive particularly after adrenalectomy (Nelson syndrome) Gigantism in children and adolescents; acromegaly in adults Suprasellar extension relatively common Approximately 15% of cases Hyperthyroidism without TSH suppression May be large and invasive Rare, approx. 1–2% Usually non-functioning May result in ovarian overstimulation, increases testosterone level, testicular enlargement or pituitary insufficiency due to compression of the stalk or destruction of pituitary tissue by the tumour Uncommon May have one cell population producing two or more hormones or two or more distinct cell types Usually functional (ACTH and Prl producing) Varying degrees of nuclear atypia and cellular polymorphism but often high mitotic rate and cell proliferation Rare (1.5 mL and CSF metastases. There has been a dramatic increase in survival in children with medulloblastoma over the last two decades from 4.9 to 10 years. Current therapy for children comprises craniospinal irradiation (CSI) and now also includes the routine use of adjuvant chemotherapy which increases 3-year event-free survival by about 10%. The data in adults are limited. Hydrocephalus is a poor prognostic factor. The majority of reported cases of adult medulloblastoma (MB) come from retrospective studies from single institutions spanning many decades. It is therefore difficult to draw firm conclusions about the best treatment. However, certain principles are

clear, namely the need for maximal resective surgery followed by CSI. What is not clear is whether CSI is adequate treatment alone for good prognosis patients and whether adjuvant chemotherapy improves survival. Surgery has three aims – histological diagnosis, maximal safe tumour resection and relief of hydrocephalus, thus avoiding the need for a CSF diversion procedure with attendant risks of upward brainstem herniation, CSF dissemination and infection. Mortality should be less than 1%, morbidity 5–10%, with the most feared complication being cerebellar mutism. This is thought to arise from damage to the dentate nuclei but it gradually improves, although it does delay the start of adjuvant radiotherapy. All patients are then treated with CSI, usually 36 Gy to the whole neuraxis followed by a boost to the posterior fossa of 18–20 Gy. Higher doses (45 Gy) are given to nodular metastases in the spine. The role of chemotherapy is not yet established for adults with MB, as standard treatment (surgery plus CSI) yields a 60% 5-year progression-free survival. There is a perception that radiotherapy is less harmful to adults than to children in the long term and that survival benefit from chemotherapy in adults is less convincing than in children. However, most neuro-oncologists would treat high-risk adult MB patients with adjuvant chemotherapy. The most commonly used protocol in children is the Packer regimen which consists of weekly vincristine during CSI followed by eight cycles of CCNU, cisplatin and vincristine. The doselimiting toxicity is peripheral neuropathy, hearing loss, renal failure and myelosuppression. In adults, there is some evidence to suggest that carboplatin, vincristine and ifosfamide (or cyclophosphamide) may be less toxic than the Packer regime. Relapse in adult MB patients occurs in 20–50% by 5 years and is usually in the posterior fossa or in the spine. Treatment at relapse is therefore directed at resection or highly focused radiotherapy (e.g. stereotactic radiosurgery) to the posterior fossa followed by high-dose myeloablative chemotherapy and stem cell rescue. Unfortunately, almost all patients experience eventual recurrence either in the CNS or at distant non-CNS sites and succumb. Overall survival ranges are 25–85% at 5 years and 35–50% at 10 years. Clinical trials are needed for adult patients, but until further results become available we must be guided by paediatric trials.

Pineal region tumours A variety of tumours occur in the pineal region (Table 20.6), including germ cell tumours, non-germ cell tumours or pineal parenchymal tumours (pineocytoma and pineoblastoma) as well as gliomas and metastases. The clinical syndromes associated with pineal region tumours are determined by the close anatomical relationship of the gland with the quadrigeminal plate and midbrain tectum ventrally, the third ventricle rostrally and the cerebellar vermis caudally. Typical syndromes include:

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Chapter 20 Table 20.6 Tumours of the pineal region. Tumours of pineal origin (20%) Pineocytoma Pineoblastoma Tumours of germ cell origin (>50%) Germinoma Non-germinomatous germ cell tumours Teratoma Embryonal carcinoma Choriocarcinoma Yolk sac tumour Tumours of supporting or adjacent tissues Glioma Ganglioneuroma Ganglioglioma Meningioma Non-neoplastic cysts Arachnoid cyst Pineal cyst Vascular lesions Aneurysm of vein of Galen AVM Cavernous malformation AVM, arteriovenous malformation.

•

Obstructive hydrocephalus: headache, nausea, vomiting and obtundation; • Parinaud’s syndrome: vertical gaze palsy, light-near dissociated mid-point pupils, loss of convergence and convergence-retraction nystagmus (Chapter 13); and • Ataxia: caused by involvement of the superior cerebellar peduncle. Germ cell tumours can produce diabetes insipidus, amenorrhoea, growth arrest and pseudo-precocious puberty. The diagnostic work-up of a pineal region tumour includes a gadoliniumenhanced MRI scan and tumour markers in serum and CSF alpha-fetoprotein (AFP) and human chorionic gonadotrophin (βHCG). High levels are pathognomic of malignant germ cell tumours and obviate the need for biopsy. There is a high morbidity and mortality associated with pineal region surgery and thus debate about the pros and cons of biopsy alone versus open resection. The ultimate choice of procedure will depend largely on the individual surgeon but, as a general rule, a stereotactic biopsy is preferred where there is disseminated disease, clearly invasive malignant tumour or the patient has multiple other medical problems. The mortality and morbidity of stereotactic biopsy in modern series is around 1.3% and 2 min Stiffness, shaking Astonished Normal

Table 21.3 (a) Clues to a diagnosis of non-epileptic attacks. Frequent seizures with a normal EEG (ictal or interictal) Status epilepticus, especially repeated status (is rare) with normal ictal or interictal EEG Past psychiatric history, especially personality disorders Paramedical professions Variability of phenomenology, multiple seizure descriptions Pelvic thrusting seen during the attack (seen with frontal seizures but rarely) Crying and emotional displays after the attack Failure to respond to antiepileptic drugs with some features above

A number of clinical clues to the diagnosis of non-epileptic seizures are given in Table 21.3(a). A practical guide is that the patient who experiences many seizures a day and who has a normal interictal EEG either has seizures with a deep-seated frontal focus or has non-epileptic seizures. However, in such frontal seizures, in which bizarre uncoordinated movements can occur, the attacks can appear to the untutored eye to be non-epileptic; the ictal EEG with surface electrodes is also sometimes deceptively normal. About 70% of patients with epilepsy respond well to standard antiepileptic therapy. Failure to respond, with continuing frequent attacks and a normal interictal EEG, should raise doubts about the diagnosis. Status epilepticus is quite rare. It is estimated that some 50% of patients admitted to ITU with status epilepticus actually have non-epileptic status. Thus, repeated bouts of apparent status epilepticus with a normal interictal EEG again suggest non-epileptic

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Table 21.3 (b) Common myths about features said to suggest epilepsy that may well occur in non-epileptic attack disorder (NEAD). Myth Self-injury is common in epilepsy but not in NEAD Urinary incontinence is uncommon in NEAD An abnormal interictal EEG does not always mean an epileptic seizure Third-party eye-witness descriptions are very valuable and reliable

attacks. Any hint that it took ‘seven men to hold the patient down’ is not likely to be referring to an epileptic seizure. The patient who reports several different kinds of event probably has either non-epileptic attacks or a combination of the latter with epilepsy. Further, variability in the semiology of the attacks over time is more in keeping with non-epileptic attacks than with epilepsy. Incontinence is of little diagnostic help. However, injuries are frequently seen in patients with non-epileptic attacks. They tend to have a different quality and occur at different sites from those injuries seen in epilepsy. Generally, in epilepsy, the bony prominences are damaged as the patient falls and hits their limb or head on protruding objects. Lesions are thus often found under the chin or under the eyebrows, the nose may be broken, and bones fractured. In non-epileptic attacks, the injuries are often carpet burns on the forehead, cheek, elbows or knees. Fractures are rare and burns from scalding very rare. Repetitive injury to the same part of the body or opening up wounds are highly suggestive of non-epileptic attacks. Table 21.3 (b) summarizes some diagnostic hints and myths surrounding non-epileptic attacks.

Psychogenic movement disorders Like non-epileptic attacks, this well-recognized entity deserves special mention. Its history is revealing. It was clearly recognized in the 19th century, by neurologists such as Charcot, that patients developed all kinds of movement disorders, some acute and others chronic. Most of these conditions were, for Charcot, variants of hysteria. With the discovery of levodopa in the 1960s and the realization of close links between movement and dopamine, the idea that some movement disorders could have nonneurological antecedents tended to rejected. Almost all abnormal movements were considered organic and thus neurological. However, in the last two decades the concept of psychogenic movement disorders has undergone a certain revival A variety of presentations are now recognized, from psychogenic parkinsonism through to tremors, gait disorders, and tics and myoclonic jerks. Estimates suggest that 3–25% of patients attending movement disorder clinics probably have some form of psychogenic movement disorder. Ten per cent of patients diagnosed as having Parkinson’s disease have a normal DAT scan. Psychogenic dystonia is one interesting variant. Patients frequently present with a focal dystonia, e.g. as a spasmodic torticollis, but it is often more widespread and can involve the trunk, leading to bizarre posturing. The abnormal movements may come on quite suddenly and can be precipitated by minor trauma. In the upper limb, dystonia begins with contraction and flexion

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Comment Self-injury is common, especially carpet burns in NEAD Urinary incontinence is of little diagnostic value; it occurs infrequently in NEAD Many patients with epilepsy also have NEAD Third party eye-witness descriptions can also be misleading

Table 21.4 Diagnostic features pointing towards psychogenic dystonia. After Fahn & Williams (1988). False weakness Sensory complaints, severe pain and false sensory findings Multiple somatizations Self-inflected injuries Obvious psychiatric disturbances Inconsistent dystonic movements over time Incongruous dystonic movements and postures Dystonia usually presents as a fixed dystonia or as a paroxysmal dystonia Other movement disorders, usually presenting as incongruent or bizarre movements including bizarre gait and often as a paroxysmal disorder

of the fingers, then affects the wrist and eventually moves up the arm. In the legs, classically the foot becomes inverted. Eventually the patient begins to walk entirely on the lateral border of the foot and even on the dorsum. There are overlaps between psychogenic dystonia and the causalgia-dystonia syndrome and regional pain syndrome also called reflex sympathetic dystrophy. In contrast to organic dystonias, the psychogenic dystonias are characteristically fixed, the patient being unable to move the affective part and they are sometimes initially painful. Any initial causalgia tends to wane. The dystonia may become progressive. Having first affected the lower limb on one side it can spread to the other or even to all four limbs. It is not unknown for amputation to be carried out by surgeons unfamiliar with the condition. Table 21.4 lists some clues to the diagnosis of psychogenic dystonia. There is an overlap with multiple somatizations and also a link with factitious disorder and malingering. Psychogenic dystonia is not improved with sleep. The patient commonly shows a slowness of any voluntary movement and a curious resistance to passive movement: resistance from the patient increases as the examiner, when testing a movement, gradually increases force. With organic spasmodic torticollis many patients develop curious tricks to reduce abnormal head posture, e.g. moving a hand to touch the chin or neck. These movements are known as gestes antagonistes, and are not reported in psychogenic dystonia.

Some basic psychiatric principles Personality disorders It is important for an assessment of a patient’s personality to be taken into account when trying to understand neurological

Psychiatry and Neurology symptoms generally but particularly so where there is some failure of symptoms and/or signs to correspond to the neurologist’s expectations. A brief overview of the more important terms for neurological practice is given here. It is useful to begin with distinctions made between psychogenic development and organic process. The psychopathologist Karl Jaspers put it thus: ‘We differentiate abnormal personality types that are anlage (genetic predisposition to a given trait or personality characteristic) variants, the sick personalities in the narrower sense, from those where a change has been brought about by a process.’ Thus, personality change induced by a process, either a neurological illness or a psychiatric disorder, needs to be distinguished from the enduring characteristics by which we come to know a person over time. In psychiatric settings several different personality styles are recognized that have clinical importance. Those of most relevance to neurologists are briefly noted here. The fuller details of these disorders can be found in standard diagnostic manuals. The term ‘psychopathic personality’ implies antisocial personality traits; sociopathy, sociopathic personality and antisocial personality are alternative terms. This personality type is characterized by a disregard for social obligations, a lack of feeling for others, cruelty, impetuous violence or callous unconcern. Such a personality emerges from an early life history of conduct disturbance at school, with disturbed family relationships leading to a poor work record and difficulty forming enduring interpersonal relationships. An interesting feature of the psychopathic personality is the tendency to remit or improve over time. The onset of such a personality style in midlife usually implies the development of an underlying process – organic, psychological, or both. The obsessional personality is characterized by a lifelong tendency to meticulousness and punctuality. Patients have difficulty in expressing their emotions. They check and recheck their actions. Many patients attending clinics with neurological symptoms but no obvious neurological disease have such a personality style. The meticulous circumstantiality of these patients can make history-taking a laborious process and obtaining what is relevant may be difficult. This cognitive style is to be contrasted with the features of the hysterical personality, whose impressionistic views of their own world have already been mentioned. The paranoid personality is distinguished by continued suspiciousness and excessive sensitivity. Schizoid personalities have little affective or social contact with others and have a tendency to detachment and eccentricity. The borderline personality is particularly important to recognize in neurological practice because the tendency to somatize often presents with somatic symptoms that have no neurological substance. The personality style is characterized by unstable personal relationships, impulsivity that often leads to self-harm or outbursts of intense anger, affective instability and sometimes transient paranoid episodes. They seem particularly susceptible to dissociative episodes which may underpin a presentation with non-epileptic attacks. Anxious personality defines those who display lifelong anxiety and who, under stress, readily develop anxiety or panic disorders. In a neurological setting they appear with fleeting neurological

symptoms. Panic disorder is probably the psychiatric disorder most commonly misdiagnosed as epilepsy. Finally of some neurological relevance is the explosive personality. This defines those who are liable to intemperate bursts of anger but who do not otherwise have the characteristics of the psychopathic personality. Such patients have paroxysmal episodes of rage, referred to as episodic dyscontrol. In contrast to the above, the anlages of Jaspers, neurological processes that lead to personality changes, are referred to by the all-embracing term ‘organic personality change’. Damage or disease processes of the frontal and temporal lobes are most likely to be involved, providing an identifiable stamp on the person’s behaviour which is recognized clinically as bringing about a change in their behavioural patterns. Following this account of some of the more relevant personality disorders, some important psychiatric diagnoses met in neurological settings are discussed. It should at this point be made clear that the following psychiatric disorders can develop in patients with any style of personality. However, some personality disorders lend themselves to certain psychiatric diagnoses, e.g. the continually anxious is more liable to develop anxiety disorder, and the anankastic or obsessive will have an increased tendency to develop an obsessive-compulsive disorder. As noted, neurological disease is a powerful influence on personality and changes of personality combined with the development of psychiatric illness can represent a difficult diagnostic conundrum.

Anxiety disorders The hallmark of an anxiety disorder is the anxiety itself. The most important disorders are panic disorder with or without agoraphobia, generalized anxiety disorder, specific phobias, posttraumatic stress disorder and obsessive-compulsive disorder. The manifestations of the anxiety are multiple and affect every bodily system. Because the symptoms of anxiety are so common and lead to the reporting of somatic symptoms, patients with anxiety disorders are often referred for unnecessary investigations and treated inappropriately. Common symptoms include palpitations, sometimes associated with anterior chest pain, dyspnoea with a sense of choking and not being able to get enough breath, dry mouth often with an unpleasant metallic taste, abdominal tension associated with nausea and sometimes even vomiting, constipation and diarrhoea, urinary retention, poor concentration and memory, dizziness, vertigo, fainting feelings and on occasion blackouts which can resemble epileptic seizures. Other symptoms include fatigue and loss of energy, sensory symptoms such as tingling, and diminished vision or auditory hyperaesthesia in which sounds are distorted or magnified. In panic disorder, relatively frequent discrete episodes of panic are associated with apprehension and fear. The paroxysmal nature and sudden onset of these episodes in which an obvious precipitating factor may be unclear can lead to a diagnosis of a complex partial seizure. A variant of this disorder is the phobic anxiety depersonalization syndrome. This can be a much more pervasive disorder with generalized anxiety, affective symptoms and a substantial

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risk of suicide. In some patients depersonalization may persist and become chronic. Other patients complain that they feel like automatons. Such symptoms, when prolonged, are very unpleasant. In neurological practice, anxiety states are misinterpreted as epilepsy, vertigo, benign essential tremor, multiple sclerosis and even states of dementia. Hyperventilation is common, although patients are often unaware that they are hyperventilating. This leads to neurological symptoms with a worsening of the anxiety and can ultimately present as episodes of loss of consciousness. Post-traumatic stress disorder has become a popular diagnosis. The clinical criteria have changed over time to become less rigid but the essence of the syndrome, referred to at one time as posttraumatic neurosis, is the development of a combination of anxiety and other affective symptoms following a specific stress. A special emphasis is given to the re-experiencing of a trauma psychologically, usually in the form of flashbacks or nightmares.

The former may be triggered by specific stimuli reminiscent of the original trauma. The other symptoms are related to the development of avoidance of stimuli that remind the patient of the psychological trauma, and a numbing of emotional responses. Patients typically will not talk about what has happened, they avoid watching television programmes that may be in some way associated with their trauma and develop cognitive strategies to divert their thinking away from unpleasant thoughts. Two symptoms are of particular interest in neurological practice. One is the increased startle response which can be so severe to be misdiagnosed as startle epilepsy or Gilles de la Tourette’s syndrome. The second is psychogenic amnesia. Patients are simply unable to remember the details of their traumatic event, which in patients who have had some kind of head injury may be misinterpreted as an organic post-traumatic amnesia. The current diagnostic criteria for post-traumatic stress disorder are shown in Table 21.5.

Table 21.5 Post-traumatic stress disorder (DSM-IV-TR criteria). A The person has been exposed to a traumatic event in which both of the following were present: 1 The person experienced, witnessed, or was confronted with an event or events that involved actual or threatened death or serious injury, or a threat to the physical integrity of self or others 2 The person’s response involved intense fear, helplessness, or horror. Note: In children, this may be expressed instead by disorganized or agitated behaviour B The traumatic event is persistently re-experienced in one (or more) of the following ways: 1 Recurrent and intrusive distressing recollections of the event, including images, thoughts or perceptions. Note: In young children, repetitive play may occur in which themes or aspects of the trauma are expressed 2 Recurrent distressing dreams of the event. Note: In children, there may be frightening dreams without recognizable content 3 Acting or feeling as if the traumatic event were recurring (including a sense of reliving the experience, illusions, hallucinations and dissociative flashback episodes, including those that occur on awakening or when intoxicated). Note: In young children, trauma-specific re-enactment may occur 4 Intense psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event 5 Physiological reactivity on exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event C Persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness (not present before the trauma), as indicated by three (or more) of the following: 1 efforts to avoid thoughts, feelings, or conversations associated with the trauma 2 efforts to avoid activities, places, or people that arouse recollections of the trauma 3 inability to recall an important aspect of the trauma 4 markedly diminished interest or participation in significant activities 5 feeling of detachment or estrangement from others 6 restricted range of affect (e.g. unable to have loving feelings) 7 sense of a foreshortened future (e.g. does not expect to have a career, marriage, children, or a normal life span) D 1 2 3 4 5

Persistent symptoms of increased arousal (not present before the trauma), as indicated by two (or more) of the following: difficulty falling or staying asleep irritability or outbursts of anger difficulty concentrating hypervigilance exaggerated startle response

E Duration of the disturbance (symptoms in Criteria B, C, and D) is more than 1 month F The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning Specify if: Acute: if duration of symptoms is less than 3 months Chronic: if duration of symptoms is 3 months or more Specify if: With delayed onset: if onset of symptoms is at least 6 months after the stressor

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Psychiatry and Neurology Obsessive-compulsive disorder is not uncommon in neurological practice. The anankastic personality may be overrepresented in those presenting with unexplained neurological symptoms. A secondary obsessive-compulsive disorder is reported in post-encephalitic parkinsonism, in some cases the compulsions being awakened by levodopa. In Gilles de la Tourette’s syndrome approximately 50% of patients display obsessive-compulsive behaviour and a co-morbid obsessive-compulsive disorder is commonly found. In this condition, in which multiple tics – including vocal tics – present as a chronic disorder, other interesting features include complicated stereotypes and rituals, echo and copro phenomena and, in about 30% of patients, compulsive self-harm. Obsessional slowness can sometimes be so excessive that patients will hardly move, e.g. for fear of catching something by touch. This can even be misinterpreted as a movement disorder linked to a failure of motor planning.

Affective disorders

ity, hostility and even overt aggressive episodes may develop, especially in the family setting, leading to considerable distress. This can obstruct the diagnosis of the depression. The above mental states need to be distinguished from the lability of mood seen in pseudobulbar palsy or in a frontal lobe syndrome in which rapid oscillations between one mood state and another are seen such as excessive laughing and crying. Mania is an alternative affective state, hypomania being a less severe clinical presentation of an upswing in mood. Usually patients have bipolar expressions referred to in the past as a manic depressive disorder. There is an increased sense of well-being. The patient expresses euphoria, they may demonstrate accelerated thoughts with a flight of ideas and pressure of speech. Motor activity is excessive. Concentration is poor, patients are distractible and irritable, sleep is brief and appetite increased. In classic mania, patients are restless, they show disordered speech with rhyming, punning and wordplay and their mood is more dysphoric than euphoric.

The term ‘affective’ generally means that condition in which an alteration of mood is the central feature. As such, disorders of affect – particularly depression – are frequently encountered in neurological practice. However, in the clinical setting a common but important error is to confuse depressive symptoms, sadness and demoralization in the setting of physical illness with a depressive illness itself. The latter has quite specific features, central being the disturbance of mood, which is prolonged and continuous. Episodes of more transient changes of mood are often referred to as dysthymic disorder. In the assessment of depressive symptoms, personality factors are often insufficiently taken into account, particularly premorbid neuroticism, and in reality many patients with dysphoric symptoms have long-standing personality disorder and tolerate life’s stresses poorly. The change of mood in depressive illness is associated with a loss of vitality; the patient ceases to enjoy life and has loss of emotional well-being. Libido is diminished. Concentration difficulties, with complaints of poor memory, increased apathy with diminution of movement, loss of appetite and alteration of the sleep pattern are noted. Patients will complain that food is tasteless; they may lose weight; they have nocturnal restlessness and may have typical early morning waking with morbid ruminations and a feeling of being unrefreshed by sleep. Diurnal variation is sometimes reported, with symptoms improving as the day progresses. Feelings of anxiety and tension are invariably present. Some patients, in contrast to having psychomotor retardation, become agitated with indecision and display excessive motor activity. In the extreme form intense aimless pacing is seen. Some patients with depression do not report or under-report any change of mood, and present with somatic symptoms referable to any part of the body. The latter then become the focus of attention for both patient and physician, leading to unnecessary investigations and a failure to diagnose the underlying disorder of mood. It is important to enquire about suicidal ideas that may be embedded within other thoughts of worthlessness, guilt and a certainty that the patient has let people down. Increased irritabil-

Depression in neurological disorders In some patients depression is not occasioned by some life crisis, a genetic miss-gift or an understandable consequence of a chronic physical disorder. Depression can be directly interlinked with a neurological condition touching therefore on the neuroanatomical and neurochemical underpinnings of affective expression. The reported frequency of depressive illness in neurological disorders is shown in Table 21.6. However, even in these settings the symptoms of the depression may be subtly different from those of a typical depressive illness in the absence of neurological illness. For example, in Parkinson’s disease an excess of anxiety is reported, while in epilepsy some episodes are brief with excess of irritability and dysphoria, the socalled interictal dysphoric disorder. The depression secondary to cerebrovascular disease may present with quite bizarre somatic symptoms with delusional features, and depression secondary to Huntington’s disease is linked with a high frequency of suicide. Some of these associations are discussed further below. Several neurological disorders have been associated with secondary mania (Table 21.7). Interestingly, most reported cases of mania in this setting emphasize damage to the right hemisphere and involve either the orbital frontal cortex, caudate nuclei, thalamus and/or medialtemporal areas. There is thus an association with the cortical– subcortical circuits briefly described below. As with depression, the clinical picture of these neuropsychiatric disorders is often different from an equivalent psychiatric disorder where no underlying neurological damage is apparent. The manias can erupt suddenly without any prior history or genetic backing. The associated delusions are often unusual. In Parkinson’s disease delusions are often occupational or linked with some past situation (e.g. service in the armed forces) and the accompanying hallucinations are complex and visual. In epilepsy they are often religiose. In syphilitic general paralysis delusions tend to be grandiose and extravagant.

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Chapter 21 Table 21.6 Depression in neurological disorders. From Cummings & Trimble (2002). Neurological condition

Frequency of depressive syndromes (%)

Characteristics of depressive syndrome

Stroke

30–60

Parkinson’s disease

30–50

Huntington’s disease Epilepsy

35–45 10–50

Traumatic brain injury

25–50

MS Alzheimer’s disease Vascular dementia

25–50 30–40 25–60

Psychomotor retardation often severe; depression more common in patients with brain atrophy, with left frontal and left caudate lesions and when lesion approaches left frontal pole Anxiety common; mood-congruent delusions; suicide rare. PET: diminished orbito-frontal + caudate glucose metabolism Suicide common. PET: diminished orbito-frontal glucose metabolism Frequency of suicide and delusions increased. PET: diminished orbito-frontal or left brain glucose metabolism History of psychiatric disorder (including substance abuse) common among those who develop post-traumatic depression Depression often not related to degree of disability Major depressive episodes rare; depressive symptoms common Depression common in lacunar state and Binswanger’s disease

MS, multiple sclerosis; PET, positron emission tomography. Table 21.7 Neurological disorders associated with secondary mania. From Trimble (1996).

Table 21.8 Brain disorders associated with delusions. From Cummings & Trimble (2002).

Stroke Temporal lobe tumours Epilepsy Parkinson’s disease with dopamine agonist therapy Idiopathic basal ganglia calcification (Fahr’s disease) Huntington’s disease Traumatic brain injury Multiple sclerosis Frontal lobe degeneration Cerebral syphilis

Schizophrenia Mania with psychosis Depression with psychosis Epilepsy (especially temporal lobe epilepsy) Alzheimer’s disease Fronto-temporal dementias (e.g. Pick’s disease) Dementia with Lewy bodies Huntington’s disease Parkinson’s disease after treatment with dopaminergic agents Idiopathic basal ganglia calcification Post-traumatic encephalopathy Viral encephalitis (especially herpes simplex encephalitis) Creutzfeldt–Jakob disease Stroke (particularly involving the temporal lobes, such as in Wernicke’s aphasia) Wernicke–Korsakoff syndrome Vascular dementia Multiple sclerosis Porphyria Metachromatic leucodystrophy Adrenoleucodystrophy Brain tumours (particularly involving temporal lobes, R > L) Vitamin B12 deficiency GM2 gangliosidosis Neuronal ceroid lipofuscinosis Mitochondrial encephalopathy Prader–Willi syndrome (excessive appetite, etc.)

Note: most reported cases where laterality can be established affect the right hemisphere.

Psychoses The term ‘psychosis’ generally refers to a condition in which there are hallucinations and delusions associated with abnormalities in behaviour in which insight is diminished or lost. Excitement and over-activity or psychomotor retardation and even catatonia occur. In contrast to disorders of affect, psychotic states, although implying a severe disturbance of psychological function, are less often encountered in neurological practice. Ontologically the brain must allow the individual to interpret the world in a logical and adaptive way. Hallucinations and delusions suggest deviant processing and underlying this are disturbances of neurological function secondary to structural disease. Hallucinations are perceptions in the absence of an adequate sensory stimulus. They must be distinguished from illusions which are misinterpretations of perceptions. Pseudohallucinations are hallucinatory experiences that occur in subjective rather than objective space, are less clearly delineated and often perceived as being unreal. Thus, they lack the objectivity of hallucinations proper. The latter have concrete reality, are substantial and linked with a lack of insight into their nature.

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Delusions are unshakable convictions that are manifestly incorrect. They have to be interpreted within the cultural setting of the patient, but it is the tenacity with which patients hold on to their beliefs against all logic that inevitably reveals the delusion. They need to be distinguished from over-valued ideas which are strongly held beliefs that are not incorrigible. Neurological conditions associated with delusions are shown in Table 21.8.

Psychiatry and Neurology Delusions are the hallmark of a paranoid illness and occur in a spectrum of psychiatric disorders including schizophrenia. In the affective disorders they are characteristically mood congruent, whereas mood incongruent delusions are typical of schizophrenia. In the Capgras syndrome a significant person in that patient’s life is replaced by a supposed identical double, while in the Fregoli syndrome a supposed persecutor can change his or her appearance and appear as other people. These are referred to as misidentification syndromes. In depressive disorders hallucinations are characteristically morbid and often refer to the body, for example, being afflicted by some terrible disease. Auditory hallucinations are damning and condemnatory. Visual hallucinations are exceptional. The latter are more characteristic of organic brain syndromes in which settings they may be florid, frightening and often dimly perceived as unreal. Hypnogogic and hypnopompic hallucinations occur as patients are falling asleep or awakening, respectively. They may be auditory, visual or tactile and can be terrifying. Hallucinations that occur in clear consciousness for which there is no insight and which are mood incongruent are very suggestive of schizophrenia. In this condition the hallucinations are usually auditory although patients may experience them in any modality. Specific auditory hallucinations are noted in association with schizophrenia and constitute some of the Schneiderian First Rank symptoms. These are listed in Table 21.9. When present in clear consciousness such hallucinations and delusions usually signify schizophrenia, although this is not diagnostic because they are sometimes noted in other psychotic disorders, e.g. in mania. The diagnosis of schizophrenia can also be made in their absence, based upon history and other observed abnormal behaviour. Visual hallucinations, particularly of small animals, are characteristic of delirium tremens. Formication, the sensation of ants crawling under the skin has been associated with cocaine psychosis. Olfactory hallucinations are reported in schizophrenia and in simple partial seizures of uncinate origin. In epilepsy these experiences are typically brief, unpleasant, hard to characterize and conTable 21.9 Psychosis: First Rank Symptoms of Schneider. Alone, these are not diagnostic of anything, but when present in the setting of clear consciousness support a diagnosis of schizophrenia: • Thought insertion • Thought withdrawal • Thought broadcasting • Hearing one’s thoughts spoken aloud • Hearing voices arguing about or discussing one • Hearing voices comment on one’s actions • Delusional perception: abnormal significance attached to a real perception with no logical explanation • Experiencing bodily sensations as if imposed from outside • Experiencing affects as if imposed and controlled from outside, e.g. mood change • Experiencing impulses as if imposed and controlled from outside • Experiencing motor actions as if imposed and controlled from outside

sistent in their phenomenology. In schizophrenia they are much more variable and can last for hours at a time. In coenaesthetic hallucinations the body or part of the body will feel distorted often in quite fantastic ways. While often reported in schizophrenia such hallucinations can occur in migraine or following stroke. A characteristic feature of schizophrenia is alteration of thought and language and this may vary from a subtle flattening of the expression and concrete thinking to florid schizaphasia. In this, neologisms (paraphasias), loose connections between thoughts, tangential thinking and intrusive delusional content can lead to a veritable word salad. Sometimes features suggestive of Wernicke’s aphasia may be present.

Other clinical neuropsychiatric syndromes Fugue states refer to episodes of wandering in which patients either complain of, appear to have, or confess to, amnesia for a period during which, for example, they will have left home and appear at a destination in an apparently confused state. During the fugue, in contrast to an epileptic automatism, patients maintain good contact with their surroundings and rarely draw attention to themselves. There may be a complete loss of personal identity and autobiographical memory extending back many years. The most common association of fugues is with an underlying depressive illness but there may be an association with compulsive lying and possibly a minor concussive head injury. Fugues last much longer than epileptic automatisms. In the latter the accompanying confusional state is usually obvious. In transient global amnesia (TGA; Chapter 7) there is sudden onset of amnesia but personal identity is retained and significant persons usually readily identified. When the TGA episode is complete there is amnesia for the period of the event with prompt return of clear awareness. Somnambulism refers to episodes of nocturnal wandering in which patients behave in a semi-purposeful way and again express amnesia for what has happened. Catatonia is characterized by mutism and bizarre motor activity that ranges from stupor to episodes of agitated excitement. Sustained postures and waxy flexibility of the limbs may be present, associated features being negativism, echo phenomena, stereotypies and mannerisms. There is a wide differential diagnosis embracing many neurological and psychiatric disorders from encephalitis and metabolic disorders to depression and schizophrenia. Lethal catatonia is a rare psychosis in which catatonia is associated with intense autonomic activity and fever: the condition has links with the neuroleptic malignant syndrome (Chapter 18) but it was observed in the pre-neuroleptic era.

Psychiatric disorders secondary to neurological illness Underlying neuro-anatomical concepts Although this is not the appropriate place to discuss neuroanatomy in any depth, some of the underlying principles of neuropsychiatry are embedded in neuroanatomy in a way that the ‘new neuroanatomy’ of the past 30 years has unravelled.

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Chapter 21

In 1994, the Nobel scientist and neurobiologist, Sir Francis Crick, wrote of his ‘astonishing hypothesis’: ‘You, your joys and your sorrows, your memories and ambitions, your sense of personal identity and free will are in fact no more than the behaviour of a vast assembly of nerve cells and their associated molecules.’ The astonishing feature of this hypothesis is why it should be, at the turn of the second millennium, astonishing at all. After all, Hippocrates had presented the same hypothesis some 2500 years earlier. Writing about epilepsy, then referred to as ‘the sacred disease’, he opined that: ‘Men ought to know that from the brain and from the brain only, arise our pleasures, joys, laughter and jests as well as our sorrows, pains, griefs and tears.’ In his own philosophy, the brain was considered the seat both of madness and of epilepsy. Neuroscience has taken a veritable backseat in the public and scientific imagination for such a long time that even in the current era the concept that the brain is the central organ of thoughts, feelings and emotive energy and that without the human brain there is no human endeavour, is still found astonishing. It is a fact, not an hypothesis, that consciousness, awareness and all that flows from them are dependent on the brain and its functioning in an appropriate manner. Although great strides in neuro-anatomy and neurophysiology were made in the 19th century, little progress was made in understanding how emotions were represented neurologically. The James–Lange hypothesis suggested that the emotions were derived from sensory inputs to the brain which activate motor outputs and thus the resulting bodily sensations are perceived as the emotion. For example, this hypothesis suggested that we do not run away from something because of fear but we experience fear because we are running away. However, with such theories there were no obvious cerebral locations for the generation of the emotion, although the sensory experiences were known to be received cortically, namely in the parietal regions of the brain. The James–Lange hypothesis was soon tested and shown to be wrong, from two avenues. First it was shown in animals that removal of the cortex of the brain on both sides did not abolish the expression of emotion. Further, it was revealed that stimulation of various structures buried deep within the brain could lead to the release of emotion. These observations formed the basis for a neuroscientific revolution, the impact of which is still poorly appreciated, not only by many in the scientific community – hence Crick’s astonishment – but also by the public and media generally.

The limbic lobe The unravelling of the cerebral mysteries of our emotional being has been one of the most fascinating neuroscience endeavours of the last hundred years. We now appreciate that certain brain structures and pathways are crucial for the mediation and experience of emotion and these are parts of our old evolutionary inheritance that developed aeons before homo developed into sapiens. The key structures of the limbic lobe are the amygdala and the hippocampus, both neuronal aggregates of considerable complexity, and their immediate connecting structures, such as the orbital part of the frontal cortex and the ventral striatum, that

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part of the brain’s extrapyramidal system that relates to emotional motor expression. Each amygdala is located at the anterior part of the temporal lobe and is central to the brain’s regulation of emotion.The lateral cortical part has extensive connections with the neocortex, from which it receives polysensory information; a central–medial division forms part of the extended amygdala. The amygdala provides affective valence to sensory representations and is crucial for the emotional tone of memories. The amygdala thus has reciprocal connections with the same cortical structures it receives information from, including even the primary sensory cortical areas allowing for an influence of emotional tone directly on cortical sensory impressions. The hippocampus is also situated in the temporal lobe, an elongated structure composed of several subdivisions, together referred to, with the dentate gyrus, as the hippocampal formation. The main outflow path of the hippocampus is the fornix, which like several other limbic components curves around the thalamus and then descends to the mammillary bodies of the hypothalamus, forming a crucial link structure still referred to as the Papez circuit. The latter name refers to an initially identified collation of structures that modulated emotion and for the first time gave the emotional disorders (psychiatry) a firm neuro-anatomical base. Other crucial structures include the parahippocampal gyrus and the entorhinal cortex which input much integrated polysensory information to the hippocampus via the perforant path. The cingulate gyrus surrounds the corpus callosum forming a C-shaped band, linking posteriorly with the parahippocampal gyrus connecting extensively with neocortical structures, such as the precuneus. The gyrus has widespread connections with the entorhinal area, the amygdala, the ventral striatum, the hypothalamus and subcortical structures which allow the cingulate gyrus to have a very important role in attention, motivation and emotion. The inputs to the limbic lobe are thus both interoceptive (visceral) and exteroceptive (conveying information about the environment). The former derive from many structures that give information about the internal state of the organism, and include modulating influences from substantial neurotransmitter autonomic pathways which originate in the mid- and hindbrain that help drive behaviour and modulate mood, via transmitters such as dopamine, serotonin and noradrenaline. The exteroceptive afferents derive from all sensory systems and ultimately present complex integrated sensory information from the cortex to the hippocampus and the amygdala (Chapter 2). The frontal lobes of the brain have many demarcated subregions. The orbital, medial and dorsolateral areas are those most frequently discussed. The orbito-frontal cortex lies over the floor of the anterior cranial fossa and has intimate connections with the anterior insula, the amygdala, the ventral striatum and sensory projection pathways. The insula is a large limbic structure, which in contrast to most of the limbic lobe is not visible from the medial surface of the brain. It lies laterally, buried beneath folds of neocortex. This too has many functions, including integration of limbic and cortical information and it links with the frontal cortex anteriorly and with the hippocampal structures posteriorly.

Psychiatry and Neurology An understanding that the cortical afferents to the corpus striatum involve the whole of the cortical mantle, including from the limbic lobe, has allowed for a theoretical differentiation to be made between the ventral and dorsal striata, respectively receiving their main inputs from the limbic lobe and the neocortex. One main area of the ventral striatum is the accumbens, heavily afferented from the cortical amygdala and hippocampus, and the prefrontal and temporal association cortices. The main output from the ventral striatum is to the ventral globus pallidus and thence to the thalamus which then projects back to the frontal cortex. This is but one of several cortico-striato-pallidal-thalamiccortical parallel re-entrant loops, possibly segregated that have been defined in the vertebrate brain and have important regulatory properties governing behaviour. The loop from the motor cortex (dorsal striatum) is involved with somato-motor activity, while the ventral limbic–striatal circuits modulate reward and motivation. However, there are efferents from the ventral to the dorsal striatum. The so-called extended amygdala forms a bridge between the amygdala (central and medial nuclei), the limbic forebrain (ventral striatum) and the hypothalamus, with its autonomic and endocrine influences. These anatomical principles reveal how emotion drives motion, providing an understanding of the motor aspects of all psychiatric disorders and the emotional dysfunction that accompanies many neurologically described disorders, especially disorders of movement. The concept that certain major brain structures could form the foundation of an emotional brain system was a stunning departure for neurology and the launch pad of the discipline of behavioural neurology – that branch of neurology which tries to understand how the brain modulates and relates to behaviour. This also gave a neuro-anatomical framework for the renaissance of neuropsychiatry. A problem with the initial conceptions of the limbic system (which became viewed as a self-contained system, hence the preferred term ‘limbic lobe’ – after Broca), were the earlier accepted anatomical facts which suggested that there were very few direct cortical projections from the neocortex to the hypothalamus (a structure that is so important in regulating autonomic activity), and that the hypothalamus was to be regarded as the principal subcortical projection of the limbic system. This led to an interesting but damaging conclusion that had implications not only for understanding brain behaviour relationships but also for the developing fields of behavioural neurology and neuropsychiatry. Thus, those neurologists who 50 years ago might reluctantly concede that there was an underlying neurology of behaviour, would say that the limbic system–hypothalamic axis was explanatory enough for them – it explained how there might be a neurology of the emotions (and hence a biological psychiatry). This was very different from the known neuro-anatomy of neurological disorders. The latter involved essentially the neocortex and its main outputs, especially the basal ganglia and the pyramidal motor system. A fundamental flaw in this scheme was that it did not correspond to many clinical observations in which a blending of neurological and psychiatric signs and symptoms were seen. Also,

Earlier limbic system concept Limbic system Neocortex

Hypothalamus (psychiatry) Basal ganglia (neurology)

Modified (current) limbic lobe concept Limbic system Basal ganglia Neocortex Figure 21.1 Concepts of the limbic system.

it also failed to connect with everyday observations and language, namely that (in English, for example) emotion is six-sevenths movement (e + motion). We express our states of distress and emotion with movements, including of course speech. This conceptual change is shown in outline form in Figure 21.1. Once it became appreciated that the rostral parts of the basal ganglia, far from being exclusively motor in function were actually innervated by the limbic structures and that there was a much stronger connectivity between limbic structures and the basal ganglia than with the hypothalamus, our understanding of the neuro-anatomical basis of neuropsychiatric disorders changed fundamentally.

Epilepsy Epilepsy is central to the discipline of neuropsychiatry. Seizures are not the same as epilepsy. Each has a separate classification developed by the International League Against Epilepsy. Seizure classification allows for a variety of clinical signs and symptoms, while that of the epilepsies relates more to underlying biological processes. Antiepileptic drugs are in fact not antiepileptic; they are antiseizure medications. To date there is scant evidence that they halt or ameliorate the process of the underlying epilepsy. This means effectively that suppression of seizures, the goal of treating epilepsy, may not lead to an end of a patient’s difficulties and is a signal that suppression of seizures in the setting of continuing underlying neurophysiological abnormalities may sometimes have adverse consequences. A classic example is the phenomenon of forced normalization described below.

Psychiatric disorders of epilepsy A classification of the behaviour disorders encountered in patients with epilepsy must embrace the straightforward psychiatric symptoms that any patient with epilepsy may have, e.g. depression or anxiety that would follow DSM-IV-TR or other psychiatric classifications. However, there are seizure-related and epilepsyrelated psychiatric disorders as shown in Table 21.10. It is traditional to refer to ictal and interictal syndromes. Ictal syndromes are closely entwined with the seizure itself while the interictal syndromes are not seizure-dependent. The classic ictal

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Chapter 21

Table 21.10 Classification of psychiatric disorders of epilepsy.

Table 21.11 Risk factors for interictal psychoses. From Trimble (1991).

Co-morbid disorders (classified after standardized manuals): • e.g. Anxiety, depression, phobias Integrated disorders (directly linked to epilepsy) with distinguishing features: • Interictal dysphoric disorder (Kraepelin; Blumer) • Interictal schizophrenia-like psychoses (Slater) • Postictal psychoses/states • Interictal personality disorder (Gastaut, Geschwind) • Forced normalization (Landolt)

Age of onset Interval Sex Seizure type Seizure frequency Seizure focus Neurological findings Pathology

syndromes include a pre-ictal dysphoria, the aura – particularly with a seizure focus in a temporal lobe – which can cause psychological phenomena such as déjà vu or depersonalization episodes and the postictal delirium. The latter rarely last more than half an hour although sometimes longer, especially in those with learning disability. Postictal delirium is an organic brain syndrome associated with considerable confusion but one from which the patient usually recovers completely and comes to no harm. Ictal status epilepticus, particularly arising from a focus in the temporal lobes, can lead to a psychotic presentation resembling schizophrenia, although close examination will often reveal some minor and fluctuating clouding of consciousness. The EEG will almost certainly indicate the diagnosis. Postictal psychosis should be viewed as a separate syndrome. Classically, this erupts some 24–48 hours after a cluster of seizures. The patient has a seizure cluster or a seizure that is unusual for them such as a prolonged generalized tonic–clonic attack. There is then a lucid interval between the expression of the seizures and onset of the psychosis. During this period, the patient is often quieter than usual, then some warning signs of the impending psychosis may emerge such as irritability, restlessness, sleeplessness or emotional lability. The psychosis can come quite suddenly and is often paranoid in nature. Hallucinations and delusions are common of a schizophrenia-like nature. Many are religious in content and it is during this phase of the psychosis that patients are in danger of harming themselves. Fear of impending death is another often reported symptom. Some 50% of patients in a postictal psychosis have clear consciousness (in contrast to the postictal delirium) and can therefore plan and work out elaborate acts. Because their hallucinations are often command hallucinations and may demand either self-injury or injury to others, they are able to carry such instructions forward. Clearly, this can be a medical emergency. It is recognized that suicide is increased in people with epilepsy, particularly temporal lobe epilepsy (with estimates of up to 25 times that of the normal population) and it is during postictal states that the risk is probably at its highest. These postictal psychoses last from hours to days and may be recurrent. Approximately 25% of patients who have postictal psychoses will eventually to develop an interictal psychotic state. Variants of the postictal psychopathology that do not reach levels of psychoses are seen with postictal anxiety states or postictal depressive syndromes. These are far more common but often

not noted or even enquired about. They have a constancy of presentation and phenomenology that suggests that they are intimately linked with the seizure process, rather than with some environmentally cued aetiological factor. Interictal syndromes bound in with epilepsy vary from anxiety states through to psychoses, although certain specific syndromes need to be clarified. Thus, while people with epilepsy can easily develop a depression, either in the setting of such an unpleasant disorder or perhaps even secondary to long-term sedatives (barbiturates were a major problem in the past), a rather specific form of depression has been recognized and is referred to as the interictal dysphoric disorder (IDD). This refers to patients who have a collection of dysphoric symptoms (irritability, anergia, depressed mood, insomnia, atypical pains, anxiety and euphoria) without the prolonged melancholia of a major depressive illness. The episodes are often short-lived, lasting sometimes a matter of days. It is thought that these are interlinked with the underlying biological processes of the epilepsy. This syndrome is important to recognize because mood lability and recurrent dysphoria easily leads to discord within a family and affects quality of life. The interictal psychoses typically have a paranoid or schizophrenia-like presentation, often including Schneiderian First Rank symptoms but with certain features which were first specified by the papers of Eliot Slater. These include the absence of a personality deterioration over time, with the maintenance of affective warmth and a tendency to depressive episodes of the IDD type. The risk factors for developing these psychoses are shown in Table 21.11. They are linked with a limbic focus, often – initially at least – stemming from the left hemisphere and are seen in patients with long-standing and refractory epilepsy. Interestingly, bipolar disorders and affective psychoses are rarely reported as interictal syndromes. A common site of pathology of patients with chronic epilepsy is in the medial temporal structures and it is of considerable interest that schizophrenia in the absence of epilepsy has now been shown to be associated with pathology at a similar site, albeit of a different characteristic. The difference between idiopathic schizophrenia and temporal lobe epilepsy is that the pathology of schizophrenia does not seem to include hippocampal gliosis. The similarities are disorganization of neurones primarily in the hippocampus and the fact that in both syndromes the pathology is established early in life while the main manifestations appear some years later in late adolescence or early adulthood. Both

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Often early adolescence Onset of seizures to onset of psychosis: approx. 14 years F>M Complex partial, often with automatisms Diminished, especially temporal lobe Temporal, especially left-sided Sometimes sinistrality Gangliogliomas, hamartomas

Psychiatry and Neurology syndromes present with a wide range of psychological and behavioural signs and symptoms. The association between epilepsy and a schizophrenia-like psychosis has now been well established in a number of epidemiological studies. The lifetime prevalence is around 10% in chronic epilepsy cases. In contrast to patients with schizophrenia, however, such patients often manage well in the community, they may be married and hold down a job and often will not report psychotic symptoms, even to their physicians. A variant of the interictal psychosis noted in those with learning disability is one of increasing cognitive deterioration and failure to continue within the lifestyle set up by relatives or longterm carers. Such patients present with an apparent deterioration of behaviour and cognition. One possible cause for this would be a progressive neurological disorder. However, careful observation, particularly in an in-patient setting, may reveal either an undisclosed partial status epilepticus or an evolving psychosis with paranoid features that are neither well elaborated nor readily evident on account of linguistic and intellectual handicaps. Forced normalization Forced normalization refers to the observation that certain patients develop psychiatric symptoms when their seizures come under control. Originally this phenomenon was thought to involve psychoses alone, but other behaviours are now recognized in this setting, including depression, anxiety, agitation or even occasionally the presentation of non-epileptic seizures. In children and adolescents, a hyperactivity disorder or conduct disorder can result. The phenomenon (Landolt phenomenon) refers to the fact that the EEG normalizes during the behaviour disturbance and that as the behaviour problems resolve the EEG resorts to its abnormal configuration. Another, perhaps better term for this is paradoxical normalization. Thus, as a general rule, if behaviour deteriorates in someone with epilepsy, the EEG also deteriorates (e.g. in non-convulsive status or with an encephalopathy). However, in the Landolt phenomenon the EEG becomes paradoxically normal when behaviour is abnormal. The phenomenon is usually seen as an acute onset disorder, often in response to the sudden switching off of seizures in a patient with chronic epilepsy with a new anticonvulsant drug. While all anticonvulsants may lead to this problem, it is seen especially commonly following prescription of benzodiaze-pines, barbiturates, ethosuximide, vigabatrin and topiramate. A common theme to these is their GABA agonism, although this is not exclusive. Forced normalization essentially is an EEG diagnosis, but the clinical counterpart, referred to as alternative psychosis, is also seen. In other words, patients whose behaviour alternates between deterioration with control of seizures and improvement with return of seizures over a period of time. Although these may represent episodes of forced normalization, it is only possible to confirm the latter with serial EEG recordings which may not be feasible to perform. Finally, there is a group of patients who, over years, gradually lose their seizures but in this context develop a slowly evolving psychosis which then becomes the main clinical problem. This

may represent a variant of the theme. It remains relatively unrecognized, although many cases were recorded in the older literature before effective anticonvulsant therapy was available. Personality changes The interictal personality syndrome, sometimes referred to as the Gastaut–Geschwind syndrome, is characterized by the following features: hyper-religiosity, with deepening concern for philosophical and mystical preoccupation; disorders of sexual function (often hyposexuality); hypergraphia (with a tendency to excessive and compulsive writing); and viscosity (stickiness of thought, bradyphrenia). The proportion of patients who develop this syndrome is unclear and it may be up to 10% of patients with temporal lobe origins for their epilepsy and difficult to control seizures. The behaviour changes are often subtle, evolving over a matter of months or years and coming to light via the patient’s relatives. Distinguishing when the behaviour becomes pathological can sometimes be difficult and not all patients show all elements of the syndrome. Geschwind considered hypergraphia to be one of the most missed neurological signs in neurological practice. In order to diagnose this syndrome it is often necessary to ask patients details about their religious beliefs, practices and observances and their writing habits, e.g. asking to see their personal diaries. This is not usually done during a conventional interview, one reason for under-reporting. This syndrome is an example of an organic personality change consequent upon chronic limbic lesions.

Movement disorders In the same way that understanding the neurobiology of epilepsy and its behavioural consequences and associated psychiatric disorders has informed many current practices in neuropsychiatry, study of the behavioural associations with movement disorders reveals a similar constellation of concepts. Abnormalities of movement accompany all psychiatric disorders, whether this is a mild tremor of an anxiety state or the tics, mannerisms and gestures of a schizophrenic patient or catatonia. Psychopathology is intimately bound with movement. It is often easier to recognize an emotion by the movement and gestures that accompany it than with any verbal counterpart. This association also works in reverse. Thus, a number of traditionally accepted neurological movement disorders present with a high frequency of psychopathology. Examples are Huntington’s disease, Parkinson’s disease and Gilles de la Tourette’s syndrome. As already described, the recent unravelling of the neuro-anatomy and chemistry of the basal forebrain and related striatal structures has illuminated these relationships giving, as with epilepsy, clinical observations clear neurobiological foundations. Thus, we now know that the basal ganglia are not simply associated with extrapyramidal movement disorders, they subserve emotion and some aspects of cognition. The major outputs from the limbic lobe to the limbic forebrain use ventral striatal afferents that themselves form but one of the cortical–subcortical–cortical re-entrant pathways (Chapter 2).

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Parkinson’s disease Aside from intellectual impairment – so common in Parkinson’s disease – about 40% of patients meet criteria for dementia and perhaps an additional 30% have more subtle cognitive impairments – the most common psychopathologies are depression and psychoses. A dysphoric mood is frequently found. Up to 50% of patients report depressive symptoms, often with some atypical features, particularly anxiety and often an absence of guilt and selfdepreciation. A lesser number on evaluation, perhaps 10%, have a typical major depressive disorder. The depression does not seem to correlate well with the extent of the physical limitations. Biological associations have been noted between Parkinson’s disease and depressive illness by PET scanning which reveals decreased glucose metabolism in the frontal lobes, particularly in severely depressed patients. In some patients there is a clear history of a mood disturbance before the onset of the movement disorder. One of the main management problems is psychosis. The psychoses of idiopathic Parkinson’s disease vary considerably. Often the entry to a more malignant phase is the onset of nocturnal hallucinations, associated with some confusion. The psychosis may progress to a more pervasive and consistent form or may have started with daytime simple, or sometimes complex, hallucinations. These then gradually take on a paranoid form and a full-blown delusional state emerges. Delusions of jealousy are common and the hallucinations are most commonly visual, complex and often frightening. The psychoses are more commonly found in association with dementia with Lewy bodies and often seem to be accelerated by the anti-parkinsonian medication. Dopamine is powerfully psychotogenic. When the effectiveness of levodopa for the physical symptoms wanes, the psychosis emerges. Sometimes this follows an increase in levodopa dosage and at others the use of dopamine agonists or polytherapy. Hallucinations occur in 30%, delusions in 10% and euphoria in 10% of patients treated with all dopaminergic agents. Sometimes these occur in the absence of an obvious delirium. Occasionally they reflect excessive use of drugs by the patient in an attempt to relieve motor symptoms. The features of the dopamine dysregulation syndrome are shown in Table 21.12. Table 21.12 Dopamine dysregulation syndrome. Overuse of dopaminergic medication Risk factors: male sex and young age Increasing doses of dopaminergic drugs despite severe dyskinesia Behavioural and mood changes: • Hypomania and mania • Irritability and aggression • Paranoia • Repetitive purposeless motor acts (punding) • Walking aimlessly • Pathological gambling • Drug hoarding • Hypersexuality

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The development of psychosis in Parkinson’s disease often heralds a breakdown in community care, tolerant relatives no longer being able to accept the wayward thoughts and actions of the patient. The management is complicated because dopamine antagonists, the mainstay of treatment for psychoses, tend to make the motor symptoms worse. Parkinsonism, as opposed to Parkinson’s disease, is a not an uncommon secondary problem in people with psychoses who are treated with neuroleptic agents. Some degree of akinesia is common in such situations, but more florid presentations with typical parkinsonian rigidity and tremor is still often noted. With the advent of the atypical antipsychotic drugs the more florid manifestations of tardive dystonia and dyskinesia are now less commonly seen. Nonetheless, balancing the patient on the fine edge between mobility and psychosis represents a considerable clinical challenge.

Other movement disorders Progressive supranuclear palsy often presents with a dementia with subcortical features. Depression and obsessive-compulsive disorder are often described in these patients. In Huntington’s disease (HD), a variety of psychopathologies may be seen, to some extent independent of the progression of the subcortical dementia. Personality changes are ubiquitous and include irritability, disinhibition, conduct disorder, antisocial behaviour and often drug or alcohol dependency. The early symptoms include emotional lability and increased excitability. Relatives complain that the person becomes more and more difficult to live with. Irresponsible and promiscuous behaviour may be reported. Loss of interest in work and the family ensues. Depression occurs in 40–50% of HD patients, often with psychotic features. A manic presentation occurs in about 2%. Suicide is a major complication of the depression and can occur in the absence of knowledge of the diagnosis. Psychosis occurs in 5–15% of HD patients and is typically paranoid rather than schizophrenia-like, and may precede the onset of the chorea in perhaps one-third of cases. There is no clear relationship between the expression of the abnormal movements and the severity of the psychosis. Other forms of chorea that are particularly relevant for neuropsychiatry include Sydenham’s chorea and the paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). Sydenham’s chorea has been associated with the development of an obsessive-compulsive disorder, while PANDAS is characterized by tics and obsessive-compulsive disorder. Affective disturbances and behaviour abnormalities are reported and patients sometimes appear hypomanic. Gilles de la Tourette’s syndrome is characterized by the onset of body and vocal tics usually in or before teenage years. The symptoms characteristically wax and wane over the years. However, tics are not just simple tics but also involve a host of complex tics, often with tortuous motor rituals. The latter can lead on to secondary neurological damage, such as repetitive neck tics causing cervical spine damage, root lesions and myelopathy.

Psychiatry and Neurology The vocal tics are characteristic and necessary to clinch the diagnosis. Coprolalia occurs in some 30% of patients. Secondary forms of this disorder can be seen following stroke, the prescription of various stimulant drugs or after withdrawal from neuroleptics. Similar problems have also been described rarely with lamotrigine. There are three main co-morbid neuropsychiatric disorders with Gilles de la Tourette’s. In childhood, attention deficit hyperactivity disorder (ADHD) is common, occurring in about 50% of patients and at such an age can lead to severe management problems, not the least being difficulties in the home environment and with education. Obsessive-compulsive disorder (OCD) occurs in some 30–40% of patients. This can emerge during childhood but is more common in the teenage and adult years. The presentations are not typical for OCD. For example, handwashing rituals and phobias of contamination are not common. Arithmomania (a strong need to count actions or objects), sadistic and sexual obsessional thoughts are seen. The third problem is self-mutilation which has a compulsive nature to it. Some 30–40% of patients have self-mutilation in various forms, from simple cigarette burning or body punching to the more disturbing eye-poking. The desire to touch, particularly sexual parts of others, is quite often a forensic problem in these patients and the vocalizations can be so disturbing that the patient becomes socially reclusive. It is interesting that OCD and Gilles de la Tourette’s syndrome appear to be inherited in an autosomal dominant fashion. Some members of the family have OCD, some Gilles de la Tourette’s syndrome and others aspects of both conditions. Other basal ganglia disorders sometimes associated with psychoses include idiopathic calcification of the basal ganglia and metabolic disorders such as hypoparathyroidism with excessive calcium deposition in these structures. Patients with Wilson’s disease are not particularly liable to psychotic breakdown but do display episodes of bizarre behaviour with periods of dystonia or posturing which may last for hours at a time. The earliest psychiatric manifestations are increased restlessness but with progression of the disorder lability of affect, euphoria and obvious personality changes are seen. Cognitive impairment develops as the years go by.

White matter disorders While so many neuropsychiatric disorders reflect on disturbed neuronal and glial functioning, it is often forgotten that disorders of white matter also can provoke psychopathology. The classic disorder is multiple sclerosis but acquired disorders of white matter and leucoencephalopathies also present clinically as behaviour problems. In multiple sclerosis, the main neuropsychiatric problem is disturbed cognition which occurs early on in the course of the disease. This is often unrecognized, but the thinking of patients becomes more rigid and inflexible, memory complaints occur and an alteration of mood may become apparent. Often the latter is a depressive-like syndrome but with organic

overtones. Fatigue is common as are emotional lability and suicidal ideation. The estimated lifetime prevalence for a major depression is about 40%. Occasionally onset of a relapse or even the first clinical episode of the disorder is an acute psychiatric presentation. A mental state consisting of euphoria and eutonia (a sense of bodily well-being) was described earlier as rather specific for multiple sclerosis. While this picture is noted, it is essentially associated with a combination of intellectual decline and cerebral pathology particularly with multiple peri-ventricular plaques seen on MRI and cerebral atrophy. This leads to disconnection between the frontal lobes and subcortical structures and in association with the cognitive changes, denial of the severity of the illness. Interestingly, in contrast to grey matter disorders, psychoses are quite rare in multiple sclerosis. When they occur, they tend to be associated with plaques around the temporal horns of the lateral ventricles. Treatments for multiple sclerosis may be associated themselves with psychopathology, depression being a particularly common side-effect of beta-interferon. Suicide is an ever present risk and any threat to self-harm should be taken seriously. Patchy deep white matter lesions are often seen on MR T2W scans and are in many settings apparently of little clinical significance. However, it has been shown that there is an increased risk of depression with such scan abnormalities when they are florid. The depression tends to occur more after the age of 50 and it is often quite treatment-resistant. Again, changes in relation to frontal basal ganglia circuitry are most often linked with the psychopathology. Another syndrome of myelin destruction, subacute combined degeneration secondary to vitamin B12 depletion is rarely seen these days, but B12 deficiency can present with anything from mild forgetfulness and irritability to psychoses, confusional states and dementia. Folate deficiency has for a long time been linked with depression and occasionally a patient is found with intractable depression who responds to folic acid. Central pontine myelinolysis is a rare disorder but which can occur following alcoholism with states of malnutrition, especially with electrolyte imbalance and hyponatrenia if this is rapidly reversed. Subtle changes of the mental state including a pseudobulbar palsy may be seen and in dilapidated patients this presentation may accompany a Wernicke–Korsakoff encephalopathy (Chapter 18). One of the challenges of neuropsychiatry is the identification of genetic disorders affecting white matter which in childhood present with severe neurological symptomatology and often early death. In variants that affect patients in teenage years or early adulthood, there is often an initial presentation with florid psychiatric problems. At first these may be rather non-specific, but they soon progress to overt cognitive dysfunction with loss of behavioural control and ultimately to a psychotic state. A typical example is metachromatic leucodystrophy: patients with juvenile and adult onset forms presenting with personality changes and dementia and a schizophrenia-like illness.

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In adrenoleucodystrophy, dementia, learning difficulties and behaviour changes are the most frequent presenting psychiatric problems but again schizophrenia-like states have been reported. Homocystinaemia can present with cognitive impairment and behavioural change. There are a number of glycogen storage disorders that present with psychiatric symptomatology as the age of the patient increases. Most are inherited as autosomal recessive or X-linked conditions and many reveal the CNS symptoms as part of a more generalized metabolic problem. Psychoses are reported in association with subacute sclerosing panencephalitis and with tuberous sclerosis, in the latter usually associated with accompanying epilepsy. The psychoses are schizophrenialike, patients having good affective responsivity and little deterioration over time, with unusual auditory hallucinations of a constant nature, e.g. the reported hearing of a favourite rock band. The term ‘progressive disintegrative psychosis’ is sometime used to distinguish these psychotic presentations from, for example, childhood autism, where the behaviour abnormality characterized by disturbances of language and an inability to form normal interpersonal relationships is recognized from early childhood. The hallmark is progression of the psychopathology, out of proportion to any suggested environmental stress, leading to the frank psychotic disorder. In the non-progressive disintegrative psychoses, there is normal development for the first few years of life with a subsequent loss of skills, but no progressive disintegration. Examples are Heller’s syndrome, or in epilepsy the Landau–Kleffner syndrome.

Other interesting neuropsychiatric disorders Many neuropsychiatric presentations can be understood as a consequence of disorders of the limbic-related motivational–motor neuro-anatomical interface. However, particularly in the 19th and early 20th century, neuropsychiatry was involved in the identification of neocortical focal signature syndromes. Some of these are covered in other chapters of this book, but classically alterations of behaviour involve frontal and temporal cortical circuitry disorders and much has been written about the neuropsychiatry of frontal lobe syndromes. Because the frontal lobes comprise almost one-third of the cortical surface area, complete myelination late in early to mid adult life, and have intimate connections with limbic and the posterior sensory association cortices, they are anatomically poised, both to integrate environmental and emotional information and to formulate and to execute motor action plans. Hence their relationship to so-called executive function and to a number of behavioural syndromes. It may be asserted that any psychiatric disorder includes aspects of a frontal lobe syndrome. There is much mythology about these syndromes and some of this has been driven by the identification of frontal lobe dysfunction using neuropsychological test batteries. However, the validity and reliability of these are still unclear. More importantly,

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many patients with psychopathology have been shown to have disturbed frontal functioning as a feature of their psychopathology. The ubiquitous nature of frontal activity with such extensive cortical and subcortical connectivity means that failure to perform as expected on these so called frontal-executive tasks is quite nonspecific. Central executive systems are not modular and localized, and the so-called frontal lobe tests do not therefore necessarily test activity only of the frontal lobes. Frontal task-solving problems are impaired in patients with schizophrenia, depressive illness and obsessive-compulsive disorder. Further, patients with personality disorders, e.g. borderline personality disorder, also have frontal lobe dysfunctions when tested on neuropsychological batteries. Any person with limited intellectual abilities will also have difficulty performing such tasks. It is for these reasons that apparent frontal lobe dysfunction based purely on neuropsychological test findings cannot be a valid indicator of frontal lobe damage. Other signature syndromes that often involve the neuropsychiatric assessment include some aphasic syndromes and the right hemisphere syndrome. The confusion of a fluent aphasia (Wernicke’s) punctuated with neologisms can occasionally be mistaken for a schizophasia, but close evaluation will reveal the associated neurological impairments or the underlying nature of the paranoid delusions in schizophrenia. Aprosodias, in which the melodic and intonational aspects of speech are lost, occur following non-dominant hemisphere lesions in the equivalent areas that deal with language in the left hemisphere. Gesture is usually reduced in patients with dysprosody and such patients often have considerable difficulty communicating their feelings, leading to an under-estimation of their distress. The angular gyrus syndrome following lesions of the left angular gyrus produces agraphia, acalculia, right–left disorientation and finger agnosia (Gerstmann’s syndrome) with, in addition, constructional disturbances, apraxia and alexia and memory problems. The clinical picture can be so confusing that it is easily mistaken for Alzheimer’s disease or for a non-neurologically based pseudodementia. Neuropsychiatric syndromes following right hemisphere dysfunction are often unrecognized. If a patient has a left hemisphere stroke, the resulting aphasia will lead to an instant referral to neurology. However, non-dominant hemisphere lesions often present with psychopathology and the neurological underpinnings of their problem missed. Apathy and sometimes abulia result, which are often misinterpreted as a depression. Secondary manias occur following lesions of the orbitofrontal cortex–basal ganglia circuitry. Depression is most frequently associated with right posterior cortical lesions while delusions may arise with lesions of the right temporal lobe or temporoparietal junction. Misidentification syndromes, such as the Capgras syndrome, are more common with right-sided lesions. The psychiatric syndromes, particularly psychoses and depressions, following right hemisphere insults are difficult to treat and have a poor prognosis. A table of neuropsychiatric syndromes reported in patients with right brain lesions is given in Table 21.13.

Psychiatry and Neurology Table 21.13 Right hemisphere psychiatric syndromes. From Cummings & Trimble (2002).

Table 21.14 Aetiological factors in psychiatric disturbance after head injury. After Lishman (1998).

Syndrome

Lesion location

Depression Depression with anxiety Psychosis Visual hallucinations

Frontal lobe, temporal lobe, caudate nucleus Frontal cortex Temporal lobe Geniculocalcarine radiation, occipital cortex, temporal lobe Parietal lobe, frontal lobe, corpus callosum Parietal lobe Temporal lobe Parietal lobe Temporoparietal region

Mental constitution Premorbid personality Emotional impact of the injury Emotional repercussions of the injury Environmental factors Compensation and litigation Response to intellectual impairments Epilepsy Extent of brain damage Location of brain damage History of substance abuse

Apraxia Primary acalculia Verbal amnesia Spatial neglect Denial of language deficit

Psychogenic amnesias Memory disorders are discussed elsewhere within this book. However, so much is written about the structural basis of memory disorders, linked with hippocampal circuitry, that the dynamic and autobiographical nature of our memory is overlooked. In many languages ‘to remember’ is expressed reflexively (German: ich erinnere mich). The brain recalls things past; remembering is a creative form of forgetting. What is represented in our memory and how it is represented is entirely elusive and illusive. Psychogenic amnesia is also referred to as dissociative amnesia. Essentially this refers to an episode of inability to recall important personal information, usually related to traumatic or stressful events. There is preservation of the ability to comprehend environmental information and to perform complex learned skills. However, psychogenic amnesia may occur in the setting of subtle neurological illness, particularly following minor head injury. Situational psychogenic amnesias occur in association with psychologically traumatic events and may form part of a larger clinical picture of a post-traumatic stress disorder, with psychological intrusions, increased arousal or the development of phobias or fugue states. The Ganser syndrome is a complex of hallucinations, cognitive disorientation, some conversion symptoms and the symptom of approximate answers (Vorbeireden). It has been described in a number of settings and has been associated with head injury, depression, schizophrenia, and epilepsy, but it is also noted in malingering. Vorbeireden is the inability to answer simple questions correctly even though the nature of the question is known: approximate answers are given. Pseudodementia is an all-embracing term for cognitive and memory impairments that are seen in a variety of settings from depression through to schizophrenia and in some people with early onset dementia who present with a catastrophic loss of memory and other cognitive abilities. Embraced under this term is also the Ganser syndrome and hysterical dementia. Patients with the latter have a bizarre memory loss, associated with variable and inconsistent results on neuropsychological

testing but often seen in conjunction with other conversion phenomena. The memory loss may be acute or chronic but is out of keeping with the patient’s observed abilities in everyday life. The condition may be precipitated by a minor head injury and in a compensation setting often leads to the suspicion of malingering. Reduplicative paramnesia is a syndrome in which a patient is certain that a familiar place, person, object or body part has been duplicated. For example, the patient will insist that a familiar place (the hospital room) exists in an impossible location, e.g. in their house. It is usually discussed in the context of a misidentification syndrome.

Post-concussional syndrome The nosological status of this condition is always in doubt. It is often reported in patients who have minor head injuries. They complain of headache, dizziness, diplopia, fatigue, noise sensitivity and poor concentration. Normally, patients recover within a few weeks but there is a small percentage who remain symptomatic in the long term. In some patients there may be subtle signs of damage noted on brain imaging or with abnormal vestibular tests, but it should be noted that similar symptoms are reported in people involved in accidents with bodily trauma who have no head injury. However, the symptoms can blend in with those of anxiety, depression and post-traumatic stress disorder. It is generally accepted that the longer the symptoms go on the less likely they are to be caused by any underlying neurological impairment. It is often forgotten that the head holds a special place in the personal concept of the body image and head injury, of whatever severity, poses a threat that injury to other parts of the body usually does not. In addition, head injury often is the result of an accident and someone else may well be to blame or it can be related to some complicated psychosocial setting leading to unresolved conflict or guilt. In these settings psychological factors are most likely to be predominant in determining symptoms. Some of the aetiological factors of psychiatric disturbance following head injury are shown in Table 21.14.

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Table 21.15 Classification of psychotropic drugs.

Treatments Drug treatments This is not the correct setting to describe in any detail the use of psychotropic drugs for psychiatric disorders secondary to neurological diseases. However, a few comments of clinical relevance should be made, and some of the neurological consequences of psychiatric treatments noted. In general, psychotropic medication should be started with low doses and built up to effective ones, and they should never be stopped suddenly. Some of them have dependence potential (e.g. benzodiazepines), while others, such as antidepressants and antipsychotics, do not. However, reassuring patients that they will not develop a dependency is often important in management, because such is a frequently expressed fear. All of the psychotropic drugs are neuromodulators and there is of necessity overlap between the use of many of these drugs in neurology and psychiatry. The main target neurotransmitters are dopamine, noradrenaline, serotonin, GABA and glutamate. A classification is given in Table 21.15. With regards to antidepressants, there are the monoamine oxidase inhibitors (MAOIs) and tricyclic drugs but selective serotonin re-uptake inhibitors (SSRIs) are most popular. There are a number of variants available, including drugs such as venlafaxine and duloxetine, serotonin–noradrenaline re-uptake inhibitors, and mirtazapine, a noradrenergic but selective serotonergic antidepressant. Their main advantages are the lack of cardiac effects and therefore safety in overdose and lack of sedation. They are best given in daytime doses. Side effects of non-MAOI antidepressants are shown in Table 21.16, some of which obviously have neurological significance including tremor, dyskinesias and myopathy. The SSRIs can cause extrapyramidal disorders including akathisia and dystonia. Seizures can be precipitated. These are more common with certain antidepressants of which maprotiline, mianserin, clomipramine and buproprion are representative. The risk of an increase in seizures in epilepsy, however, needs always to be mentioned, but this is not usually a problem in clinical practice, partly because patients with epilepsy are on antiepileptic drugs and partly because patients most susceptible to depression are often those with refractory epilepsy, who already have quite frequent seizures. In some patients, who respond to the psychotropics but who do experience an exacerbation of seizures, a judicious increase in the antiepileptic drug therapy may be warranted. The problem is the more difficult patient who has been seizure free for a long time, but who develops a psychiatric disorder requiring treatment. Such patients are susceptible to the provocation of a seizure, either on account of the pro-convulsant potential of the drugs or because of a pharmacokinetic interaction. Careful discussion of the possibility of a seizure with the patient is mandatory. Pharmacokinetic interaction possibilities are legion. Most psychotropic drugs utilize the CYP 450 enzyme system. For details

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Antidepressants Monoamine oxidase inhibitors (MAOIs) Moclobemide, phenelzine

Tricyclic antidepressants (TCAs) Amitriptyline, nortriptyline, clomipramine, imipramine, desipramine, maprotiline Tetracyclic antidepressants Mianserin Selective serotonin re-uptake inhibitors (SSRIs) Fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram Noradrenergic uptake inhibitors (NARIs) Reboxetine Noradrenaline–serotonin uptake inhibitors (NSRIs) Venlafaxine, duloxetine Noradrenaline–selective serotonin antidepressants (NASSAs) Mirtazapine Serotonin antagonist and re-uptake inhibitors (SARIs) Trazodone, nefazodone Antipsychotics Typical Phenothiazines, e.g. thioridazine, mesoridazine, chlorpromazine, prochlorperazine Butyrophenones, e.g. haloperidol

Atypical Benzioxazoles and benzisothiazoles, e.g. risperidone, ziprasidone, perospirone Thienobenzodiazepine, dibenzothiazepine and dibenzothiazepine derivatives, e.g. clozapine, olanzapine, quetiapine Others Sulpiride, amisulpiride Minor tranquillizers Barbiturates, benzodiazepines, others Mood stabilizers Lithium carbonate, valproic acid, carbamazepine, lamotrigine Others Beta-blockers, amfebutamone (bupoprion)

of specific interactions the reader is referred to recent reviews. However, in clinical practice the main problems are the lowering of levels of the psychotropic drugs by enzyme inducers, such as anticonvulsants and the provocation of anticonvulsant toxicity with some antidepressants, especially fluoxetine and citalopram. If there is concern about possible interactions, then serum levels of anticonvulsants should be taken before the administration of the psychotropic for later comparison and any deterioration of behaviour checked against repeated serum level assessments. Antidepressants need to be given for at least 6 months in a patient who has developed a major depressive disorder, but variants, such as the interictal dysphoric disorder of epilepsy, may

Psychiatry and Neurology Table 21.16 Side effects of non-MAOI antidepressant drugs. Sedation Dry mouth Palpitations and tachycardia ECG changes Visual difficulties Postural difficulties Postural hypotension Nausea, vomiting, heartburn Constipation Glaucoma Urinary retention, impotence, delayed ejaculation Paralytic ileus Galactorrhoea Sweating Fever

Tremor Dyskinesia Myopathy, neuropathy Convulsions Ataxia Delirium Agitation Transient hypomania Depersonalization Aggression Jaundice (cholestatic) Weight gain Impairment of cognitive function Rashes Extrapyramidal reactions

resolve without therapy after a few days, although they may become repetitive and persistent requiring longer term mood stabilization. The antipsychotics include two large groups: typical and atypical. The former group divide into the phenothiazines (such as chlorpromazine), the butyrophenones (such as haloperidol) and others. The atypical drugs have become more popular recently and include sulpiride, risperidone, olanzapine, quetiapine, amisulpiride and clozapine. While all neuroleptics that are antipsychotic block dopamine receptors, the atypical drugs preferentially act on dopamine receptors outside the dorsal striatum, which leads to much less of a tendency to provoke extrapyramidal problems. The atypical antipsychotic drugs also have a greater affinity for antagonism of cortical 5-HT2 receptors, thought to be important in their antipsychotic action. Again there are metabolic interactions through the CYP 450 system, but these are less with the newer generation of drugs. Enzyme-inducing drugs will lower the serum levels of some, and possibly therefore their effectiveness. Traditional antipsychotics have long been recognized as a class of drugs that can increase the risk of seizures. To determine the risk for drug-induced seizures, different approaches have been adopted: observational studies (case–control studies and case reports), drug-induced EEG changes, animal models and in vitro techniques in isolated tissue samples. One of the problems of the recent literature is that most of the studies have been performed on psychiatric patients and it is not known whether drug-related seizures in non-epileptic patients really predict risk in patients with epilepsy or whether different neurological syndromes have different risks for psychotropic-induced seizures. Patients with a prior history of head injury and stroke may be at increased risk. Generally, chlorpromazine and clozapine are considered proconvulsant, the former only at high doses (1000 mg/day) and the latter at medium and high doses (>600 mg/day). Clozapine frequently causes epileptiform EEG changes and seizures in 3–5% of patients treated, even at therapeutic doses. The EEG changes

may be recorded at low doses and the seizures are often myoclonic, but can be generalized tonic–clonic or partial. Olanzapine is structurally related to clozapine; it is in the thienobenzodiazepine class of atypical antipsychotics and, along with quetiapine, premarketing studies showed a low seizure rate of seizure provocation. It should be noted that studies of the frequency of seizures have been gathered from patients with psychiatric disorders and not on patients with neurological disorders. However, some cross-generalizations may be expected; for example, there is little reason to believe that a drug that is proconvulsant in psychiatric populations will not also be pro-convulsant in people with epilepsy or other disorders that lower the seizure threshold. Finally, the special role of clozapine in the psychoses of neurological patients should be noted. This drug may seem contraindicated in patients with epilepsy, especially on account of its pro-convulsant liability. However, it has been used successfully in the management of the interictal psychoses of epilepsy with certain provisions. It is a remarkably useful antipsychotic in patients whose psychosis fails to respond to other atypical antipsychotics. The use of clozapine is most successful when given to a patient who has developed a psychosis and become seizure free, suggesting some variant of the theme of forced normalization, requiring perhaps a more pro-convulsant antipsychotic for a clinical effect. It is also used in the management of psychoses in Parkinson’s disease where, in small doses, it will control a psychosis without leading to deterioration of the motor disorder. Atypical antipsychotics are also used in the management of Huntington’s disease, states of delirium, Gilles de la Tourette’s syndrome and in the control of mood. The side effects of drooling and weight gain are problems with the use of clozapine, and it should not be used in patients who are taking carbamazepine. However, a change of the latter to oxcarbazepine is an acceptable clinical manoeuvre. A complication of clozapine and some other atypical drugs is development of a metabolic syndrome – increased weight, high cholesterol and Type 2 diabetes. In epilepsy, an EEG should be performed before administration of clozapine, in case of a deterioration of behaviour, so that development of a non-convulsive status epilepticus can be identified and managed. Clozapine should be introduced slowly, white cell counts monitored and increased in doses up to 300–600 mg/day, although some patients respond to lower doses. Extrapyramidal side effects were a problem with the typical antipsychotic drugs and included a spectrum from acute akinesia, akathisia, dystonias and parkinsonism, to chronic variants such as tardive dyskinesias, the rabbit syndrome (oral pouting/ sniffing), dystonias, parkinsonism and Gilles de la Tourette’s syndrome. However, higher doses of atypicals such as risperidone do lead to extrapyramidal signs. The neuroleptic malignant syndrome remains a low but present risk, even with clozapine. With regards to the sedative drugs, barbiturates are rarely used nowadays, the main medications being benzodiazepines, which have tranquilizing, anticonvulsant and muscle relaxant properties. However, some of them are also quite amnestic. Their side effects

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Table 21.17 Toxic effects of lithium. Neuropsychiatric

Gastrointestinal

Renal Cardiovascular Endocrine

Other

Drowsiness Confusion Psychomotor retardation Restlessness Stupor Headache Weakness Tremor Ataxia Myasthenia gravis-like fatiguability Peripheral neuropathy Choreoathetoid movements Cerebellar syndrome Dysarthria Dysgeusia Blurred vision Seizures Dizziness, vertigo Impaired short-term memory and concentration Anorexia, nausea, vomiting Diarrhoea Dry mouth, metallic taste Weight gain Microtubular lesions Impairment of renal concentrating capacity Low blood pressure ECG changes Myxoedema Hyperthyroidism Hyperparathyroidism Polyuria and polydipsia Glycosuria Hypercalcinuria Rashes

carbamazepine, valproic acid and lamotrigine. Carbamazepine can increase the incidence of lithium toxicity and alters several hematological parameters (mainly leucocyte count). It also causes a significant modification in thyroid function with a decrease in T4 and free T4. The opposing effects of carbamazepine and lithium on electrolyte regulation are well known, with the potential occurrence of severe hyponatremia when lithium alone is stopped. The combination of lithium and valproic acid is widely used in rapid cycling, manic, depressive and mixed episode bipolar disorder. This combination seems to have a higher tolerability than the co-administration with carbamazepine and a pharmacodynamic synergistic interaction has been suggested. However, the combination of lithium and valproic acid may induce additive side effects, such as weight gain, sedation and tremor. Some of the side-effects of lithium can be avoided by regular monitoring of serum levels, but polyuria and polydipsia can be troublesome and occasionally a picture of nephrogenic diabetes insipidus can be seen. Severe intoxication may lead to an encephalopathy and may present with hyperactive reflexes, tremor, seizures and focal signs. The anticonvulsant drugs (Chapter 6) may provoke psychopathology in patients with epilepsy, in part through their sedative action and in part on account of their neurochemical action and the phenomenon of forced normalization. It is the case that not all anticonvulsants are mood stabilizing and their spectrum of positive and negative effects on mood has helped unravel the underlying neurochemistry of mood instability – another aspect of neuropsychiatry. The precipitation of an acute psychiatric disorder, sometimes with psychotic features, by anticonvulsant medications as seizures are suddenly switched off (forced normalization) has already been discussed.

ECT, ablative surgery and neurostimulation

include withdrawal seizures, but also a return of acute anxiety on too rapid withdrawal. Concentration and memory problems occur not uncommonly especially in the elderly, and also ataxia. Considerable interest has been shown recently in mood stabilizers; the classic prescription is lithium. Many patients cannot tolerate this and it has a considerable number of neuropsychiatric side effects. These are shown in Table 21.17. Seizures are most common when plasma levels exceed 3.0 mEq/L. At therapeutic levels, the effect of lithium on seizure frequency in individuals with epilepsy is inconsistent and unpredictable. Thus, although reports are conflicting, it appears that lithium can be prescribed safely in patients with epilepsy when mood-stabilizing therapy is necessary and alternative agents either fail or are not tolerated. In these situations, vigilant monitoring of lithium blood levels and clinical signs of neurotoxicity is important. Lithium carbonate is frequently used for manic episodes in bipolar disorder and for the long-term prophylaxis of unstable mood. Other drugs in use with proven efficacy for the latter are

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Electroconvulsive therapy (ECT) is still used in some centres and is valuable in patients with an acute or chronic depressive illness of severity that has not responded to conventional medications. The main indication is mood disorder, especially delusional states, but it has been shown to be helpful in catatonia (where it is the treatment of choice) and in Parkinson’s disease to help both depression and the motor disorder. Very occasionally, ECT has been shown to help resolve epilepsia partialis continua. Contraindications are few but it is best avoided if possible following a recent stroke or in the presence of any condition where there may be raised intracranial pressure. Vagus nerve stimulation has become popular for the treatment of epilepsy in recent years; it appears in epilepsy to have some beneficial effects on mood and has now been introduced into clinical practice for the treatment of chronic resistant depression. It is one of a growing number of techniques that are becoming available for alteration of brain function by stimulation. Transcranial magnetic stimulation is also used in some centres, and is an evolving method of treatment for depression. Neurosurgical procedures for psychiatric disorder have been used frequently in the

Psychiatry and Neurology past, e.g. various frontal leucotomies. Operations included orbital undercutting and capsulotomy, the main anatomical circuits interrupted by such surgery being fronto-thalamic. These procedures traditionally worked best in patients with chronic remitting depressive illnesses, with good premorbid personalities and with severe obsessive-compulsive disorder. The introduction of stereotactic techniques has rendered such procedures much safer, but all ablative procedures are now rarely performed for psychiatric illness. Deep brain stimulation has, however, ushered in a new era of surgical treatment.

have become specialties in their own right. There has always been a psychiatry of neurology and a neurology of psychiatry. The artificial separation between the two disciplines has now been largely dispelled. With new neuro-anatomical and neurochemical concepts, we have a more complete understanding of clinical signs, symptoms and behaviour – for our own illumination and for the treatment of our patients.

Psychological treatments

General

Psychological intervention in neurological practice has increased considerably in recent years, not only in the management of somatoform disorders but also in dealing with the psychiatric co-morbidities of patients with diseases such as stroke, epilepsy and Parkinson’s disease. The available treatments vary from prolonged and intensive psychodynamic psychotherapy (e.g. in the borderline patient with non-epileptic seizures) to the widely used and brief cognitive behavioural therapy that is symptom targeted. These treatments have been shown to be particularly valuable in the management of non-epileptic seizures with a predominantly anxiety-related basis. They are also used in settings where self-confidence has collapsed, such as in patients who are dizzy, elderly patients with falls and patients with epilepsy who have become increasingly fearful of having seizures in public. Psychological education and social skills training may also benefit patients with a wide variety of neurological conditions: the skills of specialist nurses in movement disorder, epilepsy, stroke and multiple sclerosis clinics have provided important additions to management. Additional therapies that have become available using psychological mechanisms include biofeedback: patients autogenically change their own physiological activity in response to sensory biofeedback. Such techniques have been used to help neurological conditions from migraine through to epileptic seizures. While in the past the introduction of psychological perspectives into neurological practice was often considered inappropriate and intrusive, recently psychological interventions have become widely accepted far beyond the field of psychiatry.

American Psychiatric Association. (2000). Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), 4th edn. Text Revision. Washington, DC: American Psychiatric Association. Cummings J, Trimble MR. A Concise Guide to Behavioural Neurology and Neuropsychiatry, 2nd edn. Washington: American Psychiatric Association, 2002. Lishman WA. Organic Psychiatry, 3rd edn. Oxford: Blackwell, 1998. Moore DP. Textbook of Neuropsychiatry. London: Arnold, 2001. Trimble MR. Biological Psychiatry, 2nd edn. Chichester: J. Wiley and Sons, 1996. World Health Organization (WHO). ICD-10 Classifications of Mental and Behavioural Disorders. 10th Revision 2007, Geneva: WHO, 2007.

Conclusions Neuropsychiatry is an old discipline with a long and distinguished history. The first neuropsychiatrist at the National Hospital was Dr John Hughlings Jackson (1835–1911) whose elegant theories relating brain function to structure still deserve careful consideration. The intellectually dishonest break between neurology and psychiatry which involved the first 60 or so years of the 20th century has been surpassed by huge advances in the neurosciences, aided much by inventive techniques of investigating the brain unavailable to earlier generations. Behavioural neurology and neuropsychiatry are now well represented conceptually and

References

Somatoform disorders and abnormal illness behaviour Bass C, Benjamin S. The management of chronic somatisation. Br J Psychiatry 1993; 162: 472–480. Crimlisk H, Bhatia K, Cope H, et al. Slater revisited, a six year follow-up study of patients with medically unexplained symptoms. Br Med J 1998; 316: 582–586. Creed F, Firth D, Timol M, Metcalf R, Pollock S. 1990. Somatisation and illness behaviour in a neurology ward. J Psychosomat Res 1990; 34: 427–437. Fahn S, Williams DT. Psychogenic dystonia. In Fahn S, Mardsen CD, Calne DB (eds.) Dystonia: Advances in Neurology, Vol. 50. New York: Raven Press, 1988: 431–455. Ford CV. The Somatising Disorders: Illness as a Way of Life. New York, Elsevier, 1983. Malleson A. Whiplash and Other Useful Illnesses. Montreal: McGill– Queen’s University Press, 2002. Perkin GD. An analysis of 7836 successive new outpatient referrals. J Neurol Neurosurg Psychiatry 1989; 52: 447–448. Pilowsky I. Abnormal Illness Behaviour. Chichester: J. Wiley and Sons, 1997. Trimble MR. Somatoform Disorders: a Medico-legal Guide. Cambridge: Cambridge University Press, 2004. Wessely S, Hotopf M, Sharp M. Chronic Fatigue and its Syndromes. Oxford: Oxford University Press, 1998.

Epilepsy Blumer D. Epilepsy and suicide. In: Schmitz B, Trimble MR. The Neuropsychiatry of Epilepsy. Cambridge: Cambridge University Press, 2002: 107–117. Brown RJ. Epilepsy, dissociation and nonepileptic seizures. In: Schmitz B, Trimble MR (eds.) The Neuropsychiatry of Epilepsy. Cambridge: Cambridge University Press, 2002: 189–209.

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Krishnamoorthy ES. Neuropsychiatric disorders in epilepsy: epidemiology and classification. In: Schmitz B, Trimble MR (eds.) The Neuropsychiatry of Epilepsy. Cambridge: Cambridge University Press, 2002: 5–17. Logsdaile S, Toone B. Post-ictal psychosis. Br J Psychiatry 1988: 152: 246–252. Mula M, Monaco F, Trimble MR. Use of psychotropic drugs in patients with epilepsy: interactions and seizure risk. Expert Rev Neurother 2004; 4: 953–964. Schmitz B, Trimble MR. The Neuropsychiatry of Epilepsy. Cambridge: Cambridge University Press, 2002. Trimble MR. The Psychoses of Epilepsy. New York: Raven Press, 1991. Waxman S, Geschwind N. The interictal behaviour syndrome of temporal lobe epilepsy. Arch Gen Psych 1975; 32: 1580–1586.

Other relevant publications in neuropsychiatry Bhatia KP, Bhatt MH, Marsden D. The causalgia-dystonia syndrome. Brain 1993; 116: 843–851. Coffey CE, Figiel GS, Djang WT, Weiner RD. Subcortical hyperintensities on MRI: a comparison of normal and depressed subjects. Am J Psych 1990; 147: 187–189.

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Collins M, Hawthorne M, Gribbin N, Jacobson R. Capgras syndrome with organic disorders. Post Grad Med 1990; 6: 1064–1067. Cummings J. Frontal-subcortical circuits and human behaviour. Arch Neurol 1993; 50: 873–880. Cutting J. The Right Hemisphere and Psychiatric Disorders. Oxford: Oxford University Press, 1990. Heimer L, Switzer RD, van Hoesen GW. Ventral striatum and ventral pallidum. Trends Neurosci 1982; 5: 83–87. Kitchin W, Cohen-Cole SA, Mickel, SF. Adrenoleucodystrophy: frequency of presentation as psychiatric disorder. Biol Psychiat 1987; 22: 1375–1387. Mace CJ, Trimble MR. Psychogenic amnesias. In: Yanagihara T, Petersen RC (eds.) Memory Disorders. New York: Dekker, 1991: 429–456. Ron MA. Multiple sclerosis and the mind. J Neurol Neurosurg Psychiatry 1992; 55: 1–3. Schiffer RB, Kurian R, Rubin A, Boer S. Evidence for atypical depression in Parkinson’s disease. Am J Psychiatry 1988; 145: 1020–1022. Trimble MR. The first rank symptoms of Schneider. Br J Psychiatry 1990; 156: 195–200.

22

Pain Geoffrey Schott

Usually one of three issues concerns the neurologist confronted with a patient with pain. Does the pain have an underlying neurological cause? What part does pain play in a patient’s neurological condition? How should the pain be managed? This chapter deals with these issues and discusses some of the underlying mechanisms. The last issue, the management of difficult chronic pain, is often more the concern of colleagues in multidisciplinary pain management. Despite being a subject of interest to only a minority of neurologists, pain is a phenomenon that nevertheless shows numerous features reflecting fascinating and sometimes unexpected aspects of the nervous system. Furthermore, even seemingly straightforward issues are now known to be far more complex, as illustrated by some examples: • The subjective nature of pain. Whilst numerous pain scales and other measuring tools have been devised, both for adults and children, chronic pain is a novel experience for the individual. It is inevitably an experience which is impossible to convey with accuracy and for which words fail, making both clinical practice and research difficult and often imprecise. • The sensory and emotional components of pain. The complex and probably ever-present relationship between the sensory and the emotional and affective components intrinsic to the experience of pain is being increasingly recognized. Appreciating the twin components has major implications for theory and practice. • Peripheral versus central pains. The customary division of the nervous system into the peripheral and central nervous components is often unhelpful. A number of disorders such as shingles and brachial plexus avulsion injuries may affect both divisions; every peripheral pain is associated with ascending and descending cascades of central physiological and neurochemical changes affecting the spinal cord and brain; and central lesions of the nervous system often result in peripheral disturbances.


•

The specificity of pain-subserving pathways. On the one hand, simple notions of pain pathways that resemble tramlines may have been thoroughly overturned. On the other hand, selective lesioning of the spinal cord by anterolateral cordotomy can abolish pain sometimes for long periods, and pain resulting from a stroke can be abolished by a second small stroke – facts arguing for selective anatomical pathways mediating pain. • Stimulation of the nervous system for pain relief. This concept is counter-intuitive when treating symptoms that are by definition already positive and excessive. Nevertheless, numerous stimulation techniques have been explored, and sometimes one or more of them may prove valuable in pain management. • The relationship between pain and itch. Both are unpleasant sensory experiences, are subserved by C fibres, project to the brain through the anterolateral quadrant of the spinal cord, and can be caused by the same neurological disorders including shingles, thoracic root compression, multiple sclerosis, brain tumours and stroke. In some of these conditions pain and itch can coexist. However, pain and itch tend to inhibit each other, and are also clearly different in the types of sensation and behavioural responses induced, the population of C fibres and ascending tracts involved, and possibly the types of cerebral processing.

The terminology and classification of pain The International Association for the Study of Pain (IASP) has defined pain as ‘An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.’ Such a definition is at best an approximation, and, particularly in the case of neuropathic pain, which will be a novel phenomenon for the sufferer, the limitations of description are obvious. This is especially so in respect of those unable to express themselves, such as individuals who are mentally impaired, demented, aphasic or very young. Pain may be classified as on-going (stimulus-independent) or induced (stimulus-dependent) – whether by mechanical (brushing, pinprick, pressure, movement), chemical or thermal (warmth,

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heat, cool and cold) stimuli. Sometimes both types of pain will be present. Whenever possible, pain should be described in terms that specify the type of pain, and it should be recalled that pinprick applied to the skin induces sharpness (mediated by Aδ fibres) unless applied sufficiently deeply and vigorously so as to produce painful tissue damage (mediated by C fibres). Perhaps the single characteristic most suggestive of pain of neuropathic origin is a burning quality, although this burning is neither invariable, nor diagnostic. Patients also often demonstrate unusual sensory features, many of which have been given specific terms, clarified by IASP: • Allodynia: pain due to a stimulus that does not normally provoke pain. There are different varieties, including mechanical, cold and heat allodynia, in which stimuli such as a light brush, cooling or warmth trigger pain. The two crucial features are the change in quality (i.e. modality) of sensation from one that is normally innocuous to one that is painful, and the lowered pain threshold. An everyday example is pain over an area of sunburn – pain is produced by gentle touch. • Hyperalgesia or hypoalgesia: increased or decreased pain response to a normally and specifically painful stimulus. This is a threshold phenomenon, and, contrasting with allodynia, there is no change in modality. • Hyperpathia: an abnormally painful reaction to a stimulus, which may occur with other heightened sensory states such as allodynia, hyperalgesia, hyperaesthesia and dysaesthesia. There is an increased threshold to sensory stimuli, often with other clinical phenomena, e.g. delay in response, radiation and after-sensations, and impaired identification and localization of stimuli. • Hyperaesthesia or hypoaesthesia: increased or decreased sensitivity to stimulation. If pain results from innocuous stimulation, allodynia often results. • Dysaesthesia: an unpleasant abnormal sensation, whether spontaneous or evoked. • Anaesthesia dolorosa: pain in an anaesthetic area. Often the most revealing signs, at least in pain of central origin, are impaired pain from pinprick and/or impaired thermal sensation – the latter sometimes detectable simply by impaired cold appreciation from skin contact with a tuning fork. Apart from standard neurological examination and investigations, with emphasis on assessment of small nerve fibre function, more sophisticated investigations are sometimes used, particularly in research. In humans, methods for assessing peripheral mechanisms of pain include quantitative sensory testing (QST), sweat measurement, skin biopsy for assessment of intraepidermal nerve fibre density and for immunohistochemical studies, e.g. on substance P and calcitonin gene-related peptide (CGRP), and trophic factors such as nerve growth factor (NGF). Other studies include sympathetic skin responses, scintigraphy to measure plasma extravazation, and nerve, muscle and synovial biopsies. Neurophysiological techniques include microneurographic recordings from single sensory units in intact human nerves and recordings from intraneural electrical microstimulation. Methods used to study central pain processes include func-

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tional magnetic resonance imaging (MRI) and positron emission tomography (PET) studies of the brain and more recently functional MRI of the spinal cord; laser-evoked potentials to assess pain-subserving central sensory pathways; and EEG and magneto-encephalography (MEG) to study spinal and cerebral mechanisms. Pain has been divided into two categories: nociceptive and neuropathic (neurogenic). Nociceptive pain results from lesions affecting non-neural structures, e.g. a burn, arthritis, myocardial infarction or a limb fracture. Neuropathic pain results from lesions affecting the peripheral or central nervous systems. Once again, such a division is sometimes more theoretical than real; thus, a fracture will very often also involve neural structures, and arthritis will be associated with chemical changes in and around the joint, which have major effects on the local innervation. Conversely, many patients with neurological disorders have musculoskeletal complications which are painful. There are also some conditions where non-neural and neural structures are so intimately involved that separation into nociceptive or neuropathic components becomes unhelpful. Examples are the glomus tumour of a finger and complex regional pain syndromes (reflex sympathetic dystrophy), both of which are discussed below. Accepting the limitations of arbitrary classification, the clue that pain is primarily neuropathic is the presence of accompanying neurological signs. These signs are in particular sensory. They may include sensory loss, the various sensory phenomena defined above, other phenomena such as delayed or prolonged aftersensations following a peripheral stimulus, and faulty identification and localization of pain. There may also be radiation of both stimulus-induced and spontaneous pain, and referred pain, including mirror image pain. Such features, particularly when accompanied by non-sensory phenomena such as weakness, wasting, tremor, dystonia and other involuntary movements, indicate that the nervous system has changed in the way it processes sensory information. However, a word of caution is necessary in interpreting sensory deficits in the presence of pain: intriguingly, if pain is relieved, the sensory deficit may improve. This has been found both in experimental studies and through clinical observation; both peripheral but more particularly central mechanisms have been invoked. Although patients with neuropathic pain may also have coexisting nociceptive pain, and evaluation of these different components is crucial, it is neuropathic pain that is mainly considered in the topics that follow.

Some painful neuropathic conditions Central pain The three most common causes of central pain, which share many features, comprise: • Central post-stroke pain (CPSP); • Multiple sclerosis; • Spinal cord injury.

Pain Table 22.1 Classic features of central post-stroke pain (the thalamic syndrome). A mild, rapidly improving hemiplegia without contractures Persistent superficial hemi-anaesthesia or hyperaesthesia, with impaired deep sensation Mild hemi-ataxia and astereognosis Choreo-athetotic movements on the paralysed side ‘Sharp, enduring, paroxysmal, often intolerable pain on the hemiplegic side which does not respond to any analgesic treatment’

Central post-stroke pain (the thalamic syndrome) In 1906, Dejerine and Roussy, in their seminal paper ‘Le syndrome thalamique’, brought to attention the pain syndrome that can follow a stroke. They reported five patients who had suffered from pain following a thalamic infarct, three of whom at postmortem had destruction predominantly affecting the posterolateral ventral thalamus, with some lateral extension. This pain syndrome comprised a number of features (Table 22.1). Concepts surrounding CPSP have developed considerably in the past century: • Although mechanical shoulder pain associated with hemiplegia is probably the most common type of post-stroke pain, it is now known that 8–10% of patients have central post-stroke pain a year after their stroke. Far from being a rarity as often thought, this pain syndrome is therefore common. It afflicts many thousands of patients, most of whom will be at home, with their pain often remaining unrecognized. • Reflected in the change in terminology from thalamic pain to CPSP, the same type of pain can occur following a stroke affecting any part of the somatosensory central nervous system. The original reports were founded on clinical observations, but subsequently neuro-imaging has confirmed the numerous and sometimes non-specific potential sites from where pain can arise. Apart from the posterolateral ventral thalamus, strokes involving the medulla (particularly in the posterior inferior cerebellar artery territory – Wallenberg’s syndrome) and occasionally the parietal cortex (the parietal pseudo-thalamic pain syndrome) are those most likely to cause pain. Most cerebral ischaemic lesions are due to infarcts, which may be very small, although there is no correlation between size of lesion and pain. Furthermore, when there are numerous lesions on a scan, it may be impossible to know which is the causative one. • The same type of pain can be caused by vascular lesions other than those due to cerebral or spinal infarcts, including subarachnoid and other intracranial haemorrhage. • Similar central pain can also result from non-vascular causes that affect the brain or spinal cord, including multiple sclerosis and spinal trauma, as well as rarer disorders such as cerebral trauma, tumours, syringomyelia and syringobulbia, infections, and iatrogenic surgical and needling procedures. CPSP can be viewed as the prototypic central pain, and accounts for 90% of supraspinal central pain. Whatever its cause, central

Table 22.2 Clinical features of central pain. Is often very difficult for the patient to describe Can be on-going, triggered, or a combination; superficial, deep, or a combination Most often has a burning quality May not disturb sleep Patients may not appear to be in pain May be in odd distribution (e.g. a quadrant of the body; corner of mouth; ipsilateral mouth and hand – the cheiro-oral syndrome) Onset may be delayed by weeks, months or years Is usually persistent, but influenced by factors such as movement, emotion, temperature change

Table 22.3 Some clinical findings in central pain. Pain is experienced within the area of the sensory deficit or a smaller area The sensory deficit, if selective, is most typically thermal or for pain, and sometimes only detectable by quantitative sensory testing There may be various spontaneous or evoked sensory phenomena (e.g. allodynia), typically seen with neuropathic pain Rarely, central pain occurs in the absence of detectable sensory impairment; conversely, pain can occur in an anaesthetic area (anaesthesia dolorosa) There may be variable accompanying motor and autonomic features

pain often comprises a number of similar characteristic features (Table 22.2) and various clinical findings (Table 22.3).

Multiple sclerosis Whilst once thought uncommon and rarely mentioned in textbooks, pain in multiple sclerosis (MS) (see Chapter 10) is now known to be an important, common and often a major and dominating feature of the illness. Over 50% of patients with MS have chronic pain, and sometimes pain can be the presenting feature. Again, and similar to the pains seen in spinal cord injury, there are often a number of components. These range from nociceptive musculoskeletal pains due to factors such as spinal deformity, frozen shoulder, contractures and bedsores, to neuropathic pain from somatosensory damage in the spinal cord, brainstem and other cerebral structures. In contrast to spinal cord injury, the precise time of onset of the lesion is rarely known, and in view of the multiple lesions present, identification of the specific lesion responsible for the pain is rarely feasible. Both acute and chronic pain states may occur, as shown in Table 22.4. Some further aspects of pain suffered by MS patients deserve comment: • Surprisingly, the prevalence of pain in patients with MS is not significantly different to the prevalence of pain in the general population: pain is very common in the community. Pain intensity, the need for analgesics, and the impact on activities of daily living, however, are greater in patients with MS.

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Table 22.4 Acute and chronic pain in multiple sclerosis. Acute

Chronic

1 month Dysaesthetic lower extremity pain Back, joint and musculoskeletal leg pains Painful leg spasms Visceral pain

Treatment: often responds to carbamazepine or phenytoin

Treatment: those used for neuropathic pain (including, rarely, intrathecal drugs, e.g. baclofen); standard treatments for back pain when present; antispastic agents for leg spasms

Mechanisms: in paroxysmal symptoms, ?ephaptic transmission at site of demyelination

Mechanisms of central pain: uncertain – spinothalamic tract fibre loss +/− posterior column involvement probably implicated

•

There is controversy as to whether pain in MS is associated with increasing duration of the illness and with age. In respect of depression or cognitive impairment, there does not appear to be any difference between patients who have pain and those who do not. • Back pain often arises from muscle and joint structures. • Trigeminal neuralgia may occur as an isolated phenomenon, or as part of the established disease. It is often due to a plaque in the region of the trigeminal nerve root entry zone. MS accounts for over 1% of patients with trigeminal neuralgia, and about 1–5% of patients with MS have trigeminal neuralgia. MS should be suspected in younger patients with trigeminal neuralgia, if the neuralgia is bilateral but not necessarily simultaneous, and if there are abnormal sensory signs. Drug treatment is the same as for the idiopathic condition, but surgical or other invasive intervention is only occasionally considered because of the commonly remitting course of MS. • Optic neuritis is painful in 90% of patients. Pain, which rarely affects sleep and generally subsides in a few days, may result from the swollen optic nerve causing traction on the meninges. • Brief paroxysmal pains, including tonic painful spasms, are typical but not diagnostic of MS. These usually respond to carbamazepine, often at low dosage. • Lhermitte’s phenomenon rarely needs treatment, but carbamazepine is an appropriate drug to consider. • About one-third of patients with MS and pain have central pain, and the most distressing dysaesthetic pains are often accompanied by allodynia and other abnormal sensory phenomena. As with CPSP and spinal cord injury pain, impaired spino-thalamic function is often detected on examination. This impairment is probably necessary but not sufficient for pain to develop. There is also evidence that involvement of other tracts, in particular the posterior columns, may be implicated. Whilst experimental MRI of the cord in animals is beginning to be helpful in identifying pain-subserving pathways, precise clinical correlation between the painful symptoms and signs is rarely possible.

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Table 22.5 Pain following spinal cord injury. Musculoskeletal pains, including spinal pain from instability and deformity, shoulder disorders, muscle spasm, secondary overuse, and pressure syndromes Segmental pain, sometimes with a band of hyperaesthesia, at the level of injury: central (from the spinal cord) +/− peripheral (from nerve roots, including cauda equina damage) Spinal cord pain below the level of injury: central pain, sometimes with persistent dysaesthesias. Like central post-stroke pain, onset may be delayed months or years. Spinothalamic dysfunction is probably a necessary but not a sufficient factor. Particular conditions include the central cord syndrome and post-traumatic syringomyelia Deep visceral pain, which may be a form of central pain. There may be associated autonomic dysreflexia Phantom pain below the level of injury ?Complex regional pain syndrome

Spinal cord injury Over two-thirds of patients with spinal cord injury have chronic pain and in one-third of them this is severe. Central pain can occur even when the cord lesion is complete, and after spinal cord surgical transection. Thus, severing the cord has no therapeutic benefit because rostral sequelae ensue: for example, abnormal spontaneous firing in dorsal horn neurones has been recorded immediately above a lesion at L1 in a paraplegic patient. Incomplete cord lesions and gun-shot injuries possibly more frequently cause pain than other cord injuries. Pain following spinal cord injury often comprises an unusually large number of possible components, ranging from musculoskeletal nociceptive to neuropathic spinal cord pain (Table 22.5). It is important to dissect out these various components, the mechanisms of which are different, in order to try and manage the pain appropriately. As usual, it may be easier to deal with the nociceptive (musculoskeletal) than the neuropathic pains. For example, attention to abnormal spinal posture, or management of a frozen shoulder, is more likely to be rewarding than dealing with central neuropathic pain.

Pain The central pain associated with spinal cord trauma has similar characteristics to the pain associated with other lesions of the spinal cord, not only including MS, but also expanding or compressive lesions such as tumours and syringomyelia, and vascular damage. Management of pain from spinal cord lesions is the same as for other central pains and is discussed below. Surgery rarely has a part to play. The exceptions are pain due to post-traumatic syringomyelia, which rarely may respond to decompression; and pain at the level of injury which occasionally responds to dorsal root entry zone (DREZ) lesioning – whereby afferent impulses are interrupted as they enter the dorsal horn. DREZ lesioning has also been used to treat pain due to brachial plexus lesions, in which segmental central and peripheral pains may both occur. Spinal cord stimulation may be helpful in patients with partial lesions. The central cord syndrome An unusual syndrome is occasionally seen following sometimes even minor hyperextension or flexion injuries of the cervical cord. There is often weakness greater in the upper than lower limbs, and a striking feature is pain, with burning and stinging sensations and hyperpathia, affecting the chest and upper limbs. This pain is sometimes sufficiently severe that investigations are carried out to exclude upper limb fractures. The pain, which often resolves over some weeks, is probably due to damage to the spino-thalamic fibres at their decussation in the spinal cord.

•

Drugs with enhancing effects on noradrenaline and serotonin, neurotransmitters thought to inhibit pain and present in descending inhibitory pathways, may alleviate pain. Conversely, drugs and toxins such as reserpine, p-chlorophenylalanine and strychnine that block serotonin and GABA can produce pain. • Stimulation of cerebral and spinal structures thought to be implicated in inhibitory processes can improve pain. This phenomenon is discussed below in the context of management of neuropathic pain. Recently, the importance of descending excitatory pathways has been recognized, the key relay station being the rostroventromedial medulla, the output from which contributes to hyperalgesia. The evidence that excitation of the central nervous system can cause pain in humans includes: • Pain can occur in an epileptic attack, including post-stroke epilepsy. • Therapeutic stimulation of parts of the somato-sensory central nervous system can inadvertently cause pain. • Abnormal neural activity coinciding with pain has been recorded – for example, in the thalamus, midbrain and spinal cord in some patients with on-going central pain. • Anticonvulsants and local anaesthetics may alleviate central pain. Apart from excitation and inhibition, numerous other factors, including effects resulting from cortical and thalamic plasticity and changes in affective processing of pain, are of major importance, and some of these factors are referred to elsewhere.

Central spinal pain: some anatomical and pathological considerations

Pain and dementia

How spinal, and indeed cerebral, lesions affecting somatosensory pathways cause central pain is unclear. Most theories invoke either excitation of damaged sensory pathways, or diminution of inhibitory processes, or perhaps both. There are tracts in the dorsal and ventral segments of the spinal cord that mediate transmission of excitatory and inhibitory influences to and from the brain. Pain transmission reaches the brain via two types of ascending spinal pathways: • The spino-parabrachial pathway: this originates in Lamina I within the superficial dorsal horn and projects to the parabrachial region of the brainstem, peri-aqueductal grey matter and more rostral structures including hypothalamus and amygdala. The pathway is concerned with affect. • The classic spinothalamic pathway: this ascends in the anterolateral quadrant of the spinal cord, terminates in the more posterolateral thalamus and projects to sensory cortex. It is implicated in discrimination and localization of pain. Increasingly recognized as distinct entities, these ascending pathways mediate distinct sensory and affective components inherent in pain. There are major descending pathways from the sensory cortex, thalamus, hypothalamus and brainstem to the spinal cord. Some of these pathways inhibit spinal nociceptive processes. Evidence in humans for central inhibition includes:

As cognition worsens, the reporting of pain by patients decreases. Pain in dementia presents a number of difficult issues: • When communication and memory are impaired, assessing pain becomes problematic and often relies more on observation than on enquiry or use of a pain scoring system. • Dementia tends to occur in older people, in whom co-existing degenerative joint and other often painful diseases become more frequent. Thus whether pain is due to a nociceptive cause, rather than a neuropathic component inherent in the dementing processes itself, may be difficult to determine. • There tends to be under-treatment of pain in the elderly, or at least less consumption of analgesics, regardless of the presence of dementia, but particularly if dementia is present. Patients with dementia have for long been known to have a reduced incidence of headache following lumbar puncture (2%, compared with up to 40% of non-demented patients). However, whether this finding necessarily results from the dementing process itself or from brain shrinkage is unclear. Compared with patients with Alzheimer’s disease, those with frontotemporal dementia often show a loss of awareness and response to pain and can sustain injuries of which they appear unaware. This contrasts with the exaggerated response to sensory stimuli shown by some patients with semantic dementia (see Chapter 7). Also of note are patients with variant Creutzfeldt–Jakob disease (CJD) who may complain of pain in the limbs, trunk and face, and other sensory

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disturbances. MR imaging reveals characteristic hyperintensity of the posterior thalamus (pulvinar), a structure likely to be involved in pain processing. There has been an increased understanding of the two systems thought to be implicated in the experience of pain. As discussed elsewhere, the medial pain system is thought to be important in the emotional and affective processing of pain, and the lateral pain system in the sensory and discriminatory pain processing. Furthermore, there is now compelling evidence that within the brain there are different circuits involved in the parallel processing of pain: the sensory components are predominantly processed in the somato-sensory cortex, and the affective and motivational components in the cingulate, insular and prefrontal cortex. In the later stages of frontotemporal dementia, in keeping with the impaired response to pain, limbic structures including the hyopothalamus and amygdala are involved. In patients with Alzheimer’s disease the medial structures such as intralaminar thalamic nuclei tend to be affected, and consistent with this distribution is that these patients have unchanged or only a moderate reduction in thresholds for pain perception. However, their experience of pain is less intense, and experimentally they have impaired autonomic responses to acute pain stimuli.

Parkinson’s disease and other movement disorders The prevalence of pain in Parkinson’s disease has been estimated to occur in 40–85% of patients. Apart from central neuropathic pain associated with the neurodegeneration, pains from osteoarthritis and other musculoskeletal causes are common, often severe and frequently overlooked, although they tend to be more amenable to treatment (see Chapter 5). In some patients these musculoskeletal pains are due to the degenerative changes associated with ageing. In others the Parkinson’s disease itself contributes to their development. Pain in Parkinson’s disease may be due to various factors (Table 22.6). The presumed central pain of Parkinson’s disease comprises a variety of types, including burning, stabbing, tingling, itching, tense feelings and restlessness. These symptoms can precede the onset of the motor symptoms sometimes by several years. Pain is often bilateral but can sometimes be more marked on one side, either ipsilateral or contralateral to the predominant motor features. Of interest because of its midline distribution, pain may involve the mouth, throat, or genital regions, suggesting in some

Table 22.6 Pain in Parkinson’s disease. Musculoskeletal factors: shoulder stiffness, spinal deformity including scoliosis and camptocormia (bent spine), arthritis, contractures Limb rigidity and stiffness Dystonia, dyskinesia, akathisia Restless legs and sleep-related pains Visceral pains: abdominal pain. This is sometimes (but not necessarily) related to constipation. Also: non-cardiac chest pain Central neuropathic pain

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instances a link with the burning mouth syndrome and vulvodynia (see below). The diurnal relationship between pain and any relief with levodopa or dopaminergic medication often seems unclear. Although levodopa has occasionally been used as an analgesic drug in other conditions, it is rare that pain experienced by a Parkinson’s patient can be switched off simply by anti-parkinsonian drugs. Whilst pain due to stiffness may improve when the stiffness improves, any temporal relationship between dystonia, dopaminergic deficiency and drug administration needs to be evaluated on an individual basis, but is unpredictable. Pain due to focal dystonia, as might affect the hallux or produce a clenched fist, sometimes responds to botulinum toxin injections. The mechanisms of central pain in Parkinson’s disease are poorly understood. Compared with controls, these patients have lower pain thresholds to heat, especially in their affected limbs, and regardless of whether the patients are ‘on’ or ‘off ’. This is the opposite to the raised thresholds sometimes seen in CPSP, suggesting there may be different mechanisms. Dopamine has analgesic properties and is present in descending spinal as well as ascending pathways. Furthermore, there are inhibitory pathways which project from the basal ganglia and brainstem to the spinal cord and which contain enkephalins, substance P, noradrenaline, serotonin and other neurotransmitters implicated in endogenous pain control. It is therefore not surprising if degeneration of these extrapyramidal pathways in the brain and spinal cord gives rise to central pain, and conversely that pallidal deep brain stimulation may improve pain. Mechanisms underlying the pain of the co-morbidities such as osteoarthritis, spinal deformity and muscle stiffness are of course entirely different. Pain may also be associated with other extrapyramidal and related degenerative disorders. In pure autonomic failure (Chapter 23) and multi-system atrophy (Chapter 5), intense discomfort known as coat-hanger pain may occur. This pain around the shoulders and upper arms is likely to be due to ischaemia in suboccipital and paracervical muscles. The ischaemia is associated with increasing degrees of postural hypotension, and thus the pain occurs when the patient is upright, particularly in the mornings and after meals, and is relieved by lying flat. Amongst various often ill-defined sensory symptoms, pain may be an important feature of various dystonias and tics, in particular Tourette’s syndrome and spasmodic torticollis – in which there is evidence of central pain in addition to pain related to musculoskeletal components. Other combinations of pain and involuntary movements are encountered in the syndrome of painful legs and moving toes, complex regional pain syndromes (CRPS), and stump and phantom phenomena.

Painful legs and moving toes syndrome On the borderland between a central and peripheral neurological disorder and with movement-related and sensory components, the clinical features are summarized in the title: there is pain in the distal lower limbs accompanied by spontaneous movements of the toes, foot or sometimes lower leg. The pain varies from

Pain being a mild discomfort to a very severe intractable pain; rarely, instances of suicide have occurred. The pain is often difficult to describe and can be burning, crushing, cramping or twisting. The movements are rather slow and irregular with sinuous fanning and clawing of the toes. The number of toes affected is very variable. Sometimes the movements can be briefly stopped with effort, but then they break through again. In some patients pain precedes the onset of the movements; in others, it is vice versa. The condition may start unilaterally, although it tends to become bilateral, if sometimes asymmetrical. A similar phenomenon, ‘painful arm and moving fingers’, has also been described. Often the cause is unknown, but lumbar root lesions associated with degenerative spine disease, peripheral neuropathy and peripheral limb trauma may be relevant factors. Rarely, other involuntary movements may be seen, which, as with the upper limb syndrome, suggests there may be a central rather than peripheral cause in some patients – a distinction that might possibly be clarified in future from neurophysiological studies. Treatment is usually ineffective, for both the movements and the pain. For the pain, drugs including anticonvulsants such as gabapentin, antispasticity agents, benzodiazepines, phenothiazines, dopaminergic drugs and beta-blockers have not proven effective in the long term. Epidural opiates and local anaesthetics have been tried, and whilst initially lumbar sympathetic blockade was thought promising, this has not proved beneficial in most patients. The main disorder with which painful legs and moving toes is confused is the restless legs syndrome, although the distinction can usually be made with ease (Table 22.7).

Epilepsy Pain may be a feature of an epileptic attack, as first noted by Gowers in 1901. Although rare, some studies have reported about 2% of patients with epilepsy have painful seizures, but this figure is probably an overestimate due to selection bias. The pains have been divided into three categories: 1 Unilateral pain in the face, arm, leg or trunk. Seizures tend to originate from the hemisphere contralateral to the pain, usually in the Rolandic area. Parietal, or occasionally centro-parietal or other lesions may be present, but sometimes no obvious

structural lesion is detectable. Pain may be due to direct excitatory involvement of the primary sensory area or spread there from elsewhere. Ictal depression of inhibitory processes could be an alternative mechanism. 2 Headache. Distinct from the common post-ictal headache, headache and other head pains, sometimes with a migrainous element, may be part of the seizure. Temporal lobe involvement may be more common in these patients although localizing value is often poor. Increased cerebral blood flow occurs during a seizure, and it is thought that vascular factors may contribute to these pains. 3 Abdominal pain, rather than nausea, is a very rare feature of an epileptic attack and may be associated with temporal or frontal lobe seizures. The treatment is that of the seizure disorder.

Peripheral nerve pain Anatomical and pathological considerations Pain from the periphery is conveyed to the central nervous system by primary afferent nociceptors: sensory neurones that are activated by noxious mechanical, thermal and chemical stimuli. These neurones contain thinly myelinated, faster conducting Aδ fibres and unmyelinated, slower conducting C fibres; the former mediate brief, acute, sharp first pain, and the latter the delayed, more diffuse, dull second pain. The majority of Aδ and C fibres are polymodal, i.e. they react to a variety of noxious stimuli, and these fibres use numerous signal-transduction mechanisms in order to convert noxious environmental stimuli into electrochemical signals. C fibres have been further tentatively subdivided into: • Fibres that, amongst other properties, express P2X3 purine receptors (one type of ATP-responsive channel) and receptors for glial cell line-derived neurotrophic factor (GDNF). These fibres are sensitive to GDNF, terminate deep in the substantia gelatinosa of the spinal cord, and may be important in mediating neuropathic pain. • Fibres that contain peptides including substance P and CGRP, and express the high affinity NGF receptor TrkA. These fibres are sensitive to NGF, terminate more superficially in the dorsal horn

Table 22.7 Painful legs and moving toes and restless legs syndromes. Painful legs and moving toes

Restless legs syndrome

Spontaneous movements of toes and feet Present throughout day No known family history Involuntary irregular, fanning, sinuous, dystonic movements affecting toes in particular Pain deep, diffuse, of various sorts Underlying causes sometimes seen, including peripheral neuropathy and radiculopathy, infections, and trauma; rarely, central causes Rarely responds to dopaminergic drugs

Irresistible desire to move legs around Worse in evening and night, sometimes associated with periodic limb movements during sleep Often positive family history No spontaneous involuntary movements Pains of various sorts, also dysaesthesias, discomfort Underlying causes occasionally seen, including peripheral neuropathy and radiculopathy, iron deficiency anaemia, pregnancy, renal failure May respond to levodopa and dopaminergic drugs, benzodiazepines, opioids, anticonvulsants

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of the spinal cord, and mediate plasma extravasation and vasodilatation – also called neurogenic inflammation. This inflammation, whether resulting from tissue damage or from release of peptides and neurotransmitters from the sensory nerve endings themselves, sensitizes nociceptor endings. This results in peripheral sensitization. These fibres are an important component of visceral afferents and have a more diffuse pattern of innervation compared with those fibres innervating skin. They also appear to regulate the behavioural sensitivity to pain through projections to deep central brain structures in the brainstem, hypothalamus and amygdala. Both groups of C fibres respond to noxious stimulation and express the vanilloid (capsaicin) TRPV1 receptor which transduces noxious chemical and heat (>43°C) stimuli. Noxious cold (60 years; proximal pain, stiffness and tenderness, particularly around shoulder girdle; raised ESR and CRP. Responds well to steroids. No true weakness; normal CK and EMG; muscle biopsy usually normal or may show interstitial inflammation. Not strictly myopathic but inflammatory/ vasculitic; may co-exist with giant cell arteritis Polymyositis: painful in acute and severe cases, otherwise usually painless, as is inclusion body myositis Alcoholic myopathy Myopathic pain, generalized or focal, from viral, bacterial or parasitic infection. Usually transient. Enquire about precipitating infection, particularly viral, and foreign travel Myopathies of metabolic bone disease: triad of myopathy typically producing a waddling gait, pain (from muscle and/or bone), and brisk reflexes Myopathies due to certain defects in muscle energy metabolism – usually exercise related: early-onset pain from defect of glycogenolysis and ‘second wind’ pain (e.g. myophosphorylase deficiency [McArdle’s disease]); later-onset pain in patients with defects in lipid oxidation (e.g. carnitine palmitoyl transferase deficiency) Idiopathic paroxysmal myoglobinurias Some idiopathic myopathies Acute and sub-acute drug-induced myopathies: at least 30 drugs and toxins incriminated, including heroin, amphetamine, phencyclidine, statins, vincristine, AZT, cimetidine, drugs producing profound hypokalaemia. Steroid myopathy is nearly always painless CK, creatine kinase; CRP, C-reactive protein; EMG, electromyogram; ESR, erythrocyte sedimentation rate.

and responsiveness of high threshold mechano-sensitive muscle receptors is increased by the presence of algesic substances. In severe post-exertional pain, with onset after 1–2 days and lasting 5–7 days, the cause of the pain may relate to micro-trauma perhaps with an inflammatory reaction. Such properties of afferent nerves may explain why muscles become tender, and more so on movement or pressure. The secondary central changes that follow, which are extensive, diffuse and lack the more point-to-point characteristics of sensory afferents from skin, account for clinical phenomena particularly seen when muscle is involved. These phenomena include wide spread of pain outside the local area of damage or disease, referred pain, and also the common clinical phenomenon of reversible sensory symptoms (accompanied by lowered sensory thresholds) in skin overlying the painful muscle, due to central interaction of muscle and skin afferents. Despite standard investigations for muscle disease, sometimes including muscle biopsy, and rarely more extensive metabolic and other specialized tests, the cause of muscle pain is often not found. Treatment of muscle pain is, where possible, that of the underlying cause. Drug-induced pain is usually reversible when the drug is discontinued.

Fibromyalgia Distinct from painful myopathies are the numerous tender muscular points which are the hallmark of fibromyalgia, often a vexed diagnosis. The American College of Rheumatology diagnostic criteria comprise widespread pain for at least 3 months, and pain on palpation of at least 11 of 18 specific tender points. Nearly all patients also complain of sleep disturbance and fatigue. Other neurological symptoms including headaches and paraesthesias

are common. No definite pathological cause has been found so far, but there is currently no evidence to suggest depression as an aetiology. Many different treatments have been tried, including drugs such as amitriptyline, pregabalin and intravenous lidocaine, acupuncture, exercise and other physical measures, and behavioural techniques. Their efficacy is variable and unpredictable. A multi-disciplinary approach is often the best, but in many patients the condition remains troublesome.

Phantom pain One of the most curious phenomena within medicine is that whenever a body part is removed, a sensation of the missing part may persist (the phantom sensation) and sometimes there will be pain in that missing part (phantom pain). The subject of much literature, folklore and artistic representation, phantom phenomena have become increasingly studied and their mechanisms investigated. Phantom pain most commonly develops in a missing limb or part of that limb, but phantom teeth, breasts, eyes, genitalia and various viscera have been described. Phantom pain also occurs in a body part that has been denervated but nevertheless remains intact – for instance, the body below a complete or partially transected spinal cord, or an arm denervated following a brachial plexus injury. Because patients often suspect they may be disbelieved or thought insane, phantom sensations including pain are probably under-reported and thus more common than generally appreciated. Phantom pain in a limb needs to be distinguished from stump pain. In the latter, pain is in the region of the stump, where neuromas (although not necessarily painful) will inevitably be present, sometimes with other abnormal tissues including scars and musculoskeletal changes. There is therefore often a

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combination of neuropathic and nociceptive pains. Local measures may be needed to try and ease the pain, particularly if there are poorly fashioned skin flaps or local infections. Sometimes surgery is needed, but it is very rarely indicated for pain control itself. Surgery for a neuroma is seldom required unless there are particular circumstances, such as the neuroma being situated where pain is induced by pressure from wearing a prosthesis. This is because removing the neuroma simply results in the formation of one more proximally. Phantom pain often has certain features: • It occurs unpredictably in those with missing body parts, particularly when the missing part is distal. • It is felt in, or within, the area of the missing part. • The pain varies from the mild to the intolerable. Suicide has occasionally been reported. • It may have various qualities, e.g. burning, aching, crushing, and gnawing; it can be continuous or intermittent, sometimes with brief paroxysms; and can be influenced by stimulation of other parts of the body, visceral influences such as micturition, and psychological factors. It may be associated with cramps, spasms, painful postures and distortions within the phantom. It is worse if the patient perceives they have no ability to move the phantom, although paradoxically pain may prevent this feeling of being able to move. • Pain prior to amputation may be a risk factor for the development of phantom pain. The phantom pain may resemble that previous pain. • When phantom pain is present, the phantom sensation persists. • With time the area of the phantom sometimes shrinks, particularly its proximal part, and this feature can affect phantom pain as well. This ‘telescoping’ can give rise to curious phantom phenomena – for instance, a phantom hand may be felt tucked up near the shoulder with nothing intervening. • It may develop instantaneously, or soon after removal of the part. Occasionally pain may come on months or years later. Phantom pain is often very long-lasting, but sudden resolution rarely occurs spontaneously, and even more rarely after a stroke affecting the phantom area represented in the brain. • Phantom sensations and pain occur regardless of the cause of loss of the body part, i.e. whether due to trauma, surgical removal or disease. Usually loss of a body part will have been quick, but the same phantom phenomena are described in the slow loss that occurs with leprosy. • Phantom phenomena including pain are relatively rarely experienced in congenital absence of a limb, or after amputation of a body part in childhood, although childhood phantom pain may be more common than previously thought. • Some very curious temporal painful phantom phenomena have been reported. For example, phantom lower limbs felt after thoracic spinal cord transaction disappeared when cord compression from a cervical disc developed, only to return when the disc was removed. Conversely and paradoxically, phantom pain in a paraplegic became manifest following spinal anaesthesia.

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The treatment of phantom pain is extremely disappointing. Over 68 different types of treatment have been reported, ranging from numerous drugs to neurosurgical and other invasive treatments. Although the use of opioids is being explored further, currently treatment is usually ineffective. Unfortunately preemptive analgesia does not prevent the development of phantom pain. It is hoped that recent studies on neural plasticity may lead to new approaches. When a body part loses its sensory innervation, changes in somato-sensory cortical and thalamic representation take place. Changes can be very rapid; for example, even an anaesthetic ring block of a finger results in cortical changes within a few minutes. The area of brain from which input has been deprived is physiologically ‘invaded’ by innervation from adjacent areas. Such phenomena have been studied extensively in humans, and shifts in cortical representation may be more extensive in the presence of pain, normalize with treatment of the pain, and account for peculiar referred patterns of sensation – for instance, a touch on the face being felt in the phantom limb of amputees. The specific role of pain in these phenomena remains to be clarified. In order to try to modify these neuroplastic changes, graded motor imagery techniques have been tried, as has the mirror box, particularly for patients with a phantom upper limb. A mirror is placed vertically in front of the patient, at right angles to the chest. The patient is asked to mimic the position of the phantom limb with the intact limb, and then to look into the mirror on the side of the intact limb. The patient sees the mirror reflection of the intact hand superimposed on the perceived position of the missing limb. By attempting symmetrical movements of the two limbs, the patient may feel the phantom limb move. Intriguingly, the ability to exert apparent control over the phantom limb can result in pain relief. Beneficial results have been reported with these techniques, but pain relief is unpredictable and may be transient. Further studies are needed.

Management The most important prelude to management of chronic pain is correct diagnosis. Pain in a patient with a neurological disorder does not necessarily mean that the pain is primarily due to that disorder. In the author’s view, by far the most common misdiagnosis is overlooking a complicating, additional or even unrelated musculoskeletal component or cause. Indeed, very often a musculoskeletal cause mimics a neurological condition. Pain due to nociceptive causes is almost always easier to treat than neuropathic pain; this makes exclusion of nociceptive causes particularly important, and avoids inappropriate neurological management. An example is a sensory disturbance in the forearm, often associated with rather vague numbness and tingling and sometimes hyperalgesia along the posterolateral aspect of the forearm. These symptoms are often attributed to a peripheral nerve lesion or C6 radiculopathy. However, palpation over the lateral

Pain epicondyle typically elicits marked discomfort and exacerbation of the symptoms. Treatment of the tender muscular point, possibly some form of tennis elbow, curiously results not only in resolution of the pain but also the sensory features, which, as mentioned above, are mediated by central processes. Management of nociceptive pain will be dictated by the underlying cause. For example, the finding of tender muscular points, stiffness, pain on active or passive movement, or abnormal posture may well lead to effective treatment, particularly with physical forms of treatment from a physiotherapist or other allied medical practitioner. The same approach will be required in a patient with MS or spinal injury with a spinal deformity resulting from weakness, or the arthritis that commonly accompanies Parkinson’s disease. Surgery will be required for a few, specific painful disorders sometimes seen by neurologists, including the osteoid osteoma and glomus tumour discussed earlier.

Management of neuropathic pain Often the management of neuropathic pain is unsatisfactory, and the evidence base for any particular form of treatment is weak. The methods of treating neuropathic pain, often used in combination, comprise: • Drugs; • Neuro-ablative or neuro-stimulation procedures; • Other physical forms of treatment; • Psychological approaches to management.

Drugs The ideal analgesic drug would be one in which the mode of action was precisely tailored to the underlying mechanism subserving the pain. Unfortunately, in any specific patient, there is rarely an effective symptom-related approach to guide therapy, nor a rationale for using any specific drug. Many drugs used do not necessarily produce analgesia, but may reduce abnormal sensations such as hyperalgesia and allodynia. The mechanisms of actions of drugs used in pain management are more complex than previously thought: • The once clear-cut division of those drugs that act peripherally and those that act centrally is now less secure. For instance, opiates have peripheral as well as central effects, and anti-inflammatory drugs have central as well as peripheral effects. • The properties of nerves on which drugs act change in the presence of disease or injury, and the effects of drugs may change. For example, certain sodium channels on sensory afferents are upregulated after nerve injury. Occasionally, pain management specialists use short-duration intravenous drug challenges to try and predict benefit of a particular class of drug, and sometimes one of these drug challenges will lead to pain relief that long outlasts the duration of action of the drug. These drug challenges include: • Lidocaine (lignocaine) to predict benefit of sodium-channel blockers such as mexiletine; • Phentolamine to predict benefit of sympatholytic agents;

• Ketamine to predict benefit of ketamine and other NMDAblocking agents; • Opiates to predict benefit of opiates. Anticonvulsants and antidepressants are the mainstay of drug treatment, and these have been the subject of several metaanalyses. More recently, the use of opiates in non-malignant neuropathic pains has expanded. A huge number of other drugs have been tried, often with little if any evidence of benefit as judged from adequate, appropriately controlled and long-term studies. There is increasing interest in exploring the usefulness of drugs whose efficacy might be predicted from mechanisms mediating pain, for instance, those with effects on NMDA receptors (e.g. ketamine) and on the TRPV1 receptor (e.g. cannabis and synthetic cannabinoids). However, with the exceptions of gabapentin, pregabalin and duloxetine, and carbamazepine for trigeminal neuralgia, none of these is licensed in the UK for management of pain, and patients should be informed of this. With many drugs, but particularly tricyclic antidepressants, patients need to be warned about the risk of drowsiness in respect of driving and potentially hazardous occupations. To reduce the chance of side effects, the key to any success is to start with a very low dose, often given at bedtime, and increase very slowly. Combination therapy, using drugs with different modes of action, e.g. gabapentin and morphine, has also been advocated for peripheral neuropathic pain. Antidepressants and anticonvulsants are the first drugs to try. Although there is no evidence favouring one or other group in respect of efficacy or side-effects, there is a clinical impression that the anticonvulsants may be better tolerated, particularly in the elderly.

Antidepressants Antidepressants may be effective in peripheral and central neuropathic pain states. Tricyclic antidepressants, particularly those with mixed effects on noradrenaline and serotonin, are probably superior to selective serotonin re-uptake inhibitor (SSRI) antidepressants, although there may be no benefit in painful HIV neuropathy. There is little evidence to support one drug being superior to another, although more data are available for amitriptyline. The efficacy of tricyclic antidepressants may also be related to their important local anaesthetic effects, probably through blocking voltage-gated sodium channels. Duloxetine, a dual serotonin and noradrenaline re-uptake inhibitor, has been licensed for treatment of painful diabetic peripheral neuropathy, but should be discontinued if there has been no benefit after 2 months. The dose of a drug used is typically lower than that used for depression, e.g. amitriptyline, starting at 10 mg nocte, building up by 10 mg weekly to 50–70 mg nocte. Benefit is usually apparent within a few days or weeks, and is unrelated both in time and efficacy to the drug’s psychotropic properties. If there is no benefit after 2–3 months, it is appropriate to withdraw the drug slowly. Measurement of drug levels has been used in an attempt to correlate dosage with efficacy but is rarely undertaken in practice.

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Anticonvulsants Almost all anticonvulsants have been used to try to manage neuropathic pain, but benefits are unpredictable. Their use in treating trigeminal neuralgia is considered elsewhere. Lamotrigine has been found to have little benefit in peripheral neuropathic pain, and despite various reports of benefit from drugs such as valproate, levetiracetam and topiramate, efficacy remains to be established in more major studies. In the UK, the majority of these drugs remain unlicensed for treatment of pain. • Carbamazepine is the treatment of choice, not only in trigeminal neuralgia, but in any other truly neuralgic pain in which there is a brief, severe, stabbing component. Thus, it may be effective for glossopharyngeal and other neuralgias, paroxysmal pain of MS, and tabetic lightning pain. It may be effective for painful diabetic neuropathy, but is usually ineffective for CPSP and other neuropathic pain. • Gabapentin may be helpful for neuropathic pain; it is only licensed for peripheral neuropathic pain. Somnolence is usually the dose-limiting side effect. • Pregabalin, related to gabapentin, has been licensed for both peripheral and central neuropathic pains. Preliminary evidence suggests it might be more effective than gabapentin. It has the advantage of an easy twice daily dose regimen; again somnolence may be troublesome but might be a useful feature in patients with difficulty in sleeping. Different anticonvulsants may involve effects on abnormal neural excitability through effects on different ion channels, such as voltage-gated sodium channels (e.g. carbamazepine) or the α2δ voltage-gated calcium channel subunit (e.g. gabapentin – which, despite its name, is not involved with GABA-mediated mechanisms). Mexiletine This drug acts as an oral local anaesthetic, but evidence for its efficacy in neuropathic pain has been conflicting. Bradycardia and heart block are contraindications. Opiates Opiates are increasingly used for non-malignant and other neuropathic pains. Guidelines on their use are published by the British Pain Society. For example, oxycodone and tramadol may be useful for post-herpetic neuralgia, and methadone may occasionally have a place. The use of opiates in non-malignant pain has been controversial and is greatly complicated by issues concerning dependency and addiction, misuse, legal constraints (in some countries), and even cost. There are also other potential issues, such as possible reduction in testosterone levels when some opioids are used long-term. Because of these issues it is usually wise for long-term opiate therapy to be instituted by a specialist in pain management, and then in a shared-care arrangement with the patient’s general practitioner. Cannabinoids Despite their effects on the vanilloid receptor involved in nociception, there is at present conflicting evidence whether

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cannabinoids are useful in chronic neuropathic pain. Trials have been carried out in patients with MS and brachial plexus lesions but, as with so many pain-relieving agents, claims of benefit are difficult to evaluate. Furthermore, cannabinoids, which comprise a number of different components, have psychotropic properties, and may also affect spasticity. Further trials are pending, but currently, whilst a cannabinoid is licensed in Canada for use in pain, cannabinoids remain unlicensed in the UK. Ketamine and other NMDA-blocking agents Attempts have been made to block NMDA-mediated processes thought to subserve pain caused by central hyperexcitability. Memantine appears ineffective, but occasional patients respond to subcutaneous or oral ketamine. Amantadine and dextromethorphan have also been used. Ketamine should only be prescribed by specialists in pain management. Topical agents There is evidence supporting the use of 5% lidocaine patches, recently licensed in the UK for the treatment of post-herpetic neuralgia. Capsaicin cream, licensed for treatment of postherpetic and diabetic neuropathic pains, may be useful, but side effects including burning and stinging at the site of application often occur, and great care has to be taken to avoid contact with the eyes. Botulinum toxin Botulinum toxin may have pain-relieving properties in addition to those resulting from treatment of muscle spasm and abnormal posture. Pain relief can occur well before, and outlast, improvement in these musculoskeletal components. There have been anecdotal reports of pain relief in various other disorders including post-herpetic neuralgia, migraine and chronic facial pain. Botulinum toxin does not seem to improve acute pain, and the role of this toxin in relief of pain is uncertain. There is experimental evidence that, apart from effects on acetylcholine, the toxin blocks release of substance P, release of glutamate and other neurotransmitters involved in sensory processing. Intrathecal drugs Several drugs have been used intrathecally for pain management. These include baclofen especially for central pain, clonidine, opioids and, most recently, ziconotide. Phenol has also been used, but as a neurolytic agent. The evidence base is poor, benefit unpredictable, and this form of treatment should only be carried out in specialized pain management units.

Neuro-ablative and neuro-stimulation procedures Neuro-ablative procedures Over the past century, except in the treatment of trigeminal neuralgia, there has been a steady decline in neurosurgical and other procedures designed to interrupt pain pathways, particularly in those whose pain has a non-malignant cause. Apart from the risks of the procedure itself and of causing damage affecting other

Pain neurological functions, even successful procedures may result in sensory loss that can be painful (termed ‘anaesthesia dolorosa’ after somatic nerve lesioning, and ‘sympathalgia’ after sympathectomy). Furthermore, paradoxically pain will often return, sometimes after a long interval, although obviously this is less important in management of those painful malignant conditions in which life expectancy is short. These sequelae are due to a variety of often poorly understood adaptive central phenomena. Certain destructive procedures are still occasionally performed, for instance DREZ lesions for treatment of pain from spinal cord injury or brachial plexus lesions discussed earlier. Here too the evidence base for their efficacy is frequently poor. The same reservations apply to destructive chemical procedures. The use of phenol and other neurolytic chemicals applied around nerve roots or intrathecally is rarely undertaken, apart from treating spasticity and its accompanying pain. Phenol applied peripherally can induce further pain (phenol neuritis). Neuro-stimulation procedures Every part of the somato-sensory nervous system has been stimulated to try and relieve pain, but apart from transcutaneous electric nerve stimulation (TENS), these techniques are complex and are only carried out in specialized centres. Much of the rationale for stimulation procedures is based on the seminal paper by Melzack and Wall (1965) that led to the gate control theory of pain. This paper, which reported physiological experiments on dorsal root potentials in rats, gave rise to the novel concept that stimulation of large afferent fibres might inhibit (gate) the activity of small diameter, pain subserving fibres in the dorsal horn of the spinal cord, and possibly elsewhere. Although the subject of heated controversy, the paper led to the development of various techniques that provide innocuous neural stimulation, with the aim of alleviating pain. Transcutaneous electrical nerve stimulation This involves applying electrodes to the skin with an interposed gel or other appropriate contacting substance. The electrodes are usually placed either side of the painful area, and are attached via wires to a small battery-operated stimulation unit. Impulses can be of variable frequency and intensity, the parameters being selected by the patient usually so as to cause non-painful tingling sensations. Stimulation can be continuous, intermittent or in bursts, and applied for minutes, hours or days. Side effects are infrequent and minor, usually comprising skin irritation beneath the electrodes. Contraindications include open or infected skin, pregnancy (other than in labour), and the presence of a pacemaker. TENS is useless and can cause burns if applied to anaesthetic skin. Benefit is unpredictable, and may only develop some time after stimulation. Some pains may be transiently worsened, particularly if there is tactile allodynia. Controlled trials are obviously difficult, but the technique is simple, safe and cheap, and patients can obtain devices over the counter. The mechanism of action may include segmental inhibition at the dorsal horn, distinct from painful counter-irritation

(pain inhibiting another pain) in which there is diffuse noxious inhibitory control (DNIC) through ascending and descending pathways. Peripheral nerve stimulation Implanting stimulating electrodes around a peripheral nerve to obtain pain relief is rarely undertaken now. Spinal cord stimulation An electrode is implanted percutaneously or at open operation so as to stimulate the spinal cord by means of electrical stimuli provided by a pulse generator. The aim is to stimulate the posterior columns, but this stimulation is probably not its only mode of action which remains ill understood. One of its most useful indications is angina; other good indications are said to include CRPS, neuropathic pain secondary to peripheral nerve damage or lumbar or cervical spine surgery, and post irradiation and partial traumatic brachial plexus lesions. Up-to-date recommendations for best clinical practice, details of conditions that may or may not respond, contraindications, technical details and a literature review are well set out in a consensus document from the British Pain Society and the Society of British Neurological Surgeons. Deep brain stimulation This highly specialized technique originated from two startling discoveries: in humans, stimulation of the fornix and septal regions during psychosurgery produced analgesia; and in rats, stimulation of the central midbrain grey matter allowed them to be operated on without an anaesthetic. The three areas most frequently targeted include the peri-aqueductal grey matter, periventricular grey matter and the somato-sensory nuclei of the thalamus. Whilst experimental pain relief has been attributed predominantly to stimulation of endogenous opioid systems at the first two sites, and stimulation of inhibitory pathways at the third, the underlying mechanisms in humans remain unclear. Debate continues on many aspects, including the indications for deep brain stimulation (probably patients with constant, burning or aching neuropathic pain unresponsive to other measures), appropriate targets and stimulation parameters. Motor cortex stimulation This counter-intuitive procedure involves the extradural placement of electrodes over the motor cortex. Pain relief is thought to be subserved by effects on descending inhibition, in turn mediated by sensory nerves present in the motor cortex. Recently, repetitive transcranial magnetic stimulation over the motor cortex has been reported to provide analgesia in patients with central pain and trigeminal neuralgia, an effect that might usefully predict benefit from long-term motor cortex stimulation.

Other physical methods of treatment Many treatment modalities are used, including different forms of physiotherapy for nociceptive pains, and treatment is usually

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carried out by physiotherapists, occupational therapists and other allied therapists such as osteopaths and chiropractors. TENS is one such procedure and has been discussed earlier. Another technique often used for musculoskeletal and other pains, and a form of peripheral stimulation, is acupuncture. Acupuncture Acupuncture, the insertion of needles into the body for pain relief, has been used for 5000 years. Various techniques are employed: • Needle stimulation of local points in painful areas, such as for treatment of tennis elbow. • Needle stimulation of distant points, sometimes multiple and sometimes situated along classic Chinese acupuncture lines. The importance of classic acupuncture points, however, is doubtful. • Needle(s) may be simply inserted, repetitively rotated, or stimulated electrically, and they may be inserted to different depths. • Treatment is often given for about 30 minutes, but the optimum duration is unclear. Acupuncture has been used in treatment of both acute and numerous chronic painful and other disorders. It is most commonly and perhaps effectively used for musculoskeletal rather than neuropathic pain; contraindications include local skin lesions, anticoagulation and pregnancy. Side effects are infrequent, but infection, bleeding, syncope, paraesthesias and, depending on the site and depth of needle insertion, pneumothorax and other internal complications may very rarely occur. Attempts have been made to undertake controlled trials of efficacy using specially adapted needles, but in practice acupuncture is usually given on a trial and error basis. Despite its potential for placebo effects, acupuncture provides a form of powerful peripheral stimulation. The physiological basis underpinning acupuncture is complex, and includes effects mediated by release of endogenous opioids, not least because analgesia can be reversed by naloxone. Acupuncture also induces both segmental and supraspinal descending inhibitory effects. Acupuncture carried out for prolonged periods and in a way to cause pain raises the pain threshold and can induce analgesia. This acupuncture-induced analgesia, different from treatment of pain, is a method for allowing surgery to take place without general anaesthesia.

Psychological approaches to management of chronic pain The psychological components of pain are extraordinarily complex, but the tendency to assume that pain intensity correlates with perceived pain severity can easily be disproved. Rather than being closely linked to sensory dysfunction, from the psychological perspective it is the affective, cognitive, behavioural and social aspects for the patient as well as the family that are crucial. As consistently shown by functional imaging, magnetoencephalography and other investigative tools, non-sensory brain

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changes occur alongside the sensory phenomena that characterize acute and chronic pains. Structures, particularly including the anterior cingulate, prefrontal cortex and insula, are implicated in encoding pain affect. It is thus increasingly recognized that any firm division between psychological and somato-sensory aspects of pain is probably meaningless. Currently, normal psychological aspects of pain are thought to comprise four concepts: attention, catastrophizing, avoidance and depression. The neurophysiological bases underlying these are starting to be investigated. Building on these concepts and coinciding with the decrease in invasive procedures, there has been a rapid increase in the use of psychological strategies for management of neuropathic pain. Patient management falls to pain psychologists, the majority of whom work as members of a multi-disciplinary pain management team. It is important for the patient to accept that pain psychologists are concerned with management and not cure of the pain. Individual psychologists tend to have expertise in one or more specific therapeutic approaches, and whilst it is difficult to compare different forms of psychological intervention, cognitive behavioural therapy (CBT) is one of the most widely used techniques that meta-analyses have shown to be effective. In-patient management for selected patients may be particularly beneficial. Psychiatric treatment may also be required. It is usually unwise to attribute chronic pain to a psychological cause, and patients with significant depression will need appropriate treatment and when necessary referral to a psychiatrist. Malingering as a cause of chronic pain is well recognized but very rare.

The placebo phenomenon The placebo phenomenon in treating pain encapsulates the concept that the individual believes that receiving an effective analgesic treatment can reduce pain. Although it is often stated that one-third of beneficial responses to inert analgesic drugs are due to placebo, the range varies from 0 to 100% of patients. Cultural, experiential, experimental and numerous other factors are relevant. Often thought that pain relief following an inert substance was due to imagination or a psychological sleight of hand, there is compelling evidence that placebo effects have a physiological basis. This evidence, from acute pain studies, includes findings that: • Placebo ultrasound can reduce pain and swelling after tooth extraction. • Naloxone can reverse placebo, suggesting opioid mechanisms are important, although naloxone can also produce hyperalgesia that can offset the placebo effect. • Placebo analgesia is associated with changed patterns of cerebral blood flow similar to those seen with opioids. • Functional MRI evidence suggests that placebo decreases activity in pain-subserving brain regions; conversely, during anticipation of pain, brain activity increases in prefrontal cortex.

Pain •

Placebo analgesic effects, including physiological phenomena, are seen following technically abortive surgery, even when the patient is under general anaesthesia and therefore unaware. • Placebo is a phenomenon also seen in treatment of other, non-painful and chronic disorders, including Parkinson’s disease, Alzheimer’s disease and depression. The placebo phenomenon is proving to be an intriguing and important phenomenon in pain and other conditions, and the mechanisms are likely to include those subserving expectancy and desire. Although pain relief by means of placebo would appear to be an ideal outcome, there are major ethical considerations when using placebo in clinical practice and in clinical trials. Current views are controversial, but the prevailing consensus is that patients should not receive placebo without consent, even if that consent includes placebo being one of a number of treatment options offered.

dates from birth. They do not react to painful stimuli anywhere over the body, but other sensory modalities and reflexes seem to be normal. They sustain painless injuries including skin lesions and fractures dating from childhood. Autosomal dominant and recessive families have been reported. In some patients insular damage perhaps leading to sensory-limbic disconnection has been reported, but in most patients no consistent pathological abnormalities have been found in either the peripheral or central nervous system. The cause of these very rare disorders remains unknown, although the clinical features recall those patients with other conditions in which medial pain-subserving circuits may well be implicated – for example, patients with frontotemporal dementia, and patients who in previous decades had a frontal lobotomy for treatment of intractable pain. However, it is now evident that, in some patients, their supposed indifference to pain is due to impaired function of the voltage-gated sodium channel gene SCN9A, and is in reality a channelopathy-associated insensitivity to pain.

Absence of pain Transient indifference to pain Patients may not experience pain, either because there is a defect in sensory pathways, insensitivity to pain or, extremely rarely, due to lack of concern in response to a normally received stimulus, indifference to pain.

Insensitivity to pain In these conditions, stimuli that would normally be painful are not transmitted to the brain. This lack of pain input may be congenital and occurs in some rare hereditary small fibre neuropathies, notably, but not exclusively, HSAN Type IV (see below). Patients with this autosomal recessive neuropathy develop serious painless injuries amongst other defects, and have absence of unmyelinated peripheral axons, small sensory neurones in the dorsal root ganglia, and Lissauer’s tracts. The mechanisms for the lack of pain perception may relate to mutations in the TrkA gene that encodes the high affinity receptor for NGF, which in turn is crucial for development of nociceptive and sympathetic neurones. Acquired causes include occasional cases of diabetes, syphilitic tabes dorsalis, and lesions interrupting second-order central crossing spinothalamic fibres as seen in syringomyelia. As a result of the lack of protective innervation, patients may develop painless scars, burns and ulcers, inadvertently bite their tongue and otherwise self-mutilate, and have disorganized (Charcot’s) joints, and osteomyelitis. Such injuries need to be contrasted with the self-mutilation that can occur in association with anaesthesia dolorosa, in which the positive sensory disturbances (possibly including itch) give rise to constant scratching and damage, the human equivalent of autotomy in animals.

Indifference to pain In congenital indifference to pain (also known as asymbolia for pain, congenital pure analgesia, congenital universal insensitivity to pain), patients appear to have absent pain recognition which

It has long been noted that in acute situations in which pain would be expected, quite paradoxically pain may not be experienced at all. Classic studies came from Beecher who described this phenomenon in battle-injured soldiers in the Second World War, but the same phenomenon has been documented in other wartime situations and in occasional patients with very severe injuries admitted to a hospital A&E department. This analgesia is shortlived and localized to the site of injury. The mechanisms are thought to include stress-induced release of endorphins and massive cortical and spinal inhibitory processes. Perhaps having a similar basis is the impaired pain perception in those patients with parasomnias who sustain injuries during sleep-related violence. Pain appreciation is also impaired as a result of the transient effects of drugs such as opiates.

Conclusions There has been an explosion of knowledge about how pain is detected and processed by the nervous system and how pain impacts on those who experience it. This knowledge extends from molecular mechanisms at the peripheral nociceptor endings to neural networks at the cortical level. But the management of pain remains in its infancy, and some would argue that there have been rather few major therapeutic advances in the past century. Paradoxically, rather than neurologists, it has been two physicians in other disciplines who have contributed most to alleviating patients’ pain, and whose contributions serve as beacons for the future. One pioneer was John Bonica, an anaesthetist who envisaged the concept of pain as a multidisciplinary speciality and who with others initiated the International Association for the Study of Pain. The other was Dame Cicely Saunders, founder of the modern hospice movement, who at the age of 85 quoted so aptly: ‘there’s so much more to be learned about pain’.

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References Birklein F. Complex regional pain syndrome. J Neurology 2005; 252: 131–138. Boulton AJM. Management of diabetic peripheral neuropathy. Clin Diabetes 2005; 23: 9–15. Cervero F, Laird JMA. Visceral pain. Lancet 1999; 353: 2145–2148. Finnerup NB, Jensen TS. Spinal cord injury pain: mechanisms and treatment. Eur J Neurol 2004; 11: 73–82. Finniss DG, Benedetti F. Mechanisms of the placebo response and their impact on clinical trials and clinical practice. Pain 2005; 114: 3–6. Graven-Nielsen T, Mense S. The peripheral apparatus of muscle pain: evidence from animal and human studies. Clin J Pain 2001; 17: 2–10. Hunt SP, Mantyh PW. The molecular dynamics of pain control. Nat Rev Neurosci 2001; 2: 83–91. Jaeckle KA. Neurological manifestations of neoplastic and radiationinduced plexopathies. Semin Neurol 2004; 24: 385–393. Johnson RW, Whitton TL. Management of herpes zoster (shingles) and postherpetic neuralgia. Expert Opin Pharmacother 2004; 5: 551–559. Kalso E. Opioids for persistent non-cancer pain. Br Med J 2005; 330: 156–157. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet 2006; 367: 1618–1625. Layzer RB. Hot feet: erythromelalgia and related disorders. J Child Neurol 2001; 16: 199–202. Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965; 150: 971–979. Morley S, Eccleston C, Williams A. Systematic review and meta-analysis of randomized controlled trials of cognitive behaviour therapy and behaviour therapy for chronic pain in adults, excluding headache. Pain 1999; 80: 1–13. Musheb RM, Nash JM, Brondolo E, Kerns RD. Vulvodynia: an introduction and critical review of a chronic pain condition. Pain 2000; 86: 3–10. O’Connor AB, Schwid SR, Herrmann DN, Markman JD, Dworkin RH. Pain associated with multiple sclerosis: Systematic review and proposed classification. Pain 2008; 137: 96–111.

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Rainville P, Duncan GH, Price DD, Carrier B, Bushnell MC. Pain affect encoded in human anterior cingulate but not somatosensory cortex. Science 1997; 277: 968–971. Ramachandran VS. Plasticity and functional recovery in neurology. Clin Med 2005; 5: 368–373. Scherder E, Oosterman J, Swaab D, Herr K, Ooms M, Ribbe M, et al. Recent developments in pain in dementia. Br Med J 2005; 330: 461–464. Schott GD. From thalamic syndrome to central post-stroke pain. J Neurol Neurosurg Psychiatry 1996; 61: 560–564. Schott GD. Pain and the sympathetic nervous system. In: Mathias CJ, Bannister R. (eds.) Autonomic Failure, 4th edn. Oxford: Oxford University Press, 1999: 520. Schott GD. Complex? Regional? Pain? Syndrome? Pract Neurol 2007; 7: 145–157. Schweinhardt P, Lee M, Tracey I. Imaging pain in patients: is it meaningful? Curr Opin Neurol 2006; 19: 392–400. Sommer C. Painful neuropathies. Curr Opin Neurol 2003; 16: 623–628. Spillane JD, Nathan PW, Kelly RE, Marsden CD. Painful legs and moving toes. Brain 1971; 94: 541–556. Sunderland S. Nerves and Nerve Injuries, 2nd edn. Edinburgh: Churchill Livingstone, 1978: 421–447. Waseem S, Gwinn-Hardy K. Pain in Parkinson’s disease. Postgrad Med 2001; 110: 33–40, 46. Whitworth LA, Fernández J, Feler CA. Deep brain stimulation for chronic pain. Semin Neurosurg 2004; 15: 183–193. Wolfe GI, Trivedi JR. Painful peripheral neuropathy and its nonsurgical treatment. Muscle Nerve 2004; 30: 3–19. Wynn Parry CB. Pain in avulsion lesions of the brachial plexus. Pain 1980; 9: 41–53. Yosipovitch G, Greaves MW, Schmelz M. Itch. Lancet 2003; 361: 690–694. Young GB, Blume WT. Painful epileptic seizures. Brain 1983; 106: 537–554. Zakrzewska JM. The burning mouth syndrome remains an enigma. Pain 1995; 62: 253–257.

23

Autonomic Dysfunction Christopher Mathias

The last 25 years have seen major advances in the recognition, investigation and treatment of a variety of disorders that cause or contribute to autonomic dysfunction. This has been a result of many factors. Many clinicians consulted by patients with symptoms that cannot be explained now consider autonomic disorders as a possible cause. Advances in non-invasive technology have resulted in more accurate and reproducible methods of investigation, thus aiding diagnosis, understanding pathophysiological mechanisms and enabling targeted therapy for autonomic dysfunction. Collaboration between specialties within neurology, such as with movement disorders groups and with other medical disciplines such as diabetology and cardiology, has been helpful in understanding autonomic involvement in common neurological and medical diseases. Advances in basic science have enabled neurological repair, e.g. in the spinal cord, and have refocused attention on the many autonomic abnormalities that occur in patients with spinal cord injuries. Finally, new autonomic disorders have been described, examples being dopamine beta hydroxylase deficiency (DβH), immune disorders affecting autonomic ganglia and the postural tachycardia syndrome (PoTS); and in the latter its close association with the joint hypermobility (Ehlers– Danlos III) syndrome. Autonomic investigation units began to be established in UK during the 1970s. Their scope of activity varied, depending much upon research funding. Established units have seen exponential growth in clinical service and research activity, which have advanced greatly the recognition, investigation and management of autonomic disorders. Activities now encompass a wide range of disorders, from autonomic failure syndromes to common


disorders such as parkinsonian syndromes, hyperhidrosis and neurally mediated syncope. This chapter summarizes our usual diagnostic approach and the range of tests and treatments available.

Classification of autonomic dysfunction The autonomic nervous system has cranio-sacral parasympathetic and thoraco-lumbar sympathetic pathways (Figure 23.1) and supplies every organ in the body. The system influences target organ function locally and also operates more centrally, i.e. it controls vital functions such as arterial blood pressure and body temperature. Specific neurotransmitters in each pathway influence ganglionic and post-ganglionic activity (Figures 23.2 and 23.3). Autonomic diseases thus may occur with lesions or dysfunction at different sites of the neural axis, in the brain, spinal cord or periphery. Autonomic disorders may be classified in a variety of ways. One approach is to divide them into localized and generalized disorders. Localized disorders affect an organ or region of the body but they may be part of generalized disease, such as gustatory sweating in diabetes mellitus (Table 23.1). Generalized disorders often affect systems, such as those involved in blood pressure control and thermoregulation. They can be primary when the cause is often unclear, or secondary when associated with a specific disease or its complications (Table 23.2). Drugs are a common cause of autonomic dysfunction, either because of their pharmacological effects or because of autonomic nerve damage (Table 23.3). Damage to the autonomic nervous system often causes irreversible abnormalities. This contrasts with intermittent autonomic dysfunction, the common transient abnormalities that generate so much morbidity. These conditions include neurally mediated syncope, PoTS and essential hyperhidrosis.

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Sympathetic nervous system

Parasympathetic nervous system Eye

Mesencephalon

III

Pons Tear and salivary glands

Superior cervical ganglion

IX, VII X Vagus n. Cervical

Medulla oblongata

Lung Stellate ganglion

Coeliac ganglion

Thoracic

Heart Superior mesenteric ganglion

Liver Stomach

Small intestine Inferior mesenteric ganglion

Sacral

Large intestine Rectum

Lumbar

Pancreas

Bladder Sympathetic trunk Reproductive organs

Adrenal

Figure 23.1 Scheme outlining details of the cranio-sacral parasympathetic and thoraco-lumbar sympathetic outflow to various target organs. (From Janig & McLachlan 2002, with permission.)

Ganglia Parasympathetic

Sympathetic

ACh

Target organ ACh Glands Smooth muscle Heart Blood vessels Heart

ACh

NA

ACh

ACh Sweat glands

ACh

Adrenal medulla

Figure 23.2 Outline of the major transmitters at autonomic ganglia and post-ganglionic sites on target organs supplied by the sympathetic and parasympathetic efferent pathways. The acetylcholine receptor at all ganglia is of the nicotinic subtype. Ganglionic blockers such as hexamethonium thus prevent both parasympathetic and sympathetic activation. However, atropine acts only on the muscarinic (ACh-m) receptor at post-ganglionic parasympathetic and sympathetic cholinergic sites. The cotransmitters along with the primary transmitters are also indicated (ACh, acetylcholine; NA, noradrenaline). After Mathias (1998).

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Autonomic Dysfunction Table 23.2 Outline classification of autonomic disorders.

Tyrosine TH – DOPA DOC DA

Sympathetic nerve terminal

NA

Uptake 1

– α2

DβH NA

Synaptic cleft Effector cell

MAO

DA DβH NA + –

+ β

Primary Acute/subacute dysautonomias Pure pan-dysautonomia Pan-dysautonomia with neurological features Pure cholinergic dysautonomia

β

α1

Uptake 2 COMT

Figure 23.3 Steps involved in the formation of noradrenaline (NA) from tyrosine within a sympathetic nerve terminal (DA, dopamine; DβH, dopamine beta hydroxylase; DDC, dopadecarboxylase; DOPA, dihydroxyphenylalanine; TH, tyrosine hydroxylase). NA in granules is released by a process of exocytosis into the synaptic cleft, following which it acts on various alpha or beta adrenoreceptors, either pre- or post-synaptically. NA is subject to various processes which involve uptake 1 into the nerve terminal, following which it is either incorporated into granules, exerts negative feedback on TH or is metabolized by monoamine oxidase (MAO). Some is taken up into non-neuronal tissues (uptake 2), some metabolized by catechol-O-methyltransferase (COMT), while the rest spills over into the circulation. From Mathias (2004) with permission.

Table 23.1 Examples of localized autonomic disorders. Horner’s syndrome Holmes–Adie pupil Crocodile tears (Bogorad’s syndrome) Gustatory sweating (Frey’s syndrome) Reflex sympathetic dystrophy Idiopathic palmar or axillary hyperhidrosis Chagas disease (Trypanosoma cruzi)* Surgical procedures† Sympathectomy (regional) Vagotomy and gastric drainage procedures in ‘dumping’ syndrome Organ denervation following transplantation (heart, lungs) * Listed here because the disease targets specifically intrinsic cholinergic plexuses in the heart and gut. † Surgery also may cause other localized disorders, such as Frey’s syndrome after parotid surgery.

Chronic autonomic failure syndromes Pure autonomic failure Multiple system atrophy (Shy–Drager syndrome) Autonomic failure with Parkinson’s disease Secondary Congenital Nerve growth factor deficiency

Hereditary Autosomal dominant trait Familial amyloid neuropathy Autosomal recessive trait Familial dysautonomia – Riley–Day syndrome Dopamine beta hydroxylase deficiency Metabolic diseases Diabetes mellitus Chronic renal failure Chronic liver disease Alcohol-induced Inflammatory Guillain–Barré syndrome Transverse myelitis Infections Bacterial – tetanus Viral – HIV infection Neoplasia Brain tumours – especially of third ventricle or posterior fossa Paraneoplastic, especially adenocarcinoma of lung and pancreas Surgery Vagotomy and drainage procedures – ‘dumping syndrome’ Trauma Cervical and high thoracic spinal cord transection Drugs, chemical toxins (see also Table 23.3) By direct effects By causing a neuropathy Neurally mediated syncope Vasovagal syncope Carotid sinus hypersensitivity Situational syncope Postural tachycardia syndrome

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Chapter 23 Table 23.3 Drugs, chemicals, poisons, and toxins causing autonomic dysfunction. Decreasing sympathetic activity Centrally acting Clonidine Methyldopa Moxonidine Reserpine Barbiturates Anaesthetics

Peripherally acting Sympathetic nerve endings (guanethidine, bethanidine) α-Adrenoceptor blockade (phenoxybenzamine) β-Adrenoceptor blockade (propranolol) Increasing sympathetic activity Amphetamines Releasing noradrenaline (tyramine) Uptake blockers (imipramine) Monoamine oxidase inhibitors (tranylcypromine) β-Adrenoceptor stimulants (isoprenaline) Decreasing parasympathetic activity Antidepressants (imipramine) Tranquillizers (phenothiazines) Antidysrhythmics (disopyramide) Anticholinergics (atropine, probanthine, benztropine) Toxins (botulinum)

Table 23.4 Some clinical manifestations of autonomic dysfunction. Cardiovascular Postural hypotension Lability of blood pressure Tachycardia Sudomotor Hypohidrosis or anhidrosis Gustatory sweating Hyperpyrexia

Heat intolerance

Alimentary Xerostomia Gastric stasis Constipation

Dysphagia Dumping syndromes Diarrhoea

Miscellaneous Alcohol, thiamine (vitamin B1) deficiency Vincristine, perhexiline maleate Thallium, arsenic, mercury Mercury poisoning (pink disease) Ciguatera toxicity Jellyfish and marine animal venoms, scombroid posioning First dose of certain drugs (prazosin, captopril, propranolol) Withdrawal of chronically used drugs (clonidine, opiates, alcohol)

Clinical features Clinical features of autonomic disease cover a wide spectrum (Table 23.4) and result from underactivity or overactivity. The history is of particular importance in consideration and recognition of autonomic disease and in distinguishing dysfunction from other disorders. In brief:

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Hyperhidrosis

Urinary Nocturia Urgency Retention

Frequency Incontinence

Sexual Erectile failure Retrograde ejaculation

Ejaculatory failure

Eye Pupillary abnormalities Alachryma

•

Increasing parasympathetic activity Cholinomimetics (carbachol, bethanechol, pilocarpine, mushroom poisoning) Anticholinesterases Reversible carbamate inhibitors (pyridostigmine, neostigmine) Organophosphorous inhibitors (parathion, sarin)

Supine hypertension Paroxysmal hypertension Bradycardia

Ptosis Abnormal lachrymation with food ingestion

Sympathetic adrenergic failure causes orthostatic (postural) hypotension and ejaculatory failure in the male; • Sympathetic cholinergic failure causes anhidrosis; • Parasympathetic failure causes dilated pupils, fixed heart rate, sluggish urinary bladder, atonic large bowel and, in the male, erectile failure. The extent of dysfunction is dependent on the degree of autonomic damage. With autonomic hyperactivity, the reverse occurs. In some disorders, particularly in neurally mediated syncope, there may be a combination of over-activity and under-activity, with bradycardia caused by increased parasympathetic activity and hypotension brought about by withdrawal of sympathetic activity. Autonomic disease may present in any age group. At birth it is seen in the rare condition familial dysautonomia (Riley–Day syndrome), in teenage years in the common disorder vasovagal syncope and between the ages of 30 to 50 in familial amyloid polyneuropathy (FAP). Neurodegenerative disorders affecting the autonomic nervous system often occur after the age of 50 years. The majority of autonomic diseases are sporadic. However, genetically transmitted disorders include the Riley–Day syndrome and FAP. There often is a family history in vasovagal syncope, especially in those presenting below the age of 20 years. Druginduced autonomic disease may be caused by impaired metabolism or the production of toxic metabolites, as with perhexiline maleate neuropathy. A detailed history relating to drug usage, chemical and toxin exposure is always necessary (Table 23.3).

Autonomic Dysfunction Autonomic involvement, even if it affects only a single organ or system (Table 23.5), may be an important feature of an underlying disease. For example, Horner’s syndrome, with mainly cosmetic effects, may be the harbinger of underlying non-autonomic disease (such as apical tuberculosis or lung neoplasm in Pancoast syndrome). The usually benign Holmes–Adie pupil may occur in isolation, or with absent tendon reflexes and other autonomic features, such as an afferent baroreceptor defect causing orthostatic hypotension and labile hypertension, sweating abnormalities and a dry cough (Holmes–Adie syndrome). In generalized disorders such as multiple system atrophy (MSA), a single system may be involved initially. Thus, erectile failure in the male,

Table 23.5 Some clinical manifestations in patients with pure autonomic failure. Cardiovascular system Sudomotor system Alimentary tract Urinary system Reproductive system Respiratory system Ocular Other neurological features

Orthostatic (postural) hypotension Anhidrosis, heat intolerance Xerostomia, oro-pharyngeal dysphagia, constipation, occasionally diarrhoea Nocturia, frequency, urgency, incontinence, retention Erectile and ejaculatory failure (in the male) Stridor, involuntary inspiratory gasps, apnoeic periods Alacrima, aniscoria, Horner’s syndrome Parkinsonian, cerebellar and pyramidal signs

Oropharyngeal dysphagia, incontinence and respiratory features, along with additional neurological features suggest multiple system atrophy.

constipation or urinary bladder dysfunction in either gender can pre-date other autonomic or neurological features. The clinical features are now considered under each major system.

Cardiovascular system Orthostatic hypotension Symptoms of orthostatic hypotension are often the reason for requesting medical advice and may provide initial clues to underlying autonomic disease. Orthostatic or postural hypotension is defined as a fall in blood pressure of 20 mmHg systolic or 10 mmHg diastolic on sitting, standing or during 60° head-up tilt (Figures 23.4 and 23.5). In neurogenic orthostatic hypotension, levels of plasma noradrenaline do not rise when upright, as occurs in normal subjects (Figure 23.6), the lack of rise reflecting impaired sympathetic activity. Hypoperfusion of organs, especially above heart level such as the brain, cause the malaise, nausea, dizziness and visual disturbances that often precede loss of consciousness (Table 23.6). The fall in blood pressure and associated symptoms during postural change often varies within the same individual. If blood pressure falls precipitously, syncope tends to occur instantly and is likely to cause injury. Occasionally, seizures may occur as a result of cerebral hypoxia in syncope. With time and frequent exposure to orthostatic hypotension, some come to tolerate a low cerebral perfusion pressure with few or even no symptoms, presumably because of improved cerebrovascular autoregulation. A variety of symptoms result from hypoperfusion elsewhere. Neck pain in a coat-hanger distribution (suboccipital and shoulder regions) differs from other types of neck pain by developing when upright. It is relieved by sitting or lying flat, when the blood

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Figure 23.4 Blood pressure and heart rate before, during and after head-up tilt in (a) a normal subject, and (b) a patient with autonomic failure. In the normal subject there is no fall in blood pressure during head-up tilt, unlike a subject with autonomic failure in whom blood pressure falls promptly and remains low with a blood pressure overshoot on return to the horizontal. In this subject there is only a minimal change in heart rate despite the marked blood pressure fall. In both subjects continuous blood pressure and heart rate was recorded with the Portapress II. (From Mathias 2006, with permission.)



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Figure 23.5 Blood pressure and heart rate measured continuously with the Portapres II in a patient with a high cervical spinal cord lesion. There is a fall in blood pressure because of impairment of the sympathetic outflow disrupted in the cervical spine. Heart rate rises because of withdrawal of vagal activity in response to the rise in pressure. (From Mathias 2006, with permission.)

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Figure 23.6 Plasma noradrenaline, adrenaline and dopamine levels (measured by high pressure liquid chromatography) in normal subjects (controls), patients with multiple system atrophy (MSA), pure autonomic failure (PAF) and two individual patients with dopamine β-hydroxylase (DBH) deficiency while supine and after headup tilt to 45° for 10 minutes. The asterisk indicates levels below the detection limits for the assay, which are less than 5 pg/mL for noradrenaline and adrenaline and less than 20 pg/mL for dopamine. Bars indicate ± standard error of mean (SEM). (From Mathias & Bannister 1999, with permission.)

Autonomic Dysfunction Table 23.6 Symptoms resulting from orthostatic hypotension and impaired perfusion.

Muscle hypoperfusion Paracervical and suboccipital (‘coat-hanger’) ache Lower back/buttock ache Subclavian steal-like syndrome Renal hypoperfusion Oliguria Spinal cord hypoperfusion Non-specific Weakness, lethargy, fatigue Falls

pressure recovers. The pain probably is caused by reduced perfusion of neck muscles that need to be tonically active to maintain upright head posture. Using arm muscles especially when upright can increase cerebral symptoms of orthostatic hypotension by a subclavian steal-like mechanism further reducing brainstem blood flow. Central chest pain, suggestive of angina pectoris, can occur with normal coronary arteries and may be caused by chest wall ischaemia. Oliguria, especially during the day when upright, is the result of reduced renal perfusion pressure. This may be difficult to separate from retention of urine resulting from urinary sphincter abnormalities, e.g. in high spinal cord lesions. The reverse – polyuria – occurs when supine, especially at night when blood pressure is restored or even elevated. In the elderly, falls may occur even without other symptoms of orthostatic hypotension. Other less specific symptoms include weakness, tiredness and fatigue. A key component in the history is the relationship between symptoms and head-up postural change. Symptoms may be more prominent with rapid head-up change, e.g. getting out of bed in the morning and on rising after a large meal, excessive alcohol or exercise (Figures 23.7 and 23.8). A variety of factors influence orthostatic hypotension and should be sought in the history (Table 23.7). Many patients recognize the association with head-up postural change and either sit down, lie flat, stoop or assume curious postures, such as squatting. These positions prevent the fall in blood pressure or even may elevate blood pressure. Orthostatic hypotension often is worsened by drugs that have vasodilator

Systolic and diastolic blood pressure (mmHg)

Cerebral hypoperfusion Dizziness Visual disturbances Blurred – tunnel Scotoma Greying out – blacking out Colour defects Syncope Cognitive deficits

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Figure 23.7 Changes in blood pressure (BP) before and after a standard meal in a group of normal subjects (stippled area) and in a patient with autonomic failure (IR), while in the supine and horizontal position. Bars indicate ± standard error of mean (SEM). In the normal subjects there is no change in BP. In the patient with autonomic failure there is a marked fall in BP soon after food ingestion, with levels falling to around 80/50 mmHg and remaining low for 3 hours, even in the supine position. (From Mathias & Bannister 2002, with permission.)

effects and are used to treat associated disease (levodopa or insulin), alleviate symptoms (nitrates) or reverse organ failure (sildenafil).

Syncope without orthostatic hypotension Syncope has many causes (autonomic, cardiac, neurogenic and metabolic). Autonomic causes of syncope without orthostatic hypotension include neurally mediated syncope, where there is transient hypotension and bradycardia. There are three major forms: vasovagal syncope, carotid sinus hypersensitivity and situational syncope. Blood pressure falls because of sympathetic withdrawal while heart rate falls because of increased vagal activity. This is more likely to occur when upright. Between attacks usually there are no autonomic abnormalities. The history of the syncopal attack and its recovery often separates neurally mediated syncope from other neurological diseases, such as epilepsy. Recovery on lying flat usually is rapid, as this restores blood pressure and cerebral perfusion. Tongue biting normally does not occur. In some, convulsions result from hypoxia, especially if the subject is not laid flat and blood pressure recovery is delayed. Urinary incontinence may occasionally occur. In vasovagal syncope (common faints or emotional syncope) provoking factors include fear, pain, the sight of blood and medical procedures, especially involving needles. Nausea and other gastrointestinal upsets, probably through activation of visceral afferents, may be causative. Palpitations and sweating may occur in the pre-syncopal phase. In those with an adequate

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Exercise

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Figure 23.8 Systolic and diastolic blood pressure in two patients with autonomic failure before, during and after bicycle exercise performed with the patient in the supine position at different workloads, ranging from 25 to 100 W. In the patient on the left there is a marked fall in blood pressure on initiating exercise; she had to crawl upstairs because of severe exercise-induced hypotension. In the patient on the right, there are minor changes in blood

pressure during exercise, but a marked decrease soon after stopping exercise. This patient was usually asymptomatic while walking, but developed postural symptoms when he stopped walking and stood still. It is likely that the decrease in blood pressure post-exercise was a result of vasodilatation in exercising skeletal muscle, not opposed by the calf muscle pump. (From Mathias & Williams 1994, with permission.)

Table 23.7 Factors influencing orthostatic hypotension.

In situational syncope, various factors predispose the individual to syncope. These include induction of a Valsalva manoeuvre and hyperventilation. This occurs in weight-lifters, trumpetblowers, in mess tricks (deliberate manoeuvres) and following paroxysms of coughing. In micturition syncope, hypotension results probably from a combination of vasodilatation caused by warmth and/or alcohol and straining during micturition (which raises intrathoracic pressure and induces a Valsalva manoeuvre), compounded by release of the pressor stimulus arising from a distended bladder while standing upright. Swallowing-induced syncope may occur with glossopharyngeal neuralgia.

Speed of positional change Time of day (worse in the morning) Prolonged recumbency Warm environment (hot weather, central heating, hot bath) Raising intrathoracic pressure – micturition, defaecation or coughing Food and alcohol ingestion Water ingestion* Physical exertion Physical manoeuvres and positions (bending forward, abdominal compression, leg crossing, squatting, activating calf muscle pump)† Drugs with vasoactive properties (including dopaminergic agents) * This raises blood pressure in autonomic failure. † These manoeuvres usually reduce the postural fall in blood pressure, unlike the others.

warning, sitting or lying flat prevents syncope. The reverse, prolonged standing or assumption of the upright position on a tilt table, may provoke a response. The latter is the basis for the laboratory investigation. Tilt table testing usually is for 10 minutes, with a provocative stimulus such as venepuncture; sometimes prolonged tilt testing for 45 minutes is needed. It is important to determine the underlying mechanism contributing to syncope as this influences the management of vasovagal syncope (Figures 23.9–23.11). In the elderly, carotid sinus hypersensitivity is increasingly recognized as a cause of falls (Figure 23.12). There may be a classic history of syncope induced while shaving, turning the head or buttoning the collar, when carotid afferents are stimulated. However, this history may not be obtained. Falls and syncope of unknown aetiology should arouse suspicion of this disorder.

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Orthostatic intolerance with posturally induced tachycardia When orthostatic intolerance occurs without orthostatic hypotension, but with a substantial rise in heart rate (of over 30 beats/ minute), the term ‘postural tachycardia syndrome’ (PoTS) is used (Figure 23.13). It predominantly affects women below the age of 50 years. Symptoms include marked dizziness on postural change or modest exertion; syncope may occur. There usually are no features of generalized autonomic failure. Associated disorders include the joint hypermobility syndrome (Ehlers–Danlos III; Figures 23.14 and 23.15), chronic fatigue syndrome, mitral valve prolapse and hyperventilation. A relationship to disorders described in wartime, such as da Costa’s syndrome and soldier’s heart, when dizziness and syncope on effort is accompanied by exhaustion, dyspnoea, headache, palpitations, and pain over the heart seems probable. Hypertension Unlike hypotension, hypertension typically causes few symptoms other than headaches – and these only occasionally.

Autonomic Dysfunction

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Figure 23.9 Blood pressure and heart rate with continuous recordings from the Portapres II in a patient with the mixed (cardio-inhibitory and vasodepressor) form of vasovagal syncope. (From Mathias 2006, with permission.)



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Figure 23.10 Blood pressure and heart rate with continuous recordings from the Portapres II in a patient with the predominantly vasodepressor form of vasovagal syncope.



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Figure 23.11 Blood pressure and heart rate with continuous recordings from the Portapres II in a patient with the cardio-inhibitory form of vasovagal syncope.



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Figure 23.12 Continuous blood pressure and heart rate measured non-invasively (by Portapres) in a patient with falls of unknown aetiology. Left carotid sinus massage caused a fall in both heart rate and blood pressure. The findings indicate the mixed (cardio-inhibitory and vasodepressor) form of carotid sinus hypersensitivity. (From Mathias & Bannister 2002, with permission.)

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In high spinal cord lesions, severe paroxysmal hypertension can develop as part of autonomic dysreflexia, when an uninhibited increase in spinal sympathetic activity is caused by contraction of the urinary bladder, irritation of the large bowel, noxious cutaneous stimulation or skeletal muscle spasms. This can cause hypertension, a throbbing pounding headache, palpitations with bradycardia and sweating/flushing over the face and neck. The limbs tend to be cold as a result of peripheral vasoconstriction. • In tetanus, hypertension in ventilated patients may be precipitated by muscle spasms or tracheal suction.

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Figure 23.13 Blood pressure and heart rate measured continuously before, during and after 60° head-up tilt by the Portapres II in (a) a normal subject, and (b) in subject with the postural tachycardia syndrome (PoTS). (From Mathias 2002, with permission.)

Intermittent hypertension may occur in the Guillain–Barré syndrome, porphyria, posterior fossa tumours and phaeochromocytoma (Figure 23.16), often without any evident precipitating cause. • Sustained hypertension resulting from increased sympathetic activity may occur in subarachnoid haemorrhage. • Hypertension in the supine position may complicate orthostatic hypotension in pure autonomic failure (PAF). The mechanisms include impaired baroreflex activity, adrenoceptor supersensitivity, an increase in central blood volume because of


Figures 23.14 and 23.15 Joint hyperextensibility as demonstrated by a subject with the joint hypermobility syndrome and postural tachycardia syndrome (PoTS).

a shift from the periphery and the effects of drugs used to prevent orthostatic hypotension.

Heart rate disturbances Bradycardia, along with hypertension, may occur in cerebral tumours with or without raised intracranial pressure and during autonomic dysreflexia in high spinal cord injuries. In the latter, the afferent and vagal efferent components of the baroreflex arc are intact, and the heart slows in an attempt to control the rise in blood pressure. In phaeochromocytoma, bradycardia with escape

rhythms and atrioventricular dissociation may occur in response to a rapid rise in blood pressure. Severe bradycardia can occur in artificially ventilated high cervical cord injuries with diaphragmatic paralysis. Their intact vagi are sensitive to hypoxia. Stimuli such as tracheal suction can readily induce bradycardia and even cardiac arrest. The inability to increase sympathetic activity is likely to contribute. Similar responses also may occur in tetraplegic patients during general anaesthesia, especially when muscle paralysis followed by intubation is performed without atropine.

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In neurally mediated syncope, severe bradycardia may occur in conjunction with hypotension. Syncope can even occur when the heart rate is preserved by a cardiac demand pacemaker, because sympathetic withdrawal alone can cause substantial vasodilatation resulting in hypotension. In diabetes mellitus, the presence of a cardiac vagal neuropathy may result in higher resting heart rate and impaired sinus arrhythmia and other tests of cardiac parasympathetic function (Figure 23.17). Disorders of cardiac conduction are common in Chagas disease (South American trypanosomiasis) and may occur in amyloidosis. In PoTS, tachycardia usually is associated with head-up postural change and exertion. Tachycardia resulting from increased sympathetic discharge may occur along with hypertension in the Guillaine–Barré syndrome and in tetanus. In phaeochromocytoma, tachycardia results from catecholamine release and βadrenoceptor stimulation.

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Figure 23.16 Plasma noradrenaline levels in a patient with a phaeochromocytoma (black triangles) and in a group of patients with essential hypertension (open triangles) before and after intravenous clonidine, indicated by an arrow (2 μg/kg over 10 minutes). Plasma noradrenaline levels fall rapidly in the essential hypertensives after clonidine and remain low over the period of observation. The stippled area indicates the +/− standard error of mean (SEM). Plasma noradrenaline levels are considerably higher in the phaeochromocytoma patient and are not affected by clonidine. (From Mathias & Bannister 2002, with permission.)

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Facial and peripheral vascular changes When blood pressure falls in postural hypotension or neurally mediated syncope, there is usually facial pallor with an ashen appearance. Restoration of colour follows promptly on assuming the supine position when blood pressure rises. Facial pallor also may occur during an attack in phaeochromocytoma but usually is accompanied by sweating, headache and hypertension. In longstanding tetraplegia, hypertension during autonomic dysreflexia is often accompanied by flushing and sweating over the face and neck. The precise mechanisms are unknown. In Harlequin syndrome (see below) there is vasodilatation and anhidrosis on one side of the face caused by sympathetic

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Figure 23.17 (a) Rise and fall in heart rate (sinus arrhythmia) in a normal subject. (b) These responses are diminished in autonomic failure affecting the cardiac parasympathetic.

Autonomic Dysfunction impairment, with sparing of the pupil. The lesion spares the first thoracic segment (from which oculomotor fibres often leave) but affects sympathetic fibres of the second and third thoracic roots. Raynaud’s phenomenon may be seen in both PAF and MSA, for uncertain reasons. In the latter, cold purplish blue hands and feet can be particularly troublesome. Livedo reticularis can accompany sympathetic over-activity, as in phaeochromocytoma. In erythromelalgia (Chapter 22) there is limb discomfort with vascular changes. The precise reasons for the cutaneous, vascular and sudomotor changes in reflex sympathetic dystrophy (chronic region pain disorder), remain debatable.

Sudomotor system The eccrine glands concerned with temperature regulation are innervated by sympathetic cholinergic fibres, unlike apocrine glands on palms and soles which are influenced by circulating substances, including catecholamines. Anhidrosis or hypohidrosis is common in PAF and differences in sweating may first be noticed during exposure to warm temperatures. Occasionally, hyperhidrosis in segmental areas may be a disconcerting symptom, as a compensatory response to diminished sudomotor activity elsewhere. Anhidrosis may be congenital and occur without any other deficit. It may be an integral component of certain hereditary sensory and autonomic neuropathies, such as congenital insensitivity to pain with anhidrosis (HSAN Type IV; Chapter 22). Localized or generalized anhidrosis, sometimes with compensatory hyperhidrosis, may be associated with the Holmes–Adie pupil (Plates 23.1–23.3). This association is known as Ross’s syndrome. In spinal cord injuries, there often is a band of hyperhidrosis above the lesion with anhidrosis below. During autonomic dysreflexia in high spinal lesions sweating occurs mainly over the face and neck. Facial and truncal hyperhidrosis may occur in Parkinson’s disease. Hyperhidrosis is seen intermittently in phaeochromocytoma and accompany hypertension in tetanus. Localized hyperhidrosis over the face and neck caused by food (gustatory sweating) can be socially distressing. It occurs in diabetes mellitus, following Bell’s palsy and after parotid surgery, as a result of aberrant connections between nerve fibres supplying the salivary and sweat glands. Minimally invasive endoscopic techniques for sympathectomy often are successful in reducing axillary and palmar hyperhidrosis, but some develop troublesome compensatory hyperhidrosis over innervated areas of the trunk and lower limbs. The mechanisms are unclear. Hypothermia can occur in hypothalamic disorders and in the elderly, in whom degenerative hypothalamic lesions are sometimes postulated. In high spinal injuries, especially in the early phases, the absence of ‘shivering thermogenesis’ and inability to vasoconstrict and thus prevent heat loss can readily result in hypothermia. Hypothermia may be missed if oral temperature only is recorded without a low-reading thermometer. Measurement of core tympanic or rectal temperature is essential. Hyperpyrexia may be a problem with anhidrosis, with exposure to high ambient temperatures. Heat also increases vasodilatation and can enhance orthostatic hypotension leading to collapse.

Alimentary system Reduced salivation and a dry mouth (xerostomia) occur in autonomic disease, especially in pure cholinergic dysautonomia. It may cause dysphagia, prominent when eating dry food. The lower two-thirds of the oesophagus contains smooth muscle innervated autonomically. Diseases affecting these pathways often cause dysphagia. Dysphagia is unusual in PAF, but often occurs in the later stages of MSA, where the problem often is in the oropharyngeal region and may result in tracheal aspiration. The oesophagus often is involved in Chagas disease, with achalasia and megaoesophagus causing vomiting. Gastric stasis in diabetes mellitus may cause abdominal distension and vomiting of undigested food. Constipation is common in PAF. Diarrhoea also may occur as result of overflow. Diarrhoea, especially at night, can be a distressing problem in diabetes mellitus. Reasons postulated include incomplete digestion, altered bowel flora and abnormal motility, but the cause remains poorly understood.

Kidneys and urinary tract Nocturnal polyuria is a frequent symptom in PAF. The causes include restitution of blood pressure sometimes to elevated levels while supine, redistribution of blood from the peripheral into the central compartment, and alteration in release of hormones that influence salt and water handling (such as renin, aldosterone and atrial natriuretic peptide). In MSA, where there is additional autonomic impairment of bladder and sphincter control, nocturia can be particularly troublesome. By day, the low level of blood pressure when upright is likely to cause oliguria. Autonomic disease can cause urinary frequency, urgency, incontinence or retention. Loss of sacral parasympathetic function, as in the early phase of spinal cord injury, causes an atonic bladder with urinary retention, whereas recovery of isolated spinal cord function results in a neurogenic bladder. Dyssynergia, with detrusor contraction but without sphincter relaxation, causes autonomic dysreflexia. Ureteric reflux predisposes to renal damage, especially in the presence of infection. In PAF, urinary symptoms initially may be attributed in older men to prostatic hypertrophy and in women to pelvic muscle weakness, especially in those who are multiparous. In MSA, surgery in suspected prostate enlargement usually is of no benefit. The use of drugs with anticholinergic effects may unmask urinary bladder dysfunction in autonomic failure. Infection is common when bladder dysfunction causes urinary stasis. Some, such as those with spinal injuries, are prone to urinary calculi, especially when immobility increases calcium excretion.

Sexual function In the male, failure of erection, dependent partly on the parasympathetic system, may cause impotence. Ejaculation is controlled by the sympathetic system. Retrograde ejaculation may occur, especially if there are urinary sphincter abnormalities. Dissociating the effects of increasing age, systemic illness and depression

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from definable organic causes of impotence may be difficult. The effect of drug therapy needs consideration. The 5-HT uptake inhibitor, fluoxetine, prolongs ejaculation. Others normally not considered to have autonomic side effects, such as thiazides used in hypertension, may diminish sexual potency. Priapism resulting from abnormal spinal reflexes may occur in patients with spinal cord lesions. In women, autonomic impairment does not appear directly to affect sexual function, although this has been inadequately studied.

Eyes and lacrimal glands The non-striated component of the levator palpebrae superioris (Müller’s muscle) is innervated by sympathetic fibres. Mild ptosis is part of Horner’s syndrome. If sympathetic lesions are bilateral, as in high spinal cord transection, Horner’s syndrome is difficult to detect. A variety of pupillary abnormalities may occur with autonomic involvement, miosis in Horner’s syndrome and dilated myotonic pupils in Holmes–Adie syndrome (Plates 23.2 and 23.3). Symptoms directly relating to ocular function may be minimal in such disorders. Night vision is impaired in sympathetic denervation. There is reduced tolerance to sunlight when pupils are dilated following parasympathetic failure. The ciliary muscle is innervated by parasympathetic nerves: blurred vision caused by cycloplegia may follow disease or anticholinergic drugs. The latter also may raise intra-ocular pressure and cause glaucoma. Impaired tear production may occur in PAF, sometimes as part of a presumed sicca or Sjögren’s syndrome, along with diminished salivary secretion. Excessive and inappropriate lacrimation occurs in crocodile tears syndrome (gusto-lacrimal reflex).

Respiratory system Involuntary inspiratory sighs, stridor and snoring of recent onset are more frequent in MSA than in Parkinson’s disease. Stridor results from weakness of the crico-arytenoid muscles, the main laryngeal abductors. Nocturnal apnoea, which occurs in the later stages of the disorder, is caused by involvement of brainstem respiratory centres. Abnormal responses following activation of reflexes from the respiratory tract, such as during tracheal suction, may cause profound cardiovascular disturbances. The following occur: • In tetanus, severe hypertension and tachycardia; • In high cervical cord transaction, bradycardia and cardiac arrest.

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Autonomic Parkinsonian Cerebellar/ pyramidal Dementia

Figure 23.18 The major clinical features in parkinsonian syndromes and allied disorders with autonomic failure. These include the three major neurological forms of multiple system atrophy (MSA); the parkinsonian form (MSA-P, also called striatonigral degeneration), the cerebellar form (MSA-C, also called olivopontocerebellar atrophy) and the multiple or mixed form (MSA-M, which has features of both other forms), pure autonomic failure (PAF), idiopathic Parkinson’s disease (IPD), Parkinson’s disease with autonomic failure (PD + AF), progressive supranuclear palsy (PSP) and diffuse Lewy body disease (LBD). After Mathias (1997, 2005).

Parkinson’s disease with autonomic failure, extrapyramidal features often have been present for a long period and usually remain responsive to levodopa therapy. In the non-parkinsonian forms of MSA, cerebellar features predominate with an ataxic gait, intention tremor, scanning speech and nystagmus. Ataxia may be difficult to separate from or may be compounded by unsteadiness caused by orthostatic hypotension. There also may be pyramidal involvement with increased tone, exaggerated tendon reflexes and extensor plantar responses. In the mixed form of MSA, a varying combination of extrapyramidal, cerebellar and pyramidal features is seen. Sensory deficits are uncommon in MSA. Patients with secondary autonomic failure have neurological features that are a part of, or a complication of, a primary disease. In diabetes mellitus, a sensorimotor neuropathy often coexists with, or precedes the autonomic neuropathy.

Psychological and psychiatric disturbances Additional features of neurological conditions: MSA and Parkinson’s disease In the parkinsonian form of MSA, bradykinesia and rigidity with minimal tremor are more likely than in idiopathic Parkinson’s disease (Figure 23.18). This causes difficulties in mobility, especially turning in bed and changing direction. Facial expression is affected to a lesser degree in MSA than in idiopathic Parkinson’s disease. In MSA there often is a response to antiparkinsonian agents in the early stages. Drug side effects, such as orthostatic hypotension, are likely to occur as the disease progresses. In

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Dementia is unusual in PAF. Most patients with MSA are not clinically depressed, despite their disabilities and the probable deficit in central catecholamine levels. Overall, they tend to have a normal affective state, especially when comparisons are made with Parkinson’s disease. In PAF there is no psychological disorder, but the absent autonomic responses may result in subtle emotional deficits. They appear less emotional than normal subjects and, when compared with similarly disabled patients with Parkinson’s disease without autonomic failure, are less anxious. Cognitive function may transiently be affected when blood

Autonomic Dysfunction pressure falls below critical cerebral perfusion pressure limits. Whether this affects certain tasks, e.g. involving attention, rather than others, is unclear. Anxiety and tremulousness may occur in phaeochromocytoma. Psychological factors may contribute to vasovagal syncope (hence the term ‘emotional syncope’) and also in essential hyperhidrosis. Whether this is the cause, or result, of the autonomic condition can be difficult to dissect. Psychiatric disturbances may also complicate conditions such as porphyria.

Clinical examination A detailed physical examination is essential and, with the symptoms elicited, may provide important clinical pointers towards autonomic disease. Features on general examination include dryness of skin, hyperhidrosis or cold hands in Raynaud’s disease, and pupillary changes. Measurement of blood pressure, both lying and standing (or sitting), is needed to determine if orthostatic hypotension is present, as is recording the pulse rate changes in patients with PoTS. The extent and distribution of the neurological abnormalities provide important clues to underlying central or peripheral autonomic disorders. Examination of other systems, as in hepatic disease or diabetes, is necessary along with urine testing for glucose and protein. The combination of a detailed history and physical examination is crucial in determining if autonomic disease is present, in ascertaining the probable underlying diagnosis, and also for interpreting the results of autonomic tests in the context of the associated disorder.

Investigations The aims of investigations in autonomic dysfunction are twofold. The first relates to diagnosis. The second is to understand the pathophysiological basis of disturbed autonomic function, as this often forms the basis of treatment strategies and their evaluation. An outline is provided in Table 23.8. Details of the tests are provided elsewhere.

Management The management of autonomic dysfunction encompasses a number of aspects. Of immediate and practical importance is alleviation of symptoms. The ideal is to rectify the autonomic deficit and cure the underlying disorder but this rarely is achieved. Autonomic disease often involves various systems. Basic principles in relation to management of the major clinical features are provided here. Specific aspects will vary in different diseases and always should be directed to the needs of the individual patient.

Table 23.8 Outline of investigations in autonomic disease. Cardiovascular Physiological Head-up tilt (60º);* standing;* Valsalva maneouvre* Pressor stimuli* (isometric exercise, cold pressor, mental arithmetic) Heart rate responses – deep breathing,* hyperventilation,* standing,* head-up tilt,* 30 : 15 R–R interval ratio Liquid meal challenge Exercise testing Carotid sinus massage

Biochemical Plasma noradrenaline: supine and head-up tilt or standing; urinary catecholamines; plasma renin activity and aldosterone Pharmacological Noradrenaline: alpha-adrenoceptors, vascular Isoprenaline: beta-adrenoceptors, vascular and cardiac Tyramine: pressor and noradrenaline response Edrophonium: noradrenaline response Atropine: parasympathetic cardiac blockade Imaging Cardiac sympathetic innervation with MIBG or fluoro-dopamine Endocrine Clonidine – alpha-2 adrenoceptor agonist: noradrenaline suppression; growth hormone stimulation Sudomotor Central regulation thermoregulatory sweat test Sweat gland response to intradermal acetylcholine, quantitative sudomotor axon reflex test, localized sweat test Sympathetic skin response Gastrointestinal Video-cine-fluoroscopy, barium studies, endoscopy, gastric emptying studies, lower gut studies Renal function and urinary tract Day and night urine volumes and sodium/potassium excretion Urodynamic studies, intravenous urography, ultrasound examination, sphincter electromyography Sexual function Penile plethysmography Intracavernosal papaverine Respiratory Laryngoscopy Sleep studies to assess apnoea and oxygen desaturation Eye and lacrimal function Pupil function, pharmacological and physiological Schirmer’s test * Screening tests widely used.

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Cardiovascular system Orthostatic hypotension Orthostatic hypotension may cause few symptoms in some but can cause considerable distress in others. It may contribute to disability and even death because of the potential risk of substantial injury. Treatment may be needed even in those who are asymptomatic, as they are at risk in situations such as fluid depletion or treatment with vasodilator drugs when there may be marked falls in blood pressure. No single drug or treatment can effectively replace the actions of the sympathetic nervous system in different situations. A multi-pronged approach, combining non-pharmacological and pharmacological measures, is usually needed (Table 23.9). The doctor and patient should be aware of the limitations of treatment. Furthermore, associated deficits (such as cerebellar features in MSA) may limit mobility in some, despite effective treatment of orthostatic hypotension. Increasing patient awareness of factors that lower blood pressure is important. Rapid postural change, especially in the morning when getting out of bed, must be avoided because the supine blood pressure often is lowest at this time. Prolonged bed rest and recumbency through factors that include decompensation may contribute to orthostatic intolerance even in healthy

Table 23.9 Approaches to management of orthostatic hypotension, e.g. in chronic autonomic failure. Non-pharmacological measures To be avoided Sudden head-up postural change (especially on waking) Prolonged recumbency Straining during micturition and defaecation High environmental temperature (including hot baths) Severe exertion Large meals (especially with refined carbohydrate) Alcohol Drugs with vasodepressor properties

To be introduced Head-up tilt during sleep Small frequent meals High salt intake Judicious exercise (including swimming) Body positions and manoeuvres To be considered Elastic stockings Abdominal binders Water ingestion Pharmacological measures Starter drug (fludrocortisone) Sympathomimetics (ephedrine, midodrine, L-DOPS) Specific targeting (octreotide, desmopressin, erythropoietin) L-DOPS, L-dehydroxyphenylserine

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individuals and can considerably worsen orthostatic hypotension in autonomic failure. Head-up tilt at night is beneficial and may reduce salt and water loss by stimulating the renin–angiotensin– aldosterone system. Straining during micturition and defaecation lowers blood pressure further by inducing a Valsalva manoeuvre. In toilets in small enclosed areas, e.g. in aircraft, the severe hypotension induced can be dangerous because of the inability to fall to the floor and thereby recover blood pressure and consciousness. In hot weather, because of impairment of thermoregulatory mechanisms, the rise in body temperature will increase cutaneous vasodilatation and worsen orthostatic hypotension. Ingestion of alcohol or large meals, especially those with a high carbohydrate content, causes splanchnic vasodilatation and postprandial hypotension which can aggravate orthostatic hypotension. Various physical manoeuvres, such as leg crossing, squatting, sitting in the knee–chest position and abdominal compression, reduce orthostatic hypotension (Figure 23.19). Drugs needed for associated symptoms (such as dopaminergic drugs) or to improve quality of life (sildenafil for erectile failure) may lower blood pressure further. Lower limb elastic compression stockings, abdominal binders and positive-gravity suits reduce venous pooling during standing. Each has its limitations and may increase susceptibility to orthostatic hypotension when not in use. Water ingestion (250–500 mL) raises blood pressure substantially in PAF by mechanisms that remain unclear (Figures 23.20 and 23.21). The ensuing diuresis may be troublesome, especially in MSA with associated urinary bladder disturbances. Drugs that act in a variety of ways to raise blood pressure often are needed in association with non-pharmacological measures in moderate to severe orthostatic hypotension (Table 23.10). A valuable starter drug is fludrocortisone in 50–100 μg at night or twice daily. It acts by retaining salt and water and increasing the sensitivity of blood vessels to pressor substances. In some ankle oedema, and with higher doses hypokalaemia, are unwanted effects. The second line of drugs include those that mimic actions of noradrenaline. They include ephedrine (15 mg t.d.s. to a maximum of 45 mg t.d.s.), which acts both directly and indirectly. It raises blood pressure in central and incomplete autonomic lesions, including MSA. In peripheral sympathetic lesions, such as PAF, it may have minimal effects. Tachycardia, tremor and insomnia may limit use of higher doses. In peripheral lesions, where ephedrine may not be effective, midodrine (2.5 μg to a maximum of 10 μg t.d.s) is used. It is converted to the active metabolite, desglymidodrine, which acts on α-adrenoceptors. Side effects include a tingling scalp, goose pimples and, in the male, urinary retention. The ergot alkaloid, dihydro-ergotamine, acts predominantly on venous capacitance vessels, but its effects are limited by its poor absorption necessitating high oral doses (5–10 mg t.d.s). In dopamine beta-hydroxylase (DβH) deficiency, a rare genetic disorder, there is an absence of plasma noradrenaline and adrenaline with increased plasma dopamine levels, resulting in severe


Finap (mmHg)

150

75

0 0

30

60

0

62 yrs PAF

30

60

0

30

60 Time (s)

Figure 23.19 Physical counter-manoeuvres using isometric contractions of the lower limbs and abdominal compression. The effects of leg crossing in standing and sitting position, placing a foot on a chair and squatting on finger arterial blood pressure in a 54-year-old female subject with pure autonomic failure (PAF) and incapacitating postural hypotension. The subject was standing prior to the manoeuvres during which there is an increase in blood pressure and the pulse pressure. The effect on finger arterial blood pressure (Finap) of standing in the crossed leg position with leg muscle contraction (left), and sitting on a Derby

chair (middle), or fishing chair (right) in a patient with autonomic failure and orthostatic hypotension. Orthostatic symptoms were present initially when standing and disappeared on crossing legs and sitting on the fishing chair. Sitting on the Derby chair caused the least rise in blood pressure and did not relieve completely the patient’s symptoms. (From Smit AAJ, Hardjowijona MA, Wieling W. Are portable folding chairs useful to combat orthostatic hypotension? Ann Neurol; 1997, 42; 975–978 with permission.)

orthostatic hypotension (Figure 23.22). Symptoms may be noted during infancy with hypotension, hypotonia and hypothermia. Children with DβH deficiency cannot exercise fully because their blood pressure falls, causing syncope. Symptoms usually worsen during the first two decades. Severe orthostatic hypotension becomes prominent in adulthood. DβH deficiency is caused by changes in DBH gene expression and inherited as an autosomal recessive disorder. Restoration of plasma noradrenaline is achieved by treatment with the precursor of noradrenaline, L-threo-3–4dihydroxyphenylserine (DOPS), which has a structure similar to noradrenaline but with a carboxyl group. It can be given by

mouth and is converted from the inert form to noradrenaline by the enzyme dopa decarboxylase, thus bypassing the Dβ-H deficiency. It thus replaces the deficient neurotransmitter and has been remarkably effective in this condition (Figure 23.23). DOPS may benefit other patient groups with PAF. Specific targeting of pathophysiological mechanisms should be introduced when the combination of fludrocortisone and sympathomimetics is not effective. Nocturnal polyuria often worsens morning orthostatic hypotension. The vasopressin-2 receptor agonist, desmopressin, orally at night (e.g. 5–40 μg intranasally) is a potent antidiuretic with minimal direct pressor activity. In

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Continuous finger blood pressure (mmHg)

Chapter 23 Table 23.10 Outline of mechanisms by which drugs may reduce postural hypotension. 160 Reducing salt loss/plasma volume expansion Mineralocorticoids (fludrocortisone)

140 Water

120

Reducing nocturnal polyuria V2-receptor agonists (desmopressin)

100 80 60 40 20 0 –5

0

5

10 15 20 25 30 35 40 45 50 55 Time (minutes)

Figure 23.20 Changes in blood pressure before and after 500 mL distilled water ingested at time ‘0’ in a patient with pure autonomic failure. Blood pressure is measured continuously using the Portapres II. (From Cariga & Mathias 2001, with permission.)

130 120

BEFORE WATER

PAF

MSA

Vasoconstriction Sympathetic On resistance vessels (ephedrine, midodrine, phenylephrine, noradrenaline, clonidine, tyramine with monoamine oxidase inhibitors, yohimbine, L-dihydroxyphenylserine) On capacitance vessels (dihydroergotamine)

Non-sympathomimetic V1-receptor agents (terlipressin) Increasing acetylcholine Acetylcholine esterase inhibitors (pyridostigmine) Preventing vasodilatation Prostaglandin synthetase inhibitors (indometacin, flurbiprofen) Dopamine receptor blockade (metoclopramide, domperidone) Beta2-adrenoceptor blockade (propranolol) Preventing postprandial hypotension Adrenosine receptor blockade (caffeine) Peptide release inhibitors (somatostatin analogue: octreotide)

Mean ± 2 SE

110 Increasing cardiac output Beta-blockers with intrinsic sympathomimetic activity (pindolol, xamoterol) Dopamine agonists (ibopamine)

100 90

Increasing red cell mass Erythropoietin

80 70 60 50

STAND1

STAND2

STAND3

Figure 23.21 Standing blood pressure in seven pure autonomic failure (PAF) and seven multiple system atrophy (MSA) patients before and 15 and 30 minutes after ingestion of 500 mL water. (From Young & Mathias 2004, with permission.)

MSA with nocturia also caused by bladder disturbances, desmopresssin may be of considerable benefit in allowing less disturbed rest. Smaller doses are needed in PAF patients who appear more sensitive than those with MSA. Plasma sodium should be measured at intervals to exclude hyponatraemia. Water intoxication can be reversed by stopping the drug, and witholding water. In postprandial hypotension large meals should be avoided; instead small meals with low carbohydrate content should be

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eaten at frequent intervals. Drinking coffee after meals may help. Caffeine blocks vasodilatatory adenosine receptors. A dose of 250 mg (present in two cups of typical espresso) can be used. Tolerance may develop. The somatostatin analogue, octreotide (25 or 50 μg, ideally 30 minutes before food) prevents postprandial hypotension by inhibiting release of a variety of vasodilatatory gastrointestinal peptides. It also may reduce postural and exercise-induced hypotension. Side effects include abdominal colic and loose stools which respond to spasmolytics (Buscopan) and opiates (codeine phosphate and loperamide). Octreotide does not appear to enhance supine nocturnal hypertension. Anaemia worsens symptoms of orthostatic hypotension and may occur in PAF and with renal impairment, in diabetes mellitus and in systemic amyloidosis. Erythropoietin (given subcutaneously) stimulates red cell production, raises red cell mass and haemoglobin levels. This reduces orthostatic hypotension and its symptoms in such situations.


CH2

CH

NH2

Tyrosine COOH

HO

Tyrosine hydroxylase HO

CH

CH2

Dopa

NH2

COOH

HO

HO

CH2

CH2

CH2

NH2

OH COOH

HO

Dopa decarboxylase HO

CH

DL-DOPS

NH2

Dopamine HO Dopamine beta hydroxylase CH

HO Noradrenaline Figure 23.22 Biosynthetic pathway in the formation of adrenaline and noradrenaline. The structure of DL-DOPS is indicated on the right. It is converted directly to noradrenaline by dopa decarboxylase, thus bypassing dopamine β-hydroxylase. (From Mathias et al. 1990, with permission.)

CH2

NH2

OH HO

Phenylethanolamine N-methyl transferase CH CH2 NH

HO Adrenaline

OH

CH3

HO

DBH deficient (1)

Blood pressure (mm Hg)

150

110

70

Figure 23.23 Blood pressure (systolic and diastolic) while lying (L) and during head-up tilt (T) in one of two siblings with dopamine beta hydroxylase (DβH) deficiency (1) before, during and after treatment with DL-DOPS (racemic mixture; DOPS, dihydroxyphenylserine) and L-DOPS (laevo form). The laevo form causes a greater rise in blood pressure and a greater reduction in postural hypotension than the racemic mixture. (From Mathias et al. 1990, with permission.)

Noradrenaline/dopamine (pg/mL)

30

L

800

T

No drugs

L

T

L

T

DL-DOPS

L-DOPS

L

L

600 400 200 0

*

* L

T

T

T

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Chapter 23 Table 23.11 Drugs used for reducing hypertension in autonomic dysreflexia. Afferent Spinal cord

Efferent

Target organs

Sympathetic ganglia Sympathetic nerve terminals Alpha-adrenoceptors Blood vessels

Topical lidocaine Clonidine* Reserpine* Spinal anaesthetics Hexamethonium Guanethidine Phenoxybenzamine Glyceryl trinitrate Nifedipine

* Clonidine and reserpine have multiple effects, some of which are peripheral.

Table 23.12 Management strategy in autonomic failure. Specific For orthostatic hypotension, and bladder, bowel, sexual dysfunction: non-pharmacological and pharmacological therapy For respiratory abnormalities: consider tracheotomy For oropharyngeal dysphagia: consider PEG For depression: drug treatment General education Of patients and partners, relatives, carers, medical practitioners, supportive therapists, to include physiotherapists, occupational therapists, speech therapists and dietitians Patient support groups To disseminate information and increase awareness: Autonomic Disorders Association, Sarah Matheson Trust in UK Shy–Drager Association in USA Autonomic nurse specialist or autonomic liaison nurse To link, coordinate and streamline specialist care with the patient, carers and community PEG, percutaneous endoscopic gastrostomy.

Difficulties in the management of orthostatic hypotension have resulted in an array of drugs that have been reported to provide benefit in individual cases or in certain disorders (Tables 23.11 and 23.12). As with all drugs they should be used cautiously. Some have serious side effects such as cardiac failure with pindolol, and gastric ulceration and haemorrhage with indometacin. The use of a noradrenaline pump in extreme cases has been used with benefit. Drugs should be used to reduce the side effects of therapy that is essential for associated disease. When levodopa is used to treat parkinsonism, higher doses of dopa-decarboxylase inhibitors should be used. The dopamine antagonists metoclopramide and domperidone also reduce the peripheral effects of dopamine.

Supine hypertension Supine hypertension occurs frequently in PAF and may be worsened by drug treatment. It is unclear if certain drugs, such as

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higher doses of fludrocortisone are more likely to cause it. Supine hypertension may increase symptoms of cerebral ischaemia during postural change through an unfavourable resetting of cerebral autoregulatory mechanisms. Head-up tilt especially at night is probably the most practical method to prevent nocturnal supine hypertension. Omission of the evening dose of vasopressor agents, a pre-bedtime snack or alcohol to induce postprandial hypotension, and sometimes even use of short-acting antihypertensive drugs should be considered. The long-term possible effects of supine hypertension include cardiac hypertrophy and damage to subcortical cerebral vessels. This may occur in PAF; these patients have a good prognosis and drugs may be used over many years. The benefits of treating orthostatic hypotension effectively, thus reducing the likelihood of trauma and improving their quality of life, should be weighed against the long-term risks.

Neurally mediated syncope Management is dependent on the cause, provoking factors, disability caused and whether the episodes are of the cardioinhibitory, vasodepressor or mixed type. Vasovagal syncope usually carries an excellent prognosis. Once the diagnosis is confirmed, an important component is positive reassurance. Advice on non-pharmacological measures includes ensuring salt repletion, an adequate fluid intake and techniques to enhance sympathetic activity and prevent pooling. The former include the use of isometric hand exercise and the latter activation of the calf muscle pump. If necessary subjects should lie flat with the legs upright or with the head between the knees. Each subject should decide on which methods to use effectively in different situations. This is of particular value when there is a window of warning before the loss of consciousness. In vasodepressor syncope low-dose fludrocortisone and sympathomimetics can be used if needed. Ephedrine is contraindicated if tachycardia is a problem; midodrine is the alternative. In those with a predominant cardio-inhibitory component, a demand pacemaker needs consideration especially when there is minimal warning before fainting. Cognitive behavioural psychotherapy is helpful if there is coexisting phobia, panic attack or anxiety disorder. 5-HT and noradrenaline uptake inhibitors such as fluoxetine, sertraline and venlafaxine have also been used. In carotid sinus hypersensitivity, a cardiac demand pacemaker often is needed in the cardio-inhibitory and mixed forms. When the vasodepressor component is present and persists following pacemaker insertion, vasopressor agents including midodrine should be considered. Caution should be exercised as these patients often are elderly and may have vascular disease and prostatic hypertrophy that may increase the tendency to side-effects. In unilateral hypersensitivity, carotid sinus denervation is sometimes carried out. In situational syncope, management should be directed towards the underlying cause and pathophysiological basis. In micturition syncope, occuring mainly in males, advice is needed to avoid contributing factors (e.g. alcohol). The bladder should be emptied

Autonomic Dysfunction while sitting rather than standing, especially if the patient has to pass urine during the night.

Postural tachycardia syndrome These patients often need a combination of measures. Tachycardia often is associated with a low supine level of blood pressure, and a substantial number also have vasovagal syncope. Treatment is similar to the vasodepressor form of vasovagal syncope, with non-pharmacological measures and if needed drugs such as fludrocortisone and sympathomimetics. Ephedrine is contraindicated. Midodrine does not cause tachycardia and is the sympathomimetic of choice. Beta-adrenoceptor blockers, especially cardioselective ones such as bisoprolol, have a role. A selective sinus node blocker, ivabradine, has also been used to reduce tachycardia.

considered. Ablation of T1/T2 also is used in facial flushing. In some, compensatory hyperhidrosis below the anhidrotic region can be extremely troublesome.

Alimentary system

Hypertension Hypertension resulting from increased sympathetic nervous activity in the Guillain–Barré syndrome and following subarachnoid haemorrhage may respond to propranolol and sympatholytic agents. In high spinal cord injuries, determining and rectifying the provoking cause of autonomic dysreflexia is crucial, as the key is prevention. A range of drugs, based on knowledge of the pathophysiological mechanisms, can be used to prevent or reduce hypertension in such patients (Table 23.11).

Xerostomia is helped by artificial saliva. Excessive salivation responds to botulinum injection. Achalasia of the oesophagus may require dilatation, botulinum injection or surgery. In MSA with oropharyngeal dysphagia, advice should be provided on the type and consistency of food; severe dysfunction increases the risk of tracheal aspiration and a feeding percutaneous gastrostomy may be needed. The dopamine antagonists metoclopramide and domperidone increase gastric emptying in gastroparesis, as does the macrolide erythromycin which stimulates motilin receptors. Peptic ulceration occurs in the early stages after high spinal cord injury and prophylaxis includes H2 antagonists (cimetidine and ranitidine) and proton-pump inhibitors (omeprazole). In diarrhoea caused by bacterial overgrowth, as in the blind loop syndrome, broad-spectrum antibiotics (neomycin or tetracycline) may be the initial step before using codeine phosphate or other opiate-based antidiarrhoeal agents. Octreotide, the somatostatin analogue, can reduce diarrhoea in amyloidosis and diabetic autonomic neuropathy. Aperients and laxatives, together with a high-fibre diet, are needed in constipation.

Sudomotor disorders

Urinary tract

Anhidrosis The ensuing problems include dry skin, hyperthermia and vasomotor collapse in hot weather. Dry skin is helped by suitable emollients. Prevention of hyperthermia is important by avoiding exposure to heat and ensuring a suitable micro-environment, ideally by air conditioning. Mechanisms to aid heat loss include tepid sponging to aid evaporation, fans to enhance convection loss and the ingestion of cool drinks. In severe hyperpyrexia, immersion in a cold bath may be needed.

In outflow tract obstruction, procedures which include prostatectomy, transurethral resection or sphincterotomy may be needed. Surgical procedures often induce or worsen incontinence in MSA. Bladder dysfunction may be helped by drugs that influence detrusor muscle activity (anticholinergics) or sphincter malfunction (alpha-adrenergic blockers). Intermittent or in-dwelling catheterization may be necessary. Nocturia in PAF is often helped by intranasal or oral desmopressin given in the evening.

Sexual function and the reproductive system Hyperhidrosis Management depends upon the underlying cause, the sites involved and the functional and emotional disability. In hyperhidrosis over the palms and soles, local application of astringents containing glutaraldehyde and antiperspirants containing aluminium salts may reduce sweating as does iontophoresis. Low-dose oral pharmacotherapy includes anticholinergics (probantheline bromide 15 mg t.d.s) and centrally acting sympatholytics (clonidine 25– 50 μg t.d.s). Side effects include a dry mouth. Glaucoma should be excluded prior to use of anticholinergics. Clonidine may reduce facial flushing. Topical anticholinergic cream (hyoscine hydrobromide or glycopyrrolate) may be helpful over small areas. Botulinum toxin is successful in hyperhidrosis affecting the axillae, palms and face. Injections may need to be repeated. When these measures fail, surgical intervention using percutaneous endoscopic transthoracic sympathectomy, with ablation of prevertebral sympathetic ganglia from T2 to T4 should be

Erectile failure in men can be treated by suction devices, an implanted prosthesis or drugs. The latter can be given locally (intracavernosal or urethral) or orally (sildenafil). Sildenafil and allied drugs have the potential through vasodilatation to lower blood pressure substantially, especially in patients with orthostatic hypotension. In DβH deficiency, difficulty in ejaculation is improved by treatment with DOPS. Pregnant women with high spinal injuries may develop severe hypertension with cardiac dysrhythmias and eclampsia during uterine contractions and delivery. Spinal anaesthesia, which reduces spinal sympathetic discharge, often permits a normal delivery.

Respiratory system A tracheostomy may be necessary in severe inspiratory stridor resulting from laryngeal abductor paresis, especially when oxygen desaturation occurs at night. With periodic apnoea, timed or triggered bilevel positive airway pressure ventilation may be

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useful. In high spinal cord lesions on artificial ventilation particular care should be taken during tracheal suction and toilet to avoid bradycardia and even cardiac arrest. In ventilated tetanus patients, the reverse – tachycardia and hypertension – may occur.

Eye and lacrimal glands In alacrima, tear substitutes such as hypromellose eye drops are needed. Cycloplegia can be reduced by local cholinomimetics. Patients should be made aware of night blindness in sympathetic denervation and about a low threshold to sunlight in parasympathetic denervation.

Treatment in MSA and Parkinson’s disease In the parkinsonian forms of MSA, levodopa is sometimes of benefit in the early stages. However, it may cause or enhance orthostatic hypotension and should be used with higher doses of dopa decarboxylase inhibitors. The monoamine oxidase-B inhibitor, selegiline, has been used in combination with levodopa and also may worsen orthostatic hypotension. It may cause hypotension also in Parkinson’s disease by mechanisms that include the central effects of its metabolites, methyl-amphetamine. Amantidine may provide motor benefit without lowering blood pressure. Dopaminergic agonists may be effective but it is unclear if they worsen orthostatic hypotension. With time there often is refractoriness to anti-parkinsonian drugs in MSA. There is no effective pharmacotherapy for cerebellar deficits in MSA. Supportive therapy using disability aids should be provided. The management of autonomic dysfunction needs to consider local organ dysfunction, the underlying or associated disease and integrative components often needing specialist care (Table 23.12). Of particular importance, especially in the generalized disorders, is the need for a holistic approach which includes the management of the autonomic deficits and the underlying disorder. Management should involve not only the patient, but the family, carers and community.

References Appenzeller O, Oribe E (eds.) The Autonomic Nervous System: An Introduction to Basic and Clinical Concepts, 5th edn. Amsterdam: Elsevier Medical Press, 1997.

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Cariga P, Mathias CJ. Haemodynamics of the pressor effect of oral water in human sympathetic denervation due to autonomic failure. Clin Sci 2001; 101: 313–319. Janig W, McLachlan EM. Neurobiology of the autonomic nervous system. In: Mathias CJ, Bannister R (eds.) Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System, 4th edn. Oxford: Oxford University Press, 2002: 3–15. Johnson RH, Lambie DG, Spalding JMK. Neurocardiology: The Interrelationship Between Dysfunction in the Nervous and Cardiovascular Systems. London: W.B. Saunders, 1984. Low PA (ed.) Clinical Autonomic Disorders, 2nd edn. Philadelphia: Lippincott Raven, 1997. Mathias CJ. Autonomic disorders. In: Bogousslavsky J, Fisher M (eds.) Textbook of Neurology. Boston, MA: Butterworth-Heinemann, 1998: 519–545. Mathias CJ. Disorders of the autonomic nervous system. In: Bradley WG, Daroff RB, Fenichel GM, Jancovich J (eds.) Neurology in Clinical Practice, 4th edn. Boston, MA: Butterworth-Heinemann, Boston, USA 2004, 2403–2240. Mathias CJ. Orthostatic hypotension and orthostatic intolerance. In: De Groot LJ, Jameson JL, de Kretser D, Grossman AB, Marshall JC, Melmed S, et al. (eds.) Endocrinology, 5th edn. Philadelphia, PA: Elsevier, 2006: 2613–2632. Mathias CJ, Bannister R. Investigation of autonomic disorders. In: Mathias CJ, Bannister R (eds.) Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System, 4th edn. Oxford: Oxford University Press, 2002: 169–195. Mathias CJ, Bannister R (eds.) Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System, 4th edn. Oxford: Oxford University Press, 2002. Mathias CJ, Bannister R. Postprandial hypotension in autonomic disorders. In: Mathias CJ, Bannister R (eds.) Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System, 4th edn. Oxford: Oxford University Press, 2002: 283–295. Mathias CJ, Bannister R, Cortelli P, Heslop K, Polak J, Raimbach SJ, et al. Clinical autonomic and therapeutic observations in two siblings with postural hypotension and sympathetic failure due to an inability to synthesize noradrenaline from dopamine because of a deficiency of dopamine beta-hydroxylase. Q J Med (New Series) 1990; 278: 617–633. Mathias CJ, Williams AC. The Shy Drager syndrome (and multiple system atrophy). In: Donald B Calne DB (ed.) Neurodegenerative Diseases. WB Saunders Company, Philadelphia, Pennsylvania, USA, 1994: 743–768. Smit AAJ, Hardjowijona MA, Wieling W. Are portable folding chairs useful to combat orthoststic hypotension? Ann Neurol 1997; 42: 975–978. Young TM, Mathias CJ. The effects of water ingestion on orthostatic hypotension in two groups with chronic autonomic failure: multiple system atrophy and pure autonomic failure. JNNP 2004, 75: 1737–1741.

24

Uro-Neurology Clare Fowler, Sohier Elneil

Neural control of the uro-genital system Because voluntary control over the uro-genital system is critical to our social existence and its peripheral innervation derives from the most distal segments of the spinal cord, the importance of the integrity of long tracts of the central nervous system for physiological function is immediately apparent (Figure 24.1). In clinical practice, as shown in a survey of the site of the underlying neurological disease affecting a sample of patients referred to the department, spinal cord involvement of various pathologies is the most common cause of bladder symptoms (Figure 24.2). It might be supposed that because of the commonality of innervation shared by the bladder and genital organs, that abnormalities of these two systems inevitably occur together. However, this is not the case, because although the organs share the same root innervation and have common peripheral nerves within the pelvis, each is controlled by its own unique set of central nervous system reflexes. In this chapter a brief account of the neurophysiological control of the bladder is given, followed by a description of the effect that neurological disease at different levels of the nervous system may have and the management of those conditions. Sexual function and neurogenic sexual dysfunction are covered in the same way.

Bladder function and its neurological control Physiology The bladder performs only two functions, storage and emptying, with control of these two mutually exclusive activities at two different anatomical locations. Storage is organized within the spinal cord and micturition results from activation by suprapontine influences of a centre in the dorsal tegmentum of the pons, the


pontine micturition centre (PMC) (Figure 24.1). Some of the proposed anatomical pathways are outlined in Chapter 2. In recent years functional brain imaging has contributed greatly to our understanding of the cortical input into bladder control. During the storage phase, raised pressure within the bladder outlet is maintained by sympathetic influences on the smooth muscle of the detrusor in the bladder neck region and by pudendal nerve activation of the striated muscle of the urethral sphincter and the pelvic floor. Inhibition of the parasympathetic outflow prevents detrusor contraction. Behaviourally, throughout the storage phase, our perception of bladder fullness enables us to make the necessary planned strategies to achieve the next appropriately located void before reaching an uncomfortable degree of bladder distension or the sensation of ‘severe urge to void’. Several functional brain imaging experiments have examined cortical activity during continent storage and a consistent finding of all these studies is that there is an activation of the periaqueductal gray (PAG) during bladder filling (for review see Kavia et al. 2005; Figure 24.3). This is in keeping with experimental studies in the cat, and it is thought that the PAG serves as a central relay centre for afferent activity from the pelvic organs and is an interface between the afferent and efferent limbs of bladder control circuits, ‘informing’ the PMC about the degree of bladder fullness. The PAG has multiple connections with higher centres such as the thalamus, insula, cingulate and prefrontal cortices. Activation of the insula is consistent with what is known about regions of activation involved in interoceptive awareness of visceral sensations. The prefrontal cortex, the seat of planning complex cognitive behaviours and of appropriate social behaviours, is activated on bladder filling and it seems likely that this region of the brain is involved in the conscious and social control of the bladder function. It has been proposed that the task of the prefrontal cortex is to make a decision as to whether or not micturition should take place at a particular place or time. With the decision to void, activation is seen in the prefrontal, insula, hypothalamus and PAG and the PMC. Activation of the

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Chapter 24

Undiagnosed 11% Cortical 9%

PMC

Retention 6%

IPD 9%

Subsacral 4%

MSA 6%

Other spinal disease 13% MS 42%

Figure 24.2 Neurological causes of bladder disorders in a small sample of patients presenting to the uro-neurology department. IPD, idiopathic Parkinson’s disease; MSA, multiple system atrophy; MS, multiple sclerosis.

Bladder Figure 24.1 Saggital MRI of man showing innervation of genito-urinary system–pontine micturition centre (PMC) to bladder.

Regions of interest with ‘full vs. empty’ bladder

Insula Anterior cingulate gyrus

Pons PAG

Prefrontal cortex

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Figure 24.3 Summary of regions of interest comparing ‘full vs. empty’ bladder conditions based on the coordinates published in five positron emission tomography (PET) studies (Athwal et al. 2001; Blok et al. 1997, 1998; Matsuura et al. 2002; Nour et al. 2000). The figure from Kavia et al. (2005) was prepared using MRIcro (Rorden & Brett 2000) with permission from Journal of Comparative Neurology.

Uro-Neurology PMC is the final brain efferent nucleus and in health results in spinal transmission of activity to sacral segments of the spinal cord. Voiding is achieved by relaxation of the urethral sphincter followed some seconds later by a contraction of the bladder, resulting in an increase in bladder pressure and the flow of urine. Relaxation of the urethral smooth muscle is mediated by activation of the parasympathetic pathway to the urethra which triggers the release of nitric oxide and by the removal of adrenergic and somatic cholinergic excitatory inputs. Secondary reflexes elicited by flow of urine through the urethra facilitate bladder emptying.

Neurological causes of bladder dysfunction Cortical disease The importance of the anterior regions of the frontal lobes in bladder control was established by Dr Peter Nathan, the first uroneurologist at Queen Square, and Mr John Andrew, a neurosurgeon at the Middlesex Hospital, in a paper published in Brain in 1964. A series of patients was reported with disturbed bladder control from various frontal lobe pathologies including tumours, damage following rupture of an intracranial aneurysm, penetrating brain wounds or the iatrogenic damage of leucotomy. The typical clinical picture was of a patient with severe urgency and frequency of micturition and urge incontinence, who is both socially aware and embarrassed by their incontinence. Only if

frontal lobe pathology is more extensive, causing loss of social inhibition, do patients become unconcerned about their loss of bladder control. Subsequent authors reported the occurrence of urinary incontinence in patients with frontal lobe lesions from a number of different pathologies. Recently, there has been a detailed analysis of the bladder symptoms of two patients with resected gliomas involving the posterior part of the right cingulate gyrus and the right inferior frontal cortex and insula, respectively, with an interesting discussion as to what insight these cases give about the cortical control of continence. Urinary retention has occasionally been described in patients with brain lesions. In the series by Andrew and Nathan two of their patients were in urinary retention at some stage and there have been a small number of case histories of patients with right frontal lobe pathology with urinary retention.

Cerebrovascular disease Incontinence following stroke is not a straightforward problem. Cystometric studies in series of patients following stroke generally conclude that detrusor over-activity (DO) is the most common urodynamic abnormality, although acute urinary retention may occur at the onset. There does not appear to be any definite lateralization of lesions causing DO, although possibly the pathology is more often right-sided, nor are there any specific locations; however, anteriorly situated damage is more likely to result in incontinence (Figure 24.4). At admission, approximately 50% of

Figure 24.4 Lesions on brain CT or MRI with micturitional disturbance (upper panel) and without (lower panel) (Sakakibara et al. 1996).

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stroke patients will have incontinence, but the incidence declines over the following 6 months to approximately 5%. Long-term incontinence is commonly caused by DO and is seen in patients with severe neurological deficits (aphasia and dysphagia, particularly) and a high level of persistent disability. The other approach to looking at stroke and urinary incontinence has been epidemiological. Following a stroke the presence of urinary incontinence within 7 days appears to be the most powerful prognostic indicator for poor survival and eventual functional dependence, more so than a depressed level of consciousness in this period. The explanation for this is not known but it has been suggested that either incontinence is the result of a severe general rather than specific loss of function, or that those who remain incontinent are less motivated, both to recover continence and more general function.

because of mental impairment this becomes a prominent cause of incontinence. The role of cortical brain disease is unclear. Frontal lobe pathology would be expected to cause DO and there is some evidence that this is a contributing factor. One of the differences between symptoms in those with and those without dementia is that urgency preceding episodes of incontinence is more frequently reported by those without. In a study of patients with cognitive decline, incontinence was associated with severe mental failure in pure Alzheimer’s disease but preceded cognitive impairment in diffuse Lewy body disease. A much less common cause of dementia, low-pressure hydrocephalus, has incontinence as a cardinal feature; improvement in cystometric function has been demonstrated within hours of lumbar puncture in patients with this disorder. Since the advent of cholinesterase inhibitors to treat symptoms in mild to moderate dementia, it is not uncommon to find a patient on such a treatment who has also been prescribed an antimuscarinic to treat their urinary urgency. No systematic study has yet been published that looks at interactions of these medications, but on theoretical grounds it would seem sensible to use an antimuscarinic to treat the bladder that does not cross the blood–brain barrier, such as tolterodine or trospium chloride or possibly the M3 specific antimuscarinic, darifenacin (Table 24.1). There are as yet no published data showing that the cholinesterase inhibitors cause or exacerbate bladder dysfunction.

Dementia Urinary incontinence in dementia is acknowledged to be a major socio-economic problem of ever-increasing proportions. In fact it is a complex problem. Incontinence in the frail elderly is common and has many potential causes. In a large group of elderly patients who were institutionalized because of their general frailty, the same variety of underlying pathophysiologies was found in those with mental impairment as those without. Although DO was the most common cause of incontinence in all cases, in 40% there were other causes and in nearly one-third incontinence was related to disorders of the urethral outlet, i.e. potentially surgically correctable conditions. There is also convincing evidence of a specific disorder of the detrusor muscle characterized by ultra-structural changes that has an increasing incidence in the elderly. This is thought to result in DO and incomplete emptying, the so-called ‘detrusor hyperactivity with impaired contractile function’ (DHIC). It seems highly likely that with loss of general ‘coping abilities’

Bladder dysfunction in Parkinson’s disease Bladder symptoms are being recognized amongst the non-motor aspects of Parkinson’s disease (PD) which are thought to be the consequence of the widespread dopaminergic and nondopaminergic neurodegeneration that occurs in the condition. The resulting ‘vegetative symptoms’ have a very negative impact on the patient and their carer as the condition advances.

Table 24.1 Anticholinergic agents used to treat symptoms of detrusor over-activity. Generic name

UK trade name

Dose (mg)

Frequency

Receptor subtype selectivity

Elimination half-life of parent drug (hour)

Propantheline bromide Tolterodine tartrate Tolterodine tartrate Trospium chloride Oxybutynin hydrochloride Oxybutynin hydrochloride XL Propiverine hydrochloride Darifenacin

Pro-Banthine® Detrusitol® Detrusitol® XL Regurin® Ditropan® Lyrinel® XL Detrunorm® Emselex®

15 2 4 20 2.5–5 5–30 15 7.5–15

t.d.s. b.d. o.d. b.d. b.d. to q.d.s. o.d. o.d. to q.d.s. o.d.

100 cells/mm3). Rheumatic fever can also cause valvular damage leading to embolism to the brain, particularly if the mitral valve is affected or atrial fibrillation develops during the illness. Sydenham’s chorea is discussed in Chapter 5.

Atrial myxoma The diagnosis of atrial myxoma is challenging: myriad symptoms can occur. This often leads to long delays in diagnosis and treatment. About 30% of atrial myxomas cause cerebral emboli – accounting for about 0.4% of all strokes and stroke is the most common neurological presentation. The majority of patients (up to 90%) present with constitutional symptoms of fatigue, fever,

Systemic Conditions and Neurology myalgia, arthralgia and weight loss. Cardiac symptoms are often present and include breathlessness in association with congestive failure and syncope. Investigations show elevated erythrocyte sedimentation rate (ESR) and C-reactive protein, anaemia and thrombocytosis or thrombocytopenia. Chest X-ray may show left atrial or ventricular enlargement and occasionally intracardiac tumour calcification. Echocardiography is the investigation of choice, but transthoracic studies have a false negative rate of about 20%. For this reason, if clinical suspicion is high, transoesophageal echocardiography must be performed. Stroke may result from embolic tumour fragments rather than fibrin thrombus, so anticoagulation may not be helpful and is probably best avoided, particularly as delayed cerebral aneurysm formation, often fusiform, in distal branches, can lead to cerebral haemorrhage. The treatment of atrial myxoma is optimization of cardiac function and urgent surgical removal. Follow-up with transoesophageal echocardiography is recommended as recurrence may occur, especially within the first 2 years – but occasionally more than 10 years later.

Endocrine conditions Thyroid disease Thyroid disorders can have a major impact on neurological function; they may affect any part of the CNS, peripheral nerves or muscle, mainly via high or low levels of circulating T4 and T3 or immune-mediated damage. It is especially important to recognize neurological manifestations of thyroid disease, as the symptoms will usually respond to appropriate treatment.

Hyperthyroidism Hyperthyroidism is most often brought about by immune mechanisms (Graves’ disease), but other causes include thyroiditis, multi-nodular goitre or, rarely, pituitary tumours. A myopathy is present to some extent in almost all patients with hyperthyroidism, although this may be asymptomatic. The onset is usually subacute, with proximal limb muscles typically affected, leading to difficulties ascending stairs, rising from a chair and raising the arms. Bulbar involvement is less common, although this may be a prominent feature in the rare acute form of thyrotoxic myopathy. Pain is common. Clinical findings are of proximal wasting especially involving shoulder and pelvic girdle muscles including quadriceps with hyper-reflexia but usually normal tone. The investigation findings usually include a normal creatine kinase (CK), in contrast to the raised CK of hypothyroid myopathy; electromyographic (EMG) abnormalities are seen, such as polyphasic motor potentials and sometimes a decrement in compound muscle action potential (CMAP) on repetitive stimulation. Rarely, hyperthyroidism can cause a form of hypokalaemic periodic paralysis, a condition seen particularly in South-East Asia. Thyroid disease is strongly associated with myasthenia gravis, probably because susceptible individuals are genetically predisposed to autoimmune disorders. About 20% of patients with

myasthenia have a thyroid disorder, more commonly hyperthyroidism than hypothyroidism. Hyperthyroidism can also cause a dramatic upper motor neurone syndrome, particularly affecting the legs, with spasticity, weakness, clonus and extensor plantars. This can cause diagnostic confusion by mimicking spinal cord compression; lower motor neurone features may also be present causing an amyotrophic lateral sclerosis-like presentation. Tremor is a near-invariable feature of hyperthyroidism, often most apparent in the outstretched arms. Myoclonus, chorea and even parkinsonism have also been described, albeit rarely. Peripheral neuropathy is an uncommon but described feature of hyperthyroidism. A flaccid paraparesis with areflexia may rarely occur (Basedow’s paraplegia). Thyroid eye disease is a common feature of Graves’ disease, occurring in up to 70% of patients depending on criteria used. The features of Graves’ ophthalmopathy are lid retraction, inflammation of orbital soft tissues, causing redness and swelling of the lids and conjunctivae, proptosis, extraocular muscle involvement causing ophthalmoplegia, corneal damage and, rarely, optic nerve compression. MR or CT imaging are helpful in showing enlarged extraocular muscles, particularly the medial and inferior recti (Figure 25.5). Although usually both eyes are affected, some patients have markedly asymmetric involvement. Treatment includes steroids, botulinum toxin, radiotherapy or surgery. Hyperthyroid encephalopathy is now rare, but may occur either in untreated patients, after radio-iodine treatment or during intercurrent illness or following surgical procedures. Florid signs of thyrotoxicosis, confusion, agitation, fever, seizures

Figure 25.5 Graves’ disease with progressive diplopia and restriction of right eye movements. Magnetic resonance imaging (MRI) shows enlarged inferior and medial recti on the right.

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and upper motor neurone signs may all be present. Mortality from this disorder remains high.

Hypothyroidism Hypothyroidism, resulting from immune-mediated mechanisms or following surgical or radiotherapy thyroid ablation, is an important treatable cause of neurological dysfunction affecting many parts of the nervous system. An encephalopathy characterized by slowness, lethargy and impaired attention is commonly seen in hypothyroidism. In its most severe form, myxoedema coma, there is a substantial mortality if not recognized early and treated. Clinical features of myxoedema coma include hypothermia, depressed conscious level and usually a precipitating event such as sepsis or trauma. Early recognition and treatment with thyroid replacement (T4 and T3), antibiotics and steroids are often life-saving. Hypothyroidism should be carefully excluded in all patients presenting with any dementing illness, because it is so readily amenable to treatment. Subtle neuropsychological features can also occur, e.g. psychosis with paranoia and hallucinations (myxoedema madness). Cerebellar ataxia is well described and does occur, if rarely, in hypothyroidism, involving gait and the limbs, but with normal eye movements. Muscular weakness is common in hypothyroidism and sometimes an early clinical feature; it occurs in some 80% of cases if carefully sought. Weakness (usually fairly mild) is accompanied by depressed or slow-relaxing reflexes (pseudomyotonia), and typically involves the pelvic and shoulder girdles. Percussion of the muscle may cause a slow rippling effect termed myo-edema. Pain during or following muscle activity is typical of hypothyroid myopathy, and all patients presenting with unexplained muscle pains, especially related to exertion, should be screened for hypothyroidism; early treatment prevents development of more severe symptoms. The CK level is usually raised, sometimes markedly so (>10 times normal). Treatment with thyroxine improves matters, usually promptly but in advanced cases it is sometimes over a year before the situation recovers fully. Hypothyroidism also causes peripheral nerve problems. An entrapment neuropathy, most frequently carpal tunnel syndrome, is seen in some 10% of hypothyroid patients. A useful working rule is to check the thyroid function in all suspected carpal tunnel cases. Treatment is restoration of the euthyroid state rather than surgical decompression. A polyneuropathy develops in up to twothirds of hypothyroid patients, usually mild and mainly sensory. Neurological aspects of Hashimoto’s thyroiditis The possible relationship between thyroid antibodies and encephalopathy has been debated since the 1960s. The term Hashimoto encephalopathy describes a subacute, sometimes relapsing encephalopathy, responding well to corticosteroids and associated with a high titre of antithyroid antibodies. The encephalopathy in such cases is not explained by thyroid status, which may be normal. The term Hashimoto’s encephalopathy has been criticized as it implies that the antibodies are pathogenic in the

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development of encephalopathy, a link for which there is little convincing evidence. It has been suggested that the thyroid antibodies may be epiphenomena, and indeed they may be seen in encephalopathies known to have an alternative cause. It is therefore important to try to establish a definitive diagnosis for an encephalopathy associated with antithyroid antibodies. For example, the recently described syndrome of encephalopathy with antibodies to voltage gated potassium channels may also need to be considered. Sometimes, invasive tests including cerebral biopsy are needed.

Diabetes mellitus Diabetes mellitus can cause many effects on the nervous system. Rare congenital causes of diabetes that may be encountered by neurologists include mitochondrial cytopathies, particularly patients with sensorineural deafness but also those with MELAS or Kearns–Sayre syndrome (Chapter 9), Friedreich’s ataxia and Wolfram’s syndrome (Type 1 diabetes, diabetes insipidus, optic atrophy and deafness [DIDMOAD]). The other main neurological conditions where diabetes can be highly important are acute metabolic disturbances (related to hyperglycaemia or hypoglycaemia) and the diabetic neuropathies.

Acute metabolic disturbances Diabetic ketoacidosis occurs because of insufficient insulin levels in patients with Type 1 diabetes, usually because of undertreatment with insulin or its omission, with or without an intercurrent illness such as sepsis. Drowsiness occurs but not usually coma. Very rarely, cerebral oedema can develop during treatment because of over-rapid correction of hyperosmolality, especially in children. This can cause death from raised intracranial pressure. Hyper-osmolar non-ketotic coma (HONK) occurs mainly in patients with Type 2 diabetes and may lead to very high blood glucose with high sodium levels and therefore high osmolality. Reduced conscious level or seizures may occur. Conversely, low blood glucose can result from excessive doses of oral hypoglycaemics or insulin. With a low blood sugar, there is often a warning prodrome, allowing the patient to react and correct the problem, but in some patients with Type 1 diabetes the warning is absent, placing them at much greater risk of prolonged hypoglycaemia. Early warning symptoms include sweating, trembling, tingling hands and palpitations. Neurological features can include confusion, dysarthria, altered behaviour and agitation, seizures and, albeit rarely, focal neurological features (e.g. hemiparesis or hemiplegia) that can mimic a TIA or stroke. Diabetic neuropathies The neuropathies caused by diabetes are covered in detail in Chapter 9. The most common is a distal sensorimotor neuropathy, affecting over 50% of patients with long-standing disease. Rarer variants include diabetic autonomic neuropathy, acute painful neuropathy, cranial neuropathy (especially oculomotor), thoraco-abdominal neuropathy and painful proximal neuropathy (diabetic amyotrophy).

Systemic Conditions and Neurology

Pituitary disorders Pituitary tumours are discussed in Chapter 20. Pituitary neoplasms either produce an excess of hormone secretion (in about two-thirds) or non-functioning – sometimes causing deficiency by mass effects (in about one-third). Tumours secreting prolactin (prolactinomas) cause secondary amenorrhoea, galactorrhoea, infertility and impotence. Other clinical syndromes include acromegaly (resulting from growth hormone secretion) and Cushing’s disease (resulting from adenocorticotrophic hormone [ACTH] secretion). Pituitary tumours can present with visual disturbances, including visual failure, headaches, and endocrine features, or simply with an unexplained high serum prolactin. Non-secreting tumours may cause hypopituitarism, with secondary amenorrhoea, infertility or impotence, loss of secondary sexual characteristics or hypothyroidism. Diabetes insipidus results from dysfunction of the posterior pituitary. Reduced secretion of arginine vasopressin and antidiTable 25.2 Causes and features of common electrolyte disturbances.

uretic hormone cause symptoms of thirst, polyuria and polydipsia. The common caues are trauma, tumours, sarcoidosis and other granulomatous conditions, and infections. Sarcoidosis is considered below. Pituitary apoplexy (Sheehan’s syndrome, Chapter 20) is a dramatic clinical syndrome of severe headache, nausea, vomiting and often hypotensive collapse with sudden bilateral visual loss. The usual cause is haemorrhage into a pituitary macroadenoma.

Inappropriate antidiuretic hormone secretion (SIADH) and cerebral salt wasting These conditions are discussed in Chapter 19.

Parathyroid glands In cases of hypoparathyroidism (or pseudohypoparathyroidism, a rare familial form with skeletal and developmental anomalies) the reduction in serum ionic calcium may cause sensory disturbances, tetany, chorea or seizures (Table 25.2); basal ganglia or

Electolyte disturbance

Causes

Clinical features

Hyponatraemia

SIADH Cerebral salt wasting Diuretic use Addison’s disease Drugs (e.g. carbamazepine) Liver disease Cardiac failure Diabetes insipidus HONK Diarrhoea Dehydration Diarrhoea Vomiting

Coma Confusion Convulsions (800,000/mm3) is associated with an increased risk of thrombosis and haemorrhage within the CNS. It may be associated with leukaemia or myelodysplasia. Thrombosis can occur in arteries, veins or venous sinuses and is related to hyperviscosity. Haemorrhage can also occur (subdural, extradural, intracerebral, subarachnoid); the mechanism presumably involves abnormal platelet function. Treatment with hydroxyurea is usually recommended to prevent neurological symptoms.

Bleeding disorders Thrombotic thrombocytopenic purpura Thrombotic thrombocytopenic purpura (TTP) is a rare disorder of early adulthood characterized by recurrent and widespread occlusion of small vessels. The pathophysiology involves microangiopathic haemolysis and formation of platelet micro-thrombi throughout the body including the nervous system. TTP may be familial or acquired but in both cases endothelial cells secrete abnormally large von Willebrand factor multimers that are not degraded because of the lack of the cleavage enzyme ADAMTS13. This allows the formation of platelet thrombi in small vessels. The clinical hallmarks are fevers, hepatic and renal disease and a low platelet count. Fragmented red cells on the blood film, elevated lactate dehydrogenase, bilirubin and reticulocyte count also point towards the diagnosis. Fluctuating neurological symptoms of altered conscious level, seizures, headache or encephalopathy may be the presenting feature in half of the patients and may be preceded by a provoking factor such as an intercurrent illness. The majority of patients will at some stage of the illness develop neurological symptoms. Low platelets lead to haemorrhage including intracerebral haemorrhage. Ischaemic stroke from large or small vessel occlusion may occur. The mainstay of treatment is plasma exchange. Antiplatelet agents or anticoagulants may also be used although evidence for efficacy is lacking. Other immunomodulatory treatments have been used including ciclosporin. Rituximab is the subject of ongoing investigation. Haemophilia, disseminated intravascular coagulation and von Willebrand’s disease are also rare causes of intracerebral haemorrhage.

Coagulation disorders The antiphospholipid antibody syndrome (Chapter 4), although usually characterized by venous thromboses, is also an important rare cause of arterial cerebrovascular events, sometimes in association with skin rashes, migraine and recurrent miscarriage. Thrombophilias including protein C and S deficiency, antithrombin III deficiency, factor V Leiden and the MTHFR mutation are associated with cerebral venous thrombosis, but not strongly with arterial events. These disorders are also discussed in more detail in Chapter 4.


Gastrointestinal disorders Hepatic encephalopathy In severe hepatic failure, toxins are not removed from portal blood and thus enter the systemic circulation. The toxins responsible for hepatic encephalopathy include ammonia, aromatic amino acids, mercaptans, short-chain fatty acids and endogenous benzodiazepines. The speed of onset of encephalopathy parallels that of the underlying hepatic failure; this may vary from hours to very slow progression over months. Delirium typically fluctuates during the day and may be accompanied by euphoria and neurological signs including a flapping postural tremor of the hands (asterixis) and constructional apraxia. Hepatic foetor is the sickly sweet odour on the breath found in many cases. Untreated, delirium progresses to stupor and coma. Treatment is mainly aimed at reducing the nitrogen burden in the bowel – a low protein diet, regular large doses of lactulose and sometimes neomycin. Hepatic transplantation may be required.

Malabsorption and coeliac disease Malabsorption is either the result of gluten sensitivity or many other processes affecting the small bowel, including surgical resection.

Vitamin B1 deficiency Vitamin B1 (thiamine) deficiency causes Wernicke’s encephalopathy, Korsakoff ’s syndrome and beri-beri (see Chapter 18). Wernicke’s encephalopathy is a subacute illness causing delirium, nystagmus – with or without ophthalmoplegia – and ataxia, typically of gait more than limbs. The syndrome is underdiagnosed and potentially treatable. Korsakoff ’s can follow Wernicke’s encephalopathy and is characterized by a more restricted syndrome of anterograde and retrograde amnesia without delirium. Although classically a result of chronic alcoholism, Wernicke’s encephalopathy and Korsakoff ’s syndrome are well known to result from other causes, such as intractable vomiting (e.g. anorexia nervosa, hyperemesis gravidarum). One of the three patients originally reported by Wernicke suffered from severe vomiting from pyloric stenosis induced by sulphuric acid poisoning. The extent of recovery is influenced by the time to diagnosis and treatment with thiamine. Some of the eye signs and ataxia often resolve but a residual amnestic syndrome is common. In any patient with cognitive disturbance or delirium in the context of heavy alcohol use, prompt treatment with high dose intravenous B vitamins is recommended – it rarely causes harm. Pellagra (niacin deficiency) Endemic niacin deficiency is rarely seen in developed countries, but is characterized by dementia, dermatitis and diarrhoea (the three D’s). The most common cause of pellagra now is chronic alcoholism, which usually presents with acute and isolated delirium. There can also be generalized rigidity (sometimes cogwheeling), dysarthria and myoclonus.

Vitamin D deficiency Proximal muscle weakness can develop as a result of vitamin D malabsorption. The symptoms usually start in the legs, affecting hip movements but with preservation of distal power, reflexes and sensation. EMG may show myopathic features with short duration polyphasic potentials. The degree of muscle weakness is not correlated with plasma calcium concentration and the underlying mechanism is unclear. Vitamin D treatment is generally helpful. Vitamin E deficiency Vitamin E deficiency results from cholestatic liver disease, fat malabsorption, abetalipoproteinaemia or as a familial absorption disorder. The clinical features include neuropathy, ataxia, ophthalmoplegia and muscle weakness. A familial condition with poor conservation of plasma α-tocopherol in very low density lipoproteins is characterized by ataxia, cerebellar signs, dysarthria, leg areflexia, impaired proprioception, bilateral extensor plantar responses, pes cavus and scoliosis. These signs are strikingly similar to those seen in Friedreich’s ataxia (Chapter 16). All patients presenting with an unexplained spinocerebellar syndrome or tremor should have vitamin E concentrations measured, as the symptoms may respond to treatment. Coeliac disease Many neurological syndromes affecting the central and peripheral nervous systems have been reported in association with coeliac disease, including epilepsy, myoclonus, ataxia, multifocal leucoencephalopathy, dementia and peripheral neuropathies, both axonal and demyelinating. It is speculated that immunological mechanisms or trace vitamin deficiency underly these associations. Substantial neurological features can occur in the absence of overt coeliac disease. Coeliac disease should certainly be considered in cryptogenic ataxias and neuropathies (Chapter 16). Infective and para-infective disorders These are discussed in Chapters 8 and 9.

Renal disease Renal diseases may be relevant to neurologists in two main ways. First, certain diseases affect both the kidneys and the nervous system – these include the vasculitides and connective tissue diseases as well as serious conditions including genetic disorders (Anderson–Fabry disease, Wilson’s disease, von Hippel–Lindau disease) infections and plasma cell dyscrasias. Secondly, renal failure, dialysis and renal transplantation can all affect neurological function in a variety of ways.

Conditions affecting both renal and neurological function These conditions are mainly covered in other sections; the key features of some selected conditions are briefly summarized in

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Table 25.3 Conditions affecting renal and neurological function. Condition

Renal effects

Neurological effects

Vasculitis PAN

Proteinuria, granular casts, hypertension

Peripheral neuropathy, encephalopathy, stroke (infarction and SAH)

Churg–Strauss syndrome

Rarely involved

Mononeuritis multiplex encephalopathy, SAH

Wegener’s granulomatosis

Proteinuria, haematuria, red cell casts, renal failure

Cranial neuropathies, mononeuropathies, polyneuropathy, ischaemic stroke

Glomerulonephritis (rare)

Polyneuropathy, mononeuropathies, cervical cord damage due to bony disease

SLE

Haematuria, proteinuria, nephritic syndrome, renal failure

Neuropsychiatric symptoms, encephalopathy, seizures, ischaemic stroke, chorea

Sjögren’s syndrome

Tubular disorders

Dorsal roots ganglionopathy, neuropathy, cranial neuropathy (especially V), encephalopathy, MS-like symptoms

Proteinuria, Bence-Jones protein, nephrotic syndrome

Nerve root/cord compromise

MGUS

Rarely abnormal

Demyelinating sensory > motor peripheral neuropathy

Waldenstrom’s macroglobulinaemia

Proteinuria, nephrotic syndrome

Sensorimotor neuropathy, encephalopathy, SAH, stroke, myelopathy

POEMS

Rarely, M protein in urine

Demyelinating neuropathy (sensory > motor) resembling CIDP (50%)

Connective tissue disorders Rheumatoid disease

Myeloproliferative disorders Multiple myeloma

CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; MGUS, monoclonal gammopathy of undetermined significance; MS, multiple sclerosis; PAN, polyarteritis nodosa; POEMS, Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, Skin changes.

Table 25.3. A neurologist should remember that renal disease in its early stages causes few or no symptoms and that renal function must therefore be screened when there is even a small degree of clinical suspicion. Vigilance is important; the consequences of progressive renal disease are severe and potentially avoidable. Routine biochemistry (urea and creatinine) are but crude measures of renal impairment. If renal disease is questioned (e.g. a patient with a mononeuritis multiplex), urine microscopy for casts and detailed urinalysis, close monitoring of blood pressure and renal ultrasound should all be performed without delay.

Neurological consequences of renal disease and its treatment Uraemic encephalopathy Neurological manifestations are usually associated with the rapid development of uraemia in acute renal failure. The onset is with subtle clouding of consciousness that may progress rapidly to apathy, irritability, confusion and disorientation. A coarse irregular tremor with asterixis can develop. Severe metabolic encephalopathy associated with uraemia is also associated with a progressive stimulus-sensitive multi-focal myoclonus and eventually the development of generalized tonic–clonic or focal motor seizures. Frank psychosis and agitation with hallucinations may supervene before the development of uraemic coma,

924

Cheyne–Stokes respiration and respiratory arrest. Uraemic encephalopathy is generally reversible with recovery from acute uraemia.

Dialysis encephalopathy Dialysis encephalopathy (dialysis dementia) is the rare but potentially fatal condition that previously complicated chronic dialysis and is still occasionally seen. Patients develop subacute progression of fluctuating symptoms in the early stages which either become fixed or progress. The condition is characterized by dysarthria, dysphasia and progressive metabolic encephalopathy with myoclonus and asterixis, culminating in generalized seizures and intellectual decline. The syndrome is caused by the aluminium content in gels and dialysate solution. Treatment with purified dialysate has led to the disappearance (almost) of this condition. Chronic haemodialysis can also lead to Wernicke’s encephalopathy, sensorimotor axonal polyneuropathy and occasionally subdural haematoma. Dialysis disequilibrium syndrome This is related to changing osmotic gradients between plasma and brain during rapid dialysis. It can present with non-specific symptoms of nausea, visual blurring and headache prior to development of worsening mental confusion, clouding of

Systemic Conditions and Neurology consciousness, seizures and tremor. The symptoms are usually mild and can be alleviated with slow flow rates during dialysis and the addition of osmotically active solutes to the dialysate.

Neuropathy associated with renal disease Uraemic neuropathy is a distal axonal degeneration with secondary myelin loss. This occurs in the majority of patients with chronic renal failure; the severity is related to the extent and duration of renal failure. Onset is often with periodic limb movements or restless legs and established neuropathy is characterized by a distal paraesthetic sensory disturbance. The neuropathy is reversible with treatment of the renal failure.

Neurological aspects of organ transplantation Organ transplantation is now widely undertaken. Kidney, liver, heart, lung, pancreas and bone marrow are successfully transplanted with relatively low morbidity and mortality. The neurological complications of these procedures are related to the effects of the underlying organ failure, immunosuppression leading to secondary infection, allograft rejection, effects of drug treatment or consequences of the surgical procedure. The neurological complications vary with time following surgery.

CNS infections CNS infections develop in less than 10% of transplant recipients and in immunosuppressed patients; these can be severe and carry a high mortality. Infections in the immunosuppressed patient are discussed in Chapter 8 but a number of issues relate specifically to post-transplant patients. The risk of infection depends on the degree of immunosuppression, the intensity of exposure to potential pathogens and the time since transplantation. It is rare for opportunistic infection to develop within 1 month of surgery and commencing immunosuppression. During this period, infection is unrelated to the degree of immunosuppression, and is usually caused by the regular nosocomial organisms such as Gram-negative bacteria, staphylococci and Candida. Patients are predisposed to these infections, as is anyone critically ill, by contamination of vascular access or drainage catheters, prolonged intubation, stents or other foreign bodies and fluid collections. Rarely, active toxoplasmosis and viral infections may be passed with the graft. More than 1 month after transplantation, as effective immunosuppression develops, the patient is at increased risk of infection with viruses (cytomegalovirus [CMV], Epstein–Barr virus [EBV], herpes simplex virus [HSV], varicella-zoster virus [VZV] and human herpesvirus [HHV]) and fungi (Aspergillus and Candida). Most patients with successful transplants are maintained on low-dose immunosuppression and are not at particularly high risk of late opportunistic infection. More than 6 months after transplantation, infection may occur if the degree of immunosuppression has been increased because of recurrent or chronic allograft rejection. These patients

are at particular risk of opportunistic infections listed above but also with other viruses (e.g. JC virus), fungi (Aspergillus, Cryptococcus, Nocardia, Histoplasmosis, Mucor), protozoa (toxoplasmosis) or bacteria (Listeria monocytogenes, Pneumocystis carinii, mycobacteria).

Viral infection The pattern of opportunistic viral infection following transplantation is highly variable. The most frequent pathogens are EBV, VZV, adenoviruses, and herpes viruses HSV1 & HSV2; HHV6 is less common. CMV and EMV may cause severe encephalitis which can be difficult to diagnose. Reactivation of VZV may lead to cutaneous dissemination (chickenpox) and/or a generalized meningo-encephalitis, transverse myelitis and cranial neuropathy. Progressive multi-focal leucoencephalopathy (Chapter 8) is associated with JC virus infection and must be distinguished in the post-transplant encephalopathic patient from central pontine myelinolysis and posterior reversible leucoencephalopathy related to treatment. Bacterial infection Bacterial infection in the transplant patient is less common than viral but can be caused by Listeria monocytogenes which causes meningo-encephalitis, often with a brainstem emphasis, multiple abscess formation or myelitis. Mycobacteria can cause pulmonary tuberculosis, TB meningitis or atypical TB CNS infection. Haemophilus or staphylococcal pneumonia and/or meningitis also occur in post-transplant patients. Nocardia infection is associated with cerebral abscess formation and often with pleural disease. Fungal infection Fungal meningitis (Chapter 8) is most commonly caused by Aspergillus in the first 6 months while typically Cryptococcus develops later than 6 months. Aspergillus species occur commonly in the environment. Primary infection is usually airborne and established in the lungs. Spread to the CNS occurs in some 50% of cases. This carries an extremely poor prognosis because of the development of severe meningitis, focal aspergilloma brain abscesses and invasion of the cerebral vessels leading to intracerebral haematomas. The spinal cord may also be occasionally affected. Disseminated cryptococcosis involves the CSF and can cause severe chronic relapsing meningitis with raised intracranial pressure. There is a high mortality in transplant recipients. Candida meningitis is a rare post-transplant infection with chronic relapsing meningitis and/ or brain abscess formation; this usually responds well to aggressive antifungal treatment. Mucor is an occasional CNS infection. Parasitic infection Toxoplasma gondii is the most frequent protozoa to infect transplant recipients. The pattern of single or multiple enhancing cerebral abscesses is similar to that described in other immunosuppressive situations in Chapter 8. There may also be an acute encephalitis, occasionally with myocardial involvement. The CSF

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shows marked mononuclear pleocytosis with elevated protein, sometimes with depressed glucose. MRI shows characteristic ring enhancing abscesses, often in the basal ganglia.

Neurological sequelae of transplantation Seizures Seizures are relatively common in transplant recipients and have a number of causes. They commonly occur as a manifestation of drug toxicity (especially with ciclosporin and OKT3). Seizures may also be associated with drug withdrawal, metabolic derangements, hypoxic ischaemic injury, cerebrovascular disease and sepsis. The initial management is correction of the underlying disturbance but in patients with ongoing impairment of consciousness it is essential to exclude non-convulsive status. Status epilepticus is treated conventionally, with benzodiazepines and phenytoin. However, titration of these drugs may be difficult because of renal and hepatic impairment, and hypoalbuminaemia. Isolated seizures following organ transplantation rarely lead to long-term epilepsy and therefore anticonvulsant medications are seldom required when the acute episode has resolved. Encephalopathy Encephalopathy develops commonly following transplantation and varies from a mild confusional state to psychosis with obtundation and coma. In the acute postoperative situation it is often brought about by a surgical complication (e.g. hypoxic-ischaemic insult), the development of a metabolic encephalopathy, acute allograft rejection, isolated or multiple organ failure, sepsis, seizures or drug toxicity (particularly ciclosporin). Stroke Stroke following transplantation is an important cause of morbidity and mortality. It is often related to the underlying disease process and in particular accelerated cerebrovascular atherosclerosis in diabetes mellitus. Stroke may also be a consequence of cardiogenic emboli and CNS infections that cause vasculopathy or vasculitis. Cardiac transplantation carries the complications of bypass – cardio-embolic stroke, air embolism and bacterial endocarditis. Fungal CNS infections (particularly aspergillosis and mucormycosis) are associated with invasion and occlusion of the cerebral vessels resulting in haemorrhagic infarction. Medication including ciclosporin and sirolimus and, to a lesser extent, tacrolimus may also lead to hypocholesterolaemia. Intracerebral haemorrhage is usually seen in the setting of haemorrhagic transformation of an ischaemic stroke, resulting from coagulopathy or following CNS infection. Subdural haematoma may occur with thrombocytopenia, particularly following bone marrow transplantation. Subarachnoid haemorrhage is particularly associated with the increased incidence of berry aneurysms that may rupture following renal transplantation for polycystic disease. Cerebral venous thrombosis can occur as

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a consequence of a hypercoagulable state, dehydration or CNS infection.

Medication Complications of immunosuppressive drugs are also discussed in Chapters 20 and 18. The drugs most frequently causing neurotoxicity are ciclosporin, tacrolimus, steroids and OKT3. Ciclosporin neurotoxicity occurs in some 25% of patients and includes tremor, headache and, less commonly, posterior reversible encephalopathy. The complications are lessened with oral administration and are usually reversible with discontinuation of the drug. Profound impairment in cognitive function has also been reported to be associated with tacrolimus and ciclosporin. OKT3 is a murine E monoclonal antibody used in the treatment of rejection and has been associated with aseptic meningitis, encephalopathy and seizures. The combination of steroids with neuromuscular junction blocking agents may cause prolonged neuromuscular blockade or a critical illness myopathy. CNS malignancy There is an increased incidence of CNS malignancy in allograft recipients who are immunosuppressed. Intracerebral B-cell lymphoma affecting the brain and spinal cord and glioblastoma multiforme are the most common CNS cancers. They may be associated with previous EBV infection. Neuro-ophthalmological problems Cortical blindness, complex visual disturbances and hallucinations, not uncommon in all critically ill patients, may be caused by dose-related toxicity from tacrolimus or ciclosporin. This is often reversible. Movement disorders Both ciclosporin and tacrolimus are associated with a high incidence of tremor. Occasionally, parkinsonism has been described in bone marrow transplant recipients. Rarely, chorea has occurred as a manifestation of rejection following cardiac transplantation. It is usually steroid responsive. Neuromuscular problems Mononeuropathies follow surgery and anaesthesia and may occur as a consequence of positioning, traction or the mechanical complications of surgery. Phrenic nerve damage can follow cold plegia of the heart (induced hypothermia) during cardiac transplantation. Rarely, systemic infection may lead to a form of polymyositis. Acute myopathy sometimes follows liver transplantation, particularly in those receiving intravenous steroids and neuromuscular blocking agents. In general, the prognosis for neuromuscular complications following most transplantation is good providing there is no major structural damage, but this is not true for graft versus host disease (GvHD, see below).


Complications related to specific allograft transplantation Renal transplantation Renal transplantation is now undertaken routinely but neurological complications remain relatively frequent. Uraemic encephalopathy can develop suddenly following acute tubular necrosis, acute accelerated rejection or renal vein thrombosis. Spinal cord ischaemia may occur when the iliac artery is diverted for graft re-vascularization; this is a particular risk when there is an anomalous vascular supply to the spinal cord from the internal iliac artery rather than the intercostals. There is an increased frequency of cerebrovascular disease related to the underlying vasculopathy and hypertension, particularly in the presence of diabetes or systemic lupus erythematosus (SLE). However, there is evidence that combined kidney and pancreas transplantation decreases the subsequent incidence of stroke in diabetic patients. Compressive neuropathies involving the femoral nerve are often related to haematoma formation. Rejection encephalopathy is extremely rare. Liver transplantation Liver transplantation carries a relatively high incidence of complications. These may be related to the underlying hepatic disease including viral hepatitis, alcoholic liver disease, primary biliary cirrhosis, acute liver failure or toxic hepatic damage. Patients with hepatic encephalopathy have usually been critically ill and carry all the consequences of their underlying disorders following surgery. Delayed rejection or failing graft function may lead to recurrent encephalopathy or central pontine myelinolysis, impairment of coagulation and failure of synthetic and metabolic hepatic functions. Encephalopathy is also a common complication – associated with drug toxicity, metabolic derangement, hypoxic ischaemic injury and sepsis. Coagulopathies may also lead to intracerebral or subarachnoid haemorrhage. The postoperative period is frequently complicated by the development of severe sepsis. Cardiac transplantation Cardiac transplantation complications are usually related to bypass. Cannulation of the diseased ascending aorta may dislodge atheromatous material leading to cerebral emboli and there is a risk of introducing air emboli when bypass is discontinued. There remains a significant instance of ischaemic and haemorrhagic stroke, ischaemic hypoxic brain injury, encephalopathy and peripheral nerve injury often affecting the lower brachial plexus because of stretching during chest wall retraction. The recurrent laryngeal nerve may also be damaged leading to vocal cord paralysis; phrenic nerve paralysis, from direct trauma or cold plegia, can cause diaphragmatic weakness. Lung transplantation Lung transplantation is often undertaken in combination with heart transplantation. The complications are similar. Encephalopathy is usually a result of metabolic causes, drug toxicity or

seizures. The cerebrovascular and neuromuscular complications are similar to those described above.

Bone marrow transplantation Bone marrow transplantation is now widely undertaken both for the treatment of haematological malignancies but also as an adjunct in the treatment of other malignancies or autoimmune disorders. Neurological complications usually occur after allogenic bone marrow transplant requiring immunosuppression. Following bone marrow infusion, pancytopenia may be present for 2–5 weeks before a significant response is mounted. During this critical period, overwhelming Gram-negative sepsis, severe bleeding from thrombocytopenia and disseminated intravascular coagulation are the most serious complications. Transplantation is combined with radiotherapy or intrathecal chemotherapy. There may be an associated posterior reversible leucoencephalopathy. However, the most serious complication is the development of GvHD. Acute GvHD occurs in the first 100 days following transplantation and primarily affects the skin, liver and intestines. Chronic GvHD is a different entity and may develop at any time later than 80 days following transplantation. The condition strongly resembles a vasculitic syndrome with scleroderma-like skin involvement, bronchiolitis, Sjögren’s syndrome, polymyositis, myasthenia gravis and neuropathy. Polymyositis may develop up to 4–5 years after allogenic bone marrow transplantation in association with GvHD. Seropositive myasthenia occurs sometimes with severe bulbar and respiratory muscle weakness. The use of neuromuscular blocking agents may lead to prolonged blockade and the development of critical illness myopathy. Acute demyelinating neuropathy has also been described in chronic GvHD. Reduction of immunosuppression usually results in improvement of the symptoms but there remains a high morbidity and mortality associated with the condition.

Neurological involvement in systemic vasculitides and related disorders Neurological involvement in systemic vasculitic disorders is common although, with the exception of giant cell arteritis (GCA) and isolated cerebral angiitis (ICA), it is rare for patients with this group of disorders to present solely with neurological symptoms. As such, many neurological episodes occur in patients who already have an established rheumatological or systemic vasculitis diagnosis and who may consequently be receiving some form of immunomodulatory therapy. Neurological symptoms presenting in such patients can be split into three broad aetiological groups, each suggesting different therapeutic considerations. First, neurological symptoms or signs may develop with increased underlying systemic disease activity, needing prompt escalation of the immunomodulatory therapy. Second, the symptoms may be iatrogenic and related to side effects of disease modifying or other agents, e.g. a proximal myopathy associated with steroid therapy

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or reversible posterior leucoencephalopathy associated with immunomodulatory treatments. Third, the symptoms may be caused by a separate, and possibly associated disease process which requires attention on its own merits, e.g. ischaemic stroke in a patient with rheumatoid arthritis (RA) and diabetes. Any part of the nervous system can be affected by the diseases described here, but the propensities vary across these conditions as do the causative mechanisms. For each disease mentioned below, the different sites of neurological involvement are ranked depending on how commonly they occur. Many of the disease mechanisms, and thus related therapeutic considerations are shared across these conditions and will be discussed first.

Pathological mechanisms Regardless of the lesion site within the neuraxis, the final common pathway of vasculitis is ischaemic damage to neural tissue, usually with permanent damage. Histological examination of tissue from both the central and peripheral nervous systems often reveals a necrotizing arteritis affecting blood vessels with a transmural infiltrate initially consisting of a variety of reactive leucocytes, typically a mixture of polymorphs, lymphocytes and eosinophils. The proportions, subtypes and behaviour of these cells vary both within and across the different types of systemic vasculitides, with granulomas (a nodular aggregation of mononuclear inflammatory cells or modified macrophages usually surrounded by a rim of lymphocytes) more common in Wegener’s granulomatosis (WG) and GCA. The cell populations at the lesion site also vary with the age of the lesion – neutrophils in the acute phase and intimal proliferation and fibrosis in the chronic phase. All these cellular responses conspire to reduce blood flow through the affected vessel. When individual nerves are involved the arteritis usually affects the pre-capillary arteries. In the CNS the calibre of blood vessel affected is associated with disease type, but overlaps are common. A nosology based primarily on vessel size is desirable but problematic, especially as immunotherapy is not yet at the stage where different populations of inflammatory cells can be targeted. With inflammatory and reactive stromal cells narrowing the arterial lumen, secondary thrombotic events can occur causing distal embolism to terminal portions of the arterial tree. However, in some systemic disorders the vasculopathy may be primarily or even solely caused by thrombotic occlusion of arteries, capillaries or veins, in which case anticoagulation may be appropriate (see SLE, below). Other causes of secondary vasculitis affecting the nervous system, although not covered in any detail here include: • Infections: fungi, TB, other bacteria, spirochaetes, viruses including VZV, HIV; • Drugs: amphetamine, cocaine; • Malignancy: either via direct involvement such as in lymphoma or as part of a paraneoplastic vasculitis. Isolated cerebral angiitis (ICA) is a rare but well-recognized disorder. The existence of its peripheral equivalent, isolated peripheral nervous system vasculitis, is moot – with the majority

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opinion that all vasculitic neuropathies are secondary to an underlying disease, although it may take months or years for this to emerge (e.g. Sjögren’s syndrome, below). Compressive spinal cord or root pathology can occur in any of the systemic disorders, especially as steroid-related osteopenia has a predilection for the vertebral bodies. However, this is most commonly seen in patients with RA. Entrapment neuropathies can be caused by nodule formation in RA (typically ulnar or median nerve) or granulomas (typically cranial nerves). Ophthalmoplegia occurs in approximately 5% of patients with WG. The cause of this may be varied or indeed multifactorial: • Contiguous extension of a granulomatous mass from a nasal or paranasal site into the orbit causing pseudotumour; • Vasculitis of the extraocular muscles; • Oculomotor palsy secondary to vasculitis; or • Granulomatous compression at some point along a cranial nerve. Dedicated MRI scanning protocols with contrast may help demonstrate the cause.

Diagnosis and treatment of vasculitides involving the nervous system Because immunosuppressive therapies for vasculitis are relatively toxic, the decision to administer them should be supported by a tissue diagnosis, if at all possible. When neurological symptoms and signs occur alongside multi-system disease activity, a diagnostic biopsy may well be from affected skin, kidney or lung. However, if the neurological syndrome occurs while disease remains quiescent in other organs then brain, nerve or muscle biopsy may be the only reasonable option. Immunosuppressive treatment of neurological involvement in systemic disorders is unlikely to be based directly on prospective randomized trials; however, indirect evidence is available from controlled trails of patients with systemic vasculitis. Given that the underlying pathology is similar in non-neurological organs, extrapolation is reasonable. In general, the majority of vasculitic disorders can be reversed or controlled in some 90% of patients with a combination of high-dose oral corticosteroids and oral cyclophosphamide. Cyclophosphamide is usually given for 3 months with less toxic drugs such as azathioprine to sustain remission while steroid therapy is gradually reduced. Newer agents or non-pharmacological treatments such as plasma exchange may need to be used in resistant or persistently relapsing conditions. Many of the current immunosuppressive drugs and their associated side-effect monitoring parameters are included in Table 25.4.

Polyarteritis nodosa and related conditions Polyarteritis nodosa (PAN) is the prototype necrotizing vasculitis. Medium-sized vessels are those usually affected and can be associated with aneurysm formation, seen on angiography. Middle-aged men are most commonly affected. Systemic symptoms include abdominal pain (from hepatic or other visceral infarcts), hypertension (from renal involvement, although glomerulonephritis is

Systemic Conditions and Neurology Table 25.4 Drug treatments for vasculitis. Drug

Class/action

Acute, induction or rescue therapy Methylprednisolone Corticosteroid

Side-effects

Monitor (prophylaxis)

Diabetes, neuropsychiatric, hypotension

Glucose, BP

Cyclophosphamide

Alkylating agent

Haemorrhagic cystitis, bone marrow suppression, neutropenia, sepsis

FBC (mesna for cystitis)

IVIG

Pooled antibodies from ~1000 human donors

As for any blood product, renal failure rarely

Check IgA levels before therapy, (absent IgA = absolute contraindication), U+E

Infliximab

Monoclonal anti-TNF antibody

Hypersensitivity (delayed), atypical infections especially TB, induction of dsDNA antibodies

FBC, U+E, LFTs. CXR (exclude TB), ANA and dsDNA. Use prophylactic isoniazid in patients at high risk for TB

Rituximab

Monoclonal anti-CD20 antibody

Infusion related

FBC, B lymphocytes

Long-term therapy Prednisolone

Corticosteorid

Diabetes, osteopenia, adrenal suppression

DEXA scan (bisphosphanates for osteoprophylaxis)

Mycophenolate mofetil

Inhibitor of inosine monophosphate dehydrogenase

Bone marrow suppression, gastrointestinal intolerance, chronic viral infections

FBC; (ideally) monitor mycophenolic acid levels

Methotrexate

Folate antagonist/adenosine agonist

Pulmonary fibrosis, liver failure, bone marrow suppression

FBC, U+E, LFT (folate prophylaxis)

Azathioprine

Blocks purine synthesis

Bone marrow suppression, squamous-cell carcinoma, chronic viral infections, hypersensitivity

FBC + (ideally) check thiopurine methyltranferase (TMPT) pre-Rx. (absent TMPT = absolute contraindication; reduced level = reduce dose)

Tacrolimus

Calcineurin inhibitor

Diabetes, hypertension

FBC, U+E, glucose, tacrolimus levels

IVIG, intravenous immunoglobulin; TNF, tumour necrosis factor.

not a feature), fever and weight loss. Diagnosis is based on the clinical features and either positive angiography or biopsy of affected tissue (skin, kidney or nerve). The only serological marker clearly associated with PAN is hepatitis B infection (20–40% HbsAg-positive). PAN is considered to be an antineutrophil cytoplasmic autoantibodies (ANCA)-negative syndrome. The most common neurological problem is a progressive mononeuritis multiplex (MNM) which occurs in up to 50% of patients with PAN. In common with other causes of vasculitic mononeuritis this tends to present with a painful sensory or sensorimotor picture. More central involvement occurs in 25% of cases, in a variety of patterns – encephalopathy, seizures, stroke, aseptic meningitis, rarely an ischaemic myelopathy and sometimes cranial nerves palsies. Microscopic polyangiitis (MPA) is related to PAN and is also more commonly seen in males. Unlike PAN, the kidneys are most commonly affected and when the lungs are simultaneously involved it is one of the causes of ‘pulmonary–renal syndrome’, along with WG, SLE, Churg–Strauss and Goodpasture’s syndromes. Other less specific features include arthralgia, purpuric rashes, myalgia and conjunctival haemorrhage. Like PAN, diagnosis rests primarily on the clinical syndrome with histological

support from affected tissue (usually kidney skin or lung). Angiography has less of a role in MPA because, as its name suggests, it tends to affect arterioles, capillaries or venules below the resolution of direct angiography. MPA, like WG, is associated with circulating ANCA. There are two main ANCA staining patterns, perinuclear (pANCA) associated with the myeloperoxidase antigen, and cytoplasmic (cANCA), associated with the neutrophil enzyme proteinase 3. Both these forms are seen in microscopic polyangiitis (60–70% pANCA and 30–40% cANCA); combined they have a sensitivity of 90% with a specificity of 70%. ANCA can also be positive in RA and SLE patients. The pattern of neurological involvement seen in MPA is similar to that of PAN. Like MPA, Churg–Strauss syndrome (CSS) affects the lungs and kidneys and also has an association with ANCA, albeit a weaker one. Unlike other systemic vasculitides, CSS produces symptoms of asthma and is almost always associated with a peripheral eosinophilia (>1.5 × 109 L−1). Cardiac, gastrointestinal and skin involvement is also common. Histology of affected tissue usually shows three cardinal features: necrotizing vasculitis, granulomas and infiltration by eosinophils. Typically, a vasculitic neuropathy is seen in CSS and sometimes with WG and MPA.

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Wegener’s granulomatosis WG is characterized by the triad of upper respiratory tract granuloma (typically affecting the nasal mucosa and/or inner ear), lower respiratory tract granuloma (typically pulmonary nodules) and a necrotizing glomerulonephritis. Non-specific generalized skin and joint symptoms akin to those described for MPA also occur. cANCA is usually found in this condition and has a specificity of 95% and a sensitivity of 80%. Some physicians use circulating levels as an indirect disease marker against which immunomodulatory therapy can be titrated. The best data for neurological complications associated with WG come from a large series from the Mayo Clinic, of over 300 cases. Patients rarely died of neurological complications, but onethird had neurological involvement at one or more sites in the nervous system at some point in their illness: • Peripheral polyneuropathy 50%; • Cranial neuropathy, including hearing loss 20%; • Ophthalmoplegia 15%; • Stroke 12%; • Seizures 10%; and • Cerebritis 5%. Peripheral nerve involvement is heavily skewed towards mononeuritis multiplex (80% of neuropathy patients) with 10% having an insidious distal symmetrical polyneuropathy; a further 10% were unclassified. The most common nerve affected by mononeuritis multiplex is the common peroneal nerve, followed by the tibial, ulnar, median, radial and femoral nerves. Fifty per cent of those with cranial nerve involvement have optic nerve pathology, usually an arteritic anterior ischaemic optic neuropathy. Cranial nerves VI and VII were the next most commonly affected. Ophthalmoplegia can be the presenting symptom in WG, and may be caused by several mechanisms. All call for an increase in immunomodulatory therapy. Acute or subacute hearing loss is associated with WG; this is often because of a combination of conduction hearing loss (otitis media or otitis interna) and sensorineural loss (granuloma or vasculitic processes affecting the auditory nerve). Sjögren’s syndrome Sjögren’s syndrome (SS) is characterized by lymphocytic infiltrates and destruction of epithelial exocrine glands. The main symptoms are dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia). SS is classified as primary (where dry eyes and dry mouth with systemic complications are more common), or secondary to other connective tissue disorders such as RA, SLE or overlap syndromes (mixed connective tissue diseases [MCTD]; see below). Systemic involvement is characterized by chronic fatigue, arthralgia, oesophageal hypomotility, haematological disorders and rarely a cutaneous vasculitis, alopecia and vitiligo. The primary syndrome usually affects females (9 : 1 female : male ratio), develops slowly and is associated with B-cell lymphoma in 5% of cases. Lymphocytic infiltration may lead to cutaneous purpura, lymphocytic alveolitis/interstitial pneumonitis and malabsorption. There may also be a renal tubular necrosis, nephritis

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and Raynaud syndrome. Antinuclear antibodies, rheumatoid factor and various ENAs (anti-extractable nuclear antigen antibodies, specifically anti-Ro and anti-La antibodies) are associated with SS; Schirmer’s test for objective evidence of dry eyes and minor salivary gland biopsy showing focal lymphocytic sialadenitis (usually of the lip) also have a role in the most recent diagnostic criteria. In SS several different types of neuropathy have been described; the most common pattern (approximately 50%) is of an asymmetric, segmental or multifocal sensory neuropathy starting with distal parasthesia but often progressing to involve the trunk or face. A large proportion of these patients have an associated sensory ataxia, severe in some cases; they are likely to have high signal intensity in the posterior columns of the spinal cord on T2 MRI. In some subjects, ataxia is less prominent but neuropathic pain more so; the general progression of symptoms tends to be over months to years. A less common pattern of peripheral nerve involvement is one of a sensory and motor syndrome indistinguishable from mononeuritis multiplex (MNM) seen in other connective tissue disorders; the progression tends to be acute or subacute rather than slowly progressive. Neuropathological studies suggest that the sensory–ataxic pattern is caused by a ganglioneuronitis with lymphocytic infiltration of the dorsal root ganglia similar to that seen in the glandular tissues of the mouth. While a vasculitic pathology is more likely to underlie the MNM type, overlap forms clearly occur. Cranial neuropathies are also associated with SS and again tend to follow one of two patterns mirroring involvement of the peripheral nerves: either a sensory neuropathy affecting one or both trigeminal nerves with no motor features, or a cranial polyneuropathy that can affect any nerve with little discrimination between motor and sensory nerve populations. Hearing loss is sensorineural because of a lesion of the VIIIth nerve and this may develop suddenly or progressively. Autonomic features are often associated with SS neuropathies (60%): abnormalities of pupillary function (Holmes–Adie pupils), sweating and orthostatic hypotension are the most common manifestations; a pure autonomic neuropathy also occurs, but is much rarer. Many older patients who are diagnosed with SS turn out to have had a chronic, apparently idiopathic, neuropathy for many years, so it is worth screening for SS in this group, especially if the symptoms are patchy or associated with autonomic features. CNS involvement is increasingly recognized and may be severe. MS-like features are often associated with a cutaneous vasculitis and optic neuropathy. Other manifestations include meningo-encephalitis with stroke-like episodes, intracerebral or subarachnoid haemorrhage resulting from vasculitis and focal abnormalities including sensorineural deafness, internuclear ophthalmoplegia, nystagmus, dystonia, athetosis, parkinsonism, focal and generalized seizures. Rarely, affective symptoms may develop as a consequence of an encephalopathic-like presentation with depression, anxiety and cognitive impairment. Spinal cord involvement can develop with an acute transverse myelitis of sudden onset, usually associated with a vasculitis; more

Systemic Conditions and Neurology progressive forms of spinal cord involvement may also occur. The MRI changes are of focal high signal abnormalities on T2 images in the brain white matter and cortex and in the spinal cord. These can be indistinguishable from those seen in MS. If there is involvement of the peripheral or central nervous system, aggressive treatment for underlying vasculitis is indicated. The first line is with intravenous corticosteroid therapy but if progression continues an alternative immunosuppressant may be indicated. The sensory axonal ganglioneuropathy responds poorly to immunosuppression. Other agents that may augment steroids include azathioprine and hydroxychloroquine.

Rheumatoid arthritis RA, also known as rheumatoid disease, is a multisystem disorder usually presenting with a symmetrical distal polyarthropathy. Stiffness of the joints is usually prominent, especially in the morning and the diagnosis is usually supported by the presence of rheumatoid nodules, positive rheumatoid factor in serum and characteristic juxta-articular changes on X-rays of affected joints. Inflammatory or vasculitic neurological complications also occur but are rare. More common are entrapment neuropathies and, most worrying, spinal cord or lower brainstem syndromes secondary to erosive skeletal involvement of the atlanto-axial, odontoid or other vertebral components. The cervical spine is most often affected by erosive disease but extradural pannus can cause compression at any spinal location, including the cauda equina. A group of rheumatological disorders overlap with RA, the mixed connective tissue diseases (MCTD) consisting of RA, scleroderma, SS, SLE and myositis. Patients with this disorder are often positive for the U1-RNP antibody which is associated with the main threat to life: pulmonary hypertension. Neurological manifestations are similar to those seen in RA or SLE; an inflammatory myopathy is present in up to 50% of cases. Evidence suggests that MCTD-associated myopathy is particularly responsive to steroids. Systemic lupus erythematosus SLE is a multi-system disorder like RA, which commonly affects the joints and almost any other organ system, although the arthritis is less erosive than that seen in RA and mucocutaneous involvement more common. Antinuclear antibodies (ANA) are often present in SLE, but the test has a high false positive rate and detection of more specific antibodies to intracellular antigens is often required (e.g. double and single stranded DNA). Neurological complications of SLE usually occur within the CNS. In the largest unselected cohort to date, up to 50% had so-called neuropsychiatric lupus (NPSLE). This proportion is closer to 30% if all those with headache alone are excluded, as they probably should be because headache is no more common in SLE patients than controls. Mood disorders, strokes and cognitive disorders all occur in 10–15% of patients; seizures, frank psychosis and acute confusional states are less common, as are disorders of the nerve or muscle.

The exact mechanism(s) involved in NPSLE are still unclear. The current evidence favours a primary thrombotic/occlusive cerebral vasculopathy over a vasculitis, with antiphospholipid antibodies, particularly those directed at cardiolipin, present in 55% of patients with NPSLE compared to 20% with SLE alone. The therapeutic implication is that NPSLE should be treated with anticoagulation rather than immunosuppressive therapy.

Isolated cerebral angiitis ICA or primary cerebral vasculitis is especially difficult to diagnose. Unlike most of the diseases mentioned above, there are neither extra diagnostic clues from involvement of nonneurological organ systems, nor specific serological nor CSF tests. ICA can present in a wide variety of ways with an acute or subacute, relapsing or even chronic time course. Three main patterns of presentation are proposed: an encephalopathic picture with accompanying headache, confusion and coma; isolated or multiple intracranial mass lesions with a mixture of focal and general CNS signs and raised ICP; an atypical MS-like syndrome with a relapsing-remitting course, optic nerve involvement, sometimes with stroke-like episodes and seizures. Although brain MRI is usually abnormal in patients with ICA, there are no pathognomic findings; intra-arterial cerebral angiograms have a disappointing specificity and sensitivity, of the order of 30%. This leaves brain biopsy as the diagnostic test of choice. Brain biopsy (including meninges) leads to a diagnosis in over 75% of cases, even when targeted at radiologically normal looking brain tissue. However, about half of positive biopsies for presumed ICA show an alternative, unsuspected cause of the problem. Infection, lymphoma and MS are high on this list. Treatment of ICA is not and may never be based on prospective placebo-controlled trials. However, as with treatment for the systemic vasculitides, more potent immunosuppression than can be provided by steroids alone is almost certainly warranted. A current reasonable therapy regimen would be: intravenous methylprednisolone 1 g/day for 3 days followed by 60 mg/day prednisolone tapering over months and eventually being superseded by a steroid-sparing agent such as azathioprine, with oral cyclophosphamide 2 mg/kg/day for 9–12 weeks, starting after the 3 days of intravenous steroid. Giant cell arteritis GCA, widely known as temporal arteritis, is the most common primary vasculitis affecting those over 50 years. Typically, the extracranial branches of the aorta and the aorta itself are involved, with intracranial involvement much more rarely, probably because intracranial vessels lack the internal elastic lamina that appears to be the focus of the inflammatory response. Headache is the most common symptom, but can be absent. Other symptoms caused by involvement of extracranial arteries include jaw claudication and scalp tenderness. Constitutional symptoms are present in at least one-third of cases as this condition overlaps with polymyalgia rheumatica (weight loss, fever and myalgia). Blindness is the most common serious neurological sequel and

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can present with either monocular (or bilateral) or homonymous visual loss. The former is caused by arteritic involvement of the posterior ciliary arteries, leading to optic nerve head infarction which may be partial causing sector or altitudinal field defects. The latter is caused by thrombo-embolism of the posterior cerebral arteries, which are preferentially affected. Sequential ischaemic optic neuropathies or bilateral occipital infarction can lead to permanent blindness. Strokes affecting the MCA territory also occur, although they are rarer. Sometimes the arteritis is clinically apparent to palpation. Affected arteries feel thickened, pulseless and cord-like, such as the superficial temporal artery or other extracranial branches of the external carotid artery, the facial artery as it runs under the mandible, or the occipital arteries as they run over the inion. The ESR is almost always raised as is the CRP; anaemia is present in two-thirds of cases with a leucocytosis and raised transaminases in one-third. Temporal artery biopsy is the most specific finding but often a diagnosis will have to be made without this confirmation as skip lesions occur. The diagnostic yield drops with the interval following initiation of steroid therapy, although this fact should not delay initiating steroids;. perusing a biopsy after the oft-quoted two week window of opportunity post-steroids is occasionally fruitful. Patients started on steroids are not completely protected from ischaemic events;

(a)

there is good evidence for starting patients also on low-dose aspirin when GCA is suspected.

Miscellaneous cerebral arteriopathies CADASIL CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) is an autosomal dominant disease of small cerebral vessels caused by mutations in the notch 3 gene on chromosome 19q13. Notch 3 is a large gene coding for a transmembrane protein involved in intracellular signalling. The condition is characterized by episodic migraine-like headaches and recurrent subcortical ischaemic strokes usually beginning in mid-adulthood. A multifocal motor and sensory deficit develops often with cognitive impairment, incoordination and progression to pseudobulbar palsy and subcortical dementia (Chapter 7). Imaging with CT or MRI shows confluent white matter disease and multiple small deep infarcts with myelin loss usually sparing the U fibres (Figure 25.6 and Figure 7.8). White matter change characteristically involves the anterior temporal horn and external capsule, areas that are less frequently affected in sporadic cerebral small vessel disease. Genetic testing for Notch 3 mutations allows non-invasive confirmation of the diagnosis in many

(b)

Figure 25.6 CADASIL. T2 axial MRI from a 54-year-old man with recurrent migraine, TIAs and subcortical stroke syndromes and progressive cognitive impairment. Note the high signal in both anterior temporal lobes, extensive and confluent high signal in the deep cerebral white matter, and bilateral subcortical infarcts. Genetic testing confirmed the diagnosis of CADASIL.

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Systemic Conditions and Neurology cases. Skin biopsy reveals pathological changes of a non-amyloid angiopathy with deposition of eosinophilic electron dense granular material within the media of the small arteries and arterioles. This leads to concentric arterial wall thickening, narrowing of the vessel lumen and impaired reactivity of the vessel culminating in chronic arterial insufficiency, ischaemia and infarction. The prognosis for CADASIL is poor with progressive stepwise deterioration leading to severe impairment of sensory and motor function and progressive dementia. However, recent data suggest that treatment of modifiable vascular risk factors including hypertension, lipid abnormalities and hyperhomocysteinaemia is appropriate and may limit the severity of phenotypic expression of the disease. Fabry’s disease This important, potentially treatable disease is discussed in Chapters 4 and 18. Susac’s syndrome Susac’s syndrome is a micro-angiopathy of unknown aetiology affecting the brain, cochlea and retina and manifests as a triad of encephalopathy, sensorineural hearing loss and branch retinal artery occlusion. The condition predominantly affects women. At presentation not all of the clinical triad may be present. The onset of encephalopathy is typically associated with prodromal headache that may last for several months before the development of cognitive and psychiatric symptoms, sometimes with seizures and myoclonus. The hearing loss is often acute, bilateral and symmetrical suggesting infarction because of occlusion of the cochlear end arteries. Sometimes hearing loss is asymmetric or even asymptomatic, being detectable only on audiometry. Visual loss is characteristically segmental, and fundoscopy reveals multiple branch retinal artery occlusions and a macular cherry red spot. The EEG shows diffuse encephalopathic changes and MRI confirms multiple small high signal white matter lesions on T2 imaging typically involving the corpus callosum, and sometimes the posterior fossa and brain parenchyma. CSF shows elevated protein with normal cells or a minimal pleocytosis; oligoclonal bands are absent. Histological changes on brain biopsy confirm micro-infarcts resulting from arteriolar occlusion but the mechanism is unclear as there is neither vasculitis nor fibrinoid necrosis. There is no clear guidance to treatment particularly given the tendency for spontaneous remission. The rarity of the condition precludes clinical trials. Antiplatelet agents and steroids are widely used and second line immunosuppression with cyclophosphamide and azathioprine has been recommended. Rarely, plasma exchange and intravenous immunoglobulin have been used. Sneddon’s syndrome Sneddon’s syndrome is a rare disorder characterized by recurrent strokes (typically in the middle cerebral artery territory) in young patients, often with a history of migraine. Cognitive impairment may develop. There is livedo reticularis (a fixed violaceous and net-like rash on the limbs and trunk); antiphospholipid

antibodies may be elevated. The pathology is of an arteriopathy affecting small and medium-sized vessels. Some MRI studies have shown extensive cortical high signal lesions and atrophy. The condition is associated with antiendothelial cell and antiprothrombin antibodies. Treatment is of standard vascular risk factors including hypertension. Anticoagulation may be considered, particularly in the presence of antiphospholipid antibodies. Degos disease Degos disease is a multi-system small vessel occlusive arteriopathy leading to ischaemia, initially involving the skin causing erythematous pink or red papules which heal to leave scars with characteristic white atrophic centres. Gastrointestinal and CNS complications may develop as the disease progresses. Ischaemic and haemorrhagic stroke may occur in the absence of vasculitis. Neurological involvement is characterized by the development of paraesthesiae, visual symptoms, weakness and myelopathy. MRI may demonstrate multi-focal ischaemic abnormalities or dural enhancement; skin biopsy shows vasculopathy but no active vasculitis.

Sarcoidosis Sarcoidosis is a multi-system granulomatous disorder of unknown aetiology that affects the nervous system in some 5% of patients. Its hallmarks are non-caseating epitheloid cell granulomas with associated inflammation and the development of secondary fibrotic change which causes irreversible tissue damage.

Clinical features and investigation The clinical presentation depends upon the pattern of organ involvement. Systemic sarcoid affects the lungs in 90% of patients; involvement may vary from bilateral hilar lymphadenopathy to severe interstitial lung disease. Other organs often involved include the liver, lymph nodes, skin, endocrine and musculoskeletal system. The diagnosis in the presence of hilar lymphadenopathy may be confirmed by bronchoscopy, bronchoalveolar lavage or tissue biopsy. The presence of elevated serum angiotensin-converting enzyme (SACE) and characteristic imaging appearances may help but have limited specificity. CSF ACE may be elevated. Gallium scans may show characteristic increased uptake in parotid salivary glands. However, in the absence of tissue evidence of non-caseating granulomas the diagnosis may be extremely difficult and is often one of exclusion. Acute presentation is associated with a good prognosis but poorer prognostic features include a later age of onset, Afro-Caribbean extraction, the presence of lupus pernio, chronic uveitis, chronic hypercalcaemia, progressive pulmonary pathology, nasal mucosal disease or cardiac involvement. Neurological involvement is uncommon but carries a worse prognosis than pulmonary disease and may be associated with ocular and cardiac involvement. In approximately 15% of patients with neurosarcoidosis the

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presenting features are neurological but in others neurological involvement develops within 2 years of presentation. Chronic neurosarcoidosis can cause multiple cranial nerve palsies, parenchymatous cerebral involvement, hydrocephalus and encephalopathy or peripheral nervous system manifestations.

Cranial neuropathy The most common neurological manifestations are isolated cranial neuropathy or aseptic meningitis. Up to 75% of neurosarcoid patients present with an isolated or bilateral facial palsy. This may be associated with dysgeusia, indicating a proximal lesion affecting the chorda tympani. Deafness from VIIIth nerve involvement occurs in 10–20% of cases; bilateral involvement strongly suggests neurosarcoidosis. Optic neuropathy occurs in up to 40% of patients and is often subacute, presenting with a progressive visual field defect, impaired acuity and pupillary dysfunction. Examination may show anterior uveitis, papillitis, papilloedema or optic atrophy secondary to granulomatous infiltration or compression of the optic nerve. Oculomotor abnormalities or bulbar weakness may occur as a result of a diffuse meningeal infiltration. Infiltration is common at the base of the brain and may lead to hydrocephalus in 6–30% of neurosarcoidosis patients which may be either obstructive or communicating. CSF diversion procedures may be necessary but tend to fail. Meningeal and parenchymatous sarcoid Meningeal involvement commonly presents as an aseptic meningitis or occasionally as a meningeal mass lesion. The CSF shows a mononuclear pleocytosis with an elevated protein and a reduced glucose level. Parenchymal lesions are unusual. Clinical manifestations depend on their location and size. They can mimic tumours or demyelination, cause raised intracranial pressure with headache and papilloedema, seizures or focal involvement of the brainstem, basal ganglia or cerebellum. Isolated spinal lesions may present as a progressive myelopathy with paraparesis and sphincter dysfunction. Pituitary and hypothalamic involvement occurs and can result in neuroendocrine disorders including diabetes insipidus, pan-hypopituitarism and hyperprolactinaemia. Sarcoid encephalopathy A diffuse or relapsing sarcoid encephalopathy may present with cognitive impairment or a confusional state often associated with memory disturbance. T2 MRI shows diffuse contrast enhancement of the meninges with increased signal. Encephalopathy may coexist with a diffuse vasculopathy characterized by arteritis, external compression of arteries by an inflammatory mass lesion or multiple cardiac emboli. Rarely, dural venous thrombosis may occur. Neuropsychiatric features are also well described, presenting with psychosis or bipolar affective disorder. There may occasionally be an isolated progressive amnesia or dementia without evidence of other neurological or systemic involvement. These patients appear to respond well to steroids.

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Peripheral neuromuscular sarcoid Peripheral neuromuscular involvement occurs in some 20% of patients with neurosarcoidosis. Peripheral nerve involvement may be either an isolated mononeuritis, or a mononeuritis multiplex caused by granulomatous vasculitis or compression from granulomas. A symmetrical chronic axonal neuropathy occurs in some 25% of neurosarcoid patients. This is usually mild and of a mixed sensorimotor pattern but a more acute form indistinguishable from Guillain–Barré syndrome with demyelinating features may also develop. Muscle involvement is common but usually asymptomatic with non-caseating granulomas found on biopsy in more than 25% of patients. Symptomatic involvement varies from acute to chronic myopathy with an inflammatory component and occasionally palpable intramuscular nodules.

Diagnosis Diagnosis can be challenging; histological confirmation should be sought if possible. MRI may show parenchymatous mass lesions – hyperintense lesions on T2 sequences, with linear enhancement of thickened meninges and focal nodular enhancement. CSF findings are non-specific but may be helpful if there is meningeal involvement. There may be a pleocytosis of up to 100 cells/mm² and elevated protein 1%), as are peripheral neuropathies. Most authors do not accept the existence of isolated NBS without pre-existing BS, arguing that those patients who present with neurological symptoms have a history of recurrent oral ulcers at least. NBS can mimic a variety of disease states with MS being high on the differential list in Western practice. Although NBS can have a relapsing remitting or progressive course like MS, it is usually differentiated on the following grounds: MRI in NBS

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often reveals symptomatic lesion(s) below the tentorium, as opposed to the multiple, clinical silent, periventricular lesions commonly seen in MS. CSF protein and lymphocyte counts are similar in both disorders, but oligoclonal bands are either absent or matched with serum in NBS and, if present, disappear on remission, compared to the persistently present unpaired intrathecal oligoclonal bands found typically in MS. Optic neuritis is rare in NBS and when associated VEPs are abnormal, the pattern is of reduced amplitude and preserved latency rather than normal amplitude and prolonged latency encountered in demyelination. Lastly, systemic symptoms and headache are seldom present in an acute attack of MS. Although NBS rarely complicates BS, parenchymal disease is sometimes a cause of major disability. 45% of patients with NBS have a single neurological episode, while half each of the remainder have either a relapsing-remitting or a progressive course. NBS is a serious disease: half of all NBS patients have an Expanded Disability Status Scale (EDSS) of >6 at 10 years from diagnosis.

Cerebral venous sinus thrombosis Symptomatic CVST should be treated with anticoagulation (either low molecular weight heparin or warfarin) in the short to medium term and, given that it rarely recurs, long-term anticoagulation is not warranted. The main caveat to this statement is that BS in general and BS complicated by CVST in particular, are associated with coexisting pulmonary artery aneurysms (PAA). These aneurysms (which can occur at other sites in the vascular tree) are probably caused by inflammatory changes in the vasa vasorum of the larger pulmonary vessels, which can result in necrosis of the vessel wall causing true aneurysms or dissection causing false ones. It is prudent therefore to screen patients with BS and CVST for PAA (usually with a CT pulmonary angiogram), before starting anticoagulation. PAA in BS can be treated with immunosuppression, endovascular intervention or surgery.

Investigation Peripheral blood is often but not always normal, with an absence of acute phase reactants. CSF examination shows pleocytosis (neutrophils and lymphocytes with an elevated protein but normal glucose). The opening pressure is increased if there is venous sinus thrombosis but oligoclonal bands are only present in a minority. The pathergy test is somewhat variable in its sensitivity. MRI in the acute stage may show lesions that appear isoor hypo-intense on T1 images and hyper-intense on T2 and FLAIR, due to venous thrombosis with reversible oedema; lesions may be single or multiple. They are seen most commonly in the mesodiencephalic junction, cerebellar peduncle, basal ganglia and brainstem but can also occur in the optic nerve and hemispheres. In chronic disease brainstem atrophy with gliosis can develop. Pathergy test in Behçet’s disease The forearm is pricked with a fine sterile needle. With a positive pathergy test, a small red bump at the site of needle insertion

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develops 1–2 days later. Histologically there is a largely lymphocytic reaction. Not all Behçet’s cases have positive pathergy tests. Behçet’s patients from the Mediterranean littoral tend to have positive tests, around 50% from the Middle East and Japan but fewer from western Europe and the USA. A positive test is not diagnostic for Behçet’s disease.

Treatment Unfortunately, drug treatment for NBS has a limited evidence base. Common practice at centres experienced with treating NBS is to treat acute episodes with high dose, usually intravenous, steroids for 3–7 days with many experts preferring to continue with a tapering dose of oral prednisolone over the next 3 months. Patients with relapsing or progressive NBS are usually treated with azathioprine, methotrexate or pulsed cyclophosphamide, with or without added prednisolone. Some of the newer immunomodulatory therapies such as tacrolimus, infliximab and antiTNF-α have been tried with NBS because there is some evidence of their efficacy in controlling systemic BS symptoms. Thalidomide and colchicine are widely used for the mucocutaneous manifestations. Neurovascular disease is managed conventionally with antiplatelet agents; the role of anticoagulation remains uncertain.

Neurological aspects of pregnancy Pregnancy is associated with a range of physiological changes including dynamic alterations in hormone levels. These changes can either change the presentation or severity of pre-existing neurological diseases, including migraine, epilepsy, multiple sclerosis and myasthenia gravis; or they may be associated with a conditions arising de novo during pregnancy, in particular cerebrovascular disorders. The management of epilepsy in women of childbearing age is of particular importance and is dealt with in some detail here.

Epilepsy and women of childbearing age Fertility Fertility rates are lower in women with treated epilepsy than in an age-matched control population. In one study of a general population of over 2 million persons in England and Wales, an overall fertility rate was found of 47.1 (95% CI 42.3–52.2) live births/1000 women with epilepsy per year compared with a national rate of 62.6. The difference in rates was found in all age categories between the ages of 25 and 39 years (Figure 25.7). There are probably several reasons for this. Women with epilepsy have low rates of marriage, marry later, suffer social isolation and stigmatization. Some avoid having children because of the risk of epilepsy in the offspring, and some because of the teratogenic potential of antiepileptic drugs. Biological factors that may be relevant include genetic influences on fecundity and adverse antiepileptic drug effects. One-third of menstrual cycles in women with temporal lobe epilepsy may be anovulatory, compared to 8% in control

Live births per 1000 women

Systemic Conditions and Neurology Table 25.6 Complications of pregnancy reported with increased frequency in women with epilepsy.

120 110 100 90 80 70 60 50 40 30 20 10 0

Women with epilepsy General UK population of women 15–19

20–24

25–29

30–34

35–39

40–44

Bleeding in utero Premature separation of the placenta Toxaemia of pregnancy and pre-eclampsia Miscarriage and stillbirth Intrauterine growth retardation, low birth weight Perinatal mortality Premature labour Breech and other abnormal presentations Forceps delivery, induced labour, caesarean section Precipitant labour Psychiatric disorders Seizures and status epilepticus

Age (years) Figure 25.7 Fertility rates amongst women with epilepsy compared to that in the general population in an unselected UK population of 2,052,922 persons. From Wallace et al. (1998) with permission.

populations. It has been suggested that valproate results in polycystic ovarian syndrome, possibly by causing obesity, peripheral insulin resistance, hyperandrogenism and hyperinsulinaemia, although this finding has not been widely replicated.

Pregnancy Effects of epilepsy on pregnancy and delivery There are 3–4 live births per 1000 women of childbearing age with epilepsy in Western populations, and epilepsy is one of the most common medical conditions encountered in obstetric units. Epilepsy increases by up to threefold the risks of various common complications (Table 25.6). The perinatal mortality rate has been found to be twice that of the general population. About 1–2% of all women with epilepsy will have tonic–clonic seizures during delivery and this can clearly complicate labour. The fetal heart rate can be dramatically slowed by a seizure, and fetal monitoring is recommended during vaginal delivery. Home birth should not generally be contemplated and obstetricians are more likely to recommend caesarean section. Effect of pregnancy on the rate of seizures Pregnancy has a little effect on seizure frequency in most patients, although there are patients whose seizures stop only during pregnancy and others, usually with severe epilepsy, whose seizures worsen. There are a number of potential causes for changes in seizure frequency: hormonal effects, non-compliance with medication, inappropriate dose reductions, changing drug disposition and serum levels, fluid retention, vomiting, stress, anxiety and sleep deprivation. New-onset epilepsy during pregnancy The annual incidence of epilepsy at childbearing age is about 20–30 cases per 100,000 persons, and so the chance development

of epilepsy during pregnancy is not uncommon. Occasionally, presumably because of hormonal or metabolic influences, some women experience epileptic seizures exclusively during pregnancy (gestational epilepsy) but this is a rare pattern. Symptomatic epilepsy may present in pregnancy with various different underlying causes. Pregnancy can stimulate an increase in size of meningiomas because of oestrogenic stimulation, resulting in newly presenting epilepsy. Arteriovenous malformations may also present more commonly in pregnancy. The risk of ischaemic stroke increases in pregnancy. The underlying causes include arterioscleroisis, cerebral angiitis and Moyamoya disease, Takayasu’s arteritis, embolic disease from a cardiac or infective source, sickle cell disease, antiphospholipid antibody syndrome, thrombotic thrombocytopenic purpura, deficiencies in antithrombin, protease C and S, and factor V Leiden. There is also a higher incidence of subarachnoid haemorrhage and of cerebral venous thrombosis. Pregnancy can also predispose to cerebral infections from bacteria (including Listeria), fungi (coccidioides), protozoa (Toxoplasma), viruses and HIV infection. The extent of investigation of newly developing epilepsy in pregnancy will depend on the clinical setting. X-rays, and thus CT should be avoided wherever possible. There are no known risks to the developing fetus of MRI and this is the brain imaging modality of choice. In the non-urgent situation, investigation is often deferred until pregnancy is completed. Eclampsia and pre-eclampsia Most new-onset seizures in the late stages of pregnancy (after 20 weeks) are caused by eclampsia. Pre-eclampsia is characterized by hypertension, proteinuria, oedema, abnormalities of hepatic function, platelets and clotting parameters. About 5% of cases, if left untreated, progress to eclampsia. The eclamptic encephalopathy results in confusion, stupor, focal neurological signs and cerebral haemorrhage as well as seizures. The epilepsy can be severe and progress rapidly to status epilepticus. The incidence of eclampsia in Western Europe is about 1 in 2000 pregnancies, but

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it is more common in some developing countries with rates as high as 1 in 100. It carries a maternal mortality rate of 2–5% and also significant infant morbidity and mortality. Traditionally, obstetricians have used magnesium sulphate in the treatment of seizures in eclampsia, and the superiority of magnesium over phenytoin and/or diazepam has been clearly demonstrated in recent randomized controlled studies. Not only does magnesium confer better seizure control, but there are less complications of pregnancy and infant survival is improved. Magnesium seems also to lessen the chance of cerebral palsy in low birth rate babies and has also been shown to decrease secondary neuronal damage after experimental traumatic brain injury. The mechanism by which magnesium sulphate acts in eclampsia is unclear; it may do so via its influence on NMDA receptors or on free radicals, prostacyclines, other neurochemical pathways or, more likely, by reversing the intense eclamptic cerebral vasospasm. It is possible that patients would benefit from both magnesium and a conventional antiepileptic, but this has not been investigated. Magnesium should be administered as an intravenous infusion of 4 g, followed by 10 g i.m., and then 5 g i.m. every 4 hours as required. Management of labour Regular antiepileptic drugs should be continued during labour. If oral therapy is not possible, intravenous replacement therapy can be given for at least some drugs. Tonic–clonic seizures occur in about 1–2% of susceptible mothers. In patients at risk, oral clobazam (10–20 mg) is useful given at the onset of labour as additional seizure prophylaxis. Fetal monitoring is advisable. Most women have a normal vaginal delivery, but sleep deprivation, over-breathing, pain and emotional stress can greatly increase the risk of seizures. Elective caesarean section should be considered in patients at particular risk. A history of status or life-threatening tonic–clonic seizures are an indication for caesarean section, and if severe seizures or status occur during delivery, an emergency section should be performed. Intravenous lorazepam or phenytoin should be given during labour if severe epilepsy develops and the patient prepared for caesarean section. There is a maternal as well as infant mortality associated with severe seizures during delivery. The hypoxia consequent on a seizure may be more profound in gravid than in non-gravid women because of the increased oxygen requirements of the fetus, and resuscitation facilities should be immediately at hand in the delivery suite. Vitamin K Maternally ingested enzyme-inducing antiepileptic drugs can induce a relative deficiency of infantile vitamin-K dependent clotting factors (factors II, VII, IX and X) and protein C and S, predisposing to infantile haemorrhage, including cerebral haemorrhage. The neonate should therefore receive 1 mg vitamin K i.m. at birth and at 28 days of life. It is also sometimes recommended that the mother take oral vitamin K (20 mg/day) in the last trimester, although the evidence that this improves neonatal

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clotting is rather contradictory. If any two of the clotting factors fall below 50% of their normal values, vitamin K i.m. will be insufficient to protect against haemorrhage and fresh frozen plasma should be given intravenously. Similarly, if there is evidence of neonatal bleeding, or if concentrations of factors II, VII, IX or X fall below 25% of normal, an emergency infusion of fresh frozen plasma is required.

Epilepsy and the fetus Effect of seizures on the fetus The exact risks are not established. Clearly, in the latter stages of pregnancy, a convulsion carries the risk of trauma to the placenta and/or fetus, especially if the women falls. However, most debate has revolved around the suggestion that seizures damage the fetus through lactic acidosis or hypoxia. The hypoxia is usually very short-lived and the placenta is a well-buffered system; intuitively these risks seem likely to be small. One study has found that first trimester seizures are accompanied by a higher risk of fetal malformation than seizures at other times, although the reliability of these conclusions is in doubt. Stillbirth has been recorded after a single seizure or series of seizures, although this must be very rare. However, status epilepticus during pregnancy or delivery is extremely hazardous, and one study of status epilepticus during delivery reported a 50% infant mortality and 30% maternal mortality. Partial seizures have no known effects upon a fetus. Teratogenicity of antiepileptic drugs There is no doubt that some maternally ingested antiepileptic drugs carry the risk of teratogenicity. This has been shown clearly both in animals and in clinical practice. However, assessment is complicated by the fact that seizures themselves can cause malformations, although this effect is probably small. Also social, dietary and socio-economic factors all increase the risk both of epilepsy and of malformations. Evidence is therefore difficult to assess, and accurate clinical advice difficult to give. Major malformations associated with antiepileptic drugs The most common major malformations associated with traditional antiepileptic drug therapy (phenytoin, phenobarbital, primidone, benzodiazepines, valproate, carbamazepine) are cleft palate and cleft lip, cardiac malformations, neural tube defects, hypospadias and skeletal abnormalities. Polytherapy carries higher risks than monotherapy, and the individual risks of some drugs has not been fully established. Phenytoin as monotherapy has a relatively low incidence of major defects although earlier studies with the drug in polytherapy showed much higher levels. One particular association is the increased risk of neuroblastoma although the absolute risk is very small. One study purported to demonstrate smaller head circumference in babies of mothers on carbamazepine, but the statistical basis of this observation was not well founded. It is unclear whether or not the benzodiazepines carry any teratogenic potential, although there are case reports of facial clefts, cardiac and skeletal abnormalities. The risk

Systemic Conditions and Neurology of spina bifida has been particularly well studied. The background population risk of spina bifida is approximately 0.2–0.5% with geographic variation. Valproate is associated with a 1–2% risk of spina bifida aperta, a risk that is strongly dose-related. Carbamazepine carries a risk of spina bifida aperta of about 0.5–1%. It is instructive to note that the induction of neural tube defects by valproate, and to a lesser extent carbamazepine, were not noticed initially during animal toxicology testing.

Table 25.7 Fetal anticonvulsant syndromes. This is a list of reported abnormalities, although many are uncontrolled observations and the frequency of the anomalies is unclear. Genetic, environmental and socio-economic factors may also have a role in their development. The following features are recorded in ‘fetal anticonvulsant syndromes’ Growth Prenatal and postnatal growth deficiencies Microcephaly

Other developmental abnormalities In addition to the major malformations, less severe dysmorphic changes occur (‘fetal syndromes’), although there is little agreement about their frequency or indeed in some cases their existence. The fetal phenytoin syndrome was the first to be described, and is said to consist of a characteristic pattern of facial and limb disturbances (Table 25.7). However, most of these features are minor and overlap with the normal variation seen in children born to healthy mothers. Recent prospective and blinded studies have shown that only hypertelorism and distal digital hypoplasia occurred at any greater frequency, and even these associations are weak. Furthermore, the nail hypoplasia tends to disappear during childhood. Cases of a ‘carbamazepine syndrome’ are reported with cranio-facial abnormalities, growth retardation, neural tube defects and fingernail hypoplasia. Reports of primidone and phenobarbital ‘syndromes’ have been published, consisting of facial changes and developmental delay. The problem is further complicated by the confounding influences of socio-economic and genetic factors. Recent interest has focused on a ‘valproate syndrome’ said to occur in up to 50% of infants born to mothers on valproate; again no blinded studies have been carried out and the true status of this syndrome is quite unclear. One report has suggested that children exposed to valproate monotherapy have significantly lower verbal IQ scores when compared with children exposed to carbamazepine or phenytoin monotherapy. However, this finding has not been replicated consistently and the current status in this regard of valproate remains uncertain. The teratogenic effects of most of the newer antiepileptic drugs have not been established. This does not imply safety, however, and three points from experience with traditional therapies are worth making. First, even today, the full range of the teratogenicity has not been not established. Second, the risk of even major malformations were not noticed until the drugs had been in extensive use for decades. Third, negative animal results are not a reliable indicator of safety.

mother’s serum cross the placenta. If maternal antiepileptic drug levels are high, the infant may experience drowsiness or withdrawal symptoms and neonatal serum levels should be measured in cases at risk.

Puerperium Maternal seizures and antiepileptic drug doses There is an increased risk of seizures in the puerperium. Clobazam 10 mg taken during delivery and for a few days after delivery can be useful to prevent seizures in this vulnerable period. If antiepileptic drug dosage has been increased because of falling levels during pregnancy, the dose should be reduced in the first week after delivery to its previous levels. Drugs circulating in the

Breastfeeding The concentration of most antiepileptic drugs in breast milk is less than 30% that of plasma; although exceptions are lamotrigine, levetiracetam and phenobarbital. Furthermore, even if a drug is present in significant concentrations in breast milk, the amount ingested by the infant is usually much less than would normally be considered needed for clinical effects. Only lamotrigine, levetiracetam and phenobarbital require special precautions.

Cranio-facial Short nose, low cranial bridge Hypertelorism Epicanthic fold Strabismus and other ocular abnormalities Low-set ears and other aural abnormalities Wide mouth, and prominent lips Wide fontenelles Cleft palate and cleft lip Limbs Hypoplasia of nails Transverse palmar crease Short fingers Extra digits Cerebral Learning disability Developmental delay General Short neck, low hairline Rib, sternal and spinal anomalies Widely spaced hypoplastic nipples Hernias Undescended testes Neuroblastoma and neural ridge tumours Cardiac and renal abnormalities Hypospadias Neural tube defects

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Maternal phenobarbital ingestion is a particular problem, as in neonates the half-life of phenobarbital is long (up to 300 hours) and the free fraction is higher than in adults; neonatal levels can therefore sometimes exceed maternal levels.

reduced drug absorption, reduced serum albumin, protein binding changes, increased clearance and fluid retention. Levels of lamotrigine can be halved and monthly blood level estimations are recommended.

Maternal epilepsy A mother at risk from seizures with altered consciousness should not be left alone with a small child. There is a danger of dropping the child or leaving the child unattended, and maternal epilepsy probably poses a greater risk to infants and toddlers than to the fetus. Sensible precautions should be taken. These might include avoiding carrying the child unaccompanied, changing and feeding the infant at ground level, and bathing the infant only when someone else is present.

Screening for fetal malformations Some malformations can be detected by prenatal ultrasound screening. If therapeutic termination of pregnancy is acceptable, screening procedures should include, where appropriate, a high quality ultrasound scan at 10, 18–20 and 24 weeks, measurement of α-fetoprotein levels and amniocentesis. About 95% of significant neural tube defects can be detected prenatally, as well as cleft palate and other midline defects, and major cardiac and renal defects. However, the mother should be informed that not all malformations are detectable even with the most sophisticated screening methods.

Reducing risks of pregnancy to mother and child Preconception review of drug therapy The patient’s antiepileptic drug regimen should be reviewed if possible before conception is contemplated, as many major malformations are established within the first 8 weeks of pregnancy. It is important to establish whether antiepileptic therapy is needed at all. This will be an individual decision, based on the risks of teratogenicity against the risks of worsening epilepsy. If tonic–clonic seizures are occurring, it is usual to continue drug therapy, as such seizures carry significant risk to mother and child. However, some women with partial or non-convulsive seizures will elect to withdraw therapy even if seizures are active or likely to become more frequent. Conversely, other women who are seizure-free will wish to continue therapy because of the social and physical risks of seizure recurrence.

Folic acid supplementation The fetus of an epileptic women is at a greater than expected risk of a neural tube defect, particularly if the mother is taking valproate. A recent Medical Research Council trial of folic acid supplementation during pregnancy showed a 72% protective effect against neural tube defects in women who had conceived a fetus previously with neural tube defects. Although there has been no specific study in epilepsy, it would seem reasonable for all epileptic women to be given folic acid supplementation during pregnancy. A dose of at least 4 mg/day is recommended on an empirical basis, as lower doses may not fully restore folate levels. Folic acid supplementation is generally recommended, in any event in all women who may become pregnant.

Cerebrovascular disorders in pregnancy Drug therapy during pregnancy In some patients, it is reasonable to withdraw therapy for the first half of pregnancy and then to reinstate the drugs; this approach is based upon the fact that the teratogenic risk is greatest in the first trimester and the physical risk of seizures greatest in the later stages of pregnancy. The relative risks need to carefully assessed, however, and a specialist review is needed before embarking upon this unusual course. If the woman elects to continue therapy, it is best to strive for monotherapy and to aim for the minimum effective dose. A few women with severe epilepsy will need combination therapy, but this should be avoided wherever possible. It is useful to measure the serum drug concentrations that give optimal control of the epilepsy before conception. These values form a useful starting point on which to base subsequent drug dosage adjustments. Valproate should be given in the slow-release form and dosage regimens of all drugs can be changed to two or three times daily regimens to minimize blood level peaks. Dose increases of lamotrigine (and to a lesser extent carbamazepine and phenytoin and phenobarbital) may be necessary as serum antiepileptic drug levels can fall in the second half of pregnancy. The mechanisms of the changing dose reqirement include

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Pregnancy is associated with an increased risk of ischaemic and haemorrhagic stroke. Ischaemic stroke in pregnancy is caused by arterial occlusion in about two-thirds of cases (most often in the middle cerebral artery territory), and venous occlusion of cortical veins or venous sinuses in the remaining third. Thus, venous events are over-represented in pregnancy and a high index of suspicion is required. Arterial stroke is most often in the third trimester or in the first week postpartum. Venous sinus thrombosis is most common in the first 2 weeks postpartum but can occur in the third trimester; presentation differs from arterial stroke in that headache, seizures and behavioural changes may be prominent, in addition to focal neurological symptoms. Cerebral haemorrhage in pregnancy may be caused by pre-existing aneurysm or arteriovenous malformation, or in association with venous infarction or uncontrolled hypertension (e.g. in the context of eclampsia). Rupture of arteriovenous malformations is most common in the second trimester, while there is no particular peak timing for aneurysmal haemorrhage. There is no evidence that vaginal delivery increases the risk of rupture from arteriovenous malformation or aneurysm; decisions on the method of delivery should be based on obstetric factors.

Systemic Conditions and Neurology Pre-eclampsia is a disorder defined by pregnancy-associated proteinuria and hypertension with multisystem involvement (renal, hepatic, neurological). The neurological manifestations include seizures (usually generalized without focal features), visual disturbance and reduced conscious level. These symptoms require urgent investigation to exclude intracranial haemorrhage or other vascular causes. Treatment of hypertension and of seizures with intravenous magnesium is appropriate, sometimes with conventional anticonvulsant drugs. Specific neurovascular syndromes associated with pregnancy include posterior reversible leucoencephalopathy syndrome (PRES) and cerebral vasoconstriction syndrome (Call–Fleming syndrome). PRES characteristically occurs in the first postpartum week, and is characterized by seizures, uncontrolled hypertension and visual symptoms. The pathophysiology is thought to be disruption of the blood–brain barrier, perhaps because perfusion exceeds the autoregulation threshold. The predilection for the posterior circulation is suggested to result from a reduced sympathetic innervation compared to the anterior circulation. The symptoms of PRES mimic those of cerebral venous sinus thrombosis and eclampsia; neuro-imaging is essential to make an accurate diagnosis. In PRES the findings on MRI are characteristic, showing altered signal in the occipito-parietal regions, usually without a major component of restricted diffusion on diffusionweighted MRI in contrast to acute ischaemia (Figure 25.8). Urgent treatment is required for the hypertension and seizures;

R

L

good recovery is the rule if treatment is started promptly. The imaging abnormalities usually resolve, and if this is the case and ongoing seizures have not occurred then anticonvulsants can be stopped. It has been suggested that the term PRES be abandoned because the condition is not only posterior in location, not always reversible and not always associated with encephalopathy. Call–Fleming syndrome (cerebral vasoconstriction syndrome) is commonly observed in the postpartum period and clinically causes a thunderclap headache followed by focal neurological deficit. Definitive diagnosis requires the demonstration of vasospasm on angiographic imaging. Areas of ischaemic change may be seen on MRI as infarction may result from vasospasm. There is clearly potential overlap and lack of firm diagnostic criteria for both PRES and Call–Fleming syndrome, and there is a need for further clarification of these diagnostic terms.

Pregnancy and other neurological diseases Pituitary disorders Pregnancy causes the pituitary gland to enlarge. Sheehan’s syndrome is a rare condition of pituitary infarction, usually caused by postpartum haemorrhage and systemic hypotension, or by the vascular demands of an enlarging pituitary gland exceeding the available vascular supply. Infarction may transform into haemorrhage. In some cases, primary haemorrhage arises in an enlarged pituitary for reasons that are unclear. Infarction or haemorrhage can result in acute pituitary insufficiency and shock, hence the term pituitary apoplexy. Lymphocytic hypophysitis is thought to be of autoimmune origin and usually self-limited. If the pituitary enlargement is causing symptoms, e.g. visual loss, then corticosteroids may be indicated. Headache Migraine is reported to improve in up to 80% of cases during pregnancy, presumably because of altered oestrogen levels. However, because migraine is so common, there are large numbers of women with significant migraine requiring treatment during pregnancy. Headache arising for the first time in pregnancy is of greater concern and may require further investigation. If migraines are frequent and disabling then propranolol can be used in pregnancy. Paracetamol is the safest acute treatment. Ergotamine is contraindicated and there is insufficient information on the safety of triptans to recommend them in pregnancy. The most common type of headache in pregnancy is tension-type headache.

Figure 25.8 Case of PRES: axial FLAIR MRI of a 17-year-old woman who presented with seizures and complete visual loss in the context of uncontrolled hypertension 1 week after delivery. Note patchy high signal abnormalities bilaterally in the parieto-occipital regions. One month later these imaging abnormalities had fully resolved.

Neuromuscular disorders Restless leg syndrome affects up to 30% of women during the third trimester. Oral folate reduces the frequency of symptoms. Pregnancy has an unpredictable effect on myasthenia gravis, with no particular trend for worsening or improvement in symptoms. Bell’s palsy is several times more common in pregnancy and the puerperium than at other times. Carpal tunnel syndrome affects about one-fifth of patients in the third trimester and is likely to

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Chapter 25

resolve after delivery. Meralgia paraesthetica can occur late in pregnancy because of stretching or compression of the lateral cutaneous nerve of the thigh and can be expected to improve following delivery. Gestational polyneuropathy may be related to nutritional deficiency because of general malnourishment or hyperemesis gravidarum. The latter can also cause Wernicke’s encephalopathy. Damage to the nerves of the lumbosacral plexus is a rare complication of delivery, particularly if there are complicating factors including cephalopelvic disproportion, shoulder dystocia or instrumentation with forceps. Neurological complications of epidural anaesthesia are rare.

Multiple sclerosis Unless there are complicating factors (e.g. severe motor disability and contractures) multiple sclerosis has no known effects on fertility, pregnancy, recommended mode of delivery, congenital malformations or perinatal death rates. Overall, pregnancy does not affect the frequency of MS relapses or rate of disease progression. There are no studies of the efficacy or safety of diseasemodifying agents including the interferons and glatiramer acetate in pregnancy. Corticosteroids may be safely used to treat relapses of multiple sclerosis in pregnancy. Chorea gravidarum Chorea gravidarum (CG) simply refers to any type of chorea occurring in pregnancy. The term does not imply a specific cause; this condition is a clinical syndrome not a distinct disease. About one-third of patients have a history of rheumatic fever or Syndenham’s chorea. It is therefore speculated that CG results from the reactivation of previous subclinical basal ganglia damage; the mechanism may involve ischaemia or increased dopamine sensitivity mediated by elevated hormone levels during pregnancy. CG may be secondary to other known causes of chorea including Syndenham’s chorea, lupus or Huntington’s disease. CG seldom requires drug treatment. If CG is mild the patient may even be unaware of the involuntary movements. Drug treatment is only used if its severity puts the mother or fetus in danger, e.g. because of poor nutrition, disturbed sleep or injury. If treatment is necessary dopamine blockers including haloperidol may be used. Tumours Overall, brain and spine tumours are no more common in pregnant than non-pregnant women of similar age. Meningiomas present more often than expected by chance during the second half of pregnancy as they may enlarge because of the effects of changes in circulating oestrogen levels on tumour oestrogen receptors. The symptoms of meningiomas may improve spontaneously postpartum, so that treatment can often be delayed until after delivery. However, surgery for large or aggressive brain tumours during pregnancy may be needed urgently if there are signs of raised intracranial pressure or papilloedema. Most women with brain tumours presenting in pregnancy are managed by caesarean section to avoid possible cerebral herniation during

942

labour. Choriocarcinoma is a malignancy seen in pregnancy and often metastasizes to the brain. Pituitary adenomas are slightly more common in pregnancy and large tumours may be associated with the onset of visual failure; careful visual field assessment is therefore mandatory in every pregnant woman presenting with new headache symptoms. Idiopathic intracranial hypertension Idiopathic intracranial hypertension is more common during pregnancy than at other times, and often presents in the second trimester. If already present it usually deteriorates in pregnancy. Treatment is guided by close monitoring of visual function including visual fields. Weight control is recommended. A short course of corticosteroids may be considered, along with serial lumbar puncture or more invasive procedures including lumboperitoneal shunting or optic nerve fenestration if vision is threatened. The teratogenic potential of acetazomlamide is unknown, but it is usually avoided in the first trimester.

Acknowledgement Dr Jeremy Levy, consultant nephrologist, Hammersmith Hospitals, London gave most helpful guidance on the section on vasculitides.

References Cardiovascular disorders Goodin DS. Neurological complications of aortic disease and surgery. In: Aminoff MJ (ed.) Neurology and General Medicine. New York: Churchill Livingstone, 1992: 27–52. Kanter MC, Hart RG. Neurologic complications of infective endocarditis. Neurology 1991; 41: 1015–1020. Selim M. Peri-operative stroke. N Engl J Med 2007; 356: 706–713.

Endocrine disorders Aminoff MJ (ed.) Thyroid disease and the nervous system. In: Neurology and General Medicine. New York: Churchill Livingstone, 1992. Watkins PJ, Thomas PK. Diabetes mellitus and the nervous system. J Neurol Neurosurg Psychiatry 1998; 65: 620–632.

Haematological disorders Austin S, Cohen H, Losseff N. Haematology and neurology and the blood. J Neurol Neurosurg Psychiatry 2007; 78: 334–341.

Gastro-intestinal disorders Perkin GD, Murray-Lyon I. Neurology and the gastrointestinal system. In: Hughes RAC, Perkin GD (eds.) Neurology and Medicine. BMJ Books, 1999: 185–209.

Renal disease Zandi MS, Coles AJ. Notes on the kidney for the neurologist. J Neurol Neurosurg Psychiatry 2007; 78: 444–449.


Vasculitis

Neurosarcoidosis

Fox RI. Sjögren’s syndrome. Lancet 2005; 366: 321–331. Mori K, Iijima M, Koike H, et al. The wide spectrum of clinical manifestations in Sjögren’s syndrome-associated neuropathy. Brain 2005; 128: 2518–2534. Nesher G, Berkun Y, Mates M, Baras M, Nesher R, Rubinow A, et al. Risk factors for cranial ischemic complications in giant cell arteritis. Medicine (Baltimore) 2004; 83: 14–22. Nishino H, Rubino FA, DeRemee RA, Swanson JW, Parisi JE. Neurological involvement in Wegener’s granulomatosis: an analysis of 324 consecutive patients at the Mayo Clinic. Ann Neurol 1993; 33: 4–9. Scolding NJ, Jayne DR, Zajicek JP, Meyer PA, Wraight EP, Lockwood CM. Cerebral vasculitis: recognition, diagnosis and management. Q J Med 1997; 90: 61–73. Younger DS. Vasculitis of the nervous system. Curr Opin Neurol 2004; 17: 317–336.

Zajicek JP, Scolding NJ, Foster O, et al. Central nervous system sarcoidosis: diagnosis and management. Q J Med 1999; 92: 103–117.

Behçet’s syndrome Kidd D, Steuer A, Denman AM, Rudge P. Neurological complications in Behçet’s syndrome. Brain 1999; 122: 2183–2194. Siva A, Altintas A, Saip S. Behçet’s syndrome and the nervous system. Curr Opin Neurol 2004; 17: 347–357.

Pregnancy Sawle GV, Ramsay MM. The neurology of pregnancy. J Neurol Neurosurg Psychiatry 1998; 64: 717–725. Wallace H, Shorvon SD, Tallis R. Age-specific incidence and prevalence rates of treated epilepsy in an unselected population of 2,052,922 and age specific fertility rates of women with epilepsy. Lancet 1998; 352: 1970–1974.

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Index

Page numbers in italics refer to figures; those in bold to tables. Aα fibres 19, 20 ABCD1 gene mutations 442 abdominal muscles, testing 84 abdominal pain acute intermittent porphyria 708 ictal 853 abducens nerve (VI) anatomy 36, 60–1, 64 examination 79–80 palsy 514–16 causes 515 clinical features 80, 540 coma 728 abducens nucleus 59, 60–1 abduction, internuclear ophthalmoplegia of 519 Aβ fibres 19, 20 abetalipoproteinaemia 512, 634 abnormal illness behaviour 106–7, 824–5 absence epilepsy childhood 195, 213 juvenile 213, 223 absence seizures 191–3, 213 atypical 193 drug treatment 223 typical (petit mal) 191, 193 abulia 255 accessory nerve (XI) 480–1 anatomy 70, 71, 479, 480 cranial 70, 71 examination 82, 480 lesions 480–1 motor nuclei 34–5 nuclei 34, 70, 71 spinal see spinal accessory nerve Access to Work scheme 664 acetaminophen (paracetamol), migraine 454–5 acetazolamide altitude illness 686, 687 central retinal artery occlusion 499 epilepsy 222, 231 idiopathic intracranial hypertension 506

periodic paralyses 398 raised CSF pressure headache 461 acetylcholine (ACh) autonomic nervous system 73, 872 gated ion channels 18 hippocampus 43 neuromuscular junction 16, 17 acetylcholine receptor (AChR) 383, 384 antibodies (AChRAb) 383, 385 achondroplasia 591 achromatopsia 250, 527–8 aciclovir Bell’s palsy 475 herpes simplex encephalitis 313 herpes zoster ophthalmicus 471 acoustic brainstem evoked responses (ABR) 568, 569 auditory neuropathy 563, 568 multiple sclerosis 578 acoustic impedance measurements 567 acoustic neuromas see vestibular schwannomas acoustic reflex pathways 68 acoustic trauma, hearing loss 572–3 acromegaly 806, 807 myopathy 406 neuropathies 369 acrylamide 679 ACTH see adrenocorticotrophic hormone actin 388, 389 activated factor VII, recombinant 126 activated protein C (APC) resistance 117 activities of daily living (ADL) rating scales 663 rehabilitation 654, 658–9, 665 acupuncture 868 acute confusional state 724 see also delirium acute disseminated encephalomyelitis (ADEM) 312, 439–41 monophasic 440, 441 multiphasic 440, 441 recurrent 440, 441 urinary retention 903 acute flaccid paralysis 316 acute haemorrhagic leucoencephalitis 441–2


acute inflammatory demyelinating polyradiculoneuropathy (AIDP) 361–2 cancer 819 see also Guillain–Barré syndrome acute lung injury (ALI) 751 acute motor and sensory axonal neuropathies (AMSAN) 361, 362 acute motor axonal neuropathies (AMAN) 361, 362 acute mountain sickness (AMS) 686–7 acute neuromuscular weakness 361–3 acute para-infectious inflammatory encephalopathies 439–42 acute quadriplegic myopathy (AQM) 759 acute respiratory distress syndrome (ARDS) 751 acute severe necrotizing myopathy 759–60, 820 Adamkiewicz, great anterior medullary artery of 913, 914 ADC see apparent diffusion coefficient Addison’s disease 406, 920 Aδ fibres 19, 20, 22, 31 gate control 40 pain conduction 853 adrenal disease 406, 920 adrenaline, biosynthesis 889 adrenoceptors 73 adrenocorticotrophic hormone (ACTH) multiple sclerosis 427–8 secreting pituitary tumours 805, 806, 807 adrenoleucodystrophy (ALD) 442–3, 720 Addison’s disease 920 ataxic variant 637 childhood cerebral (CCER) 442 dementia 277 psychiatric features 840 adrenomyeloneuropathy (AMN) 442–3, 720 adult onset 442 adult polyglucosan body disease 278 advanced sleep phase syndrome 765 adverse drug reactions see drug reactions, adverse affective disorders 255, 831 see also depression afferent fibres 19, 23 afferent pupillary defect 492, 529 complete 529 relative 492, 529

945

Index African trypanosomiasis 325 Aγ fibres 19, 20 Age antiepileptic drug withdrawal and 229 stroke risk and 115 ageing see elderly Agent Orange 689 age-related macular degeneration 490 age-specific incidence and prevalence neurological disorders 3–4, 6 population structure effects 1–2 aggressive behaviour 210, 230 agitation, acute neurological illness 754–5 agnosia auditory 251, 580 tactile 251 visual see visual agnosia visuo-spatial 250–1 agraphaesthesia 251 agraphia (dysgraphia) 97, 98, 254 central 254 peripheral 254 phonological 254 surface 254 visual pathway disorders 528 agyria 200 agyria pachygyria band spectrum 200 Aicardi’s syndrome 200 AIDS see HIV akathasia 183, 702–3 akinesia 155 akinetic mutism 724 akinetic-rigid syndromes 100, 155–64 akinetopsia 250 Alagille syndrome 586 albendazole 323 alcohol (ethanol) acute intoxication 639, 692 consumption, stroke risk and 115 injections, spasticity 656 metabolism 692 substitutes 692–3 withdrawal syndrome 693 alcohol abuse 692–6 cerebellar ataxia 639, 695 cerebellar lesions 31 dementia 281, 284, 695 hearing loss 578 neurological complications 693–6 alcoholic cirrhosis 696 alcoholic myopathy 695 alcoholic peripheral neuropathy 695 alemtuzumab, multiple sclerosis 432 Alexander’s disease 277, 445 Alexander’s law 520, 543, 551 alexia 97, 98, 528 with agraphia 254, 528 without agraphia 254, 528 see also dyslexia algodystrophy (CRPS type I) 861–2 alien limb phenomenon 252 alimentary system disorders see gastrointestinal disorders allesthenia 527 allodynia 349, 848

946

allyl chloride 679 almotriptan, migraine 454 α-adrenoceptors 73 α-blockers, incomplete bladder emptying 901 alpha-fetoprotein (AFP) 810–11 alpha-mannosidosis 277 alpha rhythm, EEG 88 alpha-synuclein 155–6, 266 alpha-synucleinopathies 156 Alport’s syndrome 571, 572 Alstrom’s syndrome 571 alteplase, acute ischaemic stroke 138–9 alternative medicine, multiple sclerosis 438 altitude medicine 686–7, Plates 18.1–18.4 aluminium toxicity 677 alveus 41, 42 Alzheimer’s disease (AD) 259–63 anosmia 466 apraxia 252, 261 clinical features 248, 260–1 cortical visual impairment 528 depression 832 driving fitness 261, 286 epilepsy 202, 285 familial 259, 260, 276 investigations 258, 261–2 Lewy body variant 266 management 262–3 memory deficits 249, 260 myoclonus 181, 261 pain and 851–2 pathology 14–16, 259–60 perceptual deficits 250, 261 speech and language deficits 253, 261 vascular disease with (mixed dementia) 123, 273 amacrine cells 53, 54 Amanita muscaria 681 Amanita phalloides 681 amantadine multiple sclerosis 433–4, 658 Parkinson’s disease 159–60 amaurosis fugax 117 amblyopia, tobacco-alcohol 504, 696 American Spinal Injury Association (ASIA) score/grading 605 American trypanosomiasis see Chagas disease amino acid catabolism, inherited disorders 716–18 amino acidurias 634 aminoglycosides, oto-toxicity 572 4-aminopyridine, multiple sclerosis 434, 437 amitriptyline chronic daily headache 459 chronic tension-type headache 455 migraine prevention 453 pain management 865 ammonia, ability to detect 465, 466 Ammon’s horn 41 amnesia acute alcohol intoxication 692 post-traumatic (PTA) 669 psychogenic (dissociative) 830, 841 transient epileptic 248, 250, 280, 282 transient global see transient global amnesia see also memory impairment amoxicillin, syphilis 302

amphetamine abuse 696–7 other complications 697–8 stroke 115, 124, 127, 697 amphetamines, narcolepsy 764 amphiphysin antibodies 820 amphotericin B aspergillosis 321 cryptococcal meningitis 329, 332 ampicillin, bacterial meningitis 292, 293, 294 Amsler’s test 491 amygdala 41, 44, 45, 834 amyloid in Alzheimer’s disease 14–16, 259 beta-amyloid (Aβ) 15, 16, 259 immunotherapy 262 beta-amyloid-42 (Aβ-42) 259, 262 amyloid angiopathy see cerebral amyloid angiopathy amyloid neuropathy acquired 365–6 familial (FAP) see familial amyloid polyneuropathy pathology 359, Plate 9.2 uro-genital symptoms 909 amyloidoses AL (light chain) 365–6 oculoleptomeningeal (OLMA) 359 amyloid precursor protein (APP) 15–16, 259 gene (APP) mutations 259, 260 amyotrophic lateral sclerosis (ALS) 377–8 cognitive impairment 381 familial (FALS) 378–9 prognosis 379 see also motor neurone disease amyotrophy diabetic 367, 368, 856 neuralgic see brachial neuritis amytal test, epilepsy surgery 237–8 anaemia 920–1 anaesthesia failure to awaken after 755–6 malignant hyperthermia 705 myasthenia gravis 386 anaesthesia dolorosa 103, 848 after Gasserian ganglion ablation 470 analgesic drugs 865–6 acute neurological illness 755 migraine 454–5 overuse headache 458 pain management 657 tension-type headache 455 anarthria, pseudobulbar palsy 484 ANCA see antineutrophil cytoplasmic antibodies Andersen’s disease (GSD type IV) 715 Andersen’s syndrome 397, 398 Andersen–Tawil syndrome 398, Plate 9.8 Anderson–Fabry disease see Fabry’s disease aneurysms, intracranial berry 124 imaging 128, 129 mycotic 124, 309 risk factors 127 rupture 124, 126, 129 seizures 203 treatment 129–30 see also subarachnoid haemorrhage angel dust 699

Index angiitis, isolated cerebral see isolated cerebral angiitis angioendotheliomatosis, malignant 808 angiography, catheter see cerebral catheter angiography Angiostrongyloides 322 angiotensin-converting enzyme, serum (SACE) 933 angular gyrus syndrome see Gerstmann’s syndrome anhidrosis 883, 891 anisocoria, physiological 528 ankylosing spondylitis 603 anomia 253 anorgasmia 907–8 anosmia/dysosmia 465 causes 466–7 drugs causing 702 unilateral visual loss with 490 anosognosia 247 see also visual anosognosia anoxic–ischaemic encephalopathy 756 anterior cerebral artery (ACA) 112 aneurysms 127 occlusion 122 anterior choroidal artery 112 aneurysms 127 occlusion 122 anterior communicating artery (ACOM) 112 aneurysms 127, 128 anterior horn cell diseases 377–83 anterior inferior cerebellar artery (AICA) aneurysms 579 occlusion 514 anterior interosseous nerve 339, 342 anterior ischaemic optic neuropathy (AION) arteritic/vasculitic 500–1, Plate 13.9 non-arteritic 500, Plates 13.7–13.8 anterior nucleus of thalamus 41, 46, 46 anterior spinal artery 913, 914 occlusion 153, 620, 914–15 anterior tarsal tunnel syndrome 373 anterior tibial compartment syndrome 373 anthrax, as biological weapon 689 anti-acetylcholine receptor antibodies (AChRAb) 383, 385 anti-AGNA antibodies 820 anti-ANNA1 antibodies see anti-Hu antibodies anti-ANNA3 antibodies 282 anti-aquaporin-4 antibodies 438, 496–7 antibasal ganglia (ABGA) syndrome 280 antibiotics bacterial meningitis 292, 293, 294, 295 brucellosis 305 cerebral abscess 296 infective endocarditis 310 Lyme disease 304 spinal infections 617 subdural empyema 297 syphilis 302 anticholinergic agents abuse 699 bladder dysfunction 657–8, 896, 900 dystonia 170 hyperhidrosis 891 multiple sclerosis 435 Parkinson’s disease 159 tardive dyskinesia/dystonia 183

anticholinergic syndrome, drug-induced 708 anticholinesterases, myasthenia gravis 385 anticoagulation acute neurological illness 754 acute stroke 140 brain haemorrhage complicating 124, 126, 144, 145 carotid and vertebral artery dissection 148–9 cerebral venous thrombosis 152–3 secondary stroke prevention 144–5 anticonvulsants see antiepileptic drugs anti-CV2/CRMP5 antibodies 282, 641, 818, 820 antidepressants 842–3 dementia 285 Gilles de la Tourette syndrome 179 multiple sclerosis 436 narcolepsy 764 pain management 865 serotonin syndrome 707 side effects 842, 843 antidiuretic hormone 50 see also syndrome of inappropriate antidiuretic hormone secretion anti-embolism stockings, thrombo-embolic stroke 140 antiemetics Parkinson’s disease 160 vestibular disorders 557 antiepileptic drugs 220–34 addition to existing regimen 227 cerebellar side effects 639 chronic treatment protocol 227–8 cognitive impairment 282 combination therapy 228 currently available 222, 231–4 deciding to initiate therapy 220–1 dosing regimens 224 EEG effects 215 emergency treatment 234, 235 epilepsy in remission 228–9 initial treatment protocol 221–7 labour 938 learning disability 230–1 monotherapy 228 mood stabilization 844 pain management 865, 866 patient information 228 pharmacokinetics 225–6 preconception review 940 pregnancy 938–9 puerperium 939–40 refractory epilepsy 227–8, 234–6 serum concentration measurements 228 teratogenicity 938–9 trial of therapy 227 withdrawal/discontinuation 228–9 chronic epilepsy 227 EEG assessment for 215, 229 during pregnancy 940 recommended rates 224, 229 seizure recurrence risk 228, 229 antiganglioside antibodies 362, 364 anti-Hu antibodies 282, 641, 818, 819, 820 antihypertensive therapy acute stroke 140–1

secondary stroke prevention 143 vascular cognitive impairment 279 anti-inflammatory therapies, spinal cord injuries 608 anti-Ma antibodies 641, 820 anti-mGLuRa antibodies 641, 820 antimuscarinic agents bladder dysfunction 896, 900 see also anticholinergic agents anti-muscle-specific kinase (MuSK) antibodies 383–4, 385 antineuronal antibodies, paraneoplastic (PNA) 820 cerebellar degeneration 641, 817 limbic encephalitis 282–3, 818 antineutrophil cytoplasmic antibodies (cANCA) 366, 929, 930 perinuclear (pANCA) 929 anti-NMDA receptor antibodies 820 antinuclear antibodies (ANA) 931 antiphospholipid antibodies 117, 137 antiphospholipid syndrome (APAS) 117, 922 cognitive impairment 275 lacunar stroke 120 antiplatelet therapy acute stroke 139–40 secondary stroke prevention 145–6 antipsychotic drugs (neuroleptics) 842, 843 atypical 843 dementia 285 dementia with Lewy bodies 162, 267 extrapyramidal side effects 183, 703, 843 tics 178–9 antiretroviral drugs myopathies induced by 334, 406–7 toxic neuropathy 334 tropical spastic paraparesis 618–19 see also highly active antiretroviral therapies anti-Ri antibodies 641, 820 antisocial personality 829 anti-striated muscle antibodies 385 anti-Ta (Ma2) antibodies 282, 641, 818, 820 antitoxin A 689 anti-Tr antibodies 641, 820 antituberculous drugs 299–300 antiviral drugs herpes zoster 471, 860 see also antiretroviral drugs anti-voltage-gated calcium channel (VGCC) antibodies 282, 387, 641, 819–20 anti-Yo antibodies 641, 820 Antoni B areas 778 Anton’s syndrome 99, 250, 525 anxiety, Parkinson’s disease 157 anxiety disorders 829–31 epilepsy 836 traumatic brain injury 660 anxious personality 829 aorta anatomy 111, 913–14 surgery 914–15 thoracic, dissection 914 aortic disease 913–15 cerebral ischaemia 914 spinal cord ischaemia 914–15

947

Index apathy 98, 255 fronto-temporal dementia 264 Apert’s syndrome 571, 591 aphasia (dysphasia) 97–8, 252–4 anomic 253 conduction 98, 253 dynamic 253 fluent (posterior, sensory or Wernicke’s) 97–8, 253, 840 logopenic 253 mixed transcortical (MTA) 98 nominal 97 non-fluent (Broca’s, motor or anterior) 97, 253 progressive non-fluent see progressive non-fluent aphasia transcortical motor (TMA) 98 transcortical sensory (TSA) 98, 253 apneustic breathing 731 apnoea autonomic disease 884, 891–2 obstructive sleep see obstructive sleep apnoea/ hypopnoea syndrome apolipoprotein A-1 related familial amyloid polyneuropathy (FAP) 359 apolipoprotein E gene (ApoE) polymorphisms 260, 275 apomorphine bladder function and 897 Parkinson’s disease 160–1 sexual function and 907 apparent diffusion coefficient (ADC) brain metastases 789, 791, 792 cerebral infarction 135 primary brain tumours 779, 781–2, 784, 785, 787–8 tumour treatment complications 795, Plate 20.10 appetite regulation 50–1 applause sign 267 aprataxin 633 apraxia 251–2 asymmetric limb 252 constructional 99, 252 dressing 99, 252 of eyelid opening 252 gait 120, 123, 252 ideational 252 ideomotor 99, 252 limb-kinetic 252 ocular see oculomotor apraxia orofacial 252, 265 aprosodias 840 aquaporin-4 antibodies 438, 496–7 arachnoiditis 604 arboviruses (arthropod-borne viruses) 312, 314, 315 as biological weapons 690 arcuate nucleus 49 area 22 58, Plate 2.3 area postrema 50 Argyll Robertson pupil 302, 529 inverse 529 arithmomania 839 arousal disorders 766 arrhythmias see cardiac arrhythmias arsenic poisoning 676–7

948

arteriovenous fistulae, dural see dural arteriovenous fistulae arteriovenous malformations (AVMs) 130–2 epilepsy 202 imaging 131–2, 135, 218 management 131–2 natural history 131 presentation 130–1 rupture in pregnancy 940 Spetzler–Martin grading 132 spinal see spinal arteriovenous malformations arthrogryphosis multiplex, X-linked 382–3 arylsulphatase A (ASA) 443, 444, 714 aspartoacylase (ASPA) gene mutation 445 aspergillosis 321 Aspergillus fumigatus 319, 321 cancer 816 Aspergillus infections 925 aspirin acute stroke 139–40 chronic daily headache 459 migraine 454–5 secondary stroke prevention 144, 145–6 side effects 145 Association of British Neurologists (ABN), multiple sclerosis guidelines 430, 431 astereognosis 99, 251 asterixis 179, 756 asthma 349 astrocytes 18, Plate 2.1 barriers to nerve fibre repair 609 astrocytomas anaplastic (grade III) 776 chemotherapy 802–3 histology 776, Plate 20.1 imaging 782, 788, Plate 20.4 radiotherapy 801–2 surgery 797–8 diffuse (grade II) 776 histology 776, Plate 20.1 imaging 782, Plate 20.4 radiotherapy 803 surgery 798 grading 774–6 imaging 782, 784, 785, 787–8 pathology 774–6, Plate 20.1 pilocytic (grade I) 776 histology 776, Plate 20.1 imaging 782, Plate 20.4 surgery 798 spinal 611, 613, 799, 805 subependymal giant cell 776 see also gliomas Asymptomatic Carotid Surgery Trial (ACST) 147 ataxia(s) 629–42 autosomal recessive late onset 633 childhood, with central hypomyelination see vanishing white matter disease congenital inherited 632 Creutzfeldt–Jakob disease 269 DNA repair defects causing 633 episodic see episodic ataxia gluten sensitivity and 641 idiopathic late onset 642 intermittent metabolic 634

investigations 630–1 multiple sclerosis 419, 435, 638 pineal region tumours 810 progressive metabolic 634–5 vitamin E deficiency 634 X-linked syndromes 637 see also cerebellar ataxia; cerebellar disease ataxia associated with oculomotor apraxia (AOA) 633 ataxia telangiectasia 173, 633, Plate 16.1 ataxia telangiectasia (AT)-like disorder 633 ataxic respiration 731 ataxin trinucleotide repeats 635 atherosclerosis ischaemic stroke 120–1 secondary stroke prevention 145 athetosis 165 athletic performance-enhancing drugs 700 atlanto-axial instability 593–4 rheumatoid arthritis 601–2 traumatic injuries 606 atlas assimilation 593 atlastin 624 ATM gene mutations 633 atonic (astatic) seizures 194, 224 ATP1A2 gene mutations 450 atrial fibrillation (AF) 915 acute stroke 752 secondary stroke prevention 144 stroke risk 115–16 atrial flutter 752 atrial myxoma 916–17 atropine, nerve agent poisoning 689 attention 247 deficits, clinical syndromes 247 testing 96 attention deficit hyperactivity disorder (ADHD), Gilles de la Tourette syndrome 178, 179, 839 atypical facial pain 456, 471–2 audiological investigations 566–9 audiometry 566, 567 pure tone 566, 567 speech 567 auditory adaptation, abnormal 563 auditory agnosia 251, 580 auditory association cortex 24 auditory cortex, primary 24, 68 auditory disconnection profile 580 auditory disorders see hearing disorders auditory hallucinations 251, 833 temporal lobe epilepsy 191 auditory nerve (cochlear nerve) 68, 69 examination 81 see also hearing auditory neuropathy 562, 563, 574–9 acquired 576, 577–9 genetic or congenital 574–7 investigations 568 management 581–2 auditory neuropathy/dys-synchrony (AN/AD) 563, 581 auditory processing disorders (APD) 562, 564, 579–80 central 564 management 582 auditory system 68, 69, 564–5

Index auditory training programmes 582 auras epileptic 190, 191, 836 migraine 451 auricle, examination 565 autoimmune disorders hearing loss 573–4 spinal inflammation 619 autoimmune inner ear disease (AIED) 573–4 automatic behaviours, on wakening 763 automatisms, ictal 191, 192, 209 autonomic dysfunction 871–92 classification 871, 873 clinical examination 885 clinical features 874–85 drug-induced 704, 874 investigations 885 localized 871, 873 management 885–92 peripheral neuropathies 349 autonomic dysreflexia 608 clinical features 880, 881, 882, 883 management 890, 891 autonomic failure (AF) multiple system atrophy 162, 163, 875 pure see pure autonomic failure see also autonomic dysfunction autonomic nervous system anatomy 72–3, 871, 872 neurotransmission 73, 871, 872, 873 autonomic neuropathies diabetic 368 paraneoplastic 819 Avellis’ syndrome 479 Avonex (interferon β1a) 429, 430 awake craniotomy, tumour resection 798 awareness, loss of 205–6 axillary nerve 338, 339, 341 neuropathy 373 axonal neuropathies idiopathic 372 Lyme disease 303 nerve conduction studies 91 vasculitis 367, Plate 9.5 axons 13 degeneration 348 Schwann cell interactions 21 azathioprine inflammatory myopathies 404 multiple sclerosis 432 myasthenia gravis 385 neuromyelitis optica 439 vasculitis 929 Babinski reflex 84 back pain, low 616 management 616, 657 red flags 615 baclofen intrathecal 434–5, 656, Plate 10.3 multiple sclerosis 434–5 spasticity management 655–6 vestibular disorders 558 bacterial infections optic neuritis 497

organ transplant recipients 925 spine 616–17 see also specific infections Bainbridge reflex 72 balance 533–6 training 653 Balint’s syndrome 250, 528 Baló concentric sclerosis 417 Baltic myoclonus 198 Bannwarth’s syndrome 476, 497 barbiturates abuse 699 myoclonus 182 raised ICP 742 Barkhof–Tintore criteria, multiple sclerosis 424 barotrauma 686 hearing loss 573 Barthel Index (BI) 663 Bartonella infections 498 basal forebrain 45 basal ganglia 24, 26–8 arteriovenous malformations 131 basic circuits 26–7 cognitive loop 27 haemorrhage 110, 749 limbic loop 27–8 motor loops 24, 26–7 oculomotor loop 28 basal ganglia disorders characteristic signs 24 psychiatric disorders 837–9 basal nucleus of Meynert 45 Basedow’s paraplegia 917 basilar artery 112 occlusion 122–3, 525, 749 see also top of the basilar syndrome basilar impression 596 basilar invagination 593 congenital 593, 594, 596 osteogenesis imperfecta 591 basilar migraine 554 Battle’s sign 743 Becker muscular dystrophy 392–3 Becker’s disease 398–9 bed rest low CSF volume headache 460 lower back pain 616 spinal cord injuries 605 Behavioural Assessment of Dysexecutive Syndrome (BADS) 96 behavioural management, dementia 285 behavioural problems fronto-temporal dementia 264 post-traumatic 669–70 Behçet’s syndrome 934–6 dementia 280 hearing loss 574 ocular involvement 507 stroke 150 Behr’s syndrome 633 Bell’s palsy 474–6 clinical features 81, 475 pregnancy 941 Bell’s phenomenon 549 bends, the 686

Benedikt’s syndrome 514 benign childhood occipital epilepsy (BCOE) 214 drug treatment 223 early onset 196, 214 benign essential tremor (BET) 100, 164, 165 benign hereditary chorea (BHC) 177 benign paroxysmal positional vertigo (BPPV) 537, 552–4 anterior canal (a-BPPV) 543, 553–4 diagnosis 543–4, 552 horizontal canal (h-BPPV) 543, 544, 552–3 particle repositioning procedures 559–60, 561 posterior canal (p-BPPV) 543, 544, 552 benign partial epilepsy with centrotemporal spikes (BECTS) 195–6, 213–14 drug treatment 223 benserazide 158 benzodiazepines abuse 699 acute neurological illness 754–5 alcohol withdrawal 693 epilepsy 231, 234 insomnia 762 multiple sclerosis 434 spasticity 655–6 teratogenicity 938 as tranquillizers 843–4 vestibular disorders 557 benzylpenicillin bacterial meningitis 292, 293 infective endocarditis 310 syphilis 302 Bereitschaftspotential 27, 182 beri-beri 370 beta activity, EEG 88 β-adrenoceptors 73 β-blockers migraine prevention 453 postural tachycardia syndrome 891 Betaferon (interferon β1b) 429, 430 betahistine 557 β-oxidation defects 719 Bethlem myopathy 392, 395–6 bevacizumab 803 B fibres 19, 20 Bickerstaff ’s encephalitis 484, 638 big blind spot syndrome, idiopathic 490 bilateral vestibular failure (BVF) 555 bilharzia 324 binaural integration tests 569 Binswanger disease 274 biofeedback techniques 654, 845 biological weapons see neurobiological weapons biopsy 95 cognitive impairment 258 see also brain biopsy; muscle biopsy; nerve biopsy biotin-dependent carboxylase deficiencies 634 bipolar cells, retinal 53–4 bipolar disorder 831, 844 birth rate 9 bismuth toxicity 677–8 bisphosphonates 591, 601 bitemporal hemianopia 523, Plate 13.27 pituitary tumours 806 Bitot spots 690

949

Index black widow spider 681 bladder incomplete emptying 901 neural control 39–40, 893–5 bladder dysfunction 895–900 autonomic disorders 883, 891 brainstem lesions 898 cerebrovascular disease 895–6 cortical disease 895 dementia 896 drug-induced 704 HTLV-associated myelopathy 318, 899 management 657–8 multiple sclerosis 419, 435, 899 multiple system atrophy 897–8 Parkinson’s disease 157, 896–7 spinal cord disease 898–9 see also detrusor over-activity; urinary incontinence bladder outflow obstruction, Parkinson’s disease 897 bleeding disorders 922 blepharospasm 166, 171 blindness see visual loss blindsight 99, 525 fibres 57 blink responses 65, 81 coma 730 Vth nerve lesions 471 blood–nerve barrier (BNB) 347, 348 blood oxygen level-dependent (BOLD) imaging 87, 218 brain tumours 780–2, Plate 20.7 blood pressure, arterial (ABP) carotid sinus hypersensitivity 880 ICP and 739, 740 management acute stroke 140–1 raised ICP 741 secondary stroke prevention 143 orthostatic hypotension 875, 876 postural tachycardia syndrome 880 vasovagal syncope 879 see also hypertension; hypotension blood transfusion, vCJD transmission 272, 273 Bobath approach 651 BOLD imaging see blood oxygen level-dependent imaging bone marrow biopsy 258 transplantation see haematopoietic stem cell transplantation bone tumours, primary spinal 612, 613 borderline personality 826, 829 border-zone infarction see watershed infarction Borrelia burgdorferi 302 botulinum toxin 307, 308 botulinum toxin (BTX) injections dystonia 171 headache syndromes 459 hemifacial spasm 476–7 hyperhidrosis 891 multiple sclerosis 434, 435 myoclonus 182 neurogenic bladder dysfunction 902

950

pain relief 866 spasticity 656 tics 179 botulism 307–8 antitoxin 308 as biological weapon 689 food-borne 307, 308 intensive care management 750–1 ocular involvement 512 wound 307, 308 bovine spongiform encephalopathy (BSE) 268, 269, 271 bowel dysfunction management 657–8 multiple sclerosis 419, 435 boxers, dementia pugilistica 284 brachial neuritis (neuralgic amyotrophy) 856 acute 377 hereditary 358 brachial plexopathies 373, 377 malignant 813, 858–9 radiation-induced 683, 801 brachial plexus 337, 338, 339 traumatic lesions 858 bradycardia 752, 881–2 bradykinesia 155, 156 bradyphrenia 255 brain blood supply 913, 914 energy metabolism 114 as seat of emotions 834–5 structure and function 23–73 brain abscess see cerebral abscess brain attack 110, 117 brain biopsy 95 cognitive impairments 258 frame-based stereotactic 796 isolated cerebral angiitis 931 neuro-navigation and frameless stereotaxy 796 pineal region tumours 810 brain death determination 735–6 EEG recording 88 Brain Fitness programme 582 brain injury (BI) primary 743 repair/restoration strategies 648 secondary 743 single incident acute in-patient rehabilitation 665, 666 rehabilitation 664–70 traumatic see traumatic brain injury brain metastases chemotherapy 803–4 imaging 786–9, 791–2 radiotherapy 804 surgical resection 799, 804 brainstem 34–7 arteriovenous malformations 131 central herniation 742–3 cranial nerve nuclear columns 36–7 encephalitis 294, 818 gaze centres 59 gliomas 776 haemorrhage 749

infarction 122–3 lesions auditory dysfunction 563–4 bladder dysfunction 898 coma 725 drop attacks 207 sensory loss 102, 104 motor fibres 34–5 reflexes, brain death 735 sensory pathways 35–6 syndromes 101 brain–thyroid–lung syndrome 177 brain tumours 771–812 chemotherapy 802–4 clinical features 772–3 cognitive impairment 279–82, 773, 795 complications of treatment 793–5, Plate 20.10 epidemiology 771–2 epilepsy 201, 773 headache 449, 772 histogenesis 773–4 imaging 218, 778–95 extra-axial tumours 789–93 monitoring 793 peri-tumoral tissue 784 physiological 778–82, 784, Plates 20.6–20.9 structural 778, 779, 780, Plates 20.4–20.5 treatment complications 793–5, Plate 20.10 incidence 771 monitoring 793 multi-disciplinary management 795 organ transplant recipients 926 pathology 773–8 pregnancy 942 radiation-induced 795, 801 radiotherapy 800, 801–2, 803–4 risk factors 772 surgery 795–800 instrumentation and methods 796–7 principles 796 specific tumours 797–800 survival 771–2 see also gliomas; specific types branched-chain α-ketoacid dehydrogenase (BCKD) 717 branched-chain amino acids (BCAA) 717, 718 branchio-otorenal syndrome 571 branch retinal artery occlusion (BRAO) 499, Plate 13.4 branch retinal vein occlusion 499 Brandt–Daroff exercises 559 breast cancer brain metastases 804 malignant meningitis 813, 814 paraneoplastic disorders 816, 817, 818 breastfeeding, in epilepsy 939–40 breathing see respiration brevetoxins 681 Brindley stimulator 899 British anti-Lewisite (BAL) 170 British dementia 276 British Hypertension Society (BHS) guidelines 143 brivudin 860 Broca, Paul 97 Broca’s area 253

Index Brodmann areas 24 bromocriptine 160, 707 Brown-Séquard syndrome 102, 104 Brown–Vialetto Van Laere disease 383 brucellosis 304–5 Brudzinski’s sign 291 bruits, cranial 131 Bruns–Garland syndrome 367, 368 bruxism 209, 766 BSCL2 mutations 357, 358 bulbar function assessment, coma 730 bulbar palsy 101, 483–4 causes 484 intensive care management 750–1 motor neurone disease 378, 380 multiple sclerosis 436–7 vagus nerve lesions 479 bulbo-spinal neuronopathy, X-linked 383 bungarotoxins 681 burden of illness 9–12 cost-of-illness studies 9–10 definitions 9 personal (stigma) 10–11 WHO studies 10 burning feet 855 burning mouth syndrome 857 butyrophenones 843 cabergoline 160 cachectic myopathy, non-necrotic 759 CACNA1A genes 450, 635, 637 CACNA1S genes 397, 398 CADASIL 932–3 cognitive impairment 275, 276 stroke 120, 150 cadherin, epithelial (E-cadherin) 20, 21 caeruloplasmin, serum 169 caffeine hypnic headache 463 intravenous, low CSF volume headache 460 postprandial hypotension 888 Cajal, Santiago Ramón y 13, 14 calcinosis, dermatomyositis 402 calcitonin gene-related peptide (CGRP) 853–4, 906 calcium metabolism, disturbances 919, 920 muscle contraction 388 calcium channel genes see CACNA1A genes; CACNA1S genes calcium channels, voltage-gated see voltage-gated calcium channels calculation assessment 96 deficits 254 Call–Fleming syndrome 941 caloric testing 521, 548–50 brain death 735 clinical value 549–50 closed-circuit and air 549 coma 730 directional preponderance 549 total canal paresis 548 calpainopathy (LGMD2A) 393, 394 Campath-1H (alemtuzumab) 432

Campylobacter, Guillain–Barré syndrome and 362 Canadian Occupational Performance Measure (COPM) 662 canal-lithiasis 552, 553 particle repositioning procedures 559–60 Canavan’s disease 445 cancer 812–21 dermatomyositis 402–3 direct effects 812–14 indirect effects 815–16 intraocular 508 Lambert–Eaton myasthenic syndrome 387, 388 multiple cranial neuropathies 485–6 myopathies 405–6 plexopathies 858–9 see also paraneoplastic neurological disorders Candida albicans 319, 320–1 candidiasis 320–1 cannabis/cannabinoids cerebellar tremor 657 multiple sclerosis 433, 434, 436 pain management 866 spasticity 655, 656 Capgras syndrome 833, 840 CAPRIE trial 145 capsaicin chronic pain 866 intravesical, multiple sclerosis 435 post-herpetic neuralgia 860 carbamazepine epilepsy 222, 224, 231–2 mood stabilization 844 multiple sclerosis 436 pain management 866 pharmacokinetics 225 teratogenicity 938, 939 trigeminal neuralgia 470 carbidopa 158 carbohydrate metabolism, inborn defects 715–16 carbon dioxide tension, arterial blood see PaCO2 carbon disulphide 679 carbon monoxide (CO) poisoning 680 carcinomatosis, dementia 281 cardiac arrest see cardiopulmonary arrest cardiac arrhythmias acute neurological illness 752 autonomic dysfunction 881–2 periodic paralysis and 398 subarachnoid hemorrhage 130 cardiac disease 915–17 coma 733 dermatomyositis 402 drop attacks 207 episodic loss of awareness 205–6 investigations 136–7 secondary anoxic seizures 207 secondary stroke prevention 144 stroke caused by 115–16 valvular 116, 205, 916 cardiac embolism 115–16, 915–17 causes 116, 916 see also stroke, cardio-embolic cardiac monitoring, Guillain–Barré syndrome 362 cardiac output, low 538

cardiac surgery, complications 915 cardiac transplantation 927 cardiomyopathies 916 cardiopulmonary arrest coma after 733, 734 lightning and electrical injuries 685 cardiorespiratory failure 281 cardiorespiratory training 653–4 cardiovascular control 38 cardiovascular disease drop attacks 207 neurological consequences 913–17 cardiovascular system autonomic disorders 875–83, 886–91 monitoring, intensive care unit 751–2 care pathways, integrated 646–7, 663 care plans 647, 661–2 carers, informal dementia 285, 286 motor neurone disease 381 stroke 668 carmustine wafers 802 carnitine palmitoyltransferase-II (CPT-II) deficiency 401, 719 carotico-cavernous fistula (CCF) 511–12, Plates 13.25–13.26 Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) 147 carotid arteries anatomy 111–12 dissection 148–9 occlusion 113, 135–6 radiation-induced damage 683, 801 stenosis see carotid stenosis stenting 146, 147 symptoms of transient ischaemia 117–18 see also internal carotid artery carotid chemoreceptors 38 carotid endarterectomy asymptomatic carotid stenosis 147 complications 146–7 cranial nerve injury after 483 indications 146 secondary stroke prevention 143, 146–7 carotid sinus hypersensitivity 878, 880 management 890 carotid stenosis 120 asymptomatic, management 147 coronary artery bypass grafting and 147, 915 imaging techniques 135–6 lacunar infarction 119–20 measuring severity 136 pathophysiology of stroke 112–13 secondary stroke prevention 146–7 stroke risk 115 symptomatic, management 146–7 carpal tunnel syndrome (CTS) 373, 374–5 hypothyroidism 918 pregnancy 941–2 cassava 682 casting, serial 651 catamenial sciatica 373 cataplexy 207, 763 management 764 cataracts, lightning and electrical injuries 685

951

Index catatonia 833 catechol-O-methyl transferase (COMT) inhibitors 159 catheter-related sepsis 754 cathinone 697 cat scratch disease 498 cauda equina syndrome 105–6 ankylosing spondylitis 603 bladder dysfunction 899 sexual dysfunction 909 signs 615 caudate nucleus 26, 27, 28, 45 haemorrhage 125 causalgia (CRPS type II) 103, 861–2 causation, neurological disease 7–8 cavernous malformations (angiomas, haemangiomas, cavernomas) 132–3 epilepsy 202 imaging 218, 219 radiation-induced 795 spinal 621 cavernous sinus abducens nerve lesions 515 cranial nerve relations 61 oculomotor nerve lesions 513, 514 syndrome 468 thrombosis 151, 152, 468, 510–11 Cawthorne–Cooksey exercises 558 CD4 counts, HIV infection 327, 328, 329 cefotaxime bacterial meningitis 292, 293 Lyme disease 304 ceftazidime, bacterial meningitis 292, 293 ceftriaxone bacterial meningitis 292, 293, 294 Lyme disease 304 cell death, ischaemic stroke 114 cellulitis, orbital 510 central core disease (CCD) 396, 397 Central European encephalitis 315 central nervous system (CNS) infections see neurological infections central nervous system (CNS) tumours 771–812 histogenesis 773–4 molecular pathogenesis 773–4 pathology 773–8 radiotherapy and chemotherapy 800–5 surgical management 795–800 WHO classification 774–8 see also brain tumours; spinal tumours central neurocytomas 784 central pain 848–53 central pontine myelinolysis 753, 757 psychiatric disorders 839 central post-stroke pain (CPSP) (thalamic pain) 105, 849 management 142, 657 central retinal artery 498 occlusion (CRAO) 499, Plate 13.5 central retinal vein occlusion (CRVO) 499 central sensitization 854 central serous maculopathy 490 cerebellar abscess 638 cerebellar ataxia 629–42 acquired syndromes 637–42

952

acute, of childhood 638 age and pattern of onset 629, 630 alcohol abuse 639, 695 autosomal dominant (ADCA) 635–6 autosomal recessive (ARCA) 632–3 clinical approach 629–31 disorders causing 631–42 inherited syndromes 632–7 investigations 630–1 management 656–7 paraneoplastic 641 see also ataxia cerebellar degenerations late onset 641–2 paraneoplastic (PCD) 641, 817 cerebellar disease 99–100 assessment 83–4, 630 drugs causing 639, 704 electronystagmography 547 eye movement disorders 541, 630 infectious causes 638 inflammatory disease 638 metabolic disorders 639 multiple sclerosis 419, 435, 638 signs 31, 630 symptoms 629 toxins and physical agents 639 vascular disease 638–9, 640 cerebellar haemangioblastomas 638–9 cerebellar haemorrhage 125, 131, 749 cerebellar hypoplasia and quadrupedal gait 632 cerebellar infarction 122, 123, 552 management 749 cerebellopontine angle (CPA) syndrome 473–4 cerebellopontine angle (CPA) tumours, hearing loss 578, 581 cerebellum 24, 28–31 afferent pathways 29–30 cellular anatomy 28–9 efferent pathways 26, 30–1 external granular layer (EGL) 777 somatotopic representation 29, Plate 2.2 cerebral abscess 295–6 cancer 816 cognitive impairment 280 epilepsy 203–4 cerebral amyloid angiopathy 259 brain haemorrhage 124–5 cognitive impairment 275, 276 cerebral angiitis, isolated see isolated cerebral angiitis cerebral arteriopathies 932–3 cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy see CADASIL cerebral blood flow (CBF) ischaemic stroke 114 raised ICP 739, 741 traumatic brain injury 746 cerebral blood volume, relative see relative cerebral blood volume cerebral catheter angiography arteriovenous malformations 131–2 intracerebral haemorrhage 126 stroke/TIA 136 subarachnoid hemorrhage 128–9

cerebral contusions and lacerations, haemorrhagic 745, 746 cerebral-evoked potentials 93 cerebral haemorrhage see intracerebral haemorrhage/haematoma cerebral herniation 742–3 cerebral infarction 110 cancer 815 classification 111 cocaine abuse 697 diagnosis 111 at high altitude 687, Plate 18.1 imaging 134–5 ischaemic penumbra 114, 139 pathophysiology 114 see also stroke cerebral ischaemia aortic disease 914 clinical syndromes 117–23 traumatic brain injury 746 see also stroke, ischaemic; transient ischaemic attacks cerebral oedema heat stroke 685 high altitude 686–7, 688, Plates 18.1–18.2 infarction-related cytotoxic 114, 115, 141 ischaemic stroke 114, 115 treatment 141 cerebral palsy, epilepsy 201 cerebral peduncle 34 cerebral perfusion pressure (CPP) 739 ICP waveforms and 740 management 741 traumatic brain injury 746, 747 cerebral salt-wasting (CSW) 130, 753 cerebral vascular malformations (CVMs) 130–3 epilepsy 202, 218 haemorrhage 124, 130–1 cerebral vasculitis, primary see isolated cerebral angiitis cerebral vasoconstriction syndrome 941 cerebral vasospasm, subarachnoid hemorrhage 130 cerebral veins, anatomy 112, 113 cerebral venous (sinus) thrombosis 110–11, 151–3 aseptic 151 Behçet’s syndrome 935, 936 complications 749 differential diagnosis 506 seizures 202 septic 151 cerebrospinal fluid (CSF) drainage, raised ICP 742 examination 93–5 acute disseminated encephalomyelitis 441 Alzheimer’s disease 262 CIDP 363 cognitive impairment 248, 258 encephalitis 313 Guillain–Barré syndrome 361 HIV infection 327 indications 94 Lyme disease 304 malignant meningitis 814 meningitis 291, 292, 299 multiple sclerosis 423, Plate 10.2

Index neuromyelitis optica 438 normal observations/values 95 primary CNS lymphoma 808 subarachnoid haemorrhage 94, 128 see also lumbar puncture low volume headache 460–1 otorrhoea 743 pressure measurement 95 raised, headache 461 rhinorrhoea 726, 743 cerebrotendinous xanthomatosis 277, 635 cerebrovascular accident (CVA) 110 cerebrovascular disease (CVD) 109–53 bladder dysfunction 895–6 cancer 815 cerebellar syndromes 638–9, 640 drugs causing 702 epilepsy 201–2, 218 hearing loss 578–9 non-atherosclerotic 147–53 parkinsonism 164 pregnancy and 940–1 see also stroke; vascular dementia ceroid lipofuscinosis (Kufs) 277 cervical disc surgery 614–15 cervical dystonia (spasmodic torticollis) 166, 171 psychogenic 828 cervical plexopathies diabetic 369 malignant 858–9 cervical spine central cord contusion, without instability 605–6 clinical assessment 588 degenerative disease 588, 614–15 fractures, surgical management 606, 607 injuries, acute management 605 rheumatoid arthritis involving 601–2 see also atlanto-axial instability cervicocephalic dissections 135, 148–9 cestodes 321, 322 C fibres 19, 20, 22, 31, 32 atrophy 854 gate control 40–1 itch and 847 responses to noxious stimuli 853–4 Chagas disease 324, 882 oesophageal dysfunction 883 challenging behaviour dementia 285 learning disability 230 Chamberlain line 593 Chamorro population (Guam), parkinsonism– dementia–amytrophic lateral sclerosis complex 682 Charcot joints 302, 368, Plate 9.6 Charcot–Marie Tooth disease (CMT) 351, 354–7 classification 352–3 clinical approach 352–4 CMT1 (demyelinating) 355 autosomal dominant 352, 355–6 autosomal recessive 353, 356 classic phenotype 355, 357 severe phenotype 355–6 type 1A (CMT1A) 350, 355, 358, Plate 9.1

type 1B (CMT1B) 355 X-linked 353, 356 CMT2 (axonal) 355 autosomal dominant 353, 356–7 autosomal recessive 353, 357 X-linked 353, 357 dominant intermediate 353, 357 genes causing 352–3, 355 genetic diagnosis 358 hearing loss 574–6 and related disorders 352–4 Charcot paralysis 684 CHARGE association 571 Charles Bonnet syndrome 251, 526 cheiralgia paraesthetica 373 chemotherapy brain metastases 803–4 cognitive impairment 282 malignant meningitis 814 neurological complications 821 primary brain tumours 802–3, 809 primary CNS lymphoma 808–9 spinal tumours 804–5 cherry red spots 508 central retinal vein occlusion 499, Plate 13.5 neoplastic infiltration Plate 13.12 Cheyne–Stokes respiration 731–2 Chiari malformations 594–5 chickenpox 149, 313 chloramphenicol, meningitis 292, 293 chloride channel gene mutations 397, 398–9 chlorpromazine 459, 843 cholestanolosis (cerebrotendinous xanthomatosis) 277, 635 cholesteatoma, aural 570 cholesterol emboli, retinal artery occlusion 499, Plate 13.6 lowering therapy 143 choline, brain tumours 780, 783 cholinergic crisis, myasthenia gravis 386 cholinesterase inhibitors (AChEIs) Alzheimer’s disease 262–3 bladder dysfunction and 896 dementia with Lewy bodies 162, 267 Parkinson’s disease dementia 267 vascular dementia 279 chondrosarcomas 811 chorda tympani 65, 66, 472 lesions 474, 475 chordomas 811 histology 778, Plate 20.3 spinal 613, 811 chorea 171–7 assessment 171–2, 173 benign hereditary 177 causes 172 drug-induced 177 drug management 177 early 100 Huntington’s disease 175 investigations 174, 174 chorea gravidarum 942 choreoathetosis drug-induced 703 paroxysmal kinesiogenic 208

choriocarcinoma 810, 942 choroid plexus tumours 775, 786 chronic daily headache (CDH) 458–9 chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) 361, 363–4 diabetes association 369 nerve biopsy 363–4, Plate 9.3 sensory ataxic 364 variants 364 chronic lymphocytic leukaemia (CLL), neuropathies 365 chronic progressive external ophthalmoplegia (CPEO) 400, 401, 512 chronic relapsing axonal neuropathy (CRAN) 364 chronic relapsing inflammatory optic neuropathy (CRION) 497 chronic wasting disease of mule deer and elk 268 Churg–Strauss syndrome 924, 929 neuropathy 366, 367 optic neuropathy 501 stroke 149 ciclosporin inflammatory myopathies 404 myasthenia gravis 385 neurological side effects 926 cidofovir 329 CIDP see chronic inflammatory demyelinating polyradiculoneuropathy ciguatera poisoning 680 ciliary ganglion 59, 72 ciliary muscle 60, 61, 62 cilioretinal artery 498 cingulate cortex 43–4 eye movements 58, Plate 2.3 right anterior (RACC) 39, 40 cingulate gyrus (motor areas 23 and 24) 24, 25, 41, 834 cinnarizine 557 ciprofloxacin, meningococcus prophylaxis 293 circadian oscillator 760 circadian rhythm disorders 765 circle of Willis 112 circle of Zinn–Haller 498 circle sign 373 circumventricular organs 50 cirrhosis, alcoholic 696 CJD see Creutzfeldt–Jakob disease Claude’s syndrome 514 claudication, neurogenic 588–9, 615 claustrum 45 ‘claw hand’ 373 CLCN1 gene mutations 397, 399 clean intermittent self-catheterization (CISC) 658, 901 climbing fibres 28–9 clindamycin, toxoplasmosis 332 clipping, aneurysm 129–30 clobazam dosing regimens 224 epilepsy 222, 231, 234 pharmacokinetics 225 postnatal period 939 clofazimine, leprosy 306 clomipramine, Gilles de la Tourette syndrome 179

953

Index clonazepam dystonia 170 epilepsy 222, 224, 231 myoclonus 182 pharmacokinetics 225 REM sleep behaviour disorder 767 spasticity 655 status epilepticus 235 vestibular disorders 558 clonic seizures 193 clonidine hyperhidrosis 891 tics 179 clopidogrel, stroke prevention 145–6 Clostridium botulinum 307 Clostridium tetani 308 clozapine 162, 843 cluster headache 455–7 chronic 459 management 456–7 pathophysiology 450, Plates 11.1–11.2 CMT see Charcot–Marie Tooth disease coagulation disorders 922 coat-hanger pain 852, 875–7 Cobb angle 589 co-beneldopa 158 cocaine abuse 697 complications 697–8 stroke 115, 124, 127, 697 Horner’s syndrome diagnosis 531 co-careldopa 158 coccidiomycosis 319, 320 cochlea 68, 69, 564 cochlear implants 581–2 cochlear microphonics 568 cochlear nerve see auditory nerve cochlear nuclei 68, 69 Cockayne’s syndrome 633 codeine, acute migraine 454 coeliac disease 923 ataxia and 641 dementia and 284 neuropathy 369 coeliac ganglion 872 coenaesthetic hallucinations 833 coenzyme Q10 401 Cogan’s lid twitch sign 384 Cogan’s syndrome 573, 574 cognitive affective cerebellar syndrome 31 cognitive assessment 77–9 cognitive behavioural therapy traumatic brain injury 660 vestibular disorders 561 cognitive impairment 245–86 autonomic dysfunction 884–5 brain tumours 279–82, 773, 795 clinical syndromes 247–55 drugs causing 246, 701, 702 epilepsy and 189, 217 Huntington’s disease 175, 267 investigations 256–8 mild see mild cognitive impairment motor neurone disease 381 multiple sclerosis 248, 419, 436

954

radiation-induced 282, 683 rehabilitation strategies 659 vitamin deficiencies 690 cognitive loop, basal ganglia 27 COL1A gene mutations 591 COL4 gene mutations 572 COL6A gene mutations 395 cold injury, non-freezing 686 collagen vascular disease see connective tissue disease collateral circulation, ischaemic stroke and 113, 114 Collet–Sicard syndrome 479 Collier’s sign 518, 529, 728 colloid cysts 812 colour saturation, assessment 491 colour vision assessment 79, 491 pathway 57, 58 perceptual disorders 250, 527–8 retina 54–5 coma 723–34 acute initial management 723, 725 assessment 725, 726–32 barbiturate-induced, raised ICP 742 causes 723, 724, 725 cerebral malaria 325 definition 724 depth 733 determining brain death 735–6 drug induced 702, 733 duration 733 eyes open 727 metabolic and toxic 732 outcome 733–4 post-anoxic 732, 733 commissural nucleus 70, 71 common carotid artery 111, 913, 914 common peroneal nerve anatomy 340, 346, 347 neuropathies 376–7 communication aids, motor neurone disease 381 intensive care unit 738, 755 community-based rehabilitation 668 compartment syndrome, rhabdomyolysis 408 compensatory treatment strategies 649 complementary medicine, multiple sclerosis 438 complex regional pain syndrome (CRPS) 860–2 type I 861–2 type II (causalgia) 103, 861–2 complex repetitive discharges, EMG 90 compound muscle action potentials (CMAPs) 91 compressive neuropathies 372–7 alcohol abuse 695–6 nerve conduction studies 91 computed tomography (CT) 86 angiography, subarachnoid hemorrhage 129 brain tumours 778, 780 cognitive impairment 257 epilepsy 217 intracerebral haemorrhage 126 radiotherapy planning 800 stroke 134 subarachnoid hemorrhage 128 transient ischaemic attacks 134

cone dystrophies 507–8 cone–rod dystrophy 508 cones 53, 54 heterogeneity 55, 56 confabulation 249 confusional arousals 766 confusional states acute 724 alcohol abuse 695 differential diagnosis 211–12 drugs causing 701 epileptic 217, 836 see also delirium congenital hypomyelinating neuropathy (CHN) 355–6 congenital insensitivity to pain with anhidrosis (CIPA) 354, 358 congenital malformations, maternal epilepsy and 938–9, 940 congenital muscular dystrophies 393 congenital myasthenic syndromes (CMS) 387 congenital myopathies 396–7 coning complicating lumbar puncture 94 ischaemic stroke 114, 141 conjugate eye movements see eye movements, conjugate connective tissue disease 931–2 inflammatory myopathies 404–5 renal and neurological involvement 924 stroke 150 trigeminal sensory neuropathy 471 connexin 26 gene mutations 570 connexin 32 (Cx32) 20, 21 gene mutations 356 consciousness 723 clouding of 724 level, assessment 726–7 states of impaired 723–35 cerebral herniation 742, 743 critical care settings 755–6 definitions 724 episodic, differential diagnosis 205–6 lightning and electrical injuries 684 raised ICP 739 seizures 190, 191 subarachnoid haemorrhage 127 see also coma constipation acute neurological illness 754 autonomic dysfunction 883 management 658 constraint induced movement therapy (CIMT) 652–3, 671 continence adviser/specialist nurse 901 continuous positive airways pressure (CPAP) 738, 764 contractures, management 654–5 contrecoup injury 745, 746 controlled mechanical ventilation (CMV) 738 contusions, haemorrhagic cerebral 745, 746 conus medullaris lesions 106 bladder dysfunction 899 sexual dysfunction 909 conversion disorders 107, 824 convulsive movements, generalized 207

Index coordination, testing 83–4 copper deficiency 696 hepatic concentration 169 urinary excretion 169 coprolalia 177 Cori’s disease (GSD type III) 715 corneal reflex anatomical basis 64, 65, 468 brain death 735 coma 730 examination technique 80–1 Vth nerve lesions 36, 468, 471 corneopterygoid reflex 730 coronary artery bypass grafting (CABG) 147, 915 corpus callosotomy 239 auditory processing disorders after 580 corpus callosum, agenesis of 200 corpus striatum see striatum cortical areas, Brodmann’s 24 cortical blindness 250, 525 cortical deafness 251, 580 cortical disorders bladder dysfunction 895 focal 97–9 sexual dysfunction 906–7 cortical dysplasia epilepsy 199–200 focal 199, 218, 238 cortical-evoked auditory responses 568 cortical eye fields 57–9, Plate 2.3 cortical hearing impairment 580 cortical mapping, tumour resection 798 cortical venous thrombosis 151, 152 cortical visual impairment 528 cortico-basal degeneration (CBD) 163 apraxia 252 clinical features 248 cognitive impairment 267 differential diagnosis 163–4 myoclonus 181 neuropathology 265, Plate 7.1 speech and language deficits 253 cortico-bulbar motor fibres 34 cortico-fugal fibres 34 corticospinal (pyramidal) system 24–6 cortical contribution 25 motor pathways 25 plasticity 26 signs of damage 24 corticospinal tracts (pyramidal tracts) 24, 25 aberrant, mirror movements 598–9 malformation 599–600 corticosteroids acute disseminated encephalomyelitis 441 Bell’s palsy 475 CIDP 364 giant cell arteritis 501 herpes zoster 471, 860 inflammatory myopathies 404 Ménière’s disease 557 multiple sclerosis 427–8 myasthenia gravis 385 myopathy induced by 407–8, 760 neuro-Behçet’s syndrome 936

neuromyelitis optica 439 optic neuritis 496 primary CNS lymphoma 808, 809 sarcoidosis 934 side effects 428 spinal cord injury 605 tuberculous meningitis 300 vasculitic neuropathies 367 see also dexamethasone; methylprednisolone; prednisolone/prednisone Corynebacterium diphtheriae 307 Costeff ’s syndrome 633 cost-of-illness studies 9–10 costs in developing countries 11 direct 9–10 indirect 10 co-trimoxazole, Toxoplasma prophylaxis 328 cough, bovine 478 cough reflex 72, 730 coup de sabre 477 cover test 539 coxsackie viruses 310, 314 cramps 389, 862 drug-induced 704 EMG features 90 nocturnal leg 766 cranial accessory nerve (XI) 70, 71 cranial nerve(s) 51–72 examination 79–82 motor fibres to nuclei 34 nuclear columns 36–7 tumours 775 see also specific nerves cranial nerve disorders bulbar and pseudobulbar palsy 483–5 coma 727–30 diabetes 369 extraocular muscles 512–16 Lyme disease 303 multiple (MCN) 485–7 peripheral nerve disease 349 sarcoidosis 934 Sjögren’s syndrome 930 syndromes involving lower four 479 tumour invasion 813 cranio-cervical junction anomalies 593–600 causes 593 clinical assessment 587–8 pathophysiology 593 rheumatoid arthritis 601–2 surgical management 593–4 cranio-pharyngiomas 807–8 craniosynostoses 591 CRASH trial 605 creatine kinase (CK) 390 inflammatory myopathies 403 rhabdomyolysis 408 Cre-recombinase-mediated transgenesis 586 Creutzfeldt–Jakob disease (CJD) 267–8, 276 ataxic 269, 638 atypical forms 269 epilepsy 202 Heidenhain’s variant 269 iatrogenic 268, 269, 270

investigations 258, 269 myoclonus 181, 185–6 pain 851–2 panencephalopathic 269 sporadic 268, 269, 270 subacute myoclonic 269 variant (vCJD) 268, 269, 270–1 prevention 273 secondary (iatrogenic) 272 cristae 66, 67, 535 critical illness neurological complications 755–60 neuromyopathy 371 polyneuropathy (CIP) 758–9 see also intensive care unit; neurological intensive care unit crocodile tears 476, 884 Crouzon’s syndrome 571, 591 CRPS see complex regional pain syndrome crutch palsy 373 cryoglobulinaemia, type II (mixed) 367 Cryptococcus neoformans (cryptococcal) meningitis 319, 320 cancer 816 HIV infection 329, 332 organ transplant recipients 925 CSF see cerebrospinal fluid CT see computed tomography CTDP1 mutations 356 Cuban epidemic neuropathy 369–70, 696 Cuban epidemic optic neuropathy 504 cubital tunnel syndrome 373 cued speech therapy 581 cueing, visual and auditory 652 cuneate fasciculus (CF) 32, 33 cuneate nucleus 33, 35 cupula 66, 67 cupulo-lithiasis 553 particle repositioning procedures 559–60 Cushing’s disease 920 Cushing’s syndrome 806, 920 myopathy 406 Cushing’s triad, raised ICP 739 cutaneous nerves of thigh 345, 346 cyanide poisoning 679, 682 cycad palm 682 cyclic nucleotide phosphodiesterases (CNPs) 20, 21 cyclophosphamide inflammatory myopathies 404 isolated cerebral angiitis 931 multiple sclerosis 432 vasculitis 367, 929 cyclosarin 688–9 cysticercosis (neuro-cysticercosis) 321–4 epilepsy 204, 218, 323 stroke 149 cytomegalovirus (CMV) infections encephalitis 313, 329 HIV infection 329, 332 lumbosacral polyradiculopathy 329 mononeuritis multiplex 329 retinitis 329 daclizumab, multiple sclerosis 433 da Costa’s syndrome 878

955

Index dantrolene malignant hyperthermia 705 multiple sclerosis 434 neuroleptic malignant syndrome 707 spasticity 655–6 dapsone, leprosy 306 darifenacin 896 DDAVP see desmopressin deafness see hearing loss decarboxylase inhibitors, peripheral (PDIs) 158 decerebrate posturing 732 decompression sickness (DCS) 686 decompressive neurosurgery infarction-related cerebral oedema 141 raised ICP 742 traumatic brain injury 746, 747 decorticate posturing 732 deep brain stimulation (DBS) chronic pain 867 dystonia 171 epilepsy 239 myoclonus dystonia 182 Parkinson’s disease 161–2 tics 179 tremor 161, 165, 657 deep haemorrhage 125 deep peroneal nerve 346 deep vein thrombosis complicating stroke 142 prophylaxis, acute stroke 140 Degos disease 933 Dejerine–Sottas disease 355–6 delayed sleep phase syndrome 765 delirium 724 cancer 815 causes 246 drugs causing 701 epidemiology 245 investigations 256–8 management 284 postictal 836 visual phenomena 526 vs. dementia 245 delirium tremens 693 delta activity, EEG 88, 760, 761 delusions 210, 832–3 dementia 245–86 alcohol abuse 281, 284, 695 Alzheimer’s type see Alzheimer’s disease behavioural management 285 bladder dysfunction 896 carers 285, 286 causes 246 clinical features 248 co-morbidity, management 284–5 controversial entities 283–4 cortical 245 definitions 245 dialysis 677, 756, 924 distinction from delirium 245 early onset 247, 259 end of life issues 286 epidemiology 7, 245–7, 259 epilepsy and 202, 280, 282, 285 hysterical 841

956

inherited 276–8 investigations 256–8 management 284–6 mixed 123, 273 movement disorders with 267 multi-infarct 123, 274 pain and 851–2 Parkinson’s disease see Parkinson’s disease dementia reversible causes 279–83 risk factor management 284 safety 285–6 specific types 259–84 subcortical 245 urinary incontinence 896 vascular see vascular dementia young adults 276–8, 279 see also specific types dementia lacking distinctive histology (DLDH) 265, 266 dementia pugilistica 284 dementia with Lewy bodies (DLB) 162, 266–7 clinical features 248, 266–7 cognitive deficits 249, 250, 266 hallucinations 251, 266 myoclonus 181 psychiatric disorders 838 demyelinating diseases 411–45 demyelination focal and compressive neuropathies 372 multiple sclerosis 413, 415, Plate 10.1 nerve conduction studies 91 peripheral 348 dendrites 13 dendropsia 527 denervation chronic partial, EMG features 89 fibrillation potentials 89–90 dengue 315 dense core vesicles 16, 18 dental disease, vs. trigeminal neuralgia 469 dentate gyrus 41, 42 dentate nucleus 28, 30–1, 41 dentato-rubro-olivary region (Mollaret’s triangle) 165, 522 dentato-rubro-pallido-luysian atrophy (DRPLA) 173, 175, 176 ataxia 636 dementia 276 epilepsy 198 myoclonus 181 dentato-rubro-thalamic tract 30–1, 35 depersonalization syndrome, phobic anxiety 829–30 depolarization 20 depression after epilepsy surgery 237 alcohol abuse 695 Alzheimer’s disease 260–1 clinical features 831 dementia and 284–5 drugs causing 701 epilepsy 832, 836 hallucinations 833 Huntington’s disease 838 management 659–60

multiple sclerosis 436, 832, 839 in neurological disorders 824, 831, 832 Parkinson’s disease 157, 831, 832, 838 post-stroke 142, 659–60, 832 dermatomes 103, 104, 344 dermatomyositis (DM) 402–3, 820 investigation 403–4, Plate 9.10 sine myositis 402 treatment 404 dermoid cysts 789, 811 designer drugs 697 desmopressin (DDAVP) bladder dysfunction 657–8 multiple sclerosis 435 neurogenic urinary incontinence 901–2 orthostatic hypotension 887–8 desmoteplase, acute ischaemic stroke 139 detrusor hyperactivity with impaired contractile function (DHIC) 896 detrusor over-activity (DO) (detrusor hyper-reflexia) dementia 896 management 657–8, 896, 900–2 multiple sclerosis 435, 899 multiple system atrophy 897 Parkinson’s disease 157, 897 spinal cord disease 898–9 stroke 895–6 detrusor–sphincter dyssynergia autonomic disease 883 management 657–8 spinal cord disease 898–9 developing countries 11 Devic’s disease see neuromyelitis optica dexamethasone altitude illness 687, 688 bacterial meningitis 294 brain metastases 804 dexamfetamine abuse 696 narcolepsy 764 DFN gene mutations 570 diabetes insipidus 919 diabetes mellitus 918 acute metabolic disturbances 918 associated neuropathies 369 hearing loss 572 heart rate disturbances 882 secondary stroke prevention 143 sexual dysfunction 909 stroke risk 115 diabetic amyotrophy see diabetic lumbosacral plexopathy diabetic ketoacidosis 918 diabetic lumbosacral plexopathy 367, 368, 856 diabetic neuropathies 368–9, 918 acute reversible hyperglycaemic 369 autonomic 368 bladder dysfunction 900 classification 368 distal symmetric sensory (DSSN) 368 focal and multifocal mononeuropathies 369 insulin neuritis 369 painful 855–6 vasculitic plexopathies 368–9

Index diabetic papillopathy 501 diagnosis elements of 75–6 formulation 85–6 diagnostic overshadowing, learning disability 230 diagnostic tests 86–96 diagonal band of Broca 45 dialysis dementia (dialysis encephalopathy) 677, 756, 924 dialysis disequilibrium syndrome 756, 924–5 3,4-diaminopyridine Lambert–Eaton myasthenic syndrome 388 multiple sclerosis 434 vestibular disorders 558 diaphragm, examination 84 diarrhoea acute neurological illness 754 autonomic dysfunction 883, 891 Diazemuls® 234 diazepam epilepsy 222, 231, 234 spasticity 655 status epilepticus 235 vestibular disorders 557 dichotic tests 569 didanosine, toxic neuropathy 334 DIDMOAD (Wolfram syndrome) 572, 918 diet inborn errors of metabolism 717, 721 multiple sclerosis relapse and 418 diffuse axonal injury (DAI) 745–6 diffuse inflammatory lymphocytosis syndrome (DILS) 334 diffusion tensor imaging (DTI), brain tumours 779–80 diffusion-weighted magnetic resonance imaging (DWI) 794, 795 brain metastases 789, 791–2 cerebral infarction 119, 121, 135 meningioma grading 789 primary brain tumours 779–80, 781–2, 784, 787–8 tumour treatment complications 795, Plate 20.10 digital subtraction angiography (DSA), subarachnoid hemorrhage 129 dihydroergotamine (DHE) benign exertional headache 462 chronic daily headache 459 migraine 454 orthostatic hypotension 886 l-threo-3–4-dihydroxyphenylserine (DOPS) 887, 889 dilator pupillae 61, 62 diltiazem, sex headache 463 dioxin 689 diphtheria 307 diplopia 490, 508–16 assessment 79–80, 509 binocular 508 chiasmal disease 523 horizontal 509 monocular 508 multiple sclerosis 419 torsional 509, 516 vertical 509

dipyridamole, stroke prevention 145 disabilities 660–1 frequency 2 single incident brain injury 665 vocational rehabilitation 664 disability-adjusted life years (DALYs) 9, 10 Disability Discrimination Act 664 Disability Employment Advisors (DEAs) 664 disinhibition 98, 255 fronto-temporal dementia 264 disseminated intravascular coagulation (DIC), cancer 815 dissociative amnesia 841 dissociative disorder 107 dissociative seizures see non-epileptic attack disorder distal acquired demyelinating sensory neuropathy (DADS) 364 distal hereditary motor neuropathies (dHMN) 352, 354, 358 distal motor latency (DML) 91 distal myopathies 396 distal sensory peripheral neuropathy (DSPN), HIV infection 331–4 distal symmetric sensory neuropathy (DSSN), diabetic 368, 856 diuretics, idiopathic intracranial hypertension 506 diving 686 Dix–Hallpike manoeuvre 543–4, 552 dizziness 533 diagnostic strategy 537 epidemiology 533 general medical causes 538 mechanisms 536–7 migraine-related 554, 558 presyncopal 536 psychological 537 see also vertigo DJ1 mutations 156 DNA repair defects, ataxic disorders 633 doll’s head manoeuvre 728–30 domoic acid 681 domperidone migraine 455 Parkinson’s disease 160 donepezil, Alzheimer’s disease 262–3 dopamine 44, 73 bladder control 897 sexual function and 907 dopamine agonists adverse effects 160 Parkinson’s disease 160–1 prolactinomas 807 restless legs syndrome 184, 765 dopamine antagonists, movement disorders 183, 703 dopamine β-hydroxylase (DBH) deficiency 886–7 orthostatic hypotension 876, 887 treatment 887, 889, 891 dopamine dysregulation syndrome 838 dopaminergic cell transplants, Parkinson’s disease 162 dopamine transporter (DaT) scanning 87, 158, 164 dopa-responsive dystonia (DRD) 167

Doppler ultrasound brightness-mode 87 stroke/TIA 136 dorsal columns see posterior columns dorsal midbrain syndrome see Parinaud’s syndrome dorsal nerve of penis/clitoris 345 dorsal respiratory nucleus 37–8, 71 dorsal root entry zone (DREZ) 31 lesions 103–4 surgical lesioning 851, 867 dorsal root (posterior root) ganglia 31, 32 termination of afferents 31–3 dorsal root ganglionitis 818 dorsal scapular nerve 338 dosulepin (dothepin) chronic daily headache 459 migraine prevention 453 double cortex syndrome 200 double vision see diplopia Down syndrome atlanto-axial instability 594, 597 hearing loss 571 doxycycline, Lyme disease 304 Dravet syndrome 197 driving fitness dementia 261, 285–6 epilepsy 240–1 narcolepsy 764 drop attacks 207–8 atonic seizures 194 idiopathic 208 dropped head syndrome 485 drug abuse 696–700 athletes 700 epidemiology 696 hallucinogens 699 infective endocarditis 309 investigation 700 sedatives 698–9 solvents see solvent abuse stimulants 696–8 stroke risk 115, 124 subarachnoid haemorrhage 115, 127 wound botulism 307 drug reactions, adverse 700–8 autonomic dysfunction 704, 874 cerebellar disease 639, 704 chorea 177, 703 cognitive impairment 246 delirium 246, 701 dementia 246 dizziness 537 flashbacks 210 meningitis 311 movement disorders 183, 702–3 myasthenia-like syndromes 384, 705 myoclonus 182 myopathies 406–8, 706 organ transplant recipients 926 ototoxicity 572, 704 peripheral neuropathies 370, 704 seizures 700, 842 sleep disorders 702, 762 tremor 165, 703 seizures 843

957

Index drusen, optic disc 505, Plate 13.16 Duane’s syndrome 514–15 Duchenne muscular dystrophy 391, 392–3 duloxetine 865 Duodopa 158–9 dural arteriovenous fistulae (DAVF) intracranial 133 spinal 153, 621, 622, 623 dural ectasia, spinal, NF1 612 dural sinuses 112 dural tail sign, meningiomas 779, 789 dynactin (DCTN1) gene mutations 358 dynein 14 dysaesthesia 848 dysarthria 97 cortical 97 management 659 motor neurone disease 381 dysautonomia acute 362 familial (Riley–Day syndrome) 358, 874, 900 dyscalculia 254 dysdiadochokinesia 83 dysembryoplastic neuro-epithelial tumours (DNET or DNT) epilepsy 201, 218 imaging 218, 786, 789 surgical resection 238 dysferlin 389 dysferlinopathy (LGMD2B) 393, 394 dysgeusia 251 drugs causing 702 dysgraphia see agraphia dyskinesias 100 drug-induced, Parkinson’s disease 158–9, 160 paroxysmal 170 tardive 183, 703 dyslexia 97, 98, 254 central 254 peripheral 254 phonological 254 surface 254, 264 see also alexia dysmetria, testing 83 dysosmia see anosmia/dysosmia dysostosis 591 dysphagia autonomic disease 883, 891 management 659 motor neurone disease 380 multiple sclerosis 436 post-stroke 141–2 dysphasia see aphasia dysphonia 97 vagus nerve lesions 478, 479, 480 dysphoria, pre-ictal 836 dysphoric disorder, interictal (IDD) 836 dysprosody 840 dyssomnias 761–3 dysthymic disorder 831 dystonia 165–71 cervical see cervical dystonia classification 166 complicating stroke 142, 168 cranio-cervical 166–7

958

diagnosis 100 differential diagnosis 207 dopa-responsive (DRD) 167 drug-induced 159, 183, 702, 703 epidemiology 166 exercise-induced leg 158 focal or segmental 166–7 genetic syndromes 167 investigations 170 laryngeal 166 myoclonus see myoclonus dystonia neurophysiological tests 185 nocturnal paroxysmal (NPD) 767 primary 166–7 psychogenic 182–3, 828 secondary/heredodegenerative 166, 168–70 during sleep 767 surgery 171 tardive 183 treatment 170–1 dystonia musculorum deformans 166 dystonia-parkinsonism, X-linked (Lubag) 164 dystonia-plus syndromes 167–8 dystonic tremor 164–5, 185 dystroglycans 388, 389 dystrophia myotonica see myotonic dystrophy dystrophin 388, 389, 392 dystrophinopathies 392–3 DYT1 gene deletion 166, 167 DYT5 gene mutations 167 DYT11 gene mutations 167–8 ear 68, 69, 564 clinical examination 565–6 disorders 562 middle see middle ear early onset distal myopathy (EODM) 396 Eastern equine encephalitis 315 Ebola fever 315 E-cadherin 20, 21 Echinococcus 322 echocardiography, cardiogenic embolism 136–7 echolalia 177 echopraxia 177, 255 echoviruses 310, 314 eclampsia 937–8 posterior reversible leucoencephalopathy 757–8 economics 9–10 multiple sclerosis 411–12 single incident brain injury 665 ecstasy 697 ECT (electroconvulsive therapy) 844 Edinger–Westphal nucleus 59, 60, 61, 524 edrophonium, Tensilon test 384–5 EEG see electroencephalography EGFR gene 776 EGR2 gene mutations 355, 356 Ehlers–Danlos III 878, 881 eighth (VIII) nerve see vestibulo-cochlear nerve ejaculation 906 ejaculatory disorders 883–4, 907–8 elderly anosmia 466 carotid sinus hypersensitivity 878 intervertebral disc degeneration 616

orthostatic hypotension 877 post-herpetic neuralgia risk 860 urinary incontinence 896 electrical injuries 683–5 complications 684–5 mechanisms of damage 684 electrical stimulation physiotherapy techniques 652 see also neurostimulation therapies electrical synapses 16 electro-acoustic tests 567–8 electro-cochleography (ECochG) 568 electroconvulsive therapy (ECT) 844 electroencephalography (EEG) 87–9 absence seizures 191, 193 Alzheimer’s disease 258, 262 antiepileptic drug effects 215 antiepileptic drug withdrawal 215, 229 artefacts 88 benign partial epilepsy syndromes 195–6 clinical interpretation of reports 88–9 cognitive impairment 248, 258 coma 733, 734 Creutzfeldt–Jakob disease 269, 271 epilepsy 88, 212–17 classification 213–15 cognitive deterioration 217 diagnosis 204, 212 predicting seizure recurrence 215, 221 pre-operative evaluation 215–16, 237 epileptiform phenomena 88, 212 forced normalization 837 intensive care patients 216 Lennox–Gastaut syndrome 196 long-term monitoring (LTM) 215 myoclonus 185–6 routine testing 212–13 sleep stages 760, 761 status epilepticus 216 tonic seizures 193 videotelemetry 87, 215 electrolyte disturbances 919, 920 electromyography (EMG) 89–91 congenital mirror movements 598–9 movement disorders 184–5, 186 muscle disease 90, 390–1 parkinsonism 164 urethral sphincter 897–8 electronystagmography (ENG) 546–7, 549 electrophysiological tests see neurophysiological tests eletriptan, migraine 454 eleventh (XI) nerve see accessory nerve ELLDOPA trial 158 embolism cardiac see cardiac embolism gas, in divers 686 infective endocarditis 309 ischaemic stroke 112–14 paradoxical 116 retinal artery occlusion 499, Plate 13.6 embryonal tumours 775 emerin 393 Emery–Dreifuss muscular dystrophy 392, 393 EMG see electromyography

Index emotions defective processing 255 James–Lange hypothesis 834 neuro-anatomical concepts 834–5 employment 664, 669 empyema, subdural 296–7 encephalitis 289, 312–14 brainstem 294, 818 cognitive impairment 280 epilepsy after 203 viruses causing 312–14, 315 encephalitis lethargica 280 encephalomyelitis acute disseminated see acute disseminated encephalomyelitis paraneoplastic (PEM) 817–18 post-infectious disseminated 638 with rigidity 184 encephalopathy acute, causes 211 chemotherapy-induced 821 critical care settings 756–8 drugs causing 701 organ transplant recipients 926, 927 post-vaccination 201 see also specific types endocarditis infective see infective endocarditis Libman–Sacks 116, 150 non-bacterial thrombotic (marantic) 815 endocrine disorders 917–20 brain tumours 773 dementia 281 myopathies 406 peripheral neuropathies 368–9 pituitary tumours 806 endolymph 66, 67, 535 endolymphatic hydrops see Ménière’s disease endoneurium 347, 348 endoscopic third ventriculostomy 748 endovascular treatment acute ischaemic stroke 139 aneurysms 129–30 arteriovenous malformations 132 carotid stenosis 147 dural arteriovenous fistulae 133 vertebral artery stenosis 147 entacapone 159 enteral nutrition acute neurological illness 754 dementia 285 motor neurone disease 381 post-stroke 142, 659 enteroception 31 enteroviruses acute flaccid paralysis 316 encephalitis 314 meningitis 310, 311 entorhinal cortex 41, 42, 43, 834 entrapment neuropathies see compressive neuropathies environmental factors 7–8 eosinophilia myalgia syndrome 405 eosinophilic myopathic syndromes 405 ependyma 18

ependymomas 777 chemotherapy 805 grading 777 imaging 784, Plate 20.5 radiotherapy 804 spinal 611, 613, 799 ephedrine 886 epidemiology, neurological disease 1–9 epidermoid cysts (tumours) 793, 811 epidural abscess intracranial 297–8, 487 spinal 297, 298, 617 epidural haematomas, spinal 620–1, 623 epilepsia partialis continua 179, 208, 732 epilepsy 189–241 absence 191–3 benign childhood occipital see benign childhood occipital epilepsy causes 197–204 chronic, treatment protocol 227–8 clinical presentation 205, 207, 208, 209 complex (polygenic) inheritance 197 cortical dysplasia 199–200 definition 189 dementia and 202, 280, 282, 285 depression 832, 836 diagnosis 204–5, 212 before initiating therapy 220 learning disability 230 differential diagnosis 204–12, 826–8 driving regulations 240–1 EEG see electroencephalography epidemiology 6, 189 fertility rates 9, 189, 936–7 forced normalization 837 generalised with febrile seizures (GEFS) 197 idiopathic (IGE) 195, 213 gestational 937 with grand mal seizures on awakening 195 idiopathic 197–200 ILEA classification 194–7 imaging 217–20 incidence 3, 6, 7, 189 information for patients 241 intractable 227–8, 234–6 investigations 212–20 medical treatment 220–31 deciding to initiate 220–1 emergency 234 in learning disability 229–31 patients in remission 228–9 protocol for chronic disease 227–8 protocol for initiating 221–7 see also antiepileptic drugs mortality 8 multiple sclerosis 419 myoclonic see myoclonic epilepsy neurocutaneous syndromes 199 non-epileptic seizures 826 pain 853 partial (focal) benign syndromes 195–6 classification by site 191, 192 drug treatment 223

EEG features 214–15 sensory 105 see also specific types post-traumatic 202–3 preconception care 940 prevalence 5, 7, 189 psychiatric disorders 835–7 risk factors 8 sexual dysfunction 906–7 single gene disorders 197–9 sleep and 767–8 specialist centres 239–40 startle 181 stigma 11 sudden unexpected death (SUDEP) 189, 236 surgery 234–9 cognitive impairment after 282 curative resective 236, 238–9 follow-up 239 palliative 236, 239 pre-operative evaluation 215–16, 236–8 selection criteria 236 symptomatic 200–4 treatment gap 11 tumour-associated 201, 773 women of childbearing age 936–40 see also specific types epilepsy centres 240 epilepsy clinics 239–40 epileptic myoclonus 179, 180 epileptic syndromes benign partial 195–6, 213–14 definition 194 drug treatment 223 EEG for classification 213–15 ILEA classification 194–7 epineurium 346 episodic ataxia 636–7 type 1 637 type 2 558, 637 episodic (temper) dyscontrol 98, 829 episodic nocturnal wanderings 766, 768 Epley particle repositioning procedure 560, 561 Epstein–Barr virus (EBV) encephalitis 313–14 multiple sclerosis and 412 primary CNS lymphoma (PCNSL) 328 Equitest balance platform 550 erectile dysfunction (ED) management 909 neurological causes 906, 907, 908, 909 erection, penile 906 ergotamine benign exertional headache 462 migraine 454, 455 sex headache 463 erythema migrans (EM) 302, 304 erythromelalgia 855 erythromycin, syphilis 302 erythropoietin, orthostatic hypotension 888 Escherichia coli meningitis, in neutopaenic patients 816 esophoria 539 esotropion 539 ESPRIT trial 145

959

Index essential tremor (ET) 100, 164, 165 ethambutol 299–300 ethanol see alcohol ethionamide 299 ethnic differences 7 stroke 109 ethosuximide 222, 232 dosing regimens 224 pharmacokinetics 225 ethyl alcohol see alcohol ethylene glycol 693 ethylene oxide 678 European Atrial Fibrillation Trial 144 European Carotid Surgery Trial (ECST) 136 European Stroke Cooperative Study, Second (ESCS-2) 145 evoked potentials coma 733, 734 multiple sclerosis 423 excessive daytime somnolence (EDS) 762, 763 management 764 excitatory post-synaptic potentials (EPSP) 18 executive dysfunction 254–5 executive function, assessment 96 exercise induced hypotension 877, 878 testing, muscle diseases 391 training, rehabilitation 653–4 exophoria 539 exotropion 539 Expanded Disability Status Scale (EDSS) 417 exploding head syndrome 766 explosive personality 829 extensor plantar response 84 external anal sphincter, nerve to 345 external auditory meatus (EAM), examination 565 external carotid arteries 112 exteroceptive sensation 31 extracranial arteries 111–12 extradural haematoma (EDH) 743–4 extraocular muscles assessment of weakness 79–80 motor innervation 60–1 motor units and sensory connections 61 myopathies 512 paresis 540 extrapyramidal, use of term 24, 26 extrapyramidal disorders, sleep disturbances 767 ‘extrapyramidal pathways’ 24, 26 extrapyramidal signs/syndromes 24, 26 eye(s) autonomic disease 884, 892 dysconjugate deviation 727, 728 horizontal conjugate deviation 728 horizontal misalignment 539 skew deviation 519, 539–40 sympathetic pathway 61–2 vertical misalignment 539–40 eyelid opening, coma 727 eye movement disorders 508–23 assessment 539–46 central 517–19 cerebellar disease 541, 630 coma 727–30 differential diagnosis 209

960

Huntington’s disease 175 idiopathic intracranial hypertension 506 see also diplopia; nystagmus eye movements 535–6 changing angle of gaze 536 clinical assessment 79–80, 539–46 conjugate 540 neuro-anatomy 57–9, 59 vertical, in coma 728, 729 disconjugate 540 recording 546–8 spontaneous, coma 728–30 spontaneous roving, coma 728 stabilizing angle of gaze 536 vestibulo-ocular reflex 535 Fabry’s disease 277, 710–13 pain 856 stroke 150, 713 face, sympathetic pathway 61–2 face perception 57, 58 impaired see prosopagnosia facial canal syndrome 474 facial colliculus 64 facial expression, muscles of 64–5 facial movements, involuntary 209, 476–7 facial myokymia 477 facial nerve (VII) 472–7 anatomy 37, 64–5, 472 examination 81, 472–3 motor nucleus 34, 472 parasympathetic fibres 72–3 principle branches 472, 473 reflexes involving 65 facial nerve (VII) lesions 472–7 cerebellopontine angle syndrome 473–4 coma 730 at and distal to stylomastoid foramen 474–6 facial canal syndrome 474 nuclear 473 supranuclear 473 facial pain, atypical 456, 471–2 facial pallor, autonomic dysfunction 882 facial palsy/weakness acute, causes 475 assessment 81, 473 bilateral 476 facial canal syndrome 474 HIV infection 475 Lyme disease 303, 304, 475, 476 recurrent 476 supranuclear 473 vestibular schwannoma resection 812 see also Bell’s palsy facial sensory symptoms non-specific 471 trigeminal neuropathy 471 facial vascular changes, autonomic dysfunction 882–3 facioscapulohumeral muscular dystrophy (FSHD) 394–5 diagnostic strategies 391, 392 hearing loss 577 factitious disorders 107, 826, 827 factor VII, recombinant activated 126

factor V Leiden 117 faecal incontinence dementia 285 myotonic dystrophy 900 fainting see syncope falls carotid sinus hypersensitivity 878, 880 orthostatic hypotension 877 famciclovir, herpes zoster ophthalmicus 471 familial amyloid polyneuropathy (FAP) 352, 358 apolipoprotein A-1 related 359 autonomic dysfunction 874 gelsolin-related 360, 476 transthyretin-related 358–9, Plate 9.2 familial hemiplegic migraine (FHM) 118, 450 Far East encephalitis 315 far response 61 fasciculation 90 fasciitis, eosinophilic 405 fastigial nucleus 28, 30 fatal familial insomnia 267–8, 272–3, 276, 762 fatigue management 658 multiple sclerosis 419, 433–4 muscle disease 389 fatty acid oxidation, inherited defects 718–19 Fazio–Londe disease 383 febrile seizures 196–7 generalized epilepsy with (GEFS) 197 felbamate 222, 232 female sexual dysfunction 909 femoral nerve 337, 340, 345, 346 femoral neuropathy 374 diabetic 367, 368, 856 fertility rates defined 9 epilepsy 9, 189, 936–7 fetal alcohol syndrome 695 fetal anticonvulsant syndromes 939 fetal malformations, maternal epilepsy 938–9, 940 fetus effect of seizures 938 maternal epilepsy and 938–9 fever see pyrexia fibrillation 89–90 fibromuscular dysplasia, carotid and vertebral dissection 148 fibromyalgia 863 fifth (V) nerve see trigeminal nerve finger–nose test 83 fingolimod, multiple sclerosis 433 Fisher syndrome 362, 638 fistula sign 565 flail arm/leg syndrome 378 flashbacks, drug-induced 210 flucloxacillin, bacterial meningitis 292 fluconazole, cryptococcal meningitis 332 flucytosine, cryptococcal meningitis 329, 332 fludrocortisone 886 fluid management intensive care unit 751–2 post-stroke 142 raised ICP 741 flukes (trematodes) 321, 324

Index flunarizine hypnic headache 463 migraine prevention 453 vestibular disorders 557 fluoxetine Gilles de la Tourette syndrome 179 multiple sclerosis 434 focal CNS infections 289, 295–8 focal cortical disorders 97–9 focal neurological deficits arteriovenous malformations 131 brain tumours 773 coma with 725 focal neuropathies 372–7 folate deficiency 691, 839 folic acid supplementation 597, 940 folinic acid, toxoplasmosis 332 follicle-stimulating hormone (FSH)-producing pituitary tumours 805, 806 fomepizole 693 foot, diabetic 856 foot drop 376, 653 foot-tapping test 83 forced normalization 837 forced vital capacity (FVC) 736 forebrain, basal 45 formication 833 forms, recognition 57, 58 formulation, diagnostic 85–6, 96 fornix 41, 42, 43 foscarnet, cytomegalovirus infection 332 fosphenytoin, status epilepticus 235 Foster Kennedy syndrome 503 FOUR (Full Outline of UnResponsiveness) score 727 14-3-3 protein 258, 269 fourth (IVth) nerve see trochlear nerve fovea 55, 56 foveola 55, 56 Fowler’s syndrome 904 fractional anisotropy (FA), brain tumours 780, 784 fragile X tremor ataxia syndrome (FXTAS) 165, 642 Francisella tularensis 690 frataxin 632–3 free nerve endings 21 Fregoli syndrome 833 frequency of micturition, Parkinson’s disease 157 Friedreich’s ataxia 173, 632–3 hearing loss 577 frontal eye fields 28, 57, 58, Plate 2.3 lesions 541 frontal function, assessment 96 frontal lobe 834 haemorrhage 125 syndromes 840 frontal lobe epilepsy autosomal dominant nocturnal (ADNFLE) 197 clinical features 190–1, 192 EEG features 214, 215 imaging 219, 220 sleep-related phenomena 210, 767 surgery 238 frontal lobe lesions 98 bladder dysfunction 895 executive dysfunction 254–5 gaze palsy 518

fronto-temporal dementia (FTD) 248, 264, 276 motor neurone disease 265, 266, 276, 381 with motor neurone disease-type inclusions (FTD-MND) 255, 265 pain and 851–2 and parkinsonism linked to chromosome 17 (FTDP-17) 181, 265, 276 fronto-temporal lobar degeneration (FTLD) 263–6 clinical features 248, 249, 264–5 differential diagnosis 261, 265 familial 265 frontal variant (fvFTLD) see fronto-temporal dementia investigations 258, 265 natural history 265 neuropathology 265–6, Plate 7.1 progressive non-fluent aphasia see progressive non-fluent aphasia temporal variant (tvFTLD) see semantic dementia ubiquitin positive (FTLD-U) 265, 266, Plate 7.1 frovatriptan 454 FTD see fronto-temporal dementia FTLD see fronto-temporal lobar degeneration FTY720, multiple sclerosis 433 fugue state 833 differential diagnosis 211–12 hysterical 212 fukutin-related protein dystrophy (LGMD2I) 393, 394 Full Outline of UnResponsiveness (FOUR) score 727 functional electrical stimulation (FES) 653 functional magnetic resonance imaging (fMRI) 87 brain tumours 780–2, Plate 20.7 epilepsy 218, 237 post-stroke changes 648 fundus examination 79 coma 726 unilateral visual loss 492–3 fungal infections 319–21 dementia 281 diagnosis 320 organ transplant recipients 925 pseudohyphae 320–1 risk factors 319–20 spine 618 true hyphae 321 yeasts 320 fungal poisons 681–2 as biological weapons 689 funnel-web spider 681 furosemide, raised ICP 741 fusimotor fibres 23 F waves 91, 92 GABA 16, 18 GABA hydroxybutyrate (GHB) 699 gabapentin epilepsy 222, 224, 232 migraine prevention 453 multiple sclerosis 434, 436 pain management 866 pharmacokinetics 225 spasticity 655–6

gag reflex 82, 730 brainstem death 735 gait apraxic 120, 123, 252 assessment 82 cerebellar ataxia 629, 630 peripheral neuropathies 349 rehabilitation 653, 654 tests 546 galactosaemia 715–16 galactosylsulphatide 443–4 galantamine 262–3 ganciclovir, cytomegalovirus infection 332 gangliocytomas 784 gangliogliomas 201, 784 gangliosidoses GM1 712 GM2 278, 712, 713–14 Ganser syndrome 841 gap junctions 16 GARS mutations 357, 358 gas emboli, divers 686 Gasserian ganglion 63 ablation, trigeminal neuralgia 470 lesions involving 468 Gastaut–Geschwind syndrome 837 gastrointestinal bleeding, acute neurological illness 754 gastrointestinal disorders acute neurological illness 753–4 autonomic disease 883, 891 neurological complications 923 gastroplasty/gastrectomy, neuropathies after 370 gate control 40–1 Gaucher’s disease 277, 710, 711 gaze brainstem centres 59 distractibility 518 evoked nystagmus 521, 543 eye movements changing angle 536 eye movements stabilizing angle of 536 periodic alternating disturbance 728 testing 540 gaze palsy (paresis) 540 coma 727–8 horizontal 518, 728 vertical 518–19, 728 disconjugate 519, 728 GDAP1 mutations 356, 357 gefitinib 804 gelastic seizures 190, 201 gelsolin-related familial amyloid polyneuropathy (FAP) 360, 476 generalised tonic–clonic (grand mal) seizures (GTCS) 194 on awakening 195 drug treatment 223 emergency drug treatment 234 general paralysis 302 genetic anticipation 636 Huntington’s disease 172–5 myotonic dystrophy 395 genetic factors 7–8 genetic mapping, spinal developmental anomalies 586

961

Index genetics, spinal development 585–6, 587 geniculate ganglion 65, 66, 472 geniculo-calcarine tract see optic radiation genitofemoral nerve 345 Gennari, Francesco 55 gentamicin bacterial meningitis 292 infective endocarditis 310 intratympanic, Ménière’s disease 557 germ cell tumours 775, 810–11 germinomas 810 Gerstmann, Josef 99 Gerstmann’s syndrome 99 cognitive impairment 254 neuropsychiatric features 840 visual impairment 524, 528 Gerstmann–Sträussler–Scheinker (GSS) syndrome 267–8, 272, 276, 638 gestational epilepsy 937 gestational polyneuropathy 942 gestes antagonistes 166, 828 GHB (GABA hydroxybutyrate) 699 giant cell arteritis (GCA) 931–2 clinical features 500–1, Plate 13.10 histology Plate 13.11 optic neuropathy 500–1, Plate 13.9 stroke 149 gigantism 806 Gilles de la Tourette syndrome (GTS) 177–8 management 178–9 psychiatric disorders 178, 831, 838–9 Gillespie’s syndrome 632 GJB2 gene mutations 570 Glasgow Coma Scale (GCS) 726–7 glatiramer acetate multiple sclerosis 428, 430, 431, 433 side effects 430 glaucoma 493 rubeotic 502 glia 13, 18–19 Gliadel (carmustine) wafers 802 glial derived neurotrophic factor (GDNF) intraputaminal, Parkinson’s disease 162 sensitive fibres 853 glial fibrillary acidic protein (GFAP) gene mutations 445 glioblastoma multiforme (GBM) (WHO grade IV) chemotherapy 802–3 imaging 782, 785, Plate 20.4 pathology 776, Plate 20.1 primary 776 radiotherapy 801–2 secondary 776 surgical management 797–8 gliomas 774–7 brainstem 776 epilepsy 201 grading 774–6, 784 high-grade 774, 776 chemotherapy 802–3 imaging 784, 788, Plate 20.9 radiotherapy 801–2 surgery 797–8 histogenesis 773 imaging 780, 781, 782–4, Plate 20.4

962

low-grade 774, 776 imaging 784, 787 radiotherapy 803 surgery 798 mixed 776 monitoring progression 793 optic nerve 503, 776 optochiasmal 503 pathology 774–6, Plate 20.1 peri-tumoral tissue imaging 784 radiotherapy, quality of life aspects 8 risk factors 772 see also astrocytomas; oligodendrogliomas globoid cell leucodystrophy (GLD) 277, 443, 712, 714 globus pallidus see pallidum glomus arteriovenous malformations, spinal cord 621–2 glomus tumours 570, 857 glossodynia 857 glossopharyngeal nerve (IX) 477–8 anatomy 37, 70, 477–8, 479 examination 82, 478 lesions 478 nuclei 34, 70, 71 parasympathetic fibres 72–3 glossopharyngeal neuralgia 478 glucocerebrosidase replacement therapy 710 glucose blood, acute stroke 140 utilization by brain 114 glue sniffing see solvent abuse glutamate 16, 18 glutaric aciduria type II (GA-II) 719 gluten sensitivity 641 see also coeliac disease glycine 16, 18 glycogenoses (glycogen storage diseases) 401, 715, 840 glycosphingolipidoses 710–15 GM1 gangliosidosis 712 GM2 gangliosidosis 278, 712, 713–14 Goal Attainment Scaling (GAS) 662 goal-setting 661–2 Goldenhar syndrome 586 Goldmann perimeter 492 Golgi tendon organs 23 gonadotrophin-secreting pituitary tumours 805, 806 Gordon Holmes syndrome 633 Gottron papules 402 G-protein-coupled receptors 18 gracile fasciculus (GF) 32, 33 gracile nucleus 33, 35 Gradenigo syndrome 297, 468 graft-vs.-host disease (GvHD) 927 grammar of clinical neurology 96–107 Gram-negative meningitis 292, 295 Gram-positive meningitis 295 grand mal seizures see generalized tonic–clonic seizures granule cells cerebellar 28, 29 dentate nucleus 41 granulomatous myopathies 405 grasp reflex 732

Graves’ disease 509, 917 Gray’s Type I synapses 16 Gray’s Type II synapses 16 great anterior medullary artery of Adamkiewicz 913, 914 greater petrosal nerve 65, 66, 472 great vessels, anatomy 111, 913–14 group B streptococcus, meningitis 294–5 growth hormone (GH)-secreting pituitary tumours 805–6, 807 GTP cyclohydrolase 1 gene (GTPCH1) 167 Guadeloupe, atypical parkinsonism 164 Guam parkinsonism–dementia–amytrophic lateral sclerosis complex 164, 682 guanfacine, tics 179 Guglielmi Detachable Coil (GDC) 129 Guillain–Barré syndrome (GBS) 361–3 bladder dysfunction 900 Fisher variant 362, 638 HIV infection 327 intensive care management 750 pain 856 pathogenesis 362 pharyngo-cervico-brachial variant 362 sexual dysfunction 909 treatment 362–3 variants 360, 362 Guillain–Mollaret triangle 165, 522 gustatory hallucinations 190 gustatory nucleus 66, 71, 472 gustatory sweating 883 Guttman, Ludwig 663 Guyon canal syndrome 373 HAART see highly active antiretroviral therapies habit reversal training (HBT) 178 haemangioblastomas 811–12 cerebellar 638–9 spinal 611, 621 haem arginate 709 haematological disorders 920–2 stroke 116–17 haematopoietic stem cell (bone marrow) transplantation (HSCT) 927 inborn errors of metabolism 443, 444, 714, 720 multiple sclerosis 432, 433 Haemophilus influenzae meningitis 292, 294 hair cells auditory 68, 69 vestibular 66, 67, 535 hair follicles, sensory nerve endings 21, 22 Hallervorden–Spatz syndrome see neurodegeneration with brain iron accumulation Hallpike–Fitzgerald bithermal caloric test 548 hallucinations 832, 833 alcohol withdrawal 693 auditory see auditory hallucinations coenaesthetic 833 cognitive impairment 251 dementia with Lewy bodies 251, 266 epilepsy 190–1, 836 extracampine 251 hypnagogic see hypnagogic hallucinations hypnopompic 526, 763

Index loss of primary sense causing 210 olfactory 467, 833 Parkinson’s disease dementia 267 peduncular 526–7 psychotic 210 visual see visual hallucinations hallucinogens 699 Halmagyi headthrust test 545–6 haloperidol alcohol withdrawal 693 tics 178–9 hamartomas, epilepsy 201 hangman’s fracture 606 Harlequin syndrome 882–3 Harrington rods 592 Hartnup’s disease 634 harvester’s palsy 373 Hashimoto’s encephalopathy 283, 284, 918 Hashimoto’s thyroiditis 918 hatter’s shakes 676 Hayling Sentence Completion Test 96 hazard ratio (HR) 8 headache 449–63 anatomy and physiology 450 arteriovenous malformations 131 benign Valsalva manoeuvre-related 462 brain tumours 449, 772 cerebral venous thrombosis 151 chronic daily (CDH) 458–9 chronic ‘post-event’ 449–50, 461 classification 449, 450 cluster see cluster headache cough 462 drugs causing 700–1 exertional 462 hypnic 463, 766 ictal 853 idiopathic intracranial hypertension 461, 506 low CSF volume 460–1 medication overuse 454, 458–9, 700–1 migraine see migraine new daily persistent (NDPH) 459–61 primary 461 types 459 post-lumbar puncture 95, 460 post-traumatic 461 pregnancy 941 primary 449, 450, 461–3 raised CSF pressure 461 raised ICP 739 secondary 449–50 sex 462–3 stabbing (ice-pick) 462 subarachnoid hemorrhage 127–8 tension-type (TTH) 455 thunderclap 127, 463 vascular 450 warning signs 449, 450 weight-lifter’s 462 head injury 743–6 alcohol intoxication 695 anosmia 466 carotico-cavernous fistula 511 coma prognosis 733 dementia pugilistica 284

facial nerve lesions 474 hearing loss 573 loss of awareness 206 optic neuropathy 504, Plate 13.15 post-concussional syndrome 669, 841 post-traumatic epilepsy 202–3 psychiatric disturbances after 841 severe, management guidelines 747 see also traumatic brain injury head movements encoding in space 535 planes 533, 534 vestibulo-ocular reflex 535 head nodding 521 head positioning, raised ICP 741 head tilt acquired strabismus 539 ocular tilt reaction (OTR) 540 hearing 68 assessment 81, 565–6 hearing aids 580, 581 hearing disorders 562–82 anatomy and physiology 564–5 basic concepts 562–4 clinical assessment 565–6 investigations 566–9 management 580–2 retro-cochlear 574–9 hearing loss (deafness) 562 aetiology 569–79 age-related 570 autosomal dominant 570 autosomal recessive 570 cochlear 570–4 conductive 562, 569–70 management 580–1 congenital or childhood onset, with ataxia 633 cortical 580 drugs causing 572, 704 genetic causes 570–2 investigations 566–8 management 580–2 Ménière’s disease 555 sensorineural 562–3, 570–4 management 581 syndromic 570–2 heart block 752 heart disease see cardiac disease Heart Protection Study 143 heart rate carotid sinus hypersensitivity 880 disturbances 881–2 orthostatic hypotension 875, 876 postural tachycardia syndrome 878, 880 vasovagal syncope 879 heat stroke 639, 685 heavy metal poisoning 675–8 cerebellar ataxia 639 peripheral neuropathies 369 heel–shin test 83 Heller’s syndrome 840 hemianopia bitemporal 523, 806, Plate 13.27 homonymous 523–5 hemicrania continua 461

hemifacial atrophy, progressive 477 hemifacial spasm 476–7 differential diagnosis 209 EMG features 90 hemifield slide 527 hemimegalencephaly 199 hemiparesis 99 hemiplegia 99 congenital 599–600 hemispherectomy, seizure control 238–9 heparin acute thrombo-embolic stroke 140 cerebral venous thrombosis 152–3 hepatic encephalopathy 281, 756, 923 hepatitis B polyarteritis nodosa 366, 368 vaccination, multiple sclerosis 418 hepatitis C, vasculitic neuropathy 367, 368 hereditary motor and sensory neuropathies (HMSN) see Charcot–Marie Tooth disease hereditary motor and sensory neuropathy III (HMSN III) 355–6 hereditary motor neuropathies, distal 352, 354, 358 hereditary neuralgic amyotrophy (HNA) 352, 353, 358 hereditary neuropathy with liability to pressure palsies (HNPP) 352, 354, 356 hearing loss 574–6 hereditary sensory and autonomic neuropathy (HSAN) 352, 354, 357–8 classification 354 pain 856 hereditary spastic paraplegia (HSP) 623–5 Hering–Breuer reflex 72 heroin abuse 115, 698–9 herpes, sacral, urinary retention 902, 903 herpes simplex encephalitis (HSE) 312–13 complications 203, 249, 313 management 313, 750 herpes simplex myelitis, HIV infection 330 herpes simplex virus type 1 (HSV-1) Bell’s palsy and 474 vestibular neuritis and 551 herpes sine zoster 859 herpes zoster (shingles) 313 disseminated 313 HIV infection 329–30 ophthalmicus (HZO) 471, 860 pain 859–60 stroke 149 see also post-herpetic neuralgia Heschl’s gyrus 68 hexacarbon solvents 679 n-hexane 679 hexosaminidase-A deficiency 383, 634–5 hiccups 179, 731 high altitude, cerebral oedema, acute mountain sickness 686–7 highly active antiretroviral therapies (HAART) 327 cryptococcal meningitis 329 HIV-associated dementia 331 immune reconstitution inflammatory syndrome 334 progressive multifocal leucoencephalopathy and 328, 329

963

Index hippocampal formation 41, 42, 834 hippocampal sclerosis 200 imaging 217 pre-operative assessment 236, 237 surgical resection 238 hippocampus 41–5, 834 afferent connections 41, 42, 43 cornu ammonis (CA) zones 41, 42 efferent connections 43 Hippocrates 834 hippus 727 histoplasmosis 319, 320 history, clinical 75–6 difficulties with 86 HIV 327–35 ataxia 638 direct neurological complications 330–4 drug treatment of infections 332–3 encephalitis (HIVE) 330–1 facial palsy 475 hearing disorders 577–8 neurological disorders 327 opportunistic infections and tumours 327–30 primary CNS lymphoma 328, 808 seroconversion illness 327 stroke 327 vasculitic neuropathy 367 viral entry to CNS 330 wasting disease (slim) 405 HIV-associated dementia (HAD) (HIV encephalopathy; AIDS dementia complex) 281, 327, 330–1 HIV-associated myopathy 334, 405 HIV-related neuropathy 331–4 HIV-related vacuolar myelopathy 331 HLA associations multiple sclerosis 412 narcolepsy 763–4 Hodgkin’s disease 922 paraneoplastic disorders 817, 819 hoeing palsy 373 Hoffmann reflex 84 Holmes–Adie pupil 875 Holmes–Adie syndrome 530, 875 pupillary abnormalities 884, Plates 23.2–23.3 sweating abnormalities 883, Plate 23.1 Holmes tremor 165 homocystinaemia 840 homonymous hemianopia 523–5 bilateral 525 honeymoon period, Parkinson’s disease 158 Hoover sign 825 horizontal cells, retinal 53, 54 horizontal gaze palsy with progressive scoliosis (HGPPS) 600 Horner’s syndrome 530–1, 875, 884 carotid artery dissection 148 causes 530–1 coma 727 trigeminal nerve lesions 468, 469 Hox genes 586 H reflexes 91–2 HSAN see hereditary sensory and autonomic neuropathy HSN2 gene mutations 358

964

HSP22 gene mutations 357, 358 HSP27 gene mutations 357, 358 HTLV-I 318–19 myopathy 405 tropical spastic paraparesis (TSP) 318, 618–19, 899 HTLV-II 319 Hughlings Jackson syndrome 479 human chorionic gonadotrophin (βHCG) 810–11 human immunodeficiency virus see HIV human T-cell lymphotropic virus-1 see HTLV-I Humphrey automated perimeter 492 Hunter’s syndrome (MPS II) 571, 709, 711 huntingtin 172 Huntington’s disease (HD) 172–6, 276 clinical features 173, 175, 181, 248 cognitive impairment 175, 267 depression 832, 838 diagnosis 175–6 epilepsy 202 juvenile 175 phenocopies 175–6 psychiatric disorders 175, 838 Westphal phenotype 164, 175 Huntington’s disease-like 2 (HDL2) 173, 175 Huntington’s disease-like 3 (HLD3) 175, 176 Hurler’s syndrome (MPS I) 571, 709, 711 Hurst’s disease 441–2 Hutchinson’s sign 471 hydatid disease 322 hydranencephaly, left hemisphere 599 hydrocephalus 747–8 acute and chronic 747–8 arrested 748 cognitive impairment 280 communicating 747 ex vacuo 748 investigations 748 management 748 non-communicating 747 normal pressure (NPH) 284, 748 pineal region tumours 810 stroke 141 subarachnoid hemorrhage 130 X-linked 600 hydromyelia 595 hydrophobia 317 hydroxyamphetamine, Horner’s syndrome 531 hygiene hypothesis, multiple sclerosis 412 hyoscine (scopolamine) 43, 557 hyperacusis 562 facial nerve lesions 474, 475 hyperaesthesia 349, 848 hyperalgesia 848 hyperbaric oxygen therapy decompression sickness 686 Ménière’s disease 557 hypercalcaemia 919 hyperchromatopsia 527 hypercoagulable states cancer 815 ischaemic stroke 117 hyperekplexia 181, 207 hyperglycaemic neuropathy, acute reversible 369 hypergraphia 837

hyperhidrosis 883, 891, Plate 23.1 hyperkalaemia 919, 920 malignant hyperthermia 705 hyperkalaemic periodic paralysis (hyperPP) 397–8 hypermagnesaemia 919 hypernatraemia 919 hyper-osmolar non-ketotic coma (HONK) 918 hyperparathyroidism 920 hyperpathia 349, 848 hyperperfusion syndrome, after carotid surgery 146–7 hyperprolactinaemia 806 hyperpyrexia 883 coma 726 management 891 primary neurogenic 726 see also malignant hyperthermia hypersomnia, primary (idiopathic) 762 hypertension acute neurological illness 752 acute stroke 140–1 autonomic dysfunction 878–80 brain haemorrhage 124 coma 726 drugs causing 701 management 891 optic disc swelling 501 stroke risk 115 subarachnoid haemorrhage risk 127 supine 880–1, 890 hypertensive encephalopathy reversible posterior leucoencephalopathy 757–8 stroke 150–1 hyperthermia, malignant see malignant hyperthermia hyperthyroid encephalopathy 917–18 hyperthyroidism 917–18 myopathy 406, 917 pituitary tumours 806 see also thyroid ophthalmopathy hypertonia, interventions 651 hypertropia 539–40 hyperventilation anxiety states 830 controlled, raised ICP 741 primary central neurogenic 731 syncope 878 vestibular symptoms 538 hypnagogic hallucinations 251, 526, 766 narcolepsy 763 hypnic headache 463, 766 hypnic jerks 179, 210, 766 hypnopompic hallucinations 526, 763 hypnotic drugs 762 hypoaesthesia 349, 848 hypoalgesia 848 hypobetalipoproteinaemia 634 hypocalcaemia 919, 920 hypochondriasis 107, 826, 827 hypocretin–orexin system 763 hypoglossal nerve (XII) 481–3 anatomy 70, 72, 477, 481, 482 brainstem origin 36 examination 82, 481–2 lesions 481–3

Index hypoglossal nucleus 34, 71 hypoglycaemia 918 loss of awareness 206 neuropathy 369 hypogonadism, autosomal recessive cerebellar ataxia with 633 hypohidrosis 883 hypokalaemia 919, 920 drug-induced 706 hypokalaemic periodic paralysis (hypoPP) 397, 398 hypokinesia 155 hypomagnesaemia 919 hypomania 831 hyponatraemia 752–3, 919, 920 after subarachnoid hemorrhage 130 classification of causes 752 hypoparathyroidism 919–20 hypoperfusion, ischaemic stroke 112–14, 123 hypopituitarism, post-traumatic 883 hyposmia 465 hypotension acute neurological illness 751 acute stroke 141 coma 726 orthostatic (postural) see orthostatic hypotension postprandial 877, 888 hypothalamus 47–51 arterial and capillary supply 48 circumventricular organs 50 hamartomas causing epilepsy 201 limbic lobe 835 neuroendocrine cells 48–50 nuclei 48, 49, 49 sympathetic and parasympathetic activity 50–1 tumours involving 806–7 hypothermia 883 accidental 639, 686 coma 726 determining brain death 735 therapeutic acute stroke 141 raised ICP 742 hypothyroidism 918 myopathy 406, 918 neuropathy 369, 918 hypotropia 539–40 hypovolaemia, acute neurological illness 751–2 hypoxia, cerebellar effects 639 hypoxic-ischaemic brain injury 756 hysterectomy, radical, incontinence after 900 hysteria 824 hysterical personality 826, 829 ibuprofen, migraine 454, 455 idiopathic intracranial hypertension see intracranial hypertension, idiopathic IgA paraprotein-associated neuropathies 365 IgG paraprotein-associated neuropathies 365 IGHMBP2 gene mutations 358 IgM paraprotein-associated neuropathies 165, 365, Plate 9.4 IKBKAP gene mutations 358 ILAE see International League Against Epilepsy iliacus, nerve to 345, 346 iliohypogastric nerve 345

ilioinguinal nerve 345 illness behaviour, abnormal 106–7, 824–5 illusions 526, 527 caused by loss of primary sense 210 epilepsy 190 imagery, mental 651–2 imaging 86–7 brain tumours 218, 778–95, Plates 20.4–20.10 cognitive impairment 257–8 epilepsy 217–20, 237 stroke and TIA 134–5 see also specific modalities immune reconstitution inflammatory syndrome (IRIS) 334 immunosuppressed patients bacterial meningitis 290 brain abscesses 295 CNS infections 925 fungal infections 319 see also HIV immunosuppressive therapy CIDP 364 myasthenia gravis 285 reversible posterior leucoencephalopathy 757–8 systemic vasculitides 928, 929 see also corticosteroids; specific agents impairments defined 660 management 654–60 impulsivity 255 inborn errors of metabolism 709–21 ataxias 634–5 cognitive impairment 276–8, 279 incidence of disease defined 1 difficulties of estimating 6–7 neurological disorders 2, 3–4, 6 inclusion body myositis (IBM) 402, 403 clinical features 403, Plate 9.11 investigation 403–4 treatment 404 incontinence see faecal incontinence; urinary incontinence indometacin benign exertional headache 462 hemicrania continua 461 paroxysmal hemicrania 457 primary cough headache 462 primary stabbing headache 462 sex headache 463 indometacin test (indotest) 461 infantile spasms 196 infant mortality rate 9 infection control, intensive care unit 754 infections acute disseminated encephalomyelitis (ADEM) and 439–40 biological weapons 688, 689–90 cerebellar ataxia 638 Guillain–Barré syndrome and 361, 362 hearing loss 577–8 multiple sclerosis aetiology 412 multiple sclerosis relapse and 417–18 myopathies 405 nosocomial 754

optic neuritis 497, Plate 13.2 optic perineuritis 498 orbital 510 spinal 616–19 see also neurological infections infective endocarditis 309–10, 916 embolic stroke 116, 309 mycotic aneurysms 124, 309 inferior colliculus 60, 68, 69 inferior gluteal nerve 340, 345, 347 inferior mesenteric ganglion 872 inferior salivatory nucleus 71 infiltration, tumour 813 inflammation multiple sclerosis 413–14 neurogenic 854 inflammatory bowel disease 369 inflammatory encephalopathies, acute para-infectious 439–42 inflammatory myopathies 401–5 classification 402 connective tissue disease 404–5 idiopathic 401–3 infection associated 405 investigation 403–4 treatment of idiopathic 404 inflammatory neuropathies 360–8 acute 360, 361–3 chronic 360, 363–8 intermediate 360 infliximab 929 influenza vaccination, multiple sclerosis 418 influenza virus 314 H5N1 (avian flu virus) 314 infratentorial haemorrhage 123, 124, 125 inhibitory post-synaptic potentials (IPSPs) 18 injuries, non-epileptic attack disorder 828 innominate artery 111, 913, 914 insertion activity, EMG 90 insomnia 762 see also fatal familial insomnia inspiratory pressure support 738 inspiratory volume support 738 insula 41, 43–4, 834 insulin neuritis 369 integrated care pathways (ICP) 646–7, 663 intellectual function, testing 96 intensity modulated radiotherapy (IMRT) 800 intensive care unit (ICU) EEG monitoring 216 neurological see neurological intensive care unit neurological complications 755–60 interference pattern, EMG 89 interferon alpha, progressive multifocal leucoencephalopathy 329 interferon β comparative studies 430 discontinuation of therapy 430 multiple sclerosis 428, 429–30, 431 neutralizing antibodies 430 side effects 429–30 interferon β1a (Avonex) 429, 430 interferon β1a (Rebif) 429, 430 interferon β1b (Betaferon) 429, 430 interhemispheric lesions, hearing disorders 580

965

Index interictal dysphoric disorder (IDD) 836 interictal personality syndrome 837 intermediate cutaneous nerve of thigh 345, 346 intermittent mandatory ventilation (IMV) 738 internal capsule 34 internal carotid artery (ICA) 111–12, 914 disease/stenosis 120 see also carotid stenosis dissection 148 imaging techniques 135–6 innervation 64, 70 occlusion 113, 135–6 orbital supply 499, 502 pathophysiology of stroke 112–13 pseudo-occlusion or near occlusion 146 International Association for the Study of Pain (IASP) 847, 848, 861 International Classification of Function (ICF) 660 International Headache Society (IHS) classification scheme 449 International League Against Epilepsy (ILAE) classification of epilepsies and epilepsy syndromes 194–7 classification of seizure types 189–94 indications for MRI 217 International Pediatric MS Study Group 440 International Subarachnoid Aneurysm Trial (ISAT) 129 internuclear ophthalmoplegia (INO) 80, 519, 541 of abduction 519 coma 728 wall-eyed bilateral 519 interpeduncular nucleus 38, 45 interpositus nucleus 28, 30 interstitial nucleus of Cajal (iC) lesions 518, 519 intervertebral discitis 617 intervertebral discs ageing changes 616 prolapse 614, 615 intracerebral haemorrhage/haematoma (ICH) 123, 124 cancer 815 causes 124–5 clinical syndromes 125 epilepsy 202 infratentorial 749 management issues 126 organ transplant recipients 926 pregnancy 940 prognosis 126 secondary prevention 143 supratentorial 749 traumatic 745 see also intracranial haemorrhage; microhaemorrhages, cerebral intracranial arteries 111–12 intracranial haemorrhage 110, 123–6 anticoagulation-associated 124, 126, 144, 145 arteriovenous malformations 130–1 cavernous malformations 133 clinical syndromes 125 cognitive impairment 275 deep 125 diagnosis 111

966

drug-related 115, 124, 697 dural arteriovenous fistulae 133 imaging 126, 134–5 lobar 110, 125 microhaemorrhages see microhaemorrhages, cerebral risk factors and causes 124–5 secondary prevention 143 see also intracerebral haemorrhage/haematoma intracranial hypertension idiopathic (IIH) 505–7 diagnostic criteria 505–6 headache 461, 506 pregnancy and 942 secondary 506 intracranial pressure (ICP) 738–43 indications for monitoring 739 measurement 739 raised 739–43 cerebral herniation 742–3 cerebral venous thrombosis 151 headache 461 ischaemic stroke 114, 115 lumbar puncture 94 management 741–2 papilloedema 505 waveforms 739, 741 traumatic brain injury 746, 747 waveforms 739, 740, 741 intralaminar nucleus of thalamus 46, 46, 47 intrathecal therapy 94 inappropriate 94 malignant meningitis 814 multiple sclerosis 434–5, Plate 10.3 pain management 866 primary CNS lymphoma 808 intravenous immunoglobulin (IVIG) CIDP 364 Guillain–Barré syndrome 363 inflammatory myopathies 404 multiple sclerosis 428, 432 myasthenia gravis 385 paraproteinaemic neuropathies 365 vasculitis 929 intraventricular haemorrhage 125, 128 investigations 86–96 ioflupane 87 iron deficiency 921 irritability 98, 255 Isaac’s syndrome 283, 819 ischaemic encephalopathy 123 ischaemic ocular syndromes 498–502 chronic 501–2 nosology 498–9 ischaemic penumbra 114, 139 Ishihara pseudoisochromatic plates 491 isolated cerebral angiitis (ICA) 150, 280, 928, 931 isoniazid 299–300 isotope (99mTc-pertechnetate) imaging 87 itch 847 ITPR gene mutations 635 itraconazole 321 ivabradine 891 IVIG see intravenous immunoglobulin

Jackson, John Hughlings 845 Jackson’s syndrome 479 jactatio capitis nocturna 767 James–Lange hypothesis 834 Japanese encephalitis 315 jargon speech 253 Jarisch–Herxheimer reaction 302, 305 Jaspers, Karl 829 jaw jerk 64, 65, 468 coma 730 jaw-winking 476 JC virus (JCV) 328, 329 Jefferson fracture 606 Jendrassik manoeuvre 84 Jervell–Lange–Nielsen syndrome 571 jet lag 765 jitter phenomenon, myasthenia gravis 93, 385 joint hypermobility syndrome 878, 881 joint position sense (JPS) testing 85 Jongkees formula 549, 550 Joubert’s syndrome 632 jugular foramen 481 jugular foramen syndrome 479, 483 Junctophilin-3 gene 175 Kallmann’s syndrome 465, 599–600 Kayser–Fleischer (K-F) rings 169 KCNA1 gene mutations 637 KCNC3 gene mutations 635 KCNJ2 gene mutations 397, 398 Kearns–Sayre syndrome 400 ataxia 637 chronic progressive external ophthalmoplegia 512 hearing loss 575, 577 retinal involvement 508 Kelch-like 1 CTG repeat 635 Kennedy’s disease 383 keratoconjunctivitis sicca 930 keraunoparalysis 684 Kernig’s sign 291 Kernohan’s notch phenomenon 742 ketamine abuse 699 chronic pain 865, 866 khat 697 KIAA1985 mutations 356 kidneys, autonomic disease 883 kindling 43 kinesin 14 kinocilia 66, 535 Kjellin’s syndrome 624 Klein–Levin syndrome 762 Klippel–Feil syndrome 597–8 cranio-cervical junction anomaly 593, 597–600 genetics 586, 598 mirror movements 598–9 pyramidal tract malformation 600 Klumpke paralysis 530 Klüver–Bucy syndrome 98, 255, 265 Konzo 682 Korsakoff ’s syndrome 694, 923, Plate 18.5 Krabbe’s disease see globoid cell leucodystrophy Kufs disease 277

Index Kugelberg–Welander disease 382 Kunijin encephalitis 315 kuru 268, 269 Kuzniecky syndrome 200 kyphosis 590 congenital 586 management 591–2, 593 neurofibromatosis type 1 612 spinal tuberculosis 617 L1CAM mutations 600, 624 labetalol, acute stroke 141 labour eclampsia and pre-eclampsia 938 seizures during 937 labyrinth 66 kinetic 66 static 66 labyrinthitis 551 lacerations, haemorrhagic cerebral 745, 746 lacrimal disorders 884, 892 La Crosse encephalitis 315 lacunar stroke (lacunar infarction; lacunes) 110, 119–20 clinical features 119–20 cognitive impairment 120, 274 rarer causes 120 Lafora body disease 198, 277 Lambert–Eaton myasthenic syndrome (LEMS) 387–8, 816, 819–20 electrophysiological studies 92, 387–8 prolonged neuromuscular blockade 759 lamin A/C (LMNA) mutations 357, 393 laminectomy 613–14, 615 laminin 388, 389 lamivudine, tropical spastic paraparesis 619 lamotrigine epilepsy 222, 224, 232 HIV-related neuropathy 334 learning disability 230–1 multiple sclerosis 433 pain management 866 pharmacokinetics 225 SUNCT/SUNA 458 Lance–Adams syndrome 180, 732, 758 Landau–Kleffner syndrome 214, 239, 840 Landolt phenomenon 837 language 97 assessment 96 system, Lichtheim’s concept 97, 252–3 language disorders 97–8, 252–4 rehabilitation, speech therapy 659 large cerebral vessel occlusions clinical syndromes 120–3 cognitive impairment/dementia 123, 274 Lassa fever 314 late onset distal myopathy (LODM) 396 lateral cutaneous nerve of calf 346 lateral cutaneous nerve of thigh 345, 346 neuropathy 374 lateral dorsal nucleus of thalamus 46, 46, 47 lateral geniculate body (LGB) lesions 524 thalamic anatomy 45, 46, 46, 47 visual pathway 53, 55, 57

lateral medullary syndrome (Wallenberg’s syndrome) 122, 148 central pain 849 trigeminal nuclear lesions 469 vagus nerve involvement 479 lateral olivo-cochlear system 564 lateral pectoral nerve 338 lateral plantar nerve 347 lateral posterior nucleus of thalamus 46, 47 lateral rectus palsy 80, see sixth (VI) nerve palsy lathyrism 682 laxatives, multiple sclerosis 435 lead poisoning 675–6 learning cerebellar function 29–30 hippocampal function 43 learning disability definition 229 epilepsy 229–31 assessment 229–30 prevalence 189, 201, 229 psychiatric disorders 230, 837 treatment 230–1 Lennox–Gastaut syndrome 196 Leber’s hereditary optic neuropathy (LHON) 503–4 clinical features 503–4, Plate 13.14 genetics 400, 401 Leigh’s disease 508 Lempert roll manoeuvre 560 Lennox–Gastaut syndrome 196, 231 lens, drug-induced changes 704 lenticulo-striate arteries 112 Lepromin test 306 leprosy 305–7 borderline 305, 306 lepromatous 305 multibacillary 305, 306 nerve thickening 350 paucibacillary 305, 306 primary neuritic 306 tuberculoid 305 leptospirosis 305 leuco-araiosis 120 cognitive impairment 274, 275 secondary stroke prevention 145 leucodystrophies 442–5 leucoencephalitis, acute haemorrhagic 441–2 leucoencephalopathy posterior reversible see posterior reversible leucoencephalopathy syndrome progressive multifocal see progressive multifocal leucoencephalopathy radiation-induced 795 toxic 702 with vanishing white matter 278, 445, 638 leukaemia 921 chronic lymphocytic (CLL) 365 levator ani, nerve to 345 levator palpebrae superioris 60 levetiracetam 222, 232 dosing regimens 224 pharmacokinetics 225 levodopa bladder function and 897

controlled release (CR) preparations 158–9 long-term syndrome 158, 159 multiple system atrophy 892 Parkinson’s disease 158–9, 160–1 psychiatric complications 838 restless legs syndrome 765 vascular parkinsonism 164 young-onset dystonia 167 Lewis–Sumner syndrome 364 Lewy bodies 266 dementia with see dementia with Lewy bodies preclinical Parkinson’s disease 157 Lewy body disease, ‘incidental’ 157 Lhermitte’s sign 104, 419, 588, 850 liaison neuropsychiatry 823–4 Libman–Sacks endocarditis 116, 150 Lichtheim, Ludwig 97, 252–3 lidocaine, pain management 865, 866 life expectancy 8 lifestyle modification, after stroke/TIA 143 light level, effect on visual performance 490 light-near dissociation 529 lightning injuries 683–5 complications 684–5 mechanisms of damage 683–4 limb(s) innervation 337–46, 347 principal movements 106 swelling, complicating stroke 142 limb girdle muscular dystrophies (LGMD) 394 diagnostic strategies 391, 392 genes/proteins causing 393 limbic encephalitis autoimmune 280, 283 cognitive impairment 248, 280, 282–3 paraneoplastic (PLE) 280, 282–3, 817–18 limbic lobe concept 834–5 limbic loop, basal ganglia 27–8 limbic system 41–5, 835 linoleic acid, multiple sclerosis and 418 lipids, serum, stroke risk and 115 Lissauer, tract of 31 lissencephaly 200 Listeria monocytogenes 292, 294, 816 lisuride 160 literacy assessment 96 deficits 254 lithium 844 hypnic headache 463 toxicity 639, 701, 844 livedo reticularis 883, 933 liver biopsy 258 liver transplantation 927 familial amyloid polyneuropathy 359 Wilson’s disease 170 lobar haemorrhage 110, 125 locked-in syndrome 723, 734–5 causes 735 respiration 731 locus caeruleus 37 long-term potentiation (LTP) 43 long thoracic nerve 338 neuropathies 373

967

Index lorazepam epilepsy 222, 231, 234 status epilepticus 235 lordosis 590 Lorenzo’s oil 443, 720 loss of heterozygosity (LOH) 776–7, 803 loudness recruitment 562, 563 lower limbs abnormalities causing drop attacks 207 focal neuropathies 373–4 innervation 337–46, 347 lower motor neurone (LMN) lesions assessment 84–5 facial palsy 81, 473 LRKK2 gene mutations 155–6 Lubag (X-linked dystonia-parkinsonism) 164 lumbar canal stenosis 588–9, 615 lumbar disc surgery 615 lumbar puncture (LP) 94–5 contraindications 94 headache after 95, 460 indications 94 informed consent 94 meningitis 292 primary cough headache 462 risks 94 subarachnoid haemorrhage 94, 128 technique 94–5 lumbar spine disease clinical assessment 588–9 degenerative 615 lumbar splanchnic nerves 72 lumbar sympathetic ganglion 72 lumboperitoneal shunts 748 lumbosacral plexopathies 377 childbirth-related 942 diabetic 367, 368, 856 malignant 858–9 radiation-induced 683 lumbosacral plexus 337, 345 lung cancer brain metastases 791 malignant meningitis 813 paraneoplastic disorders 816, 817, 818 small cell see small cell lung cancer lung disease, dermatomyositis 402 lung function testing, Guillain–Barré syndrome 62 lung transplantation 927 luteinizing hormone (LH)-producing pituitary tumours 805, 806 Lyme disease (neuroborreliosis) 302–4 ataxia 638 dementia 281 diagnosis 304, 423 early stage 302–3 facial palsy 303, 304, 475, 476 hearing loss 578 late stage 303 myositis 405 optic neuritis 497 post Lyme syndrome 304 treatment 304 lymphocytic choriomeningitis virus 314 lymphocytic hypophysitis 941

968

lymphoma 922 cerebral 922 cognitive impairment 280, 282 histology 778, Plate 20.3 intraocular 808 intravascular 808 neuropathies associated with 365 orbital 510 paraneoplastic disorders 817, 819 primary CNS (PCNSL) 808–9, 922 HIV infection 328, 808 imaging 778, 780, 786, 790 intraocular involvement 508 lymphomatosis, dementia 281 lympho-proliferative disease, motor neurone disease and 379 lysergic acid diethylamide (LSD) 699 lysosomal storage disorders 709–11 McArdle’s disease 401, 715 McDonald 2001 criteria, multiple sclerosis 424 McDonald 2005 criteria, multiple sclerosis 424–5 McGregor’s line 593 McLeod’s syndrome 173, 176, 278, 637 McRae’s line 593 macrogyria 200 macrophagic myofasciitis 405 macropsia 526, 527 macula (of the eye) examination 493 sparing, occipital lobe lesions 525 maculae, utricular and saccular 66, 67 macular degeneration, age-related 490 macular oedema, drug-induced 704 macular star 493, 498 maculopathy bull’s eye 508 central serous 490 Madopar 158 magnesium deficiency 696 disorders 919, 920 magnesium sulphate, eclampsia 938 magnetic resonance angiography (MRA) 87 stroke/TIA 135, 136 subarachnoid hemorrhage 129 magnetic resonance imaging (MRI) 86–7 acute disseminated encephalomyelitis 441 Alzheimer’s disease 261–2 brain tumours 778, 779 cerebellar ataxia 630–1 cerebral venous thrombosis 151–2 CIDP 363 cognitive impairment 248, 257–8 Creutzfeldt–Jakob disease 269, 270, 271 diffusion-weighted imaging see diffusion-weighted magnetic resonance imaging epilepsy 217–18, 219, 237 functional (fMRI) see functional magnetic resonance imaging intracerebral haemorrhage 126 intra-operative/interventional (iMRI) 797 lacunar infarction 119 multiple sclerosis 420–3

neuromyelitis optica 438, 439 optic neuritis 496 parkinsonism 163–4 perfusion imaging, brain tumours 778, 784, Plate 20.6, Plate 20.9 permeability imaging (Ktrans), brain tumours 779 radiotherapy planning 800 spinal tumours 611 spinal vascular disease 623 stroke 134–5, 139 subarachnoid hemorrhage 128 transient ischaemic attacks 134–5 vascular cognitive impairment 274, 275 Wernicke–Korsakoff syndrome 694 magnetic resonance spectroscopy (MRS) brain metastases 789 brain tumours 780, 783, 784 epilepsy 218–19 magneto-encephalography 89, 237 magnus raphe nucleus 38, 40, 41 major histocompatibility complex (MHC) expression 347–8 malabsorption 923 neuropathies 369–70 malaria 325–6 cerebral 325–6 acute management 325–6 ataxia 638 diagnosis 325 stroke 149 epilepsy after 204 malformations of cortical development (MCD) epilepsy 199–200 imaging 217, 218 malignant disease see cancer malignant hyperthermia (MH) 397, 704, 708 central core disease 396 malingering 107, 826, 827 mammillary bodies 41, 43, 49, 51 mandibular nerve see trigeminal nerve (V), mandibular division mandibular repositioning splints, obstructive sleep apnoea 764 manganese toxicity 677 mania 831 drug treatment 844 in neurological disorders 831, 832 mannitol 293, 741 maple syrup urine disease (MSUD) 717 marantic endocarditis 815 Marburg’s disease 315 Marchiafava–Bignami disease 284, 695 Marcus Gunn phenomenon, inverse 476 Marcus Gunn pupil 529 Marfan’s syndrome cervicocephalic dissection 148 spinal deformity 591 marijuana 699 Marin Amat syndrome 476 Marinesco–Sjögren’s syndrome 633 marine toxins 680–1 masticatory muscles examination 468 motor innervation 62 reflexes 64

Index MATCH trial 146 maxillary nerve see trigeminal nerve (V), maxillary division MDM2 gene 776 MDMA (ecstasy) 697 meals, hypotension after 877, 888 mean arterial pressure (MAP), raised ICP 741 measles 317 encephalitis 314 mechanic’s hands 402 mechano-receptors 22–3, 31 medial cutaneous nerve of arm 338, 343 medial cutaneous nerve of forearm 338, 343 medial cutaneous nerve of thigh 345, 346 medial dorsal nucleus of thalamus 41, 47 medial geniculate body auditory pathway 68, 69 thalamic anatomy 45, 46, 46, 47 medial lemniscus 33, 35 medial longitudinal fasciculus (MLF) 59, 67, 68 lesions 519, 541 see also rostral interstitial nucleus medial olivo-cochlear system 564 medial pectoral nerve 338 medial plantar nerve 347 median eminence 49, 50 median forebrain bundle 48, 49 median nerve anatomy 338, 339, 342 injuries at elbow 374 neuropathies 373, 374–5 medical conditions, general 913–42 Medical Research Council (MRC) antiepileptic drug withdrawal study 228, 229 muscle weakness scale 83 spinal tuberculosis trial 617–18 medium-chain acyl-Co A dehydrogenase deficiency (MCADD) 719 medulla motor fibres 34 respiratory nuclei 37–8 rostroventromedial, pain relay station 851 sensory pathways 35 medulloblastomas 809 imaging 786, Plate 20.5 pathology 777 Mees’ lines 676, 677 Meige syndrome 166 Meissner’s corpuscles 22 MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) 399, 400 hearing loss 575, 577 retinal involvement 508 stroke 150 Melkersson–Rosenthal syndrome 476 memantine Alzheimer’s disease 263 multiple sclerosis 436 memory components 247–9 declarative 43 hypothalamic function 51 neuro-anatomy 249 testing 96, 257

memory impairment 98 Alzheimer’s disease 249, 260 clinical syndromes 247–50 dementia 245 drugs causing 701, 702 Korsakoff ’s syndrome 694 partial seizures 190 see also amnesia Ménière’s disease 554–5 treatment 557–8, 561, 581 Meniett device 557, 581 meningeal biopsy 95 meningeal irritation, subarachnoid haemorrhage 127 meninges, tumours of 775 meningiomas 777–8 epilepsy 201 imaging 778, 779, 789, Plates 20.5–20.6 olfactory groove 466 optic nerve compression 502–3 prediction of recurrence 798–9 pregnancy 942 primary optic nerve 502 radiation-induced 795 radiotherapy 803 risk factors 772 spinal 613, 799, Plate 15.3 surgery 798–9 meningism bacterial meningitis 291 coma 725, 726 meningitis aseptic 311 bacterial 289–95 clinical presentation 291 epidemiology 289, 290 hearing loss 578 intensive care management 750 investigation 291–2 pathogenesis 290–1 risk factors 289, 290 specific causes 293–5 treatment 292, 293 of unknown aetiology 295 cancer 816 chronic 280–1, 311 epilepsy after 203 fungal 291, 319, 320 malignant (MM) 813–14 recurrent 311–12 stroke 149 tuberculous see tuberculous meningitis viral 291, 310–11 meningitis retention syndrome 902, 903 meningococcal meningitis 292, 293–4 meningococcal vaccination 293–4 meningocoele 597 mental imagery 651–2 mental retardation, stereotyped or repetitive movements 207 mental state examination 77–9, 257 meralgia paraesthetica 374, 942 mercury poisoning 676 Merkel–neurite complexes 21, 22, 23 meropenem, bacterial meningitis 292

MERRF (myoclonic epilepsy with ragged red fibres) 399, 400–1 hearing loss 575, 577 myoclonic epilepsy 198–9 mesaxon 19 mesenchymal tumours 775, 811–12 metabolic disorders cerebellar syndromes 639 cognitive impairment 248, 281, 283 confusional states 211 diabetes mellitus 918 drop attacks 208 hearing loss 572 neuropathies 371 spinal cord 625–6 see also inborn errors of metabolism metabolic encephalopathy 675 cancer 815 critical care settings 756 distinction from structural coma 732 metabolic muscle disease 392, 399–401 metabolic storage disorders, spinal deformity 591 metabolic testing, muscle diseases 391 metachromatic leucodystrophy (MLD) 443–4, 712, 714 dementia 278 psychiatric features 839 meta-iodobenzyl guanidine (MIBG) scanning, parkinsonism 164 metals, heavy see heavy metal poisoning metamorphopsia 99, 527, 528, Plate 13.30 metamphetamine 696 metastases brain see brain metastases intraocular 508 neurological complications 813–14 pituitary 806 spinal see spinal metatases methanol 692–3 methcathinone 697 methicillin-resistant Staphylococcus aureus (MRSA), meningitis 292, 295 methionine, HIV-related vacuolar myelopathy 331 methotrexate inflammatory myopathies 404 multiple sclerosis 432 neurotoxicity 794, 795 primary CNS lymphoma 808–9 vasculitis 929 methyl alcohol 692–3 beta-methylamino-l-alanine (BMAA) 682 methyl bromide 679 methyl chloride 679 3-methylglutaconic aciduria 633 O6-methylguanine-DNA methyltransferase (MGMT) 802 methylmalonic acidaemia 718 methyl mercury 676 methyl n-butyl ketone (MnBK) 679 methylphenidate 697 methylphenyltetrahydropyridine (MPTP) 697 methylprednisolone inflammatory myopathies 404 intrathecal, post-herpetic neuralgia 860 isolated cerebral angiitis 931

969

Index methylprednisolone (cont.) multiple sclerosis 427–8 spinal cord injury 605 vasculitis 929 4-methylpyrazole 693 methysergide benign exertional headache 462 migraine prevention 453 metoclopramide, migraine 455 mexiletine 866 Meyer’s loop 55, 57, 524 microfilaments 14, 15 microglia 18 microhaemorrhages, cerebral 124 causing TIAs 118 cognitive impairment 275 imaging 134–5 micropsia 526, 527 microscopic polyangiitis (or polyarteritis) (MPA) 929 neuropathy 366, 367 stroke 149 microsleeps 206 microsurgical techniques, tumour resection 797 microtubule associated protein tau (MAPT) mutations 265 microtubules 14, 15 microvascular decompression hemifacial spasm 477 trigeminal neuralgia 470 micturition control 39–40, 893–5 micturition control centre, pontine see pontine micturition centre midazolam epilepsy 231 status epilepticus 235 midbrain lesions pupillary light reflex 529 vertical gaze palsy 518–19 midbrain tremor (Holmes tremor) 165 middle cerebral artery (MCA) 112 aneurysms 127 deep infarction 121–2 distal embolism 121 malignant oedema 121, 141 occlusion 120–2, 134, 139 branch 121 management 748–9 total 120–1 middle cervical ganglion 72 middle ear disorders 569–70, 580–1 implants 581 middle latency responses, auditory 568 midodrine 886, 891 miglustat 710, 714 migraine 451–5 acute attack therapies 454–5 basilar 554 burden of illness 11 chronic 459 clinical features 451 diagnostic criteria 450, 451 distinction from TIA 118 familial hemiplegic (FHM) 118, 450

970

management 451–5, 558 non-pharmacological measures 452 pathophysiology 450, 451, Plate 11.1 pregnancy 941 preventive treatments 452–4 psychic experiences 209 related dizziness 554, 558 stroke and 151 visual symptoms 209, 526 Migraine Disability Assessment Scale (MIDAS) 451, 452 migration studies, multiple sclerosis 411 mild cognitive impairment (MCI) 245 amnestic 260 vascular 274–5 Millard–Gubler syndrome 473, 514 Miller–Dieker syndrome 200 minimally conscious state 734 Minimata disease 676 Mini Mental State Examination 77, 257 miosis, drugs causing 704 mirror box technique, phantom pain 864 mirror movements, congenital 598–9, 600 misidentification syndromes 833, 840 mitochondrial (respiratory chain) diseases 399–401, Plate 9.9 ataxia 637 chorea 173 chronic progressive external ophthalmoplegia 400, 401, 512 classification 399 dementia 277 diagnostic strategies 392, 401 epilepsy 198–9 hearing loss 575, 577 retinal involvement 508 stroke 150, Plate 9.9 treatment and support 401 mitochondrial DNA (MtDNA) mutations 399–400 mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes see MELAS mitochondrial encephalomyopathy with ragged red fibres see MERRF mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) 400, 512 mitochondrial trifunctional protein (TFP) deficiency 719 mitofusin 2 (MFN2) gene mutations 357 mitoxantrone multiple sclerosis 428, 431 neuromyelitis optica 439 side effects 431 mixed connective tissue disease (MCTD) 931 Miyoshi myopathy 394, 396 mobility aids 653 Möbius syndrome 476, 514–15 modafinil multiple sclerosis 434 narcolepsy 764 modiolus 68, 69 Mohr–Tranebjaerg syndrome 577 Mollaret’s meningitis 312 Mollaret’s (Guillain-Mollaret) triangle 165, 522 monoamine oxidase B (MAO-B) inhibitors, Parkinson’s disease 159

monoamine oxidase inhibitors (MAOIs), tyramine reaction 708 monoclonal antibody therapies multiple sclerosis 431–3 see also specific agents monoclonal gammopathy of undetermined significance (MGUS) 364–5, 922, 924 mononeuritis multiplex (MNM) cytomegalovirus 329 polyarteritis nodosa 929 Sjögren’s syndrome 930 Wegener’s granulomatosis 930 mononeuropathies 105, 372–7 diabetic 369 multiple 105 organ transplant recipients 926 Monro–Kellie doctrine 739 mood 38, 51 mood disorders see affective disorders mood stabilizers 844 Moore’s lightning streaks 526 morphine abuse 698–9 Morquio syndrome 591 mortality 8 mortality ratio proportional 8 standardized (SMR) 8 Morvan’s syndrome 283, 819 mossy fibres 28, 29, 41 motion detection, visual 57, 58 selective deficits 250 motion sickness 556 motor attacks, transient focal 208 motor conduction velocity (MCV) 91 motor control 24–31 cerebellar system 24, 26–8 corticospinal (pyramidal) system 24–6 striatal (basal ganglia) system 24, 26–8 see also motor system motor cortex Brodmann’s areas 24 primary see primary motor cortex stimulation, chronic pain 867 motor fibres brainstem 34 cranial nerve nuclei 34–5 motor loops basal ganglia 24, 26–7 cortex–cerebellum–cortex 24 motor nerve conduction studies 92 motor neurone disease (MND) 377–81 aetiology 378–9 cancer 818 cognitive impairment 381 diagnosis 379 differential diagnosis 378 dropped head syndrome 485 fronto-temporal dementia and 265, 266, 276, 381 incidence and prognosis 379 investigation 379 management 379–81 pain 857 palliative care 381 websites 380

Index Motor Neurone Disease Association (MNDA) 380, 381 motor neurones 13, 15 motor neurone syndromes cancer 818 hyperthyroidism 917 Lyme disease 303 motor neuropathies 349, 350 distal hereditary (dHMN) 352, 354, 358 lead toxicity 676 multi-focal, with conduction block (MMNCB) 364 paraneoplastic 819 see also specific neuropathies motor problems Huntington’s disease 175 multiple sclerosis 419 motor re-learning approach 651 motor responses brainstem testing 735 coma 732 motor system abnormalities of brain and spinal cord 99–101 examination 82–5 post-injury reorganization 648–9 see also motor control motor units, normal recruitment 89 mountain sickness see cerebral oedema 686–7 movement(s) involuntary, coma 732 mechanisms of 23–31 primitive 38–9 principal limb 106 movement disorders 100, 155–86 akinetic-rigid syndromes 100, 155–64 assessment 82 cocaine and amphetamine abuse 698 dementia associated with 267 drop attacks 207 drug-induced 183, 702–3 facial muscle and eye movements 209 functional (somatoform) 100 generalized convulsive movements 207 hyperkinetic 164–82 hyperthyroidism 917 neurophysiological assessment 184–6 organ transplant recipients 926 pain 852–3 paroxysmal 208 psychiatric disorders 837–9 psychogenic (PMD) 182–3, 828 see also dyskinesias; specific disorders Moyamoya angiopathy 151 Moyamoya syndrome 151 MPTP 697 MSA see multiple system atrophy MTMR2 mutations 356 MTMR13 mutations 356 mucolipidosis 710 mucopolysaccharidoses (MPS) 709–10, 711 hearing loss 571 spinal deformity 591 mucormycosis 319, 321 orbital involvement 510

multi-disciplinary teams management of brain tumours 795 rehabilitation 646–7, 660 multi-focal acquired demyelinating sensory and motor neuropathy (MADSAM) 364 multi-focal motor neuropathy with conduction block (MMNCB) 364 multi-infarct dementia 123, 274 multiple acyl-CoA dehydrogenase deficiency (MADD) 719 multiple cranial neuropathies (MCN) 485–7 causes 486 recurrent, of unknown cause 487 multiple organ dysfunction syndrome (MODS) 755 multiple sclerosis (MS) 411–45 aetiology 412–13 aggressive 416–17 anosmia 466 Asian optico-spinal form 496 autoantibodies 414, 423–4 autoimmune pathogenesis 414–15 benign 416 bladder dysfunction 419, 435, 899 cerebellar ataxia 419, 435, 638 clinical course 415–18 clinical features 418–19 clinically isolated syndromes (CIS) 416 diagnostic criteria 424–5 disease-modifying therapy 429, 430, 431 investigations 420, 423–4 cognitive impairment 248, 419, 436 complementary and alternative medicine 438 CSF examination 423, Plate 10.2 depression 436, 832, 839 diagnosis 419–27 diagnostic criteria 424–5 diagnostic process 425–7 differential diagnosis 422, 425, 426, 440 disease-modifying therapy 428–33 early onset 417 environmental factors 412–13 epidemiology 411–12 established 416 fundus examination 493 genetic susceptibility 412 hearing disorders 578 investigations 420–4 magnetic resonance imaging 420–3 management 427–38 Marburg variant 416–17, 418 mortality 417 natural history and prognosis 416–17 neurological rehabilitation 428, 437 optic neuritis 418–19, 495, 496 pain 419, 436, 657, 849–50 palliative care 437 pathology 413–14, Plate 10.1 patient education and support 427 pregnancy and 418, 942 primary progressive 415 diagnostic criteria 425 disease-modifying therapy 431, 433 progressive relapsing 415 psychiatric disorders 436, 660, 839 relapse 427–8

assessment 427 definition 415 factors affecting 417–18 supportive measures 428 treatment 427–8 relapsing remitting 415, 416 disease-modifying therapy 429, 430, 431–2 secondary progressive 415 disease-modifying therapy 429, 430, 431, 432 sexual dysfunction 419, 435, 908 symptom management 433–7, 656, 657, 658, 660 tonic spasms 208, 419 trigeminal neuralgia 436, 470, 850 types 415 uveomeningitic involvement 507 Multiple Sclerosis Impact Scale (MSIS-29) 437 Multiple Sclerosis Walking Scale (MSWS-12) 437 Multiple Sleep Latency Test (MSLT) 763 multiple subpial transection 239 multiple system atrophy (MSA) 162–3 autonomic failure 162, 163, 875 bladder dysfunction 897–8 cerebellar disease 641 clinical features 884 coat-hanger pain 852 differential diagnosis 163–4, Plate 5.1 dysphagia 883 eye movement disorders 541 management 886, 888, 891, 892 myoclonus 181 orthostatic hypotension 876 Raynaud’s phenomenon 883 sexual dysfunction 907 urinary tract dysfunction 883 mumps encephalitis 314 mumps virus, hearing loss and 577 Munchausen’s syndrome 826, 827 Murray Valley encephalitis 315 muscarinic receptors 73 muscle(s) biology 388 contractile apparatus 388, 389 damage, lightning and electrical injuries 685 innervation of limb 339, 340 pain sensation 862–3 principal limb movements 106 muscle action potentials, compound (MAPs or CMAPs) 91 muscle biopsy 95, 391 cognitive impairment 258 inflammatory myopathies 403, 404, Plate 9.10 mitochondrial disease 399, 401, Plate 9.9 muscle cramps see cramps muscle diseases (myopathies) 106, 388–408 acquired 401–8 alcoholic 695 clinical assessment 388–90 congenital 396–7 critically ill patients 759 distal 396 drug induced 406–8, 706 EMG changes 90, 390–1 endocrine disorders 406, 917, 918 extraocular muscles 512 genetic 391–9

971

Index muscle diseases (cont.) hearing loss 577 HIV-associated 334, 405 inflammatory 401–5 investigation 390–1 malignancy associated 405–6 metabolic 392, 399–401 organ transplant recipients 926 painful 862–3 see also specific diseases muscle power, assessment 83, 390 muscle-specific kinase (MuSK) antibodies 383–4, 385 muscle spindles 23 muscle strengthening interventions 652 muscle wasting neurogenic 105 non-necrotic cachectic myopathy 759 muscle weakness see weakness muscular dystrophies 391–5 musculocutaneous nerve 338, 339, 341 myalgia 862 drug-induced 704 myasthenia congenital 387 drugs causing 384, 704 transient neonatal 386 myasthenia gravis (MG) 383–6 anaesthesia and peri-operative care 386 clinical features 384 diagnostic tests 384–5 electrophysiological studies 92, 93, 385 hyperthyroidism and 917 intensive care management 750 management 385–6 ocular 386, 512 as paraneoplastic condition 820 pregnancy and 386, 941 prolonged neuromuscular blockade 759 rippling muscle disease 406 seronegative (SNMG) 383–4, 385 myasthenic crisis 386 Mycobacterium leprae 305, 306 Mycobacterium tuberculosis 298 mycolipidosis 277 mycophenolate mofetil myasthenia gravis 385 vasculitis 929 mycotoxins 681–2 as biological weapons 689 mydriasis, drugs causing 704 myelin 20–1 peripheral nerve 20, 348 sheath composition 20–1 myelin-associated glycoprotein (MAG) 20, 365 myelinated nerve fibres, optic disc 505, Plate 13.17 myelination axon–Schwann cell interactions 21 CNS 18 peripheral neurones 19 myelin basic proteins (MBP) 20, 21 myelin protein zero (P0) 20 gene (MPZ) mutations 355, 356 myelitis, transverse see transverse myelitis

972

myeloma multiple 921, 924 neuropathies 365 spinal involvement 612 solitary 365 myelomeningocoele 597 myelopathy arachnoiditis 604 cervical (degenerative cervical spine disease) 614 HTLV-1 associated see tropical spastic paraparesis necrotizing 818 radiation-induced 683, 801 rheumatoid arthritis 601, 602 myeloproliferative disorders 924 myeloscisis 597 myocardial contractility, decreased 752 myocardial infarction (MI) prevention after stroke/TIA 142–7 stroke risk 116 myoclonic encephalopathies, non-progressive 179 myoclonic epilepsy benign autosomal dominant familial 179 of infancy, severe (Dravet syndrome) 197 juvenile 195, 223 progressive 198–9, 214 with ragged red fibres see MERRF myoclonic seizures 193, 224 myoclonic status 732, 733, 758 myoclonus 179–82 Baltic 198 brainstem 186 classification 179, 180 coma 732 cortical 181, 182, 185–6 drug-induced 182 epileptic 179, 180 essential 179, 180, 186 lower limb 100 neurophysiological tests 185–6 ocular 728 palatal see palatal tremor pathological fragmentary 210 peripheral 181 physiological 179, 180 postanoxic action 180 proprio-spinal 181, 186 psychogenic 181–2 reticular 186 secondary 179–82 segmental 181, 186 sleep 766 spinal 181, 186 subcortical 181, 208 treatment 182 myoclonus dystonia 167–8, 171, 182 myo-edema 918 myofibrillogenesis regulator gene (MR-1) 170 myofibrils 388 myoglobinuria 408, 705 myokymia 90–1, 477 myopathies see muscle diseases myosin 388, 389 myosin (thick) filaments, myopathy with selective loss of 759

myositis drug-induced 706 infection associated 405 see also inflammatory myopathies myotonia assessment 390 drug-induced 706 EMG changes 90 inherited 397–9 potassium aggravated (PAM) 397, 398 myotonia congenita 397, 398–9 myotonic dystrophy 395 bladder dysfunction 900 clinical features 395, Plate 9.7 diagnosis 391, 392, 395 genetics 395, 397 hearing loss 577 myxoedema coma 918 myxoma, atrial 916–17 N-acetyl-aspartate (NAA), brain tumours 780, 784 naloxone 698, 868 naming tasks, confrontational 253 naproxen chronic daily headache 458 migraine 454, 455 naratriptan, migraine 454 narcolepsy 206, 763–4 NARP see neurogenic ataxia and retinitis pigmentosa nasal disease, anosmia 466 nasopharyngeal carcinoma, cranial neuropathies 482, 486 Nasu–Hakola disease 278 natalizumab, multiple sclerosis 428–9, 431–2 National Acute Spinal Cord Injury Studies (NASCIS) 605 National Adult Reading Test (NART) 96, 257 National Institute for Health and Clinical Excellence (NICE) Alzheimer’s disease treatment 263 epilepsy diagnosis 213, 240 multiple sclerosis 426, 427, 428 secondary stroke prevention 145 National Institute of Neurological Disease and Stroke (NINDS) study 138 National Service Framework (NSF) for long-term neurological conditions 437, 646, 665 N-butyl cyano-acrylate (NCBA) 132 NDRG1 mutations 356 near response 61 nebulin 389 neck pain, coat-hanger distribution 852, 875–7 neck–tongue syndrome 468 necrotizing myelopathy 818 necrotizing myopathy, acute severe 759–60, 820 neglect syndrome 99, 247 rehabilitation 659 Neisseria meningitidis meningitis 292, 293–4 Nelson’s syndrome 806 nemaline myopathy (NM) 396–7 nematodes 321, 322 neo-cerebellum 28, 30–1 neologisms 253 neonates benign familial convulsions 197

Index hypotonia 396 mothers with epilepsy 938–9, 940 organic acidaemias 718 transient myasthenia 386 nerve agents, biological weapons 688–9 nerve biopsy 95 CIDP 363–4, Plate 9.3 cognitive impairment 258 Guillain–Barré syndrome 362 leprosy 306 peripheral neuropathies 351, 356 vasculitic neuropathies 367 nerve conduction studies (NCS) 91–3 CIDP 363 Guillain–Barré syndrome 361 normal values 92 nerve conduction velocities, fibre types 19 nerve growth factor (NGF) peripheral pain perception 853–4 recombinant human, HIV-related neuropathy 334 nerve root lesions see root lesions nervus intermedius 64, 65, 66, 472 neuralgia 103 neuralgic amyotrophy see brachial neuritis neural reorganization post-injury 648–9, 670–1 see also plasticity, neural neural repair pathway hypothesis 609 spinal cord injuries 608–10 treatments to promote 648 neural synchrony disorders 563 neural tube defects 597 maternal epilepsy 939, 940 neurites 13 neuro-ablative procedures, chronic pain 866–7 neuro-acanthocytosis ataxia 637 cognitive impairment 278 movement disorders 173, 176 neuro-anatomy 23–73 neuropsychiatric disorders 833–5 neuro-Behçet’s syndrome (NBS) 935–6 neurobiological weapons 688–90 modes of release 688 nerve agents 688–9 toxins and infectious agents 689–90 neuroblastoma, opsoclonus-myoclonus 180, 818 neuroborreliosis see Lyme disease neurocutaneous syndromes, epilepsies 199 neuro-cysticercosis see cysticercosis neurocytomas, central 784 neurodegeneration with brain iron accumulation (NBIA) (pantothenate kinase-associated neurodegeneration; PKAN) cognitive impairment 278 movement disorders 168, 173, 176 neurodegenerative disorders anosmia 466 epilepsy 202 eye movement disorders 518 myoclonus 181 young onset and inherited dementias 276 neuro-endoscopy 797

neuro-enteric cysts 812 neuro-epithelial tumours 775 imaging 782–4 pathology 774–7 neuroferritinopathy 176, 276 neurofibrillary tangles 14, 259–60 neurofibromas 812 spinal nerves 612, 613 neurofibromatosis type 1 (NF1) 812 clinical features 589 ocular involvement 508 spinal deformity 591, 612 spinal manifestations 611–12 neurofibromatosis type 2 (NF2) 812 hearing loss 576–7 ocular involvement 508 neurofibrosarcomas, spinal nerves, in NF1 612 neurofilament light polypeptide (NEFL) gene mutations 355 neurofilaments 14, 15 neurogenic ataxia and retinitis pigmentosa (NARP) 508, 637 neurogenic inflammation 854 neurohypophysis 49, 50 neuroleptic drugs see antipsychotic drugs neuroleptic malignant syndrome (NMS) 183, 705–7, 708 neurological examination 76–86 brief 77 detailed 77–86 preliminary assessment 76–7 neurological infections 289–335 cancer 815–16 cerebellar ataxia 638 cognitive impairment 280–1, 283 CSF examination 94 epilepsy after 203–4 focal 289, 295–8 organ transplant recipients 925–6 stroke 149 neurological intensive care unit (NICU) 736–60 acute bacterial meningitis 750 acute stroke 748–9 general medical care 751–5 alimentary system 753–4 anticoagulation 754 cardiovascular system 751–2 communication 755 hyponatraemia 752–3 infections 754 patient comfort 754–5 pulmonary complications 751 herpes simplex encephalitis 750 hydrocephalus and shunts 747–8 ICP management 738–43 indications for admission 736 infection control 754 mechanical ventilation 736–8 neuromuscular disease 750–1 principles of care 738 status epilepticus 749–50 traumatic brain injury 743–6 ventilatory failure 736, 737 neuromas 863–4 neuromuscular blockade, prolonged 759

neuromuscular disorders 337–408 critically ill patients 758–60 drug-induced 704–5 intensive care management 737, 750–1 organ transplant recipients 926 pregnancy 941–2 scoliosis 590, 592 neuromuscular junction 16, 17 neuromuscular junction blocking agents (NMBA) 759 neuromuscular junction disorders 106, 383–8 extraocular muscle involvement 512 intensive care unit 759 neuromuscular transmission drugs impairing 384, 704 electrophysiological studies 92–3 neuromyelitis optica (NMO) 438–9 optic neuritis 496–7 spinal cord inflammation 619 neuromyotonia 283, 819 neuromyotonic discharges, EMG 91 neuronal and mixed neuronal–glial tumours 775 neuro-navigation 796 neurones 13–14 cytoskeleton 14, 15 membrane 14, 15 myelination 18, 19 plasticity 13 ultrastructure 13–14, 15 neuro-oncology 771–821 neuro-ophthalmology 489–531 neuro-otology 533–82 assessment 539–46 basic concepts 533–7 investigations 546–51 see also vestibular disorders neurophysiological tests 87–93 auditory function 567–8 cerebellar ataxia 631 epilepsy surgery 215–16, 237 inflammatory myopathies 403 motor neurone disease 379 movement disorders 184–6 muscle disease 90, 390–1 myasthenia gravis 92, 93, 385 peripheral neuropathies 351 neuroprotection ischaemic stroke 140 multiple sclerosis 433 neuropsychiatric disorders 833–40 see also psychiatric disorders neuropsychiatric systemic lupus erythematosus (NPSLE) 931 neuropsychiatry see psychiatry neuropsychological testing 95–6 cognitive impairment 256–7 before epilepsy surgery 237–8 frontal lobe syndromes 840 neuroretinitis 493, 498, Plate 13.3 neurostimulation therapies chronic pain 867 deep brain see deep brain stimulation epilepsy 239 psychiatric disorders 844–5 trigeminal-autonomic-cephalgias 457, 458

973

Index neurosurgery epilepsy after 203 psychiatric disorders 844–5 neurosyphilis see syphilis neurotransmission 16 neurotransmitters 16–18 autonomic nervous system 73, 871, 872, 873 gated ion channels 18 neurotrophic factors, spinal cord injuries 608 neutropenia, CNS infections 816 niacin 690 deficiency 923 NICE see National Institute for Health and Clinical Excellence nicotinic acid 690 NICU see neurological intensive care unit Niemann–Pick disease type C 712, 714–15 ataxia 635 dementia 277 nifedipine, altitude illness 686, 687 nightmares 766 night terrors 211 nigro-striatal pathway 27 nimodipine ischaemic stroke 140 subarachnoid hemorrhage 129 ninth (IX) nerve see glossopharyngeal nerve Nipah virus, encephalitis 314 nitric oxide (NO) 73 erectile function 906, 909 nitrous oxide (N2O) 626, 679–80 NMDA-blocking agents, chronic pain 866 Nocardia asteroides, cancer 816 nociceptors, primary afferent 22, 853–4 nocturnal paroxysmal dystonia (NPD) 767 nodes of Ranvier 19, 20 noise-induced hearing loss 572–3 non-adrenergic non-cholinergic (NANC) neurones 73 Nonaka myopathy 396 non-bacterial thrombotic endocarditis (NBTE) 815 non-epileptic attack disorder (NEAD) (dissociative seizures) 206, 826–8 diagnostic clues 827, 828 hallucinations and illusions 210 motor phenomena 207 non-invasive ventilation (NIV), motor neurone disease 380 non-REM parasomnias 211, 766 non-steroidal anti-inflammatory drugs (NSAIDs) migraine 454, 455 overuse headache 458 pain management 657 noradrenaline (NA) 73, 872 biosynthesis 889 orthostatic hypotension 875, 876 phaeochromocytoma 882 sympathetic nerve terminal 873 normal-appearing white matter (NAWM) lesions, multiple sclerosis 414, 422–3 normal pressure hydrocephalus (NPH) 284, 748 Normosang (haem arginate) 709 North American Symptomatic Carotid Endarterectomy Trial (NASCET) 136 nortriptyline, migraine prevention 453

974

nosocomial infections 754 notch3 gene mutations 275, 932–3 notch genes 586 Nothnagel’s syndrome 514 notochord 585–6 split 586 novelty detection 29–30 NSAIDs see non-steroidal anti-inflammatory drugs NTRK1 gene mutations 358 nucleoside-associated lactic acidosis 407 nucleus accumbens 26, 27, 41, 44 limbic lobe 835 nucleus ambiguus cranial nerve nuclear column 36, 37 cranial nerve nuclei 34, 70, 71, 72 numb cheek syndrome 468 numb chin syndrome 468 numbness 349 numeracy (calculation) assessment 96 deficits 254 nursing homes, dementia care 285 nutritional deficiencies 675 dementia 281 neuropathies 369–71 optic neuropathies 504 nutritional support acute neurological illness 753–4 dementia 285, 286 motor neurone disease 381 post-stroke 142, 659 NXY-059 140 nyctalopsia 507 nystagmic quick phase movements 536 nystagmus 519–23 assessment 542–5 caloric 521, 548 central vestibular horizontal 521 cerebellar lesions 31, 630 childhood 520–1 congenital 520, 542, 545, 632 convergence-retraction 522–3 destructive 555 downbeat 521–2, 728 drug-induced 704 examination 82 eye lid 523 gaze evoked 521, 543 gaze paretic jerk 521 horizontal 519–21, 728 investigations 546–51 jelly 545 jerk 520, 542 latent 520, 539 monocular 521 normal subjects 520 oculo-palatal tremor 522 optokinetic see optokinetic nystagmus pathological vestibular 543 pendular 520, 545 periodic alternating 522, 545 physiological vestibular 543 positional 543–4 central 543, 544 peripheral 543–4

see-saw 522 torsional 521, 545 upbeat 522, 728, 729 vertical 521–3 vestibular jerk 521 voluntary 523 nystagmus block syndrome 520 obidoxime 689 object recognition 57 impaired 250, 527 obsessional personality 829 obsessional slowness 831 obsessive-compulsive disorder (OCD) 831 Gilles de la Tourette syndrome 177, 178, 179, 839 obstructive sleep apnoea/hypopnoea syndrome (OSA or OSAHS) 764 cognitive impairment 281 differentiation from epilepsy 206, 211 management 764 motor neurone disease 380 obtundation 724 obturator nerve 337, 340, 345, 346 occipital cortex 53, 55, 58 occipital lobe epilepsy 192 EEG features 215 visual phenomena 526, Plate 13.28 see also benign childhood occipital epilepsy occipital lobe lesions 99 clinical presentation 490 visual field defects 524–5 visual phenomena 526, Plates 13.29–13.30 occipital nerve stimulation, headache syndromes 457, 459 occupational health services 664 occupational therapy 661–2, 664 community-based 668 Octopus automated perimeter 492 octreotide, autonomic disorders 888, 891 ocular bobbing 728, 729 reverse 728, 729 ocular dipping 728, 729 reverse 728, 729 ocular flutter 518, 728 ocular muscles see extraocular muscles ocular tilt reaction (OTR) 540 oculocephalic reflex 728–30 oculo-facial-skeletal myorhythmia 165 oculogyric crises 519 oculoleptomeningeal amyloidosis (OLMA) 359 oculomasticatory myorhythmia 165, 522 oculomotor apraxia 250, 518, 528 ataxias associated with 633 oculomotor disorders see eye movement disorders oculomotor hypokinesia 28 oculomotor loop, basal ganglia 28 oculomotor nerve (III) anatomy 36, 60, 61 examination 79–80 parasympathetic fibres 72–3 oculomotor nerve (III) palsy 512–14, 540 causes 513 cavernous sinus lesions 513, 514 clinical features 80, 512–13 coma 727–8

Index diabetic 855 fascicular lesions 513, 514 nuclear lesions 513 orbital lesions 513, 514 partial 80 subarachnoid space 513, 514 uncal herniation 742 oculomotor nucleus 59, 60 oculomotor synkinesis 514 oculopalatal tremor, nystagmus in 522 oculopharyngeal muscular dystrophy (OPMD) 392, 395, 512 oculovestibular reflexes see vestibulo-ocular reflexes odontoid fractures 606, 607 odour identification deficits 251, 467 Odstock footdrop stimulator 653 OKT3 monoclonal antibody 926 olanzapine 843 olfaction (sense of smell) neurobiology 52–3, 465 testing 79, 465–6 olfactory bulb 51, 52 olfactory disorders 465–7 causes 251, 466–7 symptoms 465 olfactory ensheathing cells (OECs) 609, Plate 15.1 transplantation 609–10, Plate 15.2 olfactory epithelium 51 olfactory groove meningiomas 502–3 olfactory hallucinations 467, 833 olfactory nerve (I) 51–3, 465–7 olfactory system anatomy 51–3 regeneration 609 olfactory tract 51, 52 oligoastrocytomas 776 oligoclonal bands 423, Plate 10.2 oligodendrocytes (oligodendroglia) 18 oligodendrogliomas 776–7 anaplastic, chemotherapy 803 grading 776 imaging 782–4, 785, Plates 20.5, 20.8–20.9 molecular genetics 776–7 radiotherapy 803 oligosaccharidoses 710 oliguria, orthostatic hypotension 877 olive harvester’s palsy 373 olivo-cerebellar tract 29–30 oncogenes 774 ondansetron, cerebellar tremor 657 one and a half syndrome 519, 541 on–off fluctuations, Parkinson’s disease 158–9 Onuf ’s nucleus 897 ophthalmic artery 499 ophthalmic nerve see trigeminal nerve (V), ophthalmic division ophthalmoplegia 509–16 chronic progressive external see chronic progressive external ophthalmoplegia combined 516, 517 internuclear see internuclear ophthalmoplegia neurogenic 512–16 painful 516, 517 restrictive 509 ophthalmoscopy 79

opiates (opioids) abuse 698–9 acute neurological illness 755 bladder dysfunction and 904 pain management 865, 866 withdrawal 699 Oppenheim hand 419 Oppenheim’s dystonia 166 opsoclonus 518 coma 728, 729 opsoclonus-myoclonus, paraneoplastic 180–1, 818 optic ataxia 250, 528 optic atrophy 493 autosomal dominant 503, Plate 13.13 band 523–4, Plate 13.27 optic chiasm 53, 55, 57 disease 523 gliomas 503 lesions, visual field defects 491–2 optic disc anomalies 505 anterior ischaemic optic neuropathy 500 chiasmal lesions 523, Plate 13.27 drusen 505, Plate 13.16 examination 492–3 myelinated nerve fibres 505, Plate 13.17 tilted 505 optic disc oedema (swelling) 504 causes 504 chronic ischaemia 501 optic gliomas 503, Plate 13.12 see also papilloedema optic fixation index (OFI) 549 optic nerve (II) 57 anatomy 53, 55 blood supply 498–9 disease 494–507 examination 79 infarction, cerebral venous thrombosis 153 reflexes involving 65 tumours affecting 502–3, 776, Plate 13.12 optic nerve sheath decompression (ONSD) 506–7 optic neuritis 494–8 causes 495 clinical features 489, 490, 496, Plate 13.1 demyelinating 495, 496 differential diagnosis 426 infectious causes 497, Plate 13.2 investigations 496 multiple sclerosis-associated (MS-AON) 418–19, 495, 496 neuromyelitis optica 438, 496–7 neuroretinitis 498 nosology 494–5 pain 489, 496, 850 treatment 428, 496 Optic Neuritis Treatment Trial 428 optic neuropathies 494–507 causes 495 chronic relapsing inflammatory (CRION) 497 clinical presentation 489, 490 colour vision impairment 491 compressive or infiltrative 502–3 drug-induced 704 fundus examination 492–3

hereditary 503–4 inflammatory see optic neuritis ischaemic 500–1 Leber’s hereditary see Leber’s hereditary optic neuropathy pupil light reflex 492 radiation-induced 504, 795 sarcoidosis-associated 497–8 toxic nutritional 504 traumatic 504, Plate 13.15 optic perineuritis 498 optic radiation 53, 55, 57 lesions 524 optic tract 55, 57 lesions 523–4 optokinetic nystagmus (OKN) 520, 536, 542 orator’s hand 373, 374 orbicularis oculi, myokymia 477 orbital disease 509–10, Plate 13.24 oculomotor nerve lesions 514 orbital inflammatory syndromes 510 orbital myositis 510 orbital pseudotumour 510 orbito-frontal cortex 834 organic acidaemias 716, 718 organic personality change 829 organ of Corti 68, 69, 564 organophosphates (OPs) 386, 680 as biological weapons 688 organ transplantation 925–7 CNS infections 925–6 neurological sequelae 926 orgasm 906 ornithine transcarbamylase deficiency 277, 634 orthopaedic conditions, painful benign 857 orthostatic (postural) hypotension 538, 875–7 drugs causing 704 factors affecting 877, 878 management 886–90 physical measures 886, 887, 888 orthostatic intolerance with posturally induced tachycardia 878, 880 oscillopsia 508, 527, 536, 555 osmotic agents, raised ICP 741 os odontoidium 593, 597 osteochondrodysplasias, spinal deformity 591 osteogenesis imperfecta (OI) 571, 591 osteoid osteoma 857 osteomyelitis, spinal 616–17 osteopenic disorders, spinal deformity 590–1 osteosarcoma, spinal 612 otic ganglion 73 otitis externa, acute 580 otitis media chronic active 570 management 580 serous 570 oto-acoustic emissions (OAE) 567–8 otosclerosis 570, 580–1 otoscopy 565, 726 otosyphilis 578 oto-toxic drugs 572, 704 outcome measures, rehabilitation 662–3 ovarian tumours, paraneoplastic disorders 817, 818 β-N-oxalylamino-l-alanine (βOAA) 682

975

Index oxcarbazepine epilepsy 222, 224, 233 pharmacokinetics 225 trigeminal neuralgia 470 oxybutynin hydrochloride 896, 900 oxygen therapy altitude illness 686, 687 cluster headache 457 hyperbaric see hyperbaric oxygen therapy oxytocin 50 p53 gene 774, 776 pachygyria 200 Pacinian corpuscles 22 Packer regimen, medulloblastoma 809 PaCO2 brainstem testing 735 raised ICP 741 paediatric autoimmune disorders associated with streptococcal infection (PANDAS) 176–7, 178, 838 Paget’s disease 600–1 pain 847–69 absence of 869 acute neurological illness 755 central 848–53 central post-stroke see central post-stroke pain classification 847–8 coat-hanger 852, 875–7 congenital insensitivity to 354, 358, 869 definition 847 dementia and 851–2 diplopia and 509 epilepsy 853 gate control 40–1 indifference to 869 insensitivity to 869 management 657, 864–8 drugs 865–6 intensive care unit 755 neuro-ablative procedures 866–7 neurostimulation procedures 867 physical methods 867–8 psychological methods 868 movement disorders 852–3 multiple sclerosis 419, 436, 657, 849–50 muscle disease 389 neuropathic (neurogenic) 657, 848 management 865–8 neuropathic conditions 848–64 nociceptive 848 optic neuritis 489, 496, 850 optic perineuritis 498 Parkinson’s disease 157, 852 peripheral nerve 853–60 peripheral neuropathies 349, 854–6 phantom 863–4 processing circuits in brain 852 spinal disease 588, 657 spinal pathways 851 terminology 848 transient indifference to 869 visceral 858 Paine’s syndrome 632 painful arm and moving fingers 853

976

painful legs and moving toes 184, 852–3 painful stimuli, motor responses to 732 pain psychologists 868 palatal tremor (myoclonus) 165, 186 essential (EPM) 165 nystagmus 522 symptomatic (SPM) 165 palilalia 177, 255 palinopsia 99, 527 palliative care, multiple sclerosis 437 pallidum (globus pallidus, GP) anatomy 26, 27 internal (GPi), deep brain stimulation dystonia 171 Parkinson’s disease 161, 162 Panayiotopoulos syndrome 196, 214 Pancoast tumours 530–1, 813, 859 pancreatic encephalopathy 281 panda eyes 743 PANDAS 176–7, 178, 838 panic disorder 829–30 differentiation from epilepsy 206, 209, 827 sine panic 827 pantothenate kinase 2 gene (PANK2) mutations 168, 176 pantothenate kinase-associated neurodegeneration (PKAN) see neurodegeneration with brain iron accumulation Papez’s circuit 43, 834 papilloedema 504, 505 coma 726 disc appearances 505, Plates 13.18–13.23 idiopathic intracranial hypertension 506 see also optic disc oedema paracetamol, migraine 454–5 paradoxical embolus 116 paraesthesiae 349 paragangliomas 920 Paragonimus 324 parahippocampal gyri 41, 43–5, 834 parallel fibres, cerebellar 28, 29 paralysis acute flaccid 316 subacute 106 paramedian pontine reticular formation (PPRF) 39, 58, 59 lesions 541 paramnesias 249 reduplicative 249, 841 paramyotonia congenita (PMC) 397, 398 paranasal sinus disease, anosmia 466 paraneoplastic antineuronal antibodies see antineuronal antibodies, paraneoplastic paraneoplastic cerebellar degeneration (PCD) 641, 817 paraneoplastic encephalomyelitis (PEM) 817–18 with rigidity 818 paraneoplastic limbic encephalitis (PLE) 817–18 cognitive impairment 280, 282–3 paraneoplastic myopathies 406 paraneoplastic neurological disorders (PND) 816–21 classification 817 diagnosis 820–1 incidence and prevalence 816

predominantly CNS 816–19 predominantly peripheral 819–20 treatment 821 paraneoplastic retinopathy 508, 818 paraneoplastic sensory neuronopathy 818–19 paranoid personality 829 paraphasias 253 phonemic 253 paraplegin 624 paraproteinaemic neuropathies 360, 364–5, Plate 9.4 parasitic diseases 321–6 epilepsy 204 muscle symptoms 405 organ transplant recipients 925–6 stroke 149 parasomnias 765–7 classification 765 non-REM 211, 766 REM 211, 766–7 paraspinal nerves, tumours 775 parasympathetic nervous system 72–3, 871, 872 hypothalamus 50–1 neurotransmission 73, 872 parathyroid disease 406, 919–20 paratrigeminal syndrome 530 paraventricular nucleus 49, 50 parenteral nutrition, total 754 parietal cortex, posterior 57, 58 parietal eye field 58, Plate 2.3 parietal lobe epilepsy clinical features 190–1, 192 EEG features 215 parietal lobe haemorrhage 125 parietal lobe lesions 99 gaze palsy 518 sensory changes 105 visual field defects 524 parietal pseudo-thalamic pain syndrome 849 Parinaud’s syndrome 529 gaze palsy 518 nystagmus 522–3, 728 pineal region tumours 810 parkin mutations 156 parkinsonism cardinal motor features 155 causes 156, 162–4 classification 156 drug-induced (DIP) 183, 703, 838 environmental causes 164 ethnic or region-specific 164 psychogenic 182–3 vascular 164 parkinsonism–dementia–ALS complex of Guam 164, 682 Parkinson’s disease (PD) 155–62 anosmia 466 autonomic dysfunction 884, 892 bladder dysfunction 157, 896–7 dementia 162 depression 157, 831, 832, 838 diagnostic criteria 156 differential diagnosis 163–4, Plate 5.1 evolution 158 genetically determined 155–6

Index incidence/prevalence 3, 5, 6, 157 investigations 158, 163–4 motor presentation, typical 157–8 non-motor features 157 on–off fluctuations 158–9 overdiagnosis 100 pain 157, 852 premotor features 157 psychiatric disorders 838 rehabilitation 652 sexual dysfunction 907 sleep disorders 767 surgery 161–2 treatment 158–61 Parkinson’s disease dementia (PD-D) 162, 266–7 clinical features 248, 267 myoclonus 181 paroxysmal hemicrania (PH) 457 chronic (CPH) 457 clinical features 456 differential diagnosis 456 episodic 457 pathophysiology 450 secondary 457 paroxysmal hemicrania-tic syndrome 457 paroxysmal symptoms, multiple sclerosis 419, 436 Parry–Romberg syndrome 477 Parsonage–Turner syndrome 377 particle repositioning procedures, benign paroxysmal positional vertigo 559–60, 561 patent foramen ovale (PFO) 116, 144 pathergy test, Behçet’s syndrome 936 pathway hypothesis of repair 609 patient education migraine 452 multiple sclerosis 427 spasticity management 655 PAX gene mutations 572, 586, 594, 598 PCV chemotherapy regime 802 PDGF gene 776 pearly tumours see epidermoid cysts peduncular hallucinations 526–7 Pelizaeus–Merzbacher disease (PMD) 444–5, 637 pellagra 690, 923 pelvic nerve injuries, bladder dysfunction 900 pelvic splanchnic nerves 73 Pendred’s syndrome 571, 572 penicillamine induced myasthenia gravis 384 Wilson’s disease 170 penicillin G 292, 304 pentobarbital, status epilepticus 235 perceptual function 250 assessment 96 deficits 250–1 perchlorethylene (PCE) poisoning 678 percutaneous endoscopic gastrostomy (PEG) motor neurone disease 381 stroke 659 perfusion-weighted imaging (PWI), MR brain tumours 778, 784, Plate 20.6, Plate 20.9 monitoring tumour growth 793 radiation necrosis 795, Plate 20.10 pergolide 160

peri-aqueductal grey (PAG) 40 bladder control 893, 894 lateral (LPAG) 39–40 periaxin 20, 21 peri-lymph 66, 67 perimetry, unilateral visual loss 491–2 peri-natal injury, epilepsy after 201 peri-natal mortality rate 9 perineal nerve 345 perineurium 346–7, 348 periodic lateralized epileptic discharges (PLEDS) 88 periodic leg movements of sleep (PLMS) 184 periodic limb movement disorder (PLMD) 765 periodic paralysis 208, 397–9 cardiac arrhythmias and 398 hyperkalaemic (hyperPP) 397–8 hypokalaemic (hypoPP) 397, 398 peripheral myelin protein 22 (PMP22) 20 gene mutations/duplications 355, 356 peripheral nerve(s) 337–48 biopsy see nerve biopsy compartments 346–7 fibre types 19, 20 immunology 347–8 leprosy 306 limb movements 106 macro-anatomy 337–46 micro-anatomy 346–7, 348 pain 853–60 Schwann cells 19 stimulation, chronic pain 867 thickening 349, 350, 350 transplant studies in cord injuries 609 peripheral nerve diseases/neuropathies 348–77 acquired 360–72 alcoholic 695 bladder dysfunction 900 clinical approach 349–51 critical care settings 758–9 drug-induced 370, 704 endocrine disorders 368–9 examination 349–50 focal and compressive neuropathies 372–7 history-taking 349 HIV infection 331–4 hypothyroidism 369, 918 inflammatory see inflammatory neuropathies inherited 351–60, 856 metabolic neuropathies 371–2 motor see motor neuropathies nerve biopsy 351 neurophysiology 351 nutritional neuropathies 369–71 painful 349, 854–6 painful iatrogenic lesions 856–7 paraneoplastic 819–20 pathophysiology 348 sarcoidosis 934 scores 350–1 sensory see sensory neuropathies sensory changes 103, 349 sexual dysfunction 909 Sjögren’s syndrome 930 small fibre see small fibre neuropathies

toxic neuropathies 369, 370 tremor 165 peripheral nervous system (PNS) anatomy 337–46 pain perception 853–4 spinal reflex arc 338 synapses 16, 17 peripheral sensitization 854 peripheral vascular changes, autonomic dysfunction 882–3 peri-ventricular nodular heterotopia 200 permeability imaging (Ktrans), MR, brain tumours 779 pernicious anaemia 690 peroneal nerve anatomy 340, 346, 347 neuropathies 373, 376–7 peroxisomal disorders 719–21 perseveration, motor 98, 255 persistent vegetative state 734 personality change epilepsy 837 fronto-temporal dementia 264 organic 829 post-traumatic 669–70 personality disorders 828–9 somatization disorder and 826 personality syndrome, interictal 837 personality types 829 somatoform disorders 826, 827 pes cavus 349, 350 pesticides 680 PET see positron emission tomography phaeochromocytoma 920 facial vascular changes 882 heart rate disturbances 881 hypertension 880, 882 phakomatoses, ocular involvement 508 phantom boarder syndrome 251 phantom pain 863–4 phantosmia 465 pharyngeal reflex see gag reflex pharynx sensory and motor testing 478 sensory loss 484 weakness 484 phencyclidine 699 phenobarbital epilepsy 222, 224, 232 pharmacokinetics 225 status epilepticus 235 phenol intrathecal 435, 656, 866 neurolysis 656, 867 phenothiazines 843 phentolamine 865 phenylephrine, Horner’s syndrome 531 phenylketonuria (PKU) 716–17 phenytoin epilepsy 222, 224, 232–3 pharmacokinetics 225 status epilepticus 235 side effects 938, 939 pheromones 53 phoneme 97

977

Index phonophobia, unilateral 456 phosphenes 490, 526 phosphodiesterase type 5 (PDE-5) inhibitors 909 see also sildenafil photophobia, unilateral 456 photopsia 526 photoreceptors 53–4 heterogeneity 55, 56 physiotherapy botulinum toxin injections and 656 community-based 668 interventions 651–4 multiple sclerosis 437 pain management 867–8 vestibular rehabilitation 558–9 phytanic acid 720, 721 pica 675 Pick’s disease 265, Plate 7.1 pigmenturia 388–90 pilocytic astrocytomas see astrocytomas, pilocytic pineal gland 50 pineal region tumours 775, 809–10 pineoblastomas 809 histology 778, Plate 20.3 management 810 pineocytomas 809 PINK1 mutations 156 pinna, examination 565 pitcher’s neuropathy 373 pituitary anterior 48, 49 posterior 50 pituitary adenomas 805–6 pituitary apoplexy (Sheehan’s syndrome) 807, 919, 941 pituitary carcinoma 805, 806, 807 pituitary disorders 919 pregnancy 941 pituitary tumours 805–7, 919 classification 806 clinical presentation 806–7 management 807 pregnancy and 942 pizotifen, migraine prevention 453 PKAN see neurodegeneration with brain iron accumulation placebo phenomenon 868–9 plasma cell dyscrasias 365, 921–2 plasma exchange Guillain–Barré syndrome 363 multiple sclerosis 428, 432 myasthenia gravis 385 Plasmodium falciparum 325, 326 Plasmodium malariae 325, 326 Plasmodium ovale 325, 326 Plasmodium vivax 325, 326 plasticity, neural 13, 648 corticospinal system 26 spinal cord injuries and 609 therapeutic approaches 670–1 platysma, testing 473 plexopathies 377, 858–9 malignant 858–9 radiation-induced 683, 801, 859 traumatic 858

978

pneumococcal meningitis 292, 294 Pneumocystis carinii pneumonia, chemotherapy-associated 802 pneumonia aspiration 751 nosocomial 751 ventilator-associated 751 POEMS syndrome 365, 819, 924 POLG gene mutations 399, 400, 401 polio(myelitis) 316–17 polio vaccines 316–17 poliovirus 314, 316 poly-A binding protein 2 (PAB2) gene 395 polyarteritis nodosa (PAN) 924, 928–9 hearing loss 573 neuropathy 366, 368 optic neuropathy 501 stroke 149 polycystic lipomembranous osteodysplasia with sclerosing leucoencephalopathy (PLOSL) 278 polycythaemia 922 polyglucosan body disease, adult 278 polyglutamine tract (trinucleotide repeat) disorders 172–5, 636 polymicrogyria 200, 218 polymyalgia rheumatica 501, 863 polymyositis (PM) 402, 403, 820 eosinophilic 405 investigation 403–4 treatment 404 polyneuropathies 105 acute inflammatory demyelinating see acute inflammatory demyelinating polyradiculoneuropathy alcoholic 695 chemotherapy-induced 821 chronic inflammatory demyelinating see chronic inflammatory demyelinating polyradiculoneuropathy critical illness 758–9 diabetic 368, 856 familial amyloid see familial amyloid polyneuropathy gestational 942 nerve conduction studies 91 sensory changes 102, 103 toxic 676, 679, 680 ventilatory insufficiency/failure 737 Wegener’s granulomatosis 930 see also peripheral nerve diseases/neuropathies; specific neuropathies polyopia 99, 527 polysomnography (PSG) 763 polyuria, nocturnal 883 Pompe’s disease 715 pons haemorrhage 125 infarction 123 lesions gaze palsy 518, 728 hearing loss 579 motor fibres 34 sensory pathways 35 pontine micturition centre (PMC) anatomy 39, 40, 893–5 disorders affecting 897, 898

ponto-cerebellar tract 29, 35 ponto-cerebellum 28 population age structure 1–2 doubling time 2 porphyria 708–9 acute intermittent (AIP) 276, 371, 708–9 neuropathies 371 port wine naevus 199 Poser criteria, multiple sclerosis 424 positive end expiratory pressure (PEEP) 738 positive sharp waves, EMG 89–90 positron emission tomography (PET) 87 epilepsy 220, 237 parkinsonism 164 post-anoxic coma 732, 733 post-concussional syndrome 669, 841 posterior cerebral artery (PCA) 112 occlusion 122, 915 P1 segment 513 posterior circulation ischaemia, hearing loss 579 posterior column → medial lemniscus pathway 33, 35–6 posterior columns (dorsal columns) 33, 35 examination 85 lesions 102, 104 posterior commissure lesions 518, 529 posterior communicating (PCOM) artery aneurysms 127, 128 posterior cortical atrophy (PCA) clinical features 248 cognitive deficits 250, 254 posterior cutaneous nerve to thigh 347 posterior inferior cerebellar artery (PICA) 112 occlusion 122, 148, 552 posterior interosseous nerve 339, 342 posterior ischaemic optic neuropathy (PION) 501 posterior reversible leucoencephalopathy syndrome (PRES) 757–8, 795 pregnancy 941 posterior root ganglia see dorsal root ganglia posterior short ciliary arteries 498–9, 500 posterior spinal arteries 913–14 posterior tarsal tunnel syndrome 374 postero-lateral tract (PLT) 32 post-fixational blindness 523 post-gastroplasty/gastrectomy 370 post-herpetic neuralgia (PHN) 313, 860 after herpes zoster ophthalmicus 471 risk factors and prevention 860 post-infectious disseminated encephalomyelitis 638 post-Lyme syndrome 304 postmortem diagnosis, dementia 286 post-polio syndrome 317 post-streptococcal autoimmune disorders 176–7 post-surgical neuralgia 856–7 post-traumatic amnesia (PTA) 669 post-traumatic epilepsy 202–3 post-traumatic stress disorder (PTSD) 830 postural hypotension see orthostatic hypotension postural instability parkinsonism 155, 158 physiotherapy interventions 653 postural tachycardia syndrome (PoTS) 878, 880, 882 management 891

Index posture coma 732 outstretched upper limbs 82–3 posturography 550–1 post-vaccination encephalopathy 201 potassium aggravated myotonia (PAM) 397, 398 potassium channel gene mutations 397, 398 see also voltage-gated potassium channel gene mutations potassium disturbances 919, 920 Pott’s disease 301, 617 pout reflex 65 power, assessment 83, 390 Powessan virus 315 PPP2R2B CAG repeat 635 pralidoxime 689 pramipexole 160 praziquantel 323, 324 preconception care, epilepsy 940 prednisolone/prednisone Bell’s palsy 475 inflammatory myopathies 404 isolated cerebral angiitis 931 multiple sclerosis 428 syphilis 302 vasculitis 929 pre-eclampsia 937–8, 941 prefrontal cortex basal ganglia circuits 27, 28 bladder control 893, 894 dorso-lateral (DLPFC) 44, 58, 58, Plate 2.3 pregabalin epilepsy 222, 224, 233 pain management 866 pharmacokinetics 225 pregnancy 936–42 brain and spine tumours 942 cerebrovascular disorders 940–1 Chiari I malformation 595 chorea gravidarum 942 epilepsy and 936–40 folic acid supplementation 597, 940 headache 941 idiopathic intracranial hypertension 942 multiple sclerosis and 418, 942 myasthenia and 386, 941 neuromuscular disorders 941–2 new-onset epilepsy 937 seizures during 937 premotor cortex (PMC; PMA) 24, 25, 26 basal ganglia circuits 27 dorsolateral (PMd), post-stroke changes 648 visual pathway 57, 58 prenatal injury, epilepsy after 201 pre-optic nucleus (PON) 39, 40, 49 presbyacusis, precocious 577 presenilin (PS-1 and PS-2) gene mutations 260 pressure sores, complicating stroke 142 prevalence, disease definitions 1 difficulties of estimating 6–7 neurological disorders 2, 3, 5–6 priapism 884 primary auditory cortex 24, 68 lesions 580

primary lateral sclerosis (PLS) 377, 378 hemiplegic variant of Mills 378 prognosis 379 primary motor cortex (M1; area 4) 24–5 afferents 26 movement direction and synergy 25–6 primary visual cortex (striate cortex; V1; area 17) 24, 53, 55, 57 lesions 524–5 primidone epilepsy 222, 224, 233 pharmacokinetics 226 primitive neuro-ectodermal tumours (PNETs) 809 imaging 778, 786 see also medulloblastomas prion diseases 248, 267–73 acquired 268, 269–72 ataxic presentation 638 classification 268–9, 276 inherited 173, 176, 268, 272–3 prevention and treatment 273 sporadic 268, 269 useful websites 273 prion protein (PrP) 268, 269 PRKCG gene mutations 635 PRNP gene mutations 268, 269, 272–3 polymorphisms 269, 271, 272 probantheline bromide 891 prochlorperazine 455, 557 progressive bulbar palsy (PBP) 377, 378, 379 progressive external ophthalmoplegia (PEO) autosomal dominant/recessive with multiple deletions 400 chronic (CPEO) 400, 401, 512 progressive hemifacial atrophy 477 progressive multifocal leucoencephalopathy (PML) 319 dementia 281 HIV infection 328–9 multiple sclerosis 431–2 organ transplant recipients 925 progressive muscular atrophy (PMA) 377 progressive myoclonic ataxia see Ramsay-Hunt syndrome progressive non-fluent aphasia (PNFA) 253, 265 clinical features 248, 265 neuropathology 266 progressive supranuclear palsy (PSP) 163 dementia 267 differential diagnosis 163–4, Plate 5.1 facial weakness 473 neuropathology 265, Plate 7.1 psychiatric disorders 838 PROGRESS trial 143 prolactinomas 806, 807 propantheline bromide 896 propionic acidaemia 718 propiverine hydrochloride 896 propofol acute neurological illness 754–5 status epilepticus 235 propranolol 453, 463 proprioceptive sensation 31 proptosis Plate 13.24

prosody, abnormal 253 prosopagnosia 527 colour vision 528 dementia 250, 251 lesions causing 98, 99 progressive 251 prostatectomy Parkinson’s disease 897 radical, incontinence after 900 prosthetic heart valves 916 anticoagulation-related haematomas 126 infective endocarditis 116, 309, 310 stroke prevention 144 protease inhibitors, toxic neuropathy 334 protein 14-3-3 258, 269 protein lipoprotein (PL) 445 protein P2 (P2) 20, 21 protein zero (P0) see myelin protein zero proteolipid proteins (PLP) 20, 21 mutation 624 protozoan diseases 321, 324–6 proximal myotonic myopathy (PROMM) 392, 395 pseudobulbar affect 484 pseudobulbar palsy 101, 483, 484–5 basilar artery occlusion 123 causes 484 pseudodementia 841 pseudohallucinations 832 Pseudomonas meningitis 292, 293, 295 cancer 816 pseudomyotonic discharges, EMG 90 pseudoseizures see non-epileptic attack disorder pseudovestibular neuritis 552 psychiatric assessment, before epilepsy surgery 237 psychiatric disorders 829–45 alcohol abuse 695 autonomic dysfunction 884–5 brain tumours 773 cognitive impairment 248 differentiation from epilepsy 210 drugs causing 701 drug treatment 842–4 epilepsy 835–7 Gilles de la Tourette syndrome 178, 831, 838–9 Huntington’s disease 175, 838 learning disability and epilepsy 230, 837 motor neurone disease 381 movement disorders 837–9 multiple sclerosis 436, 660, 839 neuro-anatomical concepts 833–5 neurological patients 823–4 rehabilitation strategies 659–60 secondary to neurological illness 833–40 treatment 842–5 white matter disorders 839–40 see also specific disorders psychiatry 823–45 basic principles 828–9 liaison 823–4 medically unexplained symptoms 824–8 psychic experiences 209–10 psychogenic movement disorders (PMD) 182–3, 828 psychogenic unresponsiveness 732

979

Index psychological treatment chronic pain 868 psychiatric disorders 845 vestibular disorders 560–1 psychopathic personality 829 psychophysical tests, auditory function 568–9 psychoses 832–3 differentiation from epilepsy 210, 211 drug-induced 701 Huntington’s disease 838 inherited white matter diseases 840 interictal 836–7 Parkinson’s disease 838 postictal 836 progressive disintegrative 840 Schneider’s first rank symptoms 833 psychotropic drugs 842–4 Psycilocybe poisoning 681–2 PTEN gene 774, 776 pterygopalatine ganglion 65, 66, 73, 472 ptosis IIIrd nerve palsy 80 Horner’s syndrome 530 myasthenia gravis 384 pudendal nerve 345 puerperium, epilepsy and 939–40 puffer fish 681 Pulfrich phenomenon 527 pulmonary artery aneurysms (PAA), Behçet’s syndrome 936 pulmonary complications acute neurological illness 751 see also respiratory disorders pulmonary embolism 142, 751 pulmonary oedema high altitude 687, 688 neurogenic 751 subarachnoid hemorrhage 130 pulmonary–renal syndrome 929 pulseless disease see Takayasu’s disease pulvinar 46, 47 pupil(s) abnormalities 528–31 autonomic disease 884, Plates 23.2–23.3 brainstem death 735 constricted, coma 727 dilated, coma 727 drug effects 704 examination 79, 727 sympathetic disorders 530–1 pupillary light reflex afferent defects see afferent pupillary defect central (midbrain) lesions 529 coma 727 disorders 529–30 efferent parasympathetic defects 530 pathway 59, 529 unilateral visual loss 492–3 pure autonomic failure (PAF) 163, 882–3 anhidrosis 883 coat-hanger pain 852 gastrointestinal dysfunction 883 heart rate disturbances 882 lacrimal dysfunction 884 management 886, 888, 890

980

psychological disorders 884 Raynaud’s phenomenon 883 supine hypertension 880–1, 890 urinary tract dysfunction 883 pure-tone audiogram (PTA) 566, 567 purine receptors, P2X3 853 Purkinje cells, cerebellar 28–9, 30 putamen 26, 27 haemorrhage 125 pyomyositis, suppurative 405 pyramidal cells 41, 42, 55 pyramidal decussation 34 pyramidal lesions see upper motor neurone (UMN) lesions pyramidal system see corticospinal system pyramidal tracts see corticospinal tracts pyramids, medullary 25, 34 pyrazinamide 299–300 pyrexia acute stroke 141 coma 726 control, raised ICP 742 febrile seizures 196 see also hyperpyrexia pyridostigmine 385, 689 pyridoxine (vitamin B6) 370, 690 pyrimethamine 332 pyrolysate encephalopathy 281 pyruvate dehydrogenase deficiency 634 quadriceps femoris, nerves to 345, 346 quadriparesis 100 quadriplegic myopathy, acute (AQM) 759 quality-adjusted life years (QALYs) 9, 10 quality of life brain tumours 8, 795 post-stroke 668 rating scales 662 Queen Square Cognitive Screening Tests 79 quetiapine, dementia with Lewy bodies 162 quinto-thalamic tract 35–6, 63 RAB7 mutations 357 rabies 317–18 racoon eyes 743 radial nerve anatomy 338, 339, 342 biopsy 95 neuropathies 373, 695–6 radiation encephalopathy 682–3 acute 682, 801 early-delayed 682–3, 801 late-delayed 282, 683, 795, 801 radiation-induced leucoencephalopathy 795 radiation-induced neurological disease 682–3, 793–5, 801 radiation-induced optic neuropathy 504, 795 radiation-induced plexopathy 683, 801, 859 radiation myelopathy 683, 801 radiation necrosis 683, 795, 801, Plate 20.10 radicular pain 588 arachnoiditis 604 degenerative spinal disease 614, 615, 616 infiltrating tumours 813 radiculomyelopathy, tuberculous 301

radiculoneuropathy, Lyme disease 303 radiculopathy 105 see also root lesions radiosurgery (stereotactic radiotherapy) 800 arteriovenous malformations 132 brain metastases 799, 804 brain tumours 797 cavernous malformations 133 epilepsy 238 trigeminal neuralgia 470 vestibular schwannomas 812 radiotherapy (RT) brain tumours gliomas 8, 801–2, 803 imaging after 793–5 meningiomas 803 metastases 799, 804 pituitary tumours 807 planning 800 stereotactic 800 cranial complications 682–3, 801 secondary tumours 772, 801 craniospinal (CSI), medulloblastoma 809 intensity modulated (IMRT) 800 malignant meningitis 814 neurological complications 682–3 primary CNS lymphoma 808, 809 spinal tumours 804–5 complications 683, 801 planning 800 vestibular schwannomas 812 Raeder’s syndrome 530 Ramsay-Hunt syndrome 313 ataxia 633, 637 differential diagnosis 475 hearing loss 577 raphe nuclei 37, 38 rapid eye movement sleep see REM sleep rasagiline 159 Rasmussen’s encephalitis 204, 280 Rathke’s pouch tumours 812 Raymond’s syndrome 514 Raynaud’s phenomenon 883 reading disorders 254 Rebif (interferon β1a) 429, 430 rectal cancer surgery, pelvic nerve injury 900 rectal pain disorder, familial 855 recurrent laryngeal nerve 478 lesions 480 red nucleus 30 reflex arc, spinal 338 reflex sympathetic dystrophy (CRPS type 1) 861, 862 Refsum’s disease 720–1 hearing loss 571, 577 rehabilitation 645–71, 660 acute stage 646, 665, 666, 668–9 assessment 660–1 guidelines 665 management of impairments 654–60 mechanisms of recovery 645, 646, 647 multi-disciplinary working 646–7, 660 multiple sclerosis 428, 437 optimizing functional reorganization 649 physical therapeutic interventions 651–4

Index process and outcome 660–3 research needs 670–1 restorative strategies 647–9, 670–1 service options 645–6, 665–8 single incident brain injury 664–70 spinal cord injuries 607, 653 stroke see under stroke therapeutic and task-related training 649–51 vocational see vocational rehabilitation relative afferent pupillary defect 492, 529 relative cerebral blood volume (rCBV) brain tumours 778, 784, Plates 20.8–20.10 meningiomas 789, Plate 20.6 monitoring tumour growth 793 radiation necrosis 795, Plate 20.10 Remak bundle 348 REM sleep 760, 761 breathing during 761 regulation 760 REM sleep behaviour disorder (RBD) 157, 767 REM sleep disorders (parasomnias) 211, 766–7 remyelination, multiple sclerosis 414, 415, 433 renal-coloboma syndrome 594 renal disease 923–5 renal failure hearing loss 572 rhabdomyolysis 408 see also uraemia renal transplantation 927 reserpine 183 respiration apneustic 731–2 assessment 84 ataxic 731 brainstem testing 735 Cheyne–Stokes 731–2 coma 731–2 impaired voluntary control 731 neural control 37–8 respiratory disorders autonomic disease 884, 891–2 multiple sclerosis 436–7 secondary anoxic seizures 207 sleep fragmenting 767 respiratory failure causes 737 intensive care 736 neuromuscular disorders 386, 750–1 respiratory function, assessment 390, 736 respiratory management motor neurone disease 380 see also ventilatory support respiratory tract infections, anosmia 466 response modulation, impaired 255 restless legs syndrome (RLS) 184, 211, 764–5 pregnancy 941 vs. painful legs and moving toes 853 restoration, neural 670–1 mechanisms 647–9 therapeutic approaches 649–54 reticular activating system, ascending 38 reticular formation (RF) 37–41 anatomy 37, 38 functions 37–41 trigeminal projections 64

reticular nucleus of thalamus 45, 46, 46, 47, 48 reticulo-cerebellar tracts 29 retina 53–5 blood supply 498–9 colour recognition 54–5 structure 53–4, 56 retinal artery occlusions 499, Plates 13.4–13.5 retinal capillary haemangiomas 508 retinal degeneration, paraneoplastic 508, 817 retinal disease clinical presentation 490 colour vision impairment 491 fundus examination 493 neurological disorders 508 pupil light reflex 492 retinal ganglion cells 53, 54 heterogeneity 55, 56 retinal haemorrhages altitude-related 687, Plate 18.3 subarachnoid hemorrhage 127 retinal vein occlusions 499 retinal venous hypertension 493 retinitis pigmentosa 507–8 retinoblastoma (Rb) gene 774 retinochoroidal collateral vessels 493 retinol 690 retinopathy acute zonal occult outer 490 carcinoma-associated 508, 817 drug-induced 704 high altitude Plate 18.4 salt and pepper 508 slow flow 502 reversible posterior leucoencephalopathy see posterior reversible leucoencephalopathy syndrome rhabdomyolysis 407, 408 drugs causing 706 rheumatic fever 916 rheumatoid disease 924, 931 neuropathy 367 spinal/spinal cord disease 601–2 stroke 150 rheumatological disorders, spine and spinal cord 600–3 rhythmic movement disorders 767 Richardson syndrome 163 Rich focus 298 ricin 689 rickettsial diseases 314–16 Riddoch phenomenon 525 rifampicin leprosy 306 meningococcal prophylaxis 293 tuberculosis 299–300 right hemisphere psychiatric syndromes 840, 841 rigidity 155 assessment 83 cogwheel 155 paraneoplastic encephalomyelitis with 818 Riley–Day syndrome (familial dysautonomia) 358, 874, 900 riluzone, motor neurone disease 380 Rinne tuning fork test 566 rippling muscle disease 406

risk factors 8 risperidone, tics 179 Ritalin (methylphenidate) 697 rituximab multiple sclerosis 433 neuromyelitis optica 439 paraproteinaemic neuropathies 365 vasculitis 367, 929 rivastigmine 262–3 rizatriptan 454 robotic devices, aiding rehabilitation 654 Rocio encephalitis 315 Rocky Mountain spotted fever (RMSF) 314 rod dystrophies 507 rods 54 heterogeneity 55, 56 Rolandic epilepsy see benign partial epilepsy with centrotemporal spikes roll manoeuvre 543–4 Romana’s sign 324 Romberg sign 349 Romberg test 81–2, 546 root lesions 105 radiation-induced 801 sensory 102, 103–4 tumour invasion 813 roots, nerve 106 ropinirole 160 Rosenthal fibres 445 Ross’s syndrome 530, 883 rostral interstitial nucleus (RiN) 59 lesions 518, 519 rotary chair testing 547–8 roundworms 321, 322 rubella, congenital 638 rubral tremor (Holmes tremor) 165 rubrospinal tract 25 rucksack palsy 373 Ruffini endings 21, 22, 23 rum fits 693 Russian encephalitis 315 RYR1 gene mutations 396, 397, 705 S-100 258 saccades 536, 540–1 basal ganglia circuit 28 cortical control 58 saccadic eye movements abnormalities 517–18, 541 cerebellar disease 630 clinical assessment 541 coma 728, 729 delayed initiation 518 dysmetric (inaccurate) 518 hypermetric 518 impersistence 518 intrusions 518 slow/fast 517–18 saccadomania 518 saccule 66, 67, 535 sacral neuromodulation (SNM), urinary retention 904 sacral parasympathetic fibres/ganglia 73 sacral sparing, sensory loss 104 sacral sympathetic ganglion 72 sacrococcygeal spine disease, assessment 588–9

981

Index safety issues dementia 285–6 maternal epilepsy 940 St Louis encephalitis 315 SAINT studies 140 salivation, reduced 883 saltatory conduction 20 Sandhoff ’s disease 713–14 SANDO (sensory ataxic neuropathy dysarthria and ophthalmoplegia) 400 Sanfilippo syndrome (MPS III) 709, 711 saphenous nerve 346 sarcoglycans 388, 389 sarcoid encephalopathy 934 sarcoidosis (neurosarcoidosis) 933–4 dementia 280 fundus examination 493 hearing loss 578 meningeal and parenchymatous 934 optic neuropathy 497–8 peripheral neuromuscular 934 spinal cord involvement 619 stroke 150 uveomeningitic disease 507 sarcomas 772 sarcomeres 388 sarin 688–9 sartorius, nerve to 345 satellite cells 19, 31, 32 satiety centre 50–1 Satisfaction with Performance Questionnaire 662 Saturday night palsy 373, 696 saxitoxin 681 scalp, examination 79 scapula, winging of 480 Schilder’s disease 720 Schilling test 691 schistosomiasis 324 schizencephaly 199–200, 218 schizoid personality 829 schizophrenia 833, 836–7, 840 Schmidt’s syndrome 479 Schuermann kyphosis 590 Schumacher criteria, multiple sclerosis 424 Schwann cells 19, 348 myelination 21 transplant studies 609 schwannomas 812 histology 778, Plate 20.3 spinal 613, 799 vestibular see vestibular schwannomas sciatica, catamenial 373 sciatic nerve 337, 345, 347 muscles innervated 340 neuropathies 373 SCN1 gene mutations 197, 450 SCN4 gene mutations 397–8 SCN9A gene mutations 358, 855, 869 scoliosis 589–90 congenital 586, 590, 592 degenerative 592 familial horizontal gaze palsy with progressive (HGPPS) 600 idiopathic 589, 590, 592 management 592

982

myopathic 592 neuromuscular 590 neuropathic 592 non-structural 589 structural 589, 590 scombroid poisoning 681 scorpion stings 681 scotomas, junctional 491–2 scrapie 268 sea sickness 556 second (II) nerve see optic nerve secretory granules 16, 18 sedation acute neurological illness 754–5 critical care settings 755–6 sedative drugs 843–4 abuse 698–9 see also benzodiazepines Segawa disease 167 seizures absence 191–3, 213, 223 alcohol withdrawal 693 anoxic secondary 207 arteriovenous malformations 131 atonic (astatic) 194, 224 bacterial meningitis 291 cavernous malformations 133 clonic 193 coma 732 dissociative see non-epileptic attack disorder driving regulations 240–1 drug induced 700, 842, 843 drug options by type 223–4 eclamptic 937–8 EEG classification 213–15 emergency drug treatment 234 epidemiology 189 epileptic definition 189 diagnosis 204–5 differential diagnosis 204–12 febrile 196–7 fetal effects 938 gelastic 190, 201 generalized 190, 191–4 generalized tonic–clonic see generalized tonic–clonic seizures ILAE classification 189–94 intensive care unit 758 learning disability and diagnosis 230 maternal, safety issues 940 myoclonic 193, 224 nocturnal 210, 767–8 non-epileptic see non-epileptic attack disorder organ transplant recipients 926 orthostatic hypotension 875 painful 853 partial (focal) 190–1 anatomical location 191, 192 complex 191 drug treatment 224 facial muscle and eye movements 209 generalization 191 motor 208 simple 190–1

postoperative 203 pregnancy and 937, 938, 941 provoked 240–1 puerperium 939 recurrence risks 215, 220–1 self-induced, learning disability 230 subarachnoid hemorrhage 8, 130 tonic 193, 224 tonic–clonic (grand mal) 194 tumour-associated 201, 773 selective serotonin reuptake inhibitors (SSRIs) 842 dementia 285 Gilles de la Tourette syndrome 179 serotonin syndrome 707 selegiline 159, 892 Self Assessment of Occupational Functioning (SAOF) 662 self-mutilation, Gilles de la Tourette’s syndrome 839 sellar region tumours 775, 805 semantic dementia (SD) 264 clinical features 248, 264 knowledge deficits 251 neuropathology 266 reading and writing deficits 254 speech and language deficits 253, 264 semicircular canals 66, 67 caloric testing patterns 548–9 encoding of head movements 535 vestibulo-ocular reflex 535 Semont manoeuvre 559, 560 senataxin 633 senile plaques 14–15, 259 sensation 31–4 sensitization central 854 peripheral 854 sensory abnormalities 101–5 peripheral neuropathies 349 sensory (nerve) action potentials (SAPs or SNAPs) 91 sensory and sensorimotor neuropathy, paraneoplastic 819 sensory ataxic neuropathy dysarthria and ophthalmoplegia (SANDO) 400 sensory attacks, transient focal 208–9 sensory conduction velocity 91 sensory cortex, Brodmann’s areas 24 sensory facilitation techniques 652 sensory loss dissociated 104 peripheral neuropathies 349 sacral sparing 104 suspended 104 sensory modulation 40–1 sensory nerve conduction studies 92 sensory nerve endings 21–3 sensory neuropathies 349–50, 351 congenital type II 900 diabetic distal symmetric 368, 856 distal acquired demyelinating (DADS) 364 HIV-related 331–4 paraneoplastic 818–19 paraproteinaemic 365 Sjögren’s syndrome 930 small fibre 855

Index see also Charcot–Marie Tooth disease; hereditary sensory and autonomic neuropathy; specific neuropathies sensory pathways 31–4 brainstem 35–6 sensory retraining techniques 652 sensory root lesions 102, 103–4 sensory stimulation techniques 651–2 sensory system, examination 85 sentaxin (SETX) gene mutations 358 sepsis acute neurological illness 754 cavernous sinus thrombosis 152 cerebral venous thrombosis 151 critical care settings 755 septal area 41, 44–5 septic encephalopathy 756 septic shock 755 Septin 9 gene mutations 358 septo-hippocampal tract 45 serotonin 5-HT3 receptor antagonists, migraine 455 serotonin syndrome 707, 708 setting sun sign 570 seventh (VII) nerve see facial nerve sex-adjusted incidence rates 3–4 sexual arousal 51, 905–6 sexual dysfunction 883–4, 906–9 drug-induced 704 management 658, 891, 909 multiple sclerosis 419, 435, 908 neurological causes 906–9 prevalence 906 sexual function, neural control 905–6 sharp waves, EEG 88, 212 Sheehan’s syndrome (pituitary apoplexy) 807, 919, 941 sheep dipper flu 680 shellfish poisoning 681 shift work 765 shingles see herpes zoster short-lasting unilateral neuralgiform headache with conjunctival injection and tearing see SUNCT short-lasting unilateral neuralgiform headache with cranial autonomic symptoms (SUNA) 457–8 shoulder–hand syndrome 861 shoulder pain, stroke 142, 657 shunts, CSF 506, 748 SIADH see syndrome of inappropriate antidiuretic hormone secretion sialidosis 277 sialorrhoea motor neurone disease 378, 380 Parkinson’s disease 157 sickle cell disease 921 cognitive impairment 275 stroke 116 sick sinus syndrome 116, 915–16 siderosis, superficial causes 603–4 cerebellar ataxia 639, 640 hearing loss 579 spinal disease 603–4 sildenafil 891, 907, 908, 909 Silver’s syndrome 357, 624

simultanagnosia 250, 528 Sinemet 158 single photon emission computed tomography (SPECT) 87 epilepsy 219–20 parkinsonism 164 sixth (VIth) nerve see abducens nerve Sjögren’s syndrome (SS) 924, 930–1 hearing loss 573 myopathy 405 skeletal dysplasias, spinal deformity 591 skeletal muscle channelopathies 397–9 skew deviation 519, 539–40 skills, open and closed 650 skin biopsy 258, 306 changes, dermatomyositis 402 damage, lightning and electrical injuries 685 sensory nerve endings 21–3 skull examination 79 fractures 743, 746 SLC6A19 gene mutations 634 SLC26A4 gene mutations 572 SLE see systemic lupus erythematosus sleep 38, 760–1 breathing and 761 EEG testing in epilepsy 212–13 electrical status epilepticus in 214 epilepsy syndromes and 767–8 episodic phenomena in 210–11 functions 760 intensive care patients 755 normal physiological movement 210 regulation 760 structure of normal 760, 761, 761 sleep apnoea see obstructive sleep apnoea/ hypopnoea syndrome sleep deprivation EEG in epilepsy 212–13 intensive care unit 755 sleep disorders 761–8 drug induced 702, 762 dyssomnias 761–3 extrapyramidal disorders 767 motor neurone disease 381 sleepiness, excessive daytime see excessive daytime somnolence sleeping sickness 325 sleep myoclonus 766 sleep paralysis 763 sleep starts 766 sleep talking 766 sleep terrors 766 sleep–wake transition disorders 766 sleep walking (somnambulism) 211, 766, 833 slim (HIV wasting disease) 405 slow wave complexes, EEG 88 slow wave sleep (SWS) 760, 761 small bowel biopsy 258 small cell lung cancer (SCLC) brain metastases 789, 792, 804 Lambert–Eaton myasthenic syndrome 387, 816, 819 paraneoplastic disorders 817, 818, 819

small fibre neuropathies (SFN) 371–2 causes 371 painful 855 uro-genital symptoms 909 smallpox, as biological weapon 689 small vessel disease, cerebral cognitive impairment 123, 274–5 differentiation from multiple sclerosis 420 lacunar infarction 110, 120 stroke prevention 145 smell, sense of see olfaction SMN l gene mutations 382, 383 SMNII gene mutations 382 smoking multiple sclerosis and 413 stroke risk 115 subarachnoid haemorrhage risk 127 smooth pursuit eye movements 536, 541–2 abnormalities 542 cerebellar disease 630 clinical assessment 542 snake venoms 386, 681 Sneddon’s syndrome 150, 933 social disinhibition see disinhibition sociopathic personality 829 SOD1 mutations 378–9 sodium channel gene mutations, voltage gated see voltage-gated sodium channel gene mutations sodium disturbances 919, 920 sodium oxybate 764 sodium valproate see valproate/valproic acid soldier’s heart 878 solifenacin succinate 896 solitary nucleus cranial nerve nuclear column 36, 37 cranial nerve nuclei 70, 71 solvent abuse (glue sniffing) 699–700 cerebellar ataxia 639 specific solvents 678, 679 solvents 639, 676, 678–9 somatization disorder 107, 824, 827 somatoform disorders 106–7, 824, 825–6 spectrum 827 somato-sensory attacks, transient 208 somato-sensory cortex afferents to primary motor cortex 26 primary (SI) 24, 25 secondary (SII) 24 trigeminal projections 64 somato-sensory evoked potentials, coma 733, 734 somato-sensory pathways 31–4 somnambulism see sleep walking somnolence, excessive daytime see excessive daytime somnolence Sonic Hedgehog (Shh) gene 586, 777 South American trypanosomiasis see Chagas disease space-occupying lesions, intracranial, cognitive impairment 279–82 SPARCL study 143 sparganosis 322 spartin 624 spasmodic torticollis see cervical dystonia spasmus nutans 521

983

Index spasticity 654–6 aggravating factors 655 assessment 83 coma 732 drug treatment 655–6 multiple sclerosis 434–5, 656 physical therapeutic interventions 651 stroke 142, 656 spastic paraparesis 100–1 spastic paraplegia, hereditary (HSP) 623–5 spastin 624 spatial orientation, three-dimensional 533–5 spatial recognition 57 SPECT see single photon emission computed tomography speech and language therapies 581, 650–1 speech audiometry 567 speech impairments 252–4 cerebellar ataxia 629 multiple sclerosis 436 see also aphasia speech recognition tests 567 spelling impairments 254 sphenoid wing meningiomas 502–3 sphincter pupillae 60, 61, 62 spiders, venomous 681 spike-and-wave abnormalities, EEG 88, 212, 214 spikes, EEG 88, 212, 214–15 spina bifida 597, 939 occulta 597 spinal abscess epidural 297, 298, 617 intramedullary 298 subdural 298 spinal accessory nerve (XI) anatomy 70, 71, 477, 480 brainstem origin 37 examination 82 lesions 480–1 muscle innervated 339 spinal arteriovenous malformations (AVMs) 153, 621–2, 623 bladder dysfunction 899 spinal canal stenosis 588–9, 615 spinal claudication 588–9, 615 spinal cord blood supply 913–14 corticospinal tracts 25 infarction 620, 621, 623 aortic disease 914–15 inflammation 619 ischaemia, aortic disease 914–15 metabolic disease 625–6 pain pathways 851 reflex arc 338 somato-sensory pathways 31–4 tethered see tethered cord syndrome spinal cord compression complicating lumbar puncture 94 infiltrating tumours 813 metastatic disease 799–800 sensory changes 104 spastic paraparesis 100 spondylitic cervical 614

984

spinal cord injuries (SCI) 604–10 acute management 605–6 autonomic dysreflexia see autonomic dysreflexia bladder dysfunction 883, 898–9 grading of severity 605 long-term care 607–8 non-surgical management 607 pain following 850–1 pathway hypothesis of repair 609 prospects for repair 608–10 rehabilitation 607, 653 sexual dysfunction 907–8 strategies for repair/restoration 648 surgical management 605, 606–7 sweating abnormalities 883 transplantation studies 609–10, Plate 15.2 spinal cord lesions bladder dysfunction 898–9 central 102 decompression sickness 686 drop attacks 207 drug-induced 704 multiple sclerosis 420, 421 pain 657 sensory changes 102, 104 sensory testing 85 transverse 102 unilateral (hemisection) 102, 104 spinal cord stimulation, chronic pain 867 spinal cord syndrome differential diagnosis 425, 426 multiple sclerosis 419 spinal deformity 589–93 causes 589–91 management 591–2 neurofibromatosis 591, 612 surgical correction 591, 592–3 spinal disease 585–626 clinical assessment 587–9 cranio-cervical junction 593–600 degenerative 614–16 identifying genetic mutations 586 rheumatological disorders 600–3 vertebral segmentation defects 586–7 spinal dysraphism 597, 899 spinal fractures ankylosing spondylitis 603 surgical management 605, 606–7 spinal haemorrhage 620–1, 623 spinal infections 616–19 spinal lemniscus 33, 35 spinal metatases 611 radiotherapy and chemotherapy 805 surgery 613–14, 799–800 spinal muscular atrophy (SMA) 381–3 distal see distal hereditary motor neuropathies with respiratory distress type 1 (SMARD1) 358, 383 type I (infantile) 382 type II (intermediate) 382 type III (juvenile) 382 type IV (adult onset) 382 X-linked infantile 382–3 spinal surgery degenerative disease 614–15, 616

rheumatoid arthritis 602 spinal cord injuries 605 spinal deformities 591, 592–3 tuberculosis 617–18 tumours 613, Plate 15.4 spinal tuberculosis 301, 617–18 spinal tumours 611–14 histogenesis 773–4 intramedullary 611, 613 intramural 611, 612–13 metastatic see spinal metatases neurofibromatosis type 1 611–12 pathology 773–8 pregnancy 942 primary bone 612, 613 radiotherapy 800, 801 surgery 612–14, 799–800, Plate 15.4 treatment 612–14 WHO classification 774–8 spinal vascular disease 153, 620–3 clinical features 620–1 diagnosis 623 management 623 spine embryology 585 examination 79 genetic control of development 585–6, 587 spino-cerebellar ataxias (SCA) 173, 635–6 dementia 267, 276 Huntington’s disease (HD) phenocopies 175–6 spino-cerebellar tracts 32, 33–4, 35 spino-cerebellum 28, 30 spino-olivary tract (SOT) 32, 34 spino-parabrachial pathway 851 spino-reticular tract (SRT) 32, 34 spino-tectal tract (ST) 32, 34 spinothalamic pathway 32, 33, 851 spinothalamic tracts 32, 33, 35 examination 85 lesions 104 spiny stellate cells 55 split cervical spinal cord 598 split-cord malformations 586 spondyloarthropathies 603 spondylocostal dysostosis 586 SPTBN2 gene mutations 635 SPTLC1 mutations 357, 358 Spurling’s sign 588 squamous cell carcinoma, brain metastases 791 square wave jerks 518 squint see strabismus SSRIs see selective serotonin reuptake inhibitors Stalevo 159 stance tests 546 standardized mortality ratio (SMR) 8 stapedectomy 580–1 stapedius reflex 65, 68 measurements 567 Staphylococcus aureus infective endocarditis 310 meningitis 292, 295 spinal epidural abscess 298 startle epilepsy 181 startle response 179, 186, 830 startle syndromes 181

Index statins myopathy induced by 406, 407 stroke prevention 143 vascular dementia 279 stato-kinetic dissociation 525 status epilepticus drug treatment 234, 235 EEG monitoring 216 electrical, in sleep 214 intensive care management 749–50 non-convulsive 211, 216, 758 non-epileptic 827–8 pregnancy and delivery 938 psychiatric features 836 stavudine, toxic neuropathy 334 steal syndromes 914 Steele–Richardson–Olszewski syndrome see progressive supranuclear palsy stellate ganglion 72, 872 stem cells brain tumour origin 773 olfactory 609 stem cell therapies, multiple sclerosis 433 stereopsis 57 stereotactic frames brain radiotherapy 800 surgical biopsy 796 stereotaxy, frameless 796 sternomastoid weakness 480 steroid myopathy 407–8, 760 steroid responsive encephalopathy with autoimmune thyroiditis see Hashimoto’s encephalopathy steroids see corticosteroids Stickler’s syndrome 571 stiff limb syndrome 184 stiffness 389 drug-induced 704 stiff person syndrome 184, 818 EMG features 91 stillbirth rate 9 stimulant abuse 696–8 stimulation therapies see neurostimulation therapies storage disorders 709–15 ataxias 634–5 dementia 277–8, 279 muscle disease 401 spinal deformity 591 strabismus 539 Strachan’s syndrome 369–70, 696 strawberry picker’s palsy 373 strength training, post-stroke 652 streptococcal infection group A and D meningitis 292, 295 group B meningitis 294–5 paediatric autoimmune disorders associated with see PANDAS Streptococcus milleri 297 Streptococcus pneumonia meningitis 292, 294 Streptococcus viridian’s 309, 310 streptomycin 299–300 stress, multiple sclerosis relapse and 418 striatal toe, Parkinson’s disease 158 striate cortex see primary visual cortex striato-capsular infarction 121–2

striatum 26, 834 bladder control 897 dorsal 835 motor control system see basal ganglia ventral 44, 835 stridor 884, 891 stroke 109–53 acute anticoagulation 140 antiplatelet therapy 139–40 cerebral oedema treatment 141 imaging recommendations 135 maintenance of homeostasis 140–1 management 137–8, 748–9 mechanical recanalization 139 neuroprotection 140 stroke unit care 137–8 thrombolysis 138–9 athero-thrombotic 145 bladder dysfunction 895–6 cardio-embolic 115–16, 915–17 anticoagulation for 140 investigations 136–7 secondary prevention 144 central pain after see central post-stroke pain classification of subtypes 111 clinical approach 109–11 complications 141–2 defined 109 depression after 142, 659–60, 832 dystonia complicating 142, 168 epidemiology 109, 110 epilepsy 201–2 ethnic differences 7, 109 Fabry’s disease 150, 713 haematological causes 116–17 haemorrhagic see intracranial haemorrhage; subarachnoid haemorrhage HIV infection 327 incidence/prevalence 3, 5, 6, 109 investigations 133–7 ischaemic 110, 111–23 cancer 815 clinical syndromes 119–23 investigations 135–6 pathophysiology 112–14 pregnancy 940 risk factors and causes 114–17 vascular anatomy 111–12 see also cerebral infarction; transient ischaemic attacks neural reorganization after 648–9 neuropsychiatric presentations 840 organ transplant recipients 926 pathology underlying 110–11 physical disablement after 665 postoperative 915 pregnancy 940 progressive, management 141 recurrence risk 142–3 rehabilitation 137, 664–8 guidelines 665 physiotherapy 651–3, 654 symptom management 657, 658–60 task-related training 650

scoring systems 111 secondary prevention 142–7 seizure risk 8 sexual dysfunction 906 spasticity 142, 656 stimulant drug abuse 697 Stroke Prevention in Reversible Ischaemia Trial (SPIRIT) 145 stroke units (SU) 137–8, 665–8 Strongyloides 322 strychnine poisoning 309 stump pain 863–4 stupor 724 idiopathic recurring 763 Sturge–Weber syndrome 199, 508 stylopharyngeus, isolated weakness 478 styrene 679 subacute combined degeneration of spinal cord (SACD) 625–6, 679–80, 691 subacute inflammatory demyelinating polyradiculoneuropathy (SIDP) 361 subacute necrotizing encephalopathy 508 subacute paralytic conditions 106 subacute sclerosing panencephalitis (SSPE) 317 ataxia 638 dementia 281 myoclonus 186 psychoses 840 subarachnoid haemorrhage (SAH) 126–30 aneurysm treatment 129–30 arteriovenous malformations 131 carotid artery dissection 148 clinical features 127–8 CSF examination 94, 128 drug-related 115, 127 hypertension 880 initial management 129 intensive care management 749 investigations 128–9 management of complications 130 outcome 130 risk factors 127 seizure risk 8, 130 spinal 620–1, 623 stroke 110 superficial siderosis after 604 traumatic 744, 745 subclavian arteries 111, 913, 914 subclavian steal-like syndrome, autonomic disease 877 subclavian steal syndrome 914 subcortical band heterotopia 200 subdural empyema 296–7 subdural haematoma (SDH) 744 acute 744 chronic 280, 744 spinal 620–1, 623 subdural spinal abscess 298 subependymal giant cell astrocytomas 776 subependymal nodular heterotopia 200, 218 subfalcine herniation 743 subfornical organ (SFO) 50 subhyaloid preretinal haemorrhages 127 subiculum 41, 42 submandibular ganglion 65, 66, 73, 472

985

Index subscapular nerves 338 substance P 853–4, 906 substantia gelatinosa 31, 32, 40 substantia nigra pars compacta 26 pars reticularis (SNpr) 26, 28 substrate reduction therapy (SRT) 710, 714 subthalamic nucleus (STM) 26, 27 deep brain stimulation 161, 162 sudden unexpected death in epilepsy (SUDEP) 189, 236 Sudeck’s atrophy (CRPS type I) 861–2 sudomotor disorders 883, 891 suicide risk, multiple sclerosis 417, 436 sulfadiazine, toxoplasmosis 332 sulpirid, tics 179 sumatriptan 454, 457 SUNA 457–8 SUNCT 457–8 clinical features 456 differential diagnosis 456, 469 secondary (symptomatic) 458 sunlight, multiple sclerosis and 412–13 superficial abdominal reflexes 84 superficial peroneal nerve 346 superior cerebellar artery (SCA) 513 superior cervical ganglion 70, 72, 872 superior colliculus 28, 58, 60 superior gluteal nerve 340, 345, 347 superior laryngeal nerve 478 lesions 480 superior mesenteric ganglion 872 superior olivary nucleus 68, 69 superior orbital fissure syndrome 468 superior salivatory nucleus 65, 66, 472 supine roll manoeuvre 543–4 supplementary eye field 58, Plate 2.3 supplementary motor area (SMA) 24, 25, 26 basal ganglia motor loop 27 post-stroke changes 648 suprachiasmatic nucleus 49, 51, 63, 760 supra-optic nucleus 49, 50 suprapubic vibration, incomplete bladder emptying 901 suprascapular nerve 338 Pitcher’s neuropathy 373 supratrigeminal nucleus 62, 63 sural nerve 347 biopsy 95 surgery painful nerve lesions after 856–7 pelvic nerve injury 900 Surgical Trial in Intracerebral Haemorrhage (STICH) 126 Susac’s syndrome 933 branch retinal artery occlusion 499 hearing loss 574 stroke 150 suxamethonium 759 swallowing 483–4 swallowing problems bulbar palsy 484 post-stroke 141–2 see also dysphagia sweating abnormalities 883, 891, Plate 23.1

986

sweats, Parkinson’s disease 157 swinging flashlight test 492, 529 Sydenham’s chorea 176–7, 838 sympathectomy, hyperhidrosis 891 sympathetic nervous system 72, 871, 872 eye and face 61–2 hypothalamus 50–1 neurotransmission 73, 872, 873 pupils, disorders of 530–1 sympathetic thoraco-lumbar outflow lesions 908 symptom management 654–60 symptoms history-taking 75–6 medically unexplained 106–7, 824–5 nature of 76 synapses 16, 17 synchronized intermittent mandatory ventilation (SIMV) 738 syncope 877–8 drug-induced 704 light-headedness prior to 536 micturition 878, 890–1 neurally mediated 877–8, 882, 890–1 orthostatic hypotension 875 situational 878, 890–1 swallowing-induced 878 vasovagal see vasovagal syncope vs. epilepsy 205, 207, 826–7 syndrome of inappropriate antidiuretic hormone secretion (SIADH) 752, 920 causes 753 diagnosis 753 subarachnoid hemorrhage 130 vs. cerebral salt-wasting 753 syphilis (including neurosyphilis) 301–2 aortitis 915 Argyll Robertson pupil 302, 529 bladder dysfunction 899 cognitive impairment 281, 302 diagnosis 302 hearing disorders 577–8 meningo-vascular 301–2 optic neuritis 497, Plate 13.2 stroke 149 treatment 302 syringobulbia 588, 595–6 syringomyelia 595–6 clinical assessment 588 post-traumatic 851 sensory changes 85, 104 treatment 596 systemic inflammatory response syndrome (SIRS) 755 systemic lupus erythematosus (SLE) 924, 931 hearing loss 573 myopathy 405 neuropathy 367 neuropsychiatric (NPSLE) 931 optic neuropathy 501 stroke 150 systemic sclerosis myopathy 404–5 stroke 150 tabes dorsalis 302, 899 tabun 688–9

tachycardia 752 see also postural tachycardia syndrome tacrolimus 929 tadalafil 909 Taenia solium 321 Takayasu’s disease 149, 915 tandem gait test 546 tapeworms 321, 322 Tapia syndrome 479 tardive dyskinesia 183, 703 tardy ulnar palsy 373 tarsal tunnel syndrome 374 Tarui’s disease (GSD type VII) 715 task-related training 649–51 taste disturbances see dysgeusia olfactory function and 465 testing 473 tau 14 Alzheimer’s disease 14, 259–60 CSF 262 microtubule associated protein (MAPT), mutations 265 positive inclusions, FTLD 265–6, Plate 7.1 tauopathies 156 tau-tubulin kinase 2 635 Tay–Sachs disease 713–14 TBI see traumatic brain injury TBP CAG repeat 635 tear production, impaired 884, 892 teichopsia 526 teloglia 19, 22 temozolomide 802, 804 temperature regulation 50 temperature sensitivity multiple sclerosis 419, 437 optic neuritis 490 temporal arteritis see giant cell arteritis temporal artery biopsy 932 temporal lobe haemorrhage 125 lesions 98, 526 limbic structures 834 memory function 249 temporal lobe epilepsy (TLE) clinical features 190–1, 192 cognitive impairment 280, 282 differential diagnosis 209–10 EEG features 213, 214–15 hippocampal sclerosis 200 imaging 217, 219, 220 psychiatric disorders 836–7 sexual dysfunction 906–7 surgery 236, 238 tendon reflexes 31, 84 Tensilon test 384–5 tension-type headache (TTH) 455 tenth (X) nerve see vagus nerve tentorial herniation 742 teratogenicity, antiepileptic drugs 938–9 terminal care dementia 286 motor neurone disease 381 terminology, clinical neurology 96–107 terrorism, neurobiological weapons 688–90

Index Terson’s syndrome 127 tessellopsia 527 testicular cancer, paraneoplastic disorders 817, 818 tetanus 308–9 hypertension 880 management 751 tethered cord syndrome 597, 604 bladder dysfunction 899 scoliosis 592 tetrabenazine 179, 183 tetrachlorethylene poisoning 678 tetrahydrocannibinol, multiple sclerosis 434 tetraparesis 100 tetraplegia, autonomic dysfunction 881, 882 tetrathiomolybdate, Wilson’s disease 170 tetrodotoxin (TTX) 681 thalamic lesions gaze palsy 518 sensory changes 102, 104–5 thalamic nuclei 45, 46, 46 association 47 non-specific 47 specific (relay) 46, 47 see also specific nuclei thalamic pain see central post-stroke pain thalamic stimulation, Parkinson’s disease 161, 162 thalamus 45–7 cortical connections 45–7 haemorrhage 125 somato-sensory pathways 31–4 thalassaemia 921 thallium toxicity 677 theory of mind, impaired 255 thermal damage, lightning and electrical injuries 684 thermoreceptors 22 theta activity, EEG 88, 760, 761 thiamine (vitamin B1) 690 deficiency 370, 693–4, 923 treatment 694 thiazide diuretics Ménière’s disease 557 raised ICP 741 thiopental, status epilepticus 235 third nerve (III) see oculomotor nerve third ventriculostomy, hydrocephalus 748 thirst 50 Thomsen’s disease 398–9 thoracic outlet syndrome, neurogenic 373 thoracic spine disease clinical assessment 588 degenerative 615 thoracic splanchnic nerves 72 thoracodorsal nerve 338 thoraco-lumbar radiculopathies, diabetic 369 thoraco-lumbar spine fractures 606–7 thrombocythaemia 922 thrombo-embolism anticoagulation 140 cancer 815 prophylaxis, acute neurological illness 754 secondary prevention 143, 144–5 see also stroke, ischaemic thrombolysis acute ischaemic stroke 138–9

central retinal artery occlusion 499 cerebral venous thrombosis 153 intra-arterial 139 thrombophilia 922 investigations 137 stroke 117 thrombosis cancer 815 ischaemic stroke 112–14 thrombotic thrombocytopenic purpura (TTP) 150, 922 thymectomy, myasthenia gravis 385–6 thymoma 385–6, 820 thyroid disease 406, 917–18 thyroid ophthalmopathy 509–10, 917, Plate 13.24 thyroid-stimulating hormone (TSH)-producing pituitary tumours 805, 806, 807 thyrotoxicosis see hyperthyroidism TIA see transient ischaemic attacks tiagabine 222, 233 dosing regimens 224 pharmacokinetics 226 tibial muscular dystrophy 396 tibial nerve 340, 347 neuropathies 374 tic(s) 177–9 cognitive impairment 280 differentiation from epilepsy 208 drug-induced 703 Gilles de la Tourette syndrome 177 other diseases causing 178 during sleep 767 tic convulsif 477 tic disorders 178 chronic motor or vocal (CMTD) 178 not otherwise specified 178 transient (TTD) 178 tic douloureux see trigeminal neuralgia tick paralysis 386, 681 tilt, field of vision 527 tilt table testing, syncope 878, 879 Tinel’s sign 103 tinnitus 562 tin toxicity 677 titin 389 tizanidine 434, 655–6 tobacco-alcohol amblyopia 504, 696 α-tocopherol transfer protein (αTTP) gene 634 Todd’s paralysis 190 toilet seat neuropathy 373 tolcapone 159 tolfenamic acid 454, 455 Tolosa–Hunt syndrome 510 tolterodine tartrate 896, 900 toluene 678, 700 tone assessment 83 coma 732 tongue deviation 482, 484 examination 82, 481–2 fibrillation 89, 482 weakness 482 tonic–clonic seizures, generalised see generalised tonic–clonic seizures

tonic pupil 530 tonic seizures 193 tonic spasms, multiple sclerosis 208, 419 tonsillar biopsy 258, 271 tonsillar herniation 743 topiramate epilepsy 222, 224, 233 migraine prevention 453 pharmacokinetics 226 top of the basilar syndrome 123, 519, 915 topographical disorientation 250 Tourette syndrome see Gilles de la Tourette syndrome tourniquet palsy 373 toxic amblyopia 504 toxic exposures 675–82 anosmia 466–7 autonomic dysfunction 874 cerebellar disease 639 cognitive impairment 281, 283 coma 732 toxic leucoencephalopathy 702 toxic/metabolic encephalopathy, cancer 815 toxic neuropathies 369, 370 toxic neuropathy for antiretroviral drugs (TNA) 334 toxic nutritional optic neuropathies 504 toxins 678–82 biological 676, 680–2 biological weapons 688, 689 small molecule 676, 678–80 Toxocara canis 322 Toxoplasma gondii (toxoplasmosis) 325 cancer 816 HIV infection 327–8, 332 organ transplant recipients 925–6 tracheal intubation, neurological indications 736, 738 tracheostomy, motor neurone disease 380 tractography, MRI, brain tumours 780 training, task-related 649–51 transcranial Doppler (TCD) ultrasound 136, 139 transcranial magnetic brain stimulation (TMS) 89, 649, 844 transcutaneous electrical nerve stimulation (TENS) 867 transient epileptic amnesia 248, 250, 280, 282 transient focal motor attacks 208 transient focal sensory attacks 208–9 transient global amnesia (TGA) 249–50, 833 distinction from epilepsy 211–12 distinction from TIA 118–19 transient ischaemic attacks (TIAs) 117–19 differential diagnosis 118–19, 208 distinction from stroke 109–10 investigations 133–7 lacunar 119 secondary prevention 142–7 spinal 620 stroke risk after 117 symptoms 117–18 transmissible mink encephalopathy 268 transmissible spongiform encephalopathies see prion diseases transmitter-gated ion channels 18 trans-oesophageal echocardiography (TOE), cardiogenic embolism 136–7

987

Index transsphenoidal pituitary surgery 807 transtentorial herniation, upward 743 transthyretin (TTR) gene mutations 358–9 transthyretin-related familial amyloid polyneuropathy (FAP TTR) 358–9, Plate 9.2 transverse myelitis bladder dysfunction 899, 903 causes 619–20 neuromyelitis optica 438 trapezius weakness 480 trapezoid body 68, 69 trauma complex regional pain syndrome 861 hearing loss 572–3 optic neuropathy 504, Plate 13.15 traumatic brain injury (TBI) 743–6 anosmia 466 cerebral ischaemia 746 depression 832 diffuse axonal injury 745–6 focal lesions 743–5 intensive care management 746, 747 rehabilitation 664–5, 667, 668–70 goal-setting 661 guidelines 665 physiotherapy interventions 652–3 symptom management 659, 660 sexual dysfunction 906 see also head injury Treacher–Collins syndrome 571 treadmill training methods 653 treatment gap 11–12 trematodes 321, 324 tremor 164–5 benign essential (BET) 100, 164, 165 cerebellar 165 cortical 185 deep brain stimulation (DBS) 161, 165, 657 delirium tremens 693 differential diagnosis 208 drug and toxin-induced 165, 703 dystonic 164–5, 185 familial cortical 179 Holmes 165 intention 165 jaw 155 management 657 neuropathic 165 neurophysiological tests 184–5 orthostatic 165 palatal see palatal tremor parkinsonism 155 Parkinson’s disease 157–8 pill-rolling 155 psychogenic 182, 185 re-emergent 155 rest 155 Treponema pallidum 301 triad neuropathy 373 trichloroethylene (TCE) poisoning 678 tricyclic antidepressants chronic daily headache 459 migraine prevention 453 pain management 865 trientene, Wilson’s disease 170

988

triethyl tin 677 trifunctional protein (TFP) deficiency 719 trigeminal-autonomic cephalalgias (TAC) 455–8 clinical features 456 differential diagnosis 456, 469 trigeminal ganglion see Gasserian ganglion trigeminal lemniscus 36, 63, 64 trigeminal nerve (V) 467–72 anatomy 37, 61, 62–4 brainstem sensory pathways 35–6, 62–4 cerebral vessel innervation 64 cutaneous distribution 62, 103, 344, 467 disorders 36, 467–72 nuclear 468–9 peripheral 468 examination 80–1, 467–8 mandibular division (V3) anatomy 62, 63 examination 80, 81, 468 lesions 468 maxillary division (V2) anatomy 62, 63, 64 examination 80, 468 lesions 468 ophthalmic division (V1) anatomy 62, 63, 64 examination 80, 81, 467–8 lesions 468 reflexes 64, 65 trigeminal nerve (V) nuclei mesencephalic 62, 63 motor 34, 62, 63 lesions 469 principal (pontine) 63 sensory 62–4 lesions 469 spinal 63–4, 467 lesions 469 trigeminal neuralgia 469–70 hemifacial spasm with 477 multiple sclerosis 436, 470, 850 trigeminal schwannomas 468 trigeminal sensory neuropathy 471 trigemino-thalamic tract 64 trigemino-vascular system 450, 451 trihexyphenidyl, dystonia 170 trinucleotide repeat (polyglutamine tract) disorders 172–5, 636 triptans cluster headache 457 migraine 454, 455, 558 trisomy 21 see Down’s syndrome TrkA gene mutations 869 trochlear nerve (IV) anatomy 36, 60, 61 examination 79–80 palsy 80, 516, 540 coma 728 trochlear nucleus 60 Tropheryma whippelii 326 tropical spastic paraparesis (TSP) 318, 618–19, 899 trospium chloride 896, 900 Troyer’s syndrome 624 TRPV1 receptors 854, 858, 865 Trypanosoma brucei 325

Trypanosoma cruzi 324 trypanosomiasis African 325 American see Chagas’ disease tuberculomas (tuberculous granulomas) 300 epilepsy 203, 218 spinal intramedullary 301 tuberculosis (TB) 298–301 costs in developing countries 11 dementia 281 diagnosis 299 drug resistant 300 parenchymal CNS 300 spinal 301, 617–18 treatment 299–300 tuberculous abscess 300 spinal intramedullary 301 tuberculous meningitis 298–300 clinical features 298–9 CSF examination 291, 299 management 299–300 spinal 301 tuberculous radiculomyelopathy 301 tuberculous spondylitis 301, 617–18 tuberous sclerosis epilepsy 199 psychoses 840 retinal hamartomas 508 tubo-tympanic disease 570 tularaemia, as biological weapon 690 Tumarkin’s crises 555 tumorigenesis, molecular pathways 773–4 tumour infiltration 813 tumour suppressor genes 774 tuning fork tests 566 turnip picker’s palsy 373 twelfth (XII) nerve see hypoglossal nerve two-point discrimination testing 85 tympanic membrane (TM) colour and position 565 disorders 569–70 examination 565 perforations 565 tympanometry 566, 567 tyramine cheese reaction 708 ubiquitin 14 positive inclusions, FTLD-U 265, 266, Plate 7.1 Uhthoff ’s phenomenon 419, 490 ulnar nerve anatomy 338, 339, 343 compression 375–6 neuropathies 373, 375–6 ultrasonic aspirators 797 ultrasound, therapeutic transcranial 139 ultrasound imaging intra-operative 796–7 stroke/TIA 135–6 uncal herniation 742 unconsciousness see coma unexplained symptoms 106–7, 824–5 University of Pennsylvania Smell Identification Test (UPSIT) 466 Unterberger test 81–2, 546 Unverricht–Lundborg disease 198

Index upper airway resistance syndrome 767 upper cutaneous nerve of arm 341 upper limbs focal neuropathies 373 innervation 337, 338, 339, 341–3 posture of outstretched 82–3 upper motor neurone (UMN) lesions (pyramidal lesions) assessment 84–5 facial palsy 81, 473 hemiparesis 99 upper respiratory tract infections, anosmia 466 upward transtentorial herniation 743 uraemia dementia 281 neuropathy 371, 925 see also renal failure uraemic encephalopathy 756, 924 urea cycle enzyme defects 634, 716 urge incontinence 895, 898 urgency, urinary multiple sclerosis 899 Parkinson’s disease 157 see also detrusor over-activity urinary catheterization clean intermittent self- (CISC) 658, 901 multiple sclerosis 435 urinary incontinence algorithm for neurogenic 901, 902 dementia 285, 896 frontal lobe lesions 895 management 658, 900–2 multiple sclerosis 435 multiple system atrophy 897 non-epileptic attack disorder 828 pelvic nerve injuries 900 stroke 895–6 see also bladder dysfunction urinary retention 902–5 isolated, in women 902–5 neurological causes 895, 902, 903, 904 urinary tract autonomic disorders 883, 891 neural control 893–5 urine post-void residual (PVR) volume 901 specialized tests 93 uro-genital system, neural control 893–5 uro-neurology 893–909 Usher’s syndrome 571, 572 utilization behaviour 98, 255, 264 utricle 66, 67, 535 uveomeningitic syndromes 507 vaccination acute disseminated encephalomyelitis (ADEM) and 439–40 encephalopathy after 201 macrophagic myofasciitis after 405 multiple sclerosis relapse and 418 VACTERL syndrome 586 vagus nerve (X) 478–80 anatomy 72, 477, 478, 479 autonomic function 872 brainstem origin 37

dorsal nucleus 71, 72 examination 82 lesions 478 causes and localization 478–80 clinical features 478 investigation 480 nuclei 34, 70, 71, 72 parasympathetic fibres 72–3, 478 reflexes 72 stimulation, epilepsy 239, 844 valaciclovir, herpes zoster ophthalmicus 471 valproate/valproic acid epilepsy 222, 224, 233–4 migraine prevention 453 mood stabilization 844 myoclonus 182 pharmacokinetics 226 status epilepticus 235 teratogenicity 939 Valsalva manoeuvre related benign headache 462 syncope 878 valvular heart disease 116, 205, 916 vancomycin, bacterial meningitis 292, 293, 294 vanilloid TRPV1 receptors 854, 858, 865 vanishing white matter disease 278, 445, 638 Vannuchi manoeuvre 560 vardenafil 909 varicella (chickenpox) 149, 313 varicella zoster virus (VZV) disseminated infection 925 encephalitis 313 HIV infection 329–30 reactivation, shingles 859 see also herpes zoster vascular anatomy 111–12, 913–14 vascular changes, autonomic dysfunction 882–3 vascular dementia (VaD)/vascular cognitive impairment (VCI) 123, 273–9 Alzheimer’s disease and (mixed dementia) 123, 273 causes 274–5 clinical features 248, 249, 274 depression 832 differential diagnosis 275 management 275–9 neuropathology 123, 274 vascular disease cancer 815 cerebellum 638–9, 640 hearing loss 578–9 non-atherosclerotic 147–53 radiation-induced 801 spinal cord 153, 620–3 see also cerebrovascular disease vascular endothelial growth factor (VEGF), brain tumours 778 vascular loops, VIIIth nerve compression 579 vascular malformations cerebral see cerebral vascular malformations spinal 621 vascular organ of the lamina terminalis (VOLT) 50 vasculitic neuropathies 366–8, Plate 9.6 investigation 367, Plate 9.5 non-systemic 367

paraneoplastic 819 primary 366 secondary 367 treatment 367–8 vasculitic plexopathies, diabetic 368–9 vasculitis 927–33 dementia 248, 280 diagnosis and treatment 928–33 infective 149, 367 optic neuropathy 500–1, Plate 13.9 pathological mechanisms 928 primary cerebral see isolated cerebral angiitis renal and neurological disease 924 secondary 928 seizures 202 stimulant drug abuse 697 stroke 149–50 vasculopathies non-atherosclerotic 117 young onset and inherited dementias 276 vaso-active intestinal polypeptide (VIP) 73, 906 vasopressin 50 vasospasm, subarachnoid hemorrhage 130 vasovagal syncope 874, 877–8, 879 management 890 vestibular symptoms 538 vs. epilepsy 205 VATER syndrome 586 vegetative state 734 Venezuelan encephalitis 315 venous sinuses, cerebral 112, 113 ventilator-associated pneumonia 751 ventilatory insufficiency see respiratory failure ventilatory support 736–8 brainstem testing 735 failure to wean 758–60 modes 738 motor neurone disease 380 neurological indications 736, 738 spinal muscular atrophy 383 weaning from 738 ventral anterior (VA) nucleus of thalamus 27, 28, 46, 46, 47 ventral intermediate (VIM) nucleus of thalamus 47 ventral lateral (VL) nucleus of thalamus 27, 46, 46, 47 ventral posterior (VP) nucleus of thalamus 33, 46, 46, 47, 63 ventral posterolateral (VPL) nucleus of thalamus 46, 47 ventral posteromedial (VPM) nucleus of thalamus 46, 47 ventral respiratory nucleus 37–8 ventral striatum 44, 835 ventral tegmental area (VTA) 897 ventricular tachycardia 752 ventriculostomy, third 748 verapamil cluster headache 456–7 hypnic headache 463 paroxysmal hemicrania 457 vergence movements 536 Vernet’s movement de rideau 484 Vernet’s syndrome 479, 483 Verocay bodies 778

989

Index vertebral arteries 111, 112, 913, 914 dissection 148–9 occlusion 122 stenosis, management 147 vertebral segmental defects 586–7 vertebro-basilar circulation 112 vertebro-basilar ischaemia drop attacks 208 hearing loss 579 stroke 122–3 symptoms of transient 118 vertigo 533 acute attacks 209 assessment 539–46 benign paroxysmal positional see benign paroxysmal positional vertigo benign recurrent 554 cerebellar ataxia 629 cortical location 68 diagnostic strategy 537 drug treatment 557 duration 537 epidemiology 533 mechanisms 535 multiple sclerosis 436 surgical management 561–2 triggers 537 vertebro-basilar ischaemia 118 vestibular rehabilitation physiotherapy 558–9 see also dizziness; vestibular disorders very long-chain acylCoA dehydrogenase deficiency (VLCAD) 719 very long-chain fatty acids (VLCFA) 442, 443, 720 Vesalius, Andreas 338 vestibular disorders assessment 539–46 central 538 drug treatment 558 classification 537, 538 drug treatment 556–8 investigations 546–51 management 556–62 peripheral 538, 551–6 drug treatment 557–8 electronystagmography 547 physiotherapy 558–9 psychological treatment 560–1 symptoms aiding localization 537 vestibular failure, bilateral (BVF) 555 vestibular ganglion 66 vestibular nerve, examination 81–2 vestibular neuritis 551–2 vestibular nuclei 30, 37, 66–8 lesions, electronystagmography 547 vestibular paroxysmia 555–6 vestibular rehabilitation physiotherapy 558–9 vestibular (VIIIth nerve) schwannomas 474, 812 hearing loss 578 vestibular sedative drugs 557 vestibular symptoms 537 general medical causes 538 transient 209 treatment of acute 557 triggers 537 see also vertigo

990

vestibular system anatomy 66–8 function 533–6 vestibulo-cerebellum 28, 30 vestibulo-cochlear nerve (VIII) 65–8 examination 81–2 reflexes involving 65, 68 vascular loops compressing 579 vestibulo-ocular reflexes (VOR) 533–5, 536 brain death 735 coma 728–30 rotary chair testing 547–8 vestibulo-spinal reflexes 534 vestibulo-spinal tracts 66–8 vibration sense (VS) testing 85 video-oculography 548 videotelemetry, EEG 87, 215 vigabatrin epilepsy 222, 224, 234 learning disability 230, 231 pharmacokinetics 226 Villaret’s syndrome 479 viral infections 310–14, 316–19 acute cerebellar ataxia of childhood 638 biological weapons 689–90 encephalitis 312–14, 315 hearing loss 577 meningitis 310–11 myositis 405 optic neuritis 497 organ transplant recipients 925 retinitis 508 spine 618–19 stroke 149 vestibular neuritis and 551 see also specific infections virtual reality rehabilitation techniques 654 visceral pain 858 viscero-somatic disorders, painful peripheral 857–8 vision testing 79 visual acuity testing 79 bilateral visual loss 494 unilateral visual loss 490–1 visual agnosia 527 apperceptive 250, 527 associative 251, 527 visual anosognosia (Anton’s syndrome) 99, 250, 525 visual association cortex (areas 18 and 19) 24, 55–7 lesions 525–6 visual cortex lesions 524–6 primary see primary visual cortex V1–V5 terminology 55–7, 58 visual disorders 489–531 drugs causing 704 higher visual function 526–8 ischaemic 498–502 multiple sclerosis 418–19, 436 neurological disease causing 507–8 organ transplant recipients 926 pituitary tumours 806 rehabilitation strategies 658–9 visual disorientation 250 visual distortions 490

visual dysaesthesia 527 visual evoked potentials 93, 423 visual field defects asymptomatic unilateral 489–90 chiasmal disease 523 clinical presentation 490 idiopathic intracranial hypertension 506 junctional 491–2, 523 neuro-anatomy 53 rehabilitation strategies 658–9 retrochiasmal lesions 523–6 visual field examination 79, 491–2 visual fixation 536 visual hallucinations 251, 526–7, 833 associated with visual loss 526 epilepsy 190–1, 526, Plate 13.28 migraine 209, 526 peduncular 526–7 visual loss bilateral 494 progressive, causes 494, 495 sudden onset, causes 494 giant cell arteritis 931–2 leprosy 305–6 pendular nystagmus from 520 unilateral 489–531 causes 493, 494 examination 490–3 history 489–90 transient 499 visual illusions in partial 527 visual pathways 53–9 chiasmal and retrochiasmal disorders 523–36 visual perceptual disturbances 526–8 cognitive disorders 250–1 episodic 209 migraine 209, 526 unilateral visual loss with 490 visual simultanagnosia 528 visual synaesthesia 527 visual training 658–9 visuo-spatial deficits 250–1 rehabilitation strategies 659 vitamin deficiencies 369–71, 690–2 toxicities 690–2 vitamin A 690 vitamin B1 see thiamine vitamin B6 (pyridoxine) 370, 690 vitamin B12 deficiency 690–1, 921 functional 626 nitrous oxide and 626, 679–80 optic neuropathy 504 peripheral neuropathy 370–1 psychiatric disorders 839 subacute combined degeneration of cord 625–6, 691 treatment 691 vitamin D deficiency 692, 923 multiple sclerosis and 412–13 vitamin E deficiency 692, 923 ataxia 634 peripheral neuropathy 371 vitamin K 938

Index vocational rehabilitation 663–4 multiple sclerosis 437 traumatic brain injury 669 Vogt–Koyanagi–Harada syndrome 507, 574 voltage-gated calcium channels (VGCC) antibodies 282, 387, 641, 819–20 gene mutations 397, 398 voltage-gated potassium channel antibody (VGKC Ab) syndrome 280, 283 voltage-gated potassium channel gene mutations, epilepsy 197 voltage-gated sodium channel gene mutations epilepsy 197 familial hemiplegic migraine 450 myopathies 397–8 voluntary action, deficits 251–2 von Hippel-Lindau disease (VHL) 811 cerebellar haemangioblastomas 639 retinal capillary haemangiomas 508 spinal haemangioblastomas 611, 621 Vorbeireden 841 vulvodynia 857–8 VX 688–9 Waardenburg’s syndrome 572 waiter’s tip palsy 373 wakefulness 38, 51 regulation 760 see also consciousness; sleep Waldenström’s macroglobulinaemia 921–2, 924 neuropathies 365 paraneoplastic myopathy 406 walking rehabilitation 653, 654 Wallenberg’s syndrome see lateral medullary syndrome wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) 519 wandering dementia 285 episodic nocturnal 766, 768 fugue states 833 see also sleep walking warfare, neurobiological see neurobiological weapons warfarin, stroke prevention 144–5, 915 warm-up phenomenon 398–9 Wartenburg syndrome 373 Waterhouse–Friderichsen syndrome 293

water intake orthostatic hypotension 886, 888 regulation 50 watershed (border-zone) infarction 110, 113 clinical features 123 weakness acute neuromuscular 361–3 assessment 83, 390 give-way 83, 390 history taking 388, 389 inflammatory myopathies 402 intensive care unit 758–60 Medical Research Council (MRC) scale 83 multiple sclerosis 435 myasthenic disorders 384, 387 peripheral neuropathies 349 physiotherapy interventions 651, 652, 653 weaning from ventilator 738 failure 758–60 Weber’s syndrome 514 Weber tuning fork test 566 Wechsler Adult Intelligence Scale-Revised (WAIS-R) 96, 257 Wegener’s granulomatosis (WG) 924, 930 hearing loss 573 neuropathy 366, 367 stroke 149 Weil’s disease 305 Welander myopathy 396 Werdnig–Hoffmann disease 382 Wernicke, Carl 97 Wernicke–Korsakoff syndrome 249, 693–4, Plate 18.5 Wernicke’s area 253 Wernicke’s encephalopathy 693–4, 923 Western equine encephalitis 315 West Nile encephalitis 315 West’s syndrome 196, 231 whiplash injury 607 Whipple’s disease 326 dementia 281 oculomasticatory myorhythmia 165, 522 white matter lesions (MRI) differential diagnosis 420–2 multiple sclerosis 420, 421, 422 see also normal-appearing white matter (NAWM) lesions

white rabbit syndrome 165 whole brain radiotherapy (WBRT) brain metastases 799, 804 primary CNS lymphoma 808 Wilbrand’s knee 491–2 Wildervanck’s syndrome 571 Wilson’s disease (WD) 169–70, 173 cognitive impairment 278 psychiatric disorders 839 Wisconsin Card Sorting Test 96 witzelsucht 98 Wolfram syndrome 572, 918 women of childbearing age, epilepsy 936–40 isolated urinary retention 902–5 word deafness 253, 580 word retrieval, impaired 253–4 work, return to 664, 669 World Health Organization (WHO) burden of illness studies 10 classification of CNS tumours 774–8 writer’s cramp 166, 171 writing impairment 254 xantho-astrocytomas, pleomorphic 776, 782 xanthochromia 128 xeroderma pigmentosum 633 xerostomia 883, 891, 930 Xp21 dystrophies (dystrophinopathies) 392–3 xylene 679 yoga paralysis 373 young adults, dementia 276–8, 279 zalcitabine, toxic neuropathy 334 Zelapar 159 zidovudine -associated myopathy 334, 406–7 tropical spastic paraparesis 619 zinc, Wilson’s disease 170 zolmitriptan cluster headache 457 migraine 454 zonisamide epilepsy 222, 224, 234 pharmacokinetics 226

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Neurology: A Queen Square Textbook

Neurology : a queen square textbook

Neurology: A Queen Square Textbook

Textbook of neurology

textbook of clinical neurology

Textbook of neurology - Goetz

Textbook of Clinical Neurology

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Neurology

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The perfect square: a history of Rittenhouse Square

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washington square

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Neurology: A Queen Square Textbook