Oxford Textbook of Medicine [4, 6 ed.] 9780198746690

Citation preview

Oxford Textbook of

Medicine

More comprehensive, more authoritative, and more international than any other textbook, the Oxford Textbook of Medicine focuses on offering perspective and practical guidance on the clinical management and prevention of disease. Introductory sections focus on the patient experience, medical ethics, and clinical decision-making, outlining a philosophy which has always characterized the Oxford Textbook of Medicine. It is humane, thought-provoking, and aims to instil in readers an understanding of the role of medicine in society and the contribution it can make to the health of populations. In addition, it does not shy away from discussion of controversial aspects of modern medicine. As always, there is detailed coverage of all areas of internal medicine by the world’s very best authors. The Oxford Textbook of Medicine seeks to embody advances in understanding and practice that have arisen through scientific research. The integration of basic science and clinical practice is unparalleled, and throughout the book the implications of research for medical practice are explained. The core clinical medicine sections offer in-depth coverage of the traditional specialty areas. The Oxford Textbook of Medicine has unsurpassed detail on infectious diseases: the most comprehensive coverage to be found in any textbook of medicine. Other sections of note include stem cells and regenerative medicine; inequalities in health; medical aspects of pollution and climate change; travel and expedition medicine; bioterrorism and forensic medicine; pain; medical disorders in pregnancy; nutrition; psychiatry; and drug-related problems in general medical practice. The section on acute medicine is designed to give immediate access to information when it is needed quickly. In response to ongoing user feedback, there have been substantial changes to ensure that the Oxford Textbook of Medicine continues to meet the needs of its readers. Chapter essentials give accessible overviews of the content and a new design ensures that the textbook is easy to read and navigate. The evidence base and references continue to be at the forefront of research.

Medicine

The Oxford Textbook of Medicine is the foremost international textbook of medicine. Unrivalled in its coverage of the scientific aspects and clinical practice of internal medicine and its subspecialties, it is a fixture in the offices and wards of physicians around the world, as well as being a key resource for medico-legal practitioners.

Oxford Textbook of

VOLUME

4

SECTIONS 22-30

Firth Conlon Cox ISBN 978-0-19-885347-3

9 780198 853473

INTERNATIONAL EDITION

Oxford Textbook of

SIXTH EDITION

1

2

2

Medicine SIXTH EDITION VOLUME 4

edited by

John D. Firth Christopher P. Conlon Timothy M. Cox

ONLY FOR SA LE I N I N D I A , B A N GLA D ESH , SR I LA N K A , N EPA L, B H UTA N , A N D M YA N M A R AND NOT FOR EXP O RT T H ER EF RO M . N OT F O R SA LE I N A N Y OT H ER CO UN T RY I N T H E WO R LD

Oxford Textbook of

Medicine

Oxford Textbook of

Medicine SIXTH EDITION Volume 4: Sections 22–30

EDITED BY

John D. Firth Christopher P. Conlon Timothy M. Cox

1

3 Great Clarendon Street, Oxford, OX2 6DP, United Kingdom Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries © Oxford University Press 2020 The moral rights of the authors have been asserted First Edition published in 1983 Second Edition published in 1987 Third Edition published in 1996 Fourth Edition published in 2003 Fifth Edition published in 2010 Sixth Edition published in 2020 Impression: 1 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, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by licence or under terms agreed with the appropriate reprographics rights organization. Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016, United States of America British Library Cataloguing in Publication Data Data available Library of Congress Control Number: 2018933144 Set ISBN: 978–0–19–874669–0 Volume 1: 978–0–19–881533–4 Volume 2: 978–0–19–881535–8 Volume 3: 978–0–19–881537–2 Volume 4: 978–0–19–884741–0 Only available as part of a set Printed in Malaysia by Vivar Printing Oxford University Press makes no representation, express or implied, that the drug dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-​to-​date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publishers do not accept responsibility or legal liability for any errors in the text or for the misuse or misapplication of material in this work. Except where otherwise stated, drug dosages and recommendations are for the non-​pregnant adult who is not breast-​feeding Links to third party websites are provided by Oxford in good faith and for information only. Oxford disclaims any responsibility for the materials contained in any third party website referenced in this work.

Foreword Professor Sir John Bell, Regius Professor of Medicine, University of Oxford

In 1983, David Weatherall, John Ledingham, and David Warrell launched the first edition of the Oxford Textbook of Medicine. That era of medicine looked entirely different from today but the need for a scholarly repository of medical knowledge remains as important as ever. Medicine is now firmly in a digital age; sources of information abound and are readily available and the field is moving so quickly that it is harder than ever to provide up to date relevant information for the profession. Despite this, the sixth edition of the Oxford Textbook of Medicine still provides the foundation of knowledge upon which good clinical practice is based. Never before has there been such a rapid advance of medical knowledge and practice. Since the first edition of the Oxford Textbook of Medicine, medical practice has reduced cardiovascular mortality by up to 70% in Western countries, there are now multiple new therapies for diseases such as rheumatoid arthritis and multiple sclerosis, disorders where the descriptions of therapeutic options in the first edition were necessarily brief. Cancer is now increasingly managed with immune and targeted therapies. Whole new diseases have appeared (Hepatitis C and HIV) and have been either controlled or conquered with drug therapy. The sequencing of the human genome seemed an impossible dream in 1983 while today we have sequenced more than a million genomes and have had insights into rare disease and cancer that were unimaginable then. Life expectancy has risen by nine years for men and ten for women in the United Kingdom, creating a demographic shift that will fundamentally change society and medicine forever. The pace of change has been dramatic. The Oxford Textbook of Medicine gained a reputation by moving medical practice forward from the Oslerian view of medicine originally expounded in his text book the Principles and Practice of Medicine into an era of more molecular and scientifically based understanding of disease. Constrained by the lack of tools for exploring the molecular basis of pathogenesis, Osler was limited in how he could describe the world of disease, largely based on bedside observations or those from the post-​mortem room. The Oxford Textbook of Medicine shifted this focus and aligned it with the emerging field of molecular medicine which has begun to create a new taxonomy of disease but also an approach to therapy which is based on pathogenesis. There has been a wave of new information, with new insights appearing weekly into the underlying molecular events associated with disease. Diseases characterized by phenotype are now broken down into multiple subtypes and disease is being individualized. This is rapidly leading to a very significant change in our perception of pathogenesis as well as the classification and

nomenclature of disease, all crucial roles for a textbook of medicine. We now are aware that many of the classic definitions of diseases such as diabetes or cancer were descriptions of phenotypic characteristics. Interrogation of these disorders at a molecular level has demonstrated that these terms mask disease subtypes defined by molecular pathology where natural history and response to therapy may differ. Combine this with the explosion of new diseases coming from studies of rare disease and there is a challenge to conventional disease nomenclature. This molecular precision creates real opportunities for targeted highly effective therapies, but it also creates challenges for the model of drug discovery when novel treatments can only be used in increasingly small patient populations. These are major issues for medicine, health systems, but also textbooks such as this one where, historically, the stewardship of disease nomenclature has been maintained. The therapeutic options available to practising clinicians have also advanced beyond all recognition since the first edition of the Oxford Textbook of Medicine. We have seen an era of biologic therapy which has provided important new therapeutic alternatives for many hard-​ to-​treat diseases including cancer. We are now entering a new era where modalities such as gene therapy and interfering RNA therapeutics have demonstrated their utility in the clinic. Similarly, an era of cell therapy has also begun which will provide important new alternatives to some diseases. These new therapeutic alternatives and other opportunities for improving healthcare using medical technology or novel diagnostics such as sequencing also bring with them the challenge of how healthcare systems can continue to be affordable, either for individuals in private healthcare settings, or in state-​funded, single-​payer systems. In this context, it is remarkable that the authors and editors of the Oxford Textbook of Medicine have managed to sustain both its relevance and the accuracy of its content. The pace at which our understanding of disease, our therapeutic options, and our healthcare systems are likely to change makes it nearly impossible for a textbook of medicine to be truly comprehensive given the speed of change, the impact of new innovations and the multiple additional sources of information available to practitioners. The Oxford Textbook of Medicine has provided remarkable levels of detail in this rapidly changing world but, more importantly, the textbook continues to provide a source for readers to access information on the fundamental features of disease. This foundational knowledge remains crucial to our ability to understand, diagnose, and treat patients whether they are in the developing world or

vi

Foreword

Western healthcare systems. Having a source of such information across all major diseases accessible in a single source remains the bedrock of both teaching and practising medicine. The foundations provided by the Oxford Textbook of Medicine form a core of knowledge which practising clinicians will continue to need. The editors of this edition have been faithful to the vision of the original three editors. Science, in all its forms, is at the heart of our

understanding of disease and has enabled progress in clinical medicine to occur at a remarkable pace. By providing a textbook that describes the foundations of our understanding of disease and its management, the editors have successfully given us an authoritative text which practising clinicians will find invaluable to support their day-​to-​day decisions. David Weatherall, one of the three original editors and who died in 2018, would be gratified by this new edition.

Preface Changes in medicine The Oxford Textbook of Medicine is published online and has been regularly updated for many years, but the production of a new and very substantially updated edition provides a moment when it is natural and proper to reflect on what has changed in medicine—​and what has not—​in recent years. In the context of burgeoning social changes and inequality across the world, we have cause to weigh and consider exactly what modern medicine has to offer patients and their doctors. Here we reflect on aspects of Medicine that are changing rapidly and set out a vision for this in the sixth edition of the Oxford Textbook of Medicine.

Demand, capacity, magic solutions, and the need for perspective Within all healthcare systems, in rich and poor nations alike, most physicians feel the inexorable rise in demand and are struggling to provide adequate ‘capacity’—​the term commonly applied by healthcare managers charged with the impossible task of constraining expenditure while serving political masters who, almost without exception, promise more and more and blame inefficiency and ‘unwarranted variation’ for the failure to deliver. In response to the difficulties, claims are made that some new technological advance, be it sequencing of patients’ genomes, healthcare apps, the application of artificial intelligence or ‘Quality Improvement’ methodology, will provide the solutions. In the Oxford Textbook of Medicine, we do not shy away from these aspects and have several new chapters that consider how rich and ‘resource-​poor’ countries might best invest their revenues on health. It is often very hard for practising physicians, who care for patients as individuals, to maintain their bearings within the unfamiliar and depersonalized world of modern healthcare management. Many are left wondering whether those who organize health services ‘live on this planet’, or ‘did any working doctor check out that latest directive from above?’. When clinical outcomes that really matter are difficult to quantify, doctors find themselves and their services judged by spurious measures of ‘productivity’ in the process of healthcare ‘delivery’. Unrealistic and often clinically irrelevant targets might drive the thinking of the insurers, managers, and politicians, but who can determine the human and clinical value of the care provided? Timeliness of care is important and sometimes crucial for salutary outcomes, but disaster strikes when clock-​driven targets are blindly pursued for all patients irrespective of clinical urgency and to the exclusion of all else, including patients with greater clinical need. In the morass created by financial constraints and zealous political control of health services exercised by those without clinical

responsibility, it is rare for doctors be able to stand back and perceive genuine improvements. However, it is certainly true that today we have greater potential to prevent and treat disease and to maintain health than ever before. It is our hope that the Oxford Textbook of Medicine will inform doctors about these changes and provide good guidance as to how they can be translated into clinical practice.

Advances in biomedical sciences We seek to embody advances in understanding and practice that have arisen through scientific research. In the ten years since publication of the last edition of this book there has been spectacular progress in the application of science in medicine, especially the understanding of genomics and molecular cell biology. These include: in diagnostics, non-​invasive prenatal diagnosis of chromosome abnormalities and monogenic disease by sampling maternal plasma for cell-​free fetal DNA, a technique which also holds promise for screening and monitoring of cancers; in metabolic disease, the introduction of molecular therapies that address the defective chloride transport in cystic fibrosis; in oncology, increased understanding of cancer immunity leading to the development of immunotherapies for cancers. Our authors include the very best in their fields. The founding editor and author in this edition, the late David Weatherall, was a recipient of the Lasker-​Koshland Special Achievement Award in Medical Science. Two new authors have received the Nobel Prize recently—​Professor Tu Youyou the 2015 prize for Medicine or Physiology, and Sir Greg Winter the 2018 prize for Chemistry. Another new author, Professor Y.M. Dennis Lo, was one of two winners of China’s inaugural Future Science Prize in 2016. Beyond scientific development, the introduction of new technologies into practice typically leads to a sequence of events including initial ‘hype’ from many in the field, with extravagant claims of potential benefit. After an interval, these claims are followed by a more realistic assessment of what the technology can—​and cannot—​ provide. Frequently, this familiar pattern is driven by powerful commercial influences which can corrupt thinking in a manner that generates a climate in which those with views contrary to the big battalions are inevitably marginalized. In this edition of the Oxford Textbook of Medicine we have strived to bring an authentic perspective and realism to recommendations for treatment. We sense, for instance, that the excitement generated by the sequencing of patients’ genomes continues to increase, but that this trajectory is flattening and expectations becoming more realistic. For patients very likely to have genetic disorders, diagnoses can be made for a proportion that was unimaginable until recently, but for most patients with the degenerative and/​or polygenic diseases that are the greatest burden

viii

Preface

to health, evidence of clinical benefit from genome sequencing remains elusive. Beyond the progress in genomics and cell biology there has been immense interest in bioinformatics and, especially with the enthusiasm of major biomedical charities such as The Wellcome Trust, for ‘big data’, and the opportunities that these bring to the practice of medicine. However, while there are plentiful examples of genomics and cell biology having been translated productively from the bench to the bedside, with enormous benefit to patients, examples of transforming clinical impact from big data and bioinformatics are sparse. But examples there are, such as in the analysis of outbreaks of the scourges Clostridium difficile and methicillin-​resistant Staphylococcus aureus (MRSA). These discoveries give hope for the future as we learn which problems are tractable with this type of approach and which are not.

One hundred and fifty years ago, Darwin’s 1859 masterpiece on evolution was entitled ‘On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life’. The ‘less favoured’ undoubtedly have poorer health outcomes, due largely to the persistent social ill of inequality, in poor as well as ostensibly rich countries. Continuing the tradition of previous editions, we have contributions that discuss the impact of social determinants of health, also thoughtful chapters on human disasters (by another Nobel laureate, Prof Amartya Sen), and the practical and critically important aspects of humanitarian medicine. In addition, the modern problems of pollution and climate change are examined. We contend that all doctors would benefit from reading these chapters.

Clinical skill

There are continuing changes in patients’ expectations, particularly those of articulate patients suffering from long-​term conditions and residing in countries with a rich provision of healthcare. A paternalistic medical approach is no longer acceptable, and several patients have contributed greatly to the book by taking the opportunity to tell us how they think doctors should behave towards them and care for them. However, we are very aware that one size does not fit all, and that many patients want a doctor who will give them clear recommendations and not keep repeating a bewildering (to the patient) variety of options and ask them to choose. The mature and able physician will be alert and sensitive to those patients who want this and will provide them with clear advice, and we have endeavoured to ensure that the Oxford Textbook of Medicine will assist.

Until recently, it would have been, to paraphrase Thomas Jefferson, regarded as self-​evident that the key requirements of a good physician are the ability and will to obtain an informative history, carry out a thorough physical examination, formulate a relevant differential diagnosis, instigate appropriate investigations, advise and administer correct treatment, including best efforts to relieve symptoms in all cases. These skills, and the commitment to use them, are often forgotten when healthcare is described in the commercial terms of demand and capacity. While advances in biomedical sciences have dramatically improved the outcome for some diseases, and Paul Erhlich’s century-​ old magische Kugel (magic bullet) has whetted our appetite for wonder, it is prudent to recall Thomas Szasz: ‘Formerly, when religion was strong and science weak, men mistook magic for medicine; now, when science is strong and religion weak, men mistake medicine for magic’. The term ‘personalized’ medicine imputes remarkable and as yet unproven powers, excepting in a very few cases, to gene sequencing and molecular therapies, while the patient wants to be treated as a person. It is also alarming to us that some medical curricula increasingly focus on process, ‘behaviours’, and ‘communication skills’, to the detriment of medical content or mature guidance and attitudes to lifelong learning. There is a tendency to forget the very essence of being, and how to become, a physician in the time-​ honoured understanding of the role. In the Oxford Textbook of Medicine we unashamedly emphasize the primacy of history, examination, differential diagnosis, investigation, and treatment. Without a firm grasp of these essentials the doctor cannot provide good care for patients, and nor can anyone else. Furthermore, having a firm understanding of clinical context and a well-​informed clinical perspective is an essential prerequisite for driving biomedical research into avenues that really matter.

The broader context of health and disease The world has become a smaller place. We are now in an era when many regard not having a smartphone as an index of deprivation. An event that has happened on a different continent can, as a result of social media, become known to millions of people within hours—​the term ‘viral’ has been rightfully translated from communicable illness to global phenomenon. Narratives transmitted in this way often concern disasters, wars, and disease, and they are typically handled by the media in a sensationalized and superficial manner.

Patients and their expectations

Access to medical knowledge The ever-​expanding world of the smartphone and tablet device gives patients, families, doctors, and other healthcare professionals ready access to more information about medicine than all but a very few would have thought possible a decade ago. This has many benefits but often leaves users of the internet thoroughly perplexed, and some desperate people vulnerable to online quackery. Those wanting details of particular studies will naturally refer to the original literature. Those wanting in-​depth reviews of particular subjects can refer to diverse resources: these are typically good at apprising the reader of plentiful options for investigation, diagnosis, or management, but often leave them uncertain of what a clinically experienced expert in the field would actually recommend. In the sections that form the bulk of the Oxford Textbook of Medicine, we have selected experts with specific clinical experience and given them this task, and we contend that they have met the challenge.

Acknowledgements The Oxford Textbook of Medicine is a large undertaking: this edition, the most substantial so far, comprises 647 chapters and covers 6654 printed pages, and its production has required an extraordinary coordination of effort from many quarters. In darker moments the editors feared that the process would never end, but as we have read and edited the chapters along the way, we have experienced the joy of learning a huge amount of medicine, often in fields far removed from our own. For this we are very grateful to our contributors, including those whose submissions were delayed!

Preface

We wish to make particular acknowledgement of our friend and senior colleague, David Warrell, an editor from the first edition of this textbook, senior editor of the fourth and fifth editions, and author in this edition. We and our readers, notably those seeking information on tropical diseases and especially any who have been bitten by snakes, about which his knowledge is truly prodigious, owe him a great debt. We thank Helen Liepman, with whom we remain good friends: she has overseen and directed matters at Oxford University Press and coped in a steadfastly pleasant and professional way with expressions of editorial frustration caused by our failure to understand a

publishing process that at times seemed to be Byzantine in its complexity, as might perhaps be expected in an ancient university. We also thank Anna Kirton, Jamie Oates, and Jess White at Oxford University Press for their considerable efforts on behalf of the book. Finally, we record that the editors’ personal lives have remained calm, and we are very grateful to Helen, Jenny, and Sue for their indulgence of our bizarre editorial pursuit. John D. Firth Christopher P. Conlon Timothy M. Cox

ix

Section editors Jon G. Ayres  Emeritus Professor of Environmental and Respiratory Medicine, University of Birmingham, Birmingham, UK Section 10: Environmental medicine, occupational medicine, and poisoning Christopher P. Conlon  Professor of Infectious Diseases, Nuffield Department of Medicine, University of Oxford, Oxford, UK Section 1: Patients and their treatment; Section 2: Background to medicine; Section 3: Cell biology; Section 4: Immunological mechanisms; Section 5: Principles of clinical oncology; Section 8: Infectious diseases; Section 25: Disorders of the eye; Section 29: Biochemistry in medicine Cyrus Cooper  MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK; NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK Section 20: Disorders of the skeleton Timothy M. Cox  Professor of Medicine Emeritus, Director of Research, University of Cambridge; Honorary Consultant Physician, Addenbrooke’s Hospital, Cambridge, UK Section 1: Patients and their treatment; Section 2: Background to medicine; Section 3: Cell biology; Section 4: Immunological mechanisms; Section 5: Principles of clinical oncology; Section 12: Metabolic disorders Jeremy Dwight  Previously John Radcliffe Hospital, Oxford, UK Section 16: Cardiovascular disorders Simon Finfer  Malcolm Fisher Department of Intensive Care Medicine, Royal North Shore Hospital, and The George Institute for Global Health, University of New South Wales, Sydney, Australia Section 17: Critical care medicine John D. Firth  Consultant Physician and Nephrologist, Cambridge University Hospitals, Cambridge, UK Section 1: Patients and their treatment; Section 2: Background to medicine; Section 3: Cell biology; Section 4: Immunological mechanisms; Section 5: Principles of clinical oncology; Section 21: Disorders of the kidney and urinary tract; Section 27: Forensic medicine; Section 28: Sport and exercise medicine; Section 30: Acute medicine Mark Gurnell  University of Cambridge Medical School, Cambridge, UK Section 13: Endocrine disorders

Chris Hatton  Cancer and Haematology Centre, Churchill Hospital, Oxford, UK Section 22: Haematological disorders Deborah Hay  Honorary Consultant Haematologist, Nuffield Department of Medicine, University of Oxford, Oxford, UK Section 22: Haematological disorders Roderick J. Hay  King’s College London, London, UK Section 23: Disorders of the skin Christopher Kennard  Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK Section 24: Neurological disorders Finbarr C. Martin  Population Health Sciences, King’s College London, London, UK Section 6: Old age medicine Catherine Nelson-Piercy  Obstetric Medicine, Women’s Health Academic Centre, King’s Health Partners, King’s College London, London, UK Section 14: Medical disorders in pregnancy Jack Satsangi  Oxford Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK Section 15: Gastroenterological disorders Pallav L. Shah  Imperial College London, London, UK Section 18: Respiratory disorders Michael Sharpe  Psychological Medicine Research, University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK Section 26: Psychiatric and drug-related disorders Jackie Sherrard  Wycombe General Hospital, High Wycombe, Bucks, UK Section 9: Sexually transmitted diseases Richard A. Watts  Department of Rheumatology, Ipswich Hospital, Ipswich, UK; Norwich Medical School, University of East Anglia, Norwich, UK Section 19: Rheumatological disorders Bee Wee  Associate Professor of Palliative Care, University of Oxford, Oxford, UK Section 7: Pain and palliative care Katherine Younger  School of Biological and Health Sciences, Technological University Dublin, Ireland Section 11: Nutrition

Contents Volume 1 List of abbreviations xxxv List of contributors xlv

2.2 Evolution: Medicine’s most basic science  39 Randolph M. Nesse and Richard Dawkins

2.3 The Global Burden of Disease: Measuring the health of populations  43

SECTION 1 Patients and their treatment Section editors: John D. Firth, Christopher P. Conlon, and Timothy M. Cox 1.1 On being a patient  3 Christopher Booth†

1.2 A young person’s experience of chronic disease  6 1.3 What patients wish you understood  8 Rosamund Snow†

1.4 Why do patients attend and what do they want from the consultation?  14 Des Spence

1.5 Medical ethics  20 Mike Parker, Mehrunisha Suleman, and Tony Hope

1.6 Clinical decision-​making  26 Timothy E.A. Peto and Philippa Peto

Theo Vos, Alan Lopez, and Christopher Murray

2.4 Large-​scale randomized evidence: Trials and meta-​analyses of trials  51 Colin Baigent, Richard Peto, Richard Gray, Natalie Staplin, Sarah Parish, and Rory Collins

2.5 Bioinformatics  67 Afzal Chaudhry

2.6 Principles of clinical pharmacology and drug therapy  71 Kevin O’Shaughnessy

2.7 Biological therapies for immune, inflammatory, and allergic diseases  100 John D. Isaacs and Nishanthi Thalayasingam

2.8 Traditional medicine exemplified by traditional Chinese medicine  108 Fulong Liao, Tingliang Jiang, and Youyou Tu

2.9 Engaging patients in therapeutic development  118 Emil Kakkis and Max Bronstein

SECTION 2 Background to medicine Section editors: John D. Firth, Christopher P. Conlon, and Timothy M. Cox 2.1 Science in medicine: When, how, and what  33 William F. Bynum

2.10 Medicine quality, physicians, and patients  124 Paul N. Newton

2.11 Preventive medicine  127 David Mant

2.12 Medical screening  137 Nicholas Wald and Malcolm Law

2.13 Health promotion  152 Evelyne de Leeuw

†

It is with great regret that we report that Christopher Booth died on 13 July, 2012 and Rosamund Snow died on 2 February, 2017.

xiv

Contents

2.14 Deprivation and health  157

3.9 Circulating DNA for molecular diagnostics  299

Harry Burns

2.15 How much should rich countries’ governments spend on healthcare?  161 Allyson M. Pollock and David Price

2.16 Financing healthcare in low-​income developing countries: A challenge for equity in health  168 Luis G. Sambo, Jorge Simões, and Maria do Rosario O. Martins

2.17 Research in the developed world  177

Y.M. Dennis Lo and Rossa W.K. Chiu

SECTION 4 Immunological mechanisms Section editors: John D. Firth, Christopher P. Conlon, and Timothy M. Cox 4.1 The innate immune system  307 Paul Bowness

Jeremy Farrar

2.18 Fostering medical and health research in resource-​constrained countries  181 Malegapuru W. Makgoba and Stephen M. Tollman

4.2 The complement system  315 Marina Botto and Matthew C. Pickering

4.3 Adaptive immunity  325 Paul Klenerman and Constantino López-​Macias

2.19 Regulation versus innovation in medicine  185 Michael Rawlins

4.4 Immunodeficiency  337 Sophie Hambleton, Sara Marshall, and Dinakantha S. Kumararatne

2.20 Human disasters  188 Amartya Sen

2.21 Humanitarian medicine  193

4.5 Allergy  368 Pamela Ewan

Amy S. Kravitz

2.22 Complementary and alternative medicine  201

4.6 Autoimmunity  379 Antony Rosen

Edzard Ernst

4.7 Principles of transplantation immunology  392 Elizabeth Wallin and Kathryn J. Wood

SECTION 3 Cell biology Section editors: John D. Firth, Christopher P. Conlon, and Timothy M. Cox 3.1 The cell  209 George Banting and Jean Paul Luzio

3.2 The genomic basis of medicine  218

SECTION 5 Principles of clinical oncology Section editors: John D. Firth, Christopher P. Conlon, and Timothy M. Cox 5.1 Epidemiology of cancer  411 Anthony Swerdlow and Richard Peto

Paweł Stankiewicz and James R. Lupski

3.3 Cytokines  236 Iain B. McInnes

3.4 Ion channels and disease  246 Frances Ashcroft and Paolo Tammaro

3.5 Intracellular signalling  256 R. Andres Floto

3.6 Apoptosis in health and disease  266 Mark J. Arends and Christopher D. Gregory

3.7 Stem cells and regenerative medicine  281 Alexis J. Joannides, Bhuvaneish T. Selvaraj, and Siddharthan Chandran

5.2 The nature and development of cancer: Cancer mutations and their implications  445 James D. Brenton and Tim Eisen

5.3 The genetics of inherited cancers  456 Rosalind A. Eeles

5.4 Cancer immunity and immunotherapy  471 Charles G. Drake

5.5 Clinical features and management  487 Tim Eisen and Martin Gore†

5.6 Systemic treatment and radiotherapy  497 Rajesh Jena and Peter Harper

3.8 The evolution of therapeutic antibodies  296 Herman Waldmann and Greg Winter

†

It is with great regret that we report that Martin Gore died on 10 January, 2019.

Contents

5.7 Medical management of breast cancer  505

7.4 Care of the dying person  639

Tim Crook, Su Li, and Peter Harper

Suzanne Kite and Adam Hurlow

SECTION 6 Old age medicine

SECTION 8 Infectious diseases

Section editor: Finbarr C. Martin

Section editor: Christopher P. Conlon

6.1 Ageing and clinical medicine  511

8.1 Pathogenic microorganisms and the host  651

Claire Steves and Neil Pendleton

8.1.1 Biology of pathogenic microorganisms  651

Duncan J. Maskell and James L.N. Wood

6.2 Frailty and sarcopenia  521 Andrew Clegg and Harnish Patel

6.3 Optimizing well-​being into old age  532

8.1.2 Clinical features and general management of patients with severe infections  656

Peter Watkinson and Duncan Young

Steve Iliffe

6.4 Older people and urgent care  539 Simon Conroy and Jay Banerjee

6.5 Older people in hospital  548 Graham Ellis, Alasdair MacLullich, and Rowan Harwood

6.6 Supporting older peoples’ care in surgical and oncological services  563 Jugdeep Dhesi and Judith Partridge

8.2 The patient with suspected infection  662 8.2.1 Clinical approach  662

Christopher J. Ellis 8.2.2 Fever of unknown origin  664

Steven Vanderschueren 8.2.3 Nosocomial infections  669

Ian C.J.W. Bowler and Matthew Scarborough 8.2.4 Infection in the immunocompromised host  673

Jon Cohen and Elham Khatamzas

6.7 Drugs and prescribing in the older patient  571 Miles Witham, Jacob George, and Denis O’Mahony

6.8 Falls, faints, and fragility fractures  579 Fiona Kearney and Tahir Masud

6.9 Bladder and bowels  589 Susie Orme and Danielle Harari

6.10 Neurodegenerative disorders in older people  601 John Hindle

6.11 Promotion of dignity in the life and death of older patients  612

8.2.5 Antimicrobial chemotherapy  684

Maha Albur, Alasdair MacGowan, and Roger G. Finch

8.3 Immunization  706 David Goldblatt and Mary Ramsay

8.4 Travel and expedition medicine  713 Susanna Dunachie and Christopher P. Conlon

8.5 Viruses  723 8.5.1 Respiratory tract viruses  723

Malik Peiris 8.5.2 Herpesviruses (excluding Epstein–​Barr virus)  734

J.G.P. Sissons†

Eileen Burns and Claire Scampion

8.5.3 Epstein–​Barr virus  754

Alan B. Rickinson and M.A. Epstein

SECTION 7 Pain and palliative care Section editor: Bee Wee 7.1 Introduction to palliative care  623

8.5.4 Poxviruses  764

Geoffrey L. Smith 8.5.5 Mumps: Epidemic parotitis  769

B.K. Rima 8.5.6 Measles  772

Hilton C. Whittle and Peter Aaby

Susan Salt

7.2 Pain management  629

8.5.7 Nipah and Hendra virus encephalitides  784

C.T. Tan

Marie Fallon

7.3 Symptoms other than pain  634 Regina McQuillan

†

It is with great regret that we report that J.G.P. Sissons died on 25 September, 2016.

xv

xvi

Contents

8.5.8 Enterovirus infections  787

Philip Minor and Ulrich Desselberger 8.5.9 Virus infections causing diarrhoea and vomiting  797

Philip R. Dormitzer and Ulrich Desselberger 8.5.10 Rhabdoviruses: Rabies and rabies-​related lyssaviruses  805

Mary J. Warrell and David A. Warrell 8.5.11 Colorado tick fever and other arthropod-​borne reoviruses  819

Mary J. Warrell and David A. Warrell 8.5.12 Alphaviruses  821

Ann M. Powers, E.E. Ooi, L.R. Petersen, and D.J. Gubler 8.5.13 Rubella  827

Pat Tookey and J.M. Best 8.5.14 Flaviviruses excluding dengue  830

Shannan Lee Rossi and Nikos Vasilakis 8.5.15 Dengue  845

Bridget Wills and Yee-​Sin Leo 8.5.16 Bunyaviridae  852

James W. Le Duc and D.A. Bente 8.5.17 Arenaviruses  862

Jan H. ter Meulen 8.5.18 Filoviruses  870

Jan H. ter Meulen 8.5.19 Papillomaviruses and polyomaviruses  877

Raphael P. Viscidi, Chen Sabrina Tan, and Carole Fakhry 8.5.20 Parvovirus B19  886

Kevin E. Brown 8.5.21 Hepatitis viruses (excluding hepatitis C virus)  889

Matthew Cramp, Ashwin Dhanda, and Nikolai V. Naoumov 8.5.22 Hepatitis C virus  896

Paul Klenerman, Katie J.M. Jeffery, Ellie J. Barnes, and Jane Collier 8.5.23 HIV/​AIDS  901

Sarah Fidler, Timothy E.A. Peto, Philip Goulder, and Christopher P. Conlon 8.5.24 HIV in low-​and middle-​income countries  933

Alison D. Grant and Kevin M. De Cock 8.5.25 HTLV-​1, HTLV-​2, and associated diseases  941

Kristien Verdonck and Eduardo Gotuzzo 8.5.26 Viruses and cancer  945

Robin A. Weiss 8.5.27 Orf and Milker’s nodule  947

Emma Aarons and David A. Warrell

8.5.28 Molluscum contagiosum  949

David A. Warrell and Christopher P. Conlon 8.5.29 Newly discovered viruses  951

Susannah J.A. Froude and Harriet C. Hughes

8.6 Bacteria  958 8.6.1 Diphtheria  959

Delia B. Bethell and Tran Tinh Hien 8.6.2 Streptococci and enterococci  965

Dennis L. Stevens and Sarah Hobdey 8.6.3 Pneumococcal infections  975

Anthony Scott 8.6.4 Staphylococci  991

Kyle J. Popovich, Robert A. Weinstein, and Bala Hota 8.6.5 Meningococcal infections  1010

Petter Brandtzaeg 8.6.6 Neisseria gonorrhoeae  1025

Jackie Sherrard and Magnus Unemo 8.6.7 Enterobacteria and bacterial food poisoning  1032

Hugh Pennington 8.6.8 Pseudomonas aeruginosa  1041

G.C.K.W. Koh and Sharon J. Peacock 8.6.9 Typhoid and paratyphoid fevers  1044

Christopher M. Parry and Buddha Basnyat 8.6.10 Intracellular klebsiella infections (donovanosis and rhinoscleroma)  1051

John Richens and Nicole Stoesser 8.6.11 Anaerobic bacteria  1055

Anilrudh A. Venugopal and David W. Hecht 8.6.12 Cholera  1060

Aldo A.M. Lima and Richard L. Guerrant 8.6.13 Haemophilus influenzae  1066

Esther Robinson 8.6.14 Haemophilus ducreyi and chancroid  1071

Nigel O’Farrell 8.6.15 Bordetella infection  1073

Cameron C. Grant 8.6.16 Melioidosis and glanders  1076

Sharon J. Peacock 8.6.17 Plague: Yersinia pestis  1081

Michael Prentice 8.6.18 Other Yersinia infections: Yersiniosis  1086

Michael Prentice 8.6.19 Pasteurella  1088

Marina S. Morgan 8.6.20 Francisella tularensis infection  1091

Petra C.F. Oyston

Contents

8.6.21 Anthrax  1094

8.6.42 Coxiella burnetii infections (Q fever)  1257

Arthur E. Brown 8.6.22 Brucellosis  1102

Thomas J. Marrie 8.6.43 Bartonellas excluding B. bacilliformis  1262

Juan D. Colmenero and Pilar Morata

Bruno B. Chomel, Henri-​Jean Boulouis, Matthew J. Stuckey, and Jean-​Marc Rolain

8.6.23 Tetanus  1109

C. Louise Thwaites and Lam Minh Yen

8.6.44 Bartonella bacilliformis infection  1272

A. Llanos-​Cuentas and C. Maguiña-​Vargas

8.6.24 Clostridium difficile  1115

David W. Eyre and Mark H. Wilcox

8.6.45 Chlamydial infections  1278

Patrick Horner, David Mabey, David Taylor-​Robinson, and Magnus Unemo

8.6.25 Botulism, gas gangrene, and clostridial gastrointestinal infections  1120

Dennis L. Stevens, Michael J. Aldape, and Amy E. Bryant

8.6.46 Mycoplasmas  1295

Jørgen Skov Jensen and David Taylor-​Robinson

8.6.26 Tuberculosis  1126

Richard E. Chaisson and Jean B. Nachega 8.6.27 Disease caused by environmental mycobacteria  1150

Jakko van Ingen 8.6.28 Leprosy (Hansen’s disease)  1154

Diana N.J. Lockwood 8.6.29 Buruli ulcer: Mycobacterium ulcerans infection  1167

Bouke de Jong, Françoise Portaels, and Wayne M. Meyers

8.6.47 A checklist of bacteria associated with infection in humans  1307

John Paul

8.7 Fungi (mycoses)  1338 8.7.1 Fungal infections  1338

Roderick J. Hay 8.7.2 Cryptococcosis  1359

William G. Powderly, J. William Campbell, and Larry J. Shapiro

8.6.30 Actinomycoses  1170

Klaus P. Schaal

8.7.3 Coccidioidomycosis  1361

Gregory M. Anstead

8.6.31 Nocardiosis  1176

Roderick J. Hay 8.6.32 Rat bite fevers (Streptobacillus moniliformis and Spirillum minus infection)  1179

Andrew F. Woodhouse 8.6.33 Lyme borreliosis  1181

Gary P. Wormser, John Nowakowski, and Robert B. Nadelman 8.6.34 Relapsing fevers  1188

David A. Warrell 8.6.35 Leptospirosis  1198

Nicholas P.J. Day 8.6.36 Nonvenereal endemic treponematoses: Yaws, endemic syphilis (bejel), and pinta  1204

Michael Marks, Oriol Mitjà, and David Mabey

8.7.4 Paracoccidioidomycosis  1364

M.A. Shikanai-​Yasuda 8.7.5 Pneumocystis jirovecii  1371

Robert F. Miller and Christopher P. Eades 8.7.6 Talaromyces (Penicillium) marneffei infection  1375

Romanee Chaiwarith, Khuanchai Supparatpinyo, and Thira Sirisanthana 8.7.7 Microsporidiosis  1378

Louis M. Weiss

8.8 Protozoa  1384 8.8.1 Amoebic infections  1384

Richard Knight 8.8.2 Malaria  1395

Nicholas J. White and Arjen M. Dondorp

8.6.37 Syphilis  1210

Phillip Read and Basil Donovan

8.8.3 Babesiosis  1414

Philippe Brasseur

8.6.38 Listeriosis  1223

Herbert Hof

8.8.4 Toxoplasmosis  1416

Oliver Liesenfeld and Eskild Petersen

8.6.39 Legionellosis and Legionnaires’ disease  1226

Diego Viasus and Jordi Carratalà

8.8.5 Cryptosporidium and cryptosporidiosis  1424

Simone M. Cacciò

8.6.40 Rickettsioses  1230

Karolina Griffiths, Carole Eldin, Didier Raoult, and Philippe Parola

8.8.6 Cyclospora and cyclosporiasis  1432

Paul Kelly and Ralph Lainson†

8.6.41 Scrub typhus  1252

Daniel H. Paris and Nicholas P.J. Day

†

It is with great regret that we report that Ralph Lainson died on 5 May, 2015.

xvii

xviii

Contents

8.8.7 Cystoisosporiasis  1436

8.11.2 Liver fluke infections  1551

Louis M. Weiss

Ross H. Andrews, Narong Khuntikeo, Paiboon Sithithaworn, and Trevor N. Petney

8.8.8 Sarcocystosis (sarcosporidiosis)  1438

John E. Cooper

8.11.3 Lung flukes (paragonimiasis)  1558

Udomsak Silachamroon and Sirivan Vanijanonta

8.8.9 Giardiasis and balantidiasis  1440

Lars Eckmann and Martin F. Heyworth

8.11.4 Intestinal trematode infections  1562

8.8.10 Blastocystis infection  1449

Alastair McGregor

Richard Knight

8.12 Nonvenomous arthropods  1568

8.8.11 Human African trypanosomiasis  1451

Reto Brun and Johannes Blum 8.8.12 Chagas disease  1459

Michael A. Miles 8.8.13 Leishmaniasis  1467

Antony D.M. Bryceson and Diana N.J. Lockwood

John Paul

8.13 Pentastomiasis (porocephalosis, linguatulosis/​linguatuliasis, or tongue worm infection)  1582 David A. Warrell

8.8.14 Trichomoniasis  1475

Jane Schwebke

8.9 Nematodes (roundworms)  1478 8.9.1 Cutaneous filariasis  1478

Gilbert Burnham 8.9.2 Lymphatic filariasis  1487

Richard Knight 8.9.3 Guinea worm disease (dracunculiasis)  1495

Richard Knight 8.9.4 Strongyloidiasis, hookworm, and other gut strongyloid nematodes  1500

Michael Brown 8.9.5 Gut and tissue nematode infections acquired by ingestion  1506

Peter L. Chiodini 8.9.6 Angiostrongyliasis  1516

Richard Knight

8.10 Cestodes (tapeworms)  1520 8.10.1 Cestodes (tapeworms)  1520

Richard Knight 8.10.2 Cystic hydatid disease (Echinococcus granulosus)  1529

Pedro L. Moro, Hector H. Garcia, and Armando E. Gonzalez 8.10.3 Cysticercosis  1533

Hector H. Garcia and Robert H. Gilman

8.11 Trematodes (flukes)  1540 8.11.1 Schistosomiasis  1540

David Dunne and Birgitte Vennervald

SECTION 9 Sexually transmitted diseases Section editor: Jackie Sherrard 9.1 Epidemiology of sexually transmitted infections  1589 David Mabey and Anita Vas-​Falcao

9.2 Sexual behaviour  1597 Catherine H. Mercer and Anne M. Johnson

9.3 Sexual history and examination  1600 Gary Brook, Jackie Sherrard, and Graz A. Luzzi

9.4 Vaginal discharge  1603 Paul Nyirjesy

9.5 Urethritis  1606 Patrick Horner

9.6 Genital ulceration  1610 Patrick French and Raj Patel

9.7 Anogenital lumps and bumps  1613 Henry J.C. de Vries and Charles J.N. Lacey

9.8 Pelvic inflammatory disease  1622 Jonathan D.C. Ross

9.9 Principles of contraception  1626 Zara Haider

Index

Contents

Volume 2 List of abbreviations  xxxv List of contributors  xlv

10.3.8 Disasters: Earthquakes, hurricanes, floods, and volcanic eruptions  1713

Peter J. Baxter 10.3.9 Bioterrorism  1718

SECTION 10 Environmental medicine, occupational medicine, and poisoning Section editor: Jon G. Ayres 10.1 Environmental medicine, occupational medicine, and poisoning—​Introduction  1637 Jon G. Ayres

10.2 Occupational health  1638 10.2.1 Occupational and environmental health  1638

Raymond Agius and Debasish Sen 10.2.2 Occupational safety  1652

Lawrence Waterman 10.2.3 Aviation medicine  1656

Manfred S. Green

10.4 Poisoning  1725 10.4.1 Poisoning by drugs and chemicals  1725

John A. Vale, Sally M. Bradberry, and D. Nicholas Bateman 10.4.2 Injuries, envenoming, poisoning, and allergic reactions caused by animals  1778

David A. Warrell 10.4.3 Poisonous fungi  1817

Hans Persson and David A. Warrell 10.4.4 Poisonous plants  1828

Michael Eddleston and Hans Persson

10.5 Podoconiosis (nonfilarial elephantiasis)  1833 Gail Davey

Michael Bagshaw 10.2.4 Diving medicine  1664

David M. Denison and Mark A. Glover 10.2.5 Noise  1671

David Koh and Tar-​Ching Aw† 10.2.6 Vibration  1673

Tar-​Ching  Aw†

10.3 Environment and health  1677 10.3.1 Air pollution and health  1677

Om P. Kurmi, Kin Bong Hubert Lam, and Jon G. Ayres 10.3.2 Heat  1687

Michael A. Stroud 10.3.3 Cold  1689

Michael A. Stroud 10.3.4 Drowning  1691

Peter J. Fenner 10.3.5 Lightning and electrical injuries  1696

Chris Andrews 10.3.6 Diseases of high terrestrial altitudes  1701

Tyler Albert, Erik R. Swenson, Andrew J. Pollard, Buddha Basnyat, and David R. Murdoch 10.3.7 Radiation  1709

Jill Meara †

It is with great regret that we report that Tar-Ching Aw died on 18 July, 2017.

SECTION 11 Nutrition Section editor: Katherine Younger 11.1 Nutrition: Macronutrient metabolism  1839 Keith N. Frayn and Rhys D. Evans

11.2 Vitamins  1855 Tom R. Hill and David A. Bender

11.3 Minerals and trace elements  1871 Katherine Younger

11.4 Severe malnutrition  1880 Alan A. Jackson

11.5 Diseases of affluent societies and the need for dietary change  1891 J.I. Mann and A.S. Truswell

11.6 Obesity  1903 I. Sadaf Farooqi

11.7 Artificial nutrition support  1914 Jeremy Woodward

xix

xx

Contents

SECTION 12 Metabolic disorders Section editor: Timothy M. Cox 12.1 The inborn errors of metabolism: General aspects  1929 Timothy M. Cox and Richard W.E. Watts†

12.2 Protein-​dependent inborn errors of metabolism  1942 Georg F. Hoffmann and Stefan Kölker

12.3 Disorders of carbohydrate metabolism  1985

12.12 The acute phase response, hereditary periodic fever syndromes, and amyloidosis  2199 12.12.1 The acute phase response and C-​reactive protein  2199

Mark B. Pepys 12.12.2 Hereditary periodic fever syndromes  2207

Helen J. Lachmann, Stefan Berg, and Philip N. Hawkins 12.12.3 Amyloidosis  2218

Mark B. Pepys and Philip N. Hawkins

12.13 α1-​Antitrypsin deficiency and the serpinopathies  2235 David A. Lomas

12.3.1 Glycogen storage diseases  1985

Robin H. Lachmann and Timothy M. Cox 12.3.2 Inborn errors of fructose metabolism  1993

Timothy M. Cox 12.3.3 Disorders of galactose, pentose, and pyruvate metabolism  2003

Timothy M. Cox

12.4 Disorders of purine and pyrimidine metabolism  2015 Anthony M. Marinaki, Lynette D. Fairbanks, and Richard W.E. Watts†

12.5 The porphyrias  2032 Timothy M. Cox

12.6 Lipid disorders  2055 Jaimini Cegla and James Scott

12.7 Trace metal disorders  2098 12.7.1 Hereditary haemochromatosis  2098

William J.H. Griffiths and Timothy M. Cox 12.7.2 Inherited diseases of copper metabolism: Wilson’s disease and Menkes’ disease  2115

Michael L. Schilsky and Pramod K. Mistry

12.8 Lysosomal disease  2121 Patrick B. Deegan and Timothy M. Cox

12.9 Disorders of peroxisomal metabolism in adults  2157 Anthony S. Wierzbicki

12.10 Hereditary disorders of oxalate metabolism: The primary hyperoxalurias  2174 Sonia Fargue, Dawn S. Milliner, and Christopher J. Danpure

12.11 A physiological approach to acid–​base disorders: The roles of ion transport and body fluid compartments  2182 Julian Seifter †

It is with great regret that we report that Richard W.E. Watts died on 11 February, 2018.

SECTION 13 Endocrine disorders Section editor: Mark Gurnell 13.1 Principles of hormone action  2245 Rob Fowkes, V. Krishna Chatterjee, and Mark Gurnell

13.2 Pituitary disorders  2258 13.2.1 Disorders of the anterior pituitary gland  2258

Niki Karavitaki and John A.H. Wass 13.2.2 Disorders of the posterior pituitary gland  2277

Niki Karavitaki, Shahzada K. Ahmed, and John A.H. Wass

13.3 Thyroid disorders  2284 13.3.1 The thyroid gland and disorders of thyroid function  2284

Anthony P. Weetman and Kristien Boelaert 13.3.2 Thyroid cancer  2302

Kristien Boelaert and Anthony P. Weetman

13.4 Parathyroid disorders and diseases altering calcium metabolism  2313 R.V. Thakker

13.5 Adrenal disorders  2331 13.5.1 Disorders of the adrenal cortex  2331

Mark Sherlock and Mark Gurnell 13.5.2 Congenital adrenal hyperplasia  2360

Nils P. Krone and Ieuan A. Hughes

13.6 Reproductive disorders  2374 13.6.1 Ovarian disorders  2374

Stephen Franks, Kate Hardy, and Lisa J. Webber 13.6.2 Disorders of male reproduction and male hypogonadism  2386

P.-​M.G. Bouloux 13.6.3 Benign breast disease  2406

Gael M. MacLean

Contents

13.6.4 Sexual dysfunction  2408

Ian Eardley

14.9 Liver and gastrointestinal diseases of pregnancy  2619 Michael Heneghan and Catherine Williamson

13.7 Disorders of growth and development  2416 13.7.1 Normal growth and its disorders  2416

14.10 Diabetes in pregnancy  2627 Bryony Jones and Anne Dornhorst

Gary Butler 13.7.2 Normal puberty and its disorders  2428

Fiona Ryan and Sejal Patel 13.7.3 Normal and abnormal sexual differentiation  2435

S. Faisal Ahmed and Angela K. Lucas-​Herald

13.8 Pancreatic endocrine disorders and multiple endocrine neoplasia  2449

14.11 Endocrine disease in pregnancy  2638 David Carty

14.12 Neurological conditions in pregnancy  2642 Pooja Dassan

14.13 The skin in pregnancy  2648 Gudula Kirtschig and Fenella Wojnarowska

B. Khoo, T.M. Tan, and S.R. Bloom

13.9 Diabetes and hypoglycaemia  2464 13.9.1 Diabetes  2464

Colin Dayan and Julia Platts 13.9.2 Hypoglycaemia  2531

14.14 Autoimmune rheumatic disorders and vasculitis in pregnancy  2655 May Ching Soh and Catherine Nelson-​Piercy

14.15 Maternal infection in pregnancy  2671 Rosie Burton

Mark Evans and Ben Challis

13.10 Hormonal manifestations of nonendocrine disease  2541 Thomas M. Barber and John A.H. Wass

14.16 Fetal effects of maternal infection  2678 Lawrence Impey

14.17 Blood disorders in pregnancy  2687 David J. Perry and Katharine Lowndes

13.11 The pineal gland and melatonin  2553 J. Arendt and Timothy M. Cox

14.18 Malignant disease in pregnancy  2696 Robin A.F. Crawford

SECTION 14 Medical disorders in pregnancy

14.19 Maternal critical care  2701 Rupert Gauntlett

14.20 Prescribing in pregnancy  2706 Lucy MacKillop and Charlotte Frise

Section editor: Catherine Nelson-​Piercy 14.1 Physiological changes of normal pregnancy  2563 David J. Williams

14.21 Contraception for women with medical diseases  2711 Aarthi R. Mohan

14.2 Nutrition in pregnancy  2568 David J. Williams

14.3 Medical management of normal pregnancy  2575 David J. Williams

14.4 Hypertension in pregnancy  2583 Fergus McCarthy

14.5 Renal disease in pregnancy  2589 Kate Wiles

14.6 Heart disease in pregnancy  2597 Catherine E.G. Head

14.7 Thrombosis in pregnancy  2606 Peter K. MacCallum and Louise Bowles

14.8 Chest diseases in pregnancy  2613 Meredith Pugh and Tina Hartert

SECTION 15 Gastroenterological disorders Section editor: Jack Satsangi 15.1 Structure and function of the gastrointestinal tract  2721 Michael E.B. FitzPatrick and Satish Keshav†

15.2 Symptoms of gastrointestinal disease  2727 Jeremy Woodward

15.3 Methods for investigation of gastroenterological disease  2734 15.3.1 Colonoscopy and flexible sigmoidoscopy  2734

James E. East and Brian P. Saunders †

It is with great regret that we report that Satish Keshav died on 23 January, 2019.

xxi

xxii

Contents

15.3.2 Upper gastrointestinal endoscopy  2740

James E. East and George J. Webster 15.3.3 Radiology of the gastrointestinal tract  2748

Fiachra Moloney and Michael Maher 15.3.4 Investigation of gastrointestinal function  2757

Jervoise Andreyev

15.4 Common acute abdominal presentations  2765 15.4.1 The acute abdomen  2765

Simon J.A. Buczacki and R. Justin Davies 15.4.2 Gastrointestinal bleeding  2771

Vanessa Brown and T.A. Rockall

15.5 Immune disorders of the gastrointestinal tract  2783 Joya Bhattacharyya and Arthur Kaser

15.6 The mouth and salivary glands  2797 John Gibson and Douglas Robertson

15.7 Diseases of the oesophagus  2828 Rebecca C. Fitzgerald and Massimiliano di Pietro

15.8 Peptic ulcer disease  2849 Joseph Sung

15.9 Hormones and the gastrointestinal tract  2862 15.9.1 Hormones and the gastrointestinal tract  2862

Rebecca Scott, T.M. Tan, and S.R. Bloom 15.9.2 Carcinoid syndrome  2870

B. Khoo, T.M. Tan, and S.R. Bloom

15.10 Malabsorption  2875 15.10.1 Differential diagnosis and investigation of malabsorption  2875

Alastair Forbes and Victoria Mulcahy 15.10.2 Bacterial overgrowth of the small intestine  2879

Stephen J. Middleton and Raymond J. Playford 15.10.3 Coeliac disease  2884

Peter D. Mooney and David S. Sanders 15.10.4 Gastrointestinal lymphomas  2892

Kikkeri N. Naresh 15.10.5 Disaccharidase deficiency  2902

Timothy M. Cox 15.10.6 Whipple’s disease  2909

Florence Fenollar and Didier Raoult 15.10.7 Effects of massive bowel resection  2911

Stephen J. Middleton, Simon M. Gabe, and Raymond J. Playford 15.10.8 Malabsorption syndromes in the tropics  2916

Vineet Ahuja and Govind K. Makharia

15.11 Crohn’s disease  2925 Miles Parkes and Tim Raine

15.12 Ulcerative colitis  2937 Jeremy Sanderson and Peter Irving

15.13 Irritable bowel syndrome  2951 Adam D. Farmer and Qasim Aziz

15.14 Colonic diverticular disease  2960 Nicolas C. Buchs, Roel Hompes, Shazad Q. Ashraf, and Neil J.McC. Mortensen

15.15 Congenital abnormalities of the gastrointestinal tract  2967 Holm H. Uhlig

15.16 Cancers of the gastrointestinal tract  2977 Peter L. Labib, J.A. Bridgewater, and Stephen P. Pereira

15.17 Vascular disorders of the gastrointestinal tract  2997 Ray Boyapati

15.18 Gastrointestinal infections  3008 Sarah O’Brien

15.19 Miscellaneous disorders of the bowel  3025 Alexander Gimson

15.20 Structure and function of the liver, biliary tract, and pancreas  3032 William Gelson and Alexander Gimson

15.21 Pathobiology of chronic liver disease  3043 Wajahat Z. Mehal

15.22 Presentations and management of liver disease  3049 15.22.1 Investigation and management of jaundice  3049

Jane Collier 15.22.2 Cirrhosis and ascites  3058

Javier Fernández and Vicente Arroyo 15.22.3 Portal hypertension and variceal bleeding  3068

Marcus Robertson and Peter Hayes 15.22.4 Hepatic encephalopathy  3080

Paul K. Middleton and Debbie L. Shawcross 15.22.5 Liver failure  3089

Jane Macnaughtan and Rajiv Jalan 15.22.6 Liver transplantation  3100

John G. O’Grady

15.23 Hepatitis and autoimmune liver disease  3108 15.23.1 Hepatitis A to E  3108

Graeme J.M. Alexander and Kate Nash

Contents

15.23.2 Autoimmune hepatitis  3119

15.24.6 Primary and secondary liver tumours  3178

G.J. Webb and Gideon M. Hirschfield

Graeme J.M. Alexander, David J. Lomas, William J.H. Griffiths, Simon M. Rushbrook, and Michael E.D. Allison

15.23.3 Primary biliary cholangitis  3127

Jessica K. Dyson and David E.J. Jones 15.23.4 Primary sclerosing cholangitis  3135

Kate D. Lynch and Roger W. Chapman

15.24 Other liver diseases  3142 15.24.1 Alcoholic liver disease  3142

15.24.7 Liver and biliary diseases in infancy and childhood  3191

Richard J. Thompson

15.25 Diseases of the gallbladder and biliary tree  3196 Colin Johnson and Mark Wright

Ewan Forrest 15.24.2 Nonalcoholic fatty liver disease  3147

Quentin M. Anstee and Christopher P. Day

15.26 Diseases of the pancreas  3209 15.26.1 Acute pancreatitis  3209

R. Carter, Euan J. Dickson, and C.J. McKay

15.24.3 Drug-​induced liver disease  3155

Guruprasad P. Aithal

15.26.2 Chronic pancreatitis  3218

Marco J. Bruno and Djuna L. Cahen

15.24.4 Vascular disorders of the liver  3166

Alexander Gimson

15.26.3 Tumours of the pancreas  3227

James R.A. Skipworth and Stephen P. Pereira

15.24.5 The liver in systemic disease  3169

James Neuberger

Index

Volume 3 List of abbreviations  xxxv List of contributors  xlv

16.3 Clinical investigation of cardiac disorders  3294 16.3.1 Electrocardiography  3294

Andrew R. Houghton and David Gray 16.3.2 Echocardiography  3314

SECTION 16 Cardiovascular disorders Section editor: Jeremy Dwight 16.1 Structure and function  3241 16.1.1 Blood vessels and the endothelium  3241

Keith Channon and Patrick Vallance 16.1.2 Cardiac physiology  3253

Rhys D. Evans, Kenneth T. MacLeod, Steven B. Marston, Nicholas J. Severs, and Peter H. Sugden

16.2 Clinical presentation of heart disease  3276 16.2.1 Chest pain, breathlessness, and fatigue  3276

Jeremy Dwight 16.2.2 Syncope and palpitation  3284

K. Rajappan, A.C. Rankin, A.D. McGavigan, and S.M. Cobbe

James D. Newton, Adrian P. Banning, and Andrew R.J. Mitchell 16.3.3 Cardiac investigations: Nuclear, MRI, and CT  3326

Nikant Sabharwal, Andrew Kelion, Theodoros Karamitos, and Stefan Neubauer 16.3.4 Cardiac catheterization and angiography  3339

Edward D. Folland

16.4 Cardiac arrhythmias  3350 Matthew R. Ginks, D.A. Lane, A.D. McGavigan, and Gregory Y.H. Lip

16.5 Cardiac failure  3390 16.5.1 Epidemiology and general pathophysiological classification of heart failure  3390

Theresa A. McDonagh and Kaushik Guha 16.5.2 Acute cardiac failure: Definitions, investigation, and management  3397

Andrew L. Clark and John G.F. Cleland 16.5.3 Chronic heart failure: Definitions, investigation, and management  3407

John G.F. Cleland and Andrew L. Clark

xxiii

xxiv

Contents

16.5.4 Cardiorenal syndrome  3421

Darren Green and Philip A. Kalra 16.5.5 Cardiac transplantation and mechanical circulatory support  3428

Jayan Parameshwar and Steven Tsui

16.6 Valvular heart disease  3436 Michael Henein

16.7 Diseases of heart muscle  3459 16.7.1 Myocarditis  3459

Jay W. Mason and Heinz-​Peter Schultheiss 16.7.2 The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular  3468

Oliver P. Guttmann and Perry Elliott 16.7.3 Specific heart muscle disorders  3489

Oliver P. Guttmann and Perry Elliott

16.8 Pericardial disease  3501 Michael Henein

16.9 Cardiac involvement in infectious disease  3509 16.9.1 Acute rheumatic fever  3509

Jonathan R. Carapetis 16.9.2 Endocarditis  3519

James L. Harrison, John L. Klein, William A. Littler, and Bernard D. Prendergast 16.9.3 Cardiac disease in HIV infection  3534

Peter F. Currie 16.9.4 Cardiovascular syphilis  3539

Krishna Somers

16.10 Tumours of the heart  3544 Thomas A. Traill

16.11 Cardiac involvement in genetic disease  3551 Thomas A. Traill

16.12 Congenital heart disease in the adult  3559 S.A. Thorne

16.13 Coronary heart disease  3596 16.13.1 Biology and pathology of atherosclerosis  3596

Robin P. Choudhury, Joshua T. Chai, and Edward A. Fisher 16.13.2 Coronary heart disease: Epidemiology and prevention  3603

Goodarz Danaei and Kazem Rahimi 16.13.3 Management of stable angina  3616

Adam D. Timmis 16.13.4 Management of acute coronary syndrome  3626

Rajesh K. Kharbanda and Keith A.A. Fox

16.13.5 Percutaneous interventional cardiac procedures  3655

Edward D. Folland 16.13.6 Coronary artery bypass and valve surgery  3666

Rana Sayeed and David Taggart

16.14 Diseases of the arteries  3674 16.14.1 Acute aortic syndromes  3674

James D. Newton, Andrew R.J. Mitchell, and Adrian P. Banning 16.14.2 Peripheral arterial disease  3680

Janet Powell and Alun Davies 16.14.3 Cholesterol embolism  3688

Christopher Dudley

16.15 The pulmonary circulation  3691 16.15.1 Structure and function of the pulmonary circulation  3691

Nicholas W. Morrell 16.15.2 Pulmonary hypertension  3695

Nicholas W. Morrell

16.16 Venous thromboembolism  3711 16.16.1 Deep venous thrombosis and pulmonary embolism  3711

Paul D. Stein, Fadi Matta, and John D. Firth 16.16.2 Therapeutic anticoagulation  3729

David Keeling

16.17 Hypertension  3735 16.17.1 Essential hypertension: Definition, epidemiology, and pathophysiology  3735

Bryan Williams and John D. Firth 16.17.2 Essential hypertension: Diagnosis, assessment, and treatment  3753

Bryan Williams and John D. Firth 16.17.3 Secondary hypertension  3778

Morris J. Brown and Fraz A. Mir 16.17.4 Mendelian disorders causing hypertension  3796

Nilesh J. Samani and Maciej Tomaszewski 16.17.5 Hypertensive urgencies and emergencies  3800

Gregory Y.H. Lip and Alena Shantsila

16.18 Chronic peripheral oedema and lymphoedema  3811 Peter S. Mortimer

16.19 Idiopathic oedema of women  3823 John D. Firth

Contents

18.1.2 Airways and alveoli  3937

SECTION 17 Critical care medicine Section editor: Simon Finfer 17.1 The seriously ill or deteriorating patient  3829 Carole Foot and Liz Hickson

17.2 Cardiac arrest  3839 Gavin D. Perkins, Jasmeet Soar, Jerry P. Nolan, and David A. Gabbott

17.3 Anaphylaxis  3849 Anthony F.T. Brown

17.4 Assessing and preparing patients with medical conditions for major surgery  3860 Tom Abbott and Rupert Pearse

17.5 Acute respiratory failure  3867 Susannah Leaver, Jeremy Cordingley, Simon Finney, and Mark Griffiths

17.6 Circulation and circulatory support in the critically ill  3881 Michael R. Pinsky

17.7 Management of raised intracranial pressure  3892 David K. Menon

17.8 Sedation and analgesia in the ICU  3898 Michael C. Reade

17.9 Metabolic and endocrine changes in acute and chronic critical illness  3906 Eva Boonen and Greet Van den Berghe

17.10 Palliative and end-​of-​life care in the ICU  3914 Phillip D. Levin and Charles L. Sprung

17.11 Diagnosis of death and organ donation  3918 Paul Murphy

17.12 Persistent problems and recovery after critical illness  3925 Mark E. Mikkelsen and Theodore J. Iwashyna

SECTION 18 Respiratory disorders Section editor: Pallav L. Shah 18.1 Structure and function  3933 18.1.1 The upper respiratory tract  3933

Pallav L. Shah, J.R. Stradling, and S.E. Craig

Peter D. Wagner and Pallav L. Shah

18.2 The clinical presentation of respiratory disease  3947 Samuel Kemp and Julian Hopkin

18.3 Clinical investigation of respiratory disorders  3956 18.3.1 Respiratory function tests  3956

G.J. Gibson 18.3.2 Thoracic imaging  3970

Susan J. Copley and David M. Hansell 18.3.3 Bronchoscopy, thoracoscopy, and tissue biopsy  3992

Pallav L. Shah

18.4 Respiratory infection  4004 18.4.1 Upper respiratory tract infections  4004

P. Little 18.4.2 Pneumonia in the normal host  4008

Wei Shen Lim 18.4.3 Nosocomial pneumonia  4022

Wei Shen Lim 18.4.4 Mycobacteria  4026

Hannah Jarvis and Onn Min Kon 18.4.5 Pulmonary complications of HIV infection  4031

Julia Choy and Anton Pozniak

18.5 The upper respiratory tract  4040 18.5.1 Upper airway obstruction  4040

James H. Hull and Matthew Hind 18.5.2 Sleep-​related breathing disorders  4048

Mary J. Morrell, Julia Kelly, Alison McMillan, and Matthew Hind

18.6 Allergic rhinitis  4059 Stephen R. Durham and Hesham A. Saleh

18.7 Asthma  4067 Alexandra Nanzer-​Kelly, Paul Cullinan, and Andrew Menzies-​Gow

18.8 Chronic obstructive pulmonary disease  4098 Nicholas S. Hopkinson

18.9 Bronchiectasis  4142 R. Wilson and D. Bilton

18.10 Cystic fibrosis  4151 Andrew Bush and Caroline Elston

xxv

xxvi

Contents

18.11 Diffuse parenchymal lung diseases  4166 18.11.1 Diffuse parenchymal lung disease: An introduction  4166

F. Teo and A.U. Wells 18.11.2 Idiopathic pulmonary fibrosis  4177

P.L. Molyneaux, A.G. Nicholson, N. Hirani, and A.U. Wells 18.11.3 Bronchiolitis obliterans and cryptogenic organizing pneumonia  4185

Vasilis Kouranos and A.U. Wells 18.11.4 The lung in autoimmune rheumatic disorders  4191

M.A. Kokosi and A.U. Wells 18.11.5 The lung in vasculitis  4200

G.A. Margaritopoulos and A.U. Wells

18.12 Sarcoidosis  4208 Robert P. Baughman and Elyse E. Lower

18.13 Pneumoconioses  4219 P.T. Reid

18.15 Chronic respiratory failure  4282 Michael I. Polkey and P.M.A. Calverley

18.16 Lung transplantation  4292 P. Hopkins and A.J. Fisher

18.17 Pleural diseases  4305 D. de Fonseka, Y.C. Gary Lee, and N.A. Maskell

18.18 Disorders of the thoracic cage and diaphragm  4328 John M. Shneerson and Michael I. Polkey

18.19 Malignant diseases  4338 18.19.1 Lung cancer  4338

S.G. Spiro and N. Navani 18.19.2 Pulmonary metastases  4360

S.G. Spiro 18.19.3 Pleural tumours  4361

Y.C. Gary Lee 18.19.4 Mediastinal tumours and cysts  4368

Y.C. Gary Lee and Helen E. Davies

18.14 Miscellaneous conditions  4235 18.14.1 Diffuse alveolar haemorrhage  4235

S.J. Bourke and G.P. Spickett 18.14.2 Eosinophilic pneumonia  4238

S.J. Bourke and G.P. Spickett 18.14.3 Lymphocytic infiltrations of the lung  4241

S.J. Bourke 18.14.4 Hypersensitivity pneumonitis  4244

S.J. Bourke and G.P. Spickett 18.14.5 Pulmonary Langerhans’ cell histiocytosis  4256

S.J. Bourke 18.14.6 Lymphangioleiomyomatosis  4257

S.J. Bourke 18.14.7 Pulmonary alveolar proteinosis  4259

S.J. Bourke 18.14.8 Pulmonary amyloidosis  4261

S.J. Bourke 18.14.9 Lipoid (lipid) pneumonia  4263

S.J. Bourke 18.14.10 Pulmonary alveolar microlithiasis  4265

S.J. Bourke 18.14.11 Toxic gases and aerosols  4267

Chris Stenton 18.14.12 Radiation pneumonitis  4271

S.J. Bourke 18.14.13 Drug-​induced lung disease  4272

S.J. Bourke

SECTION 19 Rheumatological disorders Section editor: Richard A. Watts 19.1 Joints and connective tissue—​structure and function  4379 Thomas Pap, Adelheid Korb-​Pap, Christine Hartmann, and Jessica Bertrand

19.2 Clinical presentation and diagnosis of rheumatological disorders  4386 Christopher Deighton and Fiona Pearce

19.3 Clinical investigation  4395 Michael Doherty and Peter C. Lanyon

19.4 Back pain and regional disorders  4406 Carlo Ammendolia and Danielle Southerst

19.5 Rheumatoid arthritis  4415 Kenneth F. Baker and John D. Isaacs

19.6 Spondyloarthritis and related conditions  4441 Jürgen Braun and Joachim Sieper

19.7 Infection and arthritis  4457 Graham Raftery and Muddassir Shaikh

19.8 Reactive arthritis  4464 Carmel B. Stober and Hill Gaston

19.9 Osteoarthritis  4470 Andrew J. Barr and Philip G. Conaghan

Contents

19.10 Crystal-​related arthropathies  4482 Edward Roddy and Michael Doherty

20.3 Osteomyelitis  4688 Martin A. McNally and Anthony R. Berendt

19.11 Autoimmune rheumatic disorders and vasculitides  4495

20.4 Osteoporosis  4696

19.11.1 Introduction  4495

20.5 Osteonecrosis, osteochondrosis, and osteochondritis dissecans  4703

David A. Isenberg and Ian Giles 19.11.2 Systemic lupus erythematosus and related disorders  4499

Anisur Rahman and David A. Isenberg 19.11.3 Systemic sclerosis (scleroderma)  4513

Nicholas C. Harvey, Juliet Compston, and Cyrus Cooper

Gavin Clunie

20.6 Bone cancer  4709 Helen Hatcher

Christopher P. Denton and Carol M. Black 19.11.4 Sjögren’s syndrome  4532

Wan-​Fai  Ng 19.11.5 Inflammatory myopathies  4537

Ingrid E. Lundberg, Hector Chinoy, and Robert Cooper 19.11.6 Large vessel vasculitis  4546

Raashid Luqmani and Cristina Ponte 19.11.7 ANCA-​associated vasculitis  4556

David Jayne 19.11.8 Polyarteritis nodosa  4569

Loïc Guillevin 19.11.9 Small vessel vasculitis  4573

Richard A. Watts 19.11.10 Behçet’s syndrome  4579

Sebahattin Yurdakul, Izzet Fresko, and Hasan Yazici 19.11.11 Polymyalgia rheumatica  4584

Bhaskar Dasgupta and Eric L. Matteson 19.11.12 Kawasaki disease  4590

Brian W. McCrindle

19.12 Miscellaneous conditions presenting to the rheumatologist  4598 Stuart Carter, Lisa Dunkley, and Ade Adebajo

SECTION 21 Disorders of the kidney and urinary tract Section editor: John D. Firth 21.1 Structure and function of the kidney  4717 Steve Harper and Robert Unwin

21.2 Electrolyte disorders  4729 21.2.1 Disorders of water and sodium homeostasis  4729

Michael L. Moritz and Juan Carlos Ayus 21.2.2 Disorders of potassium homeostasis  4748

John D. Firth

21.3 Clinical presentation of renal disease  4764 Richard E. Fielding and Ken Farrington

21.4 Clinical investigation of renal disease  4781 Andrew Davenport

21.5 Acute kidney injury  4807 John D. Firth

21.6 Chronic kidney disease  4830 Alastair Hutchison

21.7 Renal replacement therapy  4861 21.7.1 Haemodialysis  4861

Robert Mactier

SECTION 20 Disorders of the skeleton

21.7.2 Peritoneal dialysis  4874

Section editor: Cyrus Cooper

21.7.3 Renal transplantation  4879

20.1 Skeletal disorders—​general approach and clinical conditions  4615 B. Paul Wordsworth and M.K. Javaid

20.2 Inherited defects of connective tissue: Ehlers–​Danlos syndrome, Marfan’s syndrome, and pseudoxanthoma elasticum  4670 N.P. Burrows

Simon Davies Nicholas Torpey and John D. Firth

21.8 Glomerular diseases  4909 21.8.1 Immunoglobulin A nephropathy and IgA vasculitis (HSP)  4909

Jonathan Barratt and John Feehally 21.8.2 Thin membrane nephropathy  4918

Peter Topham and John Feehally

xxvii

xxviii

Contents

21.8.3 Minimal-​change nephropathy and focal segmental glomerulosclerosis  4919

Moin Saleem and Lisa Willcocks

21.10.6 Haemolytic uraemic syndrome  5027

Edwin K.S. Wong and David Kavanagh 21.10.7 Sickle cell disease and the kidney  5032

Claire C. Sharpe

21.8.4 Membranous nephropathy  4928

An S. De Vriese and Fernando C. Fervenza

21.10.8 Infection-​associated nephropathies  5034

A. Neil Turner

21.8.5 Proliferative glomerulonephritis  4933

Alan D. Salama and Mark A. Little

21.10.9 Malignancy-​associated renal disease  5041

A. Neil Turner

21.8.6 Membranoproliferative glomerulonephritis  4937

Tabitha Turner-​Stokes and Mark A. Little 21.8.7 Antiglomerular basement membrane disease  4943

Mårten Segelmark and Thomas Hellmark

21.9 Tubulointerstitial diseases  4951 21.9.1 Acute interstitial nephritis  4951

Simon D. Roger 21.9.2 Chronic tubulointerstitial nephritis  4956

Marc E. De Broe, Channa Yamasumana, Patrick C. D’Haese, Monique M. Elseviers, and Benjamin Vervaet

21.10.10 Atherosclerotic renovascular disease  5044

Philip A. Kalra and Diana Vassallo

21.11 Renal diseases in the tropics  5049 Vivekanand Jha

21.12 Renal involvement in genetic disease  5065 D. Joly and J.P. Grünfeld

21.13 Urinary tract infection  5074 Charles Tomson and Neil Sheerin

21.14 Disorders of renal calcium handling, urinary stones, and nephrocalcinosis  5093 Christopher Pugh, Elaine M. Worcester, Andrew P. Evan, and Fredric L. Coe

21.10 The kidney in systemic disease  4975 21.10.1 Diabetes mellitus and the kidney  4975

Rudolf Bilous

21.15 The renal tubular acidoses  5104 John A. Sayer and Fiona E. Karet

21.10.2 The kidney in systemic vasculitis  4988

David Jayne 21.10.3 The kidney in rheumatological disorders  5001

Liz Lightstone and Hannah Beckwith 21.10.4 The kidney in sarcoidosis  5012

Ingeborg Hilderson and Jan Donck

21.16 Disorders of tubular electrolyte handling  5112 Nine V.A.M. Knoers and Elena N. Levtchenko

21.17 Urinary tract obstruction  5124 Muhammad M. Yaqoob and Kieran McCafferty

21.18 Malignant diseases of the urinary tract  5136 Tim Eisen, Freddie C. Hamdy, and Robert A. Huddart

21.10.5 Renal involvement in plasma cell dyscrasias,

immunoglobulin-​based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias  5016 Pierre Ronco, Frank Bridoux, and Arnaud Jaccard

21.19 Drugs and the kidney  5150 Aine Burns and Caroline Ashley

Index

Volume 4 List of abbreviations  xxxv List of contributors  xlv

22.1 Introduction to haematology  5169 Chris Hatton

22.2 Haematopoiesis  5172

SECTION 22 Haematological disorders Section editors: Chris Hatton and Deborah Hay

22.2.1 Cellular and molecular basis of haematopoiesis  5172

Paresh Vyas and N. Asger Jakobsen 22.2.2 Diagnostic techniques in the assessment of haematological malignancies  5181

Wendy N. Erber

Contents

22.3 Myeloid disease  5189

22.6 Erythroid disorders  5354

22.3.1 Granulocytes in health and disease  5189

22.6.1 Erythropoiesis  5354

Joseph Sinning and Nancy Berliner 22.3.2 Myelodysplastic syndromes  5197

Charlotte K. Brierley and David P. Steensma

Vijay G. Sankaran 22.6.2 Anaemia: pathophysiology, classification, and clinical features  5359

David J. Weatherall† and Chris Hatton

22.3.3 Acute myeloid leukaemia  5205

Nigel Russell and Alan Burnett

22.6.3 Anaemia as a challenge to world health  5366

David J. Roberts and David J. Weatherall†

22.3.4 Chronic myeloid leukaemia  5213

Mhairi Copland and Tessa L. Holyoake†

22.6.4 Iron metabolism and its disorders  5371

Timothy M. Cox and John B. Porter

22.3.5 The polycythaemias  5227

Daniel Aruch and Ronald Hoffman 22.3.6 Thrombocytosis and essential thrombocythaemia  5239

Daniel Aruch and Ronald Hoffman

22.6.5 Anaemia of inflammation  5402

Sant-​Rayn Pasricha and Hal Drakesmith 22.6.6 Megaloblastic anaemia and miscellaneous deficiency anaemias  5407

A.V. Hoffbrand

22.3.7 Primary myelofibrosis  5247

Evan M. Braunstein and Jerry L. Spivak 22.3.8 Eosinophilia  5254

22.6.7 Disorders of the synthesis or function of haemoglobin  5426

Deborah Hay and David J. Weatherall†

Peter F. Weller 22.3.9 Histiocytosis  5259

Chris Hatton

22.4 Lymphoid disease  5263

22.6.8 Anaemias resulting from defective maturation of red cells  5450

Stephen J. Fuller and James S. Wiley 22.6.9 Disorders of the red cell membrane  5456

22.4.1 Introduction to lymphopoiesis  5263

Caron A. Jacobson and Nancy Berliner

Patrick G. Gallagher 22.6.10 Erythrocyte enzymopathies  5463

22.4.2 Acute lymphoblastic leukaemia  5269

H. Josef Vormoor, Tobias F. Menne, and Anthony V. Moorman

Alberto Zanella and Paola Bianchi

22.4.3 Hodgkin lymphoma  5280

Vijaya Raj Bhatt and James O. Armitage

Lucio Luzzatto 22.6.12 Acquired haemolytic anaemia  5479

22.4.4 Non-​Hodgkin lymphoma  5288

Vijaya Raj Bhatt and James O. Armitage 22.4.5 Chronic lymphocytic leukaemia  5302

Clive S. Zent and Aaron Polliack 22.4.6 Plasma cell myeloma and related monoclonal gammopathies  5310

S. Vincent Rajkumar and Robert A. Kyle

22.5 Bone marrow failure  5325

Amy Powers and Leslie Silberstein

22.7 Haemostasis  5490 22.7.1 The biology of haemostasis and thrombosis  5490

Gilbert C. White, II, Harold R. Roberts, and Nigel S. Key 22.7.2 Evaluation of the patient with a bleeding tendency  5509

Trevor Baglin

22.5.1 Inherited bone marrow failure syndromes  5325

Irene Roberts and Inderjeet S. Dokal 22.5.2 Acquired aplastic anaemia and pure red cell aplasia  5336

Judith C.W. Marsh, Shreyans Gandhi, and Ghulam J. Mufti 22.5.3 Paroxysmal nocturnal haemoglobinuria  5348

22.7.3 Thrombocytopenia and disorders of platelet function  5520

Nicola Curry and Susie Shapiro 22.7.4 Genetic disorders of coagulation  5532

Eleanor S. Pollak and Katherine A. High 22.7.5 Acquired coagulation disorders  5546

Lucio Luzzatto

†

It is with great regret that we report that Tessa L. Holyoake died on 30 August, 2017.

22.6.11 Glucose-​6-​phosphate dehydrogenase deficiency  5472

T.E. Warkentin

†

It is with great regret that we report that David J. Weatherall died on 8 December, 2018.

xxix

xxx

Contents

22.8 Transfusion and transplantation  5563 22.8.1 Blood transfusion  5563

D.S. Giovanniello and E.L. Snyder 22.8.2 Haemopoietic stem cell transplantation  5579

23.16 Cutaneous reactions to drugs  5752 Sarah Walsh, Daniel Creamer, and Haur Yueh Lee

23.17 Management of skin disease  5761 Rod Sinclair

E.C. Gordon-​Smith and Emma C. Morris

SECTION 23 Disorders of the skin Section editor: Roderick J. Hay 23.1 Structure and function of skin  5591 John A. McGrath

23.2 Clinical approach to the diagnosis of skin disease  5596 Vanessa Venning

23.3 Inherited skin disease  5602 Thiviyani Maruthappu and David P. Kelsell

23.4 Autoimmune bullous diseases  5612 Kathy Taghipour and Fenella Wojnarowska

23.5 Papulosquamous disease  5621 Christopher E.M. Griffiths

23.6 Dermatitis/​eczema  5630 Peter S. Friedmann, Michael J. Arden-​Jones, and Roderick J. Hay

23.7 Cutaneous vasculitis, connective tissue diseases, and urticaria  5639 Volha Shpadaruk and Karen E. Harman

23.8 Disorders of pigmentation  5677 Eugene Healy

23.9 Photosensitivity  5688 Hiva Fassihi and Jane McGregor

23.10 Infections of the skin  5695 Roderick J. Hay

23.11 Sebaceous and sweat gland disorders  5699 Alison M. Layton

23.12 Blood and lymphatic vessel disorders  5709 Peter S. Mortimer and Roderick J. Hay

23.13 Hair and nail disorders  5724 David de Berker

23.14 Tumours of the skin  5732 Edel O’Toole

23.15 Skin and systemic diseases  5743 Clive B. Archer and Charles M.G. Archer

SECTION 24 Neurological disorders Section editor: Christopher Kennard 24.1 Introduction and approach to the patient with neurological disease  5775 Alastair Compston and Christopher Kennard

24.2 Mind and brain: Building bridges between neurology, psychiatry, and psychology  5778 Adam Zeman

24.3 Clinical investigation of neurological disease  5781 24.3.1 Lumbar puncture  5781

R. Rhys Davies and Andrew J. Larner 24.3.2 Electrophysiology of the central and peripheral nervous systems  5785

Christian Krarup 24.3.3 Imaging in neurological diseases  5802

Andrew J. Molyneux, Shelley Renowden, and Marcus Bradley 24.3.4 Investigation of central motor pathways: Magnetic brain stimulation  5817

K.R. Mills

24.4 Higher cerebral function  5821 24.4.1 Disturbances of higher cerebral function  5821

Peter J. Nestor 24.4.2 Alzheimer’s disease and other dementias  5830

Jonathan M. Schott

24.5 Epilepsy and disorders of consciousness  5860 24.5.1 Epilepsy in later childhood and adulthood  5860

Arjune Sen and M.R. Johnson 24.5.2 Narcolepsy  5882

Matthew C. Walker 24.5.3 Sleep disorders  5886

Paul J. Reading 24.5.4 Syncope  5896

Andrew J. Larner 24.5.5 The unconscious patient  5901

David Bates

Contents

24.5.6 Brainstem death and prolonged disorders of consciousness  5908

Ari Ercole, Peter J. Hutchinson, and John D. Pickard

24.6 Disorders of the special senses  5913 24.6.1 Visual pathways  5913

Sara Ajina and Christopher Kennard 24.6.2 Eye movements and balance  5922

Michael Strupp and Thomas Brandt 24.6.3 Hearing loss  5931

Linda Luxon

24.7 Disorders of movement  5937 24.7.1 Subcortical structures: The cerebellum, basal ganglia, and thalamus  5937

Mark J. Edwards and Penelope Talelli 24.7.2 Parkinsonism and other extrapyramidal diseases  5946

Elisaveta Sokolov, Vinod K. Metta, and K. Ray Chaudhuri 24.7.3 Movement disorders other than Parkinson’s disease  5956

Bettina Balint and Kailash Bhatia 24.7.4 Ataxic disorders  5976

Nicholas Wood

24.8 Headache  5987 Peter J. Goadsby

24.9 Brainstem syndromes  6006 David Bates

24.10 Specific conditions affecting the central nervous system  6010 24.10.1 Stroke: Cerebrovascular disease  6010

J. van Gijn (revised by Peter M. Rothwell) 24.10.2 Demyelinating disorders of the central nervous system  6026

Alasdair Coles and Siddharthan Chandran 24.10.3 Traumatic brain injury  6042

Tim Lawrence and Laurence Watkins 24.10.4 Intracranial tumours  6048

Jeremy Rees 24.10.5 Idiopathic intracranial hypertension  6054

Alexandra Sinclair

24.11 Infections of the central nervous system  6060 24.11.1 Bacterial infections  6060

Diederik van de Beek and Guy E. Thwaites 24.11.2 Viral infections  6082

Fiona McGill, Jeremy Farrar, Bridget Wills, Menno De Jong, David A. Warrell, and Tom Solomon

24.11.3 Intracranial abscesses  6097

Tim Lawrence and Richard S.C. Kerr 24.11.4 Neurosyphilis and neuro-​AIDS  6100

Hadi Manji 24.11.5 Human prion diseases  6109

Simon Mead and R.G. Will

24.12 Disorders of cranial nerves  6120 Robert D.M. Hadden

24.13 Disorders of the spinal cord  6127 24.13.1 Diseases of the spinal cord  6127

Anu Jacob and Andrew J. Larner 24.13.2 Spinal cord injury and its management  6135

Wagih El Masri(y) and Michael Barnes

24.14 Diseases of the autonomic nervous system  6150 Christopher J. Mathias and David A. Low

24.15 The motor neuron diseases  6166 Tom Jenkins, Alice Brockington, and Pamela J. Shaw

24.16 Diseases of the peripheral nerves  6176 Robert D.M. Hadden

24.17 Inherited neurodegenerative diseases  6197 Swati Sathe

24.18 Disorders of the neuromuscular junction  6295 David Hilton-​Jones and Jacqueline Palace

24.19 Disorders of muscle  6304 24.19.1 Structure and function of muscle  6304

Michael G. Hanna and Enrico Bugiardini 24.19.2 Muscular dystrophy  6310

Kate Bushby and Chiara Marini-​Bettolo 24.19.3 Myotonia  6328

David Hilton-​Jones 24.19.4 Metabolic and endocrine disorders  6334

David Hilton-​Jones and Richard Edwards 24.19.5 Mitochondrial disease  6343

Patrick F. Chinnery and D.M. Turnbull

24.20 Developmental abnormalities of the central nervous system  6350 Chris M. Verity, Jane A. Hurst, and Helen V. Firth

24.21 Acquired metabolic disorders and the nervous system  6368 Neil Scolding

24.22 Neurological complications of systemic disease  6376 Neil Scolding

xxxi

xxxii

Contents

24.23 Paraneoplastic neurological syndromes  6384 Jeremy Rees

24.24 Autoimmune encephalitis and Morvan’s syndrome  6393 Camilla Buckley and Angela Vincent

26.5.3 Organic psychoses  6482

Curtis McKnight and Jason Caplan 26.5.4 Alcohol misuse  6486

Jonathan Wood 26.5.5 Substance misuse  6490

Stephen Potts 26.5.6 Depressive disorder  6493

Joseph Cerimele and Lydia Chwastiak

SECTION 25 Disorders of the eye

26.5.7 Bipolar disorder  6498

Section editor: Christopher P. Conlon

26.5.8 Anxiety disorders  6501

25.1 The eye in general medicine  6399 Tasanee Braithwaite, Richard W.J. Lee, and Peng T. Khaw

Kate E.A. Saunders and John Geddes Ted Liao and Steve Epstein 26.5.9 Acute stress disorder, adjustment disorders, and post-​traumatic stress disorder  6506

Jonathan I. Bisson

SECTION 26 Psychiatric and drug-​related disorders Section editor: Michael Sharpe 26.1 General introduction  6445 Michael Sharpe

26.2 The psychiatric assessment of the medical patient  6447 Jane Walker, Roger Smyth, and Michael Sharpe

26.3 Common psychiatric presentations in medical patients  6454 26.3.1 Confusion  6454

Bart Sheehan and Thomas Jackson 26.3.2 Self-​harm  6457

Kate E.A. Saunders and Keith Hawton 26.3.3 Medically unexplained symptoms  6460

Michael Sharpe 26.3.4 Low mood  6462

Jane Walker

26.5.10 Eating disorders  6509

Christopher G. Fairburn 26.5.11 Schizophrenia  6513

Stephen M. Lawrie 26.5.12 Somatic symptom and related disorders  6517

Michael Sharpe 26.5.13 Personality disorders  6520

Iain Jordan

26.6 Changing unhealthy behaviours  6524 26.6.1 Brief interventions for excessive alcohol consumption  6524

Amy O’Donnell, Eileen Kaner, and Nick Heather 26.6.2 Obesity and weight management  6529

Susan Jebb and Paul Aveyard 26.6.3 Smoking cessation  6533

Paul Aveyard

26.7 Psychiatry, liaison psychiatry, and psychological medicine  6536 Michael Sharpe

26.4 Psychiatric treatments in the medically ill  6465 26.4.1 Psychopharmacology in medical practice  6465

Philip J. Cowen 26.4.2 Psychological treatments  6470

Michael Sharpe and Simon Wessely

26.5 Specific psychiatric disorders  6475 26.5.1 Delirium  6475

Bart Sheehan 26.5.2 Dementia  6478

Bart Sheehan

SECTION 27 Forensic medicine Section editor: John D. Firth 27.1 Forensic and legal medicine  6541 Jason Payne-​James, Paul Marks, Ralph Bouhaidar, and Steven B. Karch

Contents

SECTION 28 Sport and exercise medicine

SECTION 30 Acute medicine

Section editor: John D. Firth

Section editor: John D. Firth

28.1 Sport and exercise medicine  6565

30.1 Acute medical presentations  6591

Cathy Speed

Sian Coggle, Elaine Jolly, and John D. Firth

30.2 Practical procedures  6644 Elaine Jolly, Sian Coggle, and John D. Firth

SECTION 29 Biochemistry in medicine Section editor: Christopher P. Conlon 29.1 The use of biochemical analysis for diagnosis and management  6577 Brian Shine and Nishan Guha

Index

xxxiii

Abbreviations 5-​FU 5-​HIAA 5-​HT 5-​HT AAA AAFB AASLD AAV ABC ABCDE ABG ABMR ABPA ABPM ACE AChE ACPA ACR ACS ACTH AD ADEM ADH ADL ADME ADPKD ADR ADRT AECA AF AFP AGT aGVHD AHA aHUS AIF AIHA AIN AIP AIS AKI ALD

5-​fluorouracil 5-​hydroxyindoleacetic  acid 5-​hydroxytryptamine 5-​hydroxytryptamine acquired aplastic anaemia acid-​and alcohol-​fast bacilli American Association for the Study of Liver Diseases antineutrophil cytoplasm autoantibody-associated vasculitis (also aplastic anaemia ATP-​binding cassette airway, breathing, circulation, disability, and exposure arterial blood gas antibody-​mediated rejection allergic bronchopulmonary aspergillosis ambulatory blood pressure measurement angiotensin-​converting  enzyme acetylcholinesterase, define at first mention anticitrullinated peptide/​protein antibodies American College of Rheumatology (also albumin:creatinine ratio) acute coronary syndromes adrenocorticotropic hormone Alzheimer’s disease acute disseminated encephalomyelitis antidiuretic hormone activities of daily living absorption, distribution, metabolism, and excretion autosomal dominant polycystic kidney disease adverse drug reaction advanced decision to refuse treatment antiendothelial cell antibodies atrial fibrillation α-​fetoprotein alanine–​glyoxylate aminotransferase acute graft-​versus-​host disease American Heart Association atypical haemolytic uraemic syndrome apoptosis-​inducing  factor autoimmune haemolytic anaemia acute interstitial nephritis autoimmune pancreatitis (also acute interstitial pneumonia) androgen insensitivity syndromes acute kidney injury alcoholic liver disease

ALF ALL alloSCT ALP ALS ALT AMA AML AMLR AMT ANA ANC ANCA ANP AOSD AP APA APC APCM APL APS APTT AR ara-​C ARB ARDS ARF ARH ARPKD ART ARVC ARVD AS ASAS ASCT ASD ASH ASOT AST ATG ATP ATRA AV AVN

acute liver failure acute lymphoblastic leukaemia allogeneic stem cell transplantation alkaline phosphatase amyotrophic lateral sclerosis alanine aminotransferase antimitochondrial antibody acute myeloid leukaemia autologous mixed lymphocyte reactions Abbreviated Mental Test antinuclear autoantibodies absolute neutrophil count antineutrophil cytoplasmic antibodies atrial natriuretic peptide adult-​onset Still’s disease alternative pathway aldosterone-​producing adenoma antigen presenting cell active physiological conservative management acute promyelocytic leukaemia antiphospholipid syndrome activated partial thromboplastin time androgen receptor cytosine arabinoside angiotensin receptor blocker adult respiratory distress syndrome acute renal failure autosomal recessive hypercholesterolaemia autosomal recessive polycystic kidney disease antiretroviral therapy arrhythmogenic right ventricular cardiomyopathy atherosclerotic renovascular disease ankylosing spondylitis Assessment of SpondyloArthritis International Society autologous stem cell transplantation atrial septal defect Action on Smoking and Health antistreptolysin O titre aspartate aminotransferase antithymocyte globulin adenosine triphosphate all-​trans-​retinoic  acid aortic valve arteriovenous nipping

xxxvi

Abbreviations AVSD AZA BCAA BCC BCG BEN BH4 BHS BICC BKV BM BMD BMF BMI BMP BNF BNP BOS BP BPG BRAO BRVO BSEP BSP BTS BUN CA CABG CAF CAH CAM CAMT CAP CAPS CaR CAT CBT CCB CCK CCP CCQ CCV CCyR CD CDA CDC CEA CETP CF CFA cfDNA CFS CFTR CFU CGA CGRP cGVHD

atrioventricular septal defect azacitidine branched-​chain amino acid basal cell carcinoma bacillus Calmette–​Guérin Balkan endemic nephropathy tetrahydrobiopterin British Hypertension Society betaferon in chronic viral cardiomyopathy BK polyomavirus bone marrow bone mineral density bone marrow failure body mass index bone morphogenic protein British National Formulary B-​type natriuretic peptide bronchiolitis obliterans syndrome blood pressure biphosphoglycerate branch artery occlusion branch retinal vein occlusion haemolysis, elevated liver enzymes, and low platelet count bromosulphthalein British Thoracic Society blood urea nitrogen carbohydrate antigen coronary artery bypass grafting Comprehensive Assessment for Frailty congenital adrenal hyperplasia Confusion Assessment Method congenital amegakaryocytic thrombocytopenia community-​acquired pneumonia cryopyrin-​associated periodic syndromes calcium-​sensing receptor COPD assessment test cognitive behaviour therapy calcium channel blocker cholecystokinin anticyclic citrullinated peptide Clinical COPD questionnaire clathrin-​coated vesicles complete cytogenetic response cluster of differentiation congenital dyserythropoietic anaemia donation after circulatory death carcinoembryonic antigen cholesteryl ester transfer protein cystic fibrosis cryptogenic fibrosing alveolitis cell-​free  DNA Clinical Frailty Scale cystic fibrosis transmembrane regulator colony forming unit comprehensive geriatric assessment calcitonin gene-​related peptide chronic graft-​versus-​host disease

CHAD CHD CHF CHM CINAC CINCA CISN CK CKD CKD-​EPI CLL CML CMR CMS CMT CMV CNI CNS CNSHA CO CoA COPD COX CPAP CPM CPP CPPS CPR CR CRDQ CREST CRF CRH CRIM CRP CRT CS CSF CT CTA CTCA CTD CTEPH CTL CVD CVID CVS CXR CYP CZT DAEC DALY DAMP DASH DAT

cold haemagglutinin disease coronary heart disease congestive heart failure Commission on Human Medicines chronic interstitial nephritis in agricultural communities chronic infantile neurological, cutaneous, and articular syndrome coumarin-​induced skin necrosis creatine kinase chronic kidney disease Chronic Kidney Disease Epidemiology Collaboration chronic lymphocytic leukaemia chronic myeloid leukaemia cardiac magnetic resonance congenital myasthenic syndrome Charcot–​Marie–​Tooth disease cytomegalovirus calcineurin inhibitor central nervous system congenital non-​spherocytic haemolytic anaemia cardiac output coenzyme A chronic obstructive pulmonary disease cyclooxygenase continuous positive airway pressure central pontine myelosis central precocious puberty chronic pelvic pain syndrome cardiopulmonary resuscitation complete remission Chronic Respiratory Disease Questionnaire calcinosis, Raynaud’s, oesophageal dysmotility, sclerodactyly, telangiectasia chronic renal failure corticotropin-​releasing hormone cross-​immunoreactive material C-​reactive protein cardiac resynchronization therapy continuous smokers cerebrospinal fluid/​colony-​stimulating  factor computed tomography computed tomography angiography computed tomography coronary angiography connective tissue disease chronic thromboembolic pulmonary hypertension cytotoxic T-​lymphocyte cardiovascular disease common variable immunodeficiency chorionic villus sampling chest radiograph cytochrome P450 cadmium zinc telluride diffusely adherent Escherichia coli disability-​adjusted life year damage-​associated molecular pattern Dietary Approaches to Stop Hypertension direct antiglobulin test

 Abbreviations DBA DBD DBP DC DCA DCCT DCD DCI dcSSc DCT DDAVP DDD DECAF DGP DHG DIC DIC DILI DILV DIP DISC DISH DLB DLBCL DMARD DMD DMSA DNACPR DNR DOAC DOCA DOPPS DORV DPI DRE DRESS dRTA DSA DTC DTPA DVT DXA EACTS EAggEC EANM EAPCI EASL EATL EBV ECD ECF ECG ECLAM ECM

Diamond–​Blackfan anaemia donation after brain death diastolic blood pressure dyskeratosis congenita (also dendritic cell) directional coronary atherectomy Diabetes Control and Complications Trial donation after circulatory death decompression illness diffuse cutaneous systemic sclerosis distal convoluted tubule 1-​deamino-​8-​d-​arginine vasopressin dense deposit disease dyspnoea, eosinopenia, consolidation, acidosis, and atrial fibrillation deamidated gliadin peptide dihydroxyglutarate disseminated intravascular coagulation disseminated intravascular coagulation drug-​induced liver injury double-​inlet left ventricle desquamative interstitial pneumonia death-​initiating signalling complex diffuse idiopathic skeletal hyperostosis dementia with Lewy bodies diffuse large B-​cell lymphoma disease-​modifying antirheumatic drug disease-​modifying drugs (can also mean Duchenne muscular dystrophy) dimercaptosuccinic acid do-​not-​attempt-​cardiopulmonary resuscitation do not resuscitate direct oral anticoagulant desoxycorticosterone Dialysis Outcomes and Practice Patterns Study double-​outlet right ventricle dry powder inhalers digital rectal examination drug reaction with eosinophilia and systemic symptoms distal renal tubular acidosis donor-​specific antibodies direct to consumer diethylenetriaminepentaacetic acid deep vein thrombosis dual energy X-​ray absorptiometry European Association for Cardio-​Thoracic Surgery enteroaggregative Escherichia coli European Association of Nuclear Medicine European Association of Percutaneous Cardiovascular Interventions European Association for the Study of the Liver enteropathy-​associated T-​cell lymphoma Epstein–​Barr  virus extended criteria donor extracellular fluid electrocardiogram European community lupus activity measure extracellular matrix

ECV EDMD EDRF EDTA EDV EEG EELV EGF eGFR EGPA EIEC EIS ELCA ELISA EM EMA EMG EMS ENA ENaC ENT EOL EoO EPCR EPEC EPO ER ERA ERC ERCP ERNV ERS ESA ESC ESGE ESH ESKD ESR ESRD ESS ESWL ETEC EUS EVLP EVO FA FACIT FAK FAP FBC FCAS FCHL FDA FDG FDG-​PET FDP FEV FEV1

extracellular volume Emery–​Dreifuss muscular dystrophy endothelial-​derived relaxing factor European Dialysis and Transplant Association end-​diastolic  volume electroencephalography end expiratory lung volume epidermal growth factor estimated glomerular filtration rate eosinophilic granulomatosis with polyangiitis enteroinvasive Escherichia coli endoscopic injection sclerotherapy excimer laser coronary atherectomy enzyme-​linked immunosorbent assay erythema multiforme (also electron microscopy) endomysial antibody electromyography early morning urethral smear extractable nuclear antigens epithelial sodium channel ear, nose, or throat end of life eosinophilic oesophagitis endothelial cell protein C receptor enteropathogenic Escherichia coli erythropoietin endoplasmic reticulum European Renal Association endoscopic retrograde cholangiography endoscopic retrograde cholangiopancreatography equilibrium radionuclide ventriculography European Respiratory Society erythropoiesis-​stimulating  agent European Society of Cardiology European Society of Gastrointestinal Endoscopy European Society of Hypertension end-​stage kidney disease erythrocyte sedimentation rate end-​stage renal disease EULAR sicca score extracorporeal shock-​wave lithotripsy enterotoxigenic Escherichia coli endoscopic ultrasonography ex-​vivo lung perfusion endoscopic variceal obturation Fanconi’s anaemia fibril-​associated collagen with interrupted triple focal adhesion kinase familial adenomatous polyposis full blood count familial cold autoinflammatory syndrome familial combined hyperlipidaemia Food and Drug Administration fluorodeoxyglucose fluorodeoxyglucose-​positron emission tomography fibrinogen-​degradation product forced expiratory volume forced expiratory volume in 1 s

xxxvii

xxxviii

Abbreviations FFR FGF FH FISH FL FLC FMF FMTC FNAB FNH FOB FODMAPs

fractional flow reserve fibroblast growth factor familial hypercholesterolaemia fluorescent in situ hybridization follicular lymphoma free light chain familial Mediterranean fever familial medullary thyroid carcinoma fine needle aspiration biopsy focal nodular hyperplasia faecal occult blood fermentable oligosaccharides, disaccharides, monosaccharides, and polyols FRC functional residual capacity FSGS focal segmental glomerulosclerosis FSH follicular stimulating hormone FTD frontotemporal dementia FVC forced vital capacity FVU first voided urine G6PD glucose-​6-​phosphate dehydrogenase GABA γ-​aminobutyric  acid GAD generalized anxiety disorder GALT gut-​associated lymphoid tissue GAVE gastric antral vascular ectasia GBD Global Burden of Disease GBM glomerular basement membrane G-​CSF granulocyte colony-​stimulating factor GCA giant cell arteritis GCS Glasgow Coma Score GDF growth differentiation factors GEP gastroenteropancreatic GFB glomerular filtration barrier GFR glomerular filtration rate GH growth hormone GI gastrointestinal GIB gastrointestinal bleeding GIE glucocorticoid inhibitory element GIP gastric inhibitor peptide GIST gastrointestinal stromal tumour GLP glucagon-​like peptide GM-​CSF granulocyte–​macrophage colony-​stimulating  factor GM/​MS gas chromatography–​mass spectrometry GN glomerulonephritis GnRH gonadotropin-​releasing hormone GOLD Global Initiative for Obstructive Lung Disease GOMMID glomerulonephritis with organized microtubular monoclonal immunoglobulin deposits GORD gastro-​oesophageal reflux disease GOV gastro-​oesophageal varices GP glycoprotein (also general practitioner) GPA granulomatosis with polyangiitis GPCR G-​protein-​coupled-​receptors GPI glycosylphosphatidylinositol GRACE Global Registry of Acute Coronary Events GRADE Grading of Recommendations, Assessment, Development and Evaluations GRHPR glyoxylate/​hydroxypyruvate reductase

GSD GSGS GSH GU GUM GVHD GVL GWAS H&E HAART HAND HAV HBc HBeAG HBIg HBPM HBsAG HBV HCC HCG HCV HD HDF HDL HDL-​C HDU HDV HE HELLP HES hESC HETE HEV HF HFA HFnEF HFOV HFV HHT HHV HIF HIV HIV-​OL HK HL HLA HLH HLHS HMA HOGA HPA HPG HPLC HPP HPRT HPV

glycogen storage disease focal segmental glomerulosclerosis glutathione gonococcal urethritis genitourinary medicine graft-​versus-​host disease graft-​versus-​leukaemia genome-​wide association study haematoxylin and eosin stain highly active antiretroviral therapy HIV-​associated neurocognitive disorder hepatitis A virus hepatitis B core hepatitis B e antigen hepatitis B immunoglobulin home blood pressure measurement hepatitis B surface antigen hepatitis B virus hepatocellular carcinoma human chorionic gonadotropin hepatitis C virus haemodialysis haemodiafiltration high-​density lipoprotein high-​density lipoprotein cholesterol high-​dependency  unit hepatitis D virus hepatic encephalopathy or hereditary elliptocytosis haemolysis, elevated liver enzymes and low platelets hypereosinophilic syndrome human embryonic stem cell hydroxyeicosatetraenoic acid hepatitis E virus haemofiltration Heart Failure Association heart failure with a normal ejection fraction high-​frequency oscillatory ventilation high-​frequency ventilation hereditary haemorrhagic telangiectasis/​ 15-​hydroxy-​5,8,10-​hepatrotrienoic  acid human herpesvirus hypoxia-​inducible factors human immunodeficiency virus human immunodeficiency virus oral lesion high molecular weight kininogen hepatic lipase human leucocyte antigen haemophagocytic lymphohistiocytosis hypoplastic left heart syndrome hypomethylating agent 4-​hydroxy-​2-​oxoglutarate aldolase hypothalamic-​pituitary-​adrenal hypothalamic-​pituitary-​gonadal high-​performance liquid chromatography hereditary pyropoikilocytosis hypoxanthine-​guanine phosphoribosyltransferase human papillomavirus

 Abbreviations HRA HRCT HRT HS HSC HSCT HSP HSPC HSV HUS HUV IADL IAS IBD IBS IBS-​C IBS-​D IBS-​M IC ICAM ICD ICP ICS ICU IDA IDL IEC IF IFG IFN Ig IgAN IgE IGF IgG4-​RD IgG4-​SC IGV IHD IHME IIH IIP IL ILC ILD IMA INR IPAF IPEX IPF IPI iPSC IPSID IRIDA IRIS IRM IRV

high-​resolution anoscopy high-​resolution computed tomography hormone replacement therapy hereditary spherocytosis haematopoietic stem cell or hepatic stellate cell haemopoietic stem cell transplantation Henoch–​Schönlein purpura haematopoietic stem and progenitor cell herpes simplex virus haemolytic uraemic syndrome hypocomplementaemic urticarial vasculitis instrumental activities of daily living insulin autoimmune syndrome irritable bowel disease irritable bowel syndrome irritable bowel syndrome with constipation irritable bowel syndrome with diarrhoea irritable bowel syndrome with alternating constipation and diarrhoea intercalated cell intercell adhesion molecules implantable cardioverter-​defibrillator intracranial pressure inhaled oral corticosteroids intensive care unit iminodiacetic acid intermediate-​density lipoprotein intestinal epithelial cell intrinsic factor impaired fasting glucose interferon immunoglobulin immunoglobulin A nephropathy immunoglobulin E insulin-​like growth factors immunoglobulin G4-​related disease immunoglobulin G4-​related sclerosing cholangitis isolated gastric varices ischaemic heart disease Institute for Health Metrics and Evaluation idiopathic intracranial hypertension idiopathic interstitial pneumonias interleukin innate lymphoid cell interstitial lung disease inferior mesenteric artery international normalized ratio interstitial pneumonitis with autoimmune features immunodysregulation polyendocrinopathy enteropathy X-​linked idiopathic pulmonary fibrosis International Prognostic Index induced pluripotent stem cell immunoproliferative small intestinal disease iron-​refractory iron deficiency anaemia immune reconstitution inflammatory syndrome immunoradiographic assay Inspiratory and expiratory reserve volume

ISH ISHLT ISIS ISWT ITP ITU IV IVC IVF IVIG IVU JE JIA JNC KDIGO LA LAMA LBBB LCAT LCH lcSSc LDH LDL LDL-​C LFT LGE LGMD LGV LH LIC LINQ LIP LKM LMICs LMN LMWH LMWP LOLA LP LPL LPLR LTOT LV LVDD LVEF LVOT LVRS LVSD MAG3 MAGIC MAHA MALT MAO MAP MAPK MBD M-​CSF

International Society of Hypertension International Society for Heart and Lung Transplantation International Study of Infarct Survival incremental shuttle walking test immune thrombocytopenia intensive care unit intravenous inferior vena cava in vitro fertilization intravenous immunoglobulin intravenous urography Japanese encephalitis juvenile idiopathic arthritis Joint National Committee Kidney Disease: Improving Global Outcomes left atrium long-​acting antimuscarinic agents left bundle branch block lecithin–​cholesterol acyltransferase Langerhans’ cell histiocytosis limited cutaneous systemic sclerosis lactate dehydrogenase low-​density lipoprotein low-​density lipoprotein cholesterol liver function test late gadolinium enhancement limb-​girdle muscular dystrophy lymphogranuloma venereum luteinizing hormone liver iron content Lung Information Needs Questionnaire lymphocytic interstitial pneumonia liver–​kidney microsomal low-​and middle-​income countries lower motor neuron low molecular weight heparin low molecular weight protein l-​ornithine l-​arginine lumbar puncture lipoprotein lipase lipoprotein lipase receptor long-​term oxygen therapy left ventricle left ventricular diastolic dysfunction left ventricular ejection fraction left ventricular outflow tract lung volume reduction surgery left ventricular systolic dysfunction mercaptoacetyltriglycine MAGnesium in Coronaries microangiopathic haemolytic anaemia mucosa-​associated lymphoid tissue monoamine oxidase inhibitor mean arterial pressure mitogen-​activated protein kinase mineral and bone disorder macrophage colony-​stimulating factor

xxxix

xl

Abbreviations MCHC MCL MCNS MCpEF MCV MDE MDI MDRD MDS MED MELD MEN MERFF mESC MGRS MGUS MHC MHRA MIC MIDD MKD MM MMA MMF MMP MMR MN MND MoCA MPA MPO MPS MR MRA MRC MRCP MRI MRSA MS MS/​MS MSA MSC MSH MSU MTC mTOR MUS MWS NAAT NABQI NADH NADPH

mean cell haemoglobin concentration mantle cell lymphoma minimal change nephrotic syndrome myocarditis with preserved left ventricular ejection fraction mean corpuscular volume myeloma-​defining  event metered dose inhalers Modification of Diet in Renal Disease myelodysplastic syndrome minimal erythema dose Model for End-​Stage Liver Disease multiple endocrine neoplasia myoclonic epilepsy and ragged red fibres mouse embryonic stem cell monoclonal gammopathy of renal significance monoclonal gammopathy of undetermined significance major histocompatibility complex Medicines and Healthcare Products Regulatory Agency minimum inhibitory concentration monoclonal immunoglobulin deposition diseases mevalonate kinase deficiency malignant melanoma methylmalonic acid mycophenolate mofetil matrix metalloproteinase mismatch repair membranous nephropathy motor neuron disease Montreal Cognitive Assessment microscopic polyangiitis myeloperoxidase mucopolysaccharidosis (also myocardial perfusion scintigraphy) magnetic resonance magnetic resonance angiography (can also be medicine regulatory authority) Medical Research Council magnetic resonance cholangiopancreatography magnetic resonance imaging methicillin-​resistant Staphylococcus aureus multiple sclerosis tandem mass spectroscopy multiple-​system atrophy mesenchymal stromal cell melanocyte-​stimulating hormone midstream urine medullary thyroid carcinoma mammalian target of rapamycin medically unexplained symptoms Muckle–​Wells syndrome nucleic acid amplification testing N-​acetyl-​p-​benzoquinone  imine reduced nicotinamide-​adenine dinucleotide reduced nicotinamide-​adenine dinucleotide phosphate

NAFLD NAIT NASH NCAM NEP NET

nonalcoholic fatty liver disease neonatal alloimmune thrombocytopenia nonalcoholic steatohepatitis neural-​cell adhesion molecule neutral endopeptidase neuroendocrine tumour or neutrophil extracellular trap NETT National Emphysema Therapy Trial NEWS National Early Warning Score NGF nerve growth factor NGS next-​generation sequencing NHDL-​C non-​high-​density lipoprotein cholesterol NHL non-​Hodgkin’s lymphoma NHS National Health Service (UK) NICE National Institute for Health and Care Excellence NIPPV non-​invasive nasal positive-​pressure ventilation NIPT non-​invasive prenatal testing NIV non-​invasive ventilation NK natural killer NKT natural killer T NLST National Lung Screening Trial NMS neuroleptic malignant syndrome NMSC non-​melanoma skin cancer NNH number needed to harm NNT number needed to treat NOTT Nocturnal Oxygen Treatment Trial NREM non-​rapid eye movement NRT nicotine replacement therapy NSAID non-​steroidal anti-​inflammatory  drug NSCLC non-​small cell lung cancer NSIP non-​specific interstitial pneumonia NSTEMI non-​ST-​elevation myocardial infarction NTD neural tube defect NTM non-​tuberculous mycobacterial NT-​proBNP N-​terminal B-​type natriuretic peptide NYHA New York Heart Association OAF osteoclast-​activating  factor OAPR odds of being affected given a positive result OB obliterative bronchiolitis OCD obsessive–​compulsive disorder OCT optical coherence tomography OD once daily OECD Organisation for Economic Cooperation and Development OED other eating disorders OLP oral lichen planus OMIM Online Mendelian Inheritance in Man OMT optimal medical therapy OPAT outpatient parenteral antibiotic therapy OR odds ratio OS overall survival OSA obstructive sleep apnoea OTB oral tuberculosis PA pernicious anaemia (also pulmonary artery) PACAP pituitary adenylate cyclase activating polypeptide PAF platelet activating factor PAH polycyclic aromatic hydrocarbons (can also mean pulmonary hypertension)

 Abbreviations PAOP PAS PASI PASP PBD PBM PCC PCH PCI PCNSL Pco

PCP PCR PCT PCV PCWP PD PDA PDC PDD PDGF PE PEACH PEEP PEF PEG PET PFO PFS PGK PHARC PICS PID PIGN PK PKD PKU PLA2R PMN PMR PNH Po2

POC POMC PP PPI ppm PPS PPV PR3 PRCA PRI PRPP

pulmonary artery occlusion pressure periodic acid–​Schiff Psoriasis Area and Severity Index pulmonary artery systolic pressure polyglucosan body disease peripheral blood mononuclear cell prothrombin complex concentrate paroxysmal cold haemoglobinuria (also pulmonary capillary haemangiomatosis) percutaneous coronary intervention primary central nervous system lymphoma partial pressure of carbon dioxide Pneumocystis jirovecii pneumonia polymerase chain reaction (also protein:creatinine ratio) proximal convoluted tubule pneumococcal conjugate vaccine pulmonary capillary wedge pressure peritoneal dialysis (also Parkinson’s disease) patent ductus arteriosus pyruvate dehydrogenase complex Parkinson’s disease dementia platelet-​derived growth factor pleural effusion (can also mean pulmonary embolism) Pelvic Inflammatory Disease Evaluation and Clinical Health positive end expiratory pressure peak expiratory flow percutaneous endoscopic gastrostomy position emission tomography patent foramen ovale progression-​free survival phosphoglycerate kinase polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract post-​intensive care syndrome pelvic inflammatory disease postinfectious glomerulonephritis pyruvate kinase pyruvate kinase deficiency (also polycystic kidney disease) phenylketonuria phospholipase A2 receptor polymorphonuclear neutrophil polymyalgia rheumatica paroxysmal nocturnal haemoglobinuria partial pressure of oxygen point of care pro-​opiomelanocortin polypeptide proton pump inhibitor parts per million Palliative Performance Scale porcine parvovirus proteinase 3 pure red cell aplasia population reference intake phosphoribosyl pyrophosphate

PRR PRrP PSA PSC PSP PT PTC PTCA PTH PTHrP PTLD PTP PTSD PUVA PV PVE PVOD PVR PYY QALY RA RAAS RAS RAVV RBBB RBF RCA RCC RCDP RCT RDA REM RF RI RNA RNI RNP ROC RP RRT RTA RV RVOTO SA SABR SBP SCC SCD SCI SCID SCLC SCMR SCN sdLDL SDS

pattern-​recognition receptor parathyroid-​hormone-​related protein prostate-​specific antigen primary sclerosing cholangitis primary spontaneous pneumothorax prothrombin time percutaneous transhepatic cholangiography percutaneous transluminal coronary angioplasty parathyroid hormone PTH/​PTH-​related peptide post-​transplant lymphoproliferative disorder post-​transfusion purpura post-​traumatic stress disorder psoralen ultraviolet A pemphigus vulgaris (also plasmas viscosity test) prosthetic valve endocarditis pulmonary veno-​occlusive disease pulmonary vascular resistance peptide tyrosine-​tyrosine quality-​adjusted life year rheumatoid arthritis (can also mean right atrium) renin–​angiotensin–​aldosterone  system renin–​angiotensin system (also renal artery stenosis or restrictive allograft syndrome right atrioventricular valve right bundle branch block rat bite fevers right coronary artery renal cell carcinoma rhizomelic chondrodysplasia punctata randomized controlled trial recommended dietary allowance rapid eye movement rheumatoid factor resistivity index ribonucleic acid reference nutrient intake ribonucleoprotein receiver–​operator characteristic ribosomal protein renal replacement therapy renal tubular acidosis residual volume (also right ventricle) right ventricular outflow tract obstruction short-​axis stereotactic ablative body radiotherapy spontaneous bacterial peritonitis (also systolic blood pressure) squamous cell carcinoma sickle cell disease (also sudden cardiac death) spinal cord injuries severe combined immunodeficiency small cell lung cancer Society for Cardiovascular Magnetic Resonance sickle cell nephropathy or severe congenital neutropenia small dense low-​density lipoprotein Shwachman–​Diamond syndrome

xli

xlii

Abbreviations SEER SGRQ SHBG SHEC SIADH

Surveillance, Epidemiology, and End Results St George’s Respiratory Questionnaire sex hormone binding globulin Shiga toxin-​producing Escherichia coli syndrome of inappropriate antidiuretic hormone secretion SIRS systemic inflammatory response syndrome SLB surgical lung biopsy SLE systemic lupus erythematosus SM smouldering myeloma SMA superior mesenteric artery (also smooth muscle antibody) SMC smooth muscle cell sMDRD simplified Modification of Diet in Renal Disease SMR standardized mortality ratio SNGFR single-​nephron glomerular filtration rate SNP single nucleotide polymorphism SNS sympathetic nervous system SOD sphincter of Oddi disorder SPC Summary of Product Characteristics SPD storage pool deficiency SPECT single-​positron emission computed tomography SPF sun protection factor SSc systemic sclerosis SSD somatic symptom disorder SSFP steady-​state free precession SSRI selective serotonin reuptake inhibitor STEMI ST elevation myocardial infarction STI sexually transmitted infection STOPP/​START set of inappropriate combinations of medicines and disease (STOPP) and a set of recommended treatments for given conditions (START) suPAR soluble urokinase plasminogen activating receptor SVC superior vena cava SVR systemic vascular resistance TACE transarterial chemoembolization TAE transarterial embolization TALH thick ascending limb of Henle TAR thrombocytopenia with absent radii TAVI transcatheter aortic valve implantation TB tuberculosis TBLC transbronchial lung cryobiopsy TBM tuberculous meningitis TC total cholesterol TCA tricyclic antidepressant TCPC total cavopulmonary connection TCR T-​cell receptor TCT thrombin clotting time TdT terminal deoxyribonucleotidyl transferase TEC transient erythroblastopenia of childhood TEN toxic epidermal necrolysis TF transcription factor (also tissue factor) TFPI tissue factor pathway inhibitor TG triglyceride TGF transforming growth factor TGFα, TGFβ transforming growth factor-​α, -​β TGN trans Golgi network

THR THRIVE TIA TIBC TIMI TINU TIPS TK TKI TKR TLC TLR TMA t-​MDS TNF TNFα tPA TPN TPN TRAIL TRAPS Treg TROPHY TSH TTD tTG TTIP TTKG TTP TURBT TV UAER UCB UDCA UDP UI UIP UKELD UKM UKMEC UKPDS ULN UMN UPR URR URTI UTI UV UVL UVR V/​Q VARD VATS VC vCJD

total hip replacement Treatment of HDL to Reduce the Incidence of Vascular Events transient ischaemic attack total iron-​binding capacity thrombolysis in myocardial infarction tubulointerstitial nephritis uveitis transjugular intrahepatic portosystemic shunt tyrosine kinase tyrosine kinase inhibitor total knee replacement total lung capacity Toll-​like receptor thrombotic microangiopathy therapy-​related myelodysplastic syndrome(s) tumour necrosis factor tumour necrosis factor-​α tissue plasminogen activator total parenteral nutrition total parenteral nutrition TNF-​related apoptosis-​inducing  ligand tumour necrosis factor receptor-​associated periodic syndrome regulatory T (cell) Trial of Preventing Hypertension thyroid-​stimulating hormone thiazide-​type diuretic tissue transglutaminase Transatlantic Trade and Investment Partnership transtubular potassium concentration gradient thrombotic thrombocytopenic purpura transurethral resection of bladder tumour tricuspid valve urinary albumin excretion rate umbilical cord blood ursodeoxycholic acid uridine diphosphate urinary incontinence usual interstitial pneumonia United Kingdom Model for End-​Stage Liver Disease urea kinetic modelling UK Medical Eligibility Criteria United Kingdom Prospective Diabetes Study upper limit of normal upper motor neuron unfolded protein response urea reduction ratio upper respiratory tract infection urinary tract infection ultraviolet ultraviolet light ultraviolet radiation ventilation/​perfusion video-​assisted retroperitoneal debridement video-​assisted thoracoscopic surgery vital capacity variant Creutzfeldt–​Jakob disease

 Abbreviations VDRL VEGF VEOIBD VIP VKA VLA VLCFA VLDL VSD VTE VWD VWF

Venereal Diseases Research Laboratory vascular endothelial growth factor very early-​onset inflammatory bowel disease vasoactive intestinal peptide vitamin K antagonist vertical long axis very long-​chain fatty acid very low-​density lipoprotein ventricular septal defect venous thromboembolism von Willebrand’s disease von Willebrand factor

VZV WBC WCC WGS WHO WM X-​ALD XLH YLDs YLL ZASP

varicella zoster virus white blood cell white cell count whole genome sequencing World Health Organization Waldenström’s macroglobulinaemia X-​linked adrenoleukodystrophy X-​linked hypophosphataemia years lived with disability years of life lost Z-​line associated protein

xliii

Contributors Peter Aaby Bandim Health Project, INDEPTH

Network, Bissau, Guinea-​Bissau, West Africa 8.5.6: Measles Emma Aarons Consultant Virologist and Infectious Disease Physician, Rare and Imported Pathogens Laboratory, Public Health England, Salisbury, Wiltshire, UK 8.5.27: Orf and Milker’s nodule Tom Abbott William Harvey Research Institute, Queen Mary University of London, UK 17.4: Assessing and preparing patients with medical conditions for major surgery Ade Adebajo Faculty of Medicine, Dentistry and Health, University of Sheffield, UK 19.12: Miscellaneous conditions presenting to the rheumatologist Raymond Agius Occupational Medicine, University of Manchester, UK 10.2.1: Occupational and environmental health S. Faisal Ahmed School of Medicine, University of Glasgow, Royal Hospital for Children, Glasgow, UK 13.7.3: Normal and abnormal sexual differentiation Shahzada K. Ahmed Department of Otorhinolaryngology, Queen Elizabeth Hospital, Birmingham, UK 13.2.2: Disorders of the posterior pituitary gland Vineet Ahuja Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India 15.10.8: Malabsorption syndromes in the tropics Guruprasad P. Aithal NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham; Nottingham Digestive Diseases Centre, The University of Nottingham, Nottingham, UK 15.24.3: Drug-​induced liver disease Sara Ajina Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 24.6.1: Visual pathways Tyler Albert VA Puget Sound Health Care System, Division of General Internal Medicine, University of Washington, Seattle, WA, USA 10.3.6: Diseases of high terrestrial altitudes Maha Albur University of Bristol, Bristol, UK 8.2.5: Antimicrobial chemotherapy Michael J. Aldape Veterans Affairs Medical Center, Infectious Diseases Section, Boise, ID, USA 8.6.25: Botulism, gas gangrene, and clostridial gastrointestinal infections

Graeme J.M. Alexander UCL Professor, UCL

Institute for Liver and Digestive Health, Royal Free Hospital, London, UK 15.23.1: Hepatitis A to E; 15.24.6: Primary and secondary liver tumours Michael E.D. Allison Liver Unit, Cambridge Biomedical Research Centre, Addenbrooke’s Hospital, Cambridge, UK 15.24.6: Primary and secondary liver tumours Carlo Ammendolia Faculty of Medicine, University of Toronto, Toronto, Canada; Rebecca MacDonald Centre for Arthritis and Autoimmune Diseases, Division of Rheumatology, Mount Sinai Hospital, Toronto, Canada 19.4: Back pain and regional disorders Chris Andrews Faculty of Medicine, University of Queensland, Herston, Qld 4029, Australia 10.3.5: Lightning and electrical injuries Ross H. Andrews Professor, Cholangiocarcinoma Research Institute (CARI), Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Professor of Parasitology, Imperial College London, Faculty of Medicine, St Mary’s Campus, London, UK 8.11.2: Liver fluke infections Jervoise Andreyev Consultant Gastroenterologist, United Lincolnshire Hospitals Trust; Honorary Professor, The School of Medicine, University of Nottingham, UK 15.3.4: Investigation of gastrointestinal function Gregory M. Anstead Division of Infectious Diseases, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Immunosuppression and Infectious Diseases Clinics, Department of Medicine, South Texas Veterans Health Care System, San Antonio, TX, USA 8.7.3: Coccidioidomycosis Quentin M. Anstee Professor of Experimental Hepatology and Honorary Consultant Hepatologist, Faculty of Medical Sciences, Newcastle University and Freeman Hospital Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 15.24.2: Non​alcoholic fatty liver disease Charles M.G. Archer Department of Dermatology, Oxford University Hospitals NHS Trust, Oxford, UK 23.15: Skin and systemic diseases

Clive B. Archer Consultant Dermatologist and

Honorary Senior Clinical Lecturer, St John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust & King’s College London, Guy’s Hospital, London, UK 23.15: Skin and systemic diseases Michael J. Arden-​Jones Consultant Dermatologist, University of Southampton, Southampton, UK 23.6: Dermatitis/​eczema Mark J. Arends University of Edinburgh Division of Pathology, Cancer Research UK Edinburgh Centre, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK 3.6: Apoptosis in health and disease J. Arendt Emeritus Professor of Endocrinology, University of Surrey, Guildford, UK 13.11: The pineal gland and melatonin James O. Armitage The Joe Shapiro Professor of Medicine, Division of Oncology/​Hematology, University of Nebraska Medical Center, Omaha, NE, USA 22.4.3: Hodgkin lymphoma; 22.4.4: Non-​Hodgkin lymphoma Vicente Arroyo Professor of Medicine at the University of Barcelona Medical School; Chairman of the European Association for the Study of the Liver Chronic Liver Failure Consortium (EASL-​CLIF Consortium) and President of the European Foundation for the Study of Chronic Liver Failure (EF-​C LIF), Barcelona, Spain 15.22.2: Cirrhosis and ascites Daniel Aruch Icahn School of Medicine at Mount Sinai, New York, NY, USA 22.3.5: The polycythaemias; 22.3.6: Thrombocytosis and essential thrombocythaemia Frances Ashcroft Professor of Physiology, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK 3.4: Ion channels and disease Caroline Ashley Lead Specialist Pharmacist, Centre for Nephrology, Royal Free Hospital, London, UK 21.19: Drugs and the kidney Shazad Q. Ashraf Consultant Colorectal Surgeon, Department of Colorectal Surgery, Queen Elizabeth Hospital, Birmingham University Hospitals, Birmingham, UK 15.14: Colonic diverticular disease

xlvi

Contributors

Paul Aveyard Nuffield Department of Primary Care

Health Sciences, University of Oxford, Oxford, UK 26.6.2: Obesity and weight management; 26.6.3: Smoking cessation Tar-​Ching Aw† Abu Dhabi National Oil Company, United Arab Emirates 10.2.5: Noise; 10.2.6 Vibration Jon G. Ayres Emeritus Professor of Environmental and Respiratory Medicine, Universty of Birmingham, Birmingham, UK 10.1: Environmental medicine, occupational medicine, and poisoning; 10.3.1: Air pollution and health Juan Carlos Ayus Renal Consultants of Houston, Houston, TX, USA; University of California Irvine, Orange, CA, USA 21.2.1: Disorders of water and sodium homeostasis Qasim Aziz Centre for Neuroscience, Surgery and Trauma, Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK 15.13: Irritable bowel syndrome Trevor Baglin Previously Cambridge Haemophilia and Thrombophilia Centre, Department of Haematology, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, UK 22.7.2: Evaluation of the patient with a bleeding tendency Michael Bagshaw Aviation Medicine, King’s College, London, UK 10.2.3: Aviation medicine Colin Baigent Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials Kenneth F. Baker Faculty of Medical Sciences, Newcastle University and Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 19.5: Rheumatoid arthritis Bettina Balint Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute of Neurology, Queen Square, London, UK; Department of Neurology, University Hospital Heidelberg, University of Heidelberg, Germany 24.7.3: Movement disorders other than Parkinson’s disease Jay Banerjee College of Life Sciences, University of Leicester, Leicester, UK 6.4: Older people and urgent care Adrian P. Banning Oxford University Hospitals NHS Trust, Oxford, UK 16.3.2: Echocardiography; 16.14.1 Acute aortic syndromes George Banting Medical Sciences Building, University of Bristol, Bristol, UK 3.1: The cell Thomas M. Barber University of Warwick, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK 13.10: Hormonal manifestations of non-​endocrine disease †

E.J. Barnes Nuffield Department of Medicine,

University of Oxford, Oxford, UK 8.5.22: Hepatitis C virus Michael Barnes University of Newcastle, Newcastle upon Tyne, UK; Christchurch Group, Janet Barnes Unit, Birmingham, UK 24.13.2: Spinal cord injury and its management Andrew J. Barr Leeds Institute of Rheumatic and Musculoskeletal Medicine, Leeds, UK 19.9: Osteoarthritis Jonathan Barratt Professor of Renal Medicine, University of Leicester; Honorary Consultant Nephrologist, University Hospitals of Leicester, Leicester, UK 21.8.1: Immunoglobulin A nephropathy and IgA vasculitis (HSP) Buddha Basnyat Oxford University Clinical Research Unit -​Nepal; Patan Academy of Health Sciences, Nepal 8.6.9 Typhoid and paratyphoid fevers; 10.3.6: Diseases of high terrestrial altitudes D. Nicholas Bateman, Pharmacology, Toxicology and Therapeutics, University of Edinburgh, Edinburgh, UK 10.4.1: Poisoning by drugs and chemicals David Bates Clinical Neurology, Newcastle University, Newcastle on Tyne, UK 24.5.5: The unconscious patient; 24.9: Brainstem syndromes Robert P. Baughman University of Cincinnati Medical Center, Cincinnati, OH, USA 18.12: Sarcoidosis Peter J. Baxter School of Clinical Medicine, Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK 10.3.8: Disasters: Earthquakes, hurricanes, floods, and volcanic eruptions Hannah Beckwith Specialist Registrar, Imperial College Healthcare NHS Trust Renal and Transplant Centre, Hammersmith Hospital, London, UK 21.10.3: The kidney in rheumatological disorders Diederik van de Beek Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 24.11.1: Bacterial infections David A. Bender University College London, London, UK 11.2: Vitamins D.A. Bente University of Texas Medical Branch, Galveston, TX, USA 8.5.16: Bunyaviridae Anthony R. Berendt Oxford University Hospitals NHS Foundation Trust, Oxford, UK 20.3: Osteomyelitis Stefan Berg Consultant in Pediatric Rheumatology and Immunology, Queen Silvia Children’s Hospital, Goteborg, Sweden 12.12.2 Hereditary periodic fever syndromes David de Berker Bristol Dermatology Centre, University Hospitals Bristol, Bristol, UK 23.13: Hair and nail disorders

It is with great regret that we report that Tar-Ching Aw died on 18 July, 2017.

Nancy Berliner H. Franklin Bunn Professor of

Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 22.3.1: Granulocytes in health and disease; 22.4.1: Introduction to lymphopoiesis Jessica Bertrand Experimental Orthopedics, University Hospital Magdeburg, Magdeburg, Germany 19.1: Joints and connective tissue—​structure and function J.M. Best King’s College London, London, UK 8.5.13: Rubella Delia B. Bethell Oxford University Hospitals NHS Foundation Trust, Oxford, UK 8.6.1: Diphtheria Kailash Bhatia Sobell Department of Motor Neuroscience and Movement Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, UK 24.7.3: Movement disorders other than Parkinson’s disease Vijaya Raj Bhatt Assistant Professor, Division of Hematology-​Oncology, University of Nebraska Medical Center, Omaha, NE, USA 22.4.3: Hodgkin lymphoma; 22.4.4: Non-​Hodgkin lymphoma Joya Bhattacharyya Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK 15.5: Immune disorders of the gastrointestinal tract Paola Bianchi Oncohematology Unit—​ Pathophysiology of Anemias Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore, Milan, Italy 22.6.10: Erythrocyte enzymopathies Rudolf Bilous Professor of Clinical Medicine, Newcastle University, Newcastle upon Tyne; Academic Centre, James Cook University Hospital, Middlesbrough, UK 21.10.1: Diabetes mellitus and the kidney D. Bilton Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK 18.9: Bronchiectasis Jonathan I. Bisson Division of Psychological Medicine and Clinical Neurosciences, University of Cardiff, Cardiff, UK 26.5.9: Acute stress disorder, adjustment disorders, and post-​traumatic stress disorder Carol M. Black Newnham College, Cambridge, UK 19.11.3: Systemic sclerosis (scleroderma) S.R. Bloom Head of Division of Diabetes, Endocrinology and Metabolism, Hammersmith Hospital, Imperial College London, London, UK 13.8: Pancreatic endocrine disorders and multiple endocrine neoplasia; 15.9.1: Hormones and the gastrointestinal tract; 15.9.2: Carcinoid syndrome Johannes Blum Medical Services, Swiss Tropical and Public Health Institute, Basel, Switzerland 8.8.11: Human African trypanosomiasis

Contributors

Kristien Boelaert University of Birmingham,

Birmingham, UK 13.3.1: The thyroid gland and disorders of thyroid function; 13.3.2: Thyroid cancer Eva Boonen Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven University, B-​3000 Leuven, Belgium 17.9: Metabolic and endocrine changes in acute and chronic critical illness Christopher Booth† Wellcome Institute for the History of Medicine, Wellcome Building, London, UK 1.1: On being a patient Marina Botto Professor, Imperial College London, London, UK 4.2: The complement system Ralph Bouhaidar Consultant Forensic Pathologist, NHS Lothian; Honorary Senior Lecturer, Edinburgh University, Edinburgh; Training Programme Director for Forensic Histopathology (Scotland), UK 27.1: Forensic and legal medicine Henri-​Jean Boulouis Ecole Nationale Vétérinaire d’Alfort, Maisons-​Alfort, France 8.6.43: Bartonellas excluding B. bacilliformis P.-​M.G. Bouloux Centre for Neuroendocrinology, University College London Medical School, London, UK 13.6.2: Disorders of male reproduction and male hypogonadism S.J. Bourke Royal Victoria Infirmary, Newcastle upon Tyne, UK 18.14.1: Diffuse alveolar haemorrhage; 18.14.2: Eosinophilic pneumonia; 18.14.3: Lymphocytic infiltrations of the lung; 18.14.4: Hypersensitivity pneumonitis; 18.14.5: Pulmonary Langerhans’ cell histiocytosis; 18.14.6: Lymphangioleiomyomatosis; 18.14.7: Pulmonary alveolar proteinosis; 18.14.8: Pulmonary amyloidosis; 18.14.9: Lipoid (lipid) pneumonia; 18.14.10: Pulmonary alveolar microlithiasis; 18.14.12: Radiation pneumonitis; 18.14.13: Drug-​induced lung disease Ian C.J.W. Bowler Oxford University Hospitals NHS Foundation Trust, Oxford, UK; University of Oxford, Oxford, UK 8.2.3: Nosocomial infections Louise Bowles Consultant Haematologist, Barts Health NHS Trust, London, UK 14.7: Thrombosis in pregnancy Paul Bowness Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK 4.1: The innate immune system Ray Boyapati Department of Gastroenterology, Monash Health, Victoria, Australia; Faculty of Medicine, Nursing and Health Sciences, Monash University, Vic, Australia 15.17: Vascular disorders of the gastrointestinal tract Sally M. Bradberry NPIS (Birmingham Unit) and West Midlands Poisons Unit, City Hospital, †

Birmingham; School of Biosciences, University of Birmingham, Birmingham, UK 10.4.1: Poisoning by drugs and chemicals Marcus Bradley North Bristol NHS Trust, Bristol, UK 24.3.3: Imaging in neurological diseases Tasanee Braithwaite Locum Consultant, Moorfields Eye Hospital NHS Foundation Trust, London, UK 25.1: The eye in general medicine Thomas Brandt Ludwig Maximilians University, Munich, Germany 24.6.2: Eye movements and balance Petter Brandtzaeg Emeritus Professor, Department of Paediatrics, Oslo University Hospital, Oslo, Norway 8.6.5: Meningococcal infections Philippe Brasseur Institut de Recherche pour le Développement, Dakar, Sénégal, West Africa 8.8.3: Babesiosis Jürgen Braun Medical Director, Rheumazentrum Ruhrgebiet, Herne, Germany; Chair of Rheumatology, Ruhr University, Bochum, Germany 19.6: Spondyloarthritis and related conditions Evan M. Braunstein Hematology Division, Johns Hopkins University School of Medicine, Baltimore, MD, USA 22.3.7: Primary myelofibrosis James D. Brenton Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK 5.2: The nature and development of cancer: Cancer mutations and their implications J.A. Bridgewater Professor and Consultant in Medical Oncology, UCL Cancer Institute, London, UK 15.16: Cancers of the gastrointestinal tract Frank Bridoux Professor of Nephrology, Department of Nephrology, Hôpital Jean Bernard, Poitiers, France 21.10.5: Renal involvement in plasma cell dyscrasias, immunoglobulin-​based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias Charlotte K. Brierley Department of Haematology, Cancer and Haematology Centre, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, UK 22.3.2: Myelodysplastic syndromes Alice Brockington University of Sheffield, Sheffield, UK 24.15: The motor neuron diseases Max Bronstein Advocacy and Science Policy, Every Life Foundation, Washington, DC, USA 2.9: Engaging patients in therapeutic development Gary Brook London North West University Healthcare NHS Trust, London, UK 9.3: Sexual history and examination Arthur E. Brown Research Consultant, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, Thailand 8.6.21: Anthrax

It is with great regret that we report that Christopher Booth died on 13 July, 2012.

Anthony F.T. Brown Department of Emergency

Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Qld, Australia 17.3: Anaphylaxis Kevin E. Brown Virus Reference Department, Public Health England, London, UK 8.5.20: Parvovirus B19 Michael Brown Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK 8.9.4: Strongyloidiasis, hookworm, and other gut strongyloid nematodes Morris J. Brown Professor of Endocrine Hypertension, Queen Mary University of London, William Harvey Heart Centre, London, UK 16.17.3: Secondary hypertension Vanessa Brown Specialist Registrar, Royal Surrey County Hospital, Guildford, UK 15.4.2: Gastrointestinal bleeding Reto Brun Parasite Chemotherapy Unit, Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland 8.8.11: Human African trypanosomiasis Marco J. Bruno Erasmus Medical Center, University Medical Center Rotterdam, Department of Gastroenterology and Hepatology, Rotterdam, the Netherlands 15.26.2: Chronic pancreatitis Amy E. Bryant Research Professor, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, Idaho State University, ID, USA 8.6.25: Botulism, gas gangrene, and clostridial gastrointestinal infections Antony D.M. Bryceson London School of Hygiene and Tropical Medicine, London, UK 8.8.13: Leishmaniasis Nicolas C. Buchs Consultant Colorectal Surgeon, Clinic for Visceral and Transplantation Surgery, Department of Surgery, University Hospitals of Geneva, Geneva, Switzerland 15.14: Colonic diverticular disease Camilla Buckley MRC Clinician Scientist and Honorary Consultant, Department of Clinical Neurology, University of Oxford, Oxford, UK 24.24: Autoimmune encephalitis and Morvan’s syndrome Simon J.A. Buczacki Honorary Consultant Colorectal Surgeon, Cambridge Colorectal Unit, Addenbrooke’s Hospital, Cambridge, UK 15.4.1: The acute abdomen Enrico Bugiardini MRC Centre for Neuromuscular Disease, University College London, London, UK 24.19.1: Structure and function of muscle Alan Burnett Former Professor of Haematology, Cardiff University, Cardiff, UK 22.3.3: Acute myeloid leukaemia Gilbert Burnham John Hopkins Bloomberg School of Public Health, Baltimore, MD, USA 8.9.1: Cutaneous filariasis Aine Burns Consultant Nephrologist and Director of Postgraduate Medical Education, Centre for Nephrology, Royal Free NHS Trust and University College Medical School, London, UK 21.19: Drugs and the kidney

xlvii

xlviii

Contributors

Eileen Burns Leeds Centre for Older People’s

Medicine, Leeds Teaching Hospitals NHS Trust, Leeds, UK 6.11: Promotion of dignity in the life and death of older patients Harry Burns University of Strathclyde, UK 2.14: Deprivation and health N.P. Burrows Consultant Dermatologist, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 20.2: Inherited defects of connective tissue: Ehlers–​Danlos syndrome, Marfan syndrome, and pseudoxanthoma elasticum Rosie Burton Khayelitsha District Hospital, Corner of Walter Sisulu and Streve Biko Roads, Khayelitsha, Cape Town, Africa; Department of Medicine, University of Cape Town, Cape Town, Africa 14.15: Maternal infection in pregnancy Andrew Bush Imperial College London, London, UK; National Heart and Lung Institute, London, UK; Royal Brompton and Harefield NHS Foundation Trust, London, UK 18.10: Cystic fibrosis Kate Bushby Newcastle University John Walton Centre for Muscular Dystrophy Research, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, International Centre for Life, Newcastle upon Tyne, UK 24.19.2: Muscular dystrophy Gary Butler University College London Hospital and UCL Great Ormond Street Institute of Child Health, London, UK 13.7.1: Normal growth and its disorders William F. Bynum Professor Emeritus, University College London, London, UK 2.1: Science in medicine: When, how, and what Simone M. Cacciò European Union Reference Laboratory for Parasites, Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Rome, Italy 8.8.5: Cryptosporidium and cryptosporidiosis Djuna L. Cahen Erasmus Medical Center, University Medical Center Rotterdam, Department of Gastroenterology and Hepatology, Rotterdam, the Netherlands 15.26.2: Chronic pancreatitis P.M.A. Calverley School of Clinical Sciences, University of Liverpool, Liverpool, UK 18.15: Chronic respiratory failure Jason Caplan Dignity Health Medical Group; St. Joseph’s Hospital and Medical Center; Creighton University School of Medicine; Phoenix, AZ, USA 26.5.3: Organic psychoses Jonathan R. Carapetis Telethon Kids Institute, University of Western Australia and Perth Children’s Hospital, Perth, Australia 16.9.1: Acute rheumatic fever Jordi Carratalà Department of Infectious Diseases, Hospital Universitari de Bellvitge -​IDIBELL, Division of Health Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain 8.6.39: Legionellosis and Legionnaires’ disease

R. Carter Consultant Pancreaticobiliary Surgeon,

West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK 15.26.1: Acute pancreatitis Stuart Carter Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK 19.12: Miscellaneous conditions presenting to the rheumatologist David Carty Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, Glasgow, UK 14.11: Endocrine disease in pregnancy Jaimini Cegla Imperial College London, London, UK 12.6: Lipid disorders Joseph Cerimele University of Washington, Washington, DC, USA 26.5.6: Depressive disorder Joshua T. Chai Department of Cardiovascular Medicine, University of Oxford, Oxford, UK 16.13.1: Biology and pathology of atherosclerosis Richard E. Chaisson Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA 8.6.26: Tuberculosis Romanee Chaiwarith Division of Infectious Diseases, Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand 8.7.6: Talaromyces (Penicillium) marneffei infection Ben Challis University of Cambridge Medical School, Cambridge, UK 13.9.2: Hypoglycaemia Siddharthan Chandran Euan MacDonald Centre for Clinical Brain Sciences (CCBS), University of Edinburgh, Edinburgh, UK 3.7: Stem cells and regenerative medicine; 24.10.2: Demyelinating disorders of the central nervous system Keith Channon John Radcliffe Hospital, Oxford, UK 16.1.1: Blood vessels and the endothelium Roger W. Chapman Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford; Nuffield Department of Medicine, University of Oxford, Oxford, UK 15.23.4: Primary sclerosing cholangitis V. Krishna Chatterjee University of Cambridge Medical School, Cambridge, UK 13.1: Principles of hormone action Afzal Chaudhry Chief Clinical Information Officer, Cambridge University Hospitals, Cambridge, UK 2.5: Bioinformatics K. Ray Chaudhuri National Parkinson Foundation Centre of Excellence, King’s College, Denmark Hill Campus, London, UK 24.7.2: Parkinsonism and other extrapyramidal diseases Patrick F. Chinnery University of Newcastle, Newcastle upon Tyne, UK 24.19.5: Mitochondrial disease

Hector Chinoy University of Manchester,

Manchester, UK 19.11.5: Inflammatory myopathies Peter L. Chiodini Hospital for Tropical Diseases, University College London Hospitals, London, UK 8.9.5: Gut and tissue nematode infections acquired by ingestion Rossa W.K. Chiu Choh-​Ming Li Professor of Chemical Pathology, Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong, China 3.9: Circulating DNA for molecular diagnostics Bruno B. Chomel School of Veterinary Medicine, University of California, CA, USA 8.6.43: Bartonellas excluding B. bacilliformis Robin P. Choudhury University of Oxford, Oxford, UK 16.13.1: Biology and pathology of atherosclerosis Julia Choy National Health Service, London, UK 18.4.5: Pulmonary complications of HIV infection Lydia Chwastiak Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA 26.5.6: Depressive disorder Andrew L. Clark Chair of Clinical Cardiology and Honorary Consultant Cardiologist, Hull York Medical School, Castle Hill Hospital, Hull, UK 16.5.2: Acute cardiac failure: Definitions, investigation, and management; 16.5.3: Chronic heart failure: Definitions, investigation, and management Andrew Clegg Academic Unit of Elderly Care and Rehabilitation, University of Leeds, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK 6.2: Frailty and sarcopenia John G.F. Cleland National Heart and Lung Institute, Royal Brompton and Harefield Hospitals Trust London, UK; Hull York Medical School, University of Hull, Hull, UK 16.5.2: Acute cardiac failure: Definitions, investigation, and management; 16.5.3 Chronic heart failure: Definitions, investigation, and management Gavin Clunie Cambridge University Hospitals NHS

Foundation Trust, Cambridge, UK 20.5: Osteonecrosis, osteochondrosis, and osteochondritis dissecans

S.M. Cobbe Previously Consultant Cardiologist,

Glasgow Royal Infirmary; former BHF Walton Professor of Medical Cardiology, University of Glasgow, Glasgow, UK 16.2.2: Syncope and palpitation

Fredric L. Coe The University of Chicago Medicine,

Chicago, IL, US 21.1: Structure and function of the kidney

Sian Coggle Consultant Physician, Cambridge

University Hospitals, Cambridge, UK 30.1: Acute medical presentations; 30.2: Practical procedures

Jon Cohen Brighton and Sussex Medical School,

Brighton, UK 8.2.4: Infection in the immunocompromised host

Contributors

Alasdair Coles Cambridge School of Clinical

Medicine, Cambridge, UK 24.10.2: Demyelinating disorders of the central nervous system Jane Collier Consultant Hepatologist, John Radcliffe Hospital, Oxford, UK 8.5.22: Hepatitis C virus; 15.22.1: Investigation and management of jaundice Rory Collins Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials Juan D. Colmenero Infectious Diseases Service, Regional University Hospital, Málaga, Spain 8.6.22: Brucellosis Alastair Compston Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK 24.1: Introduction and approach to the patient with neurological disease Juliet Compston University of Cambridge School of Clinical Medicine and Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 20.4: Osteoporosis Philip G. Conaghan Leeds University, Leeds, UK 19.9: Osteoarthritis Christopher P. Conlon Professor of Infectious Diseases, Nuffield Department of Medicine, University of Oxford, Oxford, UK 8.4: Travel and expedition medicine; 8.5.23: HIV/​ AIDS; 8.5.28: Molluscum contagiosum Simon Conroy Department of Health Sciences, University of Leicester, Leicester, UK 6.4: Older people and urgent care Cyrus Cooper MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK; NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK 20.4: Osteoporosis John E. Cooper University of Cambridge, Cambridge, UK 8.8.8: Sarcocystosis (sarcosporidiosis) Robert Cooper University of Liverpool, Liverpool, UK 19.11.5: Inflammatory myopathies Mhairi Copland Professor of Translational Haematology, Section of Experimental Haematology, Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK 22.3.4: Chronic myeloid leukaemia Susan J. Copley Imperial College Healthcare NHS Trust, London, UK 18.3.2: Thoracic imaging Jeremy Cordingley Peri-​Operative Medicine, St Bartholomew’s Hospital, London, UK 17.5: Acute respiratory failure Philip J. Cowen University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK 26.4.1: Psychopharmacology in medical practice

Timothy M. Cox Professor of Medicine Emeritus,

Director of Research, University of Cambridge; Honorary Consultant Physician, Addenbrooke’s Hospital, Cambridge, UK 1.1: An older patient’s story; 12.1: The inborn errors of metabolism: General aspects; 12.3.1: Glycogen storage diseases; 12.3.2: Inborn errors of fructose metabolism; 12.3.3: Disorders of galactose, pentose, and pyruvate metabolism; 12.5: The porphyrias; 12.7.1: Hereditary haemochromatosis; 12.8: Lysosomal disease; 13.11: The pineal gland and melatonin; 15.10.5: Disaccharidase deficiency; 22.6.4: Iron metabolism and its disorders S.E. Craig Oxford Sleep Unit, Churchill Hospital, Oxford, UK 18.1.1: The upper respiratory tract Matthew Cramp South West Liver Unit and Peninsula Schools of Medicine and Dentistry, Derriford Hospital, Plymouth, UK 8.5.21: Hepatitis viruses (excluding hepatitis C virus) Robin A.F. Crawford Addenbrooke’s Hospital, Cambridge, UK 14.18: Malignant disease in pregnancy Daniel Creamer King’s College Hospital, London, UK 23.16: Cutaneous reactions to drugs Tim Crook North Middlesex Hospital, London, UK 5.7: Medical management of breast cancer Paul Cullinan Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK 18.7: Asthma Peter F. Currie Perth Royal Infirmary, Perth and Ninewells Hospital and Medical School, Dundee, UK 16.9.3: Cardiac disease in HIV infection Nicola Curry Consultant Haematologist, Oxford University Hospitals NHS Foundation Trust, Oxford Haemophilia and Thrombosis Centre, Churchill Hospital, Oxford, UK 22.7.3: Thrombocytopenia and disorders of platelet function Goodarz Danaei Department of Global Health and Population, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA 16.13.2: Coronary heart disease: Epidemiology and prevention Christopher J. Danpure Emeritus Professor of Molecular Cell Biology, University College London, London, UK 12.10: Hereditary disorders of oxalate metabolism: The primary hyperoxalurias Bhaskar Dasgupta University of Essex, Essex, UK; Anglia Ruskin University, East Anglia, UK; Southend University Hospital NHS Foundation Trust, Essex, UK 19.11.11: Polymyalgia rheumatica Pooja Dassan Consultant Neurologist, Imperial College Healthcare NHS Trust and London North West University Healthcare NHS Trust, London, UK 14.12: Neurological conditions in pregnancy

Andrew Davenport Professor of Dialysis and ICU

Nephrology, UCL Department of Nephrology, Royal Free Hospital, University College London, London, UK 21.4: Clinical investigation of renal disease Gail Davey Centre for Global Health Research, Brighton and Sussex Medical School, Brighton, UK 10.5: Podoconiosis Alun Davies Imperial College School of Medicine, London, UK 16.14.2: Peripheral arterial disease Helen E. Davies University Hospital of Wales, Cardiff, UK 18.19.4: Mediastinal tumours and cysts R Justin Davies Consultant Colorectal Surgeon, Cambridge Colorectal Unit, Addenbrooke’s Hospital, Cambridge, UK 15.4.1: The acute abdomen P.D.O. Davies Liverpool Heart and Chest Hospital NHS Foundation Trust, Liverpool, UK 8.6.27: Disease caused by environmental mycobacteria R. Rhys Davies Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Liverpool, UK 24.3.1: Lumbar puncture Simon Davies Professor of Nephrology and Dialysis Medicine, Institute for Science and Technology in Medicine, Keele University, Keele; Consultant Nephrologist, University Hospital of North Midlands, Stoke-​on-​Trent,  UK 21.7.2: Peritoneal dialysis Richard Dawkins New College, University of Oxford, Oxford, UK 2.2: Evolution: Medicine’s most basic science Christopher P. Day Vice-​Chancellor and President, Newcastle University and Freeman Hospital Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 15.24.2: Non​alcoholic fatty liver disease Nicholas P.J. Day Mahidol-​Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK 8.6.35: Leptospirosis; 8.6.41: Scrub typhus Colin Dayan University of Cardiff, Wales, UK 13.9.1: Diabetes Marc E. De Broe Professor of Medicine, Laboratory of Pathophysiology, University of Antwerp, Antwerp, Belgium 21.9.2: Chronic tubulointerstitial nephritis Kevin M. De Cock Center for Global Health, Atlanta, GA, USA 8.5.24: HIV in low-​and middle-​income countries An S. De Vriese Division of Nephrology, AZ Sint-​Jan Brugge-​Oostende AV, Brugge, Belgium 21.8.4: Membranous nephropathy Patrick B. Deegan Consultant Metabolic Physician, Lysosomal Disorders Unit, Cambridge University Hospitals, Cambridge, UK 12.8 Lysosomal disease

xlix

l

Contributors

Christopher Deighton Royal Derby Hospital,

Derby, UK 19.2 Clinical presentation and diagnosis of rheumatological disorders David M. Denison Emeritus Professor of Clinical Physiology, Royal Brompton Hospital and Imperial College London, London, UK 10.2.4: Diving medicine Christopher P. Denton Centre for Rheumatology, Division of Medicine, University College London (UCL) Medical School, Royal Free Hospital, London, UK 19.11.3: Systemic sclerosis (scleroderma) Ulrich Desselberger University of Cambridge, Cambridge, UK 8.5.8: Enterovirus infections; 8.5.9: Virus infections causing diarrhoea and vomiting Patrick C. D’Haese Head of Laboratory of Pathophysiology, University of Antwerp, Campus Drie Eiken, Wilrijk, Belgium 21.9.2: Chronic tubulointerstitial nephritis Ashwin Dhanda Plymouth Hospitals NHS Trust, Plymouth, UK 8.5.21: Hepatitis viruses (excluding hepatitis C virus) Jugdeep Dhesi Guys and St Thomas’ Hospitals, London, UK 6.6: Supporting older peoples’ care in surgical and oncological services Euan J. Dickson Consultant Pancreaticobiliary Surgeon, West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK 15.26.1: Acute pancreatitis Michael Doherty University of Nottingham, Nottingham, UK 19.3: Clinical investigation; 19.10: Crystal-​related arthropathies Inderjeet S. Dokal Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Barts Health NHS Trust, London, UK 22.5.1: Inherited bone marrow failure syndromes Jan Donck Department of Nephrology, AZ Sint-​ Lucas, Ghent, Belgium 21.10.4: The kidney in sarcoidosis Arjen M. Dondorp Mahidol-​Oxford Tropical Medicine Research Unit, Bangkok, Thailand 8.8.2: Malaria Basil Donovan University of New South Wales, NSW, Australia 8.6.37: Syphilis Philip R. Dormitzer Pfizer Vaccine Research and Development, Pearl River, NY, USA 8.5.9: Virus infections causing diarrhoea and vomiting Anne Dornhorst Imperial College Hospital, London, UK 14.10: Diabetes in pregnancy Charles G. Drake New York Presbyterian and Columbia University Medical Center, New York, USA 5.4: Cancer immunity and immunotherapy

Hal Drakesmith MRC Human Immunology Unit,

Weatherall Institute of Molecular Medicine, John Radcliffe Hospital and University of Oxford, Oxford, UK 22.6.5: Anaemia of inflammation Christopher Dudley Consultant Nephrologist, The Richard Bright Renal Unit, Southmead Hospital, North Bristol NHS Trust, Bristol, UK 16.14.3: Cholesterol embolism Susanna Dunachie Oxford University Hospitals NHS Trust, Oxford, UK 8.4: Travel and expedition medicine Lisa Dunkley Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK 19.12: Miscellaneous conditions presenting to the rheumatologist David Dunne University of Cambridge, Cambridge, UK; Wellcome Trust-​Cambridge, Centre for Global Health Research, UK; CAPREx, THRiVE-​Cambridge, and Cambridge-​Africa 8.11.1: Schistosomiasis Stephen R. Durham National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London, UK 18.6: Allergic rhinitis Jeremy Dwight John Radcliffe Hospital, Oxford, UK 16.2.1: Chest pain, breathlessness, and fatigue Jessica K. Dyson Newcastle University and Liver Unit, Freeman Hospital, Newcastle upon Tyne, UK 15.23.3: Primary biliary cholangitis Christopher P. Eades University College London, London, UK 8.7.5: Pneumocystis jirovecii Ian Eardley St James’s Hospital, Leeds, UK 13.6.4: Sexual dysfunction James E. East Consultant Gastroenterologist, Translational Gastroenterology Unit, John Radcliffe Hospital; Associate Professor of Gastroenterology and Endoscopy, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK 15.3.1: Colonoscopy and flexible sigmoidoscopy; 15.3.2: Upper gastrointestinal endoscopy Lars Eckmann Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA 8.8.9: Giardiasis and balantidiasis Michael Eddleston Pharmacology, Toxicology and Therapeutics, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK 10.4.4: Poisonous plants Mark J. Edwards St George’s University of London, London, UK 24.7.1: Subcortical structures: The cerebellum, basal ganglia, and thalamus Richard Edwards School of Clinical Sciences, University of Bristol, Bristol, UK 24.19.4: Metabolic and endocrine disorders Rosalind A. Eeles The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK 5.3: The genetics of inherited cancers

Tim Eisen Department of Oncology, University

of Cambridge, Cambridge, UK; Oncology Early Clinical Development, AstraZeneca, Cambridge, UK 5.2: The nature and development of cancer: Cancer mutations and their implications; 5.5: Clinical features and management; 21.18: Malignant diseases of the urinary tract Wagih El Masri(y) Keele University, Newcastle-​ under-​Lyme, UK; The Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, UK 24.13.2: Spinal cord injury and its management Carole Eldin University Hospital Institute Méditerranée Infection, Marseille, France 8.6.40: Rickettsioses Perry Elliott St Bartholomew’s Hospital, London, UK; Institute of Cardiovascular Science, University College London, London, UK 16.7.2: The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular; 16.7.3: Specific heart muscle disorders Christopher J. Ellis Heart of England Foundation Trust, Birmingham, UK; University of Birmingham, Birmingham, UK 8.2.1: Clinical approach Graham Ellis Monklands Hospital, Airdrie, Lanarkshire, UK 6.5: Older people in hospital Monique M. Elseviers Centre for Research and Innovation in Care (CRIC), University of Antwerp, Antwerp; Heymans Institute of Clinical Pharmacology, Ghent University, Ghent, Belgium 21.9.2: Chronic tubulointerstitial nephritis Caroline Elston Respiratory Medicine and Adult Cystic Fibrosis, King’s College Hospital, London, UK 18.10: Cystic fibrosis M.A. Epstein Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, UK 8.5.3: Epstein–​Barr  virus Steve Epstein MedStar Georgetown University Hospital and Georgetown University School of Medicine, Washington, DC, USA 26.5.8: Anxiety disorders Wendy N. Erber Medical School, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, WA, Australia 22.2.2: Diagnostic techniques in the assessment of haematological malignancies Ari Ercole Neurosciences Critical Care Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 24.5.6: Brainstem death and prolonged disorders of consciousness Edzard Ernst Emeritus Professor, University of Exeter, Exeter, UK 2.22: Complementary and alternative medicine Andrew P. Evan Indiana University School of Medicine, Indianapolis, IN, USA 21.14: Disorders of renal calcium handling, urinary stones, and nephrocalcinosis Mark Evans University of Cambridge Medical School, Cambridge, UK 13.9.2: Hypoglycaemia

Contributors

Rhys D. Evans Department of Physiology, Anatomy

and Genetics, University of Oxford, Oxford, UK 11.1 Nutrition: Macronutrient metabolism; 16.1.2: Cardiac physiology Pamela Ewan Allergy Department, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 4.5: Allergy David W. Eyre Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK 8.6.24 Clostridium difficile Lynette D. Fairbanks Purine Research Laboratory, Viapath, St Thomas’ Hospital, London, UK 12.4 Disorders of purine and pyrimidine metabolism Christopher G. Fairburn Oxford University Hospitals NHS Foundation Trust, Oxford, UK 26.5.10: Eating disorders Carole Fakhry Johns Hopkins Medical Institution, Baltimore, MD, USA 8.5.19: Papillomaviruses and polyomaviruses Marie Fallon St Columba’s Hospice Chair of Palliative Medicine, University of Edinburgh, Edinburgh, UK 7.2: Pain management Sonia Fargue University of Alabama at Birmingham, Birmingham, AL, USA 12.10: Hereditary disorders of oxalate metabolism: The primary hyperoxalurias Adam D. Farmer Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London; Department of Gastroenterology, University Hospitals of North Midlands, Stoke-​on-​Trent, UK 15.13: Irritable bowel syndrome I. Sadaf Farooqi Wellcome-​MRC Institute of Metabolic Science, University of Cambridge, UK 11.6: Obesity Jeremy Farrar Wellcome Trust, London, UK 2.17: Research in the developed world; 24.11.2: Viral infections Ken Farrington Lister Hospital, East and North Hertfordshire NHS Trust, Stevenage, UK 21.3: Clinical presentation of renal disease Hiva Fassihi King’s College London, London, UK 23.9: Photosensitivity John Feehally Emeritus Consultant Nephrologist, University Hospitals of Leicester; Honorary Professor of Renal Medicine, University of Leicester, Leicester, UK 21.8.1: Immunoglobulin A nephropathy and IgA vasculitis (HSP); 21.8.2: Thin membrane nephropathy Peter J. Fenner School of Public Health, Tropical Medicine and Rehabilitation Sciences, James Cook University, Townsville, Qld, Australia 10.3.4: Drowning Florence Fenollar Aix-​Marseille Université, URMITE, UM63, CNRS 7278, IRD 198, INSERM 1095, IHU Méditerranée Infection, Marseille, France 15.10.6: Whipple’s disease

Javier Fernández Consultant Hepatologist, Head of

Liver ICU, Liver Unit, Hospital Clinic Barcelona; Associate Professor, University of Barcelona Medical School, Barcelona, Spain; Member of the European Foundation for the Study of Chronic Liver Failure (EF-​CLIF) 15.22.2: Cirrhosis and ascites Fernando C. Fervenza Professor of Medicine, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, MN, USA 21.8.4: Membranous nephropathy Sarah Fidler Professor of HIV Medicine, Imperial College London, London, UK 8.5.23: HIV/​AIDS Richard E. Fielding Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 21.3: Clinical presentation of renal disease Roger G. Finch Nottingham University Hospitals, NHS Trust, Nottingham, UK 8.2.5: Antimicrobial chemotherapy Simon Finney Peri-​Operative Medicine, St Bartholomew’s Hospital, London, UK 17.5: Acute respiratory failure Helen V. Firth Addenbrookes Hospital Cambridge, Cambridge, UK 24.20: Developmental abnormalities of the central nervous system John D. Firth Consultant Physician and Nephrologist, Cambridge University Hospitals, Cambridge, UK 16.16.1: Deep venous thrombosis and pulmonary embolism; 16.17.1: Essential hypertension: Definition, epidemiology, and pathophysiology; 16.17.2: Essential hypertension: Diagnosis, assessment, and treatment; 16.19: Idiopathic oedema of women; 21.2.2: Disorders of potassium homeostasis; 21.5: Acute kidney injury; 21.7.3: Renal transplantation; 30.1: Acute medical presentations; 30.2: Practical procedures A.J. Fisher Professor of Respiratory Transplant Medicine, Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK 18.16: Lung transplantation Edward A. Fisher Departments of Medicine, Pediatrics, and Cell Biology, Smilow Research Centre, New York, NY, USA 16.13.1: Biology and pathology of atherosclerosis Rebecca C. Fitzgerald Professor of Cancer Prevention and MRC Programme Leader, MRC Cancer Unit, University of Cambridge, Hutchison/​MRC Research Centre, Cambridge, UK 15.7: Diseases of the oesophagus Michael E.B. FitzPatrick Department of Gastroenterology, Oxford University Hospitals, Oxford; Senior Research Fellow, Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK 15.1: Structure and function of the gastrointestinal tract R. Andres Floto Molecular Immunity Unit, Department of Medicine, University of Cambridge,

UK; Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge, UK 3.5: Intracellular signalling Edward D. Folland University of Massachusetts Medical School, MA, USA 16.3.4: Cardiac catheterization and angiography; 16.13.5: Percutaneous interventional cardiac procedures D. de Fonseka Academic Respiratory Unit, University of Bristol, Bristol, UK 18.17: Pleural diseases Carole Foot Royal North Shore Hospital, NSW, Australia 17.1: The seriously ill or deteriorating patient Alastair Forbes Norwich Medical School,  University of East Anglia, Norwich, UK 15.10.1: Differential diagnosis and investigation of malabsorption Ewan Forrest Consultant Hepatologist and Honorary Clinical Associate Professor, Department of Gastroenterology, Glasgow Royal Infirmary and the University of Glasgow, Glasgow UK 15.24.1: Alcoholic liver disease Rob Fowkes Royal Veterinary College, London, UK 13.1: Principles of hormone action Keith A.A. Fox Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK 16.13.4: Management of acute coronary syndrome Stephen Franks Imperial College London, London, UK 13.6.1: Ovarian disorders Keith N. Frayn Radcliffe Department of Medicine, University of Oxford, Oxford, UK 11.1: Nutrition: Macronutrient metabolism Patrick French Mortimer Market Centre, Central and North West London NHS Trust, London, UK; University College London, London, UK 9.6: Genital ulceration Izzet Fresko Division of Rheumatology, Department of Medicine, Cerrahpasa Medical Faculty, University of Istanbul, Istanbul, Turkey 19.11.10: Behçet’s syndrome Peter S. Friedmann Emeritus Professor of Dermatology, University of Southampton, Southampton, UK 23.6: Dermatitis/​eczema Charlotte Frise Obstetric Medicine and Acute General Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK 14.20: Prescribing in pregnancy Susannah J.A. Froude Consultant Microbiology and Infectious Diseases, Public Health Wales, Cardiff, UK 8.5.29: Newly discovered viruses Stephen J. Fuller Associate Professor, Medicine Sydney Medical School Nepean, The University of Sydney, Sydney, Australia 22.6.8: Anaemias resulting from defective maturation of red cells David A. Gabbott Gloucestershire Hospitals NHS Foundation Trust, Gloucester, UK 17.2: Cardiac arrest

li

lii

Contributors

Simon M. Gabe Consultant Gastroenterologist,

Intestinal Failure and Academic Unit, St Mark’s Hospital, London, UK 15.10.7: Effects of massive bowel resection Patrick G. Gallagher Professor of Pediatrics, Genetics and Pathology, Yale University, New Haven, CT, USA 22.6.9: Disorders of the red cell membrane Shreyans Gandhi King’s College Hospital/​King’s College London, London, UK 22.5.2: Acquired aplastic anaemia and pure red cell aplasia Hector H. Garcia Center for Global Health, Tumbes and Department of Microbiology, Universidad Peruana Cayetano Heredia, and Cysticercosis Unit, Instituto Nacional de Ciencias Neurologicas, Lima, Peru 8.10.2: Cystic hydatid disease (Echinococcus granulosus); 8.10.3: Cysticercosis Hill Gaston University of Cambridge, Cambridge, UK 19.8: Reactive arthritis Rupert Gauntlett Critical Care Medicine and Obstetric Anaesthesia, Royal Victoria Infirmary, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK 14.19: Maternal critical care John Geddes University of Oxford, Oxford, UK 26.5.7: Bipolar disorder William Gelson Consultant Hepatologist, Hepatobiliary and Liver Transplant Unit, Addenbrooke’s Hospital, Cambridge, UK 15.20: Structure and function of the liver, biliary tract, and pancreas Jacob George Department of Clinical Pharmacology and Therapeutics, University of Dundee, Dundee, UK 6.7: Drugs and prescribing in the older patient G.J. Gibson Newcastle University, Newcastle upon Tyne, UK 18.3.1: Respiratory function tests John Gibson Professor of Oral Medicine and Honorary Consultant in Oral Medicine, Institute of Dentistry, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK 15.6: The mouth and salivary glands J. van Gijn University Medical Center Utrecht, Utrecht, the Netherlands 24.10.1 Stroke: Cerebrovascular disease Ian Giles Centre for Rheumatology, Department of Medicine, University College London, London, UK 19.11.1: Introduction Robert H. Gilman Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD, USA 8.10.3: Cysticercosis Alexander Gimson Consultant Hepatologist, Hepatobiliary and Liver Transplant Unit, Addenbrooke’s Hospital, Cambridge, UK 15.19: Miscellaneous disorders of the bowel; 15.20: Structure and function of the liver, biliary tract, and pancreas; 15.24.4: Vascular disorders of the liver Matthew R. Ginks Oxford University Hospitals NHS Trust, Oxford, UK 16.4: Cardiac arrhythmias †

D.S. Giovanniello Medical Director, American Red

Cross, Biomedical Services, Connecticut Blood Services Region, Farmington, CT, USA 22.8.1: Blood transfusion Mark A. Glover Hyperbaric Medicine Unit, St Richard’s Hospital, Chichester, UK 10.2.4: Diving medicine Peter J. Goadsby NIHR-​Wellcome Trust King’s Clinical Research Facility, King’s College London, London, UK 24.8: Headache David Goldblatt University College London, London, UK 8.3: Immunization Armando E. Gonzalez Center for Global Health, Tumbes, Universidad Peruana Cayetano Heredia, and Department of Veterinary Epidemiology and Economics, School of Veterinary Medicine, Universidad Nacional Mayor de San Marcos, Lima, Peru 8.10.2: Cystic hydatid disease (Echinococcus granulosus) E.C. Gordon-​Smith Professor of Haematology, St George’s Hospital, University of London, London, UK 22.8.2: Haemopoietic stem cell transplantation Martin Gore† The Royal Marsden, London, UK; The Institute of Cancer Research, University of London, London, UK 5.5: Clinical features and management Eduardo Gotuzzo Universidad Peruana Cayetano Heredia, Lima, Peru 8.5.25: HTLV-​1, HTLV-​2, and associated diseases Philip Goulder University of Oxford, Oxford, UK 8.5.23: HIV/​AIDS Alison D. Grant Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK 8.5.24: HIV in low-​and middle-​income countries Cameron C. Grant The University of Auckland, New Zealand; Starship Children’s Health, Auckland, New Zealand 8.6.15: Bordetella infection David Gray Department of Cardiovascular Medicine, Nottingham University Hospitals NHS Trust, Nottingham, UK 16.3.1: Electrocardiography Richard Gray Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials John R. Graybill Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA 8.7.3: Coccidioidomycosis Darren Green Division of Cardiovascular Sciences, University of Manchester, Manchester, UK 16.5.4: Cardiorenal syndrome Manfred S. Green Hyperbaric Medicine Unit, St Richard’s Hospital, Chichester, UK 10.3.9: Bioterrorism

It is with great regret that we report that Martin Gore died on 10 January, 2019.

Christopher D. Gregory University of Edinburgh

Centre for Inflammation Research, Queen’s Medical Research Institute, Edinburgh, UK 3.6: Apoptosis in health and disease Christopher E.M. Griffiths Salford Royal NHS Foundation Trust, University of Manchester, Manchester, UK 23.5: Papulosquamous disease Karolina Griffiths University Hospital Institute Méditerranée Infection, Marseille, France 8.6.40: Rickettsioses Mark Griffiths Peri-​Operative Medicine, St Bartholomew’s Hospital, London, UK; Imperial College London, London, UK 17.5: Acute respiratory failure William J.H. Griffiths Consultant Hepatologist, Department of Hepatology, Addenbrooke’s Hospital, Cambridge, UK 12.7.1: Hereditary haemochromatosis; 15.24.6: Primary and secondary liver tumours J.P. Grünfeld Hôpital Universitaire Necker, Paris, France 21.12: Renal involvement in genetic disease D.J. Gubler Director, Program on Emerging Infectious Disease, Duke-NUS Graduate Medical School, Singapore; Asian Pacific Institute of Tropical Medicine and Infectious Diseases, University of Hawaii, Honolulu 8.5.12: Alphaviruses Richard L. Guerrant Center for Global Health, School of Medicine, University of Virginia, VA, USA 8.6.12: Cholera Kaushik Guha Portsmouth Hospitals NHS Trust, Portsmouth, UK 16.5.1: Epidemiology and general pathophysiological classification of heart failure Nishan Guha Oxford University Hospitals NHS Foundation Trust, Oxford, UK 29.1: The use of biochemical analysis for diagnosis and management Loïc Guillevin Department of Internal Medicine, National Referral Center for Rare Autoimmune and Systemic Diseases, INSERM U1060, Hôpital Cochin, Assistance Publique–​ Hôpitaux de Paris, University Paris Descartes, Paris, France 19.11.8: Polyarteritis nodosa Mark Gurnell University of Cambridge Medical School, Cambridge, UK 13.1: Principles of hormone action; 13.5.1 Disorders of the adrenal cortex Oliver P. Guttmann St Bartholomew’s Hospital, London, UK; Institute of Cardiovascular Science, University College London, London, UK 16.7.2: The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular; 16.7.3: Specific heart muscle disorders Robert D.M. Hadden Consultant Neurologist, King’s College Hospital, London, UK 24.12: Disorders of cranial nerves; 24.16: Diseases of the peripheral nerves

Contributors

Zara Haider Kingston Hospital NHS Trust,

Surrey, UK 9.9: Principles of contraception Sophie Hambleton Institute of Cellular Medicine, Newcastle University Medical School, Newcastle upon Tyne, UK; Paediatric Immunology and Infectious Diseases, Great North Children’s Hospital, Newcastle upon Tyne, UK 4.4: Immunodeficiency Freddie C. Hamdy Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK 21.18: Malignant diseases of the urinary tract Michael G. Hanna National Hospital for Neurology and Neurosurgery, Queen Square, London, UK 24.19.1: Structure and function of muscle David M. Hansell Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK 18.3.2: Thoracic imaging Danielle Harari Guy’s and St Thomas’ Hospitals and King’s College London, London, UK 6.9: Bladder and bowels Kate Hardy Faculty of Medicine, Department of Surgery and Cancer, Imperial College London, London, UK 13.6.1: Ovarian disorders Karen E. Harman Department of Dermatology, University Hospitals of Leicester NHS Trust, Leicester, UK 23.7: Cutaneous vasculitis, connective tissue diseases, and urticaria Peter Harper London Oncology Centre, London, UK 5.6: Systemic treatment and radiotherapy; 5.7: Medical management of breast cancer Steve Harper Consultant Renal and Transplant Medicine, Southmead Hospital, Bristol; Honorary Professor, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK; Honorary Professor, School of Medicine, University of Exeter, Exeter, UK 21.1: Structure and function of the kidney James L. Harrison London Deanery, London, UK 16.9.2: Endocarditis Tina Hartert Division of Pulmonary and Critical Care, Vanderbilt University Medical Center, Nashville, TN, USA 14.8: Chest diseases in pregnancy Christine Hartmann Institute of Musculoskeletal Medicine, University of Münster, Münster, Germany 19.1: Joints and connective tissue—​structure and function Nicholas C. Harvey MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK 20.4: Osteoporosis Rowan Harwood Nottingham University Hospitals NHS Trust and University of Nottingham, Queens Medical Centre, Nottingham, UK 6.5: Older people in hospital

Helen Hatcher Consultant Medical Oncologist,

Cambridge University Hospitals, Cambridge, UK 20.6: Bone cancer Chris Hatton Cancer and Haematology Centre, Churchill Hospital, Oxford, UK 22.1: Introduction to haematology; 22.3.9: Histiocytosis; 22.6.2: Anaemia: Pathophysiology, classification, and clinical features Philip N. Hawkins Professor of Medicine, National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, University College London, London, UK 12.12.2 Hereditary periodic fever syndromes; 12.12.3 Amyloidosis Keith Hawton Centre for Suicide Research, University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK 26.3.2: Self-​harm Deborah Hay Honorary Consultant Haematologist, Nuffield Department of Medicine, University of Oxford, Oxford, UK 22.6.7: Disorders of the synthesis or function of haemoglobin; 22.6.9: Disorders of the red cell membrane Roderick J. Hay King’s College London, London, UK 8.6.31: Nocardiosis; 8.7.1: Fungal infections; 23.6: Dermatitis/​eczema; 23.10: Infections of the skin; 23.12: Blood and lymphatic vessel disorders Peter Hayes Professor of Hepatology, Liver Unit, University of Edinburgh; and Royal Infirmary of Edinburgh, Edinburgh, UK 15.22.3: Portal hypertension and variceal bleeding Catherine E.G. Head Consultant Cardiologist, Guy’s and St Thomas’ NHS Foundation Trust, London, UK 14.6: Heart disease in pregnancy Eugene Healy Dermatopharmacology, Southampton General Hospital, University of Southampton, UK 23.8: Disorders of pigmentation Nick Heather Department of Psychology, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, UK 26.6.1: Brief interventions for excessive alcohol consumption David W. Hecht Loyola University Health System, IL, USA 8.6.11: Anaerobic bacteria Thomas Hellmark Department of Clinical Sciences, Lund University, Lund, Sweden 21.8.7: Antiglomerular basement membrane disease Michael Heneghan Professor of Hepatology and Consultant Hepatologist, Institute of Liver Studies, King’s College Hospital, London, UK 14.9: Liver and gastrointestinal diseases of pregnancy Michael Henein Umeå University, Sweden; Canterbury Christ Church University, Canterbury, UK 16.6: Valvular heart disease; 16.8: Pericardial disease

Martin F. Heyworth Department of Medicine,

Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 8.8.9: Giardiasis and balantidiasis

Liz Hickson Royal North Shore Hospital, NSW,

Australia 17.1: The seriously ill or deteriorating patient

Tran Tinh Hien Oxford University Clinical Research

Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam 8.6.1: Diphtheria

Katherine A. High Professor of Pediatrics Emerita,

Perelman School of Medicine, University of Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; President and Head of R&D, Spark Therapeutics, Philadelphia, PA, USA 22.7.4: Genetic disorders of coagulation

Ingeborg Hilderson Department of Medical

Oncology, University Hospital Ghent, Ghent, Belgium 21.10.4: The kidney in sarcoidosis

Tom R. Hill Population Health Sciences

Institute, Newcastle University, Newcastle upon Tyne, UK 11.2: Vitamins

David Hilton-​Jones Muscular Dystrophy

Campaign, Muscle and Nerve Centre, Department of Clinical Neurology, John Radcliffe Hospital, Oxford, UK 24.18: Disorders of the neuromuscular junction; 24.19.3: Myotonia; 24.19.4 Metabolic and endocrine disorders

Matthew Hind Royal Brompton Hospital

and National Heart and Lung Institute, Imperial College School of Medicine, London, UK 18.5.1: Upper airway obstruction; 18.5.2: Sleep-​ related breathing disorders

John Hindle Betsi Cadwaladr University Health

Board, Llandudno Hospital; School of Psychology, Bangor University, Bangor, UK 6.10: Neurodegenerative disorders in older people

N. Hirani Royal Infirmary, Edinburgh, UK

18.11.2: Idiopathic pulmonary fibrosis

Gideon M. Hirschfield Lily and Terry Horner

Chair in Autoimmune Liver Disease Research, Toronto Centre for Liver Disease, Department of Medicine, University of Toronto, Toronto General Hospital, Toronto, Canada 15.23.2: Autoimmune hepatitis

Sarah Hobdey Veterans Medical Hospital, Boise,

ID, USA 8.6.2: Streptococci and enterococci

Herbert Hof MVZ Labor Limbach, Heidelberg,

Germany 8.6.38: Listeriosis

A.V. Hoffbrand Emeritus Professor of Haematology,

University College, London, UK 22.6.6: Megaloblastic anaemia and miscellaneous deficiency anaemias

liii

liv

Contributors

Ronald Hoffman Albert A. and Vera G. List,

Professor of Medicine, Division of Hematology/​ Oncology; Director, Myeloproliferative Disorders Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA 22.3.5: The polycythaemias; 22.3.6: Thrombocytosis and essential thrombocythaemia Georg F. Hoffmann Department of General Pediatrics, University of Heidelberg, Heidelberg, Germany 12.2 Protein-​dependent inborn errors of metabolism Tessa L. Holyoake† Professor of Experimental Haematology, Section of Experimental Haematology, Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK 22.3.4: Chronic myeloid leukaemia Roel Hompes Consultant Colorectal Surgeon, Academic Medical Centre Amsterdam, University of Amsterdam, the Netherlands 15.14: Colonic diverticular disease Tony Hope St Cross College, University of Oxford, Oxford, UK 1.5: Medical ethics Julian Hopkin Medicine and Health, School of Medicine, Swansea University, Swansea, UK 18.2: The clinical presentation of respiratory disease P. Hopkins Medical Director, Queensland Lung Transplant Service, Chermside, Qld, Australia 18.16: Lung transplantation Nicholas S. Hopkinson National Heart and Lung Institute, Imperial College, London, UK 18.8: Chronic obstructive pulmonary disease Patrick Horner Population Health Sciences, University of Bristol, Bristol, UK 8.6.45: Chlamydial infections; 9.5: Urethritis Bala Hota Rush University, Chicago, IL USA 8.6.4: Staphylococci Andrew R. Houghton Grantham and District Hospital, Grantham, UK; University of Lincoln, Lincoln, UK 16.3.1: Electrocardiography Robert A. Huddart The Institute of Cancer Research, London, UK 21.18: Malignant diseases of the urinary tract Harriet C. Hughes Consultant Microbiology and Infectious Diseases, Public Health Wales, Cardiff, UK 8.5.29: Newly discovered viruses Ieuan A. Hughes University of Cambridge, Cambridge, UK 13.5.2: Congenital adrenal hyperplasia James H. Hull The Royal Brompton Hospital, London, UK 18.5.1: Upper airway obstruction Adam Hurlow Leeds Teaching Hospitals NHS Trust, Leeds, UK 7.4: Care of the dying person Jane A. Hurst Great Ormond Street Hospital, London, UK 24.20: Developmental abnormalities of the central nervous system

†

Alastair Hutchison Medical Director and Professor

of Renal Medicine, Dorset County Hospital, Dorchester, UK 21.6: Chronic kidney disease Peter J. Hutchinson University of Cambridge, Cambridge, UK 24.5.6: Brainstem death and prolonged disorders of consciousness Steve Iliffe Research Department of Primary Care and Population Health, University College London, London, UK 6.3: Optimizing well-​being into old age Lawrence Impey Obstetrics and Fetal Medicine, The Women’s Centre, John Radcliffe Hospital, Oxford, UK 14.16: Fetal effects of maternal infection Jakko van Ingen Radboud University Medical Centre, Nijmegen, the Netherlands 8.6.27: Disease caused by environmental mycobacteria Peter Irving Department of Gastroenterology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK 15.12: Ulcerative colitis John D. Isaacs Faculty of Medical Sciences, Newcastle University and Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 2.7 Biological therapies for immune, inflammatory, and allergic diseases; 19.5: Rheumatoid arthritis David A. Isenberg Centre for Rheumatology, Department of Medicine, University College London, London, UK 19.11.1: Introduction; 19.11.2: Systemic lupus erythematosus and related disorders Theodore J. Iwashyna Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Center for Clinical Management Research, Department of Veterans Affairs, Ann Arbor, MI, USA; Australian and New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Vic, Australia 17.12: Persistent problems and recovery after critical illness Arnaud Jaccard Service d’hématologie clinique et de thérapie cellulaire, CHU de Limoges—​Hôpital Dupuytren, Limoges, France 21.10.5: Renal involvement in plasma cell dyscrasias, immunoglobulin-​based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias Alan A. Jackson Southampton General Hospital, Southampton, UK 11.4: Severe malnutrition Thomas Jackson Queen Elizabeth Hospital, Birmingham, UK 26.3.1: Confusion Anu Jacob National Neuromyelitis Optica Service, Walton Centre for Neurology and Neurosurgery, Liverpool, UK 24.13.1: Diseases of the spinal cord

It is with great regret that we report that Tessa L. Holyoake died on 30 August, 2017.

Caron A. Jacobson Division of Hematologic

Malignancies, Dana-​Farber Cancer Institute, Boston, MA, USA 22.4.1: Introduction to lymphopoiesis N. Asger Jakobsen Clinical Research Fellow, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK 22.2.1: Cellular and molecular basis of haematopoiesis Rajiv Jalan Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK 15.22.5: Liver failure Hannah Jarvis Respiratory Medicine, St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK 18.4.4: Mycobacteria M.K. Javaid Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford, UK 20.1: Skeletal disorders—​general approach and clinical conditions David Jayne Professor of Clinical Autoimmunity, Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, UK 19.11.7: ANCA-​associated vasculitis; 21.10.2: The kidney in systemic vasculitis Susan Jebb Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK 26.6.2: Obesity and weight management Katie J.M. Jeffery Oxford University Hospitals NHS Foundation Trust, Department of Microbiology, John Radcliffe Hospital, Oxford, UK 8.5.22: Hepatitis C virus Rajesh Jena Cambridge University Hospitals, Cambridge, UK 5.6: Systemic treatment and radiotherapy Tom Jenkins University of Sheffield, Sheffield, UK 24.15: The motor neuron diseases Jørgen Skov Jensen Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark 8.6.46: Mycoplasmas Vivekanand Jha Executive Director, The George Institute for Global Health, New Delhi, India; Professor of Nephrology, University of Oxford, Oxford, UK 21.11: Renal diseases in the tropics Tingliang Jiang Professor, Department of Pharmacology, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China 2.8: Traditional medicine exemplified by traditional Chinese medicine Alexis J. Joannides University of Cambridge, Cambridge, UK 3.7: Stem cells and regenerative medicine Anne M. Johnson Centre for Molecular Epidemiology and Translational Research, Institute for Global Health, University College London, London, UK 9.2: Sexual behaviour

Contributors

Colin Johnson Emeritus Professor of Surgical Sciences,

University of Southampton, Southampton, UK 15.15: Diseases of the gallbladder and biliary tree M.R. Johnson Professor of Neurology and Genomic Medicine, Faculty of Medicine, Department of Brain Sciences, Imperial College, London, UK 24.5.1: Epilepsy in later childhood and adulthood Elaine Jolly University of Cambridge, Cambridge, UK 30.1: Acute medical presentations; 30.2: Practical procedures D. Joly Necker-​Enfants Malades Hospital, Paris, France 21.12: Renal involvement in genetic disease Bryony Jones Imperial College Hospital, London, UK 14.10: Diabetes in pregnancy David E.J. Jones Institute of Cellular Medicine, Newcastle University and Liver Unit, Freeman Hospital, Newcastle upon Tyne, UK 15.23.3: Primary biliary cholangitis Bouke de Jong Institute of Tropical Medicine, Antwerp, Belgium 8.6.29: Buruli ulcer: Mycobacterium ulcerans infection Menno De Jong Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 24.11.2: Viral infections Iain Jordan Oxford University Hospitals NHS Foundation Trust, Oxford, UK 26.5.13: Personality disorders Emil Kakkis Ultragenyx Pharmaceutical Inc., Novato, CA, USA 2.9: Engaging patients in therapeutic development Philip A. Kalra Consultant and Honorary Professor of Nephrology, Department of Renal Medicine, Salford Royal NHS Foundation Trust, Salford, UK 16.5.4 Cardiorenal syndrome; 21.10.10: Atherosclerotic renovascular disease Eileen Kaner Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK 26.6.1: Brief interventions for excessive alcohol consumption Theodoros Karamitos Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK 16.3.3: Cardiac investigations: Nuclear, MRI, and CT Niki Karavitaki Queen Elizabeth Hospital, Birmingham, UK 13.2.1: Disorders of the anterior pituitary gland; 13.2.2: Disorders of the posterior pituitary gland Steven B. Karch Consultant in Cardiac Pathology and Toxicology, Berkeley, CA, USA 27.1: Forensic and legal medicine Fiona E. Karet Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 21.15: The renal tubular acidoses Arthur Kaser Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK 15.5: Immune disorders of the gastrointestinal tract

†

David Kavanagh Institute of Genetic Medicine,

Newcastle University, Newcastle upon Tyne, UK 21.10.6: Haemolytic uraemic syndrome Fiona Kearney Nottingham University Hospitals Trust, Nottingham, UK 6.8: Falls, faints, and fragility fractures David Keeling Oxford Haemophilia and Thrombosis Centre, Churchill Hospital, Oxford, UK 16.16.2: Therapeutic anticoagulation Andrew Kelion Oxford University Hospitals NHS Foundation Trust, Oxford, UK 16.3.3: Cardiac investigations: Nuclear, MRI, and CT Julia Kelly Royal Brompton and Harefield NHS Trust, London, UK 18.5.2: Sleep-​related breathing disorders Paul Kelly Professor of Tropical Gastroenterology, Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK; TROPGAN Group, Department of Internal Medicine, University of Zambia School of Medicine, Lusaka, Zambia 8.8.6: Cyclospora and cyclosporiasis David P. Kelsell London Medical School, London, UK 23.3: Inherited skin disease Samuel Kemp Royal Brompton Hospital, London, UK 18.2: The clinical presentation of respiratory disease Christopher Kennard Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 24.1: Introduction and approach to the patient with neurological disease; 24.6.1: Visual pathways Richard S.C. Kerr Oxford University Hospitals NHS Foundation Trust, Oxford, UK 24.11.3: Intracranial abscesses Satish Keshav† Department of Gastroenterology, Oxford University Hospitals NHS Foundation Trust, Oxford; Professor of Gastroenterology, Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK 15.1: Structure and function of the gastrointestinal tract Nigel S. Key Harold R. Roberts Professor of Medicine, Division of Hematology-​Oncology, University of North Carolina, Chapel Hill, NC, USA 22.7.1: The biology of haemostasis and thrombosis Rajesh K. Kharbanda John Radcliffe Hospital, Oxford, UK 16.13.4: Management of acute coronary syndrome Elham Khatamzas Regional Infectious Diseases Unit, NHS Lothian, Edinburgh, UK 8.2.4: Infection in the immunocompromised host Peng T. Khaw Professor and Consultant Ophthalmic Surgeon; Director of Research, Development and Innovation; Director, NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK 25.1: The eye in general medicine

It is with great regret that we report that Satish Keshav died on 23 January, 2019.

B. Khoo University College London, London, UK

13.8: Pancreatic endocrine disorders and multiple endocrine neoplasia; 15.9.2: Carcinoid syndrome Nine V.A.M. Knoers Professor in Clinical Genetics, Department of Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands 21.16: Disorders of tubular electrolyte handling Stefan Kölker Consultant, Pediatric Metabolic Medicine, University Children’s Hospital, Heidelberg; Department of General Pediatrics, Division of Inborn Metabolic Diseases, Heidelberg, Germany 12.2 Protein-​dependent inborn errors of metabolism Nils P. Krone University of Sheffield, Sheffield, UK 13.5.2: Congenital adrenal hyperplasia Narong Khuntikeo Director, Cholangiocarcinoma Research Institute (CARI), Director, Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Thailand; Faculty of Medicine, Khon Kaen University, Thailand; Associate Professor, Department of Surgery, Faculty of Medicine, Khon Kaen University, Thailand 8.11.2: Liver fluke infections Gudula Kirtschig Tübingen, Germany 14.13: The skin in pregnancy Suzanne Kite Leeds Teaching Hospitals NHS Trust, Leeds, UK 7.4: Care of the dying person John L. Klein Guy’s and St Thomas’ NHS Foundation Trust, London, UK 16.9.2: Endocarditis Paul Klenerman Nuffield Department of Medicine, University of Oxford, Oxford, UK 4.3: Adaptive immunity; 8.5.22: Hepatitis C virus Richard Knight Department of Microbiology, University of Nairobi, Nairobi, Kenya 8.8.1: Amoebic infections; 8.8.10: Blastocystis infection; 8.9.2: Lymphatic filariasis; 8.9.3: Guinea worm disease (dracunculiasis); 8.9.6: Angiostrongyliasis; 8.10.1: Cestodes (tapeworms) David Koh PAPRSB Institute of Health Sciences, Universiti Brunei Darussalam, SSH School of Public Health, National University of Singapore, Singapore 10.2.5: Noise G.C.K.W. Koh Diseases of the Developing World, Alternative Drug Development, GlaxoSmithKline, UK 8.6.8: Pseudomonas aeruginosa M.A. Kokosi Royal Brompton and Harefield NHS Trust, London, UK 18.11.4: The lung in autoimmune rheumatic disorders Onn Min Kon Respiratory Medicine, St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK; National Heart and Lung Institute, Imperial College London, London, UK 18.4.4: Mycobacteria

lv

lvi

Contributors

Adelheid Korb-​Pap Institute of Experimental

Musculoskeletal Medicine, University Hospital Münster, Münster, Germany 19.1: Joints and connective tissue—​structure and function Vasilis Kouranos Royal Brompton and Harefield NHS Trust, London, UK 18.11.3: Bronchiolitis obliterans and cryptogenic organizing pneumonia Christian Krarup Region Hovedstaden, Denmark 24.3.2: Electrophysiology of the central and peripheral nervous systems Amy S. Kravitz United States Agency for International Development (USAID), Washington DC, USA 2.21: Humanitarian medicine Dinakantha S. Kumararatne Depatment of Clinical Immunology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 4.4: Immunodeficiency Om P. Kurmi Hyperbaric Medicine Unit, St Richard’s Hospital, Chichester, UK 10.3.1: Air pollution and health Robert A. Kyle Professor of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA 22.4.6: Plasma cell myeloma and related monoclonal gammopathies Peter L. Labib Clinical Research Fellow, Institute for Liver and Digestive Health, Royal Free Campus, University College London, London, UK 15.16: Cancers of the gastrointestinal tract Charles J.N. Lacey Hull York Medical School, University of York, York, UK 9.7: Anogenital lumps and bumps Helen J. Lachmann Senior Lecturer, National Amyloidosis Centre and Centre for Acute Phase Proteins, University College London Medical School, London, UK 12.12.2: Hereditary periodic fever syndromes Robin H. Lachmann Consultant in Inherited Metabolic Disease, Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK 12.3.1: Glycogen storage diseases Ralph Lainson† Ex Director, the Wellcome Parisitology Unit, and research-worker, Department of Parasitology, Instiuto Evandro Chagas, Rodovia, Barro Levilầndia, Ananindeua, Pará, Brazil 8.8.6: Cyclospora and cyclosporiasis Kin Bong Hubert Lam University of Oxford, Oxford, UK 10.3.1: Air pollution and health D.A. Lane Faculty of Medicine, Department of Medicine, Imperial College London, London, UK 16.4: Cardiac arrhythmias Peter C. Lanyon Nottingham University Hospitals Trust, Nottingham, UK 19.3: Clinical investigation Andrew J. Larner Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Liverpool, UK 24.3.1: Lumbar puncture; 24.5.4: Syncope; 24.13.1: Diseases of the spinal cord †

Malcolm Law Wolfson Institute of Preventive

Medicine, St Bartholomew’s and the Royal London School of Medicine and Dentistry, Queen Mary University of London, London, UK 2.12 Medical screening Tim Lawrence Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 24.10.3: Traumatic brain injury; 24.11.3: Intracranial abscesses Stephen M. Lawrie Division of Psychiatry, University of Edinburgh, Edinburgh, UK 26.5.11: Schizophrenia Alison M. Layton Harrogate and District NHS Foundation Trust, Harrogate, UK 23.11: Sebaceous and sweat gland disorders James W. Le Duc Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX, USA 8.5.16: Bunyaviridae Susannah Leaver St George’s NHS Foundation Trust, London, UK 17.5: Acute respiratory failure Y.C. Gary Lee Faculty of Health and Medical Sciences, UWA Medical School, University of Western Australia, Perth, WA, Australia 18.17: Pleural diseases; 18.19.3 Pleural tumours; 18.19.4 Mediastinal tumours and cysts Haur Yueh Lee National Heart Centre Singapore, Singapore, China; Kings Drugs Reaction Group, King’s College London, London, UK 23.16: Cutaneous reactions to drugs Richard W.J. Lee Director, Uveitis and Scleritis Service, National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and University College London Institute of Ophthalmology, London, UK 25.1: The eye in general medicine Evelyne de Leeuw Centre for Health Equity Training, Research and Evaluation, UNSW Sydney, South Western Sydney Local Health District, Ingham Institute, Australia 2.13: Health promotion Yee-​Sin Leo National Centre for Infectious Disease, Tan Tock Seng Hospital, Singapore; Yong Loo Lin School of Medicine and Saw Swee Hock School of Public Health, National University of Singapore, Singapore; Lee Kong Chian School of Medicine, Singapore 8.5.15: Dengue Phillip D. Levin Intensive Care Unit, Shaare Zedek Medical Center, Jerusalem, Hebrew University of Jerusalem, Faculty of Medicine, Jerusalem, Israel 17.10: Palliative and end-​of-​life care in the ICU Elena N. Levtchenko Professor in Pediatric Nephrology, Catholic University Leuven, Leuven, the Netherlands 21.16: Disorders of tubular electrolyte handling Su Li Department of Epidemiology, Guangxi Medical University, Nanning, Guangxi, China 5.7: Medical management of breast cancer Fulong Liao Professor, Biomechanopharmacology, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China 2.8: Traditional medicine exemplified by traditional Chinese medicine

It is with great regret that we report that Ralph Lainson died on 5 May, 2015.

Ted Liao MedStar Georgetown University Hospital

and Georgetown University School of Medicine, Washington DC, USA 26.5.8: Anxiety disorders Oliver Liesenfeld Roche Molecular Systems, Pleasanton, CA, USA 8.8.4: Toxoplasmosis Liz Lightstone, Professor of Renal Medicine, Centre for Inflammatory Disease, Faculty of Medicine, Imperial College London, London, UK 21.10.3: The kidney in rheumatological disorders Wei Shen Lim Consultant Respiratory Physician and Honorary Professor of Medicine, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK 18.4.2: Pneumonia in the normal host; 18.4.3: Nosocomial pneumonia Aldo A.M. Lima Biomedicine Center and Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil 8.6.12: Cholera Gregory Y.H. Lip Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Liverpool, UK; Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark 16.4: Cardiac arrhythmias; 16.17.5: Hypertensive urgencies and emergencies Mark A. Little Professor of Nephrology and Consultant Nephrologist, Trinity Health Kidney Centre, Trinity College Dublin; Tallaght and Beaumont Hospitals, Dublin, Ireland 21.8.5: Proliferative glomerulonephritis; 21.8.6: Membranoproliferative glomerulonephritis P. Little University of Southampton, Southampton, UK 18.4.1: Upper respiratory tract infections William A. Littler The Priory Hospital, Birmingham, UK 16.9.2: Endocarditis A. Llanos-​Cuentas School of Public Health and Administration, Universidad Peruana Cayetano Heredia, Lima, Peru 8.6.44: Bartonella bacilliformis infection Y.M. Dennis Lo Li Ka Shing Professor of Medicine, Department of Chemical Pathology, The Chinese University of Hong Kong, China 3.9: Circulating DNA for molecular diagnostics Diana N.J. Lockwood London School of Hygiene and Tropical Medicine, London, UK 8.6.28: Leprosy (Hansen’s disease); 8.8.13: Leishmaniasis David A. Lomas Vice Provost (Health) and Head of UCL Medical School, University College London, London, UK 12.13: α1-​Antitrypsin deficiency and the serpinopathies; 15.24.6 Primary and secondary liver tumours Alan Lopez University of Melbourne, Melbourne, Vic, Australia 2.3: The Global Burden of Disease: Measuring the health of populations

Contributors

Constantino López-Macias Mexican Society of

Immunology, Mexico; University of Oxford, Oxford, UK 4.3: Adaptive immunity David A. Low Liverpool John Moores University, Liverpool, UK 24.14: Diseases of the autonomic nervous system Elyse E. Lower University of Cincinnati Medical Center, Cincinnati, OH, USA 18.12: Sarcoidosis Katharine Lowndes Department of Haematology, Royal Hampshire County Hospital, Winchester UK 14.17: Blood disorders in pregnancy Angela K. Lucas-​Herald School of Medicine, University of Glasgow, Royal Hospital for Children, Glasgow, UK 13.7.3: Normal and abnormal sexual differentiation Ingrid E. Lundberg Rheumatology Unit, Department of Medicine, Sloan, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden 19.11.5: Inflammatory myopathies James R. Lupski Department of Molecular and Human Genetics, Department of Pediatrics, Human Genome Sequencing Center, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA 3.2: The genomic basis of medicine Raashid Luqmani Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford Rheumatology Department, Nuffield Orthopaedic Centre, Oxford, UK 19.11.6: Large vessel vasculitis Linda Luxon National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Queen Square, London, UK 24.6.3: Hearing loss Jean Paul Luzio Cambridge Institute for Medical Research, Cambridge, UK 3.1: The cell Lucio Luzzatto Department of Haematology, Muhimbili University of Health and Allied Sciences Dar es Salaam, Tanzania 22.5.3: Paroxysmal nocturnal haemoglobinuria; 22.6.11: Glucose-​6-​phosphate dehydrogenase deficiency Graz A. Luzzi Wycombe General Hospital, High Wycombe, UK 9.3: Sexual history and examination Kate D. Lynch Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford; Nuffield Department of Medicine, University of Oxford, Oxford, UK 15.23.4: Primary sclerosing cholangitis David Mabey Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK 8.6.36: Non-​venereal endemic treponematoses: Yaws, endemic syphilis (bejel), and pinta; 8.6.45: Chlamydial infections; 9.1: Epidemiology of sexually transmitted infections Peter K. MacCallum Senior Lecturer in Haematology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK 14.7: Thrombosis in pregnancy

Alasdair MacGowan Department of Medical

Microbiology, North Bristol NHS Trust, Bristol, UK 8.2.5: Antimicrobial chemotherapy Lucy Mackillop Obstetric Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK 14.20 Prescribing in pregnancy Gael M. MacLean Oxford University Hospitals NHS Foundation Trust, Oxford, UK 13.6.3: Benign breast disease Kenneth T. MacLeod National Heart and Lung Institute (NHLI) Division, Faculty of Medicine, Imperial College London, London, UK 16.1.2: Cardiac physiology Alasdair MacLullich Edinburgh University, Edinburgh, UK 6.5: Older people in hospital Jane Macnaughtan Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK 15.22.5: Liver failure Robert Mactier Consultant Nephrologist, Glasgow Renal and Transplant Unit, South Glasgow University Hospital, NHS Greater Glasgow and Clyde, Glasgow, UK 21.7.1: Haemodialysis C. Maguiña-​Vargas School of Medicine, Universidad Peruana Cayetano Heredia, Lima, Peru 8.6.44: Bartonella bacilliformis infection Michael Maher Professor of Radiology, University College Cork and Consultant Radiologist, Cork University Hospital and Mercy University Hospital, Cork, Ireland 15.3.3: Radiology of the gastrointestinal tract Malegapuru W. Makgoba National Health Ombud, Pretoria, South Africa; College of Health Science, University of KwaZulu-​Natal, Durban, South Africa; National Planning Commission of South Africa; Universities of Natal and KwaZulu-​Natal, Durban, South Africa; MRC (SA), Cape Town, South Africa 2.18: Fostering medical and health research in resource-​constrained countries Govind K. Makharia Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India 15.10.8: Malabsorption syndromes in the tropics Hadi Manji The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK 24.11.4: Neurosyphilis and neuro-​AIDS J.I. Mann Edgar Diabetes and Obesity Research Centre (EDOR), Department of Human Nutrition, University of Otago, Dunedin, New Zealand 11.5: Diseases of affluent societies and the need for dietary change David Mant University of Oxford, Oxford, UK 2.11: Preventive medicine G.A. Margaritopoulos Royal Brompton and Harefield NHS Trust, London, UK 18.11.5: The lung in vasculitis

Anthony M. Marinaki Purine Research Laboratory,

Viapath, St Thomas’ Hospital, London, UK 12.4: Disorders of purine and pyrimidine metabolism Chiara Marini-​Bettolo Newcastle University John Walton Centre for Muscular Dystrophy Research, Newcastle upon Tyne Hospital NHS Foundation Trust, Institute of Genetic Medicine, International Centre for Life, Newcastle upon Tyne, UK 24.19.2: Muscular dystrophy Michael Marks Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK 8.6.36: Non-​venereal endemic treponematoses: Yaws, endemic syphilis (bejel), and pinta Paul Marks Honorary Consultant Neurosurgeon, Harrogate District Hospital, Harrogate; Her Majesty’s Senior Coroner for the City of Kingston upon Hull and the County of the East Riding of Yorkshire; Vice President, Faculty of Forensic and Legal Medicine, London, UK; Honorary Professor of Neurosurgery, College of Medicine, University of Malawi, Malawi 27.1: Forensic and legal medicine Thomas J. Marrie Department of Medicine, Dalhousie University, Nova Scotia, Canada 8.6.42: Coxiella burnetii infections (Q fever) Judith C.W. Marsh King’s College Hospital, King’s College London, London, UK 22.5.2: Acquired aplastic anaemia and pure red cell aplasia Sara Marshall Wellcome Trust, London, UK 4.4: Immunodeficiency Steven B. Marston National Heart and Lung Institute (NHLI) Division, Faculty of Medicine, Imperial College London, UK 16.1.2: Cardiac physiology Maria do Rosario O. Martins University Nova de Lisboa, Lisbon, Portugal 2.16: Financing healthcare in low-​income developing countries: A challenge for equity in health Thiviyani Maruthappu Kelsell Group, Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London, Queen Mary University of London, London, UK 23.3: Inherited skin disease Duncan J. Maskell University of Cambridge, Cambridge, UK 8.1.1: Biology of pathogenic microorganisms N.A. Maskell Academic Respiratory Unit, University of Bristol, UK 18.17: Pleural diseases Jay W. Mason Cardiology Division, University of Utah College of Medicine, Salt Lake City, UT, USA 16.7.1: Myocarditis Tahir Masud Nottingham University Hospitals Trust, Nottingham, UK 6.8: Falls, faints, and fragility fractures Christopher J. Mathias Stoke Poges, UK 24.14: Diseases of the autonomic nervous system

lvii

lviii

Contributors

Fadi Matta Associate Professor, Department of

Osteopathic Medical Specialties, Collage of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA 16.16.1: Deep venous thrombosis and pulmonary embolism Eric L. Matteson Division of Rheumatology, Divisions of Rheumatology and Epidemiology, Mayo Clinic College of Medicine, Rochester, MN, USA 19.11.11: Polymyalgia rheumatica Kieran McCafferty Consultant Nephrologist, Barts Health NHS Trust, London, UK 21.17: Urinary tract obstruction Fergus McCarthy Division of Women’s Health, Women’s Health Academic Centre KHP, St. Thomas’ Hospital, London, UK 14.4: Hypertension in pregnancy Brian W. McCrindle University of Toronto, Toronto, Canada; The Hospital for Sick Children, Toronto, ON, Canada 19.11.12: Kawasaki disease Theresa A. McDonagh King’s College Hospital, Denmark Hill, London, UK 16.5.1: Epidemiology and general pathophysiological classification of heart failure A.D. McGavigan Flinders University, SA, Australia 16.2.2: Syncope and palpitation; 16.4: Cardiac arrhythmias Fiona McGill Institute of Infection and Global Health, University of Liverpool, Liverpool, UK 24.11.2: Viral infections John A. McGrath Genetic Skin Disease Group, St John’s Institute of Dermatology, King’s College London (Guy’s Campus), London, UK 23.1: Structure and function of skin Alastair McGregor Department of Tropical Medicine and Infectious Diseases, London Northwest Hospitals NHS Trust, London, UK; Department of Medicine, Imperial College London, London, UK 8.11.4: Intestinal trematode infections Jane McGregor Clinical Senior Lecturer and Honorary Consultant Dermatologist, Blizard Institute, Barts and the London School Medicine and Dentistry, London, UK 23.9: Photosensitivity Iain B. McInnes University of Glasgow, Glasgow, UK 3.3: Cytokines C.J. McKay Consultant Pancreaticobiliary Surgeon, West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK 15.26.1: Acute pancreatitis William J. McKenna The Heart Hospital, University College London, London, UK 16.7.2: The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular Curtis McKnight Dignity Health Medical Group; St. Joseph’s Hospital and Medical Center; Creighton University School of Medicine, Phoenix, AZ, USA 26.5.3: Organic psychoses

Alison McMillan East and North Hertfordshire NHS

Trust, Stevenage, UK 18.5.2: Sleep-​related breathing disorders Martin A. McNally The Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford University Hospitals, Oxford, UK 20.3: Osteomyelitis Regina McQuillan St Francis Hospice and Beaumont Hospital, Dublin, Ireland 7.3: Symptoms other than pain Simon Mead MRC Prion Unit, University College London, Institute of Prion Diseases; NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, Queen Square, London, UK 24.11.5: Human prion diseases Jill Meara Hyperbaric Medicine Unit, St Richard’s Hospital, Chichester, UK 10.3.7: Radiation Wajahat Z. Mehal Section of Digestive Diseases Yale University, New Haven, CT, USA 15.21: Pathobiology of chronic liver disease Tobias F. Menne Consultant Haematologist, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK 22.4.2: Acute lymphoblastic leukaemia David K. Menon Division of Anaesthesia, University of Cambridge, UK; Neurosciences Critical Care Unit, Royal College of Anaesthetists, London, UK; Queens’ College, Cambridge, UK; National Institute for Health Research, UK 17.7: Management of raised intracranial pressure Andrew Menzies-​Gow Royal Brompton Hospital, London, UK 18.7: Asthma Catherine H. Mercer Professor of Sexual Health Science, Centre for Population Research in Sexual Health and HIV, Institute for Global Health, University College London, London, UK 9.2: Sexual behaviour Vinod K. Metta Neurology, National Hospital for Neurology and Neurosurgery, University College London, London, UK 24.7.2: Parkinsonism and other extrapyramidal diseases Jan H. ter Meulen Philipps University Marburg, 35043 Marburg, Germany 8.5.17: Arenaviruses; 8.5.18: Filoviruses Wayne M. Meyers Department of Environmental and Infectious Disease Sciences, Armed Forces Institute of Pathology, Washington DC, USA 8.6.29: Buruli ulcer: Mycobacterium ulcerans infection Paul K. Middleton Clinical Research Fellow, Institute of Liver Studies, Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, UK 15.22.4: Hepatic encephalopathy

Stephen J. Middleton Consultant

Gastroenterologist, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge; Consultant Gastroenterologist (Hon.) St Mark’s Hospital, Harrow, London; Associate Professor (Hon.) Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK 15.10.2: Bacterial overgrowth of the small intestine; 15.10.7: Effects of massive bowel resection Mark E. Mikkelsen Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 17.12: Persistent problems and recovery after critical illness Michael A. Miles Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK 8.8.12: Chagas disease Robert F. Miller University College London, London, UK 8.7.5: Pneumocystis jirovecii Dawn S. Milliner Emeritus Professor of Medicine and Pediatrics at the Mayo Clinic Alix School of Medicine, Rochester, MN, USA 12.10 Hereditary disorders of oxalate metabolism: The primary hyperoxalurias K.R. Mills King’s College London, London, UK 24.3.4: Investigation of central motor pathways: Magnetic brain stimulation Philip Minor National Institute for Biological Standards and Control (NIBSC), Ridge, UK 8.5.8: Enterovirus infections Fraz A. Mir Department of Medicine, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK 16.17.3: Secondary hypertension Pramod K. Mistry Professor of Pediatrics and Medicine, Chief, Pediatric Gastroenterology and Hepatology, Yale School of Medicine, New Haven, CT, USA 12.7.2 Inherited diseases of copper metabolism: Wilson’s disease and Menkes’ disease Andrew R.J. Mitchell Jersey General Hospital, Jersey, UK 16.3.2: Echocardiography; 16.14.1: Acute aortic syndromes Oriol Mitjà Barcelona Institute for Global Health, University of Barcelona, Spain; Lihir Medical Centre, InternationalSOS, Lihir Island, Papua New Guinea 8.6.36: Non-​venereal endemic treponematoses: Yaws, endemic syphilis (bejel), and pinta Aarthi R. Mohan Obstetrics and Maternal Medicine, University Hospitals Bristol NHS Foundation Trust, Bristol, UK 14.21: Contraception for women with medical diseases Fiachra Moloney Consultant Radiologist, Department of Radiology, Cork University Hospital, Cork, Ireland 15.3.3: Radiology of the gastrointestinal tract P.L. Molyneaux Royal Brompton and Harefield NHS Trust, London, UK 18.11.2: Idiopathic pulmonary fibrosis

Contributors

Andrew J. Molyneux The Manor Hospital, Oxford, UK

24.3.3: Imaging in neurological diseases Peter D. Mooney Royal Hallamshire Hospital and University of Sheffield, Sheffield, UK 15.10.3: Coeliac disease Anthony V. Moorman Professor of Genetic Epidemiology, Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK 22.4.2: Acute lymphoblastic leukaemia Pilar Morata Department of Biochemistry and Molecular Biology, School of Medicine, University of Málaga, Málaga, Spain 8.6.22: Brucellosis Marina S. Morgan Royal Devon and Exeter NHS Foundation Trust, Exeter, UK 8.6.19: Pasteurella Michael L. Moritz Professor of Pediatrics, University of Pittsburgh School of Medicine, Clinical Director, Division of Nephrology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA 21.2.1: Disorders of water and sodium homeostasis Pedro L. Moro Immunization Safety Office, Division of Healthcare Quality Promotion, NCEZID, Centers for Disease Control and Prevention, Atlanta, GA, USA 8.10.2: Cystic hydatid disease (Echinococcus granulosus) Mary J. Morrell Imperial College London, London, UK 18.5.2: Sleep-​related breathing disorders Nicholas W. Morrell British Heart Foundation Professor of Cardiopulmonary Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals, Cambridge, UK 16.15.1: Structure and function of the pulmonary circulation; 16.15.2: Pulmonary hypertension Emma C. Morris Professor, Division of Infection and Immunity, UCL Institute of Immunity and Transplantation, Royal Free Campus, Royal Free Hospital, London, UK and Honorary Consultant, University College London Medical School, London, UK 22.8.2: Haemopoietic stem cell transplantation Neil J.McC. Mortensen Professor of Colorectal Surgery, Nuffield Department of Surgery, University of Oxford; Honorary Consultant Colorectal Surgeon, Oxford University Hospitals NHS Foundation Trust, Oxford, UK 15.14: Colonic diverticular disease Peter S. Mortimer St George’s University of London; St George’s Hospital, London; Royal Marsden Hospital, London, UK 16.18: Chronic peripheral oedema and lymphoedema; 23.12: Blood and lymphatic vessel disorders Ghulam J. Mufti King’s College Hospital/​King’s College London, London, UK 22.5.2: Acquired aplastic anaemia and pure red cell aplasia Victoria Mulcahy Norwich Medical School, University of East Anglia, Norwich, UK 15.10.1: Differential diagnosis and investigation of malabsorption

David R. Murdoch Professor and Head of

Pathology, University of Otago, Christchurch, New Zealand 10.3.6: Diseases of high terrestrial altitudes Paul Murphy NHS Blood and Transplant, Bristol, UK 17.11: Diagnosis of death and organ donation Christopher Murray University of Washington, WA, USA 2.3: The Global Burden of Disease: Measuring the health of populations Jean B. Nachega Departments of Epidemiology, Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA USA; Department of Medicine, Centre for Infectious Diseases, Stellenbosch University, Tygerberg, Cape Town, South Africa 8.6.26: Tuberculosis Robert B. Nadelman Division of Infectious Diseases, Department of Medicine, New York Medical College, Valhalla, NY, USA 8.6.33: Lyme borreliosis Alexandra Nanzer-​Kelly Guys and St Thomas’ Hospital, London, UK 18.7: Asthma Nikolai V. Naoumov Novartis Pharma, Basel, Switzerland 8.5.21: Hepatitis viruses (excluding hepatitis C virus) Kikkeri N. Naresh Department of Histopathology, Imperial College Healthcare NHS Trust and Imperial College, London, UK 15.10.4: Gastrointestinal lymphomas Kate Nash University Hospital Southampton NHS Foundation Trust, Southampton, UK 15.23.1: Hepatitis A to E N. Navani University College Hospital, London, UK 18.19.1: Lung cancer Catherine Nelson-​Piercy Obstetric Medicine, Women’s Health Academic Centre, King’s Health Partners, King’s College London, London, UK 14.14: Autoimmune rheumatic disorders and vasculitis in pregnancy Randolph M. Nesse Center for Evolution and Medicine, Arizona State University, AZ, USA 2.2: Evolution: Medicine’s most basic science Peter J. Nestor German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany 24.4.1: Disturbances of higher cerebral function Stefan Neubauer Oxford Centre for Clinical Magnetic Resonance Research (OCMR), Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK 16.3.3: Cardiac investigations: Nuclear, MRI, and CT James Neuberger Hon Consultant Physician, Liver Unit, Queen Elizabeth Hospital, Birmingham, UK 15.24.5: The liver in systemic disease

James D. Newton Oxford University Hospitals NHS

Trust, Oxford, UK 16.3.2: Echocardiography; 16.14.1: Acute aortic syndromes Paul N. Newton Lao-​Oxford-​Mahosot Hospital-​ Wellcome Trust Research Unit (LOMWRU), Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao PDR; Nuffield Department of Medicine, University of Oxford, Oxford; Infectious Diseases Data Observatory (IDDO), University of Oxford, Oxford, UK 2.10: Medicine quality, physicians, and patients Wan-​Fai Ng Newcastle University and NIHR Newcastle Biomedical, Research Centre for Ageing and Chronic Diseases, Newcastle upon Tyne, UK 19.11.4: Sjögren’s syndrome A.G. Nicholson Royal Brompton and Harefield NHS Trust; Professor of Respiratory Pathology, National Heart and Lung Institute, Imperial College School of Medicine, London, UK 18.11.2: Idiopathic pulmonary fibrosis Jerry P. Nolan Warwick Medical School, Coventry; Royal United Hospital, Bath, UK 17.2: Cardiac arrest John Nowakowski New York Medical College, NY, USA 8.6.33: Lyme borreliosis Paul Nyirjesy Drexel University College of Medicine, Philadelphia, PA, USA 9.4: Vaginal discharge Sarah O’Brien Modelling, Evidence and Policy Group, School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne, UK 15.18: Gastrointestinal infections Amy O’Donnell Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK 26.6.1: Brief interventions for excessive alcohol consumption Nigel O’Farrell Ealing Hospital, London North West University Healthcare NHS Trust, London, UK 8.6.14: Haemophilus ducreyi and chancroid John G. O’Grady Institute of Liver Studies, King’s College Hospital, London, UK 15.22.6: Liver transplantation Denis O’Mahony Department of Medicine, University College Cork and Department of Geriatric Medicine, Cork University Hospital, Cork, Ireland 6.7: Drugs and prescribing in the older patient E.E. Ooi Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore 8.5.12: Alphaviruses Susie Orme Barnsley Hospital NHS Foundation Trust, Barnsley, UK 6.9: Bladder and bowels Kevin O’Shaughnessy Division of Experimental Medicine and Immunotherapeutics, Department of Medicine, University of Cambridge, Cambridge, UK 2.6: Principles of clinical pharmacology and drug therapy

lix

lx

Contributors

Edel O’Toole Centre for Cutaneous Research,

Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry; and Department of Dermatology, Barts and the London NHS Trust, London, UK 23.14: Tumours of the skin Petra C.F. Oyston Biomedical Sciences, DSTL Porton Down, Salisbury, UK 8.6.20: Francisella tularensis infection Jacqueline Palace Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 24.18: Disorders of the neuromuscular junction Thomas Pap Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Münster, Germany 19.1: Joints and connective tissue—​structure and function Jayan Parameshwar Consultant Cardiologist, Royal Papworth Hospital, Cambridge, UK 16.5.5: Cardiac transplantation and mechanical circulatory support Daniel H. Paris University of Oxford, Oxford, UK; Rickettsial Research (Oxford Tropical Network); Mahidol-​Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand 8.6.41: Scrub typhus Sarah Parish Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials Mike Parker Ethox Centre, Oxford, UK 1.5: Medical ethics Miles Parkes Consultant Gastroenterologist, Cambridge University Hospitals, Cambridge, UK 15.11: Crohn’s disease Philippe Parola University Hospital Institute Méditerranée Infection, Marseille, France 8.6.40: Rickettsioses Christopher M. Parry Clinical Sciences, Liverpool School of Tropical Medicine, and Institute of Infection and Global Health, University of Liverpool, UK; School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan 8.6.9: Typhoid and paratyphoid fevers Judith Partridge Guys and St Thomas’ Hospitals London, UK 6.6: Supporting older peoples’ care in surgical and oncological services Sant-​Rayn Pasricha MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital and University of Oxford, Oxford, UK 22.6.5: Anaemia of inflammation Harnish Patel Academic Geriatric Medicine, University of Southampton, Southampton, UK 6.2: Frailty and sarcopenia Raj Patel Solent NHS Trust, Southampton, UK 9.6: Genital ulceration Sejal Patel Oxford Childrens Hospital, Oxford University Hospitals NHS Trust, Oxford, UK 13.7.2: Normal puberty and its disorders

John Paul SE region, National Infection Service,

Public Health England, UK 8.6.47: A checklist of bacteria associated with infection in humans; 8.12: Non​venomous arthropods Jason Payne-​James Specialist in Forensic and Legal Medicine and Consultant Forensic Physician; Lead Medical Examiner, Norfolk and Norwich University Hospital, Norfolk, UK; Honorary Clinical Professor, William Harvey Research Institute, Queen Mary University of London, UK; Consultant Editor-​in-​Chief, Journal of Forensic and Legal Medicine; Director, Forensic Healthcare Services Ltd, Southminster, UK 27.1: Forensic and legal medicine Sharon J. Peacock University of Cambridge, Cambridge, UK 8.6.8: Pseudomonas aeruginosa; 8.6.16: Melioidosis and glanders Fiona Pearce Clinical Lecturer, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham City Hospital, Nottingham, UK 19.2: Clinical presentation and diagnosis of rheumatological disorders Rupert Pearse Queen Mary University of London, London, UK 17.4: Assessing and preparing patients with medical conditions for major surgery Malik Peiris School of Public Health, The University of Hong Kong, Hong Kong, Special Administrative Region of China 8.5.1: Respiratory tract viruses Neil Pendleton School of Biological Sciences, Faculty Biology Medicine and Health and Manchester Institute for Collaborative Research in Ageing, University of Manchester, Manchester, UK 6.1: Ageing and clinical medicine Hugh Pennington University of Aberdeen, Aberdeen, UK 8.6.7: Enterobacteria and bacterial food poisoning Mark B. Pepys Director, Wolfson Drug Discovery Unit, and Honorary Consultant Physician, National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, University College London, London, UK 12.12.1 The acute phase response and C-​reactive protein; 12.12.3 Amyloidosis Stephen P. Pereira Professor of Hepatology and Gastroenterology, Institute for Liver and Digestive Health, University College London; Consultant Hepatologist and Gastroenterologist, University College Hospital and Royal Free Hospital, London, UK 15.16: Cancers of the gastrointestinal tract; 15.26.3: Tumours of the pancreas Gavin D. Perkins Warwick Medical School, Coventry; Intensive Care Unit, Heartlands Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK 17.2: Cardiac arrest David J. Perry Previously Department of Haematology, Addenbrooke’s Hospital, Cambridge, UK 14.17: Blood disorders in pregnancy

Hans Persson Swedish Poisons Centre,

Stockholm, Sweden 10.4.3: Poisonous fungi; 10.4.4: Poisonous plants Eskild Petersen Department of Infectious Diseases and Clinical Microbiology, Aarhus University Hospital Skejby, Aarhus, Denmark 8.8.4: Toxoplasmosis L.R. Petersen Director, Division of Vector-borne Infectious Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado, USA 8.5.12: Alphaviruses Trevor N. Petney Professor, Cholangiocarcinoma Research Institute (CARI), Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Department of Paleontology and Evolution, Organization/​ University State Museum of Natural History, Karlsruhe, Germany 8.11.2: Liver fluke infections Philippa Peto Consultant in Renal and Acute Medicine, Queen Elizabeth Hospital, Lewisham and Greenwich NHS Trust, London, UK 1.6: Clinical decision-​making Richard Peto Nuffield Department of Population Health, University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials; 5.1: Epidemiology of cancer Timothy E.A. Peto Nuffield Department of Clinical Medicine, University of Oxford; John Radcliffe Hospital, Oxford, UK 1.6: Clinical decision-​making; 8.5.23: HIV/​AIDS John D. Pickard University of Cambridge, Cambridge, UK 24.5.6: Brainstem death and prolonged disorders of consciousness Matthew C. Pickering Imperial College London, London, UK 4.2: The complement system Massimiliano di Pietro Senior Clinical Investigator Scientist and Consultant Gastroenterologist, MRC Cancer Unit, University of Cambridge, Hutchison/​MRC Research Centre, Cambridge, UK 15.7: Diseases of the oesophagus Michael R. Pinsky Professor Critical Care Medicine, Bio­engineering, Cardiovascular Disease and Anesthesiology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA 17.6: Circulation and circulatory support in the critically ill Julia Platts University of Cardiff, Cardiff, UK 13.9.1: Diabetes Raymond J. Playford, Professor of Medicine, University of Plymouth, Plymouth, UK; Vice President Research Strategy, Pantheryx Inc., Boulder, CO, USA 15.10.2: Bacterial overgrowth of the small intestine; 15.10.7: Effects of massive bowel resection Michael I. Polkey Royal Brompton and Harefield NHS Trust, London, UK 18.15: Chronic respiratory failure; 18.18 Disorders of the thoracic cage and diaphragm

Contributors

Eleanor S. Pollak Associate Professor of Pathology

and Laboratory Medicine (retired), Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA 22.7.4: Genetic disorders of coagulation Andrew J. Pollard Professor of Paediatric Infection and Immunity at the University of Oxford, Director of the Oxford Vaccine Group, Fellow of St Cross College and Honorary Consultant Paediatrician at the Children’s Hospital, Oxford, UK 10.3.6: Diseases of high terrestrial altitudes Aaron Polliack Emeritus Professor, Hadassah University Hospital and Hebrew University Medical School, Jerusalem, Israel 22.4.5: Chronic lymphocytic leukaemia Allyson M. Pollock Queen Mary University of London, London, UK 2.15: How much should rich countries’ governments spend on healthcare? Cristina Ponte Department of Rheumatology, Hospital de Santa Maria -​CHLN, Lisbon Academic Medical Centre, Lisbon, Portugal; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK 19.11.6: Large vessel vasculitis Kyle J. Popovich Rush University, Chicago, IL, USA 8.6.4: Staphylococci Françoise Portaels Institute of Tropical Medicine, Antwerp, Belgium 8.6.29: Buruli ulcer: Mycobacterium ulcerans infection John B. Porter Professor of Haematology and Consultant Haematologist, University College London Hospitals, London, UK 22.6.4: Iron metabolism and its disorders Stephen Potts Department of Psychological Medicine, Edinburgh Royal Infirmary, Edinburgh, UK 26.5.5: Substance misuse William G. Powderly Division of Infectious Diseases and Institute for Public Health, Washington University in St. Louis, MO, USA 8.7.2: Cryptococcosis Janet Powell Department of Surgery and Cancer, Imperial College, London, UK 16.14.2: Peripheral arterial disease Amy Powers Associate Professor of Pathology, John A Burns School of Medicine, University of Hawaii, Department of Pathology, Honolulu, HI, USA 22.6.12: Acquired haemolytic anaemia Ann M. Powers Centers for Disease Control and Prevention, Atlanta, GA, USA 8.5.12: Alphaviruses Anton Pozniak Department of HIV and GUM, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK 18.4.5: Pulmonary complications of HIV infection Bernard D. Prendergast John Radcliffe Hospital, Oxford, UK 16.9.2: Endocarditis

Michael Prentice School of Microbiology,

University College Cork, Cork, Ireland 8.6.17: Plague: Yersinia pestis; 8.6.18: Other Yersinia infections: Yersiniosis David Price Queen Mary University of London, London, UK 2.15: How much should rich countries’ governments spend on healthcare? Christopher Pugh Nuffield Department of Medicine, University of Oxford, Oxford, UK 21.14: Disorders of renal calcium handling, urinary stones, and nephrocalcinosis Meredith Pugh Division of Pulmonary and Critical Care, Vanderbilt University Medical Center, Nashville, TN, USA 14.8: Chest diseases in pregnancy Graham Raftery South Tyneside and Sunderland NHS Foundation Trust, Sunderland, UK 19.7: Infection and arthritis Kazem Rahimi The George Institute for Global Health, University of Oxford, Oxford, UK 16.13.2: Coronary heart disease: Epidemiology and prevention Anisur Rahman Centre for Rheumatology, University College London, London, UK 19.11.2: Systemic lupus erythematosus and related disorders Tim Raine IBD Lead and Consultant Gastroenterologist, Cambridge University Hospital, Cambridge, UK 15.11: Crohn’s disease K. Rajappan Oxford University Hospitals NHS Foundation Trust, Oxford, UK 16.2.2: Syncope and palpitation S. Vincent Rajkumar Edward W. and Betty Knight Scripps Professor of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA 22.4.6: Plasma cell myeloma and related monoclonal gammopathies Mary Ramsay Health Protection Agency, London, UK 8.3: Immunization A.C. Rankin Glasgow Royal Infirmary, Glasgow, UK 16.2.2: Syncope and palpitation Didier Raoult University Hospital Institute  Méditerranée Infection, Marseille, France 8.6.40: Rickettsioses; 15.10.6: Whipple’s disease Michael Rawlins Medicines and Healthcare Products Regulatory Agency, London, UK 2.19: Regulation versus innovation in medicine Phillip Read University of New South Wales, Kensington, NSW, Australia 8.6.37: Syphilis Michael C. Reade Burns, Trauma and Critical Care Research Centre, Royal Brisbane and Women’s Hospital, University of Queensland, Brisbane, Qld, Australia; Joint Health Command, Australian Defence Force, Canberra, ACT, Australia 17.8: Sedation and analgesia in the ICU Paul J. Reading Department of Sleep Medicine, The James Cook University Hospital, Middlesbrough, UK 24.5.3: Sleep disorders

Jeremy Rees National Hospital for Neurology and

Neurosurgery, London, UK; UCL Institute of Neurology, London, UK 24.23: Paraneoplastic neurological syndromes; 24.10.4: Intracranial tumours P.T. Reid Respiratory Unit, Western General Hospital, Edinburgh, UK 18.13: Pneumoconioses Shelley Renowden North Bristol NHS Trust, Bristol, UK 24.3.3: Imaging in neurological diseases John Richens Research Department of Infection and Population Health, University College London, London, UK 8.6.10: Intracellular klebsiella infections (donovanosis and rhinoscleroma) Alan B. Rickinson Institute for Cancer Studies, University of Birmingham, Birmingham, UK 8.5.3: Epstein–​Barr  virus B.K. Rima Wellcome-​Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK 8.5.5: Mumps: Epidemic parotitis David J. Roberts Radcliffe Department of Medicine, University of Oxford; Department of Haematology, Oxford University Hospitals NHS Trust and NHS Blood and Transplant, Oxford, UK 22.6.3: Anaemia as a challenge to world health Harold R. Roberts Sarah Graham Kenan Professor of Medicine, Division of Hematology-​Oncology, University of North Carolina, Chapel Hill, NC, USA 22.7.1: The biology of haemostasis and thrombosis Irene Roberts Department of Paediatrics and MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK 22.5.1: Inherited bone marrow failure syndromes Douglas Robertson Senior Lecturer and Honorary Consultant in Restorative Dentistry, University of Glasgow, Glasgow, UK 15.6: The mouth and salivary glands Marcus Robertson Gastroenterologist and Hepatologist, Monash Health, Vic, Australia; Monash University Department of Medicine, Vic, Australia 15.22.3: Portal hypertension and variceal bleeding Esther Robinson Public Health England, Birmingham, UK 8.6.13: Haemophilus influenzae T.A. Rockall Professor of Colorectal Surgery, University of Surrey; Consultant Colorectal Surgeon, Royal Surrey County Hospital Guildford, UK 15.4.2: Gastrointestinal bleeding Edward Roddy Keele University, Keele, UK 19.10: Crystal-​related arthropathies Simon D. Roger Renal Physician, Conjoint Professor, School of Medicine and Public Health, University of Newcastle, Newcastle; Director, Department of Renal Medicine, Central Coast Local Health District, Gosford, NSW, Australia 21.9.1: Acute interstitial nephritis

lxi

lxii

Contributors

Jean-​Marc Rolain IHU Méditerranée Infection,

Marseille, France 8.6.43: Bartonellas excluding B. bacilliformis Pierre Ronco Professor of Renal Medicine, University Pierre et Marie Curie, and Inserm Unit UMR_​S1155, Tenon Hospital, Paris, France 21.10.5: Renal involvement in plasma cell dyscrasias, immunoglobulin-​based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias Antony Rosen Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 4.6: Autoimmunity Jonathan D.C. Ross University Hospitals Birmingham NHS Trust, Birmingham, UK 9.8: Pelvic inflammatory disease Shannan Lee Rossi Department of Pathology, Center for Biodefense and Emerging Infectious Diseases; Member, Center for Tropical Diseases, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA 8.5.14: Flaviviruses excluding dengue Peter M. Rothwell Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 24.10.1 Stroke: Cerebrovascular disease Simon M. Rushbrook Department of Hepatology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, UK 15.24.6: Primary and secondary liver tumours Nigel Russell Professor of Haematology, Nottingham University, Nottingham, UK 22.3.3: Acute myeloid leukaemia Fiona Ryan Oxford Childrens Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK 13.7.2: Normal puberty and its disorders Nikant Sabharwal Department of Cardiology, John Radcliffe Hospital, Oxford, UK 16.3.3: Cardiac investigations: Nuclear, MRI, and CT Alan D. Salama University College London, London, UK 21.8.5: Proliferative glomerulonephritis Moin Saleem Professor of Paediatric Renal Medicine, University of Bristol Children’s Renal Unit, Bristol Royal Hospital for Children, Bristol, UK 21.8.3: Minimal change nephropathy and focal segmental glomerulosclerosis Hesham A. Saleh Charing Cross Hospital and Royal Brompton Hospital, London; Imperial College London, London, UK 18.6: Allergic rhinitis Susan Salt Trinity Hospice, Blackpool, UK 7.1: Introduction to palliative care Nilesh J. Samani Department of Cardiovascular Sciences, University of Leicester, Leicester, UK 16.17.4: Mendelian disorders causing hypertension Luis G. Sambo University Nova de Lisboa, Lisbon, Portugal 2.16: Financing healthcare in low-​income developing countries: A challenge for equity in health David S. Sanders Royal Hallamshire Hospital and University of Sheffield, Sheffield, UK 15.10.3: Coeliac disease

Jeremy Sanderson Department of Gastroenterology,

Guy’s and St Thomas’ NHS Foundation Trust, London, UK 15.12: Ulcerative colitis Vijay G. Sankaran Associate Professor of Pediatrics, Harvard Medical School, Division of Hematology/​Oncology, Boston Children’s Hospital, Dana-​Farber/​Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USA 22.6.1: Erythropoiesis Swati Sathe Rutgers New Jersey Medical School, Newark, NJ, USA 24.17: Inherited neurodegenerative diseases Brian P. Saunders Consultant Gastroenterologist, St Mark’s Hospital, North West London Hospitals Trust; Adjunct Professor of Endoscopy, Imperial College London, London, UK 15.3.1: Colonoscopy and flexible sigmoidoscopy Kate E.A. Saunders University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK 26.3.2: Self-​harm; 26.5.7: Bipolar disorder Rana Sayeed Oxford Heart Centre, Oxford University Hospitals NHS Trust, Oxford, UK 16.13.6: Coronary artery bypass and valve surgery John A. Sayer Institute Of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, UK 21.15: The renal tubular acidoses Claire Scampion Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK 6.11: Promotion of dignity in the life and death of older patients Matthew Scarborough Oxford University Hospitals NHS Foundation Trust, Oxford, UK; University of Oxford, Oxford, UK 8.2.3: Nosocomial infections Klaus P. Schaal Institute for Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn, Bonn, Germany 8.6.30: Actinomycoses Michael L. Schilsky Associate Professor of Medicine, Medical Director, Adult Liver Transplant, Yale-​New Haven Transplantation Center, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA 12.7.2: Inherited diseases of copper metabolism: Wilson’s disease and Menkes’ disease Jonathan M. Schott Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK 24.4.2: Alzheimer’s disease and other dementias Heinz-​Peter Schultheiss Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany 16.7.1: Myocarditis Jane Schwebke University of Alabama at Birmingham, AL, USA 8.8.14: Trichomoniasis Neil Scolding University of Bristol Institute of Clinical Neurosciences, Southmead Hospital, Bristol, UK 24.21: Acquired metabolic disorders and the nervous system; 24.22: Neurological complications of systemic disease

Anthony Scott KEMRI-​Wellcome Trust Research

Programme, Kilifi, Kenya; London School of Hygiene and Tropical Medicine, London, UK 8.6.3: Pneumococcal infections James Scott Imperial College London, London, UK 12.6: Lipid disorders Rebecca Scott Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK 15.9.1: Hormones and the gastrointestinal tract Mårten Segelmark Professor of Nephrology, Department of Clinical Sciences, Lund University and Department of Nephrology Skane University Hospital, Lund, Sweden 21.8.7: Antiglomerular basement membrane disease Julian Seifter Associate Professor of Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, USA 12.11: A physiological approach to acid–base disorders: The roles of ion transport and body fluid compartments Bhuvaneish T. Selvaraj University of Edinburgh, Edinburgh, UK 3.7: Stem cells and regenerative medicine Amartya Sen Harvard University, Cambridge, MA, USA 2.20: Human disasters Arjune Sen Oxford Epilepsy Research Group, NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK 24.5.1: Epilepsy in later childhood and adulthood Debasish Sen Occupational Medicine, University of Manchester, UK 10.2.1: Occupational and environmental health Nicholas J. Severs National Heart and Lung Institute (NHLI) Division, Faculty of Medicine, Imperial College London, London, UK 16.1.2: Cardiac physiology Pallav L. Shah Imperial College London, London, UK 18.1.1: The upper respiratory tract; 18.1.2: Airways and alveoli; 18.3.3: Bronchoscopy, thoracoscopy, and tissue biopsy Muddassir Shaikh James Cook University Hospital, Middlesbrough, UK 19.7: Infection and arthritis Alena Shantsila University of Liverpool, Liverpool, UK 16.17.5: Hypertensive urgencies and emergencies Susie Shapiro Consultant Haematologist, Oxford University Hospitals NHS Foundation Trust, Oxford Haemophilia and Thrombosis Centre, Churchill Hospital, Oxford, UK 22.7.3: Thrombocytopenia and disorders of platelet function Claire C. Sharpe Professor of Renal Medicine, Faculty of Life Sciences and Medicine, King’s College London, London, UK 21.10.7: Sickle cell disease and the kidney

Contributors

Michael Sharpe Psychological Medicine Research,

University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK 26.1: General introduction; 26.2: The psychiatric assessment of the medical patient; 26.3.3: Medically unexplained symptoms; 26.4.2: Psychological treatments; 26.5.12: Somatic symptom and related disorders; 26.7: Psychiatry, liaison psychiatry, and psychological medicine Pamela J. Shaw Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield; Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK 24.15: The motor neuron diseases Debbie L. Shawcross Professor of Hepatology and Chronic Liver Failure, Institute of Liver Studies, Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, UK 15.22.4: Hepatic encephalopathy Bart Sheehan Oxford University Hospitals NHS Foundation Trust, Oxford, UK 26.3.1: Confusion; 26.5.1: Delirium; 26.5.2: Dementia Neil Sheerin Professor of Nephrology, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK 21.13: Urinary tract infection Mark Sherlock General Medicine and Emergency Medicine, NHS, UK; Médecins Sans Frontières (MSF), Paris, France 13.5.1: Disorders of the adrenal cortex Jackie Sherrard Wycombe General Hospital, High Wycombe, UK 8.6.6: Neisseria gonorrhoeae; 9.3: Sexual history and examination M.A. Shikanai-​Yasuda Faculdade Medicina, University of São Paulo (FMUSP), Brazil 8.7.4: Paracoccidioidomycosis Brian Shine Oxford University Hospitals NHS Foundation Trust, Oxford, UK 29.1: The use of biochemical analysis for diagnosis and management John M. Shneerson Papworth Hospital, Papworth Everard, UK 18.18: Disorders of the thoracic cage and diaphragm Volha Shpadaruk Department of Dermatology, University Hospitals of Leicester NHS Trust, Leicester, UK 23.7: Cutaneous vasculitis, connective tissue diseases, and urticaria Joachim Sieper Free University, Berlin, Germany 19.6: Spondyloarthritis and related conditions Udomsak Silachamroon Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand 8.11.3: Lung flukes (paragonimiasis) Leslie Silberstein Director, Transfusion Medicine, Boston Children’s Hospital, Boston, MA, USA 22.6.12: Acquired haemolytic anaemia Jorge Simões University Nova de Lisboa, Lisbon, Portugal 2.16: Financing healthcare in low-​income developing countries: A challenge for equity in health †

Alexandra Sinclair Institute of Metabolism and

Systems Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, The Medical School, University of Birmingham, Birmingham, UK 24.10.5: Idiopathic intracranial hypertension Rod Sinclair Department of Dermatology, University of Melbourne, Melbourne, Vic, Australia; Epworth Healthcare, Sinclair Dermatology Investigational Research, Education and Clinical Trials, East Melbourne, Vic, Australia 23.17: Management of skin disease Joseph Sinning Regional Cancer Care Associates, Hartford, CT, USA 22.3.1: Granulocytes in health and disease Thira Sirisanthana Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand 8.7.6: Talaromyces (Penicillium) marneffei infection J.G.P. Sissons† University of Cambridge School of Clinical Medicine, Cambridge, UK 8.5.2: Herpesviruses (excluding Epstein–​Barr  virus) Paiboon Sithithaworn Professor, Cholangiocarcinoma Research Institute (CARI), Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Thailand; Professor Parasitology, Department of Parasitology, Faculty of Medicine, Khon Kaen University, Thailand 8.11.2: Liver fluke infections James R.A. Skipworth Consultant HPB and General Surgeon, Bristol Royal Infirmary, University Hospitals Bristol NHS Trust, Bristol, UK 15.26.3: Tumours of the pancreas Geoffrey L. Smith University of Cambridge, Cambridge, UK 8.5.4: Poxviruses Roger Smyth Department of Psychological Medicine, Edinburgh Royal Infirmary, Edinburgh, UK 26.2: The psychiatric assessment of the medical patient Rosamund Snow† BMJ, Tavistock Square, London, UK 1.3: What patients wish you understood E.L. Snyder Professor, Laboratory Medicine, Yale University Medical School; Director, Transfusion/​ Apheresis/​Tissue/​Cell Processing Services, Yale-​New Haven Hospital, New Haven, CT, USA 22.8.1: Blood transfusion Jasmeet Soar Intensive Care Unit, Southmead Hospital, North Bristol NHS Trust, Bristol, UK 17.2: Cardiac arrest May Ching Soh Silver Star Unit, Women’s Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, UK 14.14: Autoimmune rheumatic disorders and vasculitis in pregnancy Elisaveta Sokolov Kings College Hospital, London, UK 24.7.2: Parkinsonism and other extrapyramidal diseases Tom Solomon Institute of Infection and Global Health, University of Liverpool, Liverpool, UK 24.11.2: Viral infections

Krishna Somers Royal Perth Hospital, Perth, WA,

Australia 16.9.4: Cardiovascular syphilis Danielle Southerst NYU Langone Health, New York, NY, USA 19.4: Back pain and regional disorders Cathy Speed Consultant in Rheumatology, Sport and Exercise Medicine, Senior Physician, English Institute of Sport, Cambridge Centre for Health and Performance, Cambridge, UK 28.1: Sport and exercise medicine Des Spence Barclay Medical Centre, Maryhill Health Centre, Glasgow, UK 1.4: Why do patients attend and what do they want from the consultation? G.P. Spickett Regional Department of Immunology, Royal Victoria Infirmary, Newcastle upon Tyne, UK 18.14.1: Diffuse alveolar haemorrhage; 18.14.2: Eosinophilic pneumonia; 18.14.4: Hypersensitivity pneumonitis S.G. Spiro University College Hospital, London, UK 18.19.1: Lung cancer; 18.19.2: Pulmonary metastases David P. Steensma Institute Physician, Division of Hematologic Malignancies, Department of Medical Oncology, Dana-​Farber Cancer Institute; Associate Professor of Medicine, Harvard Medical School, Boston, MA, USA 22.3.2: Myelodysplastic syndromes Jerry L. Spivak Hematology Division, Johns Hopkins University School of Medicine, Baltimore, MD, USA 22.3.7: Primary myelofibrosis Charles L. Sprung Department of Anesthesiology, Critical Care Medicine and Pain Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Faculty of Medicine, Jerusalem, Israel 17.10: Palliative and end-​of-​life care in the ICU Paweł Stankiewicz Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA 3.2: The genomic basis of medicine Natalie Staplin Clinical Trial Service Unit, University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials Paul D. Stein Professor, Department of Osteopathic Medical Specialties, College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA 16.16.1: Deep venous thrombosis and pulmonary embolism Chris Stenton Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK 18.14.11: Toxic gases and aerosols Dennis L. Stevens Infectious Diseases Section, VA Medical Center, Boise, ID, USA 8.6.2: Streptococci and enterococci; 8.6.25: Botulism, gas gangrene, and clostridial gastrointestinal infections Claire Steves King’s College London, London, UK 6.1: Ageing and clinical medicine

It is with great regret that we report that J.G.P. Sissons died on 25 September, 2016 and Rosamund Snow died on 2 February, 2017.

lxiii

lxiv

Contributors

Carmel B. Stober University of Cambridge,

Cambridge, UK 19.8: Reactive arthritis Nicole Stoesser Nuffield Department of Medicine Medical Sciences Division, University of Oxford, Oxford, UK 8.6.10: Intracellular klebsiella infections (donovanosis and rhinoscleroma) John R. Stradling Oxford Centre for Respiratory Medicine, John Radcliffe Hospital, Oxford, UK 18.1.1: The upper respiratory tract Michael A. Stroud Department of Medicine, University of Southampton, Southampton, UK 10.3.2: Heat; 10.3.3: Cold Michael Strupp Ludwig Maximilians University, Munich, Germany 24.6.2: Eye movements and balance Matthew J. Stuckey School of Veterinary Medicine, University of California, CA, USA 8.6.43: Bartonellas excluding B. bacilliformis Peter H. Sugden National Heart and Lung Institute (NHLI) Division, Faculty of Medicine, Imperial College London, UK 16.1.2: Cardiac physiology Mehrunisha Suleman Ethox Centre, Oxford, UK 1.5: Medical ethics Joseph Sung Professor of Medicine, lately President and Vice Chancellor, The Chinese University of Hong Kong, Shatin, Hong Kong, China 15.8: Peptic ulcer disease Khuanchai Supparatpinyo Division of Infectious Diseases, Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand 8.7.6: Talaromyces (Penicillium) marneffei infection Erik R. Swenson VA Puget Sound Health Care System, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA, USA 10.3.6: Diseases of high terrestrial altitudes Anthony Swerdlow The Institute of Cancer Research, University of London, London, UK 5.1: Epidemiology of cancer David Taggart University of Oxford, Oxford, UK 16.13.6: Coronary artery bypass and valve surgery Kathy Taghipour The Whittington Health NHS Trust, London, UK 23.4: Autoimmune bullous diseases Penelope Talelli Homerton University Hospitals NHS Trust, UK 24.7.1: Subcortical structures: The cerebellum, basal ganglia, and thalamus Paolo Tammaro Associate Professor, Department of Pharmacology, University of Oxford, Oxford, UK 3.4: Ion channels and disease C.T. Tan University of Malaya, Kuala Lumpur, Malaysia 8.5.7: Nipah and Hendra virus encephalitides

Chen Sabrina Tan Harvard Medical School, Boston,

MA, USA 8.5.19: Papillomaviruses and polyomaviruses T.M. Tan Consultant in Diabetes, Endocrinology, and Metabolic Medicine, Imperial College London, London, UK 13.8: Pancreatic endocrine disorders and multiple endocrine neoplasia; 15.9.1: Hormones and the gastrointestinal tract; 15.9.2: Carcinoid syndrome David Taylor-​Robinson Section of Retrovirology and GU Medicine, Department of Infectious Diseases, Wright-​Fleming Institute, Faculty of Medicine, Imperial College London, London, UK 8.6.45: Chlamydial infections; 8.6.46: Mycoplasmas F. Teo National University Hospital, National University Health System, Singapore, China 18.11.1: Diffuse parenchymal lung disease: An introduction R.V. Thakker Academic Endocrine Unit, University of Oxford, OCDEM, Churchill Hospital, Oxford, UK 13.4: Parathyroid disorders and diseases altering calcium metabolism Nishanthi Thalayasingam Faculty of Medical Sciences, Newcastle University and Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 2.7: Biological therapies for immune, inflammatory, and allergic diseases Richard J. Thompson Professor of Molecular Hepatology, Institute of Liver Studies, King’s College London, London, UK 15.24.7: Liver and biliary diseases in infancy and childhood S.A. Thorne University Hospital, Birmingham, UK 16.12: Congenital heart disease in the adult Guy E. Thwaites Oxford University Clinical Research Unit (OUCRU), Ho Chi Minh City, Vietnam 24.11.1: Bacterial infections C. Louise Thwaites Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK 8.6.23: Tetanus Adam D. Timmis Barts Heart Centre, Queen Mary University London, London, UK 16.13.3: Management of stable angina Stephen M. Tollman University of the Witwatersrand, Johannesburg, South Africa; MRC/​Wits Rural Public Health and Health Transitions Research Unit, School of Public Health, Faculty of Health Sciences; INDEPTH Network (International Network for the Demographic Evaluation of Populations and Their Health), Accra, Ghana, South Africa; Centre for Global Health Research, Umeå University, Sweden 2.18: Fostering medical and health research in resource-​constrained countries Maciej Tomaszewski Division of Cardiovascular Sciences, University of Manchester, Manchester, UK 16.17.4: Mendelian disorders causing hypertension

Charles Tomson Consultant Nephrologist,

Freeman Hospital, Newcastle upon Tyne, UK 21.13: Urinary tract infection Pat Tookey Honorary Associate Professor, Population, Policy and Practice Research and Teaching Department, University College London Institute of Child Health, London, UK 8.5.13: Rubella Peter Topham Consultant Nephrologist, John Walls Renal Unit, University Hospitals of Leicester NHS Trust, Leicester, UK 21.8.2: Thin membrane nephropathy Nicholas Torpey Consultant Physician and Nephrologist, Cambridge University Hospitals, Cambridge, UK 21.7.3: Renal transplantation Thomas A. Traill Division of Cardiology, Johns Hopkins Hospital, Baltimore, MD, USA 16.10: Tumours of the heart; 16.11: Cardiac involvement in genetic disease A.S. Truswell University of Sydney, Sydney, NSW, Australia 11.5: Diseases of affluent societies and the need for dietary change Steven Tsui Consultant Cardiac Surgeon, Royal Papworth Hospital, Cambridge, UK 16.5.5: Cardiac transplantation and mechanical circulatory support Youyou Tu Professor, Department of Chemistry, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China 2.8: Traditional medicine exemplified by traditional Chinese medicine D.M. Turnbull Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK 24.19.5: Mitochondrial disease A. Neil Turner Professor of Nephrology, University of Edinburgh, Queen’s Medical Research Institute (CIR), Edinburgh, UK 21.10.8: Infection-​associated nephropathies; 21.10.9: Malignancy-​associated renal disease Tabitha Turner-​Stokes MRC Clinical Research Fellow, Centre for Inflammatory Disease, Department of Medicine, Imperial College London, London, UK 21.8.6: Membranoproliferative glomerulonephritis Holm H. Uhlig Translational Gastroenterology Unit and Department of Paediatrics, University of Oxford, John Radcliffe Hospital, Oxford, UK 15.15: Congenital abnormalities of the gastrointestinal tract Magnus Unemo WHO Collaborating Centre for Gonorrhoea and other STIs, Örebro University Hospital, Örebro, Sweden 8.6.6: Neisseria gonorrhoeae; 8.6.45 Chlamydial infections Robert Unwin Department of Renal Medicine, University College London, London, UK 21.1: Structure and function of the kidney

Contributors

John A. Vale National Poisons Information Service

(Birmingham Unit) and West Midlands Poisons Unit; City Hospital, Birmingham; School of Biosciences, University of Birmingham, Birmingham, UK 10.4.1: Poisoning by drugs and chemicals Patrick Vallance GlaxoSmithKline, London, UK 16.1.1: Blood vessels and the endothelium Greet Van den Berghe Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven University, B-​3000 Leuven, Belgium 17.9: Metabolic and endocrine changes in acute and chronic critical illness Steven Vanderschueren Leuven Research Department of Microbiology, Immunology and Transplantation, Laboratory for Clinical Infectious and Inflammatory Disorders, Clinical Department of General Internal Medicine, University Hospital Leuven, B-​3000 Leuven, Belgium 8.2.2: Fever of unknown origin Sirivan Vanijanonta Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand 8.11.3: Lung flukes (paragonimiasis) Anita Vas-​Falcao London School of Hygiene and Tropical Medicine, London, UK 9.1: Epidemiology of sexually transmitted infections Nikos Vasilakis Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, Center for Tropical Diseases, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA 8.5.14: Flaviviruses excluding dengue Diana Vassallo Specialist Registrar, Department of Renal Medicine, Salford Royal NHS Foundation Trust, Salford, UK 21.10.10: Atherosclerotic renovascular disease Birgitte Vennervald Section for Parasitology and Aquatic Diseases, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 8.11.1: Schistosomiasis Vanessa Venning Department of Dermatology, Churchill Hospital, Oxford, UK 23.2: Clinical approach to the diagnosis of skin disease Anilrudh A. Venugopal Los Angeles, CA, USA 8.6.11: Anaerobic bacteria Kristien Verdonck Institute of Tropical Medicine, Antwerp, Belgium 8.5.25: HTLV-​1, HTLV-​2, and associated diseases Christopher M. Verity Addenbrookes Hospital, Cambridge, UK 24.20: Developmental abnormalities of the central nervous system Benjamin A. Vervaet Laboratory of Pathophysiology, University of Antwerp, Antwerp, Belgium 21.9.2: Chronic tubulointerstitial nephritis †

Diego Viasus Division of Health Sciences, Faculty of

Medicine, Universidad del Norte, Barranquilla, Colombia 8.6.39: Legionellosis and Legionnaires’ disease Angela Vincent Hon Cons Immunology, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK 24.24: Autoimmune encephalitis and Morvan’s syndrome Raphael P. Viscidi Johns Hopkins Medical Institution, Baltimore, MD, USA 8.5.19: Papillomaviruses and polyomaviruses H. Josef Vormoor Clinical Director, Department of Hemato-​oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands 22.4.2: Acute lymphoblastic leukaemia Theo Vos University of Washington, WA, USA 2.3: The Global Burden of Disease: Measuring the health of populations Henry J.C. de Vries Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands 9.7: Anogenital lumps and bumps Paresh Vyas Professor of Haematology, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford; Consultant Haematologist, Department of Haematology, Cancer and Haematology Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK 22.2.1: Cellular and molecular basis of haematopoiesis Peter D. Wagner Division of Physiology at the Department of Medicine, University of California San Diego, CA, USA 18.1.2: Airways and alveoli Nicholas Wald Institute of Health Informatics, University College London, London; Population Health Research Institute, St George’s University of London, London; Division of Medical Screening and Special Testing, Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School of Brown University, Rhode Island, USA 2.12: Medical screening Herman Waldmann Sir William Dunn School of Pathology, University of Oxford, Oxford, UK 3.8: The evolution of therapeutic antibodies Jane Walker Psychological Medicine Research, University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK 26.2: The psychiatric assessment of the medical patient; 26.3.4: Low mood Matthew C. Walker National Hospital of Neurology and Neurosurgery and UCL Institute of Neurology, Queen Square, London, UK 24.5.2: Narcolepsy Elizabeth Wallin Transplant Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK 4.7: Principles of transplantation immunology Sarah Walsh King’s College Hospital, London, UK 23.16: Cutaneous reactions to drugs

T.E. Warkentin Professor, Department of Pathology and

Molecular Medicine and Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada 22.7.5: Acquired coagulation disorders David A. Warrell Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK 8.5.10: Rhabdoviruses: Rabies and rabies-​related lyssaviruses; 8.5.11: Colorado tick fever and other arthropod-​borne reoviruses; 8.5.27: Orf and Milker’s nodule; 8.5.28: Molluscum contagiosum; 8.6.34: Relapsing fevers; 8.13: Pentastomiasis (porocephalosis, linguatulosis/​linguatuliasis, or tongue worm infection); 10.4.2: Injuries, envenoming, poisoning, and allergic reactions caused by animals; 10.4.3: Poisonous fungi; 24.11.2: Viral infections Mary J. Warrell Oxford Vaccine Group, University of Oxford, Oxford, UK 8.5.10: Rhabdoviruses: Rabies and rabies-​related lyssaviruses; 8.5.11: Colorado tick fever and other arthropod-​borne reoviruses John A.H. Wass University of Oxford, Oxford, UK 13.2.1: Disorders of the anterior pituitary gland; 13.2.2: Disorders of the posterior pituitary gland; 13.10: Hormonal manifestations of non-​endocrine disease Lawrence Waterman Loughborough University, Loughborough, UK; Park Health and Safety Partnership, Aylesbury, UK 10.2.2: Occupational safety Laurence Watkins The National Hospital for Neurology and Neurosurgery, London, UK 24.10.3: Traumatic brain injury Peter Watkinson Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 8.1.2: Clinical features and general management of patients with severe infections Richard A. Watts Department of Rheumatology, Ipswich Hospital, Ipswich; Norwich Medical School, University of East Anglia, Norwich, UK 19.11.9: Small vessel vasculitis Richard W.E. Watts† Division of Inherited Metabolic Diseases, Northwick Park Hospital, London, UK 12.1: The inborn errors of metabolism: general aspects; 12.4: Disorders of purine and pyrimidine metabolism David J. Weatherall† Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK 22.6.2: Anaemia: Pathophysiology, classification, and clinical features; 22.6.3: Anaemia as a challenge to world health; 22.6.7: Disorders of the synthesis or function of haemoglobin G.J. Webb Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK 15.23.2: Autoimmune hepatitis Lisa J. Webber St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK 13.6.1: Ovarian disorders George J. Webster Consultant Hepatologist and Gastroenterologist, University College Hospital and Royal Free Hospital, London, UK 15.3.2: Upper gastrointestinal endoscopy

It is with great regret that we report that Richard W.E. Watts died on 11 February, 2018 and David J. Weatherall died on 8 December, 2018.

lxv

lxvi

Contributors

Anthony P. Weetman University of Sheffield,

Sheffield, UK 13.3.1: The thyroid gland and disorders of thyroid function; 13.3.2: Thyroid cancer Robert A. Weinstein Rush University, Chicago, IL, USA 8.6.4: Staphylococci Louis M. Weiss Department of Pathology, Division of Parasitology and Tropical Medicine; Department of Medicine, Division of Infectious Diseases, Albert Einstein College of Medicine, Bronx, NY, USA 8.7.7: Microsporidiosis; 8.8.7: Cystoisosporiasis Robin A. Weiss University College London, London, UK 8.5.26: Viruses and cancer Peter F. Weller William Bosworth Castle Professor of Medicine, Harvard Medical School, Boston; Chief of the Infectious Diseases and the Allergy and Inflammation Divisions, Beth Israel Deaconess Medical Center, Boston, MD, USA 22.3.8: Eosinophilia A.U. Wells Interstitial Lung Disease Unit, Royal Brompton Hospital, London, UK 18.11.1: Diffuse parenchymal lung disease: An introduction; 18.11.2: Idiopathic pulmonary fibrosis; 18.11.3: Bronchiolitis obliterans and cryptogenic organizing pneumonia; 18.11.4: The lung in autoimmune rheumatic disorders; 18.11.5: The lung in vasculitis Simon Wessely Department of Psychological Medicine, King’s College London, London, UK 26.4.2: Psychological treatments Gilbert C. White, II Aster Chair for Medical Research, Executive Vice President for Research, Director, Blood Research Institute, Versiti; Professor of Medicine, Biochemistry, and Pharmacology, Associate Dean for Research, Medical College of Wisconsin, Milwaukee, WI, USA 22.7.1: The biology of haemostasis and thrombosis Nicholas J. White Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK 8.8.2: Malaria Hilton C. Whittle Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK 8.5.6: Measles Anthony S. Wierzbicki Department of Metabolic Medicine/​Chemical Pathology, Guy’s and St Thomas’ Hospitals, London, UK 12.9: Disorders of peroxisomal metabolism in adults Mark H. Wilcox Professor of Medical Microbiology, Microbiology, Old Medical School, Leeds General Infirmary, and University of Leeds, Leeds, UK 8.6.24: Clostridium difficile Kate Wiles Department of Women and Children’s Health, King’s College London, London, UK 14.5: Renal disease in pregnancy James S. Wiley Principal Research Fellow, Florey Institute of Neuroscience, and Mental Health Honorary Professor, University of Melbourne, Melbourne, Vic, Australia 22.6.8: Anaemias resulting from defective maturation of red cells

R.G. Will Professor of Clinical Neurology,

Department of Clinical Neurosciences, University of Edinburgh, Edinburgh, UK 24.11.5: Human prion diseases Lisa Willcocks Consultant Physician and Nephrologist, Cambridge University Hospitals, Cambridge, UK 21.8.3: Minimal change nephropathy and focal segmental glomerulosclerosis Bryan Williams University College London, London, UK 16.17.1: Essential hypertension: Definition, epidemiology, and pathophysiology; 16.17.2: Essential hypertension: Diagnosis, assessment, and treatment David J. Williams Obstetric Physician, Institute for Women’s Health, University College London Hospital, London, UK 14.1: Physiological changes of normal pregnancy; 14.2: Nutrition in pregnancy; 14.3: Medical management of normal pregnancy Catherine Williamson Professor of Women’s Health, King’s College London and Honorary Consultant in Obstetric Medicine, St Thomas’ and King’s College Hospitals, London, UK 14.9: Liver and gastrointestinal diseases of pregnancy Bridget Wills Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam 8.5.15: Dengue; 24.11.2: Viral infections R. Wilson Royal Brompton and Harefield NHS Trust, London, UK 18.9: Bronchiectasis Greg Winter MRC Laboratory of Molecular Biology, Cambridge, UK 3.8: The evolution of therapeutic antibodies Miles Witham AGE Research Group, NIHR Newcastle Biomedical Research Centre, Newcastle University and Newcastle upon Tyne Hospitals Trust, Newcastle upon Tyne, UK 6.7: Drugs and prescribing in the older patient Fenella Wojnarowska Nuffield Department of Medicine, University of Oxford, Oxford, UK 14.13: The skin in pregnancy; 23.4: Autoimmune bullous diseases Edwin K.S. Wong Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK 21.10.6: Haemolytic uraemic syndrome James L.N. Wood University of Cambridge, Cambridge, UK 8.1.1: Biology of pathogenic microorganisms Jonathan Wood Substance Misuse Psychiatry, Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK 26.5.4: Alcohol misuse Kathryn J. Wood Transplant Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK 4.7: Principles of transplantation immunology Nicholas Wood University College London, London, UK 24.7.4: Ataxic disorders

Andrew F. Woodhouse Department of Infection

and Tropical Medicine, Birmingham Heartlands Hospital, Birmingham, UK 8.6.32: Rat bite fevers (Streptobacillus moniliformis and Spirillum minus infection) Jeremy Woodward Cambridge Intestinal Failure and Transplant Unit, Addenbrooke’s Hospital, Cambridge, UK 11.7: Artificial nutrition support; 15.2: Symptoms of gastrointestinal disease Elaine M. Worcester Professor of Medicine, Nephrology Section, Department of Medicine, University of Chicago, Chicago, USA 21.14: Disorders of renal calcium handling, urinary stones, and nephrocalcinosis B. Paul Wordsworth Emeritus Professor of Clinical Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, Nuffield Orthopaedic Centre, Headington, Oxford, UK 20.1: Skeletal disorders—​general approach and clinical conditions Gary P. Wormser New York Medical College, NY, USA 8.6.33: Lyme borreliosis Mark Wright Consultant Gastroenterologist, University Hospital Southampton, Southampton, UK 15.25: Diseases of the gallbladder and biliary tree Channa Jayasumana Faculty of Medicine, Rajatrata University of Sri Lanka, Anuradhapura, Sri Lanka 21.9.2: Chronic tubulointerstitial nephritis Muhammad M. Yaqoob Barts Health NHS Trust, Renal Unit, Royal London Hospital, London, UK 21.17: Urinary tract obstruction Hasan Yazici Department of Medicine (Rheumatology), Academic Hospital, Istanbul, Turkey 19.11.10: Behçet’s syndrome Lam Minh Yen Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam 8.6.23: Tetanus Duncan Young Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 8.1.2: Clinical features and general management of patients with severe infections Katherine Younger School of Biological and Health Sciences, Technological University Dublin, Dublin, Ireland 11.3: Minerals and trace elements Sebahattin Yurdakul Division of Rheumatology, Department of Medicine, Cerrahpasa Medical Faculty, University of Istanbul, Istanbul, Turkey 19.11.10: Behçet’s syndrome Alberto Zanella Oncohematology Unit—​ Pathophysiology of Anemias Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore, Milan, Italy 22.6.10: Erythrocyte enzymopathies Adam Zeman Professor of Cognitive and Behavioural Neurology, University of Exeter Medical School, Exeter, UK 24.2: Mind and brain: Building bridges between neurology, psychiatry, and psychology Clive S. Zent University of Rochester Medical Center, Rochester, NY, USA 22.4.5: Chronic lymphocytic leukaemia

SECTION 22

Haematological disorders Section editors: Chris Hatton and Deborah Hay

22.1 Introduction to haematology  5169 Chris Hatton 22.2 Haemopoiesis  5172 22.2.1 Cellular and molecular basis of haematopoiesis  5172 Paresh Vyas and N. Asger Jakobsen 22.2.2 Diagnostic techniques in the assessment of haematological malignancies  5181 Wendy N. Erber 22.3 Myeloid disease  5189 22.3.1 Granulocytes in health and disease  5189 Joseph Sinning and Nancy Berliner 22.3.2 Myelodysplastic syndromes  5197 Charlotte K. Brierley and David P. Steensma 22.3.3 Acute myeloid leukaemia  5205 Nigel Russell and Alan Burnett 22.3.4 Chronic myeloid leukaemia  5213 Mhairi Copland and Tessa L. Holyoake 22.3.5 The polycythaemias  5227 Daniel Aruch and Ronald Hoffman 22.3.6 Thrombocytosis and essential thrombocythaemia  5239 Daniel Aruch and Ronald Hoffman 22.3.7 Primary myelofibrosis  5247 Evan M. Braunstein and Jerry L. Spivak 22.3.8 Eosinophilia  5254 Peter F. Weller 22.3.9 Histiocytosis  5259 Chris Hatton 22.4 Lymphoid disease  5263 22.4.1 Introduction to lymphopoiesis  5263 Caron A. Jacobson and Nancy Berliner 22.4.2 Acute lymphoblastic leukaemia  5269 H. Josef Vormoor, Tobias F. Menne, and Anthony V. Moorman 22.4.3 Hodgkin lymphoma  5280 Vijaya Raj Bhatt and James O. Armitage

22.4.4 Non-​Hodgkin lymphoma  5288

Vijaya Raj Bhatt and James O. Armitage 22.4.5 Chronic lymphocytic leukaemia  5302

Clive S. Zent and Aaron Polliack 22.4.6 Plasma cell myeloma and related monoclonal gammopathies  5310

S. Vincent Rajkumar and Robert A. Kyle

22.5 Bone marrow failure  5325 22.5.1 Inherited bone marrow failure syndromes  5325 Irene Roberts and Inderjeet S. Dokal 22.5.2 Acquired aplastic anaemia and pure red cell aplasia  5336 Judith C.W. Marsh, Shreyans Gandhi, and Ghulam J. Mufti 22.5.3 Paroxysmal nocturnal haemoglobinuria  5348 Lucio Luzzatto 22.6 Erythroid disorders  5354 22.6.1 Erythropoiesis  5354 Vijay G. Sankaran 22.6.2 Anaemia: pathophysiology, classification, and clinical features  5359 David J. Weatherall and Chris Hatton 22.6.3 Anaemia as a challenge to world health  5366 David J. Roberts and David J. Weatherall 22.6.4 Iron metabolism and its disorders  5371 Timothy M. Cox and John B. Porter 22.6.5 Anaemia of inflammation  5402 Sant-​Rayn Pasricha and Hal Drakesmith 22.6.6 Megaloblastic anaemia and miscellaneous deficiency anaemias  5407 A.V. Hoffbrand 22.6.7 Disorders of the synthesis or function of haemoglobin  5426 Deborah Hay and David J. Weatherall 22.6.8 Anaemias resulting from defective maturation of red cells  5450 Stephen J. Fuller and James S. Wiley

SECTION 22  Haematological disorders

22.6.9 Disorders of the red cell membrane  5456

Patrick G. Gallagher 22.6.10 Erythrocyte enzymopathies  5463

Alberto Zanella and Paola Bianchi 22.6.11 Glucose-​6-​phosphate dehydrogenase deficiency  5472

Lucio Luzzatto 22.6.12 Acquired haemolytic anaemia  5479

Amy Powers and Leslie Silberstein

22.7 Haemostasis  5490 22.7.1 The biology of haemostasis and thrombosis  5490 Gilbert C. White, II, Harold R. Roberts, and Nigel S. Key 22.7.2 Evaluation of the patient with a bleeding tendency  5509 Trevor Baglin

22.7.3 Thrombocytopenia and disorders of platelet function  5520

Nicola Curry and Susie Shapiro 22.7.4 Genetic disorders of coagulation  5532

Eleanor S. Pollak and Katherine A. High 22.7.5 Acquired coagulation disorders  5546

T.E. Warkentin

22.8 Transfusion and transplantation  5563 22.8.1 Blood transfusion  5563 D.S. Giovanniello and E.L. Snyder 22.8.2 Haemopoietic stem cell transplantation  5579 E.C. Gordon-​Smith and Emma C. Morris    

22.1

Introduction to haematology Chris Hatton

ESSENTIALS Haematology is the study of the composition, function, and diseases of the blood. The approach to a patient suspected of having a haematological disorder begins with taking a history (particularly noting fatigue, weight loss, fever, and history of bleeding) and performing a clinical examination (looking for signs of anaemia, infection, bleeding, and signs of cellular infiltration causing splenomegaly and/​or lymphadenopathy). Key investigations include a full blood count, a blood film, and (in selected cases) examination of the bone marrow. Further diagnostic tests now routinely performed on blood and marrow samples include immunophenotyping and cytogenetic and molecular analysis. Mutational signatures may be diagnostically useful and potentially define treatment, keeping haematology in the vanguard of advances in modern medicine.

Introduction Haematology has always been in the vanguard of advances towards truly modern medicine. The first disease defined at a molecular level was haematological (sickle cell disease); the first molecularly targeted treatment was designed for a haematological disorder (imatinib in chronic myeloid leukaemia); and the revolution of immunological treatments, whether in the form of allogeneic bone marrow transplantation, focused therapies (such as rituximab) or cellular therapies (e.g. chimeric antigen receptor T-cells), was also begun from within haematology. This remains the case today, and the discipline is now advancing at an almost bewildering pace. However, despite the huge advances made in diagnostic techniques and imaging, the starting point for evaluating a patient relies on basic clinical skills. In this introduction, we outline the scope of haematology as a discipline, give an overview of the nature and function of blood cells, and provide a system for the newcomer to haematology to consider the likelihood of haematological disease in his or her patient.

The scope of haematology Haematology is the study of the composition, function, and diseases of the blood. Its diversity as a specialism therefore immediately

reflects the complexity of its subject. At its simplest, blood is divided into the plasma component (water, electrolytes, clotting factors, and fibrinogen—​with serum being the same substance without the clotting factors) and the cellular component, comprising red cells, platelets, granulocytes, and lymphocytes. Each has its specific and irreplaceable role in the normal function of blood, which impacts in turn the function of every tissue in the body. Not only do diseases of the blood influence every downstream organ, systemic diseases will also manifest in the blood. An appreciation of normal blood counts and appearances is therefore central to many fields of medicine.

Diseases and the blood Even a cell as apparently simple as the red blood cell, anucleate and devoid of intracellular organelles in its mature form, can manifest a variety of disorders. Inherited defects in the synthesis of globin genes, needed for the transport of oxygen to the peripheral tissues, constitute the commonest genetic diseases in the world. A host of additional genetic defects in glycolytic enzymes also impact on the survival of the red cell and the ability of the marrow to maintain a normal haemoglobin level. Meanwhile, the iron deficiency resulting from chronic occult blood loss may be the only clue to the presence of a malignant colonic tumour, and the failure to absorb vitamin B12 in pernicious anaemia may highlight the possibility of a range of additional autoimmune disorders. Erythropoietin, the key hormone controlling red cell production, is synthesized principally in peritubular interstitial fibroblasts in the juxtamedullary region of the renal cortex and renal disease may therefore result in either insufficient or excess marrow stimulation. Thus the finding of anaemia, a low haemoglobin level, may point to either haematological disorders, or may reflect primary disease elsewhere. The careful investigation of the cause of anaemia (see Chapter 22.6.2) is an important part of general medical practice. Granulocytes (neutrophils, eosinophils, and basophils, so termed to reflect the staining characteristics of the granules that are critical for their function) may also reflect both primary haematological disease and reactive conditions. The granules of neutrophils contain myeloperoxidase, needed in the cellular response to bacterial infection, and a high neutrophil count (neutrophilia) is commonly seen

5170

SECTION 22  Haematological disorders

in the context of infection or inflammation. The specific function of eosinophils in combating multicellular parasites means that a reactive eosinophilia may also be seen in infection with these organisms, as well as in allergic reactions. The uncontrolled proliferation of granulocytes of all kinds is seen in the myeloproliferative disorder chronic myeloid leukaemia, one of the first haematological malignancies to be defined at the molecular level. Neutropenia, by contrast, describes an inadequate number of circulating neutrophils, and may reflect primary marrow dysfunction (e.g. aplastic anaemia), the result of myelotoxic chemotherapy administration, or immune attack. The key role of neutrophils in maintaining the integrity of mucosal surfaces is highlighted by the increased risk of Gram-​negative infection in severe neutropenia, and the rapidly progressive sepsis that accompanies it is one of haematology’s most urgent medical emergencies. Along with red cells and granulocytes, platelets form the last of the ‘myeloid’ components of the blood. Their role in primary haemostasis (again effected in part by the presence of cell-​specific granules) is highlighted in Chapter 22.7.3; they are the target of some of the most widely prescribed agents used in medical practice (aspirin and other antiplatelet agents are discussed in more detail in the Section 16 on cardiovascular disease). Lymphocytes divide into B cells, T cells, and NK cells. Each has its distinct role in the immune process, from the production of antibodies to cell-​ mediated immunity and the development of antitumour action (e.g. through perforins secreted in the granules of cytotoxic T cells). As well as a reactive lymphocytosis or lymphopenia seen in response to viral infection, malignant transformation of lymphoid cells may result in a circulating excess of clonal lymphocytes or lymphoid precursor cells, or in the development of lymphadenopathy. Perhaps the most protean of haematological malignancies, lymphomas can affect any organ in the body. A discussion of the nature and treatment of these varied disorders is given in Chapters 22.4.3 and 22.4.4. Disorders of haemostasis, whether hereditary or acquired, may reflect a lack of key components of the clotting cascade, platelet lack, or platelet dysfunction. The modulation of the haemostatic machinery for therapeutic purposes also highlights the increasing awareness of overefficient haemostasis—​for example, in the hereditary thrombophilias. These are discussed in more detail in Chapters 22.7.4 and 22.7.5.

How does blood develop? Haematopoiesis is the term used to describe the cellular processes that produce blood cells. The sheer magnitude of the process is apparent in the observation that the bone marrow produces 2.5 × 1011 red cells, 1 × 1011 platelets, and 1 × 1010 white cells per day. Beginning in the yolk sac in utero, the process of haematopoiesis switches to the spleen and the liver in the developing fetus before moving to the bone marrow. With increasing age, haematopoiesis becomes confined to the axial skeleton, with very little red (haematopoietically active) marrow present in the long bones of the limbs in adults. The bone marrow contains an as yet undetermined number of pluripotent stem cells that are capable of both continuous self-​ renewal and differentiation. More mature cells lose the capacity for

self-​renewal as they differentiate into fully functional mature blood cells or form the structural cellular matrix of the bone marrow stroma. As they divide, progenitors have a progressively restrictive lineage potential manifested by their use of specific transcription factors. A  number of cytokines such as erythropoietin, granulocyte colony-​stimulating factor (G-​CSF), granulocyte–​macrophage colony-​stimulating factor (GM-​CSF), and thrombopoietin induce proliferation of specific lineages; these, together with complex cellular interactions, lead to development of mature blood cells in the marrow and subsequent release into the blood. Although a detailed treatment of haematopoiesis is given in Chapter 22.2.1, it is clinically useful to consider two different populations arising from this process:  these differentiate into the two main lineages of myeloid and lymphoid cells. As described previously, myeloid maturation, or myelopoiesis, produces red cells (erythrocytes), granulocytes, and platelets; while lymphopoiesis describes the development of lymphoid cells into mature B cells, T cells, and NK cells. The identification of haematopoietic stem cells (HSCs) that traffic from the bone marrow to the blood and back provided a major step forward in haematological practice. The subsequent recognition that it was possible to harvest these HSCs from humans, and that after reinfusion they could re-​establish normal haematopoiesis, has led to the development of the flourishing practice of HSC transplantation. Although very few HSCs are present in the peripheral blood, it is possible to increase their numbers in blood using the growth factors G-​CSF or GM-​CSF, or by blocking the molecule that anchors stem cells in the marrow matrix, CXCR4. In clinical practice, autologous or allogeneic stem cell infusion can be used to reconstitute haematopoiesis after appropriate chemotherapy. The subject of HSC transplantation is covered in detail in Chapter  22.8.2. Bone marrow transplantation has had a huge impact, enabling long-​term remissions to be achieved in patients suffering from aggressive haematological malignancies and bone marrow failure syndromes.

Initial approach to the patient The approach to a patient suspected of having a haematological disorder begins with taking a history and performing a clinical examination. Potential features of the history may include fatigue (perhaps reflecting anaemia or underlying malignancy), weight loss, and fever (again suggestive of the hypercatabolic picture of malignancy). A careful bleeding history, including responses to previous haemostatic challenges such as surgery and dental work, will be useful in delineating a possible bleeding diathesis. A  general impression of the patient’s overall health status—​perhaps via recording his/​ her Eastern Cooperative Oncology Group (ECOG) performance score—​is important in assessing tolerance for treatment and in categorizing patients entering clinical trials. Examination of the patient with a suspected blood disorder should concentrate on looking for signs of anaemia, infection, bleeding, and signs of cellular infiltration causing splenomegaly and lymphadenopathy. Pallor is a frequent finding in patients with anaemia though normal pigment differences in the skin make this an unreliable sign. Pallor of the mucous membranes or palmar creases may be more useful. Jaundice, commonly seen in liver disease, is also a prominent

22.1  Introduction to haematology

sign in patients with premature red cell destruction (haemolysis), and is readily detected in the sclerae. Signs of a bleeding tendency should be sought in the skin, mucous membranes, and the retina. Haemorrhage into the skin characteristically produces petechiae and ecchymoses. Petechial haemorrhages are small (1–​2 mm), often seen in areas with high venous pressure such as around the ankles, and are a common finding in patients with severe thrombocytopenia (platelet count 1 × 109/​litre) is a defining feature of chronic myelomonocytic leukaemia and juvenile myelomonocytic leukaemia and can be seen in chronic myeloid leukaemia. Monocytopenia is rare but is seen in hairy cell leukaemia. Eosinophilia is most commonly secondary to reactions to allergens, parasites, or drugs. Primary eosinophil disorders (i.e. chronic eosinophilic leukaemia and myeloid or lymphoid disorders with abnormalities of PDGFRA, PDGFRB, or FGFR1) are rare but eosinophilia may be a ‘bystander’ feature in other haematological malignancies (e.g. Hodgkin lymphoma). Peripheral blood basophilia is exceedingly rare, and, when present, should raise suspicion of a myeloproliferative neoplasm, in particular chronic myeloid leukaemia. Thrombocytopenia, common at presentation of a haematological malignancy, is usually due to reduced megakaryopoiesis and platelet morphology is normal. Thrombocytosis can be seen with myeloproliferative neoplasms, although is more commonly seen in response to infection or inflammation. Pancytopenia, a reduction in all blood cells, suggests failure of normal haematopoiesis (inherited or acquired), bone marrow infiltration, or reduced survival of all blood cells as a consequence of drugs or infections. The diagnostic possibilities that arise from an abnormal blood count must be interpreted in the context of the patient’s age, clinical scenario, and associated findings (e.g. physical examination, biochemistry).

Blood film Morphological assessment of a stained blood film adds value to an abnormal blood count as it may provide an explanation for the quantitative and qualitative (i.e. ‘flags’) abnormalities. The film may identify abnormal morphology of red cells, leucocytes, or platelets which may be specific and diagnostic (e.g. lymphoma cells). Alternatively, they may be features that are associated with, but not diagnostic, of a clinical entity, that is, ‘the company the cells keep’.

22.2.2  Diagnostic techniques in the assessment of haematological malignancies

These accompanying abnormalities (e.g. red cell rouleaux formation in plasma cell dyscrasias) may help generate a provisional diagnosis. Some of the blood film abnormalities that may indicate a malignant bone marrow disorders are described in the following paragraphs. Abnormal leucocytes in the blood may be diagnostic of a haematological malignancy. Abnormal lymphoid cells on a blood film are most commonly reactive (e.g. secondary to viral infection) but on rare occasions may be neoplastic. Some malignant cells have characteristic morphology (e.g. hairy cell leukaemia, follicular lymphoma—​see also Chapter  22.4.3). However, this is not always the case and it can be challenging on morphology alone to distinguish between reactive and neoplastic cells. Correlation with clinical history and serology is commonly required and, in unresolved situations, flow cytometric immunophenotyping may be indicated (see ‘Flow cytometric immunophenotyping’). Most reactive lymphocytoses are of T-cells whereas neoplastic proliferations are more commonly of a B-​cell lineage and have restricted kappa/​ lambda light-​chain expression. The presence of circulating abnormal (‘dysplastic’) neutrophils (e.g. abnormal size, granularity, nuclear segmentation, or chromatin condensation) indicates dysgranulopoiesis within the bone marrow. The presence of isolated dysplastic promyelocytes in the absence of other neutrophil precursors is highly suggestive of acute promyelocytic leukaemia, which also commonly presents with pancytopenia. Blast cells are not normally present in the blood. Their presence may indicate recovery from bone marrow failure, severe sepsis, cytokine administration, or underlying bone marrow pathology. They may also indicate acute leukaemia, myelodysplastic syndromes, myelodysplastic/​myeloproliferative neoplasms, chronic myeloid leukaemia, primary myelofibrosis, or bone marrow infiltration by a nonhaematopoietic malignancy. More than 20% blast cells in the blood (or bone marrow) defines acute leukaemia. Plasma cells do not commonly appear in the circulation and their presence indicates a florid B-​cell response to infection or a B-​cell neoplasm with plasmacytoid differentiation (i.e. plasma cell myeloma, plasma cell leukaemia, or lymphoplasmacytic lymphoma/​ Waldenström macroglobulinaemia). Plasma cells may be accompanied by cytopenias, high red cell MCV, leucoerythroblastic film, rouleaux formation, and background protein staining of the film. Additional biochemical investigations (e.g. serum protein analysis) and bone marrow examination may be required. Although red cells and platelets are rarely directly involved in the malignancy per se, there are commonly ‘accompanying’ abnormalities in these lineages. Red blood cell morphological abnormalities include rouleaux (plasma cell neoplasms), spherocytes and red cell agglutination (autoimmune conditions with a mature B-​cell neoplasm), teardrop poikilocytes (myelofibrosis or metastatic infiltration of the marrow), and hyposplenic features (splenic infiltration). Circulating erythroblasts (nucleated red cells) with abnormal morphology imply bone marrow dyserythropoiesis suggestive of myelodysplastic syndrome or acute myeloid leukaemia. Abnormal platelet morphology occurs with bone marrow dysmegakaryopoiesis such as in the myeloproliferative neoplasms and myelodysplastic syndromes. A  leucoerythroblastic blood film (i.e. presence of erythroid and leucocyte precursors in the blood) is seen with bone marrow infiltration (i.e. haematological malignancy, metastatic infiltrate, or marrow fibrosis), severe sepsis, cytokine administration, and prolonged hypoxia. There may be accompanying other features

Box 22.2.2.1  Indications for bone marrow examination in the diagnosis and assessment of haematological malignancies Investigation of unexplained cytopenia/​s or pancytopenia • • Investigation of unexplained blood film morphological abnormalities • Investigation of a paraproteinaemia • To confirm a diagnosis of a haematological malignancy made on peripheral blood • To classify a haematological malignancy • To determine the extent of bone marrow involvement by a haematological malignancy • Bone marrow staging of lymphoma • To obtain prognostic information based on the pattern of marrow infiltration • To obtain specimens for ancillary studies in the investigation of haematological malignancies • Post-​ therapy and post-​ transplant assessment of haematological malignancies

(as previously mentioned) that may shed light on the diagnosis. From this it can be seen that blood film review is crucial: the findings may be diagnostic, and, if not, they guide the next step in the investigation process. Is a bone marrow examination required to reach a final diagnosis or can flow cytometric immunophenotyping be used to determine the diagnosis?

Bone marrow examination Examination of the bone marrow may be required to determine the cause of unexplained blood count or film abnormalities or to confirm a diagnosis suspected from the blood count and film. Indications for a bone marrow examination have been developed by the International Council for Standardization in Haematology and are summarized in Box 22.2.2.1. Bone marrow aspirate and trephine biopsy specimens are generally both taken and these provide complementary information. The aspirate (liquid sample) gives cytological detail, whereas the trephine biopsy provides information about the marrow cellularity, architecture, cellular distribution, and extent of fibrosis. For some disorders, the aspirate may provide sufficient information without the need for a trephine biopsy (e.g. acute leukaemia). For others, the trephine biopsy is the prime diagnostic material (e.g. lymphoma staging and myelofibrosis). In addition to morphology, the marrow sample can be used for ancillary biological tests required to reach a diagnosis and World Health Organization (WHO) classification (i.e. immunophenotyping and molecular genetics). It is beyond the scope of this chapter to describe the bone marrow morphological findings in haematological malignancies as this will be addressed in accompanying chapters.

Immunophenotyping Immunophenotyping is the method by which antibodies are used to detect cellular antigens in clinical samples and is essential in the diagnosis and classification of haematological malignancies (as per WHO criteria). It is also used for disease staging and monitoring, to detect surrogate markers of genetic aberrations, identify potential immunotherapeutic targets, and to aid prognostic prediction

5183

5184

SECTION 22  Haematological disorders

Table 22.2.2.1  Clinical applications of immunophenotyping Diagnosis and classification

Determine cell lineage Determine stage of cell differentiation Classical disease-​associated phenotypes Aberrant antigen expression Clonality assessment Undifferentiated neoplasms

Prognostic prediction

Antigen expression and prognostic stratification Staging Extent of disease Rare event analysis Surrogate phenotype–​genotype correlation Integrated phenotype and genotype

Therapeutic applications

Detection of potential immunotherapeutic targets Minimal/measurable residual disease assessment Early detection of disease relapse Bone marrow regeneration following therapy

(Table 22.2.2.1). Immunophenotyping can be performed on single cells in solution by flow cytometry or on sections of bone marrow trephine biopsies by immunohistochemistry. Immunophenotyping can be used to establish the lineage and stage of differentiation of cells and provide a surrogate of clonality. It can make or confirm a diagnosis based on ‘classical’ disease-​associated phenotypic profiles and classify according to WHO definitions. The technology and antibody panels used to achieve this vary by sample type (fresh or fixed), the suspected neoplasm, and the information required to best characterize the cells of interest.

Flow cytometric immunophenotyping Flow cytometric immunophenotyping is the technique of choice for the assessment of cells in blood or aspirated bone marrow. It requires only a small sample, performs high-​speed analysis of large numbers of cells, and allows many cellular parameters to be assessed simultaneously. It assesses individual cells in suspension for the presence (or absence) of specific antigens. The sample is incubated with preselected antibodies, each of which has an attached fluorophore. Following exposure to a laser beam, the cells with bound antibody (and fluorophore) emit light at a specific wavelength which is captured by detectors. This signal is captured and

indicates the presence of the relevant antigen. Since morphology cannot be assessed, cells of interest are ‘gated’, i.e., electronically selected based on predefined criteria. This can be on light scatter properties (related to cell size and internal complexity) and/​or fluorescence (i.e. antigen expression, such as CD45). Both surface membrane and intracellular antigens (cytoplasmic and nuclear) can be assessed (Fig. 22.2.2.1). Flow cytometers are commonly fitted with three or more lasers and there are many fluorophores available for use. Hence, with this combination, it is possible to assess eight or more antigens simultaneously in one cell. Flow cytometry can therefore provide high diagnostic precision and sensitivity. It can identify disease-​associated phenotypes and be used for low-​level disease monitoring (i.e. ability to detect one cell with a specific phenotype in 10 000 cells). Imaging flow cytometry is a new technological development which further refines flow cytometry but is yet to find its place in diagnostic practice. In addition to generating standard flow cytometric data, these instruments capture high-​resolution images of each cell using digital cameras. This enables the cells being studied to be directly visualized, thereby overcoming the major limitation of ‘standard’ flow cytometry. The cell imagery component opens possibilities for further study of neoplastic cells, such as detecting colocalized cellular molecules, ‘spot’ counting (e.g. intracellular molecules), integrating phenotype and fluorescent in situ hybridization (FISH), and studying biological process (e.g. cell cycle, mitosis, or apoptosis).

Immunohistochemistry Immunohistochemistry (also known as immunocytochemistry) is another immunophenotyping method but where the testing is performed on sections of tissue, in this case bone marrow trephines or other haematological biopsies. It is performed using antibodies (usually monoclonal) and antigen–​antibody binding is detected with an enzyme (i.e. horseradish peroxidase or alkaline phosphatase) and a chromogenic substrate. Cells of interest are identified by their morphology and location by standard light microscopy. The presence (or absence) of a chromogenic colour reaction shows whether the antigen in question is expressed. Both cell membrane and intracellular antigens can be detected.

Fig. 22.2.2.1  Example of flow cytometry of a case of acute myeloid leukaemia. The gated leukaemic (blast) cells on CD45 and side scatter (purple) are then shown to express CD33 and myeloperoxidase. The cells are HLA-​DR negative and few express CD34 antigen.

22.2.2  Diagnostic techniques in the assessment of haematological malignancies

Immunohistochemistry is widely used to refine and classify the diagnosis of haematological malignancies. Other applications include lymphoma staging, detecting antigens associated with disease prognosis and potential immunotherapeutic targets, and disease monitoring.

Cytogenetics Cytogenetics is performed to diagnose and classify a number of haematological malignancies according to WHO criteria. It assesses the number and structure of whole chromosomes (e.g. the presence of chromosomal translocations) and chromosomal regions in neoplastic cells. The ‘gold standard’ tool for basic genetic diagnosis of haematological malignancies is karyotyping. This depends on the presence of dividing cells in the sample and is therefore generally performed on aspirated bone marrow. Although the resolution of karyotyping is limited, and generally only 20 cells are studied, it provides a global analysis of the entire genome. Some karyotypic abnormalities provide a definitive diagnosis (e.g. the Philadelphia chromosome arising from t(9;22)(q34;q11) in chronic myeloid leukaemia). Other karyotypic changes have prognostic significance. In childhood lymphoblastic leukaemia, for example, near-haploidy ( 0.2 × 106/​µl) is seen in myeloproliferative disorders, hypersensitivity reactions, and with some viral infections.

Introduction Leucocytes perform a critical role in the host defence against pathogens. They mediate inflammation and modulate the immune response. Leucocytes can be divided into granulocytes (neutrophils, eosinophils, and basophils; Fig. 22.3.1.1), monocytes, and lymphocytes. This chapter will focus on the role of granulocytes and monocytes in the normal host response and pathological manifestations of abnormalities of their number and/​or function. Lymphocytes are discussed elsewhere.

Neutrophils

Maturation

Morphology Under normal conditions, neutrophils make up over one-​half of the leucocytes in the peripheral blood. The morphological hallmarks of these cells include heterogeneous granules and a multilobated or segmented nucleus. The two predominant types of granules in the neutrophil’s cytoplasm are the azurophilic (or primary) granules and the specific (or secondary) granules. Azurophilic granules arise at the promyelocytic stage of differentiation. They contain myeloperoxidase, proteases, acid hydrolases, and microbicidal proteins. Specific granules and their content proteins are synthesized at the myelocytic stage of differentiation. Their contents include lactoferrin, lysozyme, vitamin B12-​binding protein, gelatinase, and neutrophil collagenase. The specific granules are not a uniform population, and their variable content is determined mainly by the timing of their formation. Those formed

(a)

early in the myelocyte stage contain abundant lactoferrin, while those formed later are enriched for gelatinase, and are often referred to as ‘tertiary’ granules or gelatinase granules. The specific granule membrane contains the cytochrome b-​558 component of the respiratory burst oxidase, as well as chemotactic and opsonic receptors, which are transferred to the plasma membrane upon activation of the neutrophil. Finally, the neutrophil cytoplasm also contains secretory vesicles that are endocytic vesicles containing primarily plasma proteins, and are the most rapidly mobilized fraction of cytoplasmic granules in the neutrophil. The membrane of secretory vesicles is rich in receptors and cytochrome b, and the vesicles contribute these proteins to the plasma membrane upon neutrophil activation. Common variants of neutrophil morphology include the Pelger–​ Huet anomaly, hypersegmentation of the nucleus, Dohle bodies, and toxic granulations. The Pelger–​Huet anomaly is a dominantly inherited defect in nuclear segmentation that results in a dumb-​ bell-​or rod-​shaped nucleus. Neutrophils with nuclei similar to this (‘pseudo-​ Pelger–​ Huet anomaly’) may be seen in acquired myelodysplastic syndromes. Hypersegmented nuclei (containing five or more segments) are characteristic of megaloblastic haematopoiesis due to folic acid or vitamin B12 deficiency. Dohle bodies are large basophilic inclusions that may be seen in sepsis, pregnancy, and following cytotoxic chemotherapy. Toxic granulations are abnormally staining primary granules that arise when neutrophils are released prematurely from the marrow, as in severe bacterial infections.

(b)

(c)

There are three cellular compartments that contain myeloid cells: the marrow, the intravascular compartment, and the extravascular space. Maturation from the haematopoietic stem cell occurs in the bone marrow and takes from 10 to 14 days. The marrow compartment can be subdivided into the mitotic compartment and the postmitotic and storage compartment. In the marrow mitotic compartment, neutrophils arise through serial division of myeloid precursors. The mitotic compartment contains myeloid cells with the ability to replicate:  myeloblasts, promyelocytes, and myelocytes. The marrow postmitotic and storage compartment contains myeloid elements that have lost the ability to divide, including metamyelocytes, bands, and segmented neutrophils. Neutrophils are released from the storage pool into the intravascular space, where they remain for 4 to 24 h. Within this space, approximately one-​half of the neutrophils circulate freely in the peripheral blood while the other half remain ‘marginated’ along the vascular endothelium. The marginated and circulating cells are in dynamic equilibrium with one another. Neutrophils then migrate through the vascular endothelium into the extravascular space, where they survive for 1 to 3 days. At any given time, approximately 90% of neutrophils are in the marrow compartment and 2 to 3% are in the intravascular space, with the remainder in the extravascular space.

Neutrophilia

Fig. 22.3.1.1  Peripheral blood granulocytes: (a) polymorphonuclear leucocyte (neutrophil), (b) eosinophil, (c) basophil.

Neutrophilia is defined as an elevation of the circulating neutrophil count (>7.5 × 106/​µl). Although it may reflect a primary haematological process, it usually occurs as a secondary manifestation of an underlying disease process or drug. The causes of an elevated neutrophil count are summarized in Box 22.3.1.1.

22.3.1  Granulocytes in health and disease

Box 22.3.1.1  Differential diagnosis of neutrophilia Primary haematological disease • Chronic idiopathic neutrophilia • Hereditary neutrophilia • Leucocyte adhesion deficiency • Myeloproliferative disorders: —​ Chronic myeloid leukaemia —​ Polycythaemia vera —​ Myelofibrosis Secondary to other disease processes or drugs • Infection: ​ — Acute —​ Chronic • Acute stress: ​ — Exercise ​ — Surgery —​ Seizure —​ Myocardial infarction • Drugs: ​ — Steroids —​ Lithium —​ β-​Agonists —​ Cytokines (G-​CSF, GM-​CSF) • Chronic inflammation • Marrow infiltration • Marrow hyperstimulation: —​ Chronic haemolysis —​ Immune thrombocytopenia —​ Recovery from marrow suppression • Postsplenectomy/​hyposplenism • Nonhaematological neoplasms

count, which may be accompanied by an increase in circulating immature precursors (‘left shift’). This occurs more commonly with bacterial infection but can also occur with viral processes. Along with a left shift, morphological changes in the neutrophil may be seen with bacterial infection, including toxic granulation, Dohle bodies, and cytoplasmic vacuoles. Neutrophilia resolves with treatment or resolution of the infectious process. In chronic inflammation, marrow granulocyte production is stimulated, resulting in moderate neutrophilia, sometimes with monocytosis. Chronic infections such as osteomyelitis, empyema, and tuberculosis can also give rise to a leukaemoid reaction with white blood counts markedly elevated (>50 000/​µl), usually associated with a marked left shift. Drugs Drugs can cause leucocytosis by several different mechanisms. Steroids increase the release of mature neutrophils from the marrow and should not cause a left shift. β-​Agonists acutely raise the neutrophil count by inducing the demargination of neutrophils adherent to the vascular endothelium, and may result in a neutrophil count twice that of baseline. Acute stress also results in demargination of neutrophils, which is probably mediated by adrenergic stimulation. Stresses that can cause this include exercise, surgery, seizure, and myocardial infarction. The cytokines granulocyte colony-​ stimulating factor (G-​CSF) and granulocyte–​macrophage colony-​ stimulating factor (GM-​ CSF) stimulate marrow production of neutrophils and can cause dramatic elevations in the white blood count. The majority of white cells formed are neutrophils and a left shift is often seen. The use of these cytokines therefore requires careful monitoring. Primary haematological conditions

Hereditary neutrophilias Hereditary neutrophilia This is a dominantly inherited syndrome manifested by leucocytosis, splenomegaly, and widened diploë of the skull. Laboratory evaluation reveals a white blood count of 20 000 to 70 000/​µl with a neutrophilic predominance, and an elevated leucocyte alkaline phosphatase. Its clinical course is benign. Chronic idiopathic neutrophilia This is a sporadically occurring condition that manifests as a white blood count of 11 000 to 40 000/​µl with a neutrophilic predominance. Patients are otherwise well and have been followed for up to 20 years without the development of significant pathology.

In other situations, neutrophilia may reflect a primary haematological condition. Marrow hyperstimulation in the setting of autoimmune haemolytic anaemia, immune thrombocytopenia, or recovery following chemotherapy or toxic insult to the marrow may result in a reactive leucocytosis. In autoimmune haemolytic anaemia and immune thrombocytopenia, neutrophilia may reflect disease activity, but steroid therapy or splenectomy may contribute. Splenectomy or hyposplenic states (e.g. sickle cell disease) may also result in modest neutrophilia at baseline with more marked neutrophilia at times of stress or infection, reflective of the loss of the spleen as a site of margination and sequestration of leucocytes. Myeloproliferative disorders

Neutrophilia is a common feature of the myeloproliferative disorders chronic myeloid leukaemia, polycythaemia vera, and This is a rare inherited disorder characterized by recurrent life-​ myelofibrosis as well as familial myeloproliferative disorders. threatening bacterial and fungal infections, cutaneous abscesses, gingi- Elevated eosinophil and basophil counts are also often seen in these vitis, or periodontal infections. Expression of the CD11b/​CD18 integrin disorders. Leucocyte alkaline phosphatase may be low or undetectis deficient, resulting in the inability of neutrophils to migrate to sites of able in chronic myeloid leukaemia. The myeloproliferative disinfection (see ‘Disorders of neutrophil function’ for further discussion). orders are discussed in further detail elsewhere. Leucocyte adhesion deficiency

Acquired neutrophilias

Nonhaematological malignancies

Infection

Various nonhaematological malignancies including lung and breast tumours may also cause neutrophilia. Tumours may secrete colony-​ stimulating factors or may cause a leukaemoid reaction. Tumour

The most common cause of an elevated leucocyte count is infection. Acute infection often causes a modest rise in the white blood

5191

5192

SECTION 22  Haematological disorders

metastatic to the bone marrow may cause leucoerythroblastic changes, characterized by fragmented erythrocytes, teardrops, and nucleated red cells, as well as leucocytosis with a left shift. Evaluation of neutrophilia The evaluation of neutrophilia should take account of the fact that leucocytosis is usually reactive, and that primary haematological aetiologies are relatively rare. The abnormal laboratory value should be verified to rule out laboratory error or a transient unexplained leucocytosis that resolves spontaneously. A careful history and physical examination are essential to evaluate for potential infectious processes, and to obtain a history of medication use. Examination of the bone marrow is usually not necessary for the evaluation of neutrophilia, but examination of a peripheral smear may be very helpful. Evidence of leucoerythroblastic changes warrants examination of the bone marrow to rule out infiltration of the marrow. If a bone marrow aspirate and biopsy are performed, evaluation should also include culture of the marrow for fungus or mycobacteria. Features that raise the question of myeloproliferative disease include concomitant elevation of platelets and haematocrit, basophilia and/​ or eosinophilia, and splenomegaly. In that setting, evaluation should include cytogenetics or fluorescent in situ hybridization examination for BCR-​ABL1 (diagnostic of chronic myeloid leukaemia in this setting), and assay for mutations in JAK2 (for diagnosis of polycythemia vera and other non-​ bcr-​abl-​positive myeloproliferative syndromes). Evaluation for myeloproliferative disease is discussed in detail elsewhere.

Neutropenia Neutropenia is defined as an absolute neutrophil count (ANC) of less than 1.5 × 106/​µl. In some populations, such as Africans and Yemeni Jews, normal ANCs are lower, with a lower limit of normal of 1.2 × 106/​µl. Neutropenia may pose a risk of serious bacterial infection, and this risk is directly related to the degree of neutropenia. In mild neutropenia (ANC 1000–​1500 × 106/​ µl) the risk of life-​threatening infection is not increased, and in moderate neutropenia (ANC 500–​1000 × 106/​µl) the risk of severe infection is only mildly elevated. Severe neutropenia (ANC 160 g/​litre (women), or Hct >49% in men, >48% in women, or Increased red cell mass (>25% above mean normal predicted value)

2

Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size)

3

Presence of JAK2 V617F or JAK2 exon 12 mutation

1

Subnormal serum erythropoietin level

Hct, haematocrit; Hgb, haemoglobin. The diagnosis of polycythaemia vera is made in the presence of all three major criteria or the first two major criteria and the minor criterion. Bone marrow biopsy many not be required in cases with sustained haemoglobin levels >185 g/​litre in men (haematocrit 55.5%) or 165 g/​litre in women (haematocrit 49.5%) if major criterion 3 and the minor criterion are present. Source data from Arber DA, et al. (2016). The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia. Blood, 127, 2391–​405.

5233

5234

SECTION 22  Haematological disorders

correlate with the level of allele chimerism. Retrospective analyses have revealed that patients with a low burden of the mutated allele can evolve over time to a higher burden of the mutated allele. Loss of heterozygosity on the short arm of chromosome 9 (the location of the JAK2 gene) is a consequence not of gene deletion but rather uniparental disomy or mitotic recombination. Even in patients with a low burden of JAK2 V617F, erythroid progenitors that are homozygous for JAK2 V6717F are usually present. This finding is characteristic of polycythemia vera but occurs less frequently in primary myelofibrosis and rarely in essential thrombocythaemia. The burden of JAK2 V617F is correlated with disease progression and the development of complications in polycythaemia vera patients. Additional mutations of JAK2 that are associated with erythrocytosis have also been identified. Somatic gain-​of-​function mutations involving exon 12 rather than exon 14 have been identified in patients with isolated erythrocytosis and low serum EPO levels. All erythroid colonies cloned from the haematopoietic cells of such patients are heterozygous for this mutation. JAK2 exon 12 mutations could therefore identify a distinctive myeloproliferative disorder that affects patients who currently carry a diagnosis of idiopathic erythrocytosis. Finally, mutations in LNK, primarily in exon 2, have been described in patients with polycythaemia vera and other myeloproliferative neoplasms lacking JAK2 mutations. LNK, or lymphocyte-​specific adaptor protein, functions to inhibit wild-​type and mutant JAK2 phosphorylation. The exact mechanism by which mutations in LNK result in polycythaemia vera is under investigation. Pathobiology Patients with polycythaemia vera have an increased thrombotic tendency resulting from the expansion of the red cell mass which represents the main cause of mortality in these patients. There is a direct relationship between the risk of thrombosis and age, with the incidence of cardiovascular complications being higher in patients over 65 years of age. Younger individuals are also at risk for thrombotic episodes, many of them life-​threatening, such as Budd–​Chiari syndrome, cerebrovascular thrombosis, cerebral sinus thrombosis, acute myocardial infarction, and pulmonary embolism. The main rheological abnormality is elevation of the total blood viscosity. Cerebral blood flow is reduced in patients with polycythaemia vera and a haematocrit of 53 to 62%. Reductions in blood flow are correctable by phlebotomy. Even small reductions in the haematocrit result in significant reductions in blood viscosity and increased cerebral blood flow, thereby reducing the likelihood of thrombus development. Thrombocytosis and functional platelet abnormalities and increased white blood cell count (found in 50% of the patients) are frequently present, and may play a role in the development of thrombosis. Patients with polycythaemia vera are also at an increased risk of developing life-​ threatening haemorrhagic complications. Abnormalities in platelet function and number have been implicated. Qualitative platelet abnormalities include defective platelet aggregation in vitro, acquired storage pool disease, and dysregulated thromboxane A2 metabolism. Acquired von Willebrand’s disease has been described in patients who have very high platelet counts (>1000 × 109/​litre), in association with life-​threatening bleeding episodes. No laboratory test has proven useful for the a priori

identification of patients at an increased risk of developing haemorrhagic or thrombotic events. The progression to a post-​polycythaemic-​related myelofibrosis phase of the disease is a common cause of morbidity. This stage is characterized by cytopenias, marrow fibrosis, and extramedullary haematopoiesis. There are conflicting data on the incidence of this complication. Some studies reported a very low incidence after 10 to 20 years; others reported that up to 25 to 50% of patients with polycythemia vera may develop polycythemia vera-​related myelofibrosis. The fibroblastic component represents a reactive event, and may be due to the local release of growth factors, particularly transforming growth factor-​β, by haematopoietic cells. The association between the treatment modality and the development of myelofibrosis is as yet unclear. There is, however, an established association between the treatment type (alkylating agents and radioactive phosphorus (32P)), and the development of acute leukaemia. It must be emphasized, however, that even those patients treated with phlebotomy alone have a leukaemogenic risk significantly higher than that expected in the general population. Clinical manifestations The clinical manifestations of polycythaemia vera are the direct consequence of the excessive production of cellular elements of the various haematopoietic cell lineages. The routine and widespread use of laboratory screening tests during medical evaluations has led to an increased detection of asymptomatic patients. In contrast, symptomatic patients may present to their physician with a large array of nonspecific complaints including headache, weakness, pruritus, dizziness, excessive sweating, visual disturbances, paraesthesias, joint symptoms, and epigastric distress. Approximately one-​third of patients will have lost 10% of their body weight by the time they come to medical attention, presumably due to the associated hypermetabolism. Joint disease is usually the manifestation of gout, due to the increased production of uric acid. The most important signs on physical examination include ruddy cyanosis, conjunctival plethora, splenomegaly, hepatomegaly, and hypertension. Patients left without appropriate treatment are at a particularly high risk of developing thrombotic or haemorrhagic events. In fact, thrombosis may be the cause of death in up to 30 to 40% of patients. Thrombosis may occur in the deep venous system of the lower extremities, or present as a pulmonary embolism. Cerebrovascular, coronary, and peripheral vascular occlusions are not rare. Thromboses at unusual sites are also characteristic of polycythaemia vera. They include occlusion of the splenic, portal, hepatic, and mesenteric veins. Cardiac valve abnormalities affecting the aortic or the mitral valves are commonly seen, frequently in the form of leaflet thickening or frank vegetations. These lesions are associated with the occurrence of arterial thromboembolism. Hepatic venous or inferior vena caval thrombosis is known as Budd–​Chiari syndrome and is characterized by hepatosplenomegaly, ascites, oedema of the peripheral extremities, jaundice, abdominal pain, and distension of superficial abdominal veins as a result of portal hypertension. The prevalence of myeloproliferative neoplasms in patients with splanchnic vein thrombosis was estimated to be as high as 49% for hepatic vein thrombosis and 23% for portal vein thrombosis. Often these patients will present with normal haemoglobin

22.3.5 The polycythaemias

and haematocrit levels. This phenomenon is regarded as ‘inapparent polycythaemia vera’ and requires a full evaluation for the presence of myeloproliferative neoplasms. Detection of the JAK2 V617F mutation will help identify and appropriately treat these patients earlier. Up to 34% of patients with portal vein thrombosis and up to 58% of patients with Budd–​Chiari syndrome may have a myeloproliferative neoplasm, identified by the presence of JAK2 V617F. Iron deficiency may also mask the expected erythrocytosis in some patients with polycythaemia vera. ‘Masked’ polycythaemia vera may exist even in those without Budd–​Chiari syndrome or iron deficiency and describes those patients with erythrocytosis who do not meet the cut-​offs set forward by diagnostic criteria but who have bone marrow biopsies consistent with polycythaemia vera. They often have thrombocytosis, and discriminating these patients from essential thrombocythemia is important as the thrombotic risks differ between these two diagnoses. The 2016 WHO diagnostic criteria have set lower thresholds for haemoglobin and haematocrit compared to the 2008 WHO diagnostic criteria, which should reduce the number of patients that fall into this category. Leucocytosis, thrombocytosis, and splenomegaly are usually present. Neurological abnormalities occur in up to 60 to 80% of patients. They include transient ischaemic attacks, cerebral infarction, cerebral haemorrhage, confusional states, fluctuating dementia, and involuntary movement syndromes. Dizziness, paraesthesiae, tinnitus, visual problems, and headaches are common symptoms attributed to the hyperviscosity state. Small infarcts in the basal ganglia region, also known as lacunae, may explain some of the transient neurological manifestations. Symptoms of carotid, vertebral, or basilar artery insufficiency occur frequently. Peripheral vascular insufficiency may be manifested by intense redness or cyanosis of the digits, burning, classical erythromelalgia, digital ischaemia with palpable pulses, or thrombophlebitis. Erythromelalgia consists of a burning pain in the digits of either the lower and/​or upper extremities, an objective sensation of increased temperature, and relief by cooling. If left untreated it may evolve into gangrene. Antiplatelet aggregation therapy rapidly reverses the symptoms. Peripheral pulses are usually normal in these patients, as this phenomenon is due to changes in the microcirculation related to arteriolar activation and aggregation of platelets in vivo. Haemorrhagic complications are the cause of death in 2 to 10% of patients with polycythaemia vera; 30 to 40% of patients will experience a haemorrhagic event sometime during the course of their disease. Peptic ulcer disease occurs frequently and contributes to the gastrointestinal tract being the most common source of bleeding. Oesophageal varices are another common site of bleeding in patients with intra-​abdominal thromboses. The bleeding diathesis may relate to abnormalities in platelet function, and thus occurs frequently after the ingestion of anti-​inflammatory agents. Spontaneous bleeding is rare. Recent data suggest that low-​dose aspirin might not increase the frequency of life-​threatening haemorrhages. Generalized pruritus affects 50% of all patients, but its aetiology is unknown. Increased blood and urine histamine levels have been implicated. Pruritus triggered by water contact is characteristic, and very poorly tolerated. There is no relationship between the severity of the disease and the intensity of the pruritus. Up to 20% of patients experience persistent pruritus even after normalization of their counts.

The risk of postoperative complications is high in patients with polycythaemia vera. Bleeding, thrombosis, or a combination of both can occur. The risk is higher for those patients who undergo surgery with uncontrolled erythrocytosis. Inadequately controlled disease may be associated with almost an 80% risk of complications. The duration of controlled blood counts is also important: the longer this duration is, the less the risk of complications (as low as 5%). Polycythaemia vera evolves to polycythaemia vera-​ related myelofibrosis in up to 50% of the patients 10 to 20 years after the initial diagnosis. It is characterized by increased splenomegaly, teardrop red cells, a leucoerythroblastic blood picture, marrow fibrosis, and a normal or decreasing red cell mass. Fatigue, dizziness, weight loss, anorexia, progressive anaemia, and thrombocytopenia associated with bleeding are common. Patients with progressive anaemia should be evaluated for folate and iron deficiency. Occasional patients will respond to iron supplementation with resurgence of erythropoiesis. Severe hyperuricaemia may induce gout or uric acid nephropathy. Polycythemia vera-​ related myelofibrosis portends a grave prognosis, with over two-​thirds of patients dying within 3 years. In the appropriate setting, strong consideration should be given to allogeneic stem cell transplantation, which offers an opportunity for cure. The evolution to acute leukaemia is probably the natural consequence of the malignant nature of polycythaemia vera, which can be accentuated by therapeutic interventions commonly used for its treatment, such as alkylating agent or 32P. In a recent study, older age and prior exposure to 32P and busulfan, but not hydroxycarbamide therapy, was associated with an increased risk of leukaemia. Between 30 and 50% of patients who develop leukaemia have previously developed myelofibrosis whereas 50% progress directly from the erythrocytotic phase. A  significant number of patients experience a myelodysplastic interval before transforming to acute leukaemia. Patients should be treated with either decitabine or standard acute myeloid leukaemia induction in preparation for taking these patients rapidly to allogenic stem cell transplantation. Laboratory evaluation Laboratory evaluation of patents with erythrocytosis involves the careful use of a battery of diagnostic tests. The diagnosis of polycythaemia vera has been dramatically simplified with the advent of the molecular tests for the JAK2 V617F mutation. The use of analyses for the JAK2 V617F and JAK2 exon 12 mutations has proven particularly useful in diagnostically challenging cases and in patients with inapparent erythrocytosis and a serious thrombotic event occurring especially at a younger age. Allele-​specific polymerase chain reaction methods can be used to detect JAK2 V617F in at least 95% of patients with polycythemia vera. Those patients who fulfil clinical criteria for polycythemia vera but are JAK2 V617F negative should be evaluated for JAK2 exon 12 mutations. Approximately 10% of such patients who are negative for JAK2 V617F harbour an exon 12 JAK2 mutation. Rare mutations in calreticulin (CALR) and LNK have been described. Quantitation of the red cell mass to document absolute erythrocytosis remains a useful diagnostic test in characterizing patients without JAK2 mutations or erythrocytosis, though its availability is limited. Approximately two-​thirds of the patients present with leucocytosis

5235

5236

SECTION 22  Haematological disorders

and approximately 50% have thrombocytosis. Red cell morphology usually reflects an underlying iron-​ deficiency state present in the great majority of patients: microcytosis, hypochromia, polychromatophilia, poikilocytosis, and anisocytosis are frequently seen. White blood cell morphology is usually normal. Increased numbers of basophils, eosinophils, and immature myeloid cells are observed. Megathrombocytes are often seen in the peripheral blood smear. Platelet counts are usually less than 1000 × 109/​litre, but higher counts may be seen. The progression to polycythaemia vera-​related myelofibrosis is characterized by the appearance of a leucoerythroblastic blood picture with the presence in the peripheral blood of teardrop red cells (dacrocytes), immature myeloid cells, megathrombocytes, and nucleated red blood cells. Bleeding time and platelet aggregation studies are frequently, but not always, abnormal. Prolongation of prothrombin and partial thromboplastin times are frequently encountered, usually reflecting a laboratory artefact due to erythrocytosis (the volume of plasma in the collection tube might be too small relative to the amount of citrate anticoagulant present in these tubes). At diagnosis, serum EPO levels are either reduced or within the lower limits of normal. Low levels persist in two-​thirds of patients after normalization of the haematocrit. In patients with extreme thrombocytosis, acquired von Willebrand’s disease occurs, characterized by a significant decrease in large von Willebrand’s factor multimers due to their adsorption to platelets and megakaryocytes. This acquired defect occurs mainly in patients with very high platelet counts (>1000 × 109/​litre) and resembles type 2 von Willebrand’s disease. The defect is corrected by normalization of the thrombocytosis. Elevations in leucocyte alkaline phosphatase (70%), serum vitamin B12 levels (40%), and serum vitamin B12 binding proteins (70%) are common, as are hyperuricaemia and increased histamine levels. Bone marrow examination reveals a hypercellular marrow with trilineage growth (panmyelosis) with prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes. Iron stores are usually absent prior to treatment. Reticulin is often seen, but is not predictive of evolution into the myelofibrotic phase. Cytogenetic abnormalities have been observed in 25% of patients, but none is characteristic. A recent study using fluorescence in situ hybridization analyses has shown that abnormalities involving chromosome 9 rearrangements are common, being present in up to 53% of patients with polycythaemia vera. A gain in 9p is the most frequent genomic abnormality in polycythaemia vera. JAK2 is located on 9p and the duplication of 9p in polycythaemia vera is thought to be the consequence of homologous recombination. Other chromosomal abnormalities involving chromosomes 1, 5, 7, 8, 12, and 13 have been associated with disease progression. Diagnostic criteria for polycythaemia vera The diagnosis of polycythaemia vera has been greatly simplified by JAK2 molecular testing. The 2016 World Health Organization (WHO) diagnostic criteria for polycythaemia vera require the presence of all three major criteria, (an increased haemoglobin, haematocrit, or red cell mass; presence of a JAK2 mutation; and consistent bone marrow biopsy findings) or the first two major criteria plus a subnormal serum EPO level (Table 22.3.5.1). It is important to note that a bone marrow biopsy remains an important

procedure except in cases with a JAK2 mutation and subnormal EPO level as well as significant erythrocytosis (haemoglobin levels >185 g/​litre in men (haematocrit 55.5%) or 165 g/​litre in women (haematocrit 49.5%)).

Approach to the patient with polycythaemia It is wise to avoid the temptation of diagnosing polycythaemia on the basis of a single blood count unless extremely high haematocrit levels are observed. A rational diagnostic approach is required to avoid unnecessary emotional distress to the patient as well as expensive and unnecessary evaluations (Fig. 22.3.5.1). Dehydration from any cause can produce a spurious elevation in the blood counts. Heavy smokers with mild polycythaemia should be asked to stop smoking and their counts repeated after a few weeks. Once a genuine elevation of haemoglobin or haematocrit has been established, the next step is to decide whether this represents an absolute increase in total red cell mass, or merely a relative phenomenon. A blood volume study with direct quantitation of both red cell mass and plasma volume can be helpful in making this distinction if available. In patients with extreme degrees of erythrocytosis (haematocrit >55% in men and >49.5% in women) one can be assured that the red cell mass is elevated. If absolute polycythaemia is confirmed, it is essential to elucidate whether it is the consequence of a primary myeloproliferative disorder such as polycythaemia vera or a secondary condition. The determination of EPO levels may be useful in differentiating between polycythaemia vera and secondary polycythaemia. An elevated serum EPO level is indicative of the presence of a secondary polycythaemia and a low level supports the diagnosis of polycythaemia vera, but a normal EPO value does not exclude hypoxia-​ induced causes of erythrocytosis or the autonomous production of EPO leading to erythrocytosis. Normal values may also be encountered in some cases of polycythaemia vera. The presence of leucocytosis, thrombocytosis, or splenomegaly is suggestive of polycythaemia vera as the cause for the elevated red cell mass. Arterial blood gases and the direct determination of oxygen saturation in arterial blood, if decreased, may aid in the recognition of a chronic pulmonary or congenital cardiovascular abnormality. If blood oxygen saturation is normal, the quantification of haemoglobin’s oxygen affinity (P50o2) may indicate the presence of high-​affinity haemoglobin variant. Otherwise, causes for a physiologically inappropriate polycythaemia should be sought. Molecular methods to detect JAK2 V617F and exon 12 JAK2 mutations provide diagnostic tools for the evaluation of patients suspected of having polycythaemia vera. JAK2 mutation analysis provides a direct means of identifying the overwhelming number of patients with polycythemia vera. There is a small but definite group of patients in whom a specific cause for polycythaemia remains elusive, despite appropriate diagnostic testing. Examining close relatives might disclose the presence of a familial form of polycythaemia, a rare condition caused by an abnormality in EPO receptor or defects in hypoxia sensing (Chuvash polycythemia). Regular, continued surveillance is recommended for all noncategorized patients, as some of them develop polycythaemia vera in the future.

22.3.5 The polycythaemias

Peripheral blood mutation screening for JAK2 V16F and serum erythropoietin measurement; send JAK2 exon 12 if JAK2 V16F is negative

JAK2 mutation (+) AND serum EPO level ↓

JAK2 mutation (+) AND serum EPO level normal/↑

JAK2 mutation (–) AND serum EPO level ↓

JAK2 mutation (–) AND serum EPO level ↑

PV possible

PV unlikely

Hgb 16.5–18.5 g/dL in men, 16– 16.5 g/dL in women OR Hct 49–55.5% in men, 48–49.5% in women

Hgb >18.5 g/dL in men, >16.5 g/dL in women OR Hct >55.5% in men, >49.5% in women

PV likely

Bone marrow biopsy required for definitive PV diagnosis

Diagnostic for PV: Bone marrow boipsy not required for diagnosis

Bone marrow biopsy required for definitive PV diagnosis

Bone marrow biopsy required for definitive PV diagnosis

If bone marrow not diagnostic, consider congenital polycythaemia with EPOR mutation

Consider secondary polycythemia including congenital polycythaemia with VHL mutation

Fig. 22.3.5.1  Diagnostic algorithm for patients with erythrocytosis. EPO, erythropoietin; EPOR, erythropoietin receptor; Hct, haematocrit; Hgb, haemoglobin; PV, polycythaemia vera; VHL, von Hippel–​Lindau.

Management of polycythaemia vera The two main goals in the management of patients with polycythaemia vera involve the confirmation of the diagnosis and reduction of the red cell mass. The untoward effects of an increased red cell mass on tissue blood flow occur independently from the specific cause of the polycythaemia. It is thus reasonable to recommend that all patients with uncorrectable erythrocytosis be offered phlebotomy. The main therapeutic goals are the maintenance of well-​being and the prevention of complications for as long as possible. Several therapeutic strategies have resulted in dramatic increases in the survival of patients. Historical evidence suggests a median survival of approximately 18  months in untreated patients with polycythaemia vera whereas with appropriate management, survival of over 10 years is now common. The main therapeutic objective is the reduction of the haematocrit to a normal level. This is usually accomplished by the implementation of repeated phlebotomies. Every possible effort should be made to discourage patients with polycythaemia vera from smoking. A regimen of phlebotomies should be prescribed as soon as the diagnosis has been clearly established. It is often feasible to remove between 350 and 500 ml of blood every other day until the desired haematocrit level is attained. The removal of smaller aliquots might be necessary in older patients. In the landmark Cytoreductive Therapy in Polycythemia Vera (CYTO-​ PV) trial, stringent control of the haematocrit at less than 45% versus more permissive control of 45 to 50% was associated with a

decreased risk of thrombosis, making lower than 45% the standard of care. Many haematologists still target 42% for women, though this is not based on prospective data. Once the target haematocrit level is achieved, a maintenance regimen should be instituted. Venesection is preferred in those younger individuals without critical elevations in their platelet counts. Myelosuppressive therapy should be considered in elderly patients who are intolerant of phlebotomies, and in younger individuals with repeated thrombotic episodes and extremely high platelet counts. There is controversy regarding what represents the optimal myelosuppressive agent. A  major concern has been the possible ­association between exposure to some of these agents and the development of leukaemia. Hydroxycarbamide is useful for the management of patients with polycythaemia vera and represents the first-​line therapy especially in older patients in whom phlebotomy alone is insufficient or intolerable, due to its minimal leukaemogenic potential. It should, however, be used with great caution in patients formerly treated with radioactive 32P or alkylating agents as the risk of leukaemia is higher. Low-​dose aspirin (81–​100 mg/​ day) administered to patients with polycythaemia vera has been shown to decrease the risk of arterial and venous events. The European Collaboration on Low dose Aspirin for Polycythaemia Vera (ECLAP) study was a randomized study comparing low-​dose aspirin with placebo in reducing thrombosis in polycythaemia vera. A clinically significant reduction in rate of thrombosis was seen in favour of low-​dose aspirin compared to

5237

5238

SECTION 22  Haematological disorders

placebo. Although there is no overall survival benefit, no significant increased risk of bleeding was reported. In younger patients, given their potential long-​term survival, strong consideration should be given to the use of phlebotomy therapy in combination with low-​dose aspirin, as well as with other apparently nonleukaemogenic interventions such as interferon-​α and anagrelide. In two recent studies, one in polycythaemia vera patients and another in essential thrombocythaemia patients, hydroxyurea has been shown to be nonleukaemogenic, and can be used as an alternative to phlebotomy or in combination with it. Interferon-​α2a and pegylated forms of interferon have been shown to be effective in controlling the blood counts and symptoms (especially pruritus). The use of pegylated forms of interferon has been reported to be associated with a reduction of the percentage of cells bearing the JAK2 V617F mutation, suggesting its activity at the level of an early haematopoietic stem cell/​progenitor cell. In patients with a history of thrombosis where uncontrolled thrombocytosis is a problem, anagrelide, an inhibitor of megakaryocytic maturation, has proven effective. Ruxolitinib has been evaluated in the phase III RESPONSE trial, which compared best available therapy to ruxolitinib, with primary co-​endpoints of haematocrit control (450 × 109/​litre). The widespread use of automated cell counters has made the identification of platelet count abnormalities a relatively common event. The clinical consequences Pathophysiology and classification of elevated platelet counts are usually determined by the cause of the thrombocytosis, ranging from the uneventful recognition of of thrombocytosis a laboratory abnormality, to medical emergencies such as life-​ threatening thrombosis or haemorrhage. Thrombocytosis can occur in response to many underlying clinical conditions (secondary or reactive), or as a consequence of a primary abnormality in bone marrow function (primary). A classifiNormal megakaryocytopoiesis cation of the causes of thrombocytosis is provided in Box 22.3.6.1. Reactive or secondary thrombocytosis accounts for over 80% of all An understanding of disorders of platelet production requires recognized cases of thrombocytosis, iron deficiency being the most knowledge of the regulatory events that occur during normal common cause. Short-​lived, secondary thrombocytosis may be obmegakaryocytopoiesis. Megakaryocyte development is a complex served in situations such as trauma, acute bleeding, major surgery, process in which a wide variety of regulatory signals work in con- or after strenuous physical exercise. Longer-​term thrombocytosis cert to direct a highly specific response to thrombopoietic demand. A large number of cytokines including interleukins (IL-​3, IL-​6, and IL-​11), stem cell factor, granulocyte–​macrophage colony-​stimulating Box 22.3.6.1  Classification of the causes of thrombocytosis factor, thrombopoietin, and, possibly, erythropoietin have been shown to stimulate megakaryocyte development. Thrombopoietin • Autosomal dominant familial thrombocytosis • Secondary thrombocytosis (reactive): and the thrombopoietin receptor (MPL) are the primary physio —​ Iron deficiency logical regulators of in vivo megakaryocytopoiesis. Thrombopoietin —​ Infection is produced primarily by the liver, but its mRNA has also been found —​ Postsplenectomy (or hyposplenism) in the kidney, muscle, and bone marrow. Thrombopoietin acts at dif —​ Malignancy ferent levels of megakaryocyte maturation ranging from the prolif —​ Trauma eration and survival of haematopoietic stem cells/​progenitor cells —​ Inflammation (noninfectious) to megakaryocyte maturation, but does not significantly affect the —​ Blood loss release of platelets from megakaryocytes; thrombopoietin levels are —​ Major surgery regulated by the total mass of platelets and megakaryocytes, and —​ Exercise thrombopoietin is cleared by binding to receptors on the surface —​ Rebound from myelosuppression of these cells. Like erythropoietin, thrombopoietin uses the JAK–​ • Primary thrombocytosis (nonreactive): STAT signalling pathway (see Chapter 22.3.5). Activation of the re —​ Essential thrombocythaemia ceptor MPL by thrombopoietin provokes a conformational change —​ Chronic myeloid leukaemia of the JAK2 tyrosine kinase, phosphorylation of intracytoplasmic —​ Polycythaemia vera —​ Primary myelofibrosis residues, and downstream activation of the genes controlling cell —​ Unclassified myeloproliferative neoplasms cycle status, differentiation, and apoptosis. A mutation in the 617 —​ Myelodysplastic syndromes position of the JAK2 protein replacing the amino acid phenylalanine —​ Refractory anaemia with ringed sideroblasts and thrombocytosis with valine disrupts the autoinhibitory domain of JAK2 and renders (RARS-​T ) the kinase constitutively active. This mutation, JAK2 V617F, is pre • Uncertain aetiology sent in the vast majority of patients with polycythaemia vera and Adapted from The American Journal of Medicine, Vol. 96, Buss DH, et  al., in approximately 50% of patients with essential thrombocythaemia. Occurrence, etiology, and clinical significance of extreme thrombocytosis: Additional mutations found in essential thrombocythaemia include A study of 280 cases, Pages 247–​53, Copyright © 1994, with permission activating mutations in MPL and CALR. Gain-​of-​function deletions from Elsevier. or insertional mutations of CALR exon 9 result in a mutant CALR

22.3.6  Thrombocytosis and essential thrombocythaemia

is associated with the presence of chronic disorders such as malignancy, inflammation, chronic infections, and iron deficiency anaemia. The pathophysiology underlying reactive thrombocytosis is not fully understood, but probably involves the increased generation of inflammatory cytokines such as IL-​6, which appear to mediate increased transcription of thrombopoietin by the liver. Primary thrombocytosis by contrast is associated with a group of bone marrow disorders including chronic myeloid leukaemia, essential thrombocythaemia, polycythaemia vera, primary myelofibrosis, and the myelodysplastic syndromes. The level of elevation of platelet numbers is not helpful in differentiating a reactive from a primary process. An abnormality of thrombopoietin production or of the thrombopoietin receptor has been suggested as the basis of several familial disorders associated with thrombocytosis. In several families, a point mutation of the thrombopoietin gene leads to overproduction of thrombopoietin resulting in elevated levels of thrombopoietin and thrombocytosis. Patients with this autosomal dominant form of familial thrombocytosis have a benign course which is not complicated by thrombosis or haemorrhage or the development of acute leukaemia or myelofibrosis. A second familial form of thrombocytosis has been attributed to a mutation in the transmembrane mutation of MPL leading to its constitutive activation. These familial forms of thrombocytosis are the consequence of germ-​line mutations while the myeloproliferative neoplasms are the consequence of acquired somatic mutations. A  third familial form of thrombocytosis has been described with germline JAK2 mutations; some, but not all, of these mutations not only result in thrombocytosis but additionally result in vascular events. Lastly, gelsolin, which is a protein involved in actin assembly and disassembly, is currently being evaluated as another familial cause of isolated thrombocytosis; the mechanism by which a mutation in this gene results in thrombocytosis is unknown. For the most part, the underlying medical disorder leading to reactive thrombocytosis can be identified by clinical criteria. A number of laboratory tests can be useful in distinguishing primary from secondary thrombocytosis. C-​reactive protein synthesis in the liver is mediated by IL-​6, with C-​reactive protein levels being high in those patients with elevated IL-​6 levels. Elevated levels of both IL-​6 and C-​ reactive protein are strongly indicative of the elevated platelet count being reactive in origin. Cytogenetic analyses and use of the polymerase chain reaction for the BCR-​ABL1 translocation are useful to exclude the presence of a Philadelphia chromosome and a diagnosis of chronic myeloid leukaemia in a patient with thrombocytosis. Assays using probes for restriction fragment polymorphisms of genes located on the X chromosome are helpful in identifying clonal haematopoiesis in females with thrombocytosis. Clonal haematopoiesis occurs in patients with myeloid malignancies such as essential thrombocythaemia but not in cells of patients with secondary forms of thrombocytosis. More recently, the presence or absence of the JAK2 V617F mutation, calreticulin mutations, and/​or MPL mutations (MPL W515L, MPL W515K, and MPL W515N) have been used to differentiate secondary cases of thrombocytosis from a Philadelphia-​negative myeloproliferative neoplasm leading to elevated platelet numbers. The presence of these mutations in a patient with thrombocytosis is diagnostic of a myeloproliferative neoplasm. The natural history and prognosis of reactive thrombocytosis is defined by its underlying cause. The thrombocytosis per se is

probably inconsequential and does not require specific therapy; it usually resolves after the treatment of the underlying cause. In contrast, the thrombocytosis due to underlying myeloproliferative neoplasm can cause life-​threatening thromboembolic phenomena and bleeding episodes, and frequently requires specific cytoreductive therapy, emphasizing the need for accurate recognition.

Essential thrombocythaemia Essential thrombocythaemia is a chronic myeloproliferative neoplasm characterized by marked bone marrow megakaryocytic hyperplasia and peripheral blood thrombocytosis. The clinical course is punctuated by episodes of thrombosis and/​or bleeding. In 1951, Dameshek suggested that essential thrombocythaemia represented a myeloproliferative disease. The myeloproliferative neoplasms are currently thought to represent malignant stem cell disorders.

Aetiology and pathogenesis The causative factors which lead to essential thrombocythaemia have become increasingly better understood. Its pathogenesis involves the abnormal proliferation of a blood cell precursor that differentiates mainly towards the megakaryocytic/​platelet lineage. Current evidence suggests that hypersensitivity to stimulatory cytokines such as thrombopoietin might provoke the expansion of the megakaryocytic progenitor pool. The clonal origin of haematopoiesis in patients with myeloproliferative neoplasms was initially established through biochemical isoenzyme characterization of the blood cells of affected women who were heterozygous for glucose-​ 6-​ phosphate dehydrogenase. Analysis of X-​ linked restriction fragment length polymorphisms in affected women has confirmed a clonal pattern in some cases. There are, however, a significant number of patients with polyclonal myelopoiesis. These nonclonal cases may have a decreased risk for thrombosis. The finding of the JAK2 V617F mutation in Philadelphia chromosome-​ negative myeloproliferative neoplasms has provided new insight into the pathogenesis of this disease. Approximately 50% of patients with essential thrombocythaemia are JAK2 V617F positive. The patients who are positive for the mutation almost uniformly have a low burden of JAK2 V617F (1000 × 109/​ litre) induces the adsorption of larger von Willebrand’s multimers on to platelet membranes, with their subsequent degradation, triggering a haemostatic defect quite similar to that observed in type 2 von Willebrand’s disease. Erythromelalgia occurs commonly in patients with essential thrombocythaemia. Erythromelalgia refers to a syndrome characterized by redness and burning pain in the extremities which results from platelet-​mediated thrombosis of the arterial microvasculature. If left untreated it may progress to frank gangrene. The exquisite platelet response to cyclooxygenase inhibitors such as aspirin and indomethacin suggests that prostaglandin endoperoxides produced by the metabolism of arachidonic acid might play a major role in the generation of platelet-​associated thrombosis. Increased frequency of venous thrombosis in uncommon sites such as the splanchnic vasculature leading to catastrophic intra-​ abdominal thromboses such as Budd–​ Chiari syndrome have recently been reported in JAK2 V617F-​positive patients who subsequently go on to develop essential thrombocythaemia. Although the increased thrombotic risk cannot be explained exclusively by the presence of the JAK2 V617F mutation, it appears to contribute to the increased risk of thrombosis in these patients.

Clinical manifestations As many as two-​thirds of patients with essential thrombocythaemia are asymptomatic at diagnosis. Most symptomatic patients present with either a thrombotic episode or a minor bleeding episode. Bleeding can occur spontaneously but is frequently associated with the recent use of a nonsteroidal anti-​inflammatory drug (NSAID). Common sites of haemorrhage include the gastrointestinal and the genitourinary tracts; there is also easy bruising. Thrombosis leads to the most common presenting symptoms and can occur in arteries and veins, large or small. Occlusion of the splanchnic vessels and of

22.3.6  Thrombocytosis and essential thrombocythaemia

the superficial and deep veins of the lower extremities is common. Pulmonary emboli may also occur. An occasional patient presents with thrombosis of the hepatic veins causing the Budd–​Chiari syndrome or with occlusion of the renal veins manifesting clinically as nephrotic syndrome. When the microcirculation is involved, a number of clinical syndromes may occur. Palpable lesions with small areas of gangrene indistinguishable from vasculitic lesions of rheumatoid arthritis or systemic lupus erythematosus may be observed. Erythromelalgia may occur in association with transient ischaemic attacks or acute episodes of cardiac angina. Peripheral pulses are usually preserved; this helps differentiate erythromelalgia from atherosclerotic-​related ischaemia. Neurological symptoms are common and include headaches and paraesthesias of the extremities. Transient ischaemic attacks may present with symptoms of unsteadiness, dysarthria, dysphoria, motor hemiparesis, scintillating scotomas, amaurosis fugax, vertigo, dizziness, migraine headaches, and seizures. On occasion, transient ischaemic attacks may progress to established infarcts. Myocardial ischaemia with normal angiograms occurs occasionally. Splenic enlargement is observed in 40 to 50% of individuals and 20% have hepatic enlargement.

Laboratory evaluation An elevated platelet count, often above 450 to 1000 × 109/​litre, is characteristic. The absolute number of platelets, even if higher than 1000 × 109/​litre, is not diagnostic of essential thrombocythaemia, as extreme elevations in platelet numbers may be observed in reactive thrombocytosis. Marked changes in platelet morphology, which include large and bizarre-​looking platelets sometimes forming aggregates, are also characteristic and may be more useful in helping distinguishing primary from reactive thrombocytosis. The bone marrow is hypercellular with megakaryocytic hyperplasia. Clusters of hyperlobulated megakaryocytes are often observed within the marrow. Absent or diminished iron stores are seen frequently. This may be an epiphenomenon of an underlying myeloproliferative neoplasm or a true expression of iron depletion in patients with chronic bleeding. Reticulin fibrosis is present in one-​quarter of bone marrow specimens but collagen is limited. Mild leucocytosis is common. Molecular analysis for JAK2 V617F, CALR, and MPL mutations is an important diagnostic tool in identifying patients with myeloproliferative neoplasms. If thrombocytosis associated with megakaryocytic hyperplasia, and a JAK2 V617F, CALR, or MPL mutation is observed in the absence of the clinical or laboratory features of one of the other myeloproliferative neoplasms such as polycythaemia vera or primary myelofibrosis, a diagnosis of essential thrombocythaemia is certain. Unfortunately, for the other 10% of the patients with essential thrombocythaemia who lack the above-​mentioned mutations the diagnosis remains one of exclusion, although haematopoietic cell clonality assays are frequently useful in women. Such patients who are thought to have essential thrombocythaemia based upon marrow histopathology in the absence of the formerly mentioned three mutations are referred to as triple-​ negative essential thrombocythaemia. Platelet function abnormalities are commonly found and include defective platelet aggregation in response to adrenaline, ADP, and collagen. Aggregation in response to arachidonic acid and ristocetin is often normal. An acquired platelet storage pool disease also occurs

due to abnormalities in the content and release of α granules associated with a state of increased platelet activation. Cytogenetic evidence for a Philadelphia chromosome and/​or the molecular identification of the BCR-​ABL1 fusion gene aids in distinguishing essential thrombocythaemia from chronic myeloid leukaemia. The presence of dyspoietic changes in bone marrow precursor cells and of characteristic chromosomal abnormalities suggests the diagnosis of myelodysplasia. In particular, the 5q–​syndrome is associated with thrombocytosis. More recently, mutations in splicing genes (e.g. SF3B1) have been described in refractory anaemia with ringed sideroblasts and thrombocytosis (RARS-​T), which has features of both a myelodysplastic syndrome and myeloproliferative neoplasm and is classified as such in the World Health Organization (WHO) classification. The diagnostic criteria and management of the other myeloproliferative neoplasms associated with thrombocytosis are outlined in other chapters. Distinguishing essential thrombocythaemia from prefibrotic primary myelofibrosis can be challenging; the presence of an elevated lactate dehydrogenase, systemic symptoms, leucocytosis, or a leucoerythroblastic smear with minimal fibrosis on bone marrow biopsy still may suggest prefibrotic primary myelofibrosis rather than essential thrombocythaemia despite the presence of thrombocytosis. Careful consideration of the diagnostic features by WHO criteria between essential thrombocythaemia and prefibrotic myelofibrosis is important from a prognostic standpoint, as retrospective data suggest the latter have a reduced survival associated with increased risk for evolution to overt myelofibrosis and acute leukaemia. Cytogenetic abnormalities occur in approximately 5% of patients with essential thrombocythaemia, and the most common are 1q–​, 20q–​, 21q–​, and 1q+. Elevated vitamin B12 levels occur in 25% of patients.

Diagnostic criteria and differential diagnosis The revised WHO diagnostic criteria for essential thrombocythaemia are given in Box 22.3.6.2. Essential thrombocythaemia was

Box 22.3.6.2  2016 WHO criteria for the diagnosis of essential thrombocythaemia Major criteria 1 Platelet count of at least 450 × 109/​litre. 2 Bone marrow biopsy showing proliferation mainly of the megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei. There should be no significant increase or left shift in neutrophil granulopoiesis or erythropoiesis and very rarely minor (grade 1) increase in reticulin fibres. 3 Not meeting WHO criteria for chronic myeloid leukaemia, polycythaemia vera, primary myelofibrosis, myelodysplastic syndrome, or other myeloid neoplasm. 4 Demonstration of JAK2 V617F, CALR, or MPL mutations or other clonal marker. Minor criterion 1 Presence of another clonal marker or absence of evidence for reactive thrombocytosis. Diagnosis of essential thrombocythaemia requires all four of the following major criteria or presence of the first three major criteria and the one minor criterion Source data from Arber DA, et  al. (2016). The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia. Blood, 127, 2391–​405.

5243

5244

SECTION 22  Haematological disorders

previously a diagnosis of exclusion, but the advent of JAK2 V617F, CALR, and MPL mutational analyses have greatly facilitated the diagnosis in approximately 90% of cases. The presence of these mutations in the setting of thrombocytosis without evidence of polycythaemia vera is virtually diagnostic of essential thrombocythaemia. These diagnostic criteria are, however, of less use in paediatric patients since many of these individuals are JAK2 V617F negative. Thrombocytosis may be the consequence of primary bone marrow disorders associated with increased platelet production (nonreactive thrombocytosis), or a secondary response to an underlying disorder (reactive thrombocytosis). Box 22.3.6.1 summarizes the most important causes of thrombocytosis:  iron deficiency anaemia, infection/​inflammation, malignancy, trauma, and hyposplenism, are the most commonly encountered disorders. The exclusion of an identifiable cause for reactive thrombocytosis, in particular iron deficiency, is a necessary step.

Risk assessment Essential thrombocythaemia is a heterogeneous disorder associated with patients encountering a varied risk of developing life-​ threatening complications. Many patients enjoy survival fairly similar to that of their unaffected peers but a subset of patients is at a high risk of developing additional thromboses. Myelosuppressive therapy should be reserved for patients at a high risk of developing such thrombotic complications. A  risk-​based decision approach to therapy is outlined in Table 22.3.6.1 to identify such patients. Advanced age (≥60  years) and a previous history of thrombosis clearly define a group at high risk for the development of life-​ threatening complications. The degree of thrombocytosis and the presence of associated cardiovascular risk factors, particularly smoking and obesity, are also taken into consideration when making treatment decisions. The International Prognostic Score for Thrombosis in Essential Thrombocythemia (IPSET) uses patient age, thrombosis history, and cardiovascular risk factors but additionally recognizes that the presence of a JAK2 V617F mutation predisposes additional thrombotic risk. The utility of this scoring system to guide treatment decisions is unknown at this time since it has not been validated in a prospective fashion. In addition, it does not predict the risk for evolution to myelofibrosis or acute leukaemia. Isolated thrombocytosis per se is not an indication for therapy; however, it is common practice to treat extreme thrombocytosis (platelet count >1500 × 109/​litre) because of the increased risk of bleeding rather than thrombotic complications. The use of CALR, JAK2, or MPL mutation status is not currently incorporated into risk assessment for therapeutic decision although increasing data suggest that these are distinct clinicopathological entities.

Treatment The present goal of therapy in essential thrombocythaemia is to control symptoms and prevent thrombotic and haemorrhagic complications. Should a decision be made to treat the patient based on risk assessment, the platelet count should be reduced to 400 × 109/​litre. Although no target platelet count has been determined to be optimal to reduce the incidence of thrombotic episodes in rigorous clinical trials, this is considered a safe level by most practising physicians in the field. A number of agents are effective in the treatment of essential thrombocythaemia. Low-​ dose aspirin (81–​ 100 mg/​ day) has been

shown to be safe and may decrease the recurrence of microcirculatory events (erythromelalgia/​transient ischaemic attacks) and prevent the development of other thrombotic phenomena, especially in combination with myelosuppressive agents in high-​risk patients. In order to minimize the risk of iatrogenic bleeding, only patients with platelet counts less than 1500 × 109/​litre and without evidence of an acquired von Willebrand’s disease should be considered for low-​dose aspirin administration. The use of hydroxycarbamide, an antimetabolite that interferes with DNA repair, decreased the number of thrombotic events in a randomized study of high-​risk patients when given at 15 mg/​kg initially, with subsequent adjustments based on initial response. In this study, the target was a platelet count of less than 600 × 109/​litre. It is unknown whether tighter control (60 Hz). One way to try to unify these disparate aspects of basal ganglia physiology into a functional whole is to first consider the basal ganglia as having a strong inhibitory bias. Therefore, although STN neurons fire quite consistently in response to cortical activity, fed to them via the hyperdirect pathway, this is not translated on the whole into changes in firing from basal ganglia output nuclei (GPi/​SNr), due to strong inhibitory control from the striatum, and therefore the tonic inhibitory discharge of the basal ganglia output continues. However, in the presence of dopamine, this situation is reversed, and the net effect of dopamine on the direct and indirect pathways causes a shift in basal ganglia output firing, allowing the information carried in the subthalamic nucleus firing patterns to be fed through to the thalamus. This occurs in a strictly segregated way, and the topography of input is preserved. In disease, there is a shift towards more synchronous firing within the basal ganglia with, in the case of Parkinson’s disease, a shift towards low-​frequency oscillations even when movement is attempted, reflecting a loss of the normal modulation of firing patterns during movement. In dystonia, a hyperkinetic disorder, the GPi shows lower firing rates compared with Parkinson’s disease (as would be predicted by the rate model), but in addition there are more frequent and irregular bursts seen with long pauses of absent activity. This might link to the clinical picture of dystonia with excessive muscle activation that stops and starts with shifting coactivation of agonists and antagonists, leading to abnormal posture, writing movements,

and often a jerky tremor. Synchronization of firing across the basal ganglia undermines its ability to focus and concentrate activation in a topographically discrete manner.

Function and dysfunction The earlier discussion is complex, but reflects the evolving understanding of the functional role of the basal ganglia. The basal ganglia are hypothesized to have four main roles, all of which have most often been related to the motor function of the basal ganglia: 1 To release a desired movement from inhibitory control (e.g. before

a desired eye movement the tonic discharge of the basal ganglia output nuclei drops, and this allows the movement to occur). 2 To inhibit undesired movement: in the motor system this would be reflected in the highly topographically organized nature of basal ganglia input and output. Therefore, as well as releasing the desired movement, the basal ganglia appear to play a key role in inhibiting other movements. This focusing role is also known as centre-​ surround inhibition, where the desired movement (centre) is surrounded by an area of undesired movement that is actively inhibited. 3 To facilitate sequential automatic movements: in motor learning experiments, basal ganglia activity tends to increase as learning occurs. This is thought to reflect a role for the basal ganglia in coding sequences of movements that become automated. This may explain the particular difficulty showed by patients with Parkinson’s disease in performing multistage automatic movements, such as turning over in bed. 4 To integrate attentional, reward, and emotional information into movement and learning: via the connections of the limbic system with the ventral striatum, the basal ganglia form an important location for the integration of motivational and emotional information with motor behaviour. This is particularly the case for reward-​based learning. It has been suggested that the basal ganglia can be seen as integrating two aspects of reward-​based learning: the ‘critic’, the ventral striatum system that holds information on how motivated the organism is towards a particular goal; and the ‘actor’, the dorsal striatum that holds information on the motor behaviour needed to achieve that goal. These various functions are certainly biased towards the motor system, but it is clear, from both the discussion of basal ganglia connections above, and the symptoms displayed by patients with disorders of the basal ganglia, that non​motor aspects of behaviour are strongly linked to the function of the basal ganglia. It may be particularly the case for motivation and reward-​based learning, for example, lesions of the caudate nucleus have been associated with the psychiatric syndrome of abulia—​a syndrome of apathy and lack of motivation that is thought to reflect failure of normal reward-​based motivational mechanisms. The movement disorders are hypothesized to reflect dysfunction within the basal ganglia, although, surprisingly, it is difficult to mimic some of these disorders simply by lesions to the basal ganglia alone. Thus, tics and myoclonus rarely occur in humans as a consequence solely of basal ganglia lesions. Likewise, chorea rarely occurs from lesions to the caudate nucleus alone, as one might expect given the degeneration of this nucleus in Huntington’s disease. Parkinsonism, combining akinesia (slowness—​bradykinesia) and

5943

5944

section 24  Neurological disorders

progressive fatiguing of repetitive movement), rigidity (stiffness of muscles in flexion and extension), rest tremor of 5–​6 Hz, and postural instability, can be seen in response to discrete lesions of the SNc. In terms of the various functions of the basal ganglia already outlined here, both rigidity and akinesia could be seen as reflecting an inability to release the desired movement (akinesia) and a failure to inhibit undesired movement (rigidity). In Parkinson’s disease, clear deficits in reward-​related learning and performance of integrated automatic movements are seen, together with emotional and motivational problems. Dystonia can also be produced by discrete basal ganglia lesions (usually to the putamen) and, in terms of the basal ganglia functions outlined here, dystonia could reflect an inability to inhibit unwanted movement, leading to the typical clinical picture of overflow of activity into adjacent muscles and cocontraction of agonists and antagonists. The huge variety of clinical presentation of movement disorders no doubt reflects the interaction of basal ganglia dysfunction with dysfunction caused by neurological disease elsewhere in subcortical and cortical areas.

Thalamus Gross anatomy The two thalami sit at the head of the brainstem, their medial borders largely separated by the third ventricle, but often partially fused as the massa intermedia. They constitute the largest nuclear mass in the diencephalon (the others being the hypothalamus and subthalamus). On the lateral surface of the thalamus is the external medullary lamina, containing thalamocortical and corticothalamic fibres either entering or exiting the internal capsule. The external medullary lamina and the internal capsule are separated by a thalamic nucleus called the reticular nucleus. The internal structure of the thalamus, already complex, is further confused by the existence of different nomenclatures (the one used here being that of Wessler). Inside the thalamus the internal medullary lamina (consisting of fibres leaving or entering the various thalamic nuclei) roughly divides the thalamus into three groups of nuclei—​lateral, medial, and anterior—​with each subdivided into ventral and dorsal areas. There are further nuclei that are not defined by this ventral/​dorsal system such as those that lie within the internal medullary lamina (the intralaminar nuclei), and others such as the lateral and medial geniculate and the pulvinar. The blood supply to the thalamus derives from the posterior circulation via the posterior cerebral arteries and perforators from the terminal part of the basilar artery.

nuclei in the ventral thalamus (particularly the intralaminar nuclei) project mainly to the basal ganglia via glutamatergic projections.

Functional anatomy The thalamus is in an ideal position to modulate information flow to and from the cortex. Although previously this role had been thought of as a mainly passive relay station, it is clear that the thalamus has a much greater role in moulding the information that passes through it than previously realized. Thalamic afferents arrive from five main sources. 1 Afferents from special senses (except olfaction): touch (from the

body—​ventral posterolateral nucleus; face—​ventral posteromedial nucleus), taste (ventral posteromedial nucleus), vision (lateral geniculate nucleus), and hearing (medial geniculate nucleus) 2 Afferents from the output nuclei of the basal ganglia:  GPi (centromedian nucleus, ventral anterior nucleus, ventral lateral nucleus oralis and medialis) and SNr (mediodorsal nucleus and ventral anterior nucleus magnocellularis) 3 Afferents from the cerebellum: ventral lateral nucleus caudalis, to the ventral posterolateral nucleus oralis 4 Cortical afferents from many cortical areas: mainly synapse on dorsal thalamic nuclei 5 Afferents from the brainstem reticular formation Efferents from the thalamus from three main groups: 1 Efferents from thalamic nuclei to representative areas of the

cortex determined by the input to the nucleus (e.g. afferents from the retina project to the lateral geniculate nucleus, which then projects to the visual cortex) 2 Efferents to cortical areas that project directly to the thalamus (corticothalamocortical loops) 3 Efferents to the striatum (mainly from the intralaminar nuclei) The functional anatomy of thalamic circuits has been most closely studied for the visual system, and this can serve as a model for other thalamic circuits (Fig. 24.7.1.8). In the visual system, the “SECOND ORDER RELAY”

VISUAL CORTEX Areas 4 and 6

“FIRST ORDER RELAY”

Cytoarchitecture Before discussing the functional anatomy of the thalamus, we briefly summarize its cellular structure. The main output cells of the thalamus are called relay cells. These form excitatory glutamatergic projections to the cortex. These cells receive multiple inputs including GABA-​ ergic inputs from interneurons within the thalamus, cholinergic input from the brainstem reticular formation, as well as glutamatergic input from particular cortical areas (usually those areas to which the relay cells then project back, forming corticothalamocortical loops). Relay cells have two modes of firing—​a burst mode and a tonic mode—​ which may have different functions (see next). Relay cells are mainly contained in the dorsal thalamic nuclei (the relay nuclei), whereas

RELAY CELLS OF LATERAL GENICULATE NUCLEUS

SENSORY INPUT FROM RETINA

THALAMIC RETICULAR NUCLEUS

THALAMIC INTERNEURONS BRAINSTEM RETICULAR FORMATION

Fig. 24.7.1.8  Main connections of the lateral geniculate nucleus as an example of primary and secondary relays in the thalamus. Black arrows indicate inhibitory connections, white arrows indicate excitatory connections.

24.7.1  Subcortical structures

main input to be relayed to the appropriate area of cortex comes from the retina, but, interestingly, this forms only about 5% of the input to the relevant thalamic nucleus: the lateral geniculate body. The rest of the input comes from a variety of sources including inhibitory input from thalamic interneurons and the thalamic reticular nucleus, excitatory input from the brainstem reticular formation, and layer 6 of the visual cortex. Output from the lateral geniculate is then primarily to layers 4 and 6 of the visual cortex. This system therefore has a primary function: transfer of visual information from the retina to the visual cortex (sometimes called the driver function or first-​order relay), but this is subject to a huge amount of modulation from other areas, both cortical and brainstem. A secondary system, often called the higher-​order relay, is distinguished from this first-​order system. This system takes cortical information down to the thalamus (typically the dorsal nuclei), and then back again to the same area (corticothalamocortical loops). As for the first-​order system, this circuit is subject to multiple modulatory inputs at the thalamic level. Of course, the cortical areas projecting as higher-​order relays may have themselves been influenced by first-​order relays, leading to a complex series of loops integrating and modulating information flow to and from the cortex. One of the most important modulating forces at work in the thalamus arises from the brainstem reticular activating complex. This is demonstrated by the massive decease in thalamic activity seen during sleep, and the potential of certain thalamic lesions to cause coma. The influence of the reticular activating complex may occur via its ability to cause the ‘burst’ pattern of firing in thalamic relay cells. It is hypothesized that this is a ‘wake-​up’ signal to the cortex, causing diversion of attention to the particular input in question, following which relay cells switch to their normal regular tonic discharge.

Function and dysfunction The previous discussion clearly demonstrates the role of the thalamus as more than a neuronal rest stop on the way to and from the cortex. The main functions of the thalamus are thought to include: • modulation of sensory information by integration of brainstem (in particular, the reticular activating complex) and relevant cortical information • modulation of cortical activity via corticothalamocortical loops A diverse range of clinical consequences of thalamic lesions has been described, as one would expect from a region where so many different information flows coalesce (e.g. sensory abnormalities are reported with thalamic lesions), from pure hemisensory loss to deep-​seated, severe pain. Mild hemiplegia may be seen with thalamic lesions, sometimes in combination with hemisensory loss, dysaesthesia, hemiataxia, astereognosis, and hemichorea as in the thalamic syndrome of Déjèrine and Roussy. Other lesions, often spreading outside the thalamus to involve the basal ganglia, have been associated with myoclonus, dystonia, or a slow 3–​4 Hz tremor of the limbs on one side of the body. Lesions of the ventral

lateral nucleus caudalis (also known as the ventral intermediate nucleus) have been used as a treatment for parkinsonian and essential tremor.

Conclusions These three subcortical structures, the cerebellum, basal ganglia, and thalamus, provide the bridge over which information passes to and from the periphery and the cerebral cortex. Through their intricate structure and interconnections, they play a major role in modulating and integrating this information. The recent discovery of a hitherto unknown direct connection between the cerebellum and the basal ganglia again underlines the importance of considering these structures as part of a coordinated system rather than in isolation. The question ‘What does the cerebellum/​basal ganglia/​thalamus do?’ therefore becomes slightly nonsensical, because in fact they do nothing in isolation, and function only as part of a system. This system can certainly be affected in particular ways by dysfunction of one of its parts, but the results of discrete lesions are often hard to predict and may have wide-​ranging consequences for motor and non​motor behaviour.

FURTHER READING Apps R, Garwicz M (2005). Anatomical and physiological foundations of cerebellar information processing. Nat Rev Neurosci, 6, 297–​311. Brown P (2003). Oscillatory nature of human basal ganglia activity: relationship to the pathophysiology of Parkinson’s disease. Mov Disorders, 18, 357–​63. Hammond C, Bergman H, Brown P (2007). Pathological synchronization in Parkinson’s disease: networks, models and treatments. Trends Neurosci, 30, 357–​64. Hoshi E, et al. (2005). The cerebellum communicates with the basal ganglia. Nature Neurosci, 8, 1491–​3. Lehericy S, et  al. (2001). Clinical characteristics and topography of lesions in movement disorders due to thalamic lesions. Neurology, 57, 1055–​66. Lera G, et al. (2000). A combined pattern of movement disorders resulting from posterolateral thalamic lesions of a vascular nature: a syndrome with clinico-​ radiologic correlation. Mov Disorders, 15, 120–​6. Middleton FA, Strick PL (1994). Anatomical evidence for cerebellar and basal ganglia involvement in higher cognitive function. Science, 266, 458–​61. Middleton FA, Strick PL (2000). Basal ganglia and cerebellar loops: motor and cognitive circuits. Brain Res Brain Res Rev, 31, 236–​50. Nambu A (2004). A new dynamic model of the cortico-​basal ganglia loop. Prog Brain Res, 143, 461–​6. ] Obeso JA, Rodriguez MC, DeLong MR (1997). Basal ganglia pathophysiology: a critical review. Adv Neurol, 74, 3–​18. Obeso JA, et  al. (2000). Pathophysiologic basis of surgery for Parkinson’s disease. Neurology, 55, (12 Suppl 6), S7–​12. Rothwell JC (1994). Control of human voluntary movement, 2nd edition. Croom Helm, London.

5945

5946

section 24  Neurological disorders

24.7.2  Parkinsonism and other extrapyramidal diseases Elisaveta Sokolov, Vinod K. Metta, and K. Ray Chaudhuri ESSENTIALS Parkinson’s disease Parkinson’s disease affects about 0.2% of the population, including 2% of those over 80 years of age. The number diagnosed is expected to double from 4.1 million people diagnosed in 2005 to 8.7 million by 2030 owing to a rise in life expectancy and better diagnosis (Tanner CM, Brandabur M, Dorsey ER. Parkinson Report, Spring 2008). The main pathological feature is degeneration of neuromelanin-​ containing neurons and Lewy body inclusions in the pars compacta of the substantia nigra, which leads directly and indirectly to excessive inhibition of the thalamus and consequent bradykinesia. However, seminal studies in the early 2000s by Braak et al. suggest that the condition starts earlier and, from a pathological point of view, stage 1 of the disease begins with Lewy body deposition at the olfactory system and the dorsal vagal nucleus in the lower medulla, with degeneration of the olfactory bulb and the anterior olfactory nucleus. Clinically, this represents olfactory dysfunction and late-​onset hyposmia is recognized as one of the earliest symptoms of Parkinson’s disease, often preceding the development of the cardinal motor signs by up to 20 years. During stage 2 there is progression of neuropathology to the nuclei of the caudal brainstem (the locus coeruleus and other nuclei), which are key areas mediating many non​motor symptoms such as sleep homeostasis, depression, fatigue, cognitive problems, pain, and constipation. Several of these symptoms, particularly rapid eye movement behavioural disorder are now recognized as pre-​motor features of Parkinson’s disease. Stage 3 is when patients are usually referred to the clinic as the substantia nigra is involved and patients start exhibiting classical motor features. Clinical features—​ these include motor:  (1) bradykinesia; the most disabling and progressive motor symptom; (2) resting tremor (4–​7 Hz); often the presenting symptom/​sign, and often unilateral; (3) rigidity; cogwheel or lead pipe; (4) postural imbalance; fixed and stooped posture; (5) gait difficulty; shuffling and small steps, with or without festination; (6)  other features; hypomimia (‘masked’ face), freezing episodes (sudden failure of movement), seborrhoea of the scalp. Non​motor symptoms are now considered integral to Parkinson’s disease and comprise of a wide range of problems. These include: (1) hyposmia, constipation, bladder disturbance; (2) sleep disorder; (3) dementia and other cognitive dysfunctions; (4) depression and anxiety; (5) chronic and regional pain; (6) fatigue; (7) sexual and autonomic dysfunction; (8) drug-​induced problems such as impulse control disorder. Investigation and treatment—​there are as yet no specific tests for Parkinson’s disease and diagnosis remains largely clinical. However, single photon emission computed tomography imaging with DAT scan is a valuable adjunct to clinical suspicion of the diagnosis. First-​line drug treatment remains controversial and levodopa (in

combination with a decarboxylase inhibitor), dopamine agonists (oral or transdermal) or monoamine oxidase-​B inhibitors are all effective and treatment needs to be individualized depending on the patient’s age, occupation, dominant side affected as well as expectations/​life style. Additionally, local funding policies might influence treatment decisions. Many authorities believe early treatment as soon as diagnosis is made (usually motor diagnosis as the condition may have been present for many years manifesting non​motor symptoms) should be started, while some believe in a ‘wait and watch’ policy. Advanced therapeutic options consist of apomorphine injections (for rapid and reproducible ‘rescue’ from predictable off periods) and infusions, deep brain stimulation of the subthalamic nucleus or globus pallidus and intrajejunal levodopa infusion. Gastrointestinal problems such as delayed gastric emptying are highly prevalent in Parkinson’s disease and, as such, modern therapy has also focussed on non​oral therapies such as transdermal dopamine agonists as well as the advanced therapies. Stem cell, gene therapy-​based and neurotrophic factor-​related regenerative therapies remain experimental.

Other parkinsonian and extrapyramidal diseases Drug-​ induced parkinsonism; dopamine-​ blocking agents (neuroleptics) such as prochlorperazine or chlorpromazine are the most common offending agents. Vestibular sedatives (used for motion sickness) are also implicated. Progressive supranuclear palsy; typically presents with gait disturbance and falls (backwards predominantly). Examination reveals supranuclear gaze palsy, particularly of downgaze, with extension and rigidity of the neck, a staring look due to lid retraction, and bradykinesia/​akinesia. Multiple system atrophy—​comprises a variable degree of parkinsonism with autonomic (postural hypotension), pyramidal or cerebellar symptoms and signs. Any response to levodopa is commonly incomplete (except the parkinsonian variant) and short-​lived. Clinical variants of progressive supranuclear palsy (a parkinsonian variant responding to levodopa) as well as multiple system atrophy (parkinsonian, cerebellar, and minimal change) has been described. Dementia with Lewy bodies—​manifestations include fluctuations in cognition and attention, recurrent and persistent visual hallucinations, and parkinsonian motor signs. Corticobasal ganglionic degeneration—​characterized by progressive gait disturbances, cortical sensory loss, and stimulus-​sensitive myoclonus which results in a jerky, useless hand. Dopa-​responsive dystonia—​characteristically shows marked diurnal variation; may start in childhood with an odd and unusual gait; diagnosed by finding mutation in the GTP-​cyclohydrolase gene; excellent and sustained response to low-​dose levodopa. Other rare conditions mimicking parkinsonism include genetic variants of Parkinson’s disease (autosomal dominant and recessive), Wilson’s disease, neuroacanthocytosis, vascular pseudo-​parkinsonism, neuronal brain iron accumulation syndromes and neuro ferritinopathy.

Other movement disorders Dystonia—​a syndrome of sustained muscle contractions, which may be focal, multifocal, or generalized, genetic, or idiopathic. Particular causes include (1) generalized idiopathic torsion dystonia; (2) tardive dyskinesia; induced by long-​term exposure to dopamine-​blocking drugs; involuntary movements usually begin with the face and mouth. See Chapter 24.7.3 for further discussion.

24.7.2  Parkinsonism and other extrapyramidal diseases

Chorea and related disorders—​chorea is an irregular, rapid, uncontrolled, involuntary, excessive movement that seems to move randomly from one part of the body to another; athetosis is a slower writhing and twisting movement. Causes include Huntington’s disease and Sydenham’s chorea (associated with rheumatic fever). See Chapter 24.7.3 for further discussion. Tics—​these are sudden, repetitive, stereotyped, non​rhythmic, involuntary movement (motor tic) or sound (phonic tic); when treatment is required, they generally respond to drugs that decrease dopaminergic transmission.

Introduction The human basal ganglia is a complex functional organization, with important interconnections with the nigrostriatal pathway, which dominates the dopaminergic innervation of the striatum (caudate nucleus and the putamen). Additionally, the globus pallidus, thalamic nuclei, the subthalamic nucleus and the pedunculopontine nucleus all play important regulatory and excitatory/​inhibitory roles. Neuronal loops also interconnect the basal ganglia with the cerebellum as well as the cortex, and function is mediated by dopamine as well as a complex array of neuropeptides such as serotonin, acetylcholine, catecholamines, adenosine, and γ-aminobutyric acid. The principal clinical syndromes are Parkinson’s disease (PD); other syndromes with parkinsonian features (including drug-​induced parkinsonism); progressive supranuclear palsy; multisystem atrophy; dementia with Lewy bodies; neuroacanthosis; torsion dystonia; and chorea. Apart from the use of dopaminergic agents, several drugs have beneficial effects in the management of parkinsonism and other extrapyramidal diseases.

Both the incidence and prevalence of PD increase with age, and the prevalence may be as high as 1 in 50 for patients over the age of 80 years. Men are 1.5 times more likely than women to develop the condition. Hospital-​based studies and a limited number of epidemiological surveys in Africa have suggested that PD is less common in the black population, although this observation remains controversial.

Risk factors Although PD was first described almost 200 years ago, it remains difficult to define exactly which individuals are at risk. The ageing process is related to the development of PD but is not solely responsible, because some patients develop the disease early in life. Furthermore, the type of dopamine cell loss in normal ageing differs from that in PD. Certain personality traits and environmental factors may increase the risk of PD (Box 24.7.2.1). People with a family history of Parkinson’s disease, particularly first-​degree relatives, are also at higher risk of developing the disease. It has been postulated that people may be affected differently by a combination of genetic and environmental factors. A possible role of an environmental toxin was triggered by the fascinating observation that 1-​methyl-​4-​phenyl-​1,2,3,6-​tetrahydropyridine (MPTP), accidentally consumed as an illicit drug contaminant in the United States of America in the late 1970s and early 1980s, caused an outbreak of levodopa-​responsive parkinsonism. This led to the development of MPTP as an experimental agent to cause selective nigrostriatal cell loss in animal models. Recently, similar observations have been made in people in the welding trade, fuelling the hypothesis that manganese may be a causative factor. There have been conflicting reports about environmental agents that may predispose to PD. These are listed in Box 24.7.2.1.

Parkinson’s disease Parkinson’s disease was first described by the London physician James Parkinson in 1817, and later named after him by Charcot. Parkinson’s disease is one of the most important disabling illnesses of later life. It is estimated to affect 1% of those aged 70 years, but is also seen in younger people, with 10% of cases occurring before the age of 50.

Epidemiology, incidence, and prevalence The exact estimation of the incidence and prevalence of PD is problematic, because there is no ‘in-​life’ marker for idiopathic PD; estimates of the annual incidence of PD are in the range of 4–​20 per 100 000 individuals. A  widely accepted figure for the prevalence of Parkinson’s disease is approximately 200 per 100 000 population. In the United Kingdom, there are approximately 120 000 to 130 000 diagnosed cases, but there may be many more who remain undiagnosed. In the United States of America, it is estimated that between 750 000 and 1.5 million people have the condition.

Genetic factors The study of monogenetic forms of PD could lead to identification of new drug targets which may translate into new treatments for sporadic PD. Individuals with a positive family history have twice the risk of developing PD and the risk for siblings is increased significantly if there is an affected sibling with young-​onset PD. The risk increases further to 12–​24% if both a sibling and a parent are affected (see Box 24.7.2.1). α-​Synuclein was the first gene to

Box 24.7.2.1  Personality trends and environmental factors Personality trends • Obsessive–​compulsive disorder Environmental factors (poor association) • Drinking well water • Insecticide/​pesticide exposure • Manganese exposure (welding) • N-​Methyl-​4-​phenyl-​1,2,3,6-​tetrahydropyridine (MPTP) (strong association in producing parkinsonian syndrome)

5947

5948

section 24  Neurological disorders

Table 24.7.2.1  Genetics of parkinsonism Symbol

Inheritance

Product

Location

Gene

PARK1

AD

α-​Synuclein

4q21.3–​q23

SNCA

PARK2

AR, juvenile onset

Parkin

6q25.2–​q27

Parkin

PARK3

AD, Lewy body

Unknown

2p13

SNCA

PARK4

AD, Lewy body

Unknown

4p15

SNCA

PARK5

AD

Ubiquitin C-​terminal hydrolase 1

4p14

UCHL1

PARK6

AR, early onset

PTEN-​induced putative kinase 1

1p35–​p36

PARK7

AR, early onset

DJ-​1 protein

1p36

PARK8

AD

Leucine-​rich repeat kinase 2 (LRRK2)

12p11.2–​q13.1

PARK9

AR

ATPase type 13A2. Kufor-​Rakeb syndrome

1p36

Unknown

1p32

PARK10 PARK11

GRB 10 interacting GYF protein 2

2q37.1

PARK12

X-​linked

Unknown

Familial

PARK13

AD

HtrA serine peptidase 2

2p12

PARK14

AR

PLA2G6

22q13.1

PARK15

Susceptibility locus

F-​box protein 7

1q32

PARK16

AR

Glucocerebrosidase

1q21

DCTN1

AD

Dynactin 1 Perry syndrome

DYT12

AD

Dystonia 12 Rapid onset dystonia parkinsonism

VPS35

Vacuolar sorting protein 35

EIF4G1

Eukaryotic translation initiation factor 4 γ-1

be identified in a multigeneration Italian–​American family (the Contursi family) as causing an aggressive parkinsonism. Since then several genes have been identified, with Parkin and LRRK2 being the most prevalent ones (Table 24.7.2.1). LRRK2 stands for leucine-​rich repeat kinase 2 and is part of the family of Roco genes; it encodes for the protein dardarin. LRRK2 has been associated with familial late-​onset PD and a few cases of sporadic late-​ onset disease. It is possible that LRRK2 activity influences onset of symptoms and any treatment that lowers risk in LRRK2 associated monogenic PD could delay symptom onset in sporadic PD. The precise function of these genes is unknown, although α-​synuclein is the core protein in Lewy bodies whereas parkin may be active through the ubiquitin pathway. Mutations can cause autosomal dominant (SNCA, LRRK2, VPS35), or autosomal recessive (Parkin, DJ1, PINK1, ATP13A2) familial PD. Additionally some of these genes can incur polymorphisms, which are subsequent risk factors for PD. Other important and relatively common risk factors for parkinsonism include mutations in the glucocerebrosidase (GBA) gene, which encodes the lysosomal enzyme that is deficient in Gaucher’s disease. There may be a gain-​of-​function that promotes α-​synuclein aggregation. Studies have shown that patients with PD and associated Lewy body disorders had an increased frequency of GBA mutations when compared to controls. Patients with GBA-​associated

Heterozygous mutations appear to confer susceptibility for classic PD, while homozygous mutations cause Gaucher’s disease

p.Asp620Asn (D620N) Reported in monogenic and sporadic PD. Unclear as to its pathogenicity

parkinsonism can present with more cognitive features and an early age of onset. DNA methylation patterns vary with age, and ageing alone is a major confounding risk factor for PD. Epigenetic modification of α-​synuclein, for example, hypomethylation, is evident in sporadic PD patients’ blood. The analysis of α-​synuclein methylation can identify non​parkinsonian patients which offers a valuable instrument for researchers and clinicians. Overall, late-​onset PD is affiliated with autosomal dominant forms (except SNCA triplications) and early onset PD is affiliated with autosomal recessive forms and SNCA triplication. Autosomal dominant forms often present with a prominent tremor or tremor involving the legs suggesting LRRK2, and lack of tremor is associated with SNCA-​related disease. These clues may give the clinician an idea of which genes to start testing first. However, routine genetic testing for PD is not available, nor is genetic counselling currently possible.

Pathophysiology The main pathological feature of PD, is the degeneration of neuromelanin-​ containing neurons in the pars compacta of the substantia nigra, which leads to deafferentation of the striatum.

24.7.2  Parkinsonism and other extrapyramidal diseases

Cortex Prefrontal insular

Cingulate sensory motor + +

D1

−

+

++ −−

GPe

+

D2

++

−

++

Premotor prefrontal +

Stratium

SNr GPi

Glu DA GABA subst P enk

+ Thalamus VA/VL −−

SNc

STN

Suppl. motor premotor

+ = excitatory − = inhibitory

− − −−

Brainstem SC

Fig. 24.7.2.1  Pathological functional anatomy of the basal ganglia in Parkinson’s disease.

Normally, it has been suggested that the basal ganglia exert their motor and non​motor effects through a complex circuitry. The two main pathways are the direct (stimulatory) and indirect (inhibitory) pathways, a balance in favour of the direct pathway being kept by regulatory control exerted by dopamine manufactured in the substantia nigra. In PD, dopamine cell degeneration leads to overexcitation of the direct circuit, and the resultant bradykinesia, by a complex pathway that also involves paradoxical excitation of the subthalamic nucleus and internal segment of the globus pallidus. The net result of both the direct and indirect pathways in the absence of dopamine is overexcitation of the medial globus pallidus, leading to excessive inhibition of the thalamus. Thalamic input to the motor cortex is excitatory and thus thalamocortical inhibition leads to akinesia and other symptoms of PD (Fig. 24.7.2.1). Lewy bodies are intracytoplasmic eosinophilic inclusion bodies, typically found in the neurons of the substantia nigra. The pathophysiological basis of PD has recently been re-​explored by Heiko Braak, who has suggested that Lewy body formation, a hallmark of dopaminergic cell degeneration in PD, actually occurs in the brainstem, in the lower medulla and the olfactory bundle (stage 1 Parkinson’s disease—​Fig. 24.7.2.2a). In stage 2 more dorsal medulla and pons are involved (Fig. 24.7.2.2b) whereas it is at stage 3 that the midbrain and the substantia nigra are involved (Fig. 24.7.2.2c). According to this hypothesis, therefore, clinical Parkinson’s disease is being detected only at stage 3. In support of this observation is the fact that several non​motor features of PD, for example, olfactory loss and sleep disorders such as rapid eye movement disorder (RBD), seem to occur from the brainstem and olfactory bundle involvement, and in fact precede the development of motor PD. A list of such non​motor features that may actually precede the development of motor signs of PD and may in future detect people ‘at risk’ of Parkinson’s disease is listed in Box 24.7.2.2. A recent twist to the pathophysiological basis of Parkinson’s disease is the observation that positron emission tomography (PET) of the brain in Parkinson’s disease identifies neuroinflammation in the brainstem, suggesting that the pathological process in Parkinson’s disease may be initiated by an inflammatory process within the glial cells.

Symptoms and signs Parkinsonism is a clinical syndrome and typically, when the condition appears to be idiopathic and in particular responds to levodopa therapy, it is referred to as Parkinson’s disease. Often the presenting symptom is a slow resting tremor, worse at rest (4–​7 Hz) and often unilateral, although up to 30% of cases do not have a tremor at onset of the disease. The presence of an obvious tremor often leads both patients and their carers to suspect Parkinson’s disease and self-​referral. In this context, it is important to differentiate an essential tremor from a parkinsonian tremor because the former carries a more benign prognosis and is twice as common, with a prevalence of at least 400 per 100 000 (Table 24.7.2.2). Bradykinesia/​akinesia is difficulty in initiating, and slowness in executing, movement. It is the most disabling and progressive motor sign of PD and is a core feature for diagnosis of PD using the United Kingdom Parkinson’s Brain Bank criteria (Box 24.7.2.3). It first affects fine movements such as fastening buttons and handwriting, which becomes smaller and may progressively trail off (micrographia). Associated movements suffer, and arm swing may decrease unilaterally or bilaterally.

Diagnosis of parkinsonism Gait is affected in PD, with difficulty starting walking, small steps, and shuffling. ‘Festination’ occurs when the patient appears to hurry and then stops suddenly as if rooted to the ground. The face often becomes expressionless (masked face or hypomimia) with reduced blinking. Bradykinetic laryngeal movement leads to quiet, monotonous speech that is low in volume and sometimes repetitive (palilalia). Rigidity is usually detected on examination and patients tend to complain of muscular stiffness and pain. Parkinsonian rigidity, which can be activated by performing mirror movements in the opposite limb (synkinesis), presents as one of two types: 1 ‘lead-​pipe’ rigidity—​a constant resistance to passive movement,

in the absence of tremor 2 ‘cogwheel’ rigidity—​ a superimposed resistance similar to a ratchet, in the presence of tremor

5949

5950

section 24  Neurological disorders

(a)

presymptomatic phase

1

(b)

Box 24.7.2.2  The non​motor symptom complex

symptomatic phase

locus coeruleus dorsal IXIX nucleus

2

presymptomatic phase

Sleep disorders • Restless legs and periodic limb movements • REM (rapid eye movement) behaviour disorder and REM loss of atonia • Non-​REM sleep-​related movement disorders • Excessive daytime somnolence • Vivid dreaming • Insomnia • Sleep-​disordered breathing

symptomatic phase

mesocortex

1

(c)

2

3

presymptomatic phase

substantia nigra locus coeruleus dorsal IXIX nucleus

4

symptomatic phase

neocortex sec.+ prim. neocortex association mesocortex

1

2

3

4

5

6

Neuropsychiatric symptoms • Depression, apathy, anxiety • Anhedonia • Attention deficit • Hallucinations, illusion, delusions • Dementia • Obsessional behaviour (usually drug-​induced), repetitive behaviour • Confusion • Delirium (could be drug-​induced) • Panic attacks

substantia nigra locus coeruleus dorsal IXIX nucleus

Fig. 24.7.2.2  Proposed pathophysiological basis of Parkinson’s disease. (a) Stage 1 disease—​Lewy body formation in the brainstem, lower medulla, and olfactory bundle. (b) Stage 2—​more dorsal medulla and pons are involved. (c) Stage 3—​midbrain and substantia nigra involved (Fig. 24.7.2.2c). (Colour scale relates anatomical site(s) of involvement to disease progression.)

Autonomic symptoms • Bladder disturbances: — urgency — nocturia — frequency • Sweating • Orthostatic hypotension (OH): — Falls related to OH — ‘Coat hanger’ pain • Sexual dysfunction: — Hypersexuality (likely to be drug induced) — Erectile dysfunction • Dry eyes (xerostomia) Gastrointestinal symptoms • Dribbling of saliva • Ageusia • Dysphagia/​choking • Reflux, vomiting • Nausea • Constipation • Unsatisfactory voiding of bowel • Faecal incontinence Sensory symptoms • Pain • Paraesthesia • Olfactory disturbance Other symptoms • Fatigue • Diplopia • Blurred vision • Seborrhoea • Weight loss • Weight gain (possibly drug-​induced)

Clinical assessment of PD is possible using several validated PD-​specific scales and questionnaires and must have regular yearly outcome measures. These include the self-​rated, 30-​item, non​motor questionnaire (NMSQuest), the simple 8-​item, Parkinson’s disease quality-​of-​life questionnaire (PDQ-​8), the motor scale (Unified

24.7.2  Parkinsonism and other extrapyramidal diseases

Table 24.7.2.2  Comparison of parkinsonian tremor and essential tremor Feature

Parkinsonian tremor

Essential tremor

Age at onset

Usually >50 years

>10 years

Occurrence

Incidence increases with each decade of age

Incidence remains the same with each decade of age

Family history

Rare

Common

Site

Usually hands, also legs and jaw; head uncommon

Hands, head (a no–​no or yes–​yes motion), vocal

Characteristics

At rest; supination/​pronation action reduces; mental concentration increases

Postural; flexion/​extension action increases; mental concentration diminishes

Frequency (Hz)

4–​7

8–​12

Lead-​pipe rigidity

Yes

No

Cogwheel rigidity

Yes

Rare

Alcohol

No effect

Often improves

Treatment

Dopaminergics

β-​Blockers, primidone

Box 24.7.2.3  Diagnosis of parkinsonism (Parkinson’s Brain Bank criteria) Essential features • Bradykinesia and two of the following: • Tremor (rest) and/​or • Rigidity (cogwheel/​lead pipe) • Postural imbalance, fixed, stooped posture • Gait difficulty (shuffling, short-​step gait, with or without festination) Additional features • Hypomimia (‘masked’ face) • Freezing episodes (sudden onset failure of movement) • Seborrhoea of the scalp • Mental and cognitive disturbance

Parkinson’s Disease Rating Scale, UPDRS), and the nonmotor scale (NMSS) (Table 24.7.2.3).

The non​motor symptom complex A variety of non​motor symptom complexes (NMSs) is also seen in PD from an early stage, all of which are likely to have a major effect on the health-​related quality of life of patients. These symptoms Table 24.7.2.3  Recommended good practice guide for clinical assessment of people with Parkinson’s disease A

Motor assessment

B

Non​motor assessment

Hoehn and Yahr stage UPDRS (or MDS-​UPDRS)

PDSS HADS Quality of life

Confirmation of diagnosis There are no specific tests for the diagnosis of PD, which remains a clinical diagnosis (Table 24.7.2.4).

DaTSCAN This is single photon emission computed tomography (SPECT) using the labelled cocaine derivative N-​ ω-​ f luoropropyl-​ 2β-​ carboxymethoxy-​3β-​(4-​iodophenyl)tropane (123I-​labelled β-​CIT and 123I-​labelled FP-​CIT (DaTSCANn, Fig. 24.7.2.3), and is recommended in guidelines from the National Institute for Health and Clinical Excellence (NICE) and widely used to support diagnosis and differentiate PD from essential tremor (Fig. 24.7.2.4). It labels the presynaptic dopamine transporter and this provides assessment of the presynaptic neurons, which degenerate in PD. Essential tremor is likely to show a normal DaTSCAN whereas in PD there is diminished uptake of the ligand, usually correlating with the clinically affected side, and DaTSCAN also appears to have a close correlation with the progression of PD. However, DaTSCAN does not differentiate between PD and other parkinsonian syndromes.

PET scan Using 18F-​labelled dopa the PET scan has similar properties and better resolution but is currently available as a research tool only. More recently, transcranial ultrasonography has been used to

NMS Quest (empowering patient) NMSS (measurement)

C

include depression, dementia, sleep disorders, bowel and bladder problems, fatigue, apathy, pain, and autonomic dysfunction (see Box 24.7.2.2).

Table 24.7.2.4  Imaging modalities for pre-​motor Parkinson’s disease

PDQ-​8

Diffusion weighted imaging of olfactory tract

PDQ-​39

MIBG-​SPECT

HADS, hospital anxiety and depression scale; NMS Quest, non​motor symptoms questionnaire; NMSS, non​motor symptoms scale; PDQ-​8, Parkinson’s disease questionnaire—​8 questions (short version of PDQ-​39); PDQ-​39, Parkinson’s disease questionnaire—​39 questions; PDSS, Parkinson’s disease sleep scale; UPDRS, Unified Parkinson’s Disease Rating Scale.

Dopamine transporter SPECT Transcranial sonography 18-​F Dopa PET

5951

section 24  Neurological disorders

reveal characteristic hyperechogenicity of the substantia nigra in patients with early PD, possibly suggestive of excessive iron deposition in the substantia nigra. However, this technique needs to be validated in large-​scale studies before widespread use can be advocated.

(a)

CT or MRI Scans are usually not needed for diagnosis, but a brain scan should be performed if parkinsonism is purely unilateral or otherwise atypical, or if additional signs (pyramidal) are present. Computed tomography (CT) or magnetic resonance imaging (MRI) may also be used to rule out a space-​occupying lesion, vascular disease, and normal-​pressure hydrocephalus. MRI brain scan is preferable to a CT brain scan.

Management of Parkinson’s disease When to initiate treatment is a critical question and it may indeed be best to start treatment at diagnosis (Table 24.7.2.5). The decision to treat may be dictated by the following clinical issues:

(b)

• Involvement of the dominant hand relative to the non​dominant hand and the effect on employment/​occupation. • The particular subtype of Parkinson’s disease (bradykinesia-​ dominant disease may require earlier treatment than tremor-​ dominant disease). –​ The individual sentiments of patients and carers (offer informed choice). –​ Presence of non​motor symptoms such as pain, depression, or sleep problems. As initiating treatment, the NICE (National Institute of Health and Clinical Excellence (UK)) guidelines recommend levodopa, dopamine agonists, or monoamine oxidase-​B inhibitors. Levodopa is a precursor to dopamine, converted to dopamine by dopa decarboxylation, and restores the dopamine lost due to degeneration of striatonigral cells. The addition of a peripheral decarboxylase inhibitor that does not cross the blood–​brain barrier, such as carbidopa or benserazide, inhibits dopa decarboxylase in the rest of the body

Fig. 24.7.2.3  (a) A normal DaTSCAN showing the comma appearance. (b) DaTSCAN in Parkinson’s disease showing a ‘dot’ appearance on one side, indicating dopaminergic loss.

Glia cell

Tyrosine

D

5952

Levodopa

D D D D D

Dopamine D

D

Levodopa D

Cell body

D

Presynaptic neuron

Somatodentric autoreceptors

COMT catechol-O-methyltransferase

D

MAO monoamine oxidase

Fig. 24.7.2.4  Dopaminergic neuronal transmission.

Synaptic cleft Postsynaptic neuron

Presynaptic autoreceptors

Dopamine transporter

D

Dopamine

D

D

D

D

Postsynaptic autoreceptors Storage vesicle

24.7.2  Parkinsonism and other extrapyramidal diseases

Table 24.7.2.5  New therapeutic options for motor complications (investigational or in clinical trial) COMT inhibition

Opicapone

A2A antagonists

Istradefyline (approved in japan)/​Vipadenant (phase 2)

Glutamate antagnosits

Zonisamide/​Safinamide

α-​2 antagonists

Fipamezole

5HT agonist

Pimavanserine

Neurotrophic factors

GDNF (IP), PDGF (IV)

Incretin mimetic

Exenatide

Synthetic amino acid precursor

Droxidopa

Antimuscarinic

Solifenacin

Adapted from Stocchi F (2014) Neurotherapeutics 11(1): 24–​33.

and reduces side effects. The bioavailability of levodopa has been enhanced further by the emergence of drugs such as tolcapone and entacapone that inhibit catechol-​O-​methyl transferase (COMT), which also breaks down dopamine. Evidence suggests that levodopa therapy should be started at the minimal effective dose (usually 50–​100 mg/​day), in combination with a decarboxylase inhibitor given three to four times daily. Doses at or above 600 mg/​day may be associated with a dyskinesia rate as high as 17% at one year. Side effects, such as light-​headedness or nausea, may be relieved by taking the medication with food or by increasing the dose of decarboxylase inhibitor or taking domperidone, which does not cross the blood–​brain barrier and hence does not cause central dopamine antagonism. Controlled-​ release preparations of levodopa, with addition of a COMT inhibitor (entacapone) to the traditional combination of levodopa and a decarboxylase inhibitor (carbidopa), are now licensed for the treatment of later stage PD. In Parkinson’s disease refractory to other forms of conventional therapies, intraduodenal/​-​jejunal infusion of levodopa (Duodopa) provides an alternative route of drug administration. Duodopa is effective for motor fluctuations in advanced PD and decreases dyskinesias.

Dopamine agonists Dopamine agonists stimulate dopamine receptors directly and so bypass presynaptic nigrostriatal neurons which are degenerate. Five types of dopamine receptors (D1–​D5) have been identified; these are divided into:  D1-​like and D2-​like receptors. In the 1980s and 1990s ergot dopamine agonists such as bromocriptine, pergolide, and more recently cabergoline, were typically used, however now non​ergot agonists are preferentially recommended due to the risk of cardiac valvular fibrosis with ergot dopamine agonists. Ropinirole and pramipexole are the main oral non​ergot dopamine agonists. Rotigotine, a transdermal non​ergot dopamine agonist patch, has now been released. It effectively demonstrates the concept of continuous dopaminergic stimulation and is useful when given once a day. Both ropinorole and pramipexole are available as once a day therapy which leads to improved compliance with therapy in PD (Fig. 24.7.2.4). Side effects of dopamine agonists include nausea, vomiting, postural hypotension, and hallucinations/​psychosis in susceptible individuals or at high doses. More specifically somnolence or sudden onset of sleep

has been linked to non​ergot dopamine agonists, but it is clear now that somnolence can occur with progression of Parkinson’s disease. Patients, therefore, need to be warned about driving when starting on these drugs. Behavioural problems demonstrating disinhibition such as compulsive gambling, hypersexuality, and a complex medley of impulsive behaviour have been linked to use of dopaminergic drugs, particularly dopamine agonists. This has been termed dopamine-​ dysregulation syndrome; the exact prevalence is unknown but can be up to 7% in susceptible individuals.

Apomorphine injection and infusion Apomorphine is a strong non​ergot dopamine agonist that is administered subcutaneously by an infusion pump in advanced Parkinson’s disease when oral therapy is of no further benefit. Apomorphine can be administered as a subcutaneous injection and is usually effective within 10 minutes by-​passing the stomach absorption route and is extremely effective for reversing predictable off periods such as during early morning upon awakening. The subcutaneous infusion is delivered using a small pump and can be used from 12 to 24 hours. Subcutaneous apomorphine is particularly useful to control motor fluctuations and is indicated when oral or skin patch therapy is ineffective. The main side effects are skin lesions and nausea.

Monoamine oxidase-​B inhibitors Selegiline 10 mg once daily or 5 mg twice daily orally (or 1.25 mg once daily by buccal administration) is a selective, irreversible blocker of intra-​and extraneuronal monoamine oxidase B (MAOB), and reduces metabolism of dopamine. Rasagiline is a second-​generation, irreversible, selective MAOB inhibitor that is administered orally at a dosage of 0.5–​1 mg once daily. A recent study (ADAGIO) suggests a potential disease modifying effect of rasagiline. The side effects of MAOB inhibition include hallucinations, sleep disorders, agitation, postural hypotension, and withdrawal problems.

Anticholinergics not recommended Anticholinergics block the action of acetylcholine against dopamine in the basal ganglia. These drugs can occasionally be used as levodopa adjunct therapy, helping to control rest tremor and dystonia. However, they are not routinely recommended and should be utilized with caution in older patients with parkinsonian syndromes because of the risk of precipitating a confusional state and exacerbating dementia.

Other drugs The antiviral amantadine, 100–​ 400  mg, daily has a moderate antiparkinsonian effect. It acts, partly, via increased dopamine synthesis and may also be useful to manage dyskinesias.

Patients who may require surgery Surgery has gained popularity in selected patients where conventional pharmacological therapy has failed to control symptoms. It has a morbidity rate of approximately 2% due to the risk of stroke and infection, and a mortality rate of approximately 0.5%. The operation of choice is deep brain stimulation of the subthalamic nucleus, which reverses the akinesia and controls dyskinesias. Patients with severe resistant unilateral tremor may undergo single-​side thalamic stimulation of the ventral intermediate nucleus. Additional surgical

5953

5954

section 24  Neurological disorders

New patient diagnosis

PDNS consultation

Telling the diagnosis

MDT consultation

Physiotherapy

Occupational therapy

Speech and language therapy

Neuropsychology

Fig. 24.7.2.5  Multidisciplinary approach.

approaches, such as delivery of viral vectors to the striatum for gene therapy or neurotransplantation, are options still in research and development. Adenosine-​associated virus, a non​pathogenic virus, is being used in human trials for gene delivery, including genes such as neurturin, glial-​cell derived nerotrophic factor, and glutamate decarboxylase.

Intrajejunal levodopa infusion It is indicated for the treatment of advanced levodopa-​responsive Parkinson’s disease with severe motor fluctuations and dyskinesia. This involves giving L-​dopa in a gel formulation via a jejunostomy. It has proven to be extremely effective for motor dysfunction in advanced PD as well as being beneficial for some non​motor symptoms and a subsequent health-​related improvement in quality of life.

Other therapies and support A multidisciplinary approach is a requirement for optimal care of the patient with Parkinson’s. Initially, the main requirement is for information and counselling. In the later stages of the disease process, coordination of the various specialists involved in care is very important for the proper management of the patient (Fig. 24.7.2.5).

Other parkinsonian/​extrapyramidal syndromes There are several degenerative diseases that have a more complex clinical picture than Parkinson’s disease and a poorer response to therapy. It may be impossible to distinguish idiopathic Parkinson’s disease from other parkinsonian syndromes.

Drug-​induced parkinsonism This is one of the most common causes of secondary parkinsonism, and is often misdiagnosed as Parkinson’s disease because clinical features may be indistinguishable. It causes rigidity, bradykinesia, tremor and gait disturbance, and may be asymmetrical. Although several medications are associated with secondary parkinsonism,

dopamine-​blocking agents (neuroleptics) such as prochlorperazine or chlorpromazine are the most common offending agents, and are often prescribed to older people for non​specific complaints such as dizziness, and drug-​induced parkinsonism may take up to 9 months to disappear. The incidence of drug-​induced parkinsonism is estimated to be 15–​40% in patients receiving neuroleptics, and its prevalence increases with age. Vestibular sedatives are also implicated. Commonly used antiemetics and antidizziness pills need to be monitored. Treatment consists of withdrawal of the offending medication. If drug withdrawal is impractical, patients are dose reduced or changed to an atypical agent, such as clozapine or quetiapine. Occasionally emergence of parkinsonism may be permanent.

Progressive supranuclear palsy Progressive supranuclear palsy (PSP or Steele–​ Richardson–​ Olszewski syndrome) presents with gait disturbance and falls (predominantly backwards) in over 50% of cases, and is a disease of later life. The pathological hallmark is finding of tau protein-​positive filamentous inclusions, known as neurofibrillary tangles, in the glia and neurons. The clinical picture consists of supranuclear gaze palsy, particularly downgaze with extension and rigidity of the neck, a staring look due to lid retraction, and predominant truncal extensor rigidity. Varying degrees of bradykinesia, dysphagia, personality changes, and other behavioural disturbances, such as a subcortical frontal dementia, coexist. A subtype with levodopa responsiveness have been described. It has been shown that some risk variants are shared between PSP and corticobasal degeneration. In addition, it has been shown that PSP brain volume changes on vMRI capture disease progression and cognitive changes. vMRI changes may serve as a valuable biomarker or outcome to support disease modifying therapeutic efficacy in future PSP clinical trials.

Multiple system atrophy Multiple system atrophy (MSA) consists of a variable combination of parkinsonism with autonomic, pyramidal, or cerebellar

24.7.2  Parkinsonism and other extrapyramidal diseases

symptoms and signs. In the past, patients were categorized as having the striatonigral type if there were dominant parkinsonian signs, and the olivopontocerebellar type if cerebellar signs predominated. These terms are no longer in use and, currently, striatonigral-​and olivopontocerebellar-​type variants are called MSA-​P and MSA-​C, respectively. The pathological feature of MSA is α-​synuclein positive inclusions within neurones or glial cells. These changes result in progressive and profound neuronal loss in various parts of the brain. The parkinsonian features of MSA include progressive bradykinesia, rigidity, and postural instability, typically present bilaterally. Useful clinical clues include disproportionate anterocollis, truncal dystonia (this may resemble the so-​called ‘Pisa syndrome’), characteristic sighing, and the presence of cold, blue hands. Autonomic failure, particularly postural hypotension, occurs early in MSA and is more severe than in idiopathic Parkinson’s disease. The response to levodopa is commonly incomplete and benefit usually declines within 1–​2 years of treatment.

Dementia with Lewy bodies In dementia with Lewy bodies (DLB), widespread areas of neocortex as well as the brainstem and diencephalic neurons have Lewy bodies. Parkinsonian DLB can be very difficult to differentiate from Parkinson’s disease, but these patients have early onset dementia (progressive cognitive decline interfering with normal social and occupational function) and may have hallucinations, delusions, and even psychosis in the absence of dopaminergic therapy, usually within two years of disease onset. Clinical criteria for diagnosis include cognitive fluctuation and attention, recurrent and persistent visual hallucinations, and parkinsonian motor signs. Repeated early falls and neuroleptic sensitivity can be seen. Occasionally the patients develop a supranuclear gaze palsy leading to an incorrect diagnosis of PSP.

Corticobasal ganglionic degeneration Corticobasal ganglionic degeneration, also known as cortico­ dentatonigral degeneration with neuronal achromasia, typically presents in the sixth or seventh decade with slowly progressive, unilateral development of tremor, apraxia, and rigidity in an upper limb. The condition is characterized by progressive gait disturbances, cortical sensory loss, and stimulus-​sensitive myoclonus, which result in a jerky, useless hand. A jerky, useless lower extremity is uncommon, but may occur; it is known as the alien limb phenomenon and can occur in about 50% of patients. Gait disturbance consists of a slightly wide-​based, apraxic gait rather than the typical festinating gait of Parkinson’s disease. Patients with corticobasal ganglionic degeneration do not benefit from levodopa, and the disease course is relentlessly progressive. Other extrapyramidal conditions that should also be considered, including the following, are fully described in Chapter 24.7.3: • Dopa-​responsive dystonia • Wilson’s disease • Neuroacanthocytosis • Dystonia • Generalized idiopathic torsion dystonia • Tardive dyskinesia • Chorea and related disorders • Tics

FURTHER READING Albanese A, et  al. (2001). Consensus statement on the role of acute dopaminergic challenge in Parkinson’s disease. Mov Disorders, 16, 197–​201. Albin RL, Frey KA (2003). Initial agonist treatment of Parkinson’s disease: a critique. Neurology, 60, 390–​4. Barbeau A, Sourkes TL, Murphy CF (1962). Les catecholamines de la maladie de Parkinson. In: Ajuriaguerra J (ed) Monoamines et sys­ tème nerveux central, pp. 247–​62. Symposium Bel Air, Geneva. Chaudhuri KR, Healy D, Schapira AHV (2006). The non-​motor symptoms of Parkinson’s disease:  diagnosis and management. Lancet Neurol, 5, 235–​45. Chaudhuri KR, Pal S, Brefel-​Courbon C (2002). Do ‘sleep attacks’ or ‘unintended sleep episodes’ occur with dopamine agonists? Is this a class effect? Drug Safety, 25, 473–​83. Devos D, Defebvre L, Bordet R (2010). Dopaminergic and non-​ dopaminergic pharmacological hypotheses for gait disorders in Parkinson’s disease. Fundam Clin Pharmacol, 24, 407–​21. Dhawan V, et al. (2006). The sleep-​related problems of Parkinson’s disease. Age Ageing, 35, 220–​8. Fahn S, Elton R, Members of the UPDRS Development (1987). Unified Parkinson’s disease rating scale. In: Recent developments in Parkinson’s disease, pp. 153–​63. Macmillan Healthcare Information, Florham Park, NJ. Fiszer U (2007). Adverse effects of dopamine agonists. Neurol Neurochir Pol, 41(2 Suppl 1), S34–​9. Foltyne T, et  al. (2002). The genetic basis of Parkinson’s disease. J Neurol Neurosurg Psychiatry, 73, 363–​70. Hatano T, et  al. (2009). Pathogenesis of familial Parkinson’s disease: new insights based on monogenic forms of Parkinson’s disease. J Neurochem, 111, 1075–​93. Jankovic J (2005). Searching for a relationship between manganese and welding and Parkinson’s disease. Neurology, 64, 2021–​8. Kalra S, Grosset DG, Benamer HT (2010). Differentiating vascular parkinsonism from idiopathic Parkinson’s disease: a systematic review. Mov Disord, 25, 149–​56. Kashihara K (2007). Management of levodopa-​induced dyskinesias in Parkinson’s disease. J Neurol, 254 Suppl 5, 27–​31. Kouri N, et al. (2015). Genome-​wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy. Nat Commun, 6, 7247. Lindvall O, Kokaia Z (2010). Stem cells in human neurodegenerative disorders—​time for clinical translation? J Clin Invest, 120, 29–​40. Mark MH (2001). Lumping and splitting the Parkinson Plus syndromes:  dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and cortical-​basal ganglionic degeneration. Neurol Clinics, 19, 607–​27, vi. Massey LA, Yousry TA (2010). Anatomy of the substantia nigra and subthalamic nucleus on MR imaging. Neuroimaging Clin N Am, 20, 7–​27. Masson, Paris. Birkmayer W, Hornykiewicz O (1962). Der l-​ Dioxyphenylalanin (=DOPA) Effekt beim Parkinson-​ syndrom des menschen:  zur pathogenese und behandlung der parkinson-​ akinese. Arch Psychiatr Nervenkr, 203, 560–​74. McGeer PL, McGeer EG (2008). Glial reactions in Parkinson’s disease. Mov Disorders, 23, 474–​83. National Institute for Health and Clinical Excellence (2006). Clinical guidelines for management of Parkinson’s disease in primary and sec­ ondary care. Department of Health, London. Nutt JG (2007). Continuous dopaminergic stimulation: is it the answer to motor complications of levodopa? Mov Disorders, 22, 1–​9.

5955

5956

section 24  Neurological disorders

Nyholm D, et  al. (2003). Optimising levodopa pharmacokinetics: intestinal infusion versus oral sustained-​ release tablets. Clin Neuropharmacol, 26, 156–​63. Olanow CW, Watts RL, Koller WC (2001). An algorithm (decision tree) for the management of Parkinson’s disease (2001): treatment guidelines. Neurology, 56 (11 Suppl 5), S1–​88. Olanow W, Schapira AH, Rascol O (2000). Continuous dopamine-​ receptor stimulation in early Parkinson’s disease. Trends Neurosci, 23, S117–​26. Parkinson Study Group (2002). Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA, 287, 1653–​61. Rascol O, et al. (2000). A five year study of the incidence of dyskinesias in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. N Engl J Med, 342, 1484–​91. Rascol O, et  al. (2002). Treatment interventions for Parkinson’s disease: an evidence-​based assessment. Lancet, 359, 1589–​98. Stern MB, et  al. (1989). Magnetic resonance imaging in Parkinson’s disease and parkinsonian syndromes. Neurology, 39, 1524. van de Vijver RAC, et al. (2001). Estimation of incidence and prevalence of Parkinson’s disease in the elderly using pharmacy records. Pharmacoepidemiol Drug Safety, 10, 549–​54. Zhang Z, Roman G (1993). Worldwide occurrence of Parkinson’s disease: an updated review. Neuroepidemiology, 12, 195–​208.

24.7.3  Movement disorders other than Parkinson’s disease Bettina Balint and Kailash Bhatia ESSENTIALS Hyperkinetic movement disorders are characterized by involuntary (and excessive) movements. The five main forms are chorea, tics, myoclonus, dystonia, and tremor, which can sometimes occur in combination. Some movement disorders are defined by their paroxysmal occurrence (paroxysmal movement disorders) or by their presence only during sleep, and there are other conditions that lie outside the conventional list but are part of the spectrum of movement disorders, for example, stiff person syndrome. It is important to remember that drugs can cause a variety of movement disorders, including some very distinct presentations, and also that all organic movement disorders can be mimicked by so-​called psychogenic or functional movement disorders. It is important not to miss treatable disorders (e.g. Wilson’s disease, dopa-​responsive dystonia, or some of the immune-​mediated disorders), but in most cases treatment is symptomatic, both of motor and non​motor (usually neuropsychiatric) features, which may significantly contribute to poorer quality of life. Most of the recent advances in this field are due to the discovery of new genes. The indications and application of deep brain stimulation has become much wider, with beneficial results not only in

Parkinson’s disease but also dystonia and some tremor disorders, and even Tourette syndrome.

Particular movement disorders Chorea

Inherited choreiform disorders—​most are autosomal dominant, and divisible into those with onset in adulthood or childhood. Huntington’s disease is a classic form of later onset, autosomal-​dominant chorea often associated with dementia and psychiatric disturbance, whereas autosomal-​dominant ‘benign hereditary chorea’ has very early onset with a more benign prognosis. Recessive forms of chorea usually have early onset and are generally associated with a variety of other neurological or systemic signs. Acquired chorea—​possible aetiologies include drugs, immune-​ mediated, metabolic, infectious, and structural causes. The archetypical autoimmune chorea in children is Sydenham’s chorea, but anti-​N-​methyl-​d-​aspartate receptor encephalitis is another important cause. Adult autoimmune chorea can be seen in a paraneoplastic disease and also in the context of systemic autoimmunity (e.g. anti­ phospholipid syndrome or systemic lupus erythematosus). Dystonia

Dystonia as sole sign is seen in a group of disorders (previously termed primary dystonia) which can be either idiopathic or genetic. Presentation follows a typical pattern with regard age of onset and body distribution, such as young onset generalized dystonia or adult onset focal dystonia (writer’s cramp and craniocerivcal dystonia). Dystonia combined with other signs can be seen in various conditions, for example, dystonia combined with parkinsonism in dopa-​responsive dystonia (including Segawa’s disease), young onset Parkinson’s disease, and Wilson’s disease. Myoclonus

Myoclonus is characterized by very brief, shock-​ like, involuntary movements that can be positive, caused by sudden muscle contraction, or negative, due to a sudden lack of muscle tone (e.g. asterixis). Causes include metabolic, toxic, infectious, and autoimmune conditions. Symptomatic treatment is with agents such as clonazepam, valproate, levetiracetam, piracetam, and primidone, often in combination. Tremor

Tremor may be a sole and defining symptom (essential tremor) or be part of a syndrome (e.g. dystonic tremor or parkinsonian tremor). Treatment of tremor is purely symptomatic. Focal tremors (e.g. of head, jaw, voice) often show an excellent response to botulinum toxin injections. Tremor of the limbs often requires medical therapy: agents used include propranolol, clonazepam, primidone, topiramate, and gabapentin. Deep brain stimulation is considered for severe and disabling tremors, and focused ultrasound may be employed in the future. Tics

Tics mostly occur as primary disorders without any associated neurological disease. Presentation ranges from minor tics of self-​ limiting occurrence during childhood, which occur in up to 15% of school-​age children (boys more than girls), and persistent tic disorders like Tourette syndrome, which can result in significant

24.7.3  Movement disorders other than Parkinson’s disease

physical and social disability. More rarely, tics can occur secondarily to neurodegenerative disease, in developmental disorders, as part of the spectrum of paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, or due to structural brain damage. Some drugs (e.g. amphetamines), are associated with (re-​) occurrence of tics.

beneficial results not only in Parkinson’s disease, but also dystonia and some tremor disorders, and even Tourette syndrome. In the following section we will discuss each of the major forms of hyperkinetic movement disorders individually.

Chorea

Other movement disorders

These include restless legs syndrome and other sleep movement disorders, stiff person syndrome and related disorders, paroxysmal dyskinesias, drug-​ induced movement disorders, psychogenic movement disorders, and the interphase of movement disorders and peripheral nerve disorders like hemifacial spasm and myokymia.

Introduction Movement disorders remains a subspecialty wherein the observed clinical phenomenology is of paramount importance and guides further investigations to find the right diagnosis. Here we outline the different clinical forms of hyperkinetic movement disorders and discuss the different diseases in the context of the main movement disorder presentations. Hyperkinetic movement disorders or dyskinesias are characterized by involuntary (and excessive) movements. The five main forms of dyskinesias include chorea, tics, myoclonus, dystonia, and tremor. In contrast to dyskinesias, hypokinetic disorders are defined by a poverty of movement such as in parkinsonian disorders. However, sometimes there can be a combination of different movement disorders. Some movement disorders are defined by their paroxysmal occurrence (paroxysmal movement disorders), or by their presence only during sleep such as rapid eye-​movement (REM) sleep behaviour disorder (RBD), and periodic limb movements in sleep. In addition, there are still other conditions, for example, stiff person syndrome, which lie outside the conventional list of dyskinesias but are part of the spectrum of movement disorders. Also included here are miscellaneous movement disorders, such as hemifacial spasm, myokymia, and myorhythmia. It is important to remember that drugs can cause a variety of movement disorders, including some very distinct presentations, and this will be covered separately. Lastly, all organic movement disorders can be mimicked by so-​ called psychogenic or functional movement disorders, which will be discussed last. Treatment is often only symptomatic as there are mostly no cures. It is therefore important not to miss treatable disorders, such as Wilson’s disease, dopa-​responsive dystonia, or some of the immune-​mediated disorders, but also rarer entities like biotin responsive encephalopathy or glucose transporter 1 deficiency. Furthermore, apart from the movement disorder aspect, it is important to recognize and treat certain non​motor (usually neuropsychiatric) features, which may significantly contribute to poorer quality of life. Most of the recent advances in this field are due to the discovery of new genes, which start paving the way for the first genetic treatment trials, as in Huntington’s disease. The indications and applications of deep brain stimulation have become much wider with

Chorea is characterized by brief, irregular, purposeless movements that unpredictably flit from one body part to another and lend the patients a fidgety, restless appearance (see Video 24.7.3.1). Key questions in the approach to a patient with chorea are tempo and age of onset, family history, drug history, and distribution. For example, involvement of just one side (hemichorea) indicates a contralateral structural lesion. Ballism is a more severe form of chorea and often due to vascular lesions of the contralateral subthalamic nucleus (see Video 24.7.3.2). Chorea as the sole or main feature can underlie several different aetiologies, which may be broadly divided into inherited and acquired causes (for an overview see Table 24.7.3.1). Table 24.7.3.1  Overview of the main causes of chorea classified by aetiology Inherited Autosomal dominant Adulthood onset

Huntington’s disease C9ORF72 Junctophilin-​3 Spinocerebellar ataxia 17, 1, 2, 3 DRPLA Prion disease Neuroferritinopathy Aceruloplasmenaemia

Childhood onset

Benign hereditary chorea (TITF-​1) ADCY5 PDE10A

Autosomal recessive Ataxia teleangiectasia Ataxia with oculomotor apraxia type 1, 2 and 4 Friedreich’s ataxia Neuroacanthocytosis Wilson’s disease Aminoacidurias Niemann–​Pick C X-​linked recessive Lesch–​Nyhan syndrome Acquired Autoimmune Childhood onset

Sydenham’s/​PANDAS NMDAR antibody encephalitis

Adulthood onset

Paraneoplastic disease (particularly related to CRMP5 and Hu-​antibodies) (continued)

5957

5958

section 24  Neurological disorders

Table 24.7.3.1 Continued NMDAR antibody encephalitis Antiphospholipid syndrome Vasculitis Coeliac disease Systemic Lupus erythematosus Neurobehçet Drug induced L-​dopa (L-​dopa induced dyskinesia in Parkinson’s disease) Dopamine receptor blockers (tardive dyskinesia) Anticholinergics (e.g. trihexyphenidyl) Oral contraceptives Calcium channel blockers Anticonvulsants (e.g. phenytoin) Thyroxine Benzodiazepines Monoamine oxidase inhibitors Tricyclic antidepressants (e.g. amitriptyline) Digoxin Stimulants Alcohol withdrawal Metabolic abnormality Thyroid Parathyroid

variety of other neurological or systemic signs are associated with these syndromes. Huntington’s disease Huntington’s disease (HD) is an autosomal-​dominant neurode­ generative disorder with chorea, dementia, and psychiatric disturbance as the main features. It was first described by George Huntington in 1872 and proved to be the most frequent inherited cause of chorea, with a prevalence of 4–​10/​100 000 in western European populations. Aetiology The underlying genetic defect is a triplet (CAG) repeat expansion, encoding polyglutamine in the huntingtin gene on chromosome 4p16.3. The mutant gene product forms aggregates in cells that lead to cell death, and neuropathologically to atrophy mainly of the cortex and caudate, more than the putamen. The CAG repeat ranges normally between 10—​28 copies, but is expanded to a range of 36 and more in patients with HD. The number of CAG repeats correlates also with penetrance and phenotype. 40 or more CAG repeats are fully penetrant, whereas there is a borderline repeat range between 36 and 39 repeats with reduced penetrance. Usually, the higher the number of repeats, the earlier the presentation. There is a tendency for expansion of the triplet repeat during transmission, a phenomenon called anticipation, particularly if the disease is inherited through the father. This is explained by meiotic instability, which increases the CAG repeat number and is greater in spermatogenesis than in oogenesis.

Glucose

Symptoms

Sodium

The disease usually manifests in the fourth decade, but age at onset can vary from adolescence ( segmental

Prominent laryngeal involvement; rostrocaudal gradient

DYT23 (CIZ1) CIZ1 (DYT23)

AD

Adolescence—​ adulthood

Focal

(Tremulous) cervical dystonia; rare/​awaiting confirmation

DYT24 (ANO3) ANO3 (DYT24)

AD

Childhood—​ adulthood

Focal, segmental

Tremulous cervical dystonia; cranial, laryngeal, UL involvement; can present with isolated arm tremor, or as a myoclonus-​dystonia

DYT25 (GNAL) GNAL (DYT25)

AD

Childhood—​ adulthood

Focal, segmental, rarely generalized

Cervical dystonia; head or tremor; laryngeal dystonia; generalization in 10%; hyposmia in some cases

DYT27 (COL6A3) COL6A3 (DYT27)

AR

Childhood—​early adulthood

Segmental

Mainly affecting the upper body, predominant craniocervical involvement; neck or hand being mostly the site of onset

AD, autosomal dominant; AR, autosomal recessive.

acquired or heredodegenerative causes, additional neurological or other features were often present and dystonia was considered as part of a dystonia-​plus syndrome. A new classification now defines dystonia on a clinical and an aetiological axis. In this context, dystonia is considered clinically as ‘isolated’ when there are no other associated features or ‘combined’ when there are. This definition largely overlaps with the previous classification of primary generally ‘isolated dystonia’ and ‘combined dystonia’ in which it is part of a syndrome due to different aetiologies which come into the differential diagnosis. The recent advances in the field of dystonia comprise the discovery of several new genes (Table 24.7.3.2 and 24.7.3.4), and the recognition of so-​called non​motor features, such as depression, which significantly contribute to the burden of the disease and impaired quality of life.

Primary dystonia (isolated dystonia) Primary dystonia can be idiopathic or genetic (Table 24.7.3.2). Both forms present insidiously and follow a characteristic pattern with regard anatomical distribution in relation to age at onset. Discrepancy from this pattern, among other red flags (Table 24.7.3.3), cautions against primary dystonia and may suggest secondary or symptomatic dystonia.

Table 24.7.3.3  Red flags cautioning against a diagnosis of primary dystonia

• Unusual pattern with regard to age of onset and distribution • Sudden onset with rapid progression • History of perinatal birth injury • Developmental delay • Exposure to drugs (e.g. dopamine receptor blockers) • Presence of other neurological or systemic signs • Prominent bulbar involvement with tongue protrusion and dysphagia • Hemidystonia • Fixed dystonia

Young onset generalized dystonia (primary torsion dystonia) Manifestation in childhood or adolescence usually involves onset in the legs with subsequent generalization (see Fig. 24.7.3.1). Thus, first symptoms typically are in-​turning of the feet and pigeon-​toed walking before, in most of the cases, over the course of months to years, dystonia spreads to other body parts. This phenotype was described by Oppenheim in 1911 as ‘dystonia musculorum deformans’ and subsequently called primary torsion dystonia. Later on, TOR1A (Torsin1A) gene mutations emerged as a frequent cause of Oppenheim’s dystonia. TOR1A mutations (also labelled as DYT1) are autosomal-​dominantly inherited, however with reduced (30–​ 40%) penetrance. They account in primary, early-​onset dystonia for c.80% of the cases in Ashkenazi Jewish populations, and up to 50% in non-​Jewish populations. Another genetic form of young onset generalized dystonia is DYT6 due to mutations in the THAP1 (thanatos-​associated protein) gene. It differs from DYT1 inasmuch the sites of onset are the upper limbs, or the craniocervical region with prominent laryngeal involvement. Adult onset focal dystonia (writer’s cramp and craniocervical dystonia) Much more (9–​12 times) frequent than young onset, generalized dystonia are, however, the focal variants with onset in middle or late adulthood, which only rarely have genetic underpinnings. Writer’s cramp and other task-​specific dystonias Writer’s cramp usually manifests in the fourth decade as abnormal posturing when attempting to write. Patients may already have difficulty picking up or holding a pen. When writing, they hold the pen with excessive force and dystonic posture of the hand and forearm (see Fig. 24.7.3.1), and experience increasing difficulties as writing continues. In order to cope with this, patients may try a different way to hold the pen, or pens of different sizes, or even learn to write with the other hand. However, some patients may then develop writer’s

24.7.3  Movement disorders other than Parkinson’s disease

Fig. 24.7.3.1  The spectrum of primary dystonia: young onset generalized dystonia, writer’s cramp, cervical dystonia with geste antagoniste, and blepharospasm.

cramp in the other hand, or develop dystonia which is not limited only to the task of writing itself, but hampers other activities such as using cutlery, brushing teeth, and so on. Other craft or occupational cramps may occur wherever repetitive, stereotyped movements are performed, and are described in piano players, typists, and hairdressers among many others.

in more detail the syndromes of dystonia and parkinsonism, and dystonia and myoclonus, and provide a general overview of combined dystonias (Table 24.7.3.4).

Cervical dystonia

Several genetic enzymatic defects affecting the dopamine synthesis pathway can cause dopa-​responsive dystonia. The archetypic form is Segawa’s disease due to autosomal-​dominantly inherited GCH1 mutations. GCH1 stands for guanidine triphosphate cyclohydrolase 1, a gene encoding the rate-​limiting enzyme in the production of tetrahydrobiopterin, itself an essential cofactor in the dopamine synthesis. Its hallmark features are dystonia commencing in childhood or adolescence, mainly in the lower limbs, diurnal fluctuation of symptoms (increasing as the day progresses) and an exquisite response to small doses of levodopa (200–​400 mg per day). Often patients also have signs of parkinsonism and, sometimes, spasticity. There are, however, other autosomal recessive forms of childhood monoamine neurotransmitter disorders, which usually give rise to a more complex phenotype (e.g. with myoclonus and epilepsy) and have less treatment response. Examples include tyrosine hydroxylase deficiency or sepiapterin deficiency. Recognition of these entities is important for the treatment implications. Thus, every child with a phenotype of cerebral palsy and every person with young onset dystonia ( stiff person syndrome). However, brainstem encephalitis of any aetiology, just brainstem lesions, tetanus, and strychnine intoxication, can give rise to acquired hyperekplexia. Other startle syndromes include startle epilepsy (epileptic seizures triggered by startle, mostly in patients with congenital brain damage) and cultural startle syndromes such as the ‘jumping Frenchmen of Maine’, ‘Latah’ (Malaysia), and ‘Myriachit’ (Siberia). Treatment depends on the underlying cause, but benzodiazepines such as clonazepam can be effective as symptomatic therapy.

Myoclonus with epilepsy When myoclonus is part of an epileptic syndrome, the term epileptic myoclonus is often used. Several syndromes fall into this category, with a wide spectrum from benign and treatable disorders to devastating and treatment refractory epilepsies with marked encephalopathy. Epileptic myoclonus is typically accompanied by generalized epileptiform discharges, but the myoclonus itself may be focal, segmental, or generalized. Focal myoclonus can also occur in secondary symptomatic epilepsy due to a lesion. Here we focus on two representative entities where the myoclonus is very much to the fore. For an overview of the whole spectrum, see the Table 24.7.3.5. Juvenile myoclonus epilepsy Juvenile myoclonus epilepsy accounts for 5–​10% of all epilepsies. Age at onset is typically in adolescence, but can range from 8 to 25 years. The characteristic semiology consists in myoclonic attacks affecting symmetrically and proximally both arms, and there is a circadian pattern with clustering of attacks in the mornings. Thus, it is often memorized as ‘cornflakes epilepsy’ as a typical history given by patients is that of spilling the cereals at breakfast. Juvenile myoclonus epilepsy often occurs in combination with grand mal seizures (90%) upon awakening, or with absences (25%). As in other idiopathic, generalized epilepsies, seizures can be provoked by sleep deprivation, hyperventilation, or photostimulation. The treatment response overall is good, although lifelong drug therapy is required in most of the cases. However, the manifestation in adolescence renders implementation of the recommended adaptation of lifestyle (regular and sufficient sleep, avoidance of alcohol and recreational drugs) sometimes more difficult. Familial cortical myoclonus This syndrome is rare and has a confusing number of descriptions, being called ‘benign autosomal-​dominant familial myoclonic epilepsy’, ‘familial cortical myoclonic tremor and epilepsy’, or most frequently, ‘familial cortical tremor’ (just to name a few). However,

the latter is a misnomer as it only superficially resembles tremor, but is in fact a fine, shivering-​like myoclonus most prominent in the hands. It can be associated with generalized seizures. The underlying genetic heterogeneity with several genes (NOL3, ADRA2B, CNTN2) and loci identified might partly explain phenotypical variations stretching from truly benign courses to more progressive and disabling disorders.

Myoclonus with ataxia With his seminal contribution ‘Dyssynergia cerebellaris myoclonica’, James Ramsay Hunt defined a clinical syndrome characterized by progressive myoclonus, ataxia, and epilepsy. Thus, there is a wide variety of underlying aetiologies, with a considerable overlap with the group of progressive myoclonus epilepsies. The myoclonus is of cortical origin and tends to be multifocal or generalized and mainly action induced, but can often also be elicited by stimuli (touch, noise, visual; ‘reflex myoclonus’). The differential diagnosis and further investigations are guided by the associated features, first of all by the presence or absence of cognitive impairment. The so-​called ‘famous five’ aetiologies of the progressive myoclonic ataxias comprise Unverricht–​Lundborg disease with a relatively benign course and preserved cognition, mitochondrial disorders with a wide phenotypical range, and the storage disorders Lafora body disease, neuronal ceroid lipofuscinosis and sialidoses on the severe end of the spectrum, with prominent dementia and markedly reduced life expectancy (see Table 24.7.3.5). Unverricht–​Lundborg disease or Baltic myoclonus Unverricht–​Lundborg disease is the archetypical syndrome of progressive myoclonus ataxia without significant cognitive impairment. Unverricht reported the first family in Estonia, and Lundborg described 10 families in Sweden. Further cases were subsequently noted in Finland, and the term ‘Baltic myoclonus’ was coined since the disease seemed to be common in Scandinavia and related countries. Prevalence rates in Finland were numbered 4–​5 in 100 000. The disease is autosomal recessively inherited, and most patients are homozygous for the dodecamer expansion mutation in the cystatin B (CSTB) gene. Age at onset varies between 6 to 15 years (on average 10.6 years), with first symptoms being stimulus-​sensitive myoclonic jerks and generalized tonic–​clonic seizures, whereas cerebellar signs develop only later. Patients eventually become wheelchair bound, and there may be mild cognitive impairment at later stages of the disease. Pharmacotherapy usually consists of combination therapy with a cocktail of different antiepileptic drugs such as sodium valproate, clonazepam, and levetiracetam. The life expectancy is reduced with an average around 60 years. Although Unverricht–​Lundborg disease seems to remain one of the most frequent causes of progressive myoclonic ataxias without prominent cognitive involvement, there are several more recently identified disorders that resemble this phenotype. Autosomal recessive GOSR2 mutations were identified as the cause of ‘North Sea myoclonus’, the name again indicating a clustering of cases in the countries adjacent to the North Sea. Compared to Unverricht–​ Lundborg disease, this disorder starts earlier in life with ataxia and features scoliosis and potentially other skeletal deformities, and areflexia as distinguishing marks. The list of differential diagnosis keeps expanding by virtue of the advances in the genetics, but also comprises acquired causes like coeliac disease (see Table 24.7.3.5).

24.7.3  Movement disorders other than Parkinson’s disease

Lafora body disease This rare and fatal disorder is named after the Spanish neuropathologist Lafora who described the characteristic inclusion bodies consisting of polyglucosan. It is autosomal recessively inherited and caused by mutations either in the laforin gene (EPM2A) or in the malin gene (NHLRC1). Either the detection of the gene mutations or the presence of Lafora bodies in biopsied tissue (axilla) are diagnostic. Patients usually present in adolescence with seizures, followed by debilitating myoclonus and dementia. Occipital seizures and visual deterioration are characteristic. Death occurs within 2–​10 years after onset. Neuronal ceroid liposfuscinosis (Batten’s disease) Neuronal ceroid lipofuscinosis comprises a group of clinically and genetically heterogenous disorders characterized by intracellular accumulation of autofluorescent lipopigment. Different subtypes were defined by age of onset, clinical signs, and the ultrastructural pattern of the storage material. The disease runs a relentless course with dementia, epilepsy and progressive visual failure leading to blindness (not in adult onset variant). Sialidoses Both type 1 and type 2 sialidosis are rare autosomal recessive lysosomal storage diseases. Type 1 is also called ‘cherry red spot myoclonus syndrome’, because of the red spot in the retina present in nearly all the cases. It begins in the second decade, usually with a progressive loss of vision (deterioration of colour vision, night blindness, retinal degeneration, optic atrophy, corneal clouding). Further features, besides progressive myoclonic ataxia, are generalized tonic–​clonic seizures. In contrast, type 2 has an earlier age at onset, a more rapid disease progression and a reduced life expectancy. It also differs from type 1 inasmuch there is dementia, facial dysmorphia, and skeletal dysplasia as additional features.

Opsoclonus-​myoclonus This distinct syndrome is also called ‘dancing eyes-​dancing feet syndrome’, a denomination which describes the spontaneous, involuntary, multidirectional, ‘chaotic’ saccades seen in opsoclonus (see Video 24.7.3.4), and the myoclonus which is often generalized. Ataxia is often a further feature, as are sleep disturbance and behavioural changes. It seems to be immune mediated as it is often paraneoplastic, with neuroblastoma being the most frequent tumour in children, cancer of lung and breast prevailing in adults, but also can be post or parainfectious. In this regard, primary HIV infection is one of the most frequent causes. Sometimes, however, no trigger can be identified. In most cases, no antibody is detected. The therapeutic approach consists of treatment of any underlying malignancy where applicable, and immunotherapy. The outcome is variable, ranging from a monophasic course with excellent recovery to treatment-​ resistant chronic courses.

Myoclonus with parkinsonism/​dementia Myoclonus can be a feature in various neurodegenerative diseases with parkinsonism or dementia as main symptom. Please see Table 24.7.3.5 and Chapter 24.7.2 for more in-​depth coverage.

Tremor Tremor is a rhythmic, oscillatory movement, usually due to alternate activation of agonist and antagonist muscles. It can be described according to the body part affected, its frequency and amplitude, and when it occurs, namely at rest vs. posture vs. during movement vs. task or position specific. Kinetic tremor can be further subdivided into action tremor or intention tremor, the latter describing a tremor which increases throughout a performed movement. Tremor may be the sole and defining symptom, or be part of a syndrome with associated neurological signs. Here, we will discuss some specific tremor syndromes in more detail. Table 24.7.3.6 gives an overview of different causes arranged according to their main tremor presentation. Patients often find tremor socially embarrassing and very disabling (Fig. 24.7.3.4). Regardless of the different potentially underlying aetiologies, treatment of tremor is purely symptomatic. Focal tremors (e.g. of head, jaw, voice) often show an excellent response to botulinum toxin injections. Tremor of the limbs often requires medical therapy. Several options (propranolol, clonazepam, primidone, topiramate, and gabapentin) exist, but side effects and potential benefit should be weighed. The first line treatment for dystonic tremor is trihexyphenidyl, whereas parkinsonian tremors might respond to dopaminergic medication. Orthostatic tremor sometimes responds to clonazepam or levodopa. For severe and disabling tremors, deep brain stimulation is worth considering. Lastly, focused ultrasound may be a non​invasive technique available in the not-​so-​distant future.

Essential tremor Classically, essential temor is a symmetrical postural or kinetic tremor of the arms, which gradually worsens over time and which tends to be inherited in an autosomal-​dominant manner. Patients often report that small amounts of alcohol tend to decrease the tremor. Additional neurological signs, particularly dystonia, are an exclusion criterion. Isolated voice, tongue, chin, or leg tremor as well as position-​or task-​specific tremors are not consistent with essential tremor. It is thought to be one of the most frequent neurological disorders with prevalence rates around 300 per 100 000 and a bimodal peak of onset in the second and sixth decade. There are some cases reported with cerebellar or Lewy body pathology, but there is no consistent neuropathological finding. Despite being strongly familial, surprisingly the search for a common causative gene has not been successful so far, although there has been an association with the LINGO1 gene. Thus, it appears that essential temor is rather a syndrome than a single entity. There are no diagnostic tests for essential tremor, and the diagnosis is based on the clinical findings and exclusion of other causes for postural tremor. In this regard, enhanced physiological tremor comes into the differential diagnosis; this is physiological tremor enhanced by drugs, metabolic, endocrine, or other causes and may be mistaken for essential temor. Typically, it worsens with anxiety and fatigue, and usually decreases with weight loading as evident on electromyography (EMG).

Dystonic tremor Dystonia itself can be tremulous and may, therefore, manifest as head tremor in patients with cervical dystonia (see Video 24.7.3.5),

5969

5970

section 24  Neurological disorders

Table 24.7.3.6  The main forms of tremor and their most important causes Rest tremor • Parkinson’s disease (‘pill-​rolling’ tremor) • Atypical parkinsonism (multisystem atrophy, and so on) • Drug-​induced parkinsonism • Rubral tremor • Spinocerebellar ataxias • Dystonic tremor • Severe essential tremor • Fragile X-associated tremor/ataxia syndrome (FXTAS) • Neuropathic tremor Postural tremor • Enhanced physiological tremor • Metabolic disturbance (e.g. hyperthyroidism, Cushing’s syndrome) • Drugs (β-​agonists (e.g. salbutamol), anticonvulsants (e.g. sodium valproate), thyroxine, tricyclic antidepressants, theophylline, lithium, immunosuppressive drugs (e.g. cyclosporin)) • Stimulants, drugs of abuse (e.g. coffee, alcohol, nicotine, amphetamine, cocaine, marijuana) • Toxins (e.g. mercury, toluene, solvents) • Essential tremor • Neuropathic tremor (e.g. demyelinating neuropathy, particularly with MAG-​antibodies or IgM paraproteinaemia) • Dystonic tremor • Parkinson’s disease (‘re-​emergent tremor’) • Multiple system atrophy • Spinocerebellar ataxia (esp. SCA 12) • Fragile X-​associated tremor/​ataxia syndrome (FXTAS) • Orthostatic tremor Kinetic tremor • Cerebellar disease (e.g. brainstem or cerebellar outflow pathway lesions, various aetiologies, the most common cause being multiple sclerosis) • Holmes tremor (also called rubral tremor, tripartite tremor (rest < posture < intention) due to damage of cerebello-​rubrothalamic and nigro-​s triatal pathways) • Wilson’s disease (often with characteristic ‘wing-​beating tremor’)

a voice tremor (laryngeal dystonia), or hand tremor. Dystonic tremor is often rather jerky and irregular. It can be position-​or task-​ specific (e.g. like primary writing tremor). Recent evidence shows that, rarely, tremor can precede the development of actual dystonia. Often, there is also an autosomal-​dominant family history. Again, there are no biomarkers and the diagnosis relies on clinical acumen. It appears that the most common misdiagnoses are essential tremor or benign tremulous Parkinson’s disease. However, subtle or not so subtle signs of dystonia (including geste, task and position specificity) and prominent asymmetry mitigate against a diagnosis of essential tremor (Video 24.7.3.6). Where it is difficult to differentiate dystonic tremor from Parkinson’s disease on clinical grounds only, a DAT scan is very helpful.

Orthostatic tremor Orthostatic tremor is a rare, but distinct syndrome. Age at onset is typically around 50 years. The patients describe that they feel unstable on standing only and, therefore, have difficulties queuing or during parochial ceremonies. However, they have no difficulty when walking or sitting. The cause is a high-​frequency tremor of the legs, which occurs only on standing after a small latency period. Subsequently, with progression of the condition, the tremor becomes more disabling as it occurs straightaway and with higher amplitude. The history suggests the diagnosis itself and, on examination, a high-​ frequency tremor of both legs can be felt or heard with a stethoscope on the thighs (described as the sound of a helicopter). The tremor is often too fast to be seen, but can be confirmed with EMG, which reveals 13–​18 Hz tremor. Sometimes, a postural tremor of the arms can also be observed. In most, orthostatic tremor remains the sole symptom. The few who develop additional features such as parkinsonism or restless legs, are classified as having orthostatic

tremor-​plus syndrome. The main treatment options are clonazepam and levodopa.

Fragile X tremor ataxia syndrome Fragile X syndrome is one of the most frequent causes for male mental retardation. It is an x-​linked condition due to a triplet repeat expansion (>200) in the fragile site mental retardation (FMR1) gene. A repeat expansion of 55–​200 defines Fragile X permutation carriers, who typically develop a movement disorder characterized by tremor and ataxia called Fragile X tremor ataxia syndrome (FXTAS). FXTAS may sometimes mimic multisystem atrophy, given it can feature a combination of ataxia, parkinsonism, and autonomic dysfunction. However, cognitive impairment which may be present in FXTAS, but not multisystem atrophy, is a red flag. FXTAS can also occur in females, where it is often associated with premature ovarian failure. The brain MRI shows often shows T2 hyperintensity of the middle cerebellar peduncles (MCP sign).

Tic disorders Tics are defined as rapid, brief, stereotyped movements, or vocalizations. In practice, one could think of them as caricatures of normal movements, such as eye blinking, shoulder shrugging, grimacing, sniffing, or grunting. These would be examples of simple motor or vocal tics, whereas complex tics consist of a combined sequence of stereotyped movements or saying words or phrases. Typically, tics wax and wane, and are (temporarily) suppressible, but patients will describe an inner rising tension or anxiety to allow the tics to emerge. This so-​called premonitory urge resolves when allowing the tics to happen, and often there is a rebound exacerbation.

24.7.3  Movement disorders other than Parkinson’s disease

(a)

(b)

Fig. 24.7.3.4  Samples of handwriting and spiral drawing from patients with dystonic tremor, illustrating the difficulties patients may face in day to day life on writing or fine motor tasks.

Primary tic disorders and Tourette syndrome Tics mostly occur as primary disorders without any associated neurological disease. There is a very broad spectrum of tics, spanning from minor tics of self-​limiting occurrence during childhood, which occur in up to 15% of school-​age children (boys more than girls), and persistent tic disorders, like Tourette syndrome, which can result in significant physical and social disability. Tourette syndrome affects approximately 0.3–​0.5% of the adult population, with males being more often affected than females (4:1). Although no gene has been identified, there seems to be a genetic burden since first-​degree relatives have a higher risk (10–​100-​fold), and there are families with an autosomal-​dominant inheritance pattern. Our pathophysiological understanding is still limited, but existing data point to a maturation defect of the corticosubcortical and corticocortical circuits regulating motor output control, and particularly to altered cholinergic neurotransmission in the striatum. Tourette’s syndrome is diagnosed when multiple motor (at least two) tics and vocal utterances (at least one) have occurred (although not necessarily simultaneously) prior to the age of 18 years and persisted

for more than one year. Patients with Tourette’s might also exhibit echopraxia (copying movements) or echolalia (repeating words). In contrast, copropraxia (making obscene gestures) or coprolalia (uttering obscenities) are much less frequent. Often however, it is the psychiatric comorbidity (obsessive-​compulsive disorder, attention deficit hyperactivity disorder (ADHD), self-​harming behaviour, depression) which is much more relevant for the patient’s quality of life than the actual tics, and this should be considered in the therapeutic approach. Tics can be treated with dopamine receptor antagonists, A2 receptor antagonists, or benzodiazepines. Botulinum toxin injections can sometimes ease the urge and are considered particularly helpful for vocal tics. Associated psychopathology can be addressed with cognitive behavioural therapy and, if needed, with drug treatment (e.g. SSRI for depression or obsessive-​compulsive disorder; methylphenidate for ADHD).

Secondary tic disorders More rarely, tics can occur secondarily to neurodegenerative disease (e.g. neuroacanthocytosis, Huntington’s disease, Wilson’s disease,

5971

5972

section 24  Neurological disorders

neuronal brain iron accumulation), in developmental disorders (e.g. autism, fragile X syndrome, mental retardation), as part of the spectrum of paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, or due to structural brain damage (e.g. basal ganglia lesions). Lastly, there are certain drugs which are associated with (re-​)occurrence of tics (e.g. cocaine, amphetamine, methylphenidate, ecstasy; amantadine, fenfluramine; levodopa; carbamazepine).

Restless legs syndrome and other sleep movement disorders Restless legs syndrome Patients with restless legs syndrome complain of the characteristic combination of unpleasant sensations in the legs and an urge to move them as this brings relief. The problem occurs only at rest and usually in the evening. It may be a primary, often familial disorder with an autosomal-​dominant inheritance, or secondary, due to a variety of causes including pregnancy, iron deficiency anaemia, peripheral neuropathy, PD, hyperthyroidism, and multiple sclerosis. Several drugs can precipitate restless legs including interferon-α, levothyroxine, neuroleptics, or tricyclic antidepressants. Overall, it is thought to be a relatively common disorder with mild symptoms affecting up to 11% of the population, whereas clinically significant symptoms affect about 3.5%. The pathophysiology is not fully understood. Defective iron metabolism with low iron levels in neuronal cells, particularly in the substantia nigra has been implied, as well as dopaminergic dysfunction. Other studies suggested hyperexcitability or disinhibition of the nociceptive systems. Routine investigations in a patient presenting with restless legs syndrome should include serum ferritin levels, and clinical examination for signs of peripheral neuropathy and parkinsonism. The first-​line treatment is dopaminergic

medication (L-​dopa and dopamine agonists), whereas symptomatic forms can be alleviated by treating the underlying condition (e.g. iron substitution, treatment of uraemia). A caveat of dopaminergic treatment is so-​called ‘augmentation’, referring to a worsening of symptoms (earlier occurrence in the day; increased intensity; involvement of other body parts) during treatment.

Periodic limb movement of sleep Periodic limb movement of sleep consists of jerky flexion movements of the hips, knees, and ankles during non-​REM sleep. This may be idiopathic, but is often associated with restless legs syndrome, with an overlapping spectrum of symptomatic causes. Treatment with clonazepam is helpful when the disorder causes sleep disruption with consecutive daytime somnolence.

REM sleep behaviour disorder It is usually the bed partner who describes the patient shouting, or being punched or kicked out of bed. In REM sleep behaviour disorder, there is no loss of muscle tone during REM sleep, and thus, patients act out their vivid dreams. This may be an idiopathic problem, but often heralds the onset of a parkinsonian disorder, usually with α-​synuclein pathology (Parkinson’s disease, dementia with Lewy bodies, multisystem atrophy). In doubt, the diagnosis can be established by polysomnography. Clonazepam or melatonin are useful when sleep quality is poor.

Stiff person syndrome and related disorders Moersch and Woltman firstly described stiff person syndrome as a rare and enigmatic disorder of ‘progressive fluctuating muscular rigidity and spasm’, without other ‘firm’ neurological signs (Fig. 24.7.3.5). Classical stiff person syndrome features

Fig. 24.7.3.5  Paravertebral stiffness leading to lumbar hyperlordosis with skin crease in a patient with classical stiff person syndrome; the hyperlordosis does not even out when bending down.

24.7.3  Movement disorders other than Parkinson’s disease

Table 24.7.3.7  Main antibodies in stiff person syndrome and related disorders Antibodies against

Glutamic acid decarboxylase (GAD)

Mostly non​paraneoplastic; often associated with other diabetes type 1 and other organ-​specific autoimmunity (e.g. thyroid antibodies, vitiligo)

Glycine receptor (GlyR)a

Mostly non​paraneoplastic (malignancies in up to 10%, mostly thymoma, lymphomas, various cancers)

Amphiphysin

Paraneoplastic, often associated with breast cancer a

Dipeptidyl-​peptidase 6 (DPPX) a

Mostly in PERM variants, prominent gastrointestinal symptoms (diarrhoea or constipation) are a red flag; paraneoplastic and non​paraneoplastic (malignancies in up to 10%, mostly B-​cell lymphoma)

Neuronal surface antibodies.

stiffness of paravertebral and proximal muscles, leading to lumbar hyperlordosis and a stiff, wooden gait. Subsequently, a broad clinical spectrum, with stiffness and spasms as the hallmark features, emerged. Often there is also an exaggerated startle response, and falls may occur due to sudden stiffening. We recognize focal forms like stiff limb syndrome as well as progressive encephalomyelitis with rigidity and myoclonus, a variant with a more widespread involvement featuring other neurological signs and a potentially lethal disease course. Apart from the mere motor signs, patients often have a characteristic fear of walking unaided, which leads to them frequently being wrongly labelled as psychogenic. The different variants share a range of associated antibodies, which supports the notion that this is an autoimmune disease, which in some cases is triggered by an underlying neoplasm. Among them, antibodies against glutamic acid decarboxylase, glycine receptor, and amphiphysin are the most frequent and account for up to 90% of the cases. According to current paradigms in neuroimmunology, it is believed that neuronal surface antibodies (see Table 24.7.3.7) are pathogenic whereas the other antibodies, targeting intracellular antigens, are rather a marker of autoimmunity driven by T cells. Apart from antibody testing, the diagnostic work-​up includes cerebrospinal fluid analysis and electrophysiological studies (exteroceptive reflexes, continuous motor unit activity). The treatment approach comprises immunotherapy (intravenous immunoglobulins, corticosteroids, plasma exchange, rituximab), removal of tumour where appropriate, and symptomatic treatment with benzodiazepines (mostly clonazepam; high doses may be required and well tolerated) and baclofen.

Paroxysmal dyskinesia The paroxysmal dyskinesias are a group of rare, heterogeneous disorders typified by brief self-​limiting attacks of involuntary movements, which can be clinically classified according to the triggering factor and the duration of attacks. Between attacks, patients do not have any neurological symptoms. Onset is usually in childhood. Different genetic forms have been identified corresponding to particular clinical phenotypes. Paroxysmal kinesigenic dyskinesia is the most frequent from of paroxysmal dyskinesias with brief (seconds to minutes) attacks of chorea, dystonia or mixed forms precipitated by sudden movement,

or even an intention to move or acceleration of ongoing movement (hence kinesigenic). Up to hundred attacks may occur per day. Most cases are due to autosomal-​dominant PRRT2 mutations, which also associate with ‘Infantile convulsions with paroxysmal choreoathetosis’ (ICCA), benign familial infantile epilepsy and migraine. Treatment response to low doses of carbamazepine is usually excellent. Attacks of paroxysmal non​kinesiginic dyskinesias are triggered by alcohol, coffee, or fatigue. They last minutes to hours and are infrequent compared to paroxysmal kinesigenic dyskinesia with just one to three attacks a day and several months of attack free intervals. In familial cases, mutations of the myofibrillogenesis regulator gene MR-​1 are the underlying cause. Treatment consists mainly in avoidance of the precipitating factors. Paroxysmal exercise-​induced dyskinesia manifests as gradual onset of dystonia in a limb after prolonged exercise of that limb. Heterozygous mutations in the SLC2A1 gene encoding for glucose transporter 1 (GLUT1) give rise to this phenotype in about half of the cases with paroxysmal exercise-​induced dyskinesia. Apart from genetic testing, the diagnosis can be ascertained by measuring the ratio of cerebrospinal fluid to plasma glucose levels, which is below 0.45 in affected subjects. Recognition is important as a ketogenic diet can be used successfully in these cases. There are also secondary forms of paroxysmal movement disorders, for example, due to basal ganglia lesions. The red flags cautioning against a diagnosis of primary paroxysmal movement disorders are a later age at onset, abnormalities on the neurological examination between attacks, and pain during the attacks. The latter is particularly frequent in the tonic spasms seen in demyelinating disorders, and in psychogenic paroxysmal attacks. Of particular interest are two conditions where the paroxysmal attack may herald avoidable damage: limb-​shaking transient ischaemic attacks (‘limb-​shaking TIA’) are typically precipitated by rising or exercise, and often accompanied by paresis of the affected limb. They are a manifestation of an internal carotid artery occlusion and indicate a critical haemodynamic state. The so-​called faciobrachial dystonic seizures with LGI1-​antibodies are very characteristic, brief (8 at the time of writing). Autosomal dominant episodic ataxia is characterized by childhood or adolescent onset of attacks of ataxia, dysarthria, vertigo, and nystagmus. Not all patients have affected relatives. There are at least two forms of this disorder: Episodic ataxia 1 (EA1), due to mutations in a potassium channel Kv1.1, is typified by brief attacks (minutes and occasionally hours) and clinically and electrophysiologically myokymia may be seen. These patients may benefit from acetazolamide or phenytoin. Patients tend to be neurologically normal between the attacks. In episodic ataxia 2 (EA2) the attacks tend to be longer, lasting hours or even days. They are usually associated with vertigo and consequent nausea and vomiting. They tend to be more severe in childhood with associated drowsiness, headache, and fever. Although when the disease first begins the patients are well, between attacks an interictal nystagmus can be seen. As the disease progresses a slow deterioration in the ataxia is seen. MRI may reveal cerebellar atrophy. These patients tend to respond better to acetazolamide therapy than patients with EA1. However, increasingly other varieties of episodic ataxia are being recognized, see Table 24.7.4.5a. In children and young adults a metabolic disorder should be suspected, particularly defects of the urea cycle, aminoacidurias, Leigh’s syndrome, and mitochondrial encephalomyopathies. Screening investigations include serum ammonia, pyruvate, lactate and amino acids, and urinary amino acids.

24.7.4  Ataxic disorders

Ataxia with a chronic progressive course Chronic alcohol abuse is probably the most common cause of progressive cerebellar degeneration in adults. Thiamine deficiency is the main (but not sole) explanation for the chronic progressive cerebellar syndrome found in alcoholics. Patients with this syndrome are frequently malnourished. Ataxia may develop during periods of abstinence, and identical cerebellar degeneration has been observed in non​alcoholic patients with severe malnutrition. Cerebellar ataxia is common in the Wernicke–​Korsakoff syndrome, and the pathological features of both this syndrome and cerebellar degeneration are frequently found together. With administration of thiamine some improvement may occur in early cases of alcoholic cerebellar degeneration but, if the patient is already chairbound, the response to treatment is limited. There are other deficiency disorders that can give rise to a progressive ataxia. There is a rare syndrome associated with zinc deficiency that responds to oral replacement therapy. Deficiency of vitamin E, either genetic (e.g. isolated vitamin E deficiency due to mutations in α-​tocopherol transfer protein, or abetalipoproteinaemia) or acquired, may produce a progressive ataxia. Establishing the diagnosis of vitamin E deficiency is important as treatment with vitamin E may prevent progression of the neurological syndrome and can, in rare circumstances, lead to some improvement. There are several toxic agents that can produce progressive cerebellar dysfunction, including pharmaceutical products, solvents, and heavy metals. The most common cause of a cerebellar syndrome due to drug toxicity in neurological practice is that associated with anticonvulsant medication, particularly phenytoin. Transient ataxia, dysarthria, and nystagmus usually develop when serum concentrations of phenytoin, carbamazepine, or barbiturates are above the therapeutic range, and remit when they return to the therapeutic range. Chronic phenytoin toxicity may cause persistent cerebellar dysfunction, and this is associated pathologically with loss of Purkinje cells. A  persistent cerebellar deficit, with dysarthria and limb and gait ataxia and cerebellar atrophy on imaging, has also been described as a sequel to the acute encephalopathy of lithium toxicity that is usually precipitated by fever or starvation. Recreational or accidental exposure to several solvents, including carbon tetrachloride and toluene, causes cerebellar ataxia along with other neurological problems, including psychosis, cognitive impairment, and pyramidal signs in the case of toluene. The neurological deficit is potentially reversible but may persist after prolonged exposure in solvent abusers. Exposure to heavy metals, including inorganic mercury, lead, and thallium, can also produce cerebellar damage. Structural lesions such as posterior fossa tumours, foramen magnum compression, or hydrocephalus must be excluded by imaging studies. Tumours which may involve the posterior fossa include: astrocytoma, ependymoma, haemangioblastoma, and cranial nerve neuromas. Paraneoplastic cerebellar degeneration related to carcinomas of the lung or ovary usually follows a subacute course, with patients losing the ability to walk within months of onset. A variety of antineuronal antibodies may be found in these patients and help to confirm the diagnosis. Approximately half of patients with paraneoplastic cerebellar degeneration have demonstrable antibodies directed against neurons in serum and CSF. A  search for

the underlying malignancy should then be undertaken involving imaging and analysis of tumour markers. Presentation with ataxia precedes diagnosis of the malignancy in 70% of cases and is usually subacute, progressing to severe disability over several months or even weeks and then arresting. Onset may be acute and is sometimes accompanied by vertigo, mimicking a vascular event. There is severe truncal, gait and limb ataxia, and dysarthria. Opsoclonus may be combined with myoclonus, producing a disorder in adults similar to the dancing eyes syndrome of childhood. The latter is sometimes associated with neuroblastoma. There is currently no proof that immunosuppressant therapy or plasma exchange improves outlook but there are anecdotal reports of some improvement or stabilization following removal of the primary tumour. The best method of screening for the underlying malignancy is debated but standard MRI imaging may be complemented by whole body positron emission tomography (PET) technology. Searching for primary tumour markers may also be useful. Rarely, infectious agents can cause slowly progressive ataxia (see Table 24.7.4.3), these include the chronic panencephalitis of congenital rubella infection in children and, in adults, Creutzfeldt–​ Jakob disease, particularly the iatrogenic form, should be considered. A specific enquiry regarding potential risk factor exposure should be sought, especially growth hormone replacement, although following introduction of stringent controls on source material this has become extremely rare. Multiple sclerosis only exceptionally presents as an isolated chronic progressive cerebellar syndrome. Some conditions that are not generally considered primarily as ataxic disorders may present with clumsiness, tremor, or definite cerebellar signs, particularly in childhood or adolescence. These include Wilson’s disease and several inherited neuropathies, such as Charcot-​Marie-​Tooth disease. Although intention and postural tremor are quite frequent in the demyelinating type of Charcot-​ Marie-​Tooth (type I), dysarthria and pyramidal signs do not occur. Other chronic demyelinating neuropathies, such as chronic inflammatory and paraproteinemic neuropathies and Refsum’s disease, may give rise to prominent tremor and ataxia; the same applies to giant axonal neuropathy. Superficial siderosis is a rare disorder that causes slowly progressive cerebellar ataxia, mainly of gait, and sensorineural deafness, often combined with spasticity, brisk reflexes, and extensor plantar responses. The diagnosis may not be suspected clinically, but the neuroradiological abnormalities are striking, MRI showing a black rim of haemosiderin around the posterior fossa structures and spinal cord, and less often the cerebral hemispheres, on T2-​weighted images. Superficial siderosis is most commonly secondary to chronic leaking of blood into the subarachnoid space. Treatment relies on identifying the source of bleeding; chelation therapy does not appear to be effective. After excluding acquired causes of ataxic disorders, there remains a considerable number of patients with degenerative ataxias, not all of which are overtly genetically determined. The inherited ataxias can largely be classified according to their clinical and genetic features (see next) and, in a small proportion of cases, a recognizable metabolic defect can be detected. It is important to make as accurate diagnosis as possible in these disorders for the purposes of prognosis, genetic counselling and, occasionally, specific therapy.

5981

5982

section 24  Neurological disorders

Progressive metabolic ataxias Ataxia may be a minor feature of storage and other metabolic neurodegenerative disorders developing in early childhood (see Chapter 24.21). Some enzyme deficiencies that usually give rise to diffuse neurodegenerative disorders, in which ataxia is a feature, developing in infancy or early childhood, include the sphingomyelin lipidoses, metachromatic leukodystrophy, galactosylceramide lipidosis (Krabbe’s disease), and the hexosaminidase deficiencies. Also within this group is adrenoleukomyeloneuropathy, a phenotypic variant of adrenoleukodystrophy. This diagnosis is supported by an increase in very long chain fatty acids or by direct genetic analysis of the AMN gene. Although X-​linked, approximately 10% of carrier females may manifest neurological abnormalities. The role of diet and dietary supplements (e.g. oleic acid and Lorenzo’s oil) remains to be established. Ataxia may be prominent in Niemann–​Pick disease type C (juvenile dystonic lipidosis), combined with a supranuclear gaze palsy. Sphingomyelinase activity is normal but foamy storage cells are found in the bone marrow. Cholestanolosis (also called cerebrotendinous xanthomatosis or CTX) is a rare autosomal recessive disorder caused by defective bile salt metabolism, due to a deficiency of mitochondrial sterol 27 hydroxylase. It gives rise to ataxia, dementia, spasticity, peripheral neuropathy, cataract, and tendon xanthomata in the second decade of life. Treatment with chenodeoxycholic acid appears to improve neurological function. Various phenotypes that are classifiable as hereditary ataxias have been described in the mitochondrial encephalomyopathies, many of which are associated with a defect of mitochondrial DNA. These include late-​onset ataxic disorders are associated (e.g. the

Kearns–​Sayre syndrome) with such features as dementia, deafness, and peripheral neuropathy. These features overlap with the syndrome of progressive myoclonic ataxia, which may also be caused by ceroid lipofuscinosis, sialidosis, and Unverricht–​Lundborg’s disease or so-​called Baltic myoclonus. There has been substantial progress in genetic delineation of these syndromes.

Acquired metabolic and endocrine disorders causing cerebellar dysfunction Acquired metabolic and endocrine disorders causing cerebellar dysfunction include hepatic encephalopathy, pontine and extrapontine myelinolysis related to hyponatraemia, and hypothyroidism. The latter is only very rarely a cause of a cerebellar syndrome in both children and adults.

Degenerative disorders The degenerative cerebellar and spinocerebellar disorders are a complex group of diseases, most of which are genetically determined. In some there is an underlying metabolic disorder, and it is important to diagnose these, as there may be important implications for treatment and genetic counselling. There has been a rapid growth in our knowledge of the genetic basis of many of the spinocerebellar degenerations. The current phase of research is focussed on how these genes and the abnormal proteins they produce cause cell specific neuropathology. Inherited ataxic disorders can be divided according to their mode of inheritance (Tables 24.7.4.4 and 24.7.4.5). Most autosomal recessive disorders are of early-​onset (less than 20  years), and autosomal dominant disorders are usually of later onset (over 20 years). A recent review of the epidemiology points

Table 24.7.4.4  Autosomal recessive ataxias Syndrome

Gene defect

Clinical notes

Friedreich’s ataxia

GAA repeat (and rarely point mutations in FRDA gene)

Neuropathy, pyramidal signs, skeletal abnormalities, diabetes, and cardiomyopathy

ARSACs

Sacsin

Demyelinating neuropathy and hypertrophied retinal nerve fibre layer (on OCT)

Ataxia telangiectasia AT-​like disorder

ATM hMRE11

Oculomotor apraxia, Mixed movement disorder, humoral immune difficulties, increased cancer risk

Cockaynes syndrome

CS type A—​ERCC8 gene CSA type B—​ERCC6 gene

‘Cachcectic dwarfism’ Mental retardation Pigmentary retinopathy

Xeroderma pigmentosum

ERCC2 but also probably genetically complex

Skin disorder and an increased risk on skin cancer

AOA1

Aprataxin

Oculomotor apraxia

AOA2

Senataxin

Oculomotor apraxia

Hypogonadism

RNF216

Hypogonadotrophic hypogonadism

Marinesco–​Sjögren syndrome

SIL1 on chr 5q31

Cataracts and mental retardation

Gillepsie syndrome

PAX6

Aniridia

Progressive myoclonic ataxia (Ramsay Hunt syndrome)

Genetically complex

Epilepsy is common

Behr’s and related syndromes, e.g. 3-​methylglutaconic aciduria type III (Costeff syndrome)

No gene for Behr’s yet identified

Optic atrophy, spasticity, and mental retardation

Congenital or childhood onset deafness

Genetically complex

Syndromic diagnosis—​likely to have several causes

Autosomal recessive late-​onset ataxia

Heterogeneous

Wide clinical variability

Onset usually before 20 years of age.

OPA3 gene

24.7.4  Ataxic disorders

Table 24.7.4.5a  Autosomal dominant cerebellar ataxia: clinicogenetic classification. Onset usually over age of 25 years. This is a list of currently identified genes and is divided by autosomal dominant cerebellar ataxia (ADCA) subtype to facilitate clinical relevance ADCA type

Clinical features

Genetic loci and chromosomal location

Gene

ADCA I

Cerebellar syndrome plus: Pyramidal signs Supranuclear ophthalmoplegia Extrapyramidal signs Peripheral neuropathy Dementia

SCA1

Ataxin 1 CAG

SCA2

Ataxin 2 CAG

SCA3

Ataxin 3 CAG

SCA8

Kelch-​like 1 CTG repeat

SCA12

PPP2R2B CAG repeat

SCA13

KCNC3 point mutations

SCA14

PRKCG point mutations

SCA15

ITPR1

SCA17

TBP CAG

SCA28

AFG3L2

SCA36

Hexanucleotide repeat in NOP56

ADCA II

Cerebellar syndrome plus: Pigmentary maculopathy Other signs as ADCA I

SCA7 3p12-​21.1

Ataxin 7 CAG

ADCA III

‘Pure’ cerebellar syndrome Mild pyramidal signs

SCA5

SPTBN2 β-​III spectrin D

SCA6

CACNL 1Aa CAG repeat

SCA10

Ataxin 10 ATTCT repeat

SCA11

TTBK2

SCA27

FGF14 point mutations

Episodic ataxias

EA 1

Kv1.1

EA 2

CACNL 1Aa

EA3

Locus on 1q42

EA4

No gene identified

aka PATX CACNB4

EA5

SLC1A3

EA6 EA8 Plus others yet to be defined a

Locus 1p36

SCA6 and CACNL1A are allelic variants.

Table 24.7.4.5b  Clinical impact of widely available genetic tests for the ADCAs ADCA type

Genetic tests (widely available)

Relative contribution to each subclass

ADCA I

SCA 1, 2, 3,

50%

ADCA II

SCA7

99%

ADCA III

SCA6

50%

out that cumulatively these disorders represent a very significant health burden.

Autosomal recessive ataxias Friedreich’s ataxia This is the most common of the autosomal recessive ataxias (see Table 24.7.4.4) and accounts for at least 50% of cases of hereditary

ataxia in most large series reported from Europe and the United States. The prevalence of the disease in these regions is similar, between 1 and 2 per 100 000. The age of onset of symptoms, generally with gait ataxia, is usually between the ages of 8 and 15 years, but onset between 20 and 30, but fulfilling all other diagnostic criteria, have been described. In addition to the progressive ataxia, one finds several variable features, including dysarthria and pyramidal tract involvement. Initially this latter feature may be mild, with just extensor

5983

5984

section 24  Neurological disorders

plantar responses, but after five or more years’ duration of the disease, invariably a pyramidal pattern of weakness in the legs is seen. Eventually this can lead to paralysis. Distal wasting, particularly in the upper limbs, is seen in about 50% of patients with Friedreich’s ataxia. Skeletal abnormalities are also commonly found including scoliosis (85%) and foot deformities, typically pes cavus, in approximately 50% of patients. Additional clinical support for one’s suspicions include optic atrophy which can be seen in 25%; however, it is rare ( M

F > M

M = F

Type

Boring/​ throbbing

Boring/​throbbing

Stabbing/​throbbing

Stabbing

Stabbing

Throbbing

Severity

Very severe

Very severe

Very severe

Severe

Very severe

Moderate

Cranial location

Any

Any

Any

Any

V2/​V3 >V1

Generalized

Duration

15–​180 min

2–​30 min

15–​600 s

4 h daily

55 years), four patients will have a stroke per annum, versus one having a TIA. Intracerebral haemorrhage will occur about twice every 3 years, and subarachnoid haemorrhage once every 8 years.

Arterial occlusive disease The cerebral circulation and its disorders Brain tissue is critically dependent on a constant supply of oxygen and glucose. The cerebral blood flow (c.800 ml/​min)

accounts for 15–​20% of the entire cardiac output, whereas the brain (c.1350 g) accounts for only 2% of the normal adult body weight. Neurons in the brain require a constant supply of adenosine triphosphate to maintain concentration gradients of ions across their membranes, necessary for the generation of action potentials. The resting brain consumes energy at the same rate as a 20-​W light bulb. Whether occlusion of an artery in the brain or in the neck actually leads to ischaemia depends on collateral pathways. If an end-​artery is occluded and there is no collateral circulation at all, ischaemic symptoms will occur within seconds. Neurons will start dying within minutes and within hours the entire supply area of the artery will be irreversibly damaged. In contrast, permanent occlusion of a major artery (e.g. the internal carotid artery) may be asymptomatic in the presence of adequate collateral circulation. Broadly speaking, three levels of collateral circulation can be distinguished (Fig. 24.10.1.1; these can be thought of as three lines of defence): 1 The circle of Willis (Fig. 24.10.1.2)—​even if no blood at all is

flowing to the brain from one or even both internal carotid arteries, collateral flow from the other internal carotid artery or the basilar artery, via an intact circle of Willis, may ensure an adequate blood supply in the territory of the occluded artery. 2 Connections between extracranial and intracranial vessels—​ if the internal carotid artery is occluded at its origin, collateral channels may develop via the external carotid artery. Branches supplying the outer orbit may connect with branches to the retina, resulting in a reversed flow in the ophthalmic artery. From there, blood reaches the distal part of the internal carotid artery. Similarly, branches of the occipital arteries (normally supplying the neck muscles) may fill the basilar artery if this is occluded at its origin. 3 Leptomeningeal anastomoses—​if, for example, the main stem of the middle cerebral artery is occluded, its terminal branches at the surface of the brain may anastomose with similar branches of

Posterior cerebral artery

Ophthalmic Posterior artery communicating artery

Basilar artery Junction of vertebral arteries

External carotid Internal carotid Vertebral artery

Common carotid

Fig. 24.10.1.1  Arterial supply of the brain. The drawing shows, on the right side, the internal carotid artery, external carotid artery, and vertebral artery. If a main artery is occluded, then collateral flow may occur via the circle of Willis (see also Fig. 24.10.1.2).

24.10.1  Stroke: Cerebrovascular disease

Internal carotid artery

Anterior cerebral artery Middle cerebral artery

Anterior communicating artery Posterior communicating artery

Basilar artery Posterior cerebral artery

Vertebral artery

Posterior inferior cerebrellar artery

Fig. 24.10.1.2  The arterial circle of Willis, at the base of the brain.

the anterior and posterior cerebral arteries; in this way the cerebral cortex in the territory of the occluded artery is spared, partly or wholly, although the deep territory will still be ischaemic. Atherothrombosis is the major cause of occlusion of major arteries in the brain or the neck. Two important qualifications should be made. First, atherosclerosis of intracranial arteries is relatively uncommon, at least in white people at younger ages (vs. black or East Asian people). This means that, in the Western world, brain infarction is usually caused by embolism, in which thrombus has been dislodged from an upstream lesion. The source can be the carotid artery, aorta, or heart. Second, atherosclerosis is not a sufficient cause in itself: not every person with severe atherosclerotic disease has an ischaemic stroke. Other relevant factors are collateral circulation, irregularity of the plaque, blood turbulence, platelet aggregation, and the balance of clotting factors.

Diagnosis of transient ischaemic attacks (TIAs) TIAs are important to diagnose because they are potential harbingers of stroke. They precede cerebral infarction probably in about 25% of cases. The term ‘transient ischaemic attack’ is rather imprecise, because it tacitly implies three restrictions. To begin with, it refers only to the brain and not to angina pectoris or intermittent claudication. Also excluded is transient ischaemia of the entire brain, such as occurs in syncope or ventricular fibrillation. In medical usage, only ischaemia of a part of the brain corresponds with the term TIA. Finally, how transient is transient? Traditionally the limit for the duration of symptoms has been set at 24 h. Obviously, this threshold has more to do with astronomy than with biology or disease. In fact, most TIAs last minutes, not hours. The longer an attack lasts, the greater the chance that CT or MRI afterwards will show a relevant ischaemic

lesion. In terms of patient management, the essential question is not whether the attack has lasted 3 minutes, 3 days, or 3 weeks, but what its cause is and how recurrences can be prevented. Moreover, in recent years, diffusion-​weighted MRI scanning has shown that about 30% of patients with TIA have small high-​signal lesions on brain imaging that usually correspond clinically with the symptoms of the event and appear to represent areas of acute cerebral infarction. Acute diffusion-​weighted imaging (DWI) changes increase in frequency as the duration of symptoms increases and are associated with a higher early risk of major stroke. What actually happens in the brain during a given period of ischaemia can often only be guessed at. The usual assumption is that an embolus, most often consisting of platelets or loosely organized thrombus, temporarily blocks an intracerebral vessel and then dissolves into smaller fragments. There is scant evidence for this phenomenon, apart from chance observations during fundoscopy, angiography, or surgery. Other explanations, applicable only to a minority, include marginal flow, secondary to severe narrowing or occlusion of arteries. The role of hypertension is also uncertain, but many patients with TIA have high blood pressure in the acute phase, which might be important in influencing susceptibility to cerebral ischaemia in the presence of embolization. The diagnosis of a TIA is problematic. That one has to rely on the history alone is a first difficulty (it requires time, skill, and patience). A greater source of error is that the term TIA is an interpretation rather than a description. Main varieties of transient ischaemic attacks There are four kinds of symptoms that can safely be regarded as TIAs, given that the onset is sudden (within seconds), all symptoms appear at the same time, without ‘march’, and there is no better explanation. Transient weakness of one-​half of the body Apart from weakness, there may also have been numbness. Isolated numbness or pins and needles on one side of the body are a less common manifestation of transient cerebral ischaemia; other causes such as overbreathing or focal seizures should also be considered. Weakness and numbness are closely related perceptions, and one should not take these or other expressions (‘an arm gone dead’) for granted. It is important to make sure that the problem had to do with moving the limbs or the face on one side (facial weakness on one side often manifests itself through slurred speech or drooling), and not with what it felt like when those body parts were touched or with spontaneous sensations. It is also important to verify whether the problem was in two of three body areas, and that it was not just a leg or arm gone to sleep after a nap in older people. Transient loss of the ability to find words or to understand them The medical term for this type of TIA is dysphasia or aphasia; in this case patients and relatives may not recognize the episode as representing a problem of language but will often describe the attack as ‘confusion’. It is helpful to ask specific questions about the ability to put thoughts into words (motor dysphasia), and about having been able to understand what was said (sensory dysphasia). If a patient can write sentences but cannot speak, the cause is almost certainly psychological. A  frequent problem is the distinction between dysphasia (disorder of language) and dysarthria (disorder of

6013

6014

section 24  Neurological disorders

articulation). To ask whether pronunciation was difficult may not be very helpful. After all, in both cases the patient’s thoughts are clear and the distinction between the right words and the right sounds is rather academic. A more useful question is whether the words made sense and whether they were in the right order. Dysphasia implies a lesion of the left hemisphere in right-​handed people, and in 30% of strong left-​handers.

Box 24.10.1.2  Disorders that may mimic genuine TIAs • Chronic subdural haematoma • Intracranial tumour (glioma, metastasis, meningioma) • Hypoglycaemia • Focal deficits following a partial epileptic seizure • Transient global amnesia • Myasthenia gravis

Transient loss of vision in one eye The difficulty in this case is to distinguish transient monocular blindness from loss of vision on one side in both eyes (hemianopia). Either type of attack can be interpreted by the patient as a problem in one eye. The distinction has practical implications, as monocular attacks of blindness should lead to investigation of the ipsilateral internal carotid artery in the neck with a view to angiography and surgery, whereas isolated hemianopia mostly (in 80%) reflects a disorder in the vertebrobasilar circulation, in which case treatment will often be medical. The key question to ask is whether patients have alternately covered each eye during the attack. A surprisingly large proportion of patients have done so, but they will not always offer this information without prompting. On having covered the ‘good eye’ in case of hemianopia, the patient should still have been able to see with the ‘bad eye’, although only the nasal half of the visual field. With a monocular disorder the blindness should have been complete after covering the unaffected eye. In practice, however, the distinction between hemianopia and monocular visual loss can still be difficult, particularly if the hemianopia was macular-​sparing, such that central vision (i.e. faces or written text) was preserved. Transient loss of vision in one hemifield Hemianopia reflects dysfunction of the occipital lobe. It is also a common aura in migraine attacks; these auras may occur without ensuing headache, especially in older people. It is, therefore, important for the physician to enquire about the mode of onset: flashing lights, bright colours, zigzag lines, and a gradually expanding deficit all argue in favour of a migrainous attack, rather than ischaemia in its restricted sense of a stroke warning.

Differential diagnosis of TIAs Box 24.10.1.1 lists types of attacks that should in general not be regarded as TIAs, either because of positive phenomena, such as rhythmic jerking, that are rarely due to focal ischaemia, or because other causes are much more likely. In particular, the tendency to

Box 24.10.1.1  Attacks that should generally not be regarded as definite TIAs • Any attack with loss of consciousness • Any attack with involuntary jerking (with the rare exception of limb shaking TIA due to low blood flow distal to a carotid occlusion) • Any attack with positive visual phenomena (bright lights, and so on), particularly if the symptoms progressed over minutes • Any attack with only one of the following: • numbness • dizziness (with or without spinning sensations) • double vision • slurred speech • unsteady walking

label any episode of ‘dizziness’ in older people as ‘vertebrobasilar ischaemia’ or, even worse, ‘vertebrobasilar insufficiency’ should be resisted unless there is compelling evidence of severe disease of the vertebral or basilar arteries. The other isolated neurological symptoms listed in the box can sometimes be due to TIAs, but there is less diagnostic certainty and these events are sometimes referred to as transient neurological attacks (TNAs). Recent research shows that the risk of major stroke after a TNA is relatively low, but that they are associated with a relatively high long-​term risk of vascular events. In addition, some specific disorders other than atherosclerosis may cause attacks that are more or less indistinguishable from true TIAs as just defined. They are listed in Box 24.10.1.2. These rare but important causes are reason enough to order a CT or MRI scan of the brain in patients with cerebral TIAs (not necessarily in those with transient monocular blindness). A  chronic subdural haematoma should always be suspected in older people, especially if they are on anticoagulants. Hypoglycaemia should come to mind in patients with diabetes. Focal weakness may follow an epileptic seizure (Todd’s paralysis) and may be misdiagnosed as a TIA if the initial jerking is missed or misinterpreted. Tumours may also cause temporary deficits without focal epilepsy. Transient global amnesia is a disorder of memory possibly caused by migrainous vasospasm or venous congestion; although technically ischaemic in nature, it is not associated with an increased risk of stroke or other vascular disease. Prognostic implications of TIAs Without treatment, the risk of stroke after a TIA can be estimated at up to 20% in the first year and 7% in subsequent years, and the average risk of death, stroke, or myocardial infarction in the first five years at 10% per annum. Heart disease and stroke each account for about one-​third of all deaths. It is important to recognize that the risk of stroke is highest soon after the first episode if patients are not treated urgently: 8% in the first week, 12% at 1 month, and 17% at 3 months. Patients at particularly high risk can be identified by means of the ABCD2 score (see ‘Further reading’): A for age (>60 years), B for blood pressure (>140/​90 mm Hg), C for clinical features (2 points for unilateral weakness, 1 point for speech disturbance without weakness), and D for duration (2 points for >60 min, 1 point for >10 min) and for diabetes (1 point). The risk of stroke within 2 days is approximately 8% in patients with a score of 6 or 7, 4% in those with a score of 4 or 5, and much less in the others. These risks are reduced by urgent medical treatment, particularly by antiplatelet treatment.

Investigations in patients with cerebral ischaemia There is no great difference between searching for the cause of a TIA and searching for the cause of an ischaemic stroke. Very early

24.10.1  Stroke: Cerebrovascular disease

CT or MRI is mandatory, mainly to exclude intracerebral haemorrhage and the occasional structural lesion mimicking stroke and to demonstrate infarcts. Box 24.10.1.3 lists the major and contributory causes of TIA and ischaemic stroke, with corresponding investigations. In general, first-​line investigations are full blood count, erythrocyte sedimentation rate (ESR), plasma glucose, Box 24.10.1.3  Major and contributory ‘causes’ of transient ischaemic attack (TIA) or ischaemic stroke, with corresponding investigations Investigations marked with an asterisk (*) have proven implications for management. Arterial atheroma • Internal carotid artery in the neck—​duplex ultrasound study* • Intracranial arteries—​angiogram (with MR, CT, or catheter) Small vessel disease • Aorta—​transoesophageal echocardiography • MRI brain imaging to identify asymptomatic lacunes and microbleeds Other arterial disease • Congenital arterial anomalies—​angiogram (with MR, CT, or catheter) • Moya-​moya syndrome—​angiogram (with MR, CT, or catheter) • Arterial dissection—​MRI; angiogram (with MR, CT, or catheter) • Giant cell arteritisa—​ESR*, temporal artery biopsy* • Systemic vasculitis—​antinuclear antibodies*, tissue biopsy* • Embolization from arterial aneurysms—​MRI; angiogram (with MR, CT, or catheter) • Cholesterol embolization syndrome—​biopsy of skin, muscle, or kidney • Meningitis, encephalitis—​cerebrospinal fluid*, brain biopsy* • Drugs of abuse—​toxicological screening of urine • Genetic conditions (mitochondrial encephalomyopathy, lactic acidosis, and stroke-​like episodes (MELAS), analysis of mitochondrial or nuclear DNA, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), Fabry’s disease), α-​galactosidase A* • Irradiation • Migraine Embolism from the heart • Atrial fibrillation—​ECG*; long-​term monitoring of heart rhythm* • Recent myocardial infarction—​ECG* • Rheumatic valvular disease—​echocardiogram* • Infective endocarditis—​echocardiogram*, blood cultures* • Open foramen ovale—​venography*, echocardiogram, bubble TCD • Atrial myxoma—​echocardiogram* Haemostatic factors • Polycythaemia or iron deficiency anaemia —​haematocrit* • Sickle cell disease—​peripheral blood smear, sickling test • Thrombocytosis—​platelet count* • Leukaemia—​white cell count*, morphological analysis* • Disseminated intravascular coagulation—​platelet count, prothrombin, and activated partial thromboplastin times, fibrinogen, fibrinogen degradation products, D-​dimers Contributing risk factors • Hypertension—​serial measurement of blood pressure* • Diabetes—​fasting glucose*, HbA1c? • Hypercholesterolaemia—​plasma cholesterol* • Hyperhomocysteinaemia—​plasma homocysteine level ESR, erythrocyte sedimentation rate. a

Only with involvement of optic nerve or occipital lobe.

creatinine and electrolytes, plasma lipids, ECG, duplex ultrasound scanning of the arteries in the neck, and unenhanced CT or MRI of the brain. Ideally, CT or MR angiography of the intracranial arteries and the posterior circulation should also be performed, both in major stroke (to help determine the need for thrombolysis or thrombectomy) and in TIA and minor stroke (to understand aetiology and optimize secondary prevention). Prolonged ambulatory cardiac rhythm monitoring (e.g. 7-​day R-​test) is indicated to identify patients with paroxysmal atrial fibrillation if no other clear cause of the TIA or stroke is found. Evidence on the usefulness of routine echocardiography is limited and conflicting.

Diagnosis of cerebral infarction Distinction from other types of stroke From a practical point of view, the first step is to distinguish ischaemic stroke from intracerebral haemorrhage. In the past, when a certain distinction could be made only at operation or postmortem examination, a decreased level of consciousness and headache were considered typical of intracerebral haemorrhage. After CT became available in the 1970s, it soon became clear that smaller haemorrhages are not associated with headache and drowsiness. Given that 4 out of 20 strokes are haemorrhagic, and on the assumption that half of all haemorrhages lack distinctive clinical features, a diagnosis of cerebral infarction based on clinical features alone will be wrong in approximately every tenth case. Even complex clinical scoring methods hardly improve on this error rate. On CT, acute parenchymal haemorrhage is of higher density than normal brain tissue (see Fig. 24.10.1.6). The hyperdensity occurs immediately—​it is caused by the iron molecules in haemoglobin. In small haemorrhages, the hyperdensity can be lost within two to three days, such that the CT appearances are then easily confused with cerebral infarction. It is important therefore that brain imaging is performed quickly even in minor strokes. With the advent of very iron-​sensitive MR imaging techniques, such as gradient-​echo imaging, signs of previous haemorrhages are much easier to spot. These techniques often also identify multiple small areas of iron-​deposition, which are thought to be ‘microbleeds’. These lesions are associated with hypertension and with cerebral amyloid angiopathy. Signs of infarction are more difficult to detect at an early stage. In the first decade of CT this was not possible until after three days, when frank tissue necrosis caused a hypodense lesion on the scan. With improved CT technology, subtle early signs of cerebral infarction have been recognized, at least when the area of infarction is large. These features include loss of normal differentiation between grey and white matter (such as the normal outline of the insular ribbon and the lentiform nucleus) (Fig. 24.10.1.3) and effacement of cortical sulci. With the advent of diffusion-​weighted MR imaging, which is very sensitive to early changes in cerebral infarction, it is much easier to identify acute ischaemia, but not all acute stroke patients will tolerate an MRI scan and MRI is contraindicated in about 10% of older patients due to metallic implants of various kinds. Within the first few days, CT will show that the area of infarction changes into a slightly hypodense, ill-​defined, and somewhat swollen lesion; towards the end of the first week it becomes more

6015

6016

section 24  Neurological disorders

(a)

The proportion of patients in whom CT shows an appropriate infarct depends not only on the time of scanning and the generation of the scanner, but also on the size of the infarct and its location; eventually more than 90% of infarcts will show up. MRI is especially useful for demonstrating small infarcts and lesions in the posterior fossa; diffusion-​ weighted imaging is also much more sensitive than CT in the early phases of brain ischaemia. Signal changes on T2-​weighted images occur after 6 to 8 h. Infarcts of any size are visible within minutes on diffusion-​weighted imaging. The distinction from intracerebral haemorrhage is less obvious than on CT, but after a few hours the paramagnetic effects of deoxyhaemoglobin can be identified.

Classification of cerebral infarction

(b)

Fig. 24.10.1.3  Acute cerebral infarction in a 78-​year-​old man. (a) CT scan about 6 h after symptom onset. In the left brain hemisphere (on the reader’s right) there are subtle changes in the region of the basal ganglia: other than on the normal side, it is difficult to distinguish the different brain nuclei and their separation by white matter. (b) CT scan 4 days after symptom onset shows marked hypodensity in the entire territory of the left middle cerebral artery.

clearly demarcated and hypodense (Fig. 24.10.1.3). Occasionally there may be massive swelling with the potential for brain herniation or haemorrhagic transformation. During the second week the infarct may again gradually increase in density, because the degradation products of necrotic brain tissue more readily absorb X-​rays; in the third and fourth weeks the infarcted area may even become isodense, being temporarily almost indistinguishable from normal brain, the so-​called ‘fogging effect’. Eventually a sharply demarcated, atrophic, hypodense (similar to cerebrospinal fluid) defect remains. It is not always possible to determine how old an infarct is, or to distinguish it from the scar of a haemorrhage that occurred weeks or years before. Intravenous injection of X-​ray contrast may in the first weeks cause some enhancement of adjacent brain tissue.

Time course has often been the guiding principle in the classification of stroke in the era before brain imaging. From the point of view of management and prognosis, however, the distinction between ‘progressive stroke’ and ‘completed stroke’ is hardly useful, let alone that between ‘permanent stroke’ and ‘reversible ischaemic neurological deficit’ (a kind of ‘extended TIA’ with complete recovery within 3 or 6 weeks, depending on local convention). What counts is the eventual severity of the functional deficit and, conversely, the remaining functions that are at risk. The anatomical classification distinguishes infarcts according to the territory of major cerebral arteries: in the cerebral hemispheres infarcts can be located in the supply areas of anterior cerebral artery, middle cerebral artery, or posterior cerebral artery, or in the border zones between these three main branches; the cerebellum and brainstem are supplied by branches of the vertebral arteries and the basilar artery. The problems are that there is little if any relationship with handicap, mostly no distinction is made between partial and complete infarcts in a given territory, and the boundaries between different territories vary substantially between individuals. Classification according to the cause of ischaemic stroke is of interest for studies aiming to describe or influence the pathophysiological background of strokes. The so-​called TOAST classification, for example, distinguishes five subtypes of ischaemic stroke:  (1) large artery atherosclerosis, (2) cardioembolism, (3) small vessel occlusion, (4) stroke with other specific cause, and (5) stroke with undetermined cause. At present about 40% of patients would currently end up in the category ‘undetermined’, even in specialized stroke services. Also, the classification may change according to the extent of ancillary investigations. Finally, and most important, the system is not suited for assessing the severity of stroke. Rehabilitation specialists are more interested in the functional abilities of patients than in the niceties of neurological nosology. They mostly grade patients’ disability on a scale for activities of daily life (such as the Barthel scale, which ranks 10 in-​house activities in hierarchical order, from bowel continence to taking a bath), or on a scale that includes some elements of social role fulfilment (‘handicap’), such as the Rankin scale (Table 24.10.1.1). A system that strikes a useful compromise between the restrictions of lifestyle and the anatomical point of view is the classification of the Oxfordshire Community Stroke Project. Four categories are distinguished:

24.10.1  Stroke: Cerebrovascular disease

Table 24.10.1.1  Modified Rankin scale (or Oxford Handicap Scale) for measuring outcome after stroke (but suitable for other purposes as well) Grade

Description

0

No symptoms

1

Minor symptoms that do not interfere with lifestyle

2

Symptoms that lead to some restriction of lifestyle but do not interfere with the patient’s capacity to look after himself

3

Symptoms that restrict lifestyle and prevent a completely independent existence

4

Symptoms that clearly prevent independent existence though no constant attention is required (patients are usually wheelchair-​bound)

5

Totally dependent patient requiring constant attention, night and day (patients are often bed-​bound)

Infarcts in the area of the anterior cerebral artery cause contralateral hemiparesis, more marked in the leg than in the arm, with no or only mild sensory deficit. Other frontal lobe features include mutism, incontinence, and apathy or, conversely, disinhibition.

1 Total anterior circulation infarcts (TACIs), with both cortical

and subcortical involvement, representing about one-​sixth of all ischaemic strokes in the community 2 Partial anterior circulation infarcts (PACIs), with more restricted and predominantly cortical infarcts (one-​third of all infarcts) 3 Posterior circulation infarcts (POCIs), clearly associated with the vertebrobasilar arterial territory (one-​quarter) 4 Lacunar circulation infarcts (LACIs), confined to the territory of the deep perforating arteries (one-​quarter)

Although the classes are anatomically defined, they contain important prognostic information: case fatality is highest by far in the TACI group and lowest by far in the LACI group.

Syndromes of cerebral infarction Occlusion of the internal carotid artery may cause no symptoms at all or infarction, at its worst in the entire territory of the ipsilateral anterior and middle cerebral artery (and sometimes of the posterior cerebral artery or contralateral anterior cerebral artery as well), depending on the presence of a complete circle of Willis and other collaterals. If arterial dissection is the cause of carotid occlusion, subadventitial bulging of the artery may cause Horner’s syndrome and lower cranial nerve palsies, with or without infarction. Occlusion of the anterior, middle, and posterior cerebral arteries may lead to complete or partial infarction in their respective territories, depending on collaterals at the surface of the brain. Obviously, branch occlusions cause smaller infarcts. What follows is a description of syndromes associated with complete infarction in the average territory of the main cerebral arteries, although there is much individual variation in practice. Middle cerebral artery infarcts, if complete, typically present with contralateral hemiplegia (most marked in the arm), sensory deficit, hemianopia, and cognitive defects such as aphasia (dominant hemisphere) or contralateral neglect (non​dominant hemisphere). Massive infarction of the entire territory of the middle cerebral artery may lead to massive brain swelling followed by herniation, especially in young patients without cerebral atrophy.

Occlusion of a vertebral artery involving the origin of the posteroinferior cerebellar artery causes Wallenberg’s syndrome, with ipsilateral cerebellar ataxia through infarction of the inferior part of the cerebellum, and a—​for students, slightly bewildering—​ combination of deficits from infarction of the dorsolateral medulla: decreased skin sensation in the ipsilateral half of the face and the contralateral half of the body; ipsilateral Horner’s syndrome; ipsilateral weakness of the soft palate, larynx, and pharynx; and rotatory vertigo. The full basilar artery syndrome, with infarction of most of the pons and midbrain, consists of coma, tetraparesis including facial movements, and loss of all eye movements and of pupillary and corneal reflexes. There are two characteristic partial syndromes of the basilar artery. One is the locked-​in syndrome (infarction of the base of the pons), with tetraparesis, including facial movements and loss of horizontal eye movements. Consciousness is preserved through sparing of the reticular formation, but patients can communicate only through vertical eye movements; these may not always be correctly interpreted or even noticed. The other is the top-​of-​the-​basilar syndrome, with variable combinations of hemianopia or complete cortical blindness (occipital lobes), amnesia (inferior temporal lobes) and vertical gaze palsies, pupillary disturbances, and hallucinations (perforating branches to the midbrain). The posterior cerebral artery syndrome may include hemianopia (occipital lobe), amnesia (lower temporal lobe), and oculomotor disorders or disturbances of language or visuospatial function, by involvement of perforating branches to the thalamus. Occlusion of a single perforating artery, one of the many that originate at right angles from a large parent artery to supply a small area in the deep regions of the brain or brainstem (Fig. 24.10.1.4), may be clinically silent, or cause a so-​called ‘lacunar syndrome’. A necessary condition for the clinical diagnosis of a lacunar syndrome is the absence of ‘cortical’ deficits such as aphasia, neglect,

Fig. 24.10.1.4  Small, deep infarct (‘lacune’) in a 63-​year-​old woman. CT scanning shows a small area of hypodensity (distinct from sulci) in the left brain hemisphere (on the reader’s right), just lateral to the internal capsule.

6017

6018

section 24  Neurological disorders

hemianopia, or conjugate deviation of the eyes. The most common and archetypal form is pure motor stroke. In those cases, the small deep infarct strategically involves corticospinal fibres (pyramidal tract) to the motor neurons of the limbs, anywhere in its course. Analogous fibres to the facial nucleus in the pons may be affected as well. The infarct can be located in the corona radiata, adjoining the wall of the body of the lateral ventricle, or slightly more caudally, in the posterior limb of the internal capsule, or, less commonly, in the pons or the medulla. Other ‘lacunar syndromes’ are sensorimotor stroke (corona radiata or internal capsule), pure sensory stroke (thalamus), and ataxic hemiparesis (usually the base of the pons). Lacunar infarcts in the brainstem may lead to an almost infinite range of syndromes, often with the name of a French 19th-​century neurologist attached to it. Often such syndromes consist of an ipsilateral cranial nerve deficit and a contralateral hemiparesis.

Treatment of acute cerebral infarction Several interventions aim at removing (thrombectomy) or dissolving (thrombolysis) the occluding clot, or at least preventing it from growing (antiplatelet agents and anticoagulants). A different strategy, not yet proven in clinical trials, is to protect ischaemic brain tissue (neuroprotection by drugs or manipulation of physiological parameters such as fever or hyperglycaemia). In addition, some underlying causes of stroke need urgent treatment, such as endocarditis. Before considering these specific measures, it is appropriate to consider the appropriate hospital setting in which stroke patients should be cared for.

Stroke units compared with treatment on general hospital wards A specially organized stroke unit can be a ward or team that exclusively manages stroke patients (a dedicated stroke unit) or a ward or team that provides a generic disability service (a mixed assessment or rehabilitation unit). According to a meta-​analysis of 23 randomized trials, stroke unit care reduces the risk of death or institutionalized care by 14%. The observed benefits are independent of patient age, sex, or stroke severity, and appeared to be better in stroke units based in a separate ward. No single element responsible for the benefits of organized stroke care has so far been identified, and probably there is none. The strength of stroke units lies in good clinical leadership and in the integration of multidisciplinary efforts: stroke physician, nursing staff, physiotherapists, occupational therapists, speech and language therapists, rehabilitation physicians, and social workers. With the evidence that thrombolysis and thrombectomy improve stroke outcome in a significant proportion of patients, there has been a move to develop hyperacute stroke units.

Thrombolysis Restoration of blood flow, to reperfuse the ischaemic brain as soon as possible after the cerebral artery has been occluded, irrespective of its cause, should theoretically lead to reduction in the volume of brain damaged by ischaemia and to improvement in clinical outcome, analogous to myocardial infarction.

The main agents tested so far in stroke are intravenous recombinant tissue plasminogen activator (rt-​ PA) and intravenous streptokinase. Almost all patients in the trials were treated within 6 h of stroke onset. The evidence for efficacy is statistically significant for rt-​PA, if administered within 4.5 h and after exclusion of intracerebral haemorrhage by CT. Even within this period, the adage is ‘the sooner, the better’. For patients treated within 90 min, the point estimates for survival with at most moderate disability improved from 54% in the placebo groups to 63% for patients in the rt-​PA groups (absolute gain 9%), whereas for patients treated between 91 and 180 min after stroke onset the gain was 7% (from 57% to 64%). Taken together, a benefit of 8% means that some 12 patients must be treated to save a single patient from death or the nursing home. These calculations have already taken into account the fact that there is a risk of secondary haemorrhage after treatment with rt-​PA. More convenient single injection thrombolysis drugs, such as tenectoplase, are currently in large-​scale clinical trials. There are, however, many contraindications to thrombolysis in view of the risk of cerebral haemorrhage, and only a minority of patients admitted with cerebral infarction can be treated with thrombolysis.

Thrombectomy Thrombectomy is the retrieval of clot from an occluded artery by one of several intra-​arterial devices. In 2015, several randomized trials reported highly consistent results showing that thrombectomy resulted in better outcomes than control in patients who had acute stroke and an appropriate arterial occlusion on vascular imaging. Thrombectomy was beneficial as a primary treatment and also in patients who had a persisting vessel occlusion after thrombolysis. However, the logistics of providing a 24/​7 thrombectomy service are substantial and may be beyond the reach of many healthcare systems.

Antiplatelet agents More than 99% of the evidence from randomized trials in treatment of acute stroke relates to aspirin. The pooled results of two very large trials with aspirin (160–​300 mg), started within 48 h of onset, concluded that 13 fewer patients are dead or dependent for every 1000 patients treated. In some 800 patients who had been ­inadvertently randomized after a haemorrhagic stroke there was no evidence of net hazard. Much of the benefit of aspirin is in prevention of early recurrent stroke rather than in reducing the severity of the existing stroke.

Anticoagulants Anticoagulants tested in clinical trials are standard unfractionated heparin, low-​molecular-​weight heparins, heparinoids, oral anticoagulants, and thrombin inhibitors. There is no evidence that anticoagulant therapy reduces the odds of being dead or dependent at the end of follow-​up.

Neuroprotective agents There are many steps in the destructive cascade between vessel occlusion and irreversible cell death where pharmacological intervention might be beneficial, at least theoretically. The pharmaceutical industry has developed several compounds for clinical

24.10.1  Stroke: Cerebrovascular disease

development and testing. There is no doubt that in animal models many neuroprotective agents, given either before or after the onset of ischaemia, reduce the area of cerebral infarction. So far, none of these agents has been proven to reduce disability in patients, despite dozens of clinical trials.

For the demonstration of severe carotid stenosis, it is no longer necessary to perform catheter angiography, at least if the results of duplex ultrasound agree with those of CT angiography or MR angiography.

Surgical decompression of space-​occupying infarcts

The preventive effect of aspirin, in different doses, has been studied in placebo-​controlled randomized trials in over 8000 patients after a TIA or moderately disabling stroke. There is virtually no difference between the risk reduction for daily doses between 30 mg and 1300 mg. The overall relative reduction in long-​term risk of stroke is about 13% (95% confidence interval 6–​19%), but most of that benefit accrues in the first 12 weeks and the risks and benefits of longer-​ term treatment versus gradual withdrawal ae uncertain. Side effects of aspirin, mainly indigestion, nausea, heartburn, and gastrointestinal bleeding, are more common as the dose is higher. Addition of dipyridamole 200 mg twice daily to aspirin provides a further risk reduction of approximately 18%, compared with aspirin alone. Headache is a common side effect of dipyridamole; it can be avoided by starting with smaller doses. Clopidogrel, a thienopyridine derivative, is marginally more effective than aspirin, with a relative risk reduction of 8.7% (95% confidence interval 0.3–​16.5), whereas the combination of clopidogrel and aspirin has no advantage over aspirin alone; clopidogrel should be prescribed only in patients who are intolerant to aspirin. A large trial comparing clopidogrel with aspirin plus dipyridamole in long-​term secondary prevention of stroke showed no difference in effectiveness.

To prevent brain herniation and death from supratentorial infarction, a large part of the skull vault can be removed by hemicraniectomy. A  pooled analysis (three trials) of 93 patients randomized within 48 h of stroke onset showed not only that the case fatality rate was much lower in operated patients (22%) than in patients who were treated conservatively (71%), but also that operated patients survived significantly more often (43%) with mild or moderate disability (modified Rankin grade 3 or less, see Table 24.10.1.1), against 21% in the conservative group. This has to be weighed against an increased proportion of survivors with severe disability (modified Rankin grade 4 or 5): 35% against 7%. With operations for space-​ occupying infarcts of the cerebellum there is no controlled evidence, but less uncertainty. Without surgery swelling of a cerebellar infarct can be fatal, whereas the deficits after surgical evacuation are surprisingly mild. In some patients it is sufficient to relieve obstructive hydrocephalus by external ventricular drainage.

Secondary prevention of ischaemic stroke In the long-​term management of patients with TIAs or moderately disabling ischaemic strokes, control of lifestyle factors is a primary concern: cessation of smoking, reducing weight if overweight, and daily exercise. Specific measures to reduce the risk of threatened stroke are mostly pharmacological. Carotid endarterectomy or stenting is the only local treatment that is of proven value.

Carotid endarterectomy and stenting This operation was increasingly performed from the 1960s onwards, but not until the 1980s were two randomized trials performed, one in Europe, and one in North America. In patients with severe, symptomatic carotid stenosis (70–​99% lumen diameter reduction) the risk of disabling or fatal stroke substantially decreases after endarterectomy. On average, about six patients need to undergo surgery to prevent one ipsilateral ischaemic stroke within 5 years. This basic risk difference varies with age and sex, and it levels off after 3 or more years from randomization (i.e. 3.5 years after the qualifying event). It should be kept in mind that carotid endarterectomy is indicated in only a minority (20 ml). The possible interventions outlined next, of course, apply only to patients who have a chance of survival. In patients on oral coumadin anticoagulants the first step is intravenous injection of 10–​20 mg of vitamin K, at not more than 5 mg/​ min, followed by infusion of a concentrate of the coagulation factors II, VII, IX, and X, or of fresh frozen plasma. Specific agents for reversal of the newer oral anticoagulants are also in development. Intracranial pressure is often raised. Factors other than the local effects of the haematoma may contribute, such as fever, hypoxia, hypertension, seizures, and elevations of intrathoracic pressure. An unsolved question is the use, in comatose patients, of monitoring and, if judged appropriate, lowering intracranial pressure. There are many believers in this area but few controlled studies. Insertion of a ventricular catheter may be a definitive measure in patients with cerebellar haemorrhage and no signs of direct compression of the brainstem. For surgical treatment of supratentorial haematoma, randomized trials have failed to show benefit, including those employing endoscopic evacuation. In patients with cerebellar haematomas there is no doubt that surgical evacuation can be life-​saving, often with surprisingly few neurological sequelae. Sound indications for evacuation of a cerebellar haematoma are the combination of a depressed level of consciousness with signs of progressive brainstem compression (unless all brainstem reflexes have been lost for more than a few hours, in which case a fatal outcome is unavoidable), or haematoma greater than 3–​4 cm. If the patient has a depressed level of consciousness and hydrocephalus, without signs of brainstem compression and with a haematoma less than 3 cm, ventriculostomy can be carried out as an initial (and sometimes only) procedure.

Subarachnoid haemorrhage Causes of subarachnoid haemorrhage Ruptured aneurysms are by far the most common source of non​traumatic subarachnoid haemorrhage, in about 85%. Around

6023

6024

section 24  Neurological disorders

Box 24.10.1.5  Causes of subarachnoid haemorrhage

(a)

• Ruptured aneurysm (85%) • Non​aneurysmal perimesencephalic haemorrhage (of venous origin?) (10%) • Rarities (5%) — Arterial dissection (transmural) — Cerebral arteriovenous malformation — Dural arteriovenous fistula — Pituitary apoplexy — Mycotic aneurysm — Cardiac myxoma — Sickle cell disease — Tumours — Spinal arteriovenous malformation or aneurysm — Trauma (without contusion) — Cocaine abuse

10% are non​aneurysmal peri-​mesencephalic haemorrhages, the remaining 5% is made up by rarities (Box 24.10.1.5). Cerebral aneurysms are not congenital; they develop during the course of life. Therefore, aneurysmal haemorrhage in a child is extremely rare. The aneurysms are saccular in shape and mostly arise at sites of arterial branching at the base of the brain, at or near the circle of Willis (Fig. 24.10.1.7). It is largely unknown why some adults develop aneurysms. There are families with two or more affected first-​degree relatives, but these account for less than 5% of all subarachnoid haemorrhages. Many classic risk factors for stroke in general also apply to subarachnoid haemorrhage: smoking, hypertension, heavy drinking, and oral contraceptives. Not all aneurysms rupture. Their prevalence can be estimated, from angiographic studies (for other purposes) and post-​mortem studies at approximately 2–​3% in middle age, up to 5% at the end of life. On the assumption that this proportion is 1% for a standardized population across all age groups, and given that the incidence of subarachnoid haemorrhage is approximately 6 per 100 000 (of the entire population), the annual risk of rupture of an aneurysm is about 0.6%. Non​aneurysmal perimesencephalic haemorrhage is a distinct and benign variety of subarachnoid haemorrhage, in which the distribution of extravasated blood on the brain CT scan is different from that with aneurysms, in the cisterns around the midbrain or ventral to the pons. The angiogram is completely normal, and the long-​term outcome is invariably excellent. This subtype constitutes 10% of all subarachnoid haemorrhages and two-​thirds of subarachnoid haemorrhages with a normal angiogram.

Diagnosis of subarachnoid haemorrhage The key feature in the history is that of a sudden, severe, and unusual headache. In 50% there is loss of consciousness at onset; the headache may emerge only later in these patients. The diagnosis is most difficult in patients with headache as the only feature. In general practice, sudden-​onset forms of common headaches (‘thunder-​clap’ headache) outnumber ruptured aneurysms. The incidence of aneurysmal haemorrhage being about 6 per 100 000 population per year, the average general practitioner will, on average, see one such patient every 8 years. There are no single or combined features of the headache that distinguish reliably and at

(b)

Fig. 24.10.1.7  Aneurysmal subarachnoid haemorrhage in a 31-​year-​ old woman. (a) CT scanning shows evidence of extravasated blood throughout the basal cisterns. (b) CT angiogram, with intravenous contrast, shows an aneurysm at the anterior communicating artery.

an early stage between subarachnoid haemorrhage and innocuous types of sudden headache. The physical examination is unhelpful in patients with headache alone, without loss of consciousness or focal deficits. Neck stiffness takes about 6 h to develop, so its absence soon after the onset does not exclude the diagnosis of subarachnoid haemorrhage at all. CT brain imaging is the most important investigation in suspected subarachnoid haemorrhage. This will show extravasation of blood in the basal cisterns of the brain in at least 95% of patients with a ruptured aneurysm, if the scan is performed within 3 days (see Fig. 24.10.1.7). After that interval the sensitivity of CT quickly decreases. In patients with a negative CT scan but a convincing history, lumbar puncture is indicated. If the cerebrospinal fluid is blood stained, it is essential to distinguish subarachnoid haemorrhage reliably from a traumatic tap. For that purpose, at least 6 and preferably 12 h should have elapsed from symptom onset. In case of subarachnoid haemorrhage sufficient lysis of red cells will have occurred in the meantime for bilirubin and oxyhaemoglobin to have formed. These pigments give the cerebrospinal fluid a yellow tinge after centrifugation (xanthochromia); they are invariably detectable until at least 2 weeks later. The ‘three tube test’ (a decrease in red cells in consecutive tubes in the case of a traumatic puncture) can be helpful, but is unreliable. If the supernatant seems crystal

24.10.1  Stroke: Cerebrovascular disease

clear, the specimen should be stored in darkness until the absence of blood pigments is confirmed by spectrophotometry. Bilirubin can be formed only in vivo; its demonstration by spectrophotometry therefore proves that red blood cells cannot have been introduced during the lumbar puncture, whereas oxyhaemoglobin can be formed if a cerebrospinal fluid specimen with red blood cells is left standing before the sample is spun down. Catheter angiography is rapidly being replaced by CT and MR angiography as a method for demonstrating or excluding an aneurysm as the source of haemorrhage.

Treatment of aneurysmal subarachnoid haemorrhage Several complications may occur after a first episode of aneurysmal subarachnoid haemorrhage, of which rebleeding and cerebral ischaemia are the most dreaded. Despite advances in surgical and medical management, the population-​based case fatality rate is still around 50%, with half of survivors remaining more or less disabled. As general nursing measures, continuous observation and an intravenous access are essential. A bladder catheter is necessary for monitoring fluid balance. Headache should be relieved in a stepwise approach, with paracetamol and codeine as first steps. Distressing anxiety can be alleviated with short-​acting benzodiazepines. Stools should be kept soft with oral laxatives and also by an adequate intake of fluids. Prevention of rebleeding is challenging, if only because any effective measure tends to be offset by an increased risk of ischaemia. Moreover, at least 10% of all patients with subarachnoid haemorrhage suffer a further bleed within hours of the initial haemorrhage. Over the next 4 weeks the rate of rebleeding without intervention is at least 30%. The immediate case fatality of rebleeding is 50%. Endovascular treatment (‘coiling’) is the preferred method to occlude the aneurysm and prevent rebleeding, but not all aneurysms can be treated in this way and surgical treatment by clipping is still necessary for these patients. Antifibrinolytic drugs decrease the rate of rebleeding but do not improve overall outcome. Delayed cerebral ischaemia occurs in up to 25% of patients with a ruptured aneurysm, mainly between day 5 and day 14 after the initial bleed. Understanding of its pathogenesis has been impeded by simplistic notions about ‘vasospasm’ or ‘clots around vessels’. Narrowing of the arteries at the base of the brain is a factor but not a sufficient one. The total amount of subarachnoid blood is a potent risk factor, but only after rupture of an artery, and the distribution of blood in the subarachnoid space does not predict the site of ischaemia. The calcium antagonist nimodipine, in a dose of 60 mg every 4 h by mouth or nasogastric tube, reduces the frequency of cerebral ischaemia and poor outcome by about a third; its mode of action is incompletely understood. Hypertension should as a rule be left untreated; it is a compensatory reaction to maintain cerebral perfusion. The plasma volume should not be allowed to fall; hyponatraemia is caused by renal sodium depletion and not, as still often believed, by dilution as a result of inappropriate secretion of antidiuretic hormone. Fluids should therefore be replaced and not restricted. The basic intake should be at least 3 litres/​day, with intravenous fluids supplementing oral intake; compensation should be made for fever or a negative fluid balance.

FURTHER READING Antithrombotic Trialists’ (ATT) Collaboration (2009). Aspirin in the primary and secondary prevention of vascular disease:  collaborative meta-​analysis of individual participant data from randomised trials. Lancet, 373, 1849–​60. Ariesen MJ, et al. (2003). Risk factors for intracerebral hemorrhage in the general population: a systematic review. Stroke, 34, 2060–​5. Cholesterol Treatment Trialists’ (CTT) Collaboration (2015). Efficacy and safety of LDL-​lowering therapy among men and women: meta-​ analysis of individual data from 174,000 participants in 27 randomised trials. Lancet, 385, 1397–​405. de Schryver EL, et al. (2007). Dipyridamole for preventing stroke and other vascular events in patients with vascular disease. Cochrane Database Syst Rev, 3, CD001820. Diener HC, et  al. (2004). Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-​ risk patients (MATCH):  randomised, double-​blind, placebo-​controlled trial. Lancet, 364, 331–​7. EAFT (European Atrial Fibrillation Trial) Study Group (1993). Secondary prevention in non-​rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet, 342, 1255–​62. Emberson J, et al. (2014). Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke:  a meta-​analysis of individual patient data from randomised trials. Lancet, 384, 1929–​35. European Stroke Organisation (ESO) Executive Committee; ESO Writing Committee (2008). Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis, 25, 457–​507. Feigin VL, et al. (2014). Global and regional burden of stroke during 1990–​2010: findings from the Global Burden of Disease Study 2010. Lancet, 383, 245–​54. Giles MF, et al. (2007). Risk of stroke early after transient ischaemic attack:  a systematic review and meta-​analysis. Lancet Neurol, 6, 1063–​72. Johnston SC, et al. (2007). Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack. Lancet, 369, 283–​92. Kernan WN, et al. (2014). Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/​ American Stroke Association. Stroke, 45, 2160–​236. MacMahon S, et al. (2001). Randomised trial of a perindopril-​based blood-​pressure-​lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet, 358, 1033–​41. Madden KP, et al. (1995). Accuracy of initial stroke subtype diagnosis in the TOAST study. Neurology, 45, 1975–​9. Mendelow AD, et  al. (2005). Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet, 365, 387–​97. Molyneux AJ, et al. (2005). International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet, 366, 809–​17. Rodrigues FB, et  al. (2016). Endovascular treatment versus medical care alone for ischaemic stroke:  systematic review and meta-​analysis. BMJ, 353, i1754.

6025

6026

section 24  Neurological disorders

Rothwell PM, et al., on behalf of the Early use of Existing Preventive Strategies for Stroke (EXPRESS) Study (2007). Major reduction in risk of early recurrent stroke by urgent treatment of TIA and minor stroke: EXPRESS Study. Lancet, 370, 1432–​42. Rothwell PM, et al. (2003). Analysis of pooled data from the randomised controlled trials of endarterectomy for symptomatic carotid stenosis. Lancet, 361, 107–​16. Rothwell PM, et al. (2004). Change in stroke incidence, mortality, case-​ fatality, severity, and risk factors in Oxfordshire, UK from 1981 to 2004 (Oxford Vascular Study). Lancet, 363, 1925–​33. Rothwell PM, et al. (2011). Medical treatment in acute and long-​term secondary prevention after transient ischaemic attack and ischaemic stroke. Lancet, 377, 1681–​92. Sacco RL, et  al. (2008). Aspirin and extended-​release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med, 359, 1238–​51. Sandercock PA, et  al. (2014). Oral antiplatelet therapy for acute ischaemic stroke. Cochrane Database Syst Rev, 3, CD000029. Stam J (2005). Thrombosis of the cerebral veins and sinuses. N Engl J Med, 352, 1791–​8. Stroke Unit Trialists’ Collaboration (2002). Organised inpatient (stroke unit) care for stroke. Cochrane Database Sys Rev, 4, CD000197. Vahedi K, et al. (2007). Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol, 6, 215–​22. van der Zwan A, et al. (1992). Variability of the territories of the major cerebral arteries. J Neurosurg, 77, 927–​40. van Gijn J, et  al. (2007). Subarachnoid haemorrhage. Lancet, 369, 306–​18. Wang Y, et al. (2013). CHANCE Investigators. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med, 369, 11–​19. Warlow CP, et al. (2007). Stroke—​practical management, 3rd edition. Blackwells, Oxford.

24.10.2  Demyelinating disorders of the central nervous system Alasdair Coles and Siddharthan Chandran ESSENTIALS The common feature of all of the demyelinating diseases is that, initially at least, the oligodendrocyte-​myelin unit is the primary target, with the axon comparatively spared. There are a range of causes, both acquired and inherited. Multiple sclerosis is the commonest and protoypic condition. Pathophysiology—​demyelination is followed by predictable electrophysiological consequences including impaired conduction and over time progressive neuronal injury with variable re-​myelination.

Multiple sclerosis Epidemiology—​a disease of northern Europeans, occurring less frequently in other racial groups. The leading causing of acquired adult neurological disability in many industrialized nations.

Pathology—​ characterized histologically by breakdown of the blood–​brain barrier and multifocal inflammatory-​mediated demyelination leading to ‘plaques’ throughout the central nervous system. Neurodegeneration is prominent in the later stages of disease. Aetiology—​unknown, but involves interplay between genes (familial recurrence rate 15%, modest increase in risk from many genes) and the environment (possible effects from vitamin D status, smoking, and viral infection in childhood or adolescence). Clinical features—​fatigue is common. Acute demyelinating optic neuritis is a first manifestation in up to 20% of patients. Impaired mobility affects most patients, usually as a result of spinal cord disease. Altered sensation is almost universal, autonomic symptoms occur in most, and cerebellar involvement is common. Abnormalities of eye movement are frequent, including ‘internuclear ophthalmoplegia’, a sign that is nearly always due to multiple sclerosis. Cognitive impairment occurs in up to 65% of patients. Clinical course—​ variable and unpredictable. Most patients experience a relapsing and remitting course, characterized over time by three phases—​relapse with full recovery, relapse with persistent deficits, and secondary progression. Diagnosis—​ multiple sclerosis can reliably be diagnosed using clinical criteria and without laboratory support. There is no single diagnostic laboratory investigation, but the most useful investigations are (1) MRI demonstrating lesions disseminated in time and/​ or space; (2)  cerebrospinal fluid analysis revealing oligoclonal immunoglobulin bands; (3) electrophysiology showing demyelination in central pathways. Management—​the complex and progressive nature of disability requires a multidisciplinary approach. Symptomatic management may be required, for example, for bladder symptoms, constipation, or spasticity. Corticosteroids are effective in reducing the duration of acute demyelinating episodes but have no impact on the eventual degree of recovery or the subsequent disease course. Disease-​modifying treatments are effective only in the inflammatory relapse-​remitting phase of disease and include β-​interferons, glatiramer acetate, fingolimod, and the humanized monoclonal antibodies natalizumab and alemtuzumab. There is not yet a consensus on how early and how aggressively multiple sclerosis should be treated.

Introduction: demyelinating disorders as potentially treatable conditions A distinguishing feature of vertebrate development is the formation of compact myelin around axons, produced by oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. This insulating material reduces the escape of current across the axon and allows for passive propagation of the action potential down myelinated segments of the nerve until it arrives at a break in the myelin, at a node of Ranvier, where a new action potential is actively triggered. The advantage of this ‘saltatory’ conduction is speed, and greater efficiency of energy and space. Myelinated nerves conduct the action potential more rapidly than in unmyelinated fibres. In demyelinating disorders of

24.10.2  Demyelinating disorders of the central nervous system

the central nervous system, the oligodendrocyte-​myelin unit is the primary target of pathology and conduction of the nerve impulse first slows and then fails. Multiple sclerosis, the prototypic demyelinating disorder of the central nervous system, is the leading causing of neurological disability among young adults in many industrialized nations. In the last two decades therapies have been licensed with increasing capacity to suppress the inflammation which underlies the condition, leading to durable benefits to patients. The next most prevalent demyelinating disease is neuromyelitis optica. Originally thought to be a variant of multiple sclerosis, it is now recognized to be a distinct disease whose treatment is radically different from multiple sclerosis. The common feature of all of the demyelinating diseases (listed in Table 24.10.2.1) is that, initially at least, the axon is comparatively spared with the dominant pathology being inflammatory-​ mediated damage to the oligodendrocyte-​myelin unit. This means that anatomical connections are not disrupted, which makes the task of functional repair considerably easier than in disorders which destroy neuronal pathways. Treatments to promote remyelination are currently under investigation in multiple sclerosis and the leukodystrophies. In some demyelinating disorders, most notably multiple sclerosis, there is a later phase of progressive disability which is due to neuronal loss. These observations raise questions about the dependence of neuronal integrity on myelin and glial support. The predominant strategies to prevent the neurodegeneration of multiple sclerosis are early treatment to prevent demyelination along with, conceivably in the future, combinatorial neuroprotective treatments such as remyelination therapy to restore the glial-​axon relationships.

Neurobiology of demyelination and remyelination Origin of oligodendrocytes Oligodendrocytes synthesize and maintain the compact myelin that ensheathes axons. Oligodendrocytes, in contrast to neurons, are predominantly specified postnatally and continue to divide and migrate as oligodendrocyte precursor cells (OPCs). Identification of the Olig genes has significantly advanced understanding of the molecular regulation of developmental and adult oligodendrogenesis. In addition to its established role in specifying neurons and OPCs in the developing CNS, emerging evidence implicates Olig in self-​renewal of neural stem cells and adult oligodendrogenesis in the normal and injured brain. These findings—​together with accumulated insights into the proliferative, migratory, and survival requirements of OPCs—​have resulted in the oligodendrocyte lineage being the best characterized of all cells of the central nervous system. The application of that knowledge may in time lead to the development of potential neuroprotective therapeutic targets in the context of demyelinating disease.

Myelination Myelination occurs when the membranous processes of mature oligodendrocytes contact and wrap serially around axons. The result is compaction of myelin sheaths at two points of apposition, apparent on ultrastructural analysis as major and minor dense lines. Myelin is predominantly composed of lipids (70–​80% dry weight; cholesterol, phospholipid, and galactolipids) and protein (20–​30% dry weight). The major myelin-​specific lipid galactocerebroside can be used to identify myelinating glia. The major proteins are proteolipid protein, myelin basic protein, and the myelin-​specific enzyme 2’,3’-​Cyclic-​ nucleotide 3’-​phosphodiesterase.

Table 24.10.2.1  Classification of demyelinating disorders of the central nervous system Disease

Features

Multiple sclerosis

Very common: starts with relapsing-​remitting episodes of e.g. optic nerve, spinal cord, and brainstem demyelination; later secondary progressive disease

Neuromyelitis optica spectrum disorder

Common: combinations of longitudinally extensive myelopathy, area postrema, and optic nerve lesions; due to anti-​aquaporin 4 antibodies

Acute disseminated encephalomyelitis

Common: postinfectious, extensive cortical and brainstem demyelination

Longitudinally extensive myelitis

Common: postinfectious, or as part of NMO spectrum disorder

Relapsing optic neuritis

Rare: some associated with anti-​MOG antibodies and others dependent on corticosteroids

Balo’s concentric sclerosis

Rare: rings of demyelination and unaffected tissue causing lobar syndromes

Harding’s disease

Rare MS-​like disease in people with Leber’s mitochondrial mutations

Central pontine myelinolysis

Common: occurs with rapid correction of hyponatraemia

Toxic disseminated encephalomyelitis

Rare: due to inhaled vapour of opiates and cocaine

Adrenoleukodystrophy

Rare: in adults causes myelopathy, neuropathy, and adrenal failure

Metachromatic leukodystrophy

Rare: causes progressive epilepsy, neuropathy, and cognitive impairment

Pelizaeus–​Merzbacher disease

Very rare: eye movement disorders, cognitive impairment, and neuropathy; due to proteolipid protein gene mutations

Krabbe’s disease

Very rare: epilepsy, cognitive impairment, and neuropathy; due to deficiency of α-​galactocerebrosidase

Autosomal-​dominant adult leukodystrophies

Very rare as adult

Acquired Inflammatory

Non​inflammatory Inherited

6027

6028

section 24  Neurological disorders

Each high resistance myelin segment is separated by the unmyelin­ ated high conductance node of Ranvier. This specialized structure, characterized by clusters of voltage-​gated sodium channels, is the site of active generation of the action potential. Myelinated internodal segments contain dispersed sodium channels at a much lower density insufficient to support conduction.

Pathophysiology of demyelination Demyelination is followed by predictable electrophysiological consequences including impaired saltatory conduction, decreased conduction velocity, and variable degrees of conduction block. The extent to which these changes cause symptoms is less predictable and depends upon the redundancy within the pathway affected and the capacity of the nervous system to circumvent the lost function. There are several mechanisms of symptom recovery early in the course of multiple sclerosis. Plastic functional reorganization of the nervous system may circumvent the disrupted pathway. An adaptation of the axon to demyelination is that sodium channels are expressed in demyelinated patches of axon membrane. This can restore active conduction. But it may also be maladaptive; the ensuing increase in intracellular sodium concentration requires greater activity of the sodium-​potassium exchanger. Especially when nerve firing is rapid, the metabolic strain of extruding sodium may cause axonal degeneration. As with many disorders of the nervous system, the clinical symptoms and signs may be negative (loss of function), or positive (spontaneous, involuntary, and paroxysmal). Either category can prove equally disabling. But there are features specific to demyelination, not seen in axonal loss. For instance, electrophysiological tests of optic tract function (‘visual evoked potentials’) will often show slowing of conduction following inflammatory demyelination in the optic nerve. Similar slowing may also be seen in brainstem and somatosensory evoked potentials after demyelination of the relevant pathways. In partially demyelinated axons, the action potential may propagate normally but can break down more easily to external challenges. The best example is the ‘Uhthoff phenomenon’: symptoms occur on exercise or heating (e.g. in a hot bath) and disappear on cooling. As myelin is heated, so its insulating capacity reduces; current escapes from the axon, fails to trigger a new action potential at the node of Ranvier and so conduction fails. Also, the partially demyelinated nerve may discharge with mechanical stretching. Typical movement-​induced symptoms including flashes of light on eye movement, and the electric sensation that spreads down the spine, limbs, or anterior chest wall after neck flexion—​Lhermitte’s symptom and sign. Ephaptic transmission occurs between neighbouring and partially demyelinated axons giving rise to paroxysmal symptoms of demyelination usually manifesting as trigeminal neuralgia, ataxia, and dysarthria, or tonic brainstem seizures. These are often triggered by touch or movement.

Remyelination Endogenous remyelination may restore function in demyelinating disease. In multiple sclerosis, it has long been known that acute lesions frequently show an increase in the number of oligodendrocyte precursors and may undergo remyelination, evident as shadow plaques. Remyelination, found at all stages of disease, is histologically identified by inappropriately thin myelin lamellae,

with a short internode, and widened nodes of Ranvier. The finding that remyelination is associated with less axonal injury compared with inactive demyelinated plaques, suggests that remyelination is neuroprotective. The source of remyelinating cells is presumed to be the oligodendrocyte progenitor, which is found in the lesions of multiple sclerosis, although recent evidence also suggests a role for adult subventricular zone derived stem cells. It is clear that remyelination is not sufficient to prevent disability in most cases of multiple sclerosis. This may be because the waves of inflammation overwhelm endogenous capacity for repair, or that there is a primary failure of remyelination, perhaps increasing with age.

Multiple scler osis Pathology The most common demyelinating disorder is multiple sclerosis, characterized histologically by breakdown of the blood–​brain barrier and the development of multifocal foci of inflammation in the brain and cord, called ‘plaques’. In all but the most severe forms, perivascular inflammation evolves through stages of acute axonal injury, demyelination, oligodendrocyte depletion, remyelination, astrocytosis and chronic neurodegeneration (Fig. 24.10.2.1). The order and relationship of these separate components is still debated, but the consensus based on a wealth of evidence is that multiple sclerosis is primarily an inflammatory disease with secondary neurodegeneration. Plaques are widely distributed, but concentrated around venous networks, the ventricles, and in the corpus callosum, optic nerves, brainstem, and cervical cord. A simplified scheme is that multiple sclerosis starts with inappropriate activation of a peripheral T cell directed against a myelin antigen. This T cell then proliferates, crosses the intact blood-​brain-​ barrier, and enters the central nervous system. There it encounters its antigen and sets up an acute inflammation with release of cytokines and chemokines, which attract and activate microglia, and produce immunoglobulins that together culminate in damage to the myelin-​oligodendrocyte unit. These inflammatory processes lead to disruption of the myelin membrane with increased spacing, vesicular disruption, splitting, vacuolation, and fragmentation of the lamellae. Multiple sclerosis plaques can be classified into ‘acute’ or ‘chronic’, depending on the presence or absence of acute inflammatory cells. There are also different patterns of pathology. One scheme describes T cell infiltrates and macrophage associated tissue injury (pattern 1); antibody and complement-​mediated immune reactions against cells of the oligodendrocyte lineage and myelin (pattern 2); hypoxia-​ like injury, resulting either from inflammation-​induced vascular damage or macrophage toxins that impair mitochondrial function (pattern 3); and a genetic defect resulting in primary susceptibility of the oligodendrocytes to immune injury (pattern 4). The evidence for pathological heterogeneity, as opposed to complexity in which additional effector molecules are recruited to the evolving lesions following initial T cell infiltration of the CNS, has recently been challenged. Rather, the various pathological features are now seen as stages in the development of a ubiquitous pathological end-​game, in which apparent heterogeneity may disappear over time as different pathways converge on one general mechanism of demyelination—​ the presence of complement, antibody and Fc γ-receptor on

24.10.2  Demyelinating disorders of the central nervous system

(a) Disease progression and axonal loss in multiple sclerosis Clinical neurological dysfunction Axonalloss

Relapsing-remitting stage

Relapsing with persistent deficits

Progressive stage

(b) Contribution of demyelination to axonal loss Inflammation & demyelination

Loss of oligodendrocyte /myelin signals

Axonal loss

Fig. 24.10.2.1  Inflammation, demyelination, axonal loss, and disease progression in multiple sclerosis. (a) The early stage of relapsing-​remitting multiple sclerosis is characterized by transient neurological deficits that return to normal and pathology dominated by focal inflammation and demyelination. However, as the disease progresses neurological dysfunction becomes fixed and accumulates. The pathological correlate of the progressive phase of the disease is axonal loss. (b) The early events of demyelination and inflammation are believed to contribute to axonal loss by numerous mechanisms including loss of oligodendrocyte/​myelin-​ derived trophic and structural support. The schematic diagram shows a single oligodendrocyte (black and white) myelinating three axons (axon purple, myelin blue). Early in the course of multiple sclerosis, the oligodendrocyte is damaged through inflammatory driven mechanisms resulting in demyelination of the axon. The loss of oligodendrocyte contributes and culminates in axonal loss as found in progressive multiple sclerosis.

phagocytic macrophages, indicating that antibody dependent cell-​ mediated cytotoxicity is primarily responsible for demyelination in established multiple sclerosis. The focus on inflammation and demyelination had until recently obscured the extent and significance of neuronal and axonal injury. Axonal injury is present at all stages of multiple sclerosis. Recent recognition of the fundamental role oligodendrocytes play in providing metabolic support to axons through glial glycolysis products adds to the multiple mechanisms by which disruption and loss of the oligodendrocyte-​myelin unit can lead to axonal injury and ultimately neuronal loss. Key modes of injury that are now implicated, include glial-​mediated production of reactive oxygen/​nitric oxide species, mitochondrial injury, intra-​axonal cation excess, altered astroglial environment, and cellular excitotoxicity. Early axonal injury evident by axonal transection and accumulation of amyloid precursor protein tends to occur when inflammatory demyelination is prominent. Whether the immune process directly targets axons or merely involves these structures as part of non​specific collateral damage is unclear. Similarly, it is uncertain whether axonal loss in normal appearing white matter merely reflects axon dropout due to time-​delayed Wallerian degeneration. Later, chronic axonal loss is associated with microglial activation throughout the brain parenchyma and away from the postinflammatory chronic demyelinated lesions. In addition, several lines of evidence also implicate loss of oligodendrocyte-​myelin-​derived metabolic and trophic support as contributory to the mechanism of progressive neurodegeneration. The recognition that neurodegeneration is the dominant pathological substrate of progressive disability brings into focus the

importance of understanding the relationship between focal lymphocytic inflammation—​clinically manifest as relapses—​and the neurodegeneration that drives the progressive phase of the disease. A widely-​held position is that inflammation drives the cascade of events leading to neurodegeneration, or conditions a genetic predisposition to axon degeneration that would not be exposed without the inflammatory trigger.

Aetiology The aetiology of multiple sclerosis involves interplay between genes and the environment. It is a disease of northern Europeans and occurs less frequently in other racial groups. There is a female predominance that may be increasing. The familial recurrence rate is approximately 15%. Meta-​analysis among relatives of probands from three population-​based series shows that the age-​adjusted risk is highest for siblings (3%), then parents and children (2%), with lower rates in second-​and third-​degree relatives. Recurrence in monozygotic twins is around 35%. Conversely, the frequency of multiple sclerosis in adoptees is similar to the population risk for Europeans. The age-​adjusted risk for half-​siblings is intermediate between ‘social’ and biological relatives. Recurrence is higher in the children of conjugal pairs with multiple sclerosis (age-​adjusted 20%) than the offspring of single affecteds (2%) (Fig. 24.10.2.2). Population studies carried out in the 1970s, demonstrated an association between the linked class II MHC alleles (DR15 and DQ6) and their corresponding genotypes. Extensive searches, using association and linkage studies over many years, until recently, had yielded very few additional candidates for susceptibility. However,

6029

6030

section 24  Neurological disorders

Genetic sharing 100%

50%

25% 12.5% 0%

Relationship MZ twin Sibling, 2 affected parents Sibling,1 affected parent DZ twin Sibling Parent Child Half sibling Aunt/uncle Nephew/niece Cousin Adoptee General population 0

5

10

15 20 Age-adjusted lifetime risk

25

30

35

Fig. 24.10.2.2  Lifetime risk for multiple sclerosis among European people and in biological and social relatives of affected individuals. The increased risk with relatedness implicates genetic factors, whereas the incomplete concordance in identical twins reflects the contribution made by environmental conditions.

recent large-​scale genome-​wide association studies involving tens of thousands of cases and controls have identified well over 100 loci that, individually, confer a modest increase in risk. Collectively these studies underline a central role for the immune system in the development of MS beyond the longstanding HLA association, as well as revealing that multiple sclerosis clusters with other autoimmune conditions. Functional studies of these genes are broadly lacking but it is of considerable interest that most of these genes are non​coding and frequently mapping to regulatory regions on immune cell types. This evidence from genetic analysis is one of the most compelling reasons for concluding that multiple sclerosis is primarily an immunological disorder. Apart from informing ideas on the pathogenesis of multiple sclerosis, within this list of over 100 susceptibility genes are several that inform current therapeutic strategies or suggest new approaches to treatment. For example, the variant responsible for the association between multiple sclerosis and TNFRSF1A confers functional properties on immune cells that increase their production of soluble TNFα, reproducing the pattern previously shown to increase disease activity after administration of anti-​TNFα therapeutic antibody of TNFα-​receptor blockade, illustrating the potential for pharmacogenomics to inform future treatment selection and stratification. Ongoing genetic studies are aimed at discovery of further heritability genes with estimates of 30–​50% still unaccounted, along with functional studies of known genes and finally the role of genetics in determining disease course. Studies of concordance in multiplex families show that genetic factors influence the risk of progression but, as yet, no responsible loci are identified. Genetic analysis may also contribute to the debate on whether multiple sclerosis is one disease. Mutations of mitochondrial DNA are responsible for a multiple sclerosis-​like illness characterized by disproportionate involvement of the anterior visual pathway, although mitochondrial genes do not contribute generally to susceptibility in multiple sclerosis. A major part of future studies in the genetics of multiple sclerosis will be to resolve the question of disease heterogeneity. The distribution of multiple sclerosis cannot be explained only on the basis of population genetics. In white South African people and

in Australia, prevalence rates are half those documented for many parts of northern Europe. There is a gradient in frequency, both in Australia and in New Zealand, which does not follow genetic clines. The risk is higher for English-​speaking white people migrating into South Africa as adults than in childhood. Multiple sclerosis occurs at a low frequency in the Caribbean population, but the risk increases substantially in their first-​generation descendants raised in the United Kingdom. Over and above the effect of racial predisposition, migration influences distribution of the disease. Surveys of multiple sclerosis have prompted speculation on the occurrence of post-​Second World War epidemics in Iceland, the Orkney and Shetland Islands, and the Faroes, but others prefer the interpretation that these merely reflect improved case recognition. Noting the association with latitude, and other apparent epidemiological features such as seasonality for month of birth in people who later develop multiple sclerosis, it has been suggested that the environmental effect is conferred by variable light exposure and vitamin D status. Without much in the way of mechanistic interpretation or compelling evidence, this has led to widespread self-​prescribing of vitamin D among affected individuals, often condoned by physicians. Probably harmless in small doses, it will nevertheless take time to establish whether the hypothesis for a role of vitamin D, ubiquitously deficient in the normal population at risk of multiple sclerosis, is substantiated. A second risk factor that has some support from epidemiological and genetic studies is smoking. Here, the analogy with rheumatoid arthritis in which proteins are shown to be abnormally citrullated following passage through the lungs of smokers has some mechanistic logic. The widely accepted formulation that multiple sclerosis is the outcome of unknown environmental factors, conditioned by age at exposure, acting on a genetically vulnerable population has led to a largely unrewarding search for such environmental agents. However, the risk of developing multiple sclerosis is increased for individuals exposed to measles, mumps, rubella and (especially) Epstein–​Barr virus infection relatively late in childhood or adolescence. These studies suggest that an age-​linked period of susceptibility to viral exposure exists in those who are constitutionally at risk of developing the disease.

24.10.2  Demyelinating disorders of the central nervous system

Symptoms and signs of multiple sclerosis Fatigue Difficult to define and capture for analysis, nonetheless fatigue is one of the most characteristic symptoms of multiple sclerosis. Patients report overwhelming lassitude after undertaking a physical or cognitive task, forcing them to stop and rest. However, they do not feel the need to sleep. Fatigue may occur acutely, in the context of a relapse, or be a persistent symptom. It may be disabling, particularly in individuals attempting to maintain demanding occupations or hobbies. Optic neuritis and visual symptoms Acute demyelinating optic neuritis is a first manifestation of multiple sclerosis in up to 20% of patients. This presents with pain on eye movement, followed by subacute visual loss, which evolves over hours or days, sometimes to complete blindness; patients may be aware of selective loss of colour vision and flashes of light (phosphenes) on eye movement. Other signs of optic neuropathy at presentation include unilateral afferent pupillary defect and visual field loss. The pain disappears within a few days; vision begins to improve within 4 weeks and improves in 90% of patients over months, but defects of colour perception frequently persist. The lesion responsible for optic neuritis can be imaged in vivo; inflammation within the intracanalicular portion of the nerve and long lesions are associated with delayed or incomplete recovery of vision. Correlations between imaging, symptoms and neurophysiological changes indicate that the visual deficits in optic neuritis arise at the time of altered blood–​brain barrier permeability. They are associated with conduction block and precede demyelination or axonal degeneration. Optical coherence tomography provides a non​invasive quantitative measure of retinal nerve fibre loss after optic neuritis, and is increasingly being used as a surrogate outcome measure in treatment trials. Optic neuritis may be clinically silent and revealed by delayed conduction of visual evoked potentials; this can be useful in the diagnosis of multiple sclerosis. Optic neuritis can be a feature of other conditions and clinicians should be aware of the red flags of: positive family history, bilateral onset, failure to improve or dependence on steroids (see next). It can be mimicked by acute glaucoma, infection (especially viral), ischaemic optic neuropathy, sarcoidosis, systemic lupus erythematosus, and vasculitis. Visual failure in Leber’s hereditary optic neuropathy can mimic bilateral sequential optic neuritis in men, so a family history of mitochondrial inheritance should be sought. The postchiasmal visual pathway is occasionally involved in multiple sclerosis resulting in hemianopic field defects. Motor symptoms and signs Impaired mobility affects most patients with multiple sclerosis, usually as a result of spinal cord disease. Movements are slow, weakness differentially affecting extensors in the arms and flexors in the legs, and there are the expected signs of upper motor neurone lesions. Spasticity may be more problematic than weakness and all aspects of immobility are frequently complicated by fatigue. Cerebellar involvement causes incoordination of speech, bulbar control, eye movements, the individual limbs, or balance, usually in combination with corticospinal damage. Damage to the superior cerebellar

peduncle or red nucleus produces a disabling proximal wild flinging tremor. Parkinsonism does not occur in multiple sclerosis. Lower motor neurone signs occur when there is extensive demyelination adjacent to the dorsal root entry zone. Sensory symptoms and signs Altered sensation occurs at some stage in nearly every patient with multiple sclerosis, usually due to partial disruption of the spinal cord sensory pathways. Often they are described in complex and graphic terms: ‘as though water is dripping down my face’, ‘it feels as though something is twisting a towel repeatedly around my legs’. Damage to the posterior columns in the cervical cord produces tight, burning, twisting, tearing, or pulling sensations, which are usually unpleasant. Associated loss of proprioception severely compromises function. Spinothalamic tract involvement leads to loss of thermal and pain sensation. The commonest physical sign found in multiple sclerosis, in the absence of symptoms, is impaired vibration sense in the legs. Autonomic involvement Autonomic symptoms occur in most patients with multiple sclerosis. Bladder symptoms are common and can be due to impaired bladder emptying (leading to urinary retention) or filling (leading to urgency and hesitancy). Often these coexist. Impaired control of the rectal sphincter is much less common. Erectile impotence occurs frequently in males and is usually a manifestation of spinal cord disease. Mechanical difficulties, spasticity, altered sensation, skin excoriation, and indwelling catheters all may affect sexual fulfilment, in both genders. Other autonomic features in multiple sclerosis occur rarely, but include loss of thermoregulation leading to inappropriate sweating, fever, and hypothermia; Horner’s syndrome; abnormalities of cardiac rhythm and vascular responses with acute pulmonary oedema; weight loss; and inappropriate secretion of vasopressin. Eye movements Abnormalities of eye movement are frequent in multiple sclerosis. A sign that is nearly always due to multiple sclerosis, and is usually asymptomatic, is the ‘internuclear ophthalmoplegia’: slowness of the adducting eye and nystagmus in the abducting eye on horizontal gaze, due to a lesion of the medial longitudinal fasciculus. It is often bilateral and may coexist with gaze paresis to produce the ‘one and one-​half ’ syndrome. They commonest sign is first-​degree symmetrical horizontal jerking nystagmus. Weakness of the lateral rectus is more common than isolated third and fourth nerve palsy. Vertical up-​beating nystagmus can occur and is often associated with bilateral internuclear ophthalmoplegia. Down-​beating nystagmus may occur, but is a red flag for alternative, structural causes. Ocular flutter (horizontal saccadic oscillations without an intersaccadic interval) and opsoclonus, in which the saccadic movements occur in all directions, tend to occur late in multiple sclerosis and can be visually disabling. Other brainstem manifestations Feelings of unsteadiness are common. Acute brainstem demyelination causes severe positional vertigo, vomiting, ataxia, and headache. Taste may be subjectively abnormal but ageusia is rarely

6031

6032

section 24  Neurological disorders

described. Deafness may occur in multiple sclerosis, but is a red flag for other conditions (Susac’s and Cogan’s syndromes). Facial weakness, indistinguishable from Bell’s palsy, occurs in patients with multiple sclerosis, alone or in association with other signs of brainstem disease, including hemifacial spasm and diffuse rippling of muscle fibres (myokymia). Exceptionally, there may be unilateral involvement of the hypoglossal and recurrent laryngeal nerves. Extensive brainstem demyelination may produce disturbances of consciousness and respiratory failure. Occasional manifestations include the locked-​in state, persistent hiccup, and lateral medullary syndrome. Paroxysmal symptoms are invariably brief, but repetitive and usually occur in bouts lasting a few weeks or months before remitting. Symptomatic trigeminal neuralgia may begin in the first division or bilaterally, at a younger age than the idiopathic condition, and with associated signs of trigeminal involvement including motor weakness and sensory loss. It is usually associated with demyelinating lesions of the dorsal root entry zone, but may coexist with compression of the fifth cranial nerve by ectatic vessels. Other than trigeminal neuralgia, isolated involvement of the fifth nerve is rare. Paroxysmal dysarthria and ataxia with a clumsy arm, complex disturbances of sensation, and painful tetanic posturing of the limbs lasting 1 or 2 min are often triggered by movement and preceded by positive sensory symptoms on the side opposite to the muscular spasm. These are easily recognized and treated. Bursts of pain and paraesthesias, sensory distortion, itching, cough, and hiccup, painful extensor spasm, akinesia, kinesogenic choreoathetosis, and complex gaze palsies—​ any of which may respond to anticonvulsants, especially carbamazepine—​ also appear to be paroxysmal manifestations of multiple sclerosis. Cognitive and affective symptoms Cognitive impairment occurs in up to 65% of patients with multiple sclerosis. It may occur at all stages of the disease, and be compounded by cognitive fatigue and depression. Reductions in attention, information processing speed, working memory, and executive functions are typical and likely reflect both a white matter disconnection syndrome, as well as increasingly recognized cortical structural abnormalities. Specific cognitive deficits due to hypothalamic involvement, including the Korsakoff state and the syndrome of bulimia, lack of social restraint, apathy, and mutism are sometimes seen. Discrete cortical syndromes, such as aphasia, are rare and should prompt investigation for other causes. Depression occurs more frequently in multiple sclerosis than in patients with comparable neurological disability; hypomania is occasionally seen, but should not be confused with pathological laughter and crying, arising from loss of central inhibition of facial and bulbar reflexes in association with extensive brainstem disease. Psychosis is rarely a feature of multiple sclerosis. Rare manifestations of multiple sclerosis The list of rare clinical manifestations (some already described) includes massive cerebral lesions, aphasia, headache, fever, movement disorders, epilepsy, hypothalamic and pituitary symptoms, respiratory failure, and peripheral neuropathy. Narcolepsy, Sjögren’s syndrome, ankylosing spondylitis, type I  neurofibromatosis, and autoimmune thyroid disease have periodically been associated with multiple sclerosis.

Childhood multiple sclerosis 2% of patients with multiple sclerosis present before the age of 10, and up to 10% before 16 years. Fever and meningism, impaired conscious level due to cerebral oedema with swollen optic discs, and seizures are regular features and the distinction from acute disseminated encephalomyelitis can often only be made by the later occurrence of relapse and remission. A  recent European study of the natural history of childhood onset disease confirms a higher female to male ratio (3:1), disease course that is invariably relapsing-​ remitting and a delayed time by 10 years to secondary progression compared with adult-​onset disease. Current international guidelines recommend disease-​modifying treatment for childhood active relapsing-​remitting multiple sclerosis on lines similar to adult patients.

Clinical course and prognosis Most patients present as a young adult. In many, a history of symptoms attributable to demyelination may be elicited from years earlier. But where this is not the case, patients are said to have a ‘clinically isolated syndrome’ (Fig. 24.10.2.3) and magnetic resonance imaging discriminates disease that is ‘active’, indicating a high probability of further clinical attacks, or ‘inactive’. The latest diagnostic criteria (Table 24.10.2.2) would classify someone in the active group as having ‘multiple sclerosis’ already. The subsequent illness passes through the three phases of relapse with full recovery, relapse with persistent deficits, and secondary progression (Fig. 24.10.2.1). There is considerable variation in how rapidly people progress through these phases, but typically secondary progression starts around the age of 40 years. In the minority 20%, a ‘primary progressive’ syndrome starts also around the age of 40, but without preceding relapses. Few (perhaps 5%) escape disability and are classified as having ‘benign multiple sclerosis’. It is very rare to die directly from demyelination of the nervous system (although possible with, for instance, a large brainstem plaque), but the secondary effects of disability associated with the disease reduce life expectancy by around 10 years. Relapses build up over days or a few weeks and then plateau before recovery, partial or complete, occurs over weeks or months. They are most frequent (less than once a year) at the outset of the disease and

inactive Clinically isolated syndrome active

inactive Relapsing-remitting multiple sclerosis active

Fig. 24.10.2.3  Early multiple sclerosis may be classified on the basis: (i) of the number of attacks, for exmple, clinically isolated syndrome where there has been only one clinical attack and relapsing-​remitting multiple sclerosis for two or more episodes; and (ii) of activity, defined by one or more relapses, or one or more new MRI lesions, over a 12-​month period. Under the McDonald criteria, the ‘active’ form of clinically isolated syndrome may be re-​classified as multiple sclerosis.

24.10.2  Demyelinating disorders of the central nervous system

Table 24.10.2.2  Diagnosis of multiple sclerosis (McDonald 2011 criteria) History

Examination

Dissemination in space demonstrated by:

Dissemination in time demonstrated by:

Relapsing-​remitting multiple sclerosis Two clinical episodes compatible with demyelination

Signs of two or more anatomical sites affected

Examination

History

Two clinical episodes compatible with demyelination

Signs of only one anatomical site affected

MRI. More than one lesion in at least two of 4 typical sites for multiple sclerosis plaques

History

One clinical episode compatible with demyelination

Signs of only one anatomical site affected

MRI. More than one lesion in at least two of 4 typical sites for multiple sclerosis plaques

MRI. Either simultaneous presence of lesions of different age at presentation, or new lesions on a second MRI scan at any time after the first

Primary progressive multiple sclerosis One year of progression of a typical syndrome (spinal, cerebellar)

2/​3 of: 1. M  RI lesions in at least two of 4 typical sites for multiple sclerosis plaques 2. More than one spinal cord lesion on MRI 3. Ccerebrospinal fluid oligoclonal bands

decrease steadily thereafter. Some 25% of relapses are triggered by an infection, especially upper respiratory and gastrointestinal; but careful studies have shown that vaccinations do not induce attacks. Major life events, such as bereavement, increase the risk of a relapse. The timing of relapses, but not the overall relapse rate, is altered by pregnancy. There is a reduction in the prepregnancy relapse rate for each trimester, balanced by a threefold higher risk in the puerperium. The clinical course is uninfluenced by breast feeding or anaesthesia. There is no evidence that trauma influences multiple sclerosis. Counterintuitively, there is only a weak relationship between relapse rate and a patient’s long-​term prognosis. The strongest prognostic factor is a short interval between the initial episode and first relapse. Classical rules are that the prognosis is relatively good when sensory or visual symptoms dominate the illness and there is complete recovery from individual episodes; conversely, motor involvement, especially when co-​ordination and balance are disturbed, has a less good prognosis. Once progressive multiple sclerosis has started, either primary or secondary, it proceeds relentlessly. Its onset is largely age-​related, at the age of 40 years, and its rate is similar between individuals and unrelated to previous disease history or relapse rate. These observations raise unresolved questions around the relationship between inflammation, manifesting as relapse, and neurodegeneration, the primary substrate of progression. The nature of the disability that progresses in ‘secondary progression’ reflects areas of previous damage in relapses. Usually it is the spinal cord that bears the brunt of progressive multiple sclerosis, but optic nerve, cerebral, and brainstem disease may also advance slowly. Primary progressive spinal disease is the usual mode of presentation when multiple sclerosis develops beyond the fifth decade. It is characterized by an absence of acute attacks with gradual decline from onset and, although cerebrospinal fluid analysis is similar to relapsing-​remitting disease, there are comparatively more spinal and fewer brain abnormalities on MRI. Current disease-​modifying agents have no demonstrable effect on primary progressive disease.

laboratory investigation, but they can be used to demonstrate the anatomical dissemination of lesions; to provide evidence for intrathecal inflammation; to demonstrate that conduction is altered in a form consistent with demyelination; and to exclude conditions that mimic demyelinating disease.

Investigations

Fig. 24.10.2.4  Typical plaques of multiple sclerosis in a MRI brain and cord. Note the periventricular, callosal and juxtacortical lesions in the brain and that the spinal cord lesions are no greater than one vertebral segment in length.

Multiple sclerosis can reliably be diagnosed using clinical criteria and without laboratory support. There is no single diagnostic

Magnetic resonance imaging Variations in the imaging protocols are beginning to distinguish separate components of the underlying pathological process. Imaging can highlight inflammation (gadolinium–​DTPA enhancement of T1-​weighted lesions, indicating that the lesion is of recent origin), demyelination and remyelination (magnetization transfer ratio), astrocytosis (T1-​weighted lesions, the signal arising from increased water content), and axonal damage (reduction in diffusion tensor imaging anisotropy and N-​acetyl-​aspartate spectra with chemical shift imaging, or the presence of focal atrophy and T1-​weighted black holes; see Fig. 24.10.2.4). The evolving lesion starts with increased blood–​brain barrier permeability, which lasts for up to four weeks, and is revealed by demonstration of enhancement after intravenous gadolinium. These lesions may disappear

6033

6034

section 24  Neurological disorders

but reactivation is sometimes seen, the cycles lasting about 8 weeks. Fluid attenuated inversion recovery (FLAIR), proton-​density, and T2 sequences best demonstrate demyelination. The periventricular lesions, which characterize multiple sclerosis, correlate with areas of persistent demyelination and astrocytosis. A  mixture of new, evolving, and recovering lesions may be seen in an individual patient at any one time. Magnetic resonance lesions occur about 10 times more frequently than new clinical events. Eventually, there is a reduction in the frequency of new lesions as patients move from the relapsing to progressive phases of the disease and evidence for atrophy is then more apparent. The number or volume of lesions correlates poorly—​if at all—​with disease severity or course, but there is less cerebral involvement in patients who present with primary progressive disease compared with those with similar disability from secondary progression. Progressive loss of brain volume—​occurs at a rate of 0.5–​1.0% p.a. in patients with multiple sclerosis, compared to a rate of 0.1% p.a. in age-​matched controls—​is also quantifiable using T1-​weighted MR brain-​imaging and is increasingly utilized as an outcome measure in trials of putative neuroprotective agents. Brain atrophy is significantly correlated with disability and cognitive impairment in multiple sclerosis. However, the imaging abnormalities of multiple sclerosis are not specific and similar changes occur with other inflammatory or vascular lesions and with advancing age. MRI scans are used in the diagnosis, prognosis, and treatment of multiple sclerosis. In diagnosis, they are first used to determine the pathology of the lesion causing current symptoms, whether structural or not. For instance, it is mandatory to scan the spinal cord of someone presenting with a myelopathy. Secondly, scans are used to identify ‘dissemination of lesions in space’, that is to show the presence of other (asymptomatic) lesions in the brain or spinal cord. Thirdly, MRI scans can also be used to demonstrate ‘dissemination of lesions in time’. If a patient has had several discrete clinical episodes of demyelination over time, this is not necessary. But, for those patients with a clinically isolated syndrome, new lesions that appear on interval scans mean that ‘multiple sclerosis’ can be diagnosed (Table 24.10.2.2). This process can be further contracted; a MRI brain with lesions of different ages (for instance, some with and some without gadolinium enhancement) is sufficient to establish ‘dissemination in time’ and diagnose multiple sclerosis at the time of a clinically isolated syndrome. MRI scans are useful in guiding prognosis in the clinically isolated syndrome. If there are no brain lesions at presentation, the chance of having a second demyelinating clinical episode over 20 years is only 20%. However, this rises to 80% if the initial brain MRI shows three or more plaques. There is a consensus, perhaps more than justified by the evidence, that rapid accumulation of MRI lesion load is a poor prognostic sign in multiple sclerosis. It is intuitive that the early appearance of brain atrophy is also a poor sign, although this has not yet become a routine clinical MRI measure. In determining the response to treatment it is established that new MRI lesion formation during the first year of first-​line disease-​ modifying treatments, is a biomarker for a poor disability outcome. It is logical to consider augmenting treatment as a result, but while this can be effective in substantially reducing or even eliminating further radiological ‘events’, the long-​term effect on disability remains uncertain.

Cerebrospinal fluid With the increasing availability and sophistication of magnetic resonance imaging, confidence in making the diagnosis of multiple sclerosis with supportive imaging alone has risen and fewer lumbar punctures are performed. There are two situations where they are commonly done: in patients over the age of 50 years (where non-​ specific lesions obscure the ability of MRI scans to discriminate demyelination) and to diagnose primary progressive multiple sclerosis. The cerebrospinal fluid cell count rarely exceeds 50 lymphocytes/​ ml, even during periods of clinical activity, and is normal in more than 50% of patients. There is a rise in total protein (usually ½ optic nerve length

Acute myelitis

MRI lesion extending over 3 or more vertebral segments

Area postrema syndrome (hiccups, vomiting)

Dorsal medullary MRI lesion

Acute brainstem syndrome

Typical brainstem MRI lesion

Symptomatic narcolepsy or diencephalic syndrome Symptomatic cerebral syndrome with typical NMOSD brain lesions

24.10.2  Demyelinating disorders of the central nervous system

The hyperacute form of acute disseminated encephalomyelitis (Hurst’s disease) starts with headache and progresses over hours to disorientation, confusion, drowsiness, and coma. Events move quickly and the illness often proves fatal even before the diagnosis has been established. The combination of pyrexia and a marked cerebrospinal fluid pleocytosis with a predominantly neutrophil response mimics pyogenic infection of the central nervous system, but the course is not influenced by antimicrobial treatment. Occasionally, the clinical and pathological features of acute haemorrhagic leucoencephalitis are focal and suggest a rapidly expanding tumour or herpes simplex encephalitis. There is poor quality evidence to guide treatment of acute disseminated encephalomyelitis. Most important is appropriate supportive care, which often involves intensive care treatment. Monitoring of intracranial pressure can be helpful in severe cases, and decompressive hemispherectomy has been life-​saving in a few individuals. For immunotherapy, early use of high-​dose intravenous steroids is advised and, among those who do not respond to steroids, improvement is seen in 50% cases with plasmapheresis. There is little role for intravenous immunoglobulin. Acute disseminated encephalomyelitis does not recur. The entity of ‘multiphasic disseminated encephalomyelitis’ has not gained general acceptance. However, multiple sclerosis can rarely present with a similar picture, following which more typical episodes of demyelination occur. Clues to this ‘encephalopathic presentation’ of multiple sclerosis are the presence, of cerebrospinal fluid oligoclonal bands and MRI lesions of varying age, or new MRI lesions forming five or more weeks after the initial symptoms.

Longitudinally extensive transverse myelitis Longitudinally extensive transverse myelitis is a feature of neuromyelitis optica, as described earlier. But it may also occur in isolation, often but not always with an antecedent infection, similar to acute disseminated encephalomyelitis in adults. Presentation is with pain at the site of the lesion, followed by weakness in the legs, sensory symptoms, and sphincter involvement. The weakness increases, and the clinical picture is that of spinal shock—​features that are rarely seen in acute cord lesions due to multiple sclerosis. On imaging, the cord lesion usually extends over three vertebral segments. The spinal fluid shows an increased mononuclear cell count, numerically intermediate between the marked pleocytosis of acute necrotizing myelitis and the marginal abnormalities seen in multiple sclerosis; total protein is raised and oligoclonal bands may be present on electrophoresis, but the glucose is usually normal. Transverse myelitis is more common in adults than children; there is a high frequency of persistent disability, but a much lower conversion to multiple sclerosis than following optic neuritis. Acute necrotizing myelitis causes rapidly progressive flaccid areflexic paraplegia with anaesthesia and loss of sphincter control. The intensity of inflammation may result in severe pain with meningism, pyrexia, and systemic symptoms. The condition can mimic cord compression; and the cerebrospinal fluid changes often resemble pyogenic or tuberculous infection of the central nervous system. For these reasons, treatment with high-​dose intravenous steroids, which may usefully influence mortality and limit long-​term disability, is often withheld. Acute necrotizing

myelitis has been described in association with herpes virus infection, and as a complication of acute lymphocytic leukaemia, lymphoma, carcinoma, and acquired immune deficiency syndrome.

Relapsing optic neuritis Outside of multiple sclerosis, recurrent demyelinating inflammatory optic neuropathies occur with neuromyelitis optica, particularly those associated with anti-​MOG antibodies. Chronic relapsing idiopathic neuropathy is a distinct entity with important treatment implications. People with this condition typically have severe optic neuritis with considerable pain, which responds well to corticosteroids but recurs on steroid withdrawal. MRI brain and cord scans (other than the optic nerves themselves) and cerebrospinal fluid are normal. This steroid-​ dependence marks it out from regular optic neuritis. Maintenance therapy with steroids and immunotherapy, such as mycophenolate or azathioprine, should be considered to prevent what is otherwise a poor visual outcome.

Balo’s concentric sclerosis The literature on this rare phenomenon is confusing. The pathognomic feature of Balo’s lesions, seen pathologically and radiologically, are concentric rings of demyelination separated by unaffected tissue. Such lesions may be seen alongside typical plaques in cases of multiple sclerosis, in which case it is best to think of them as one of the heterogenous pathological forms of multiple sclerosis lesion. However, some patients only present with Balo’s lesions, which may be extensive and cause progressive lobar syndromes. The prognosis of these cases is very variable, from progressive deterioration causing a neurological death to spontaneous recovery. It is not even clear that this is a primary inflammatory disorder; some argue that the rings are a response to hypoxic injury with unaffected tissue protected by ‘hypoxic preconditioning’. Unsurprisingly, there is no clear treatment guidance.

Harding’s disease Patients with Leber’s mitochondrial mutations may present with a syndrome that is identical to multiple sclerosis except that visual failure is more prominent. Curiously, this is more common in women, despite the fact that Leber’s hereditary optic neuropathy is more common in men. Leber’s mitochondrial mutations are not seen more commonly in cohorts of regular multiple sclerosis. There is no evidence to guide practice, but we recommend using standard disease-​modifying therapies for multiple sclerosis.

Non​inflammatory demyelinating diseases Central pontine myelinolysis Central pontine myelinolysis seems to result from overzealous correction of a low (and occasionally also high) serum sodium. Demyelination correlates both with the degree of hyponatraemia and rate at which this is corrected; starting levels of less than 110 mmol/​litre or rates of correction of more than 2 mmol/​litre/​h substantially increase the risk of central pontine myelinolysis. Rapid changes in sodium are better tolerated in acute than chronic

6039

6040

section 24  Neurological disorders

hyponatraemia. The clinical context is usually hospital treatment of hyponatraemia, which may be due to liver disease, as a complication of uraemia and haemodialysis, after prolonged vomiting or excess diuretic therapy. The illness affects central pontine pathways and spreads centrifugally. The fully evolved clinical picture is of flaccid paralysis with facial and bulbar weakness, disordered eye movements, loss of balance, and altered consciousness. Extrapontine manifestations, including movement disorders and other features of extrapyramidal disease, may be seen. The clinical features are distinctive and present no diagnostic difficulties unless the reduction in serum sodium has been overlooked. Patients on intensive care may present with central pontine myelinolysis as a failure to wean from ventilation. The characteristic radiological changes may not appear for a few days after the clinical syndrome and often persist after clinical recovery. Prognosis depends on the underlying metabolic disorder. With stabilization of the serum sodium and management of bulbar failure, neurological recovery is usually complete, and the condition does not recur spontaneously.

Toxic disseminated encephalomyelitis Rarely, a picture very similar to inflammatory disseminated encephalomyelitis can be induced by inhalation of cocaine or heroin vapour (from ‘chasing the dragon’). Prognosis is variable.

Inherited leucodystrophies The leucodystrophies are characterized by non​inflammatory demyelination. They include a heterogeneous group of conditions, often due to mutations affecting genes that determine the synthesis, maintenance, and structure of myelin. Although rare even in paediatric practice, these need to be considered in young adults with atypical syndromes combining physical and intellectual deficits, sometimes with peripheral nerve involvement, in whom imaging shows confluent lesions confined to white matter. The term diffuse cerebral sclerosis (Schilder’s disease) was originally used to identify a mixed group of diseases affecting cerebral white matter and the term is now redundant.

Adrenoleucodystrophy This important group of disorders is characterized by deposition of saturated fatty acids in the brain and other lipid-​containing tissues as a result of defective very long chain fatty acyl-​CoA synthetase activity in peroxisomes. Mutations are present in the ABC transporter gene. The molecular defect may result from failure of the adrenoleucodystrophy gene product to anchor very long chain fatty acids into the peroxisomal membrane or translocate these into peroxisomes. Diagnosis can be made by serum analysis of very long chain fatty acids. Evidence of adrenal insufficiency is a valuable discriminator from multiple sclerosis. Pathological findings vary but may include inflammation; although considered reactive by most commentators, immunosuppression has been used in these conditions, to no useful effect. Four related syndromes share this biochemical abnormality: childhood adrenoleucodystrophy and adult-​onset adrenomyeloneuropathy

are X-​linked; neonatal adrenoleucodystrophy and Zellweger’s syndrome are autosomal recessive disorders. X-​linked childhood adrenoleucodystrophy presents with behavioural disturbance, dementia, and epilepsy, followed by involvement of special senses and motor systems. Although a significant proportion of children later develop adrenal insufficiency, Addison’s disease may precede the neurological manifestations by several years. Treatment has been proposed with a dietary supplement containing a 4:1 mixture of glyceryl trioleate and trieructate, popularly known as Lorenzo’s oil. This lowers the plasma levels of very long chain fatty acids, but does not appear to influence the phenotype in individuals with established neurological disease, although there may be a prophylactic role. Bone marrow transplantation may be successful in early symptomatic cases. Adrenomyeloneuropathy presents in young adult men with spastic paraparesis and sensory loss in the legs. Clues to the correct diagnosis are an associated peripheral neuropathy or adrenal insufficiency. It may be associated with dementia later in the disease course. Identification of the peroxisomal defect in easily sampled body tissues has led to the description of cases with obscure clinical manifestations; these include focal cerebral lesions, Kluver–​ Bucy syndrome, dementia, and spinocerebellar degeneration. Mild spastic paraparesis with sphincter involvement and peripheral neuropathy may occur in obligate heterozygote female carriers with elevated very long chain fatty acids. Carriers tend not to have adrenal insufficiency, although abnormal brain MRI and delayed evoked potentials may be present. Autosomal recessive adrenoleucodystrophy and Zellweger’s syndrome present in infancy with seizures, hypotonia, retardation, retinal degeneration, and hepatic involvement.

Metachromatic leucodystrophy Metachromatic leucodystrophy is an autosomal recessive lysosomal storage disorder due to arylsulphatase A deficiency, leading to increased urinary sulphatide excretion with a deficiency of arylsulphatase A  in urine, peripheral blood leucocytes and skin fibroblasts, or showing metachromatic material in peripheral nerve biopsies having segmental demyelination and remyelination. There is diffuse white matter involvement due to non​inflammatory demyelination with loss of oligodendrocytes, axon preservation, and reactive astrocytes which, together with macrophages, contain the metachromatic material, especially in the most extensively demyelinated areas. The clinical phenotype varies with the amount of surviving arylsulphatase A  depending on heterozygosity of the mutant allele; pseudodeficiency refers to those individuals with low levels of arylsulphatase A that are sufficiently high not to display a clinical phenotype. Some affected individuals have a genetic defect of the arylsulphatase A activator and this is associated with a more complex pattern of sphingomyelin storage, biochemically and in terms of the tissue distribution. The most common form of metachromatic leucodystrophy develops in late infancy with delayed walking due to the neuropathy, which may be painful. There are also features of brainstem involvement and the emergence of diffuse upper motor neurone signs with reduced intellectual development, optic atrophy, and death within

24.10.2  Demyelinating disorders of the central nervous system

about five years from presentation. In later-​onset childhood cases, after several years of normal development, there are behavioural changes with poor school performance, anticipating cerebellar and upper motor neurone disability, which then follows much the same course as in younger patients, although with less evidence for neuropathy. The early adult form of metachromatic leucodystrophy is rare, or perhaps seldom diagnosed, and tends to present with intellectual or emotional abnormalities. Onset with dementia and behavioural disorders is usual with ataxia, paralysis, and optic atrophy only developing at late stages; the presentation is occasionally with paraparesis or cerebellar ataxia and the condition can then more easily be mistaken for multiple sclerosis. Clinical evidence for peripheral neuropathy may be revealed by slowed nerve conduction. Treatments have included dietary manipulation with reduced vitamin A  and sulphur-​containing substances, and bone marrow transplantation, but the successes are limited. Multiple sulphatase deficiency combines the features of metachromatic leucodystrophy with mucopolysaccharidosis. It also has neonatal, early childhood, and juvenile forms. The pattern of combined motor and mental regression or lack of development reflecting widespread dysmyelination with peripheral neuropathy is associated with dysmorphic features and organomegaly. The more severe phenotype also reflects extensive neuronal loss due to the combination of stored sulphatide, sulphated steroids, and mucopolysaccharides. The enzyme defects are complex involving many sulphatases, including arylsulphatase A.

Pelizaeus–​Merzbacher disease The three phenotypes of X-​linked Pelizaeus–​Merzbacher disease usually present in childhood. The clinical features which may distinguish the otherwise ubiquitous motor and developmental delay with epilepsy are abnormal eye movements, dystonia and choreoathetosis, and laryngeal paralysis. Affected individuals often stabilize with severe disabilities and live into early adult life. Some cases do not manifest until early adult life. MRI either fails to show myelin or depicts myelin that is immature and with an atrophic brain. The molecular defect is most frequently due to duplication of a variable length of genome containing the proteolipid protein gene. Recent evidence implicates defects in the replication mechanism that leads to the complex rearrangements seen in Pelizaeus–​Merzbacher disease. Proteolipid protein is normally involved in stabilizing the lamellar structure of central myelin. Gene dosage abnormalities result in oligodendrocyte loss and failure of myelination.

Krabbe’s disease Globoid cell leucodystrophy, an autosomal recessive condition, usually presents as an early infantile disorder. The very rare late-​onset form may be mistaken initially for multiple sclerosis. However, the disease usually progresses to include:  progressive intellectual and motor deterioration, epilepsy, visual failure, and peripheral neuropathy leading to severe disabilities; pyrexia and other autonomic features usher in the onset of a vegetative state. Visual evoked potentials are delayed, and the spinal fluid has a raised protein level, but does not contain oligoclonal bands. MRI shows periventricular lesions subsequently extending into extensive white matter changes. The deficiency of α-​galactocerebrosidase,

best demonstrated in peripheral blood leucocytes or skin fibroblasts, leads to the accumulation of galactocerebroside in oligodendrocytes and Schwann cells and characteristic myelin-​laden macrophages or globoid cells.

Adult-​onset dominant leucodystrophies Forms of dominantly inherited leucodystrophy also occur ­exclusively in adults and may closely resemble chronic progressive multiple sclerosis. MRI shows diffuse, non​discrete, white matter disease, and there are no oligoclonal bands in the spinal fluid. It remains uncertain whether all the adult-​onset dominant leucodystrophies are one and the same disorder, and many are difficult to distinguish from the heterogeneous group of hereditary spastic paraplegias.

FURTHER READING Barnes D, et  al. (1997). Randomised trial of oral and intravenous methylprednisolone in acute relapses of multiple sclerosis. Lancet, 349, 902–​6. Beck RW, et al. (2003). High and low risk profiles for the development of multiple sclerosis within 10 years after optic neuritis; experience of the optic neuritis treatment trial. Arch Opthalmol, 121, 944–​9. Bloomgren G, et al. (2012). Risk of natalizumab-​associated progressive multifocal leukoencephalopathy. N Engl J Med, 366, 1870–​80. Breij EC, et al. (2008). Homogeneity of active demyelinating lesions in established multiple sclerosis. Ann Neurol, 63, 16–​25. Chandran S, et al. (2008). Myelin repair: the role of stem and precursor cells in multiple sclerosis. Phil Trans R Soc Lond B Biol Sci, 363, 171–​83. Cohen JA, et  al. (2012). Alemtuzumab versus interferon beta 1a as first-​line treatment for patients with relapsing-​remitting multiple sclerosis:  a randomised controlled phase 3 trial. Lancet, 380, 1819–​28. Coles AJ, et al. (1999). Monoclonal antibody treatment exposes three mechanisms underlying the clinical course in multiple sclerosis. Ann Neurol, 46, 296–​304. Coles AJ, et  al. (2012). Alemtuzumab treatment of multiple sclerosis:  five-​year follow-​up of the CAMMS223 trial. Neurology, 78, 1069–​78. Coles AJ, et al. (2012). Alemtuzumab for patients with relapsing multiple sclerosis after disease-​modifying therapy: a randomised controlled phase 3 trial. Lancet, 380, 1829–​39. Comi G, et al. (2001). Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet, 357, 1576–​82. Compston DAS, Coles AJ (2008). Multiple sclerosis. Lancet, 372, 1502–​17. Compston DAS, et  al. (2005). McAlpine’s multiple sclerosis. W.B. Saunders, London. Confavreux C, et al. (1998). Rate of pregnancy-​related relapse in multiple sclerosis. N Engl J Med, 339, 285–​91. Confavreux C, et  al. (2001). Vaccinations and the risk of relapse in multiple sclerosis. Vaccines in Multiple Sclerosis Study Group. N Engl J Med, 344, 319–​26. Confavreux C, Vukusic S (2006). Age at disability milestones in multiple sclerosis. Brain, 129, 595–​605.

6041

6042

section 24  Neurological disorders

De Jager PL, et al. (2009). Meta-​analysis of genome scans and replication identify CD6, ICSBP1, and TNFRSF1A as novel multiple sclerosis susceptibility loci. Nat Genet, 41, 776–​82. Dutta R, Trapp BD (2007). Pathogenesis of axonal and neuronal damage in multiple sclerosis. Neurology, 68, S22–​31. Edan G, et  al. (1997). Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis:  a randomised multi-​center study of active disease using MRI and clinical criteria. J Neurol Neurosurg Psychiatry, 62, 112–​18. Fisniku LK, et al. (2008). Disability and T2 MRI lesions: a 20 year follow up of patients with relapse onset of multiple sclerosis. Brain, 131, 808–​17. Gregory AP (2012). TNF receptor 1 genetic risk mirrors clinical outcome of anti-​TNF therapy in multiple sclerosis. Nature, 488, 508–​11. IFNβ Multiple Sclerosis Study Group, the University of British Columbia MS/​MRI Analysis Group (1995). Interferon β-​1b in the treatment of multiple sclerosis:  final outcome of the randomised controlled trial. Neurology, 45, 1277–​85. International Multiple Sclerosis Genetics Consortium (IMSGC) and the Wellcome Trust Case Control Consortium 2 (WTCCC2) (2011). Genetic analysis and a primary role for immune mechanisms in the pathogenesis of multiple sclerosis. Nature, 476, 214–​19. International Multiple Sclerosis Genetics Consortium (IMSGC) Consortium (2007). Risk alleles for multiple sclerosis identified by a genome-​wide study. N Engl J Med, 357, 851–​62. Jacobs LD, et al. (1996). Intramuscular interferon β-​1a for disease progression in relapsing multiple sclerosis. Ann Neurol, 39, 285–​94. Jacobs LD, et al. (2000). Intramuscular interferon β-​1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med, 343, 898–​904. Johnson K, et al. (1998). Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Neurology, 50, 701–​8. Kappos L, et al. (2006). Oral fingolimod for relapsing multiple sclerosis. N Engl J Med, 355, 1124–​40. Kappos L, et al. (2007). Effect of early versus delayed interferon beta-​ ib treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-​yr follow up analysis of the BENEFIT study. Lancet, 370, 389–​97. Kremenchutzky M, et al. (2006). The natural history of multiple sclerosis: a geographically based study: observations on the progressive phase of the disease. Brain, 129, 584–​94. Ligon KL, et al. (2006). Olig gene function in central nervous system development and disease. Glia, 54, 1–​10. Lublin FD, et al. (2014). Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology, 83, 278–​86 Luchinetti C, et  al. (2000). Heterogeneity of multiple sclerosis lesions:  implications for the pathogenesis of demyelination. Ann Neurol, 47, 707–​17. Martenson RE, et al. (1992). Myelin: biology and chemistry. CRC Press, Boca Raton, FL. McFarland HF, Martin R (2007). Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol, 8, 913–​19. Miller HG, Stanton JB, Gibbons JL (1956). Parainfectious encephalomyelitis and related syndromes. Q J Med, 25, 427–​505. Moser HW (1997). Adrenoleukodystrophy:  phenotype, genetics, pathogenesis and therapy. Brain, 120, 1485–​508. Polman CH, et  al. (2005). Diagnostic criteria for multiple sclerosis:  2005 revisions to the ‘McDonald Criteria’. Ann Neurol, 58, 840–​6.

Polman CH, et  al. (2006). A randomised, placebo-​controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med, 354, 899–​910. Polman CH, et al. (2011). Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 69, 292–​302. Renoux R, et  al. (2007). Natural history of multiple sclerosis with childhood onset. N Engl J Med, 356, 2603–​13. Scolding N, et al. (2015). Association of British Neurologists: revised (2015) guidelines for prescribing disease-​modifying treatments in multiple sclerosis. Pract Neurol, 15, 273–​9. Sibley WA, Bamford CR, Clark K (1985). Clinical viral infections and multiple sclerosis. Lancet, i, 1313–​15. Srivastava R, et al. (2012). Potassium channel KIR4.1 as an immune target in multiple sclerosis. N Engl J Med, 367, 115–​23. Waxman SG (2006). Axonal conduction and injury in multiple sclerosis: the role of sodium channels. Nat Rev Neurosci, 7, 932–​41. Wingerchuk DM, et al. (2007). The spectrum of neuromyelitis optica. Lancet Neurol, 6, 805–​15. Wingerchuk DM, et al. (2015). International Panel for NMO Diagnosis. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology, 85, 177–​89. Youl BD, et al. (1991). The pathophysiology of acute optic neuritis: an association of gadolinium leakage with clinical and electrophysiological deficits. Brain, 114, 2437–​50.

24.10.3  Traumatic brain injury Tim Lawrence and Laurence Watkins ESSENTIALS Traumatic brain injury is one of the leading causes of death and disability worldwide. It is an extremely heterogenous condition with respect to mechanism, pathophysiology, injury pattern, and investigation findings, with highly variable outcomes, posing a significant challenge to clinicians treating it. Essential to the management of traumatic brain injury is an integrated, multidisciplinary approach from rapid resuscitation and early intervention through to rehabilitation. The pathophysiology can be divided into primary and secondary injury, where primary represents the injury at the point of trauma and secondary the progression of injury due to a cascade of downstream events occurring as a consequence of the primary injury and subsequent physiological insults.

Treatment Adequate resuscitation in the first few minutes is vital to prevent progression of injury. Life-​ threatening extracranial injuries that compromise the airway, breathing, and circulation take priority. Attention to these also facilitates neuroprotection. All patients with head injuries should be assumed to have injury to the cervical spine until this can be excluded.

24.10.3  Traumatic brain injury

Following resuscitation identification and treatment of life-​ threatening expanding intracranial lesions becomes paramount. Deterioration in conscious level, routinely assessed by serial recording of the Glasgow Coma Score (GCS), requires immediate action, with initial management depending on the severity of head injury. (1)  Severe (GCS 3–​8/​15)—​immediate referral to a neurosurgical unit is required; elective intubation and ventilation may be required prior to transfer; ventilation should maintain Pco2 4.0 to 4.5 kPa, and mean arterial pressure should be kept above 90 mm Hg; a CT scan will be required. (2) Moderate (GCS 9–12/15)—​an urgent CT scan followed by urgent neurosurgical referral and management as for severe head injury if this reveals an intracranial abnormality. (3)  Mild (GCS 13–15)—​patients with GCS 15, no history of loss of consciousness, and none of a defined list of criteria for investigation, may be considered for discharge according to local head injury protocols. The availability of CT scanning at all times in centres receiving patients with acute head injury, together with neurological and neurointensive care facilities, is critical for the best outcomes.

Complications, prognosis, and prevention (1) Acute subdural and extradural haemaotomas—​rapid detection and surgical drainage is of proven value. (2) Infection—​most neurosurgeons recommend early use of prophylactic antibiotics in penetrating injuries. (3) Cognitive symptoms—​85% of adults with severe head injuries remain disabled at one year; long-​term care requires multidisciplinary support in focused programmes of rehabilitation. Even ‘mild’ injuries can lead to significant ‘postconcussional symptoms’ including headache, dizziness, poor concentration, memory impairment, and personality change. Prevention—​this is a major concern for health and safety legislation, town planning and traffic laws (e.g. compulsory wearing of seat belts and crash helmets).

Epidemiology Traumatic brain injury is the leading cause of death and disability in high income countries in people between the ages of 5 and 45. Epidemiological data regarding traumatic brain injury from the United States suggests that 1.7 million people seek medical help following a head injury every year. It is estimated that there are 88/​ 100 000 population hospital admissions with 5.2 million living with disability following a traumatic brain injury and 52 000 deaths per year with a total cost to society of $77 billion. In Europe there are thought to be 2.5 million traumatic brain injury sufferers per year leading to 262/​100 000 population hospital admissions and approximately 75 000 deaths. It is estimated that each year in the United Kingdom approximately 1 million people attend hospital. Almost one-​half of these are children under 16 years of age. Head injuries cause 9 deaths per 100 000 population per year in the United Kingdom. This represents 1% of all deaths, but 15–​20% of deaths for those aged between 5 and 35 years. As mainly young people are affected, the prevalence of disability caused is very significant, with an estimated 135 000 people in the United Kingdom dependent on care after brain trauma.

While the high mortality associated with traumatic brain injury is striking, there is increasing concern regarding long-​term disability following all severities of head injury, many of which have previously been considered mild or moderate by conventional classification systems. Traumatic brain injury severity can be classified using the Glasgow Coma Scale, a system for assessing levels of consciousness based on clinical signs such as eye opening, verbal response, and limb movement. Approximately 80–​90% of all traumatic brain injury patients are classified as mild injury, the remainder classified as moderate or severe. The death rate for patients admitted to hospital with a moderate brain injury (GCS low), histological grade (low > high), and genetic mutations (1p19q, IDH mutation). As a general rule, survival with glioblastoma is 1–​2 years, anaplastic astrocytomas 2–​5 years, anaplastic oligodendrogliomas and low-​grade gliomas 5–​15 years.

Benign tumours, such as meningiomas and pituitary adenomas, have over 90% 10-​year survival if diagnosed before irreversible neurological damage has occurred.

Introduction Intracranial tumours comprise primary tumours that originate from the brain, cranial nerves, pituitary gland, or meninges, and secondary tumours (metastases) that arise from organs outside the nervous system. These tumours present to many different specialists and their management is difficult because of their anatomical location, variable clinical manifestations, and innate resistance to conventional cytotoxic treatments.

Aetiology There are no known risk factors apart from prior irradiation to the skull and brain and a few rare neurogenetic syndromes, such as neurofibromatosis (optic nerve glioma, meningioma, vestibular schwannoma) (Fig. 24.10.4.1), von Hippel–​ Lindau syndrome (haemangioblastoma), and Li–​Fraumeni syndrome (glioma). The role of mobile (cellular) phones has not been proven.

Epidemiology Intracranial tumours represent the eighth most common neoplasm in adults (c.2% of all cancers) and the second most common neoplasm in children. After stroke, intracranial tumours are the leading cause of death from neurological disease in the United Kingdom and are responsible for 7% of years of life lost from cancer before the age of 70. The crude annual incidence for primary intracranial tumours is 7.4 per 100 000 (males 9.1/​100 000, females 6.1/​100 000) and for secondary tumours 14.3 per 100 000 population. Just under 10 000 new cases of brain cancer present every year in the United Kingdom. The incidence has increased by approximately 25% over the last 40  years, particularly in older patients. Different tumour types present at different ages. Supratentorial gliomas, the most frequent primary brain tumour, are rare under the age of 30 years, but become increasingly prevalent thereafter. The most frequent tumours of middle life (third and fourth decades) are astrocytomas, meningiomas, pituitary adenomas, and vestibular schwannomas, whereas glioblastoma and metastases are more frequent in the fifth and six decades of life. In contrast, children tend to have infratentorial tumours: 70% of childhood primary intracranial tumours originate in the posterior fossa, whereas in adults the figure is only 25%. There is a strong female preponderance of meningiomas and schwannomas, whereas gliomas are more common in men.

Pathogenesis Gliomas are thought to arise from neoplastic transformation of glial cells. Recently, there has been increasing incidence in the role of stem cells in the origins of brain tumours—​stem cells are defined as having the ability to renew themselves in perpetuity and to differentiate into

24.10.4  Intracranial tumours

(a)

(b)

(c)

(d)

(e)

Fig. 24.10.4.1  Contrast-​enhanced CT and MR scans of a patient with neurofibromatosis type 2 and multiple intracranial tumours. (a) CT of the brain with contrast enhancement showing a large right parietal convexity meningioma surrounded by vasogenic oedema exerting considerable mass effect. There is also a smaller falx meningioma in the right occipital region. (b) Coronal T1-​weighted MRI of the brain with gadolinium enhancement showing multiple meningiomas in the right temporoparietal region, right parafalcine region, and both cavernous sinuses. (c) Contrast-​enhanced CT scan of the orbits showing bilateral optic nerve sheath meningiomas with intracranial extension into the right cavernous sinus, causing partial right nerve III and nerve VI palsies. (d) Axial T1-​weighted MRI of the brain with gadolinium enhancement, showing bilateral vestibular nerve schwannomas and a large cisterna magna tumour. (e) Sagittal T1-​weighted MRI of the spinal cord with gadolinium enhancement showing three discrete meningiomas encroaching on the spinal column at midcervical, midthoracic, and upper lumbar levels.

mature cells. The existence of a cancer stem cell has now been proven for glioblastoma and medulloblastoma, and may explain why these tumours recur after treatment. Certain genetic lesions are associated with brain tumours. Chromosomal deletions—​particularly chromosome 10, which contains multiple tumour-​suppressor genes—​are found in astrocytic tumours, occurring in up to 70% of glioblastomas. Mutations of a tumour-​suppressor gene, TP53, located on chromosome 17p, have also been reported in approximately 40% of astrocytic tumours. A novel mutation of isocitrate dehydrogenase-​ 1 (IDH1) has been found in a large percentage of gliomas of many different grades and histologies. This is a favourable prognostic marker in low-​grade and high-​grade gliomas and is being used to help with diagnosis of various histologically ambiguous tumours. As a metabolic enzyme in the Krebs cycle, it presents a unique insight into the understanding of gliomas and raises the potential for new mechanisms of treatment. In general, the accumulation of predictable genetic alterations is associated with increasing malignant

progression. Primary glioblastomas arise in older patients and are associated with wild-​type IDH, amplification and overexpression of the epidermal growth factor receptor (EGFR) gene, whereas secondary glioblastomas occur in younger people and are associated with IDH mutations and early loss of TP53. Recent data have shown that IDH wild-​type astrocytomas (irrespective of grade) are molecularly similar to glioblastoma, with implications for management.

Clinical features With increasing sophistication of neuroimaging, tumours are being detected at an earlier stage than before. Patients typically present with one or more of four clinical syndromes: • progressive neurological deficit • seizures

6049

6050

section 24  Neurological disorders

• raised intracranial pressure • altered mental states The particular combination of clinical features varies depending on the location, histology, and rate of growth of the tumour, for example, patients with low-​grade gliomas present typically with a seizure disorder that may remain static for many years, whereas patients with malignant gliomas typically develop a rapidly progressive neurological deficit and raised intracranial pressure. More patients are being diagnosed with incidental tumours as a result of the increased availability of CT and MRI scans.

Progressive neurological deficit Focal neurological symptoms due to brain tumour are typically subacute and progressive, with over 50% of patients having focal signs by the time of diagnosis. However, they may also present as a ‘stroke’ mimic and even as a transient ischaemic attack. Cortical tumours produce contralateral weakness, sensory loss, dysphasia, dyspraxia, and visual field loss depending on their location. Bilateral tumours (e.g. butterfly gliomas), may present with confusion, unsteadiness, and urinary incontinence. Posterior fossa tumours cause ataxia and cranial nerve palsies. Vestibular schwannomas cause progressive unilateral deafness followed by ipsilateral facial sensory loss and ataxia due to brainstem compression. Pituitary tumours may cause a bitemporal hemianopia if there is chiasmal compression or endocrine disturbances due to either hypopituitarism or hypersecretion of specific hormones.

Seizure disorder Brain tumours account for about 5% of epilepsy cases although they are overrepresented in cases of intractable epilepsy. Seizures are the presenting symptom in 25–​30% of patients with brain tumours and are present at some stage of the illness in 40–​60% overall. Approximately one-​half of the patients have focal seizures (usually frontal or temporal lobe) and the other half have secondarily generalized seizures. Low-​grade gliomas are associated with seizures in over 90% of cases and these frequently remain the only complaint for many years. About 50% of low-​grade glioma patients have intractable seizures. Conversely, patients with malignant gliomas have a lower frequency of seizures, presumably because of their more rapid growth and destructive characteristics. In these patients, seizures are associated with a better prognosis. Seizures are also common initial manifestations of meningiomas (40–​60%) and metastases (15–​20%). Supratentorial tumours and those located in the cortex are particularly likely to cause seizures, particularly in the frontal and temporal lobes. Todd’s paresis, which may persist, is an uncommon but characteristic feature of tumour-​associated epilepsy. About 10% of patients presenting anew in status epilepticus have an underlying tumour.

raised intracranial pressure is well known and easily recognized, but most patients present before this develops. Less than 0.1% of patients presenting with isolated headache have a brain tumour. Most brain tumour headaches are intermittent and non​specific and may be indistinguishable from tension headaches. Supratentorial tumours typically produce frontal headaches, whereas posterior fossa tumours usually result in occipital headache or neck pain. Certain features of a headache are suggestive but not pathognomonic of raised intracranial pressure. These include headaches that wake the patient at night or are worse on waking and improve over the course of the day. Patients with rapidly expanding tumours or who have cystic components or intratumoral haemorrhage may present with increasing drowsiness, vomiting, pupillary dilatation, and visual loss due to downward uncal and transtentorial herniation.

Mental state changes These are an uncommon presentation of brain tumours, usually found in slow growing orbitofrontal tumours (e.g. meningiomas). Personality changes may initially be quite subtle and may show themselves as an inability to cope at work, apathy, and loss of social inhibition. In these cases, it is essential to obtain a collateral history from relatives or colleagues at work. Later, as the tumours progress, personality change is quite common and may lead to breakdown of family relationships.

Pathology Neuroepithelial tumours (predominantly gliomas) account for approximately 50 to 60% of all primary brain tumours. The other common types are meningiomas (20%), pituitary adenomas (15%), vestibular schwannomas (5%), and primary central nervous system (CNS) lymphomas (5%) (Fig. 24.10.4.2). Brain metastases are much

Raised intracranial pressure Intracranial tumours increase intracranial pressure by a direct mass effect, provoking cerebral oedema, or producing obstructive hydrocephalus. The most common symptom of raised intracranial pressure is headache, which is the initial presenting symptom in 25% of patients and in 50% of patients at hospital presentation; papilloedema is found in up to 50% of patients with headache due to tumours. The classic picture of headache, vomiting, and visual obscurations (transient fogging of vision usually on rapid changes in posture) due to

Fig. 24.10.4.2  Axial T1-​weighted MRI with gadolinium enhancement showing a homogeneously enhancing left anterior temporal lesion which was biopsied and shown to be a primary CNS lymphoma.

24.10.4  Intracranial tumours

Table 24.10.4.1  Pathological classification of astrocytomas WHO grades of select CNS tumours Diffuse astrocytic and oligodendroglial tumours Diffuse astrocytoma, IDH-​mutant Anaplastic astrocytoma, IDH-​mutant Glioblastoma, IDH-​wildtype Glioblastoma, IDH-​mutant Diffuse midline glioma, H3K27M-​mutant Oligodendroglioma, IDH-​mutant and 1p/​19q-codeleted Anaplastic oligodendroglioma, IDH-​mutant and   1p/​19q-​codeleted

II III IV IV IV II III

Other astrocytic tumours Pilocytic astrocytoma Subependymal giant cell astrocytoma Pleomorphic xanthoastrocytoma Anaplastic pleomorphic xanthoastrocytoma

I I II III

Ependymal tumours Subependymoma Myxopapillary ependymoma Ependymoma Ependymoma, RELA fusion–​positive Anaplastic ependymoma

I I II II or III III

Other gliomas Angiocentric glioma Chordoid glioma of third ventricle

I II

Choroid plexus tumours Choroid plexus papilloma Atypical choroid plexus papilloma Choroid plexus carcinoma

I II III

Neuronal and mixed neuronal-​glial tumours Dysembryoplastic neuroepithelial tumour Gangliocytoma Ganglioglioma Anaplastic ganglioglioma Dysplastic gangliocytoma of cerebellum (Lhermitte-​Duclos)

I I I III I

more common than primary brain tumours and are increasing in frequency due to improvements in systemic anti-cancer treatments. The most common sites of origin of brain and meningeal metastases are lung (50%), breast (15%), melanoma (10%), and unknown (15%). The classification systems that have been traditionally used to describe degrees of anaplastic change are the basis of histological diagnosis and grading correlate with prognosis. The most widely accepted classifications of gliomas is the World Health Organization (WHO) system (Table 24.10.4.1). These systems have been retrospectively applied to large series of patients and have been shown to provide reproducible and prognostically useful information. They have recently been updated to include some new diagnostic entities. The gliomas are a family of neoplasms that are thought to arise from astrocytes, oligodendrocytes, and ependymal cells. Astrocytomas are the most common type of glioma and are infiltrating neoplasms composed of fibrillary astrocytes. WHO grade II gliomas have the propensity to undergo anaplastic change to a more malignant lesion. Thus, a fibrillary astrocytoma (Fig. 24.10.4.3) progresses to an anaplastic astrocytoma (Fig. 24.10.4.4) and then to the most malignant form, glioblastoma (Fig. 24.10.4.5). The oligodendroglioma is

Desmoplastic infantile astrocytoma and ganglioglioma Papillary glioneuronal tumour Rosette-​forming glioneuronal tumour Central neurocytoma Extraventricular neurocytoma Cerebellar liponeurocytoma

I I I II II II

Tumours of the pineal region Pineocytoma Pineal parenchymal tumour of intermediate differentiation Pineoblastoma Papillary tumour of the pineal region

I II or III IV II or III

Embryonal tumours Medulloblastoma (all subtypes) Embryonal tumour with multilayered rosettes, C19MC-​altered Medulloepithelioma CNS embryonal tumour, NOS Atypical teratoid/​rhabdoid tumour CNS embryonal tumour with rhabdoid features

IV IV IV IV IV IV

Tumours of the cranial and paraspinal nerves Schwannoma Neurofibroma Perineurioma Malignant peripheral nerve sheath tumour (MPNST)

I I I II, III or IV

Meningiomas Meningioma Atypical meningioma Anaplastic (malignant) meningioma

I II III

Mesenchymal, non​meningothelial tumours Solitary fibrous tumour /​haemangiopericytoma Haemangioblastoma

I, II or III I

Tumours of the sellar region Craniopharyngioma Granular cell tumour Pituicytoma Spindle cell oncocytoma

I I I I

Fig. 24.10.4.3  Low-​grade glioma. Coronal and axial T2-​weighted MRI of the brain showing a diffuse lesion in the right frontal lobe, which returns high signal. It is seen extending from the cortex into the deep white matter and infiltrating across the corpus callosum. There is mass effect causing compression of the frontal horn of the lateral ventricle. The tumour does not enhance with gadolinium. This patient presented with generalized seizures and has remained well after 8 years of follow-​up. Biopsy revealed a fibrillary astrocytoma (WHO grade II).

6051

6052

section 24  Neurological disorders

or a resection specimen. Advanced MRI techniques include MR spectroscopy, perfusion and permeability sequences, and metabolic imaging (positron emission tomography (PET)). These may permit a non​invasive method of differentiating between low-​grade and high-​grade gliomas and between tumour recurrence and radiation necrosis. However, histology is still the gold standard, now complemented with molecular information, for example, IDH mutation, chromosomal deletions of 1p19q (found in oligodendroglial tumours and associated with a better prognosis), and methyl guanyl methyl transferase (MGMT) promoter methylation (which predicts response to temozolomide chemotherapy in glioblastoma).

Treatment

Fig. 24.10.4.4  Anaplastic astrocytoma. Coronal T1-​weighted MRI of the brain with gadolinium enhancement showing a large heterogeneous enhancing tumour arising from the right frontal lobe exerting considerable mass effect in a patient presenting with a 2-​month history of complex partial seizures, headaches, and papilloedema.

characterized by the presence of uniform round nuclei with small nucleoli. This also has the propensity to undergo anaplastic change but, unlike anaplastic astrocytomas, oligodendrogliomas are frequently chemosensitive (see next) and patients may live for many years.

Diagnosis The diagnosis of a brain tumour is made by a combination of CT/​MR scanning and pathological examination of either a biopsy

The three conventional methods of treatment for brain tumours are surgery, radiotherapy, and chemotherapy. Targeted biological agents, gene therapy and immunotherapy have still not been widely taken up because of the lack of proven benefit over and above standard therapies. In line with other areas of oncology, there is increasing use of combination therapies, particularly concomitant chemoradiation to improve survival.

Surgery Advances in tumour neurosurgery include the use of computerized frameless neuronavigation techniques, intraoperative imaging with ultrasound and MRI and intraoperative cortical mapping during awake craniotomy. Preoperatively, important anatomicofunc­ tional information can be derived from functional MRI (fMRI) which allows localization of eloquent motor, speech, and memory cortex as well as diffusion tractography, which can delineate the anatomical relationship between tumour and important white matter tracts. Fluorescence guided resection using the porphyrin 5-​aminolaevulinic acid (5-​ALA) has been shown to increase complete resection of glioblastoma, resulting in a prolonged period free of progression (but not overall survival) and delayed neurological deterioration.

Fig. 24.10.4.5  Glioblastoma. Axial T2-​weighted (a) and coronal T1-​weighted with gadolinium enhancement (b) MRI showing large vascular (dark serpiginous structures) and heterogeneous intrinsic architecture with extensive peritumoral vasogenic oedema (shown as white matter ‘fingers’ on (a)) and the irregular rim enhancement and central necrosis (on b).

24.10.4  Intracranial tumours

Surgery is indicated as a first-​ line treatment for gliomas, meningiomas, and non​ secreting pituitary adenomas. As a general rule, extra-​axial tumours (e.g. meningiomas), may be cured by surgery alone as well as a small proportion of low-​grade gliomas (e.g. pilocytic astrocytomas). For most types of glioma, however, surgical removal is not curative. Although surgery is of undoubted benefit in relieving the symptoms and signs of raised intracranial pressure or an evolving focal deficit, there are no prospective randomized data to support its use for prognostic purposes alone, particularly in patients with malignant gliomas. However, the conventional surgical wisdom is that maximal safe resection (cytoreduction) improves progression-​free survival in patients with high-​grade gliomas and that complete macroscopic or subtotal resections (leaving a residual tumour volume of 10 years) control rates for meningiomas are around 90%. Advances in technology have allowed greater accuracy of radiotherapy delivery and, in particular, the use of stereotactic frames that permit the focusing of radiation to a small tumour with minimal dosage to the surrounding normal tissue. This can be done either in a single high dose (stereotactic radiosurgery or γ knife) or in smaller fractions (stereotactic radiotherapy) and is predominantly indicated for lesions less than 3 cm in diameter which are well circumscribed, extra-​axial, and more than 5 mm away from organs at risk e.g. optic chiasm, or for brain metastases. Intensity-​modulated radiotherapy (IMRT) allows more precise ‘dose painting’ whereby different regions of the tumour are treated with varying doses of radiotherapy, and minimises the amount of normal brain tissue that is irradiated. ‘Cyberknife’ radiotherapy has incorporated a robotic mounting device with real-​time image guidance to improve accuracy of delivery and to ‘target’ the tumour during normal respiration. None of these advanced techniques have been compared against each other, and nor have they have been shown to be superior to stereotactic fractionated radiotherapy. Recently, two large randomized studies have shown similar survival benefits and functional independence between patients with 1 to 3 brain metastases treated with stereotactic radiosurgery (SRS) versus SRS plus whole-​brain radiotherapy (WBRT). As a result, WBRT is no longer used routinely in patients with solitary or oligometastases with good performance status.

Radiotherapy

Chemotherapy

Radiotherapy is the only treatment that has been proved to extend survival in patients with primary malignant brain tumours and may be given with radical or palliative intent. Patients with malignant gliomas are treated with radical radiotherapy to a dose of 60Gy in 30 fractions over 6 weeks. Temozolomide, an oral alkylating agent, has been shown to improve survival in patients with newly diagnosed glioblastoma when given together with radiotherapy (concomitantly) and then for six monthly cycles after chemoradiation (adjuvantly). This is known as the Stupp protocol and was the first significant advance in the treatment of glioblastoma for over 30 years. Although the improvement in median survival compared with radiotherapy alone is modest (12.1 vs. 14.6 months), the proportion of patients alive at 2 years increased from 10% to 26%, and at 5 years from 2% to 10%. These data were published in 2005 and rekindled enthusiasm for chemotherapy trials in tumours previously regarded as chemoresistant. Whether this treatment can improve the survival of patients with anaplastic astrocytomas is being tested in clinical trials. The elderly patient with glioblastoma poses particular challenges, as they have poorer cerebral reserve, less tolerance of brain radiotherapy and more comorbidities—​as a result, they are usually excluded from clinical trials and so the best treatment has not been determined. Early radiotherapy for adult low-​ grade gliomas prolongs progression-​free survival by about 2 years but has no effect on overall survival, compared with radiotherapy given at the time of tumour progression. Radiotherapy is effective in controlling seizures in patients with refractory brain tumour-​ associated epilepsy. Meningiomas are also partially radioresponsive and should be treated with radiotherapy where there is atypical or malignant histology or where

There has been increased awareness of the chemosensitivity of certain tumours, particularly anaplastic oligodendrogliomas and primary CNS lymphomas in adults, and diencephalic gliomas in children. Approximately two-​thirds of anaplastic oligodendrogliomas respond dramatically to a combination of treatment with procarbazine, lomustine, and vincristine; updated (12-​year follow-​up) data from a phase III trial have demonstrated a clear survival benefit for adjuvant vincristine over and above radiotherapy in patients with anaplastic oligodendrogliomas, but only those with the presence of combined deletions of chromosomes 1p and 19q. Similarly, a recently published phase III randomized trial has demonstrated a 5.5-​year improvement in survival with the addition of procarbazine, lomustine, and vincristine chemotherapy in patients with ‘high-​risk’ low-​grade glioma over radiotherapy alone. However, the trial was completed over 10  years ago and, in that time novel molecular markers (see next) and newer drugs (e.g. temozolomide) have been developed, so it is difficult to know how to best incorporate these results into clinical practice. Adjuvant nitrosurea chemotherapy is used in patients with malignant gliomas although it offers only a marginal survival advantage. Carmustine wafers allow local delivery of carmustine (a nitrosourea) into the resection cavity of a malignant glioma, hence avoiding the systemic toxicity of these compounds, but are associated with increased risk of infection, oedema and wound breakdown so are used in highly selected cases only. The role of temozolomide chemotherapy in patients with low-​grade gliomas over radiotherapy alone is currently being evaluated in a clinical trial and interim data do not suggest any survival advantage. There is no chemotherapy that is effective for the treatment of meningiomas.

6053

6054

section 24  Neurological disorders

Chemotherapy of recurrent malignant glioma is associated with poor response rates, so new agents are constantly being investigated, including dendritic cell vaccines, immune checkpoint inhibitors, and antiangiogenesis agents. To date, no new treatment has been shown to be more effective than nitrosurea-​based chemotherapy.

Prognosis Overall survival from brain tumours has increased over the last 40 years but is still poor, around 40% at 1 year and 18% at 5 years. The four most important favourable prognostic factors for patients with gliomas are young age (less than 40  years), good performance status, low-​grade oligodendroglial histology and molecular subtype (IDH1 mutation and, 1p/​19q codeletion). The survival advantage for different treatments is modest in comparison. Any trial claiming a significant survival advantage for a new treatment therefore needs to show that this effect is independent of other prognostic factors. The median survival for patients with malignant gliomas varies from 6 months to 5 years, dependent on the aforementioned conditions. Generally, patients with glioblastoma survive for 1–​2 years, whereas patients with anaplastic gliomas survive for 2 to 5 years, the exception being anaplastic oligodendrogliomas where survival can extend up to 10-20 years. The outlook for patients with low-​grade gliomas is considerably better, with a median survival of 5–​15 years depending on age, preoperative performance status, histology, and tumour growth rate. Oligodendrogliomas have a more indolent course and are more chemosensitive than astrocytomas, so their prognosis is correspondingly better, with patients surviving 15–​20 years after diagnosis, even with anaplastic histology. A recent genome wide analysis of almost 300 adult lower-​grade gliomas correlating molecular data with clinical outcomes has shown that these tumours can be categorized into three molecular classes—​those with IDH mutations and either 1p19q codeletions (most favourable outcome) or TP53 mutations and those with IDH wild-​type tumours, which behaved clinically more like glioblastoma. At least 40% of primary intracranial tumours are extra-​axial (not arising from within the brain substance itself) and are thus readily treatable, if not curable. Some tumours, such as meningiomas and pituitary adenomas, are associated with 10-​year survival rate of over 90% if diagnosed before irreversible neurological damage has occurred.

cerebral metastases: results of the EORTC 22952-​26001 study. J Clin Oncol, 29, 134–​41. Leroy HA, et  al. (2015). Fluorescence guided resection and glioblastoma in 2015: a review. Lasers Surg Med, 47, 441–​51. Louis DN, et al. (2007). The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol, 114, 97–​109. Rachett B, et al. (2008). Survival from brain tumours in England and Wales up to 2001. Br J Cancer, 99, S98–​101. Schomas DA, et al. (2009). Intracranial low-​grade gliomas in adults: 30 years’ experience with long-​ term follow-​ up at Mayo Clinic. Neuro-​Oncology, 11, 437–​45. Stupp R, et  al. (2005). Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med, 352, 987–​99. Stupp R, et al. (2009). Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-​year analysis of the EORTC-​NCIC trial. Lancet Oncol, 10, 459–​66. Taphoorn MJB, Klein M (2004). Cognitive deficits in adult patients with brain tumours. Lancet, 3, 159–​68. Van den Bent MJ, et al. (2005). Long-​term efficacy of early versus delayed radiotherapy for low-​grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet, 366, 985–​90. van den Bent MJ (2014). Practice changing mature results of RTOG study 9802:  another positive PCV trial makes adjuvant chemotherapy part of standard of care in low-​ grade glioma. Neuro-​ oncology, 16, 1570–​4.

24.10.5  Idiopathic intracranial hypertension Alexandra Sinclair ESSENTIALS Idiopathic intracranial hypertension is a condition of raised intracranial pressure of unknown cause predominantly affecting obese women of childbearing age. Impaired absorption or increased production of cerebrospinal fluid, or raised venous pressure, may be contributory. Secondary causes include cerebral venous thrombosis, anaemia, endocrinopathies, and drugs (particularly tetracycline and vitamin A derivatives or supplements).

FURTHER READING

Clinical features

Counsell CE, Collie DA, Grant R (1996). Incidence of intracranial tumours in the Lothian region of Scotland, 1989–​90. J Neurol Neurosurg Psychiatry, 61, 143–​50. Cancer Genome Atlas Research Network, Brat DJ, et  al. (2015). Comprehensive, integrative genomic analysis of diffuse lower-​grade gliomas. N Engl J Med, 372, 2481–​98. Hollon T, et al. (2015). Advances in the surgical management of low-​ grade glioma. Seminars in Radiation Oncology, 25, 181–​8. Kocher M, et  al. (2011). Adjuvant whole-​brain radiotherapy versus observation after radiosurgery or surgical resection of one to three

Characteristic presentation is with headache, which may be typical of raised intracranial pressure but is frequently non​specific. Papilloedema is present, visual field defects are common, and (rarely) there may be sixth nerve palsy.

Diagnosis, treatment, and prognosis Brain imaging, including venography, should exclude other causes of raised intracranial pressure. Lumbar puncture reveals pressure greater than 250 mm  cerebrospinal fluid with normal constituents. Treatments aim to prevent permanent visual loss and manage

24.10.5  Idiopathic intracranial hypertension

headaches. Therapy includes weight loss and acetazolamide, and other diuretics are sometimes used (without evidence of efficacy). For those with rapid visual decline, urgent surgical intervention (ventriculoperitoneal/​lumboperitoneal shunt with a valve or optic nerve decompression) is essential. A  temporizing lumbar drain should be considered if surgery is delayed. For most patients this is a chronic condition characterized by significantly disabling headaches and relapses, typically precipitated by weight gain.

Introduction Idiopathic intracranial hypertension (IIH) (also called pseudotumour cerebri and, previously, benign intracranial hypertension) is a syndrome of raised intracranial pressure in the absence of an intracranial mass lesion, enlargement of the cerebral ventricles, or venous sinus thrombosis. IIH affects predominantly obese women of childbearing age (>90%). The condition has considerable morbidity from permanent visual loss (up to 25% of cases) and chronic disabling headaches, which result in poor quality of life. Patients presenting acutely with papilloedema must be evaluated urgently for secondary causes of raised intracranial pressure (e.g. space occupying lesion and venous thrombosis). After this, the priority is to assess accurately the threat to vision. In most patients, the condition becomes chronic and the disease burden is mostly from chronic headaches, which need active management, alongside visual monitoring. This chapter does not cover paediatric IIH. The IIH management guidelines reflect the consensus from the Association of British Neurologists, The Royal Collage of Opthalmologists, The Society for British Neurological Surgeons, key international opinion leaders and patients group (open access reference below) and are a key pragmatic resource for this condition.

Aetiology Elevated intracranial pressure (ICP) is caused by alterations in the volume of either cerebral blood, cerebrospinal fluid (CSF), or brain tissue. CSF volume is tightly regulated and is dependent upon the balance between CSF secretion and drainage. The mechanisms involved in regulation of CSF dynamics are poorly understood.

Epidemiology Idiopathic intracranial hypertension is comparatively rare in the general population, with an annual incidence of approximately 1 in 100 000, but this figure rises to 19 in 100 000 in obese women of childbearing age. Although more than 90% of patients are obese women, IIH can also occur in childhood and is rarely observed in men.

Pathogenesis The underlying pathogenesis is not fully understood, but is driven by disordered CSF dynamics. This may be through either excessive CSF production at the choroid plexus, reduced CSF drainage

(predominantly by the arachnoid granulations) or elevated venous sinus pressure, or a combination of more than one of these factors. The mechanisms underlying the elevated intracranial pressure are not fully understood. As typical patients are obese and female, a pathogenic role for sex hormones and adipokines has been speculated.

Clinical features Characteristic presentation is with headache (94%) and papilloedema (although rarely patients can be diagnosed with IIH without papilloedema (IIHWOP)). Other symptoms include transient visual obscurations, pulsatile tinnitus, visual disturbance, double vision and, in some, non​specific back pain, neck pain, and dizziness.

Headache This is the most common symptom and is present to some degree in almost every case. In those with significantly raised intracranial pressure (typically at presentation) the headache phenotype typically reflects that of raised intracranial pressure (worse in the mornings, on lying down, on bending down, and with Valsalva manoeuvres). The International Headache Society criteria for the diagnosis of headache associated with IIH (criteria 7.1.1) lists a headache with daily occurrence, which is diffuse and or constant (typically non-​pulsating) and aggravated by coughing and bending. These features are not exclusive to IIH (exacerbation of headache with coughing occurs in 70% of IIH patients and 35% of migraineurs while bending exacerbates 50% of IIH headaches and 44% of migraineurs). IIH headaches can resemble migraine and additionally may coexist with migraine. IIH headaches improve after lumbar puncture and CSF drainage in 72% (but improvement is also documented in 25% of migraineurs).

Papilloedema This is a virtually universal finding, but IIH without papilledema (IIHWOP) is sometimes observed. Papilloedema results from swelling of the intraocular (prelaminar) portion of the optic nerve head. Severity of papilloedema can be classified using Frisen Grading (Fig. 24.10.5.1). Choriodal-​retinal folds may be noted in IIH. Although typically identification of papilloedema is not challenging (particularly when there is moderate to severe swelling), distinguishing between mild papilloedema and pseudopapilloedema (e.g. due to anomalous discs or optic nerve head drusen) can be a challenge. There is a risk that once a patient is labelled with papilloedema the diagnosis is then not questioned, which can lead to inappropriate investigations and treatment. An accurate assessment of the optic disc is, therefore, essential and if there is any doubt as to whether there is true papilloedema of the optic disc, an opinion by a senior ophthalmologist or neuro-​ophthalmologist should be sought. Investigations that might be helpful include optical coherence tomography to quantify elevation of the retinal nerve fibre and identify drusen; orbital ultrasound B-​scan can identify drusen and measure fluid in the optic nerve sheath and fluorescein angiography to look for early leakage from the blood vessels in papilloedema. Papilloedema and drusen may coexist in a minority of patients. Loss of spontaneous venous pulsations, particularly in a patient where they were previously noted, is an indicator of raised ICP. However, spontaneous venous pulsations cannot be identified in a large portion

6055

6056

section 24  Neurological disorders

bilateral but can be more severe in one eye or very rarely unilateral (unilateral papilloedema requires a more extensive imaging to exclude a lesion compressing the optic nerve).

BASELINE RIGHT

LEFT (b)

(a)

Visual symptoms

(d)

(c)

30

30

In patients with papilloedema, transient visual obscurations (blackening or greying out of the vision, usually in both eyes for a few seconds, particularly on Valsalva or bending) likely result from intermittent ischaemia of the optic nerve. These episodes do not correlate with visual loss. Diplopia is most frequently horizontal due to a sixth cranial nerve palsy (false localizing sign resulting from elevated ICP). Monocular diplopia is extremely rare and can occur due to macula oedema (early) or epiretinal membrane (late) in the setting of significant papilloedema. Symptoms of visual loss are common and variable (e.g. dark area (scotoma), tunnel visual from peripheral constriction).

Pulsatile tinnitus Occurring in 60% of patients with active disease, this is usually bilateral but can be unilateral. It may be described as whooshing or akin to a heartbeat. Jugular venous compression can temporarily eliminate the sound.

VFI: 85% MD: -3.51 DB P140 pg/​ml) cannot necessarily be assumed to be the cause of a neuropathy, but increased serum methylmalonic acid and homocysteine are useful markers of significant B12 deficiency which may occur even at low normal serum levels (99%) than familial cases ( 3.9 µmol/​g dry weight versus 0.2 to 0.6 µmol in normal liver) from a liver biopsy and/​or screening for mutations in the ATP7B gene. In a mixed European population, one mutation, H1069Q, accounts for 35 to 45% of disease-​causing alleles. Among Asians, 57% of the alleles contain the R778L mutation and, in Russian patients, 40 to 45% have the H714Q and delC2337 mutations. Presence of two of the following criteria is considered diagnostic:  positive family history, Kayser-​Fleischer rings, Coombs-​ negative hemolytic anaemia, low total serum copper and ceruloplasmin, elevated hepatic copper, and increased 24-​ hour urine copper. A  combination of Kayser-​Fleischer rings and a low serum ceruloplasmin are considered pathognomonic for Wilson disease. In the absence of Kayser-​Fleischer rings, an elevated hepatic copper concentration and other biochemical tests helps confirm the diagnosis. Patients with indeterminate clinical and biochemical studies should undergo sequencing for ATP7B. The primary goal of therapy is to induce a negative copper balance by inducing urinary copper excretion and preventing copper absorption from the gut. This helps to prevent or slow disease progression and reverse injury. In symptomatic patients, chelating agents such as penicillamine or trientine, which promote urinary copper excretion are mainstay of treatment. Penicillamine promotes urinary

24.17  Inherited neurodegenerative diseases

copper excretion; however, exacerbation of neurologic symptoms occurs in 10% to 50% of those treated. Penicillamine is therefore not the treatment of choice as initial therapy to patients with predominant neurologic symptoms and signs. Due to its favourable adverse event profile, Trientine is preferable to penicillamine as first-​line treatment. It shows efficacy in neurologic and hepatic disease. Zinc induces the copper-​binding protein metallothionein in the gut mucosa, inhibits intestinal copper absorption and increases excretion in the stool. Zinc, although currently an ‘off label indication’ is usually well-​tolerated and may be a used as first-​line therapy in asymptomatic patients and for maintenance of patients who have achieved adequate copper removal. The chelating agent tetrathiomolybdate is not FDA approved but is promising, alone and in combination with zinc, for the initial treatment of neurologic Wilson disease as neurologic deterioration is seen in less than 5% of patients. Lifelong maintenance therapy is requored with zinc or chelation after initial stabilization of symptoms and biochemical abnormalities which takes up to a year. Asymptomatic individuals should receive lifelong maintenance doses of zinc or trientine. Chelation is highly effective in improving hepatic and neuropsychiatric symptoms and signs; however, it may be years to reach maximum improvement in liver function or neuropsychiatric disease. Long-​term zinc therapy in a presymptomatic paediatric population improves liver function without adverse effects on growth and development. Liver transplantation may be necessary for decompensated liver disease unresponsive to medical treatment and in patients who present with acute liver failure. Liver transplant may be curative and those who survive the first year generally have a good long-​term prognosis. Further investigational therapeutics are focused on gene therapy, gene repair, and hepatocyte transplantation. Supportive therapy includes avoidance of high copper foods such as liver and shellfish indefinitely. Annual 24-​hour urinary copper excretion, zinc levels in patients taking zinc, or free copper levels in patients taking chelation therapy, are useful for monitoring. Physical, occupational, and speech therapies can help maximize residual function; counselling the risk of aspiration is important for those with neurological dysfunction. Muscle relaxants and/​or botulinum toxin may be useful for symptomatic relief of dystonia. Psychiatric disease needs therapy with antidepressant therapy or antipsychotics as deemed necessary. Vaccination against viral hepatitis A and B is recommended to prevent additional insult to the liver.

Huntington disease Huntington disease (HD) is an autosomal dominant disorder with an incidence of 3 to 7 in 100 000. It is caused in most cases by a dynamic CAG triplet-​repeat expansion in exon 1 of the IT15 gene on chromosome 4q16.3, which codes for the protein huntingtin. Fewer than 26 CAG repeats at this locus is normal; over 40 repeats is characteristic of patients with Huntington’s disease, repeats of 36–​39 have milder phenotype with reduced penetrance and more than 70 occur in the severe juvenile variant. A paternal origin of the expanded repeat is found in 80% of juvenile patients whereas small expansions or even contractions in repeat length are found in the children of women who have Huntington’s disease. HD is most often a disease of mid-​adult life but 6 to 12% of those with the condition develop symptoms before age 20. In its classic adult-​onset form it presents with changes in personality and behaviour as well as with involuntary motor movements. Either one

can occur before the other. In a patient presenting around the age of 40 years with hyperkinetic movement disorder neuropsychiatric symptoms with a similar family history suggestive of autosomal dominant mode of inheritance, HD is most likely diagnosis. Memory deficits, agitation, depression, impulsiveness, delusions and hallucinations, and poor judgement are neuropsychiatric features. Over time patients develop hand clumsiness, gait abnormalities, parkinsonism, chorea, dystonia, dysphagia, and tremor, as well as oculomotor disturbances. In juvenile patients, the clinical picture is one of bradykinesia, rigidity, seizures, and dementia. Global decline in cognition occurs with average survival of 10 years in juvenile-​onset and 15–​20 years in adult-​onset patients. The trinucleotide rereat is translated into a polyglutamine chain and this is associated with accumulation of abnormal protein within th cell. Brain imaging discloses marked flattening of the head of the caudate nucleus and atrophy of the putamen. In juvenile patients there is also generalized brain atrophy with loss of cerebellar Purkinje’s cells. Even before caudate atrophy appears on CT or MRI, PET may demonstrate hypometabolism in the caudate nucleus. Therapy for the symptoms of Huntington’s disease includes neuroleptics, antiparkinsonian agents, psychotropic drugs, and a supportive stimulating environment. Tetrabenazine, a central monoamine depleter, and amantadine have both shown improvement in the mean total maximal chorea scores from the Unified Huntington Disease Rating Scale. Family members seeking information about their risk of developing Huntington’s disease should seek psychological assessment and review of their options from a genetic counselling service. Huntington disease-​like syndromes A small percentage of patients with Huntington’s disease-​like (HDL) syndrome may test negative for a CAG repeat expansion in IT15 and could, in fact, have another genetic disorder. Four such HDL syndromes have been described: HDL1 is an autosomal dominant disorder caused by extra octapeptide repeats in the prion protein (PRNP) gene on chromosome 20p12. HDL2, especially common in the black South African population, is caused by a CTG–​CAG triplet-​ repeat expansion in the junctophilin 3 (JPH3) gene on chromosome 16q24.3. An autosomal recessive variant present in Saudi Arabia has been named HDL3 and maps to chromosome 4p15.3. HDL4 is an autosomal dominant, triplet-​repeat disorder caused by mutation of the TATA box-​binding protein (TBP) gene located on chromosome 6q27. This is synonymous with spinocerebellar ataxia type 17. As only 93% of those with the classic clinical phenotype of Huntington’s disease have a Huntington’s disease-​associated IT15 gene mutation, these HDL syndromes should be considered as alternative diagnoses in the absence of a family history or failure to show the classic Huntington’s disease molecular lesion.

Parkinson’s disease Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s disease. Incidence rates are 8 to 18/​ 100 000 person-​years with a higher prevalence among men than among women and an average age of onset of 60 years. The cardinal clinical features are tremor at rest, slowed movement (bradykinesia), rigidity, and postural instability. Secondary motor symptoms include hypomimia, dysarthria, dysphagia, sialorrhoea, decreased

6249

6250

section 24  Neurological disorders

arm swing, shuffling gait, micrographia, positive glabellar reflex, blepharospasm, and dystonia. Motor block or freezing is particularly disabling, involving a sudden inability to move the feet. Common non​motor manifestations are autonomic failure, cognitive decline, depression, apathy, hallucinations, and sleep disorders. Patients with onset below age 50 have the tremor-​dominant form of Parkinson’s disease and slower progression of their disease than older patients who have postural instability gait difficulty with more rapid disease progression. Younger patients are also at higher risk for levodopa-​induced dyskinesias than older patients. Symptoms begin typically after 50 to 80% of dopaminergic neurons in the substantia nigra are no longer functional. The remaining intact nigral neurons may contain intracytoplasmic inclusions (Lewy bodies) composed of aggregates of α-​synuclein. Neuroimaging studies with PET and SPECT are useful tools for imaging presynaptic dopaminergic neurons. The diagnosis of Parkinson’s disease is a clinical one and includes response of symptoms to levodopa. Other disorders with parkinsonian-​like symptoms include multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, essential tremor, drug-​ induced parkinsonism, postencephalitic disorders, Lewy body dementia, and Alzheimer’s disease. It is also prominent in certain genetic neurodegenerations:  SCA2 and SCA3, Huntington’s disease, dopa-​ responsive dystonia, familial prion disease, frontotemporal dementia, Wilson’s disease, and X-​linked dystonia-​parkinsonism syndrome (Lubag). Most of these other diseases do not, however, respond to levodopa. Disease susceptibility is increased by serious head trauma, exposure to environmental toxins (MPTP, pesticides), drinking well water, and rural living. Pathogenesis is believed to result from mitochondrial dysfunction (especially complex 1 deficiency), oxidative stress, and misfolding and impaired trafficking of α-​synuclein. Although 75 to 90% of cases are sporadic, single gene abnormalities have been identified in a subset of Parkinson’s disease patients. These include autosomal dominant, autosomal recessive, and X-​ linked forms. The most common known cause of familial and sporadic parkinsonism is mutations in the LRRK2 (leucine-​rich repeat kinase 2) gene. The gene is located on chromosome 12q12 and encodes the protein dardarin. The most frequent and best-​studied mutation is G2019S, which accounts for 1.5% of all index cases with late-​onset, classic parkinsonism. It is especially frequent among North African Arabs and Ashkenazi Jews with Parkinson’s disease. The lifetime penetrance is 32% so many carriers may have no sign of disease on neurological examination. LRRK2 is highly expressed in striatal neurons that receive dopaminergic input. The α-​synuclein (SNCA) gene was the first to be linked to familial parkinsonism. Besides point mutations, duplication of this gene is also observed in cases of Parkinson’s disease. The phenotypic spectrum of SNCA, which is mapped to chromosome 4q21–​q23, is broad and penetrance similar to LRRK2. Both LRRK2 and SNCA are inherited as autosomal dominant genes. Mutations in a third gene, PRKN, linked to chromosome 6q25.2–​q27, are responsible for half the early onset cases of autosomal recessive Parkinson’s disease. The gene product parkin is involved in proteasomal degradation of target proteins and may therefore play a role in Lewy body formation. Other known genes with autosomal recessive inheritance identified with mutations in Parkinson’s disease are PINK1 (chromosome 1 p35–​p36), encoding

PTEN-​induced putative kinase 1, and DJ-​1 (chromosome 1p36), producing protein DJ-​1. Other much rarer neurogenic forms of parkinsonism are also described involving mutations in only a single or very small number of families. Linkage to other loci has been described but the genes responsible have not yet been identified. In addition, several susceptibility genes have been mapped in familial cases of Parkinson’s disease. One of these, the glucocerebrosidase gene, is mutated more often in patients with Parkinson’s disease than would be expected by chance alone. This observation has been verified in both Ashkenazi Jews who are at higher risk for Gaucher’s disease, an autosomal recessive disease caused by glucocerebrosidase deficiency, and non-​Jews. Whether the cause is an elevated level of glucocerebroside at the cellular level or the presence of mutated protein, either of which might promote aggregation of α-​synuclein, has not been demonstrated.

Neuroacanthocytosis Several rare hereditary neurodegenerative diseases are associated with abnormally appearing thorny red blood cells referred to as acanthocytes (from the Greek akanthos, meaning ‘thorn’). These are contracted erythrocytes containing irregularly spaced, thorny surface projections, and are best visualized under a scanning electron microscope. They are also present in four other movement disorders, autosomal recessive chorea–​ acanthosis, X-​linked McLeod’s syndrome, HDL2 and Pantothenate kinase-​associated neurodegeneration (PKAN), and in abetalipoproteinaemia. Acanthocytosis is also a predisposing factor for non​ketotic, hyperglycaemia-​ induced hemichorea–​ hemiballism in patients with diabetes. Bassen–​Kornzweig syndrome Acanthocytosis was first recognized in conjunction with Bassen–​ Kornzweig syndrome. This is an autosomal recessive disorder manifested by fat malabsorption, pigmentary degeneration of the retina, progressive ataxia, and neuropathy. Serum apolipoprotein B-​ containing lipoproteins (apoB), very low-​ density, and low-​ density lipoproteins are absent, causing very low serum cholesterol and triglyceride levels and deficiency of fat-​soluble vitamins A, E, and K. Myelinated fibres in the posterior columns, spinocerebellar tracts, and peripheral nerves are affected. Progression of the disease can be slowed by treatment with high doses of vitamin E supplemented with vitamin A. Chorea–​acanthocytosis Chorea–​acanthocytosis is an autosomal recessive condition, the result of mutations in the VPS13A (‘vascular protein sorting’) gene on chromosome 9q21. This codes for chorein, which is believed to be involved in trafficking of membrane proteins between cellular compartments. It may play a role in polymerization of actin and its dysfunction may cause disruption of the cell membrane, which explains the abnormal shape of the erythrocyte. Presence of a specific deletion in French–​Canadian patients and another in Japanese families suggests a founder effect in these two populations. The diagnosis of chorea–​acanthocytosis may be confirmed by western blot analysis for chorein deficiency in erythrocytes or molecular sequencing of VPS13A. Genetic testing is challenging due the large size of the gene comprising of 73 exons with two splicing variants:  1A containing

24.17  Inherited neurodegenerative diseases

exons 1–​68 and 70–​73 and 1B containing exons 1–​69. Mutations can be found throughout the gene, with no specific hotspot. Chorea–​acanthocytosis manifests clinically between ages 20 and 40 (mean 35 years), with chorea and involuntary movements in the orofacial region. However, in 42% of cases, seizures may precede other clinical manifestations by up to 15 years. The orofacial and buccal dyskinesias with tongue thrusting can cause tongue and lip-​ biting, vocalizations, dysphagia, and dysarthria. Tongue thrusting dystonia may cause significant self-​mutilation, with tongue-​and lip-​ biting. Patients often learn to use an intervention, either as a mechanical block or a sensory trick, such as a stick or a piece of cloth in the mouth, to reduce biting and tooth-​grinding. To bypass the tongue protrusion, the head is extended the head and food pushed to into the back of the throat, which increases the risk of aspiration. Speech and swallow functions progressively deteriorate and are debilitating causing marked weight loss. Repetitive motor tics, trunk spasms, with anterior flexion of the trunk at the hips and leg dystonia give the appearance of a ‘rubbery’ gait. Often balance is remarkably preserved with relatively few falls despite marked gait abnormalities. Eventually the symptoms can proceed to parkinsonism, a ‘burn-​ out’ of the hyperkinetic movements. Neuropsychiatric symptoms may precede or accompany the movement disorder. A personality change associated with obsessive-​compulsive behaviour, depression, agitation, and cognitive decline is common. Autonomic disturbances include paroxysmal dyspnoea, sleep disturbance, and orthostatic hypotension. Other manifestations are ocular motor impairments, distal muscle weakness and atrophy, peripheral neuropathy, and areflexia. About 40% patients develop seizures and those patients with seizures may present with temporal lobe epilepsy and may require multidrug therapy. In most patients, muscle creatine phosphokinase is elevated in the serum. The percentage of acanthocytes in the blood varies from 5% to 50%. The findings on neuroimaging are similar to those in Huntington’s disease. There is caudate atrophy, often more generalized, with an increased T2-​weighted signal abnormality on MRI of the caudate and putamen. PET studies show a reduction in blood flow and glucose metabolism in the caudate, putamen, and frontal cortex, and reduction in [18F]fluorodopa uptake in the posterior putamen. Neuropathology examinations confirm atrophy of the caudate, putamen, and to a lesser extent the pallidum and ventrolateral part of the substantia nigra. On muscle biopsy there is neurogenic muscle atrophy and, in peripheral nerve biopsies, depletion of large myelinated fibres. Ultrastructural studies of peripheral nerve reveal axonal swellings filled with accumulations of neurofilaments. McLeod’s syndrome McLeod’s syndrome is caused by absence of functional XK gene product. The XK gene is located on chromosome Xp21 and expresses the precursor substance for Kell antigen, the third most important blood group system after ABO and rhesus. The protein XK is localized on the surface of the erythrocyte membrane and is linked to the Kell protein via a disulphide bond. Therefore, in McLeod’s syndrome, 23 antigens normally expressed by Kell are extremely reduced or absent. Kell is an endothelin-​processing enzyme and, as endothelins serve as basal ganglia neurotransmitters, the deficiency of Kell could be relevant to the pathogenesis of McLeod’s syndrome. This rare, X-​linked disorder has many of the clinical manifestations of chorea–​acanthocytosis. It develops in men in the fifth

decade and has a slowly progressive course. Women may show symptoms but they are generally milder. Limb chorea and facial hyperkinesia are common but lip and tongue biting are rare and parkinsonism is generally not present. As the disease progresses, many patients will manifest dystonic movements, epileptic seizures, cognitive impairment, and psychological disturbances. Other nervous system signs include muscle weakness and atrophy, and areflexia. Hepatomegaly and splenomegaly may occur with elevated liver enzymes. Distinguishing feature is the presence cardiac disease in two thirds of patients leading to severe cardiomyopathy and death. On neuropathologic evaluation, there is neuronal loss and reactive gliosis in the caudate nucleus, putamen, and globus pallidus, with no specific immunohistochemical markers. Biopsy specimens reveal type 2 fibre atrophy and serum levels of muscle creatine kinase are elevated. Nerve biopsies confirm electrophysiological findings of axonal degeneration. The neuroimaging findings are similar to those in chorea–​ acanthocytosis and Huntington’s disease with atrophy of the caudate nucleus and abnormal signals in the basal ganglia on MRI. SPECT indicates a reduction in striatal dopamine D2-​receptors. Analysis by PET discloses absent metabolism of the basal ganglia and reduced metabolism in the frontal and parietal cortex. Huntington’s disease-​like 2 HDL2 is an autosomal dominant disorder due to a CTG/​CAG trinucleotide repeat expansion in the junctophilin 3 gene (JPH3) on chromosome 16q24.3. The normal repeat size is 6 to 27 CTG/​CAG triplets. Expansions greater than 41 repeats cause disease. Age of onset is inversely proportional to the size of the repeat expansion. HDL2 occurs only in families of African ancestry. The gene product, junctophilin 3, seems to have a role in junctional membrane structures and is involved in calcium regulation. HDL2 pathogenesis is proposed to be related both to the formation of toxic mRNA inclusions in the cytoplasm and to loss of the mutant protein. Symptoms appear in the third or fourth decade with chorea, myoclonus, dystonia or parkinsonism, and progressive cognitive impairments. Parkinsonism and dystonia are typically more prominent than in HD, but similar to HD, the early features may be behavioural or psychiatric. Eye movements may be normal, or mildly hypometric, in contrast to HD. For reasons not known, acanthocytosis is seen in 10% of patients. The findings on neuropathological examination are intranuclear inclusions immunoreactive for ubiquitin and expanded polyglutamine repeats throughout the cortex, strikingly similar to those in HD. There is a gradient of neuronal loss from ventral to dorsal in the caudate nucleus and putamen. Imaging is similar to that observed in HD, although cortical atrophy may also be seen. Treatment of the neuroacanthosis syndrome Treatment is purely symptomatic with judicious use of the usual medications for dystonia and chorea. To control the choreiform movements, dopaminergic function is reduced through the use of atypical antipsychotic agents or tetrabenazine. L-​dopa may reduce general dystonia while focal dystonia interfering with eating may be treated with botulinum toxin injection into the genioglossus muscle. Lesioning of the subthalamic nucleus or globus pallidus pars interna and deep brain stimulation have been used to treat chorea with mixed results. Treatment of psychiatric symptoms, though challenging,

6251

6252

section 24  Neurological disorders

improves quality of life. Obsessive-​compulsive behaviours may respond to citalopram but quetiapine has also been reported to be very effective. Seizures respond well to conventional anti-​convulsant agents such as phenytoin, clonazapam, and valproate, but occasionally may be refractory to multiple drugs. Levetiracetam has been reported to reduce truncal tics. The use of carbamazepine or lamotrigine in these individuals may exacerbate the movement disorder. Generally, patients with chorea–​acanthocytosis are not candidates for epilepsy surgery. A feeding tube may be helpful in reducing aspiration and preveting weight loss. Communication devices, such as computer-​assisted speech, may be helpful in improving quality of life. Patients with McLeod’s syndrome should have periodic Holter monitoring and echocardiography for arrhythmia and cardiomyopathy. They should also have autologous blood banked to avoid potential blood transfusion reactions. Physical, occupational, and speech and language therapy are valuable adjuncts as are nutritional consultation and assistive devices.

Neurodegeneration with brain iron accumulation Neurodegeneration with brain iron accumulation (NBIA) is a heterogeneous group of inherited neurodegenerative conditions that are characterized by iron deposition in the brain, especially the basal ganglia. Pantothenate kinase-​associated neurodegeneration (PKAN) and PLA2G6-​associated neurodegeneration (PLAN) are the two main disorders. Table 24.17.8 lists the disroders and genes associated with NBIA. Pantothenate kinase-​associated neurodegeneration—​NBIA type I Pantothenate kinase-​associated neurodegeneration (PKAN) is an autosomal recessive neurodegenerative disorder of brain iron accumulation and pantothenate kinase deficiency, causing about 50% of cases f NBIA. It was first described by Julius Hallervorden and Spitz in 1922. The honour of naming the disorder after these two neuropathologists was rescinded due to their criminal activities in the Nazi T4 programme of euthanasia. PKAN is due to mutations in the gene on chromosome 20p13–​p12.3 encoding pantothenate kinase 2 (PANK2), which is a key regulatory enzyme in the biosynthesis of coenzyme A from pantothenate (vitamin B5), catalysing phosphorylation of pantothenate, N-​pantothenoyl-​cysteine, and pantetheine. Deficiency of PANK2 leads to accumulation of cysteine-​containing

neurotoxic substrates in regions of higher energy demands. These substrates chelate iron and lead to oxidative stress in the iron-​rich globus pallidus. Two forms are described:  classic and late onset. Classic pantothenate kinase-​associated neurodegeneration (PKAN) manifests in childhood before age 6 years (mean 3.4 years) with gait and postural difficulties. Extrapyramidal findings are predominant with dystonia, rigidity, and choreoathetosis. Dysarthria occurs early and tremor may also be present. Corticospinal tract involvement with spasticity, hyperflexia, and Babinski’s signs, as well as cognitive decline, are also common findings. About two-​thirds of typical patients develop retinopathy and a few have optic atrophy; Adie’s pupil has been noted. Eye movement abnormalities such as vertical saccades, saccadic pursuit, square wave jerks, poor convergence, abnormal vertical optokinetic response, and inability to suppress the vestibule-​ocular reflex are known. Acanthocytosis occurs in 10% of patients. Most become non​ambulatory within 15 years of disease onset. In patients with the atypical form of PKAN, the onset is in the second to third decade, and progression of disease is slower with most patients continuing to walk for 15 or more years. The extrapyramidal signs are less severe but parkinsonism with gait freezing and akinesia may be prdominant and corticospinal tract involvement including spasticity and hyperflexia is common. Patients with the atypical variant are also more likely to have psychiatric symptoms, speech difficulties such as pallilalia and dysarthria, and cognitive decline. A third disorder, HARP acronym for hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration, is allelic to PKAN. In addition to the early onset of extrapyramidal signs (dystonia, choreoathetosis, and rigidity), spasticity, and dementia are known. Pathological changes predominantly affected globus pallidus along with adjacent structures such as medial putamen, internal capsule, and subcortical white matter. The most prominent ultrastructural findings are iron deposition in the globus pallidus within the cytoplasm of neurons, glia, and macrophages, especially in a perivascular distribution, neuronal degeneration, and the presence of widely disseminated, rounded, or oval structures termed spheroids which may be smaller eosinophilic in nature or larger, reflecting degenerating neurons. MRI shows bilateral areas of hyperintensity within the central region surrounded by hypointensity in the medial global pallidus on T2-​weighted images, producing the ‘eye of the tiger’ sign.

Table 24.17.8  Neurodegeneration with brain iron accumulation (NBIA) NBIA

Mutated gene

Pantothenate kinase-​associated neurodegeneration (PKAN)/​NBIA1

b

PLA2G6-​associated neurodegeneration (PLAN)/​NBIA2, PARK14

Chromosomal localization

PANK2

20p13

PLA2G6c

22q12

d

Aceruloplasminemia (Acp)

CP

Neuroferritinopathy

FTLe g

a

a

3q23 19q13 f

FA2H—​Associated Neurdegeneration (FAHN)/​SPG35

FA2H

16q23

Kufor-​Rakeb Disease NBIA3/​(PARK9)

ATP13A2

1p36

Mitochondrial membrane protein-​associated neurodegeneration (MPAN)

C19orf12

19q12

Static encephalopathy of childhood with neurodegeneration in adulthood (SENDA syndrome)

nkh

nk

Pantothenate kinase 2. b Neurodegeneration with brain iron accumulation. c Phospholipase A2. d Ceruloplasmin. e Ferritin light chain. f Fatty acid 2-​hydroxylase. g Spastic paraplegia. h Not known. Reprinted from Neurologia i Neurochirurgia Polska 48(3), Popławska-​Domaszewicz K, Florczak-​Wyspiańska J and Kozubski W, Update on neurodegeneration with brain iron accumulation, pages 206–​13, Copyright © 2014 Polish Neurological Society, with permission from Elsevier.

24.17  Inherited neurodegenerative diseases

The surrounding hypointensity of the globus pallidus represents excess iron deposition and the central hyperintensity is due to necrosis and oedema. PLA2G6-​associated neurodegeneration (PLAN)—​NBIA Type 2 PLA2G6-​associated neurodegeneration (PLAN) is caused by mutations in the PLA2G6gene, which encodes a calcium-​independent phospholipase A2 (iPLA2-​VIa). This enzyme catalyses the hydrolysis of glycerophospholipids, generating a free fatty acid, mainly arachidonic acid, and a lysophospholipid. These lipids play a crucial role in cell membrane homeostasis, signal transduction, cell proliferation, and apoptosis. Defects in iPLA2-​VIa cause cellular membrane abnormalities which lead progressive neurological impairment. Two clinical phenotypes are described: infantile neuroaxonal dystrophy (INAD) and atypical neuroaxonal dystrophy (atypical NAD). INAD presents before the age of 2 years with progressive psychomotor decline as the prominent feature associated with cerebellar ataxia, gait impairment, visual disturbances due to optic atrophy, truncal hypotonia, and pyramidal signs. Fast rhythms on an EEG and general seizures may, also, be present. The clinical spectrum of late-​onset PLAN includes progressive dystonia, parkinsonism, cognitive impairment, psychiatric features, and optic atrophy. Neuropathological findings are neuroaxonal dystrophy, α-​synuclein pathology with Lewy bodies particularly severe in the neocortex, basal forebrain, hippocampal formation, and brainstem nuclei and Lewy neurites. Cerebellar atrophy with iron accumulation in the globus pallidus is highly specific for INAD. Neuroimaging in INAD shows cerebellar atrophy, hypointensity of globus pallidus, dentate nuclei, and substantia nigra on T2 weighted imaging, indicatie of iron depositions. MRI can be even normal in the initial stages. Aceruloplasminemia (aCP) Aceruloplasminemia (aCP) is an autosomal recessive disorder caused by mutations in the ceruloplasmin gene (CP), on chromosome 3q. Ceruloplasmin mobilizes iron from tissues through its ferroxidase activity and it carries 95% of plasma copper. Protein dysfunction results in excessive iron accumulation in the brain, liver, and pancreas. The classical triad of aCP is young-​adult onset diabetes mellitus, retinal degeneration, and prominent extrapyramidal features, ataxia, and cognitive impairment at mean age of onset at around 50. Laboratory findings reveal undetectable ceruloplasmin in the serum, low levels of serum copper and iron and elevated serum ferritin. T2-​weighted brain MRI shows widespread hypointensity throughout the brain in the cerebral cortex, basal ganglia, thalamus, cerebellum, and substantia nigra. Although treatment for aCP remains symptomatic, iron-​chelating agents such as desferrioxamine mesylate and deferasirox are known to be of some benefit. Neuroferritinopathy Neuroferritinopathy or hereditary ferritinopathy is an autosomal dominant disorder caused by mutations in ferritin light chain with age of onset around 40 presenting as chorea and dystonia. Serum ferritin levels are low. Neuropathology shows severe neuronal loss in the basal ganglia, atrophy of the cerebral and cerebellar cortex, abnormal iron accumulation, and the presence of ferritin inclusion bodies in neurons and glia, which may also be seen in hepatocytes,

cells of the renal tubular epithelium, endothelial cells of capillaries, and skin fibroblasts. MRI shows T2 hyperintensity due probably to cavitation involving of the dentate nuclei, globus pallidus, and putamen. Treatment is symptomatic with focal botulin toxin injections. Antioxidants are considered to be of some benefit. FA2H-​associated neurodegeneration (FAHN)/​SPG35 Autosomal recessive FA2H-​Associated Neurodegeneration (FAHN) results from the mutations in the fatty acid hydroxylase gene, FA2H. Mutations in FA2H are associated with progressive familial leukodystrophy and hereditary spastic paraplegia (SPG35). FA2H plays a role in the metabolism of major constituents of normal myelin sheaths such that it produces free 2-​hydroxy fatty acids necessary for the biosynthesis of ceramide, galactosylceramide, and sulphatide. The disease is characterized by childhood-​onset of gait impairment with prominent spastic quadriplegia, pyramidal tract signs, profound ataxia, and dystonia. Moreover, optic atrophy, nystagmus, acquired strabismus, and seizures may be present. T2-​ weighted MR shows bilateral hypointensities of the globus pallidus compatible with excess iron deposits, prominent pontocerebellar atrophy, mild generalized cortical atrophy, thin corpus callosum, and confluent periventricular white matter T2 hyperintensities. Kufor-​Rakeb disease (PARK9) Kufor-​Rakeb disease, originally described in the consanguineous Jordanian family from the village Kufor-​Rakeb, is an autosomal recessive extrapyramidal-​pyramidal syndrome caused by mutations in ATP13A2 gene on chromosome 1p36 encoding a lysosomal 5 P-​type ATPase. The protein localizes to pyramidal neurons and dopaminergic neurons in the substantia nigra. In the recent study Park et  al. demonstrated several different mechanisms by which mutations in ATP13A2 may contribute to the development of Kufor-​Rakeb disease. Pathogenic mechanisms may include impaired lysosomal function, overloading the proteasomal pathway, or impaired ion transportation or ionic imbalance that results in increased oxidative stress. Characteristic clinical features include juvenile-​ onset levodopa-​ responsive parkinsonism, with pyramidal dysfunction and eye movement abnormalities including supranuclear gaze palsy, slowing of vertical and horizontal saccades, and saccadic pursuit. Response to levodopa is transient and levodopa-​dyskinesias tend to develop early. Cognitive deterioration and overt dementia have been described. Brain MR images reveal generalized brain atrophy and hypointensities of the putamen and caudate nuclei suggestive of iron deposition. Dopamine PET imaging indicates bilateral symmetrical striatal presynaptic dysfunction. Mitochondrial membrane protein-​associated neurodegeneration (MPAN) A Polish cohort with progressive spasticity, dystonia, optic atrophy, motor axonal neuropathy, and psychiatric signs was described with mutation in the gene C19orf12. Iron deposition is evident on T2-​ weight MR with bilateral hypointensties of the globus pallidus and substantia nigra. A  single autopsy showed Lewy bodies, tangles, spheroids, and tau pathology. The acronym MPAN (mitochondrial membrane protein-​associated neurodegeneration) has been proposed.

6253

6254

section 24  Neurological disorders

Static encephalopathy of childhood with neurodegeneration in adulthood (SENDA syndrome) Recently a static encephalopathy of childhood with neurodegenera­ tion in adulthood (SENDA syndrome) of unknown genetic cause is described with early onset spastic paraplegia and cognitive impairment which remains static until the late 20s to early 30s but then progresses to dopa-​responsive parkinsonism and dystonia. Other features are sleep disorders, frontal release signs, eye movement abnormalities, and dysautonomia. Brain imaging shows iron accumulation in the globus pallidus, T2-​hypointensities in the substantia nigra and white matter changes.

Hereditary dystonia The definition of dystonia was recently revisited. Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic movements are typically patterned, twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. However, the term dystonia may refer to a type of abnormal movement (described earlier) or a disease entity. As a type of abnormal movement, dystonia can occur in a variety of neurological disorders and such as dystonia is typically accompanied by signs and symptoms characteristic of the associated illness. Classification of dystonia is complex and three terms, ‘surnames’, are assigned: ‘symptom’, ‘movement’, and ‘disorder’. A patient’s complaining of ‘twisting’ movement is a symptom, finding dystonia on exam ascribes it ‘dystonia movement’ and identifying the underlying aetiology will finalize the ‘dystonia disorder’. In the new 2013 classification, the dystonias are subdivided as clinical features (Axis I) and aetiology (Axis II). In terms of Axis II, dystonia is either acquired or hereditary. If there is no clearly defined aetiology, the dystonia can be classified as idiopathic familial or idiopathic sporadic. Younger age at onset, particularly during childhood, is more likely to be of genetic aetiology and likely to spread to involve a greater number of body parts. Hereditary dystonias are clinically and genetically heterogeneous. The known genetic forms include all monogenic inheritance patterns (autosomal recessive, autosomal dominant, and X-​linked). Table 24.17.9 shows the hereditary dystonias grouped according to their similarities. They are divided according to their clinical features (axis I) and aetiology (axis II) in line with the new 2013 classification.

DYT1 mutation has arisen de novo several times in diverse populations. Mutation carriers who do not develop dystonia by their early 20s almost always remain symptom-​free for life, suggesting the presence of a developmental window of susceptibility during which torsin A function is critical for brain function. The disease typically begins in school-​aged children, with a mean age at onset of c.12 years. Two clinical findings are observed with reasonable consistency: (1) the onset of symptoms before the age of 20 years and (2) the onset of symptoms in the limbs, mainly the legs. Subsequently the dystonia spreads to involve additional limbs and/​or the trunk. Up to 50% of affected subjects may ultimately develop generalized involvement. The tendency to generalize distinguishes DYT1 dystonia (and other childhood-​onset genetic aetiologies) from adult-​onset idiopathic isolated dystonia, which typically remains focal or segmental. DYT1 dystonia typically spares facial and laryngeal structures (present in c.11–​14% of cases), and involves the neck in a minority of cases (present in c.25% of cases). This clinical picture of DYT1 dystonia is highly stereotyped, but exceptional cases and families have been reported, including with much earlier or later onset, onset in the larynx, or a phenotype of isolated writer’s cramp. DYT2 dystonia The existence of autosomal recessive DYT2 is much debated. NO gene has been identified and case reports include cases of consanguineous parents with clinical features similar to DYT1. DYT6 dystonia Autosomal dominant DYT6 dystonia has lifetime penetrance of approximately 60% with no sex differences identified. The DYT6 gene (THAP1) consists of three exons and codes for the THAP1 protein, a nuclear proapoptotic factor that potentiates tumour necrosis factor (TNF)-​α-​induced apoptosis and serum withdrawal-​induced apoptosis. Adolescent-​onset generalized dystonia followed by the segmental form is the most common presentation in most large series of DYT6 patients. DYT13 dystonia DYT13 dystonia has autosomal dominant inheritance the age of onset of the symptoms varied between 5 and 40 years. The dystonia in most cases was slowly progressive segmental with craniocervical and upper-​limb involvement with rare generalization. ADULT-​ONSET ISOLATED DYSTONIAS

Childhood-​onset and adolescent-​onset isolated dystonias

DYT7 dystonia

DYT1 dystonia

The gene locus responsible for DYT7 was originally mapped to the short arm of chromosome 18 however, further studies failed to find a definitive gene or even a link with the 18p locus. New loci are being investigated. Clinically, focal dystonia (predominantly cervical dystonia) with minor facial involvement, upper-​ limb involvement, and spasmodic dysphonia are observed without generalization.

The gene locus responsible for DYT1 dystonia was mapped to the long arm of chromosome 9 (9q34) and the gene identified as TOR1A, made of five exons. Mutation-​carrying subjects exhibit abnormalities of brain metabolism as assessed by fluorodeoxyglucose positron emission tomography analysis, regardless of clinical status Autosomal dominant inheritance with low phenotypic penetrance (around 30% to 40%) indicates other important environmental and/​ or genetic factors that affect expression. In fact, an affected patient may have asymptomatic or paucisymptomatic relatives who carry the familial mutation. While best described in Ashkenazi Jews, the

DYT21 dystonia DYT21 locus was was recently mapped to chromosome 2 (2q14.3-​ 21.3); no gene has been identified. This is autosomal dominant form

24.17  Inherited neurodegenerative diseases

Table 24.17.9  Monogenic forms of dystonia (DYT1–​25) Type

Designation

Mode of inheritance

Gene

Gene locus

OMIM #

DYT1

Early onset generalized

Autosomal dominant

TOR1A

9q.34.11

128100

DYT2

Early onset generalized

Autosomal recessive

Unknown

Unknown

224500

DYT3

X-​linked dystonia-​parkinsonism; ‘Lubag’

X-​chromosomal recessive

TAF1

Xq13.1

314250

DYT4

Torsion dystonia (Whispering dysphonia)

Autosomal dominant

TUBB4A

19p13.3

128101

DYT5a

Dopa-​responsive dystonia—​Segawa disease

Autosomal dominant

GCH1

14q22.1–​22.2

128230

DYT5b

Dopa-​responsive dystonia

Autosomal recessive

TH

11p15.5

605407

DYT6

Adolescent-​onset mixed phenotype

Autosomal dominant

THAP1

8p11.21

602629

DYT7

Paroxysmal dystonic choreoathetosis

Autosomal dominant

Unknown

18p

602124

DYT8

Paroxysmal kinesigenic, non​kinesigenic dyskinesia

Autosomal dominant

MR-​1

2q33–​35

118800

DYT9

Paroxysmal choreoathetosis with spasticity

Autosomal dominant

CSE

1p

601042

DYT10

Paroxysmal kinesigenic dystonia

Autosomal dominant

PRRT2

16q11.2–​12.1

128200

DYT11

Myoclonus-​dystonia

Autosomal dominant

SGCE

7q21.3

159900

DYT11

Myoclonus-​dystonia

Autosomal dominant

DRD2

11q23.2

159900

DYT12

Rapid-​onset dystonia-​parkinsonism (syndrome)

Autosomal dominant

ATP1A3

19q12–​13.2

128235

DYT13

Early-​and late-​onset focal or craniocervical dystonia

Autosomal dominant

Unknown

1p36.32-​p36.13

607671

DYT14[a]‌

Dopa-​responsive generalized dystonia

DYT15

Myoclonus-​dystonia

Autosomal dominant

Unknown

18p11

607488

DYT16

Dystonia-​parkinsonism syndrome

Autosomal recessive

PRKRA

2q31.2

612067

DYT17

Adolescent onset

Autosomal recessive

Unknown

20p11.2-​q13.12

612406

DYT18

Paroxysmal exertion-​induced dyskinesia

Autosomal dominant

SLC2A1

1p34.2

612126

DYT19

Paroxysmal kinesigenic dyskinesia 2

Autosomal dominant

Unknown

16q13-​q22.1

611031

DYT20

Paroxysmal non​kinesigenic dyskinesia 2

Autosomal dominant

Unknown

2q31

611147

DYT21

Late-​onset torsion dystonia

Autosomal dominant

Unknown

2q14.3-​q21.3

614588

Unknown

Unknown

Not listed

DYT22 DYT23

Adult-​onset cervical dystonia

Autosomal dominant

CIZ1

9q34

614860

DYT24

Focal dystonia

Autosomal dominant

ANO3

11p14.2

615034

DYT25

Adult-​onset focal dystonia

Autosomal dominant

GNAL

18p11.21

615073

OMIM, Online Mendelian Inheritance in Man. DYT14; the family reported by Grötzsch et al. originally thought to be separate from DYT5, but Wider et al. restudied and determined the GCH1 gene mutation. Adapted from OMIM database. Available at: http://www.ncbi.nlm.nih.gov/omim/. Copyright © 1966–2017 Johns Hopkins University.

of dystonia presenting as blepharospasm, cervical dystonia, and upper-​limb dystonia and occasionally, spasmodic dysphonia. DYT23 dystonia DYT23 is autosomal dominant adult-​ onset cervical dystonia without generalization dystonia was not observed in any of the members. Recently, an exonic splicing enhancer mutation [c.790A > G (p.S264G)] was identified in exon 7 of the CIZ1 gene which codes for the DNA replication factor Cip1-​interacting zinc finger protein 1. DYT24 dystonia DYT24 is caused by mutations in the ANO3 gene at locus 11p14.2, which encodes a Ca2+-​gated chloride channel highly expressed in the striatum. The range of age at onset of a slowly progressive predominantly cervical dystonia varies from early childhood to the forties. Laryngeal dystonia and arm involvement is known, whereas the legs are never affected. Tremor is a consistent feature while myoclonus is observed in some cases.

DYT25 dystonia Mutations in the GNAL gene were the cause of DYT25, which presents as craniocervical dystonia with spasmodic dysphonia with or without generalization. THE DYSTONIAS COMBINED WITH PARKINSONISM DYT5 dystonia Dopa-​responsive dystonia (DYT5 or DRD) has an autosomal dominant inheritance pattern and is caused by mutations in the GCH1 gene (DRD-​1, DRD-​a, or DYT5-​a). Similar clinical presentation can be the result of mutations in the TH gene, inherited in an autosomal recessive manner (DRD-​1, DRD-​b, or DYT5-​b). The CGH1 gene encodes the enzyme GTP cyclohydrolase I  (CGH1 or GTPCHI), and the TH gene encodes the enzyme tyrosine hydroxylase (TH). Penetrance is low (approximately 30%), but may be up to 100% if atypical presentations are considered. Penetrance and prevalence is higher in females The typical DRD presentation is dystonia concomitantly with or following parkinsonism with a worsening of

6255

6256

section 24  Neurological disorders

symptoms during the day in 77% of cases and a dramatic response to levodopa therapy. An initial response in a few days can be observed with small doses of levodopa.

DYT15 dystonia

DYT3 dystonia

DYT4 dystonia

X-​linked recessive dystonia-​parkinsonism syndrome (or lubag) is a heredodegenerative movement disorder found in male Filipino adults from the island of Panay associated with sequence changes within the TAF1/​DYT3 multiple transcript system. The DYT3 gene consists of at least 43 exons that are alternatively spliced. There are alternative transcripts of exons 1–​38 that encode isoforms of the TATA box binding protein-​associated factor I  (TAF-​1) and five exons (d1-​d5) downstream to exon 38 (multiple transcript system). Over 90% patients present initially with focal dystonia of the limbs, cranial dystonia, and oromandibular dystonia is less common. The dystonia is progressive for few years and mostly becomes generalized by two years There is a gradual tendency for the dystonia to revert as the disease evolves between the fifth and seventh years after onset. The dystonia is gradually replaced by bradykinesia until an overall presentation of rigidity is reached. DYT12 dystonia The gene, DYT12/​ATP1A3, responsible rapid-​onset dystonia-​parkinsonism is dominantly inherited with reduced penetrance and encodes the Na+/​K+-​ATPase α3 (ATP1A3), a catalytic subunit of the sodium pump. Alternating hemiplegia of childhood, which has an autosomal dominant inheritance, may also be caused by ATP1A3 mutations. Onset is in adolescence or early adulthood with sudden onset of dystonia and parkinsonism, which can develop within minutes or days of onset and are frequently triggered by a psychological stressor. Although progression halts within weeks, there is no improvement either. Some patients have a ‘second’ episode one to nine years after onset. The dystonia and parkinsonism have a clear rostrocaudal gradient: the bulbar symptoms are more severe than the symptoms in the upper limbs, which in turn are more severe than the symptoms in the lower limbs. DYT16 dystonia Autosomal recessive mutations in the PRKRA gene that encodes the interferon-​inducible double-​stranded RNA-​dependent protein kinase activator cause DYT16 dystonia. Initially predominantly focal limb dystonia causing gait and writing problems is followed by generailzed dystonia occurring between two and eitgteen years of age. Most of the patients have pyramidal signs and dopa unresponsive parkinsonism is described in some patients. Combined dystonias—​myoclonia and chorea DYT11 dystonia Autosomal dominant myoclonus-​dystonia (MD), DYT11, is caused by mutations in glycoprotein ε-​sarcoglycan (SGCE) gene. This is a disorder with variable penetrance that occurs in the first or second decades of life with myoclonus as the most prominent and incapacitating symptom and mild-​to-​moderate dystonia mainly in the upper part of the body. It often improves with alcohol and is therefore sometimes known as alcohol-​responsive dystonia. Psychiatric changes such as depression, anxiety disorders, obsessive-​compulsive disorder, personality disorders, drug addiction, and attention deficit hyperactivity disorder have been reported in families with MD.

DYT15 has a phenotype very close to DYT11, including response to alcohol, however, the causative gene is not yet identified. DYT4 dystonia, caused by mutation in gene TUBB4 (tubulin β-​4), is autosomal dominant inheritance with complete penetrance. Mutations in TUBB4A causes to cause leukoencephalopathy hypomyelination with atrophy of basal ganglia and cerebellum (H-​ABC) (refer section on leukodystrophy). There is significant phenotypic overlap. H-​ABC exhibits an earlier onset and more severe phenotype than DYT4. Therefore, DYT4 may be a ‘form fruste’ of H-​ABC. Onset is between 13 and 37  years of age with significant variation in expression ranging from whispering dysphonia to complex phenotypes with choreic movements and psychiatric manifestations. There is characteristic appearance of thin face, hollow cheeks, bradykinetic uncoordinated tongue, and open mouth at rest. Dysphonia usually evolves to focal dystonias, generalized dystonia, or generalized dystonia combined with other movement disorders, such as ataxia and, primarily, chorea. Combined paroxysmal dystonias Paroxysmal dyskinesias are a heterogeneous characterized by regular intermittent attacks of hyperkinetic movements without loss of consciousness, classified into four main groups: paroxysmal kinesigenic dyskinesias (PKDs), non​paroxysmal kinesigenic dyskinesias, paroxysmal exercise-​induced dyskinesia, and paroxysmal hypnogenic dyskinesia. The PNKDs include DYT8 (PNKD-​ 1) dystonia and DYT20 (PNKD-​2) dystonia. PNKD-​1 is caused by the MR1 gene encoding the MR-​1 protein and presents as attacks of resting dystonia, chorea, athetosis, and ballism. Episodes can last from seconds to hours and can occur from a few times a year to several times a day. Symptoms can be brought on by alcohol or caffeine and to a lesser extent by nicotine, excitement, fatigue, anger, and emotional stress. Movements, physical effort, or sleep do not trigger these dyskinesias. Age at onset varies widely, and the disease can manifest for the first time during childhood, adolescence, or adulthood. The PKDs include DYT10 (PKD-​1) dystonia and DYT19 (PKD-​2) dystonia. DYT10 may be autosomal dominant or sporadic, more common in men, presenting as attacks brought on by sudden, unexpected movements starting between 6 and 16 years. Attacks consist of different hyperkinesias such as dystonia, chorea, athetosis, or ballism or isolated dystonia.

Section VIII: Hereditary ataxias The last two decades have seen a bewildering profusion in newly described genetic ataxias. In this section, we will review the ataxias based on mode of inheritance, prevalence, and available treatment. They are grouped as autosomal dominant ataxia, X-​linked and autososmal recessive ataxia, which are rare but treatable ataxias and episodic ataxias.

Dominantly inherited ataxias The autosomal dominant spinocerebellar ataxias (also known as the SCAs) are caused by degeneration and dysfunction of the cerebellum

24.17  Inherited neurodegenerative diseases

and its associated pathways. Table 24.17.10 summarizes the autosomal dominant ataxia syndromes. They are diverse and clinically heterogeneous group of disorders and therefore, diagnostic evaluation can be challenging not only due to phenotypic overlap among

numerous genetic subtypes but also the acquired and idiopathic etiologies. Molecular etiologies include DNA repeat expansions, both polyglutamine and non​coding repeats, ion-​channel dysfunction, and disorders of signal transduction. Combination of two molecular

Table 24.17.10  Summary of genes, mutations, and clinical features of autosomal dominant SCAs Name

Locus/​Gene

Protein/​Mutationa

Normal Functionb

Yearc

Pathologyd

Symptoms/​Signse

SCA1

6p23/​ATXN 1

Ataxin 1 CAG repeats 41–​81 (normal 25–​36)

Gene transcription and RNA splicing

1994

Inferior olivary nuclei Pontine nuclei Purkinje cells

Pyramidal signs Amyotrophy Extrapyramidal signs Ophthalmoparesis

SCA2

12q24/​ ATXN2

Ataxin 2 CAG repeats 35–​59 (normal 15–​24)

RNA processing

1996

Basis pontis Inferior olivary nuclei Purkinje cells

Slow saccades Extrapyramidal signs Dementia (rarely) Ophthalmoplegia Peripheral neuropathy Pyramidal signs

SCA3 (MJD)

14q24.3-​q31/​ ATXN3

Ataxin-​3 CAG repeats 62–​82 (normal 13–​36)

Deubiquitinating enzyme involved in protein quality control

1994

Anterior horn cells Clarke columns Dentate nuclei Dorsal root ganglia Pontine nuclei Purkinje cells Spinocerebellar tracts Substantia nigra Subthalamic nuclei

Pyramidal signs Amyotrophy Exophthalmos Extrapyramidal signs Ophthalmoparesis

SCA4

16q22.1/​ Unknown but distinct from SCA31

Unknown

Unknown

—​

Unknown

Sensory axonal neuropathy Pyramidal signs

SCA5

11q13/​ SPTBN2

β III Spectrin

Scaffolding protein important for glutamate signalling

2006

Unknown

Pure cerebellar ataxia (late onset) Pyramidal signs (early onset)

SCA6

19p13.2/​ CACNA1A

Cav2.1 CAG repeats 21–​30 (normal 6–​17)

Calcium channel important for regulating Purkinje neuron excitability

1997

Purkinje cells

Pure cerebellar ataxia Late onset, usually >50 y

SCA7

3p21.1-​p12/​ ATXN7

Ataxin 7 CAG repeats 38–​130 (normal 7–​17)

Gene transcription

1997

Cone-​rod dystrophy Dentate nuclei Inferior olivary nuclei Pontine neurons Purkinje cells Retinal ganglion cells

Pigmentary macular degeneration Ophthalmoplegia Pyramidal signs

SCA8

13q21.33/​ ATXN8OS ATXN8

Toxic RNA Pure polyglutamine protein CAG/​CTG repeats 80–​250 (normal 15–​50)

Unknown

1999

Purkinje cells Substantia nigra

Pyramidal signs Diminished vibratory sense Spastic and ataxic dysarthria

SCA9

Unknown

Unknown

Unknown

—​

Unknown

Central demyelination (1 patient) Extrapyramidal signs Ophthalmoplegia Posterior column loss Pyramidal tract signs

SCA10

22q13.31/​ ATXN10

Ataxin 10 Intronic ATTCT repeats 800–​4500 (normal 10–​32)

Involved in neuron survival, neuron differentiation, and neuritogenesis

2000

Unknown

Seizures Cognitive/​ neuropsychiatric impairment Polyneuropathy Pyramidal signs

SCA11

15q15.2/​ TTBK2

Tau tubulin kinase-​2

Serine-​threonine kinase; putatively phosphorylates tau and tubulin proteins Regulates the genesis of the primary cilium

2007

Unknown

Pure cerebellar ataxia

SCA12

5q32/​ PPP2R2B

Protein phosphatase PP2A CAG repeats in 5′-​UTR 51–​78 (normal 7–​32)

Serine-​threonine phosphatase implicated in the negative control of cell growth and division

1999

Unknown

Upper extremity tremor Mild or absent gait ataxia Hyperreflexia (continued)

6257

6258

section 24  Neurological disorders

Table 24.17.10 Continued Name

Locus/​Gene

Protein/​Mutationa

Normal Functionb

Yearc

Pathologyd

Symptoms/​Signse

SCA13

19q13.3-​ 13.4/​KCNC3

Kv3.3

Potassium channel involved in regulating Purkinje neuron excitability

2006

Unknown

Intellectual disability (in French pedigree) Pure cerebellar ataxia (in Filipino pedigree)

SCA14

19q13.4/​ PRKCG

Protein kinase C γ

Neuronal serine/​threonine protein kinase activated by calcium and diacylglycerol

2003

Unknown

Pure cerebellar ataxia Rarely chorea and cognitive deficits

SCA15/​ SCA16

3p26.1/​ ITPR1

Inositol 1,4,5-​ triphosphate receptor

Intracellular calcium channel involved in regulating neuronal excitability

2007

Unknown

Pure cerebellar ataxia Rare tremor or cognitive impairment

SCA17/​ HDL4

6q27/​ TBP

TATA box-​binding protein CAG repeats 46–​63 (normal 25–​42)

Gene transcription

2001

Neuronal inclusion bodies in brain Purkinje cells Reduction in brain weight

Chorea Dementia Extrapyramidal features Hyperreflexia Psychiatric symptoms

SCA18/​ SMNA

7q22-​q32

Unknown

Unknown

–​—​

Unknown

Posterior column loss Amyotrophy Early onset, usually 50 y Decreased vibratory sense

SCA25

2p21-​p15

Unknown

Unknown

—​

Unknown

Areflexia Peripheral sensory neuropathy

SCA26

19p13.3

Unknown

Unknown

—​

Unknown

Pure cerebellar ataxia

SCA27

13q34/​ FGF14

Fibroblast growth factor 14

Interacts with voltage-​ gated sodium channels and regulates Purkinje neuron excitability

2003

Unknown

Orofacial dyskinesias Cognitive impairment Tremor

SCA28

18p11.22-​ q11.2/​ AFG3L2

ATPase family gene 3–​like 2

Mitochondrial protein synthesis

2010

Unknown

Early onset, usually 50 y Pure cerebellar ataxia

SCA31

16q22/​ BEAN1and TK2

Brain expressed, associated with NEDD4 Thymidine kinase-​2 TGGAA repeat in intron shared by both genes

Unknown

2009

Purkinje cells

Pure cerebellar ataxia Late onset, usually >50 y Sensorineural hearing loss

SCA35

20p13/​ TGM6

Transglutaminase 6

Posttranslational modifications of glutamine residues

2010

Unknown

Pyramidal signs Pseudobulbar palsy (continued)

24.17  Inherited neurodegenerative diseases

Table 24.17.10 Continued Name

Locus/​Gene

Protein/​Mutationa

Normal Functionb

Yearc

Pathologyd

Symptoms/​Signse

SCA36

20p13/​ NOP56

Nucleolar protein 56 Intronic GGCCTG repeat

Pre-​mRNA processing

2011

Dentate nuclei Hypoglossal nucleus Motor neurons Purkinje cells

Lower motor neuron involvement Tongue atrophy

DRPLA

12p13.31/​ ATN1

Atrophin 1 CAG repeats 49–​75 (normal 7–​23)

Transcriptional coregulator

1994

Cerebellar white matter Dentate nuclei Globus pallidus Red nucleus Subthalamic nucleus

Myoclonic epilepsy Choreoathetosis Dementia

DRPLA, dentatorubral-​pallidoluysian atrophy; HDL4 Huntington disease-​like 4; MJD, Machado-​Joseph disease; SMNA, Sensorimotor Neuropathy with Ataxia; UTR, untranslated region. a Mutation refers to point mutations in the respective genes, unless otherwise specified. b The normal function of all proteins has not been fully established. c Year refers to initial year of publication of the identified gene. d Pathology refers to loss of neurons in the indicated regions. e Not all patients have the symptoms/​signs that are mentioned. Bold typeface refers to symptoms either characteristic or unique to the particular SCA and thus helpful to diagnosis. Reprinted from Neurologic Clinics 31(4), Shakkottai VG and Fogel BL, Clinical Neurogenetics Autosomal Dominant Spinocerebellar Ataxia, pages 987–​1007, Copyright © 2013, with permission from Elsevier.

mechanisms is suspected in certain disorders such as SCA8, where combined effects of non​coding CTG repeat expansion generation of a pure polyglutamine protein from the corresponding CAG repeat on the opposite strand are both implicated. SCA8 also exhibits the unusual property of a pathogenic repeat size ‘window’ of approximately 80–​250 repeats such that smaller and larger expansions are not associated with disease. In some ataxias such as SCA6 and SCA12, the CAG repeats occur in genes known to express proteins that are ion channels and signal transduction molecules, respectively. Of particular interest is SCA 6 which allelic with episodic ataxia type 2 (EA2, see next) and familial hemiplegic migraine type 1, which are due to nonsense and missense mutations rather than (CAG)n expansions. Polyglutamine ataxias Expansion of a glutamine-​encoding CAG repeat accounts for SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, SCA17, and DRPLA. Although, the exact mechanism for how a polyglutamine protein causes ataxia is not understood. Since none of the proteins involved in the various subtypes have any sequence or structural homology with the others apart from the polyglutamine tracts, it is implicated that their pathomechanism involves gain of (toxic) function. Several pathogenic mechansims are suspected including protein misfolding resulting in altered function, formation of toxic oligomeric complexes, transcriptional dysregulation, mitochondrial dysfunction, impaired axonal transport, aberrant neuronal signalling including excitotoxicity, cellular protein homeostasis impairment, and RNA toxicity. The polyglutamine ataxias show the phenomenon of anticipation, where disease onset occurs earlier in successive generations, especially when paternally inherited. The triplet-​repeat mutations are unstable or dynamic mutations. They undergo further expansion in successive generations. This may be related to continuous mitoses during spermatogenesis throughout adult life, whereas ova are fixed in number and do not divide. There is an inverse relation between CAG repeat expansion size and age of onset. These two facts together underlie anticipation, whereby age of onset is lower in successive generations. Ion-​channel mutations/​dysfunction Either direct ion-​channel mutations or secondary ion-​channel dysfunction has been implicated in the pathogenesis of SCA5 (mutations

in the structural protein β-​3 spectrin), SCA6 (polyglutamine expansion in the C-​terminus of a neuronal calcium channel, Cav2.1), SCA13 (mutations in KCNC3, the gene encoding the Kv3.3 potassium channel), SCA15/​16 (mutations in the inositol 1,4,5-​triphosphate receptor, an intracellular ligand-​gated calcium channel), SCA19/​22 (loss-​of-​function mutations in Kv4.3), and SCA2 (causative FGF14 mutations) likely result in perturbed expression of voltage-​gated sodium channels. Signal transduction Mutations in signal transduction molecules are the direct cause of disease in SCA11 (loss of function mutations in TTBK2, a casein kinase 1), SCA12 (CAG repeat expansion in the 5’-​untranslated region of protein phosphatase, PP2A), SCA14 (mutations in a serine-​threonine family kinase, a protein kinase C isoform) and SCA23 (Mutations in PDYN, the precursor protein for the opioid neuropeptides). Non​coding repeats/​RNA toxicity Non​coding repeats are implicated in pathogenesis of SCA8, SCA10, SCA31, and SCA36. Presumed pathogenic processes are transcriptional alterations and the generation of antisense transcripts, sequestration of mRNA-​associated protein complexes that lead to aberrant mRNA splicing and processing and activation of abnormal signalling cascades and failure of protein quality control pathways. All patients with dominant SCA exhibit cerebellar ataxia in the limbs, trunk, and/​or gait. Additional symptoms are variable and specific to the subtype, although significant overlap and heterogeneity is known. Please refer to the Table 24.17.10 for details of each sub type. In general additional neurological features are a combination of extrapyramidal features, long tract signs, peripheral neuropathy, and, in some cases, cognitive impairment and seizures. Clinical examination shows signs of cerebellar dysfunction manifesting as impairment in coordinated muscle activity in the form of dysarthria, dysphagia, limb and optic dysmetria, lack of smooth visual pursuit, direction-​changing nystagmus, gait disturbance, and/​or frequent falls. Early gait impairment is associated with a sense of imbalance, which is exacerbated when walking on uneven surfaces. Stabilization is achieved by widening the stance and patients will require ambulatory support with cane or walker.

6259

6260

section 24  Neurological disorders

Dentatorubral-​pallidoluysian atrophy Dentatorubral-​pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegeneration caused by a glutamine-​encoding repeat expansion in the atrophin gene on chromosome 12p13.3. Ataxia, dystonia, and dementia are characteristic. Juvenile patients develop progressive myoclonic epilepsy whereas, in those patients with symptoms beginning after age 20, choreoathetosis and psychiatric difficulties are more prominent. The MRI and neuropathological examinations show cerebellar and brainstem atrophy, especially of the pontine tegmentum. Nerve cell loss and gliosis occur in the dentate nucleus, red nucleus, pallidum, and corpus luysi. Degenerative changes are also found in the striatum, cerebellar cortex, and corticospinal tract. The caudate nuclei are normal and the ventricles may be enlarged. Most patients inherit the disease from their father but, if from their mother, symptoms begin earlier and are more severe even though the degree of expansion is smaller than in the case of paternal transmission. An allelic form of this disease, known as Haw River syndrome, has been described in an African-​American family. X-​linked ataxic disorders Fragile X tremor-​ataxia syndrome (FXTAS) is the commonest X-​ linked cerebellar syndrome and s discussed here. Fragile X syndrome is a severe neurodevelopmental disorder in males caused by a CTG triplet expansion (>200 repeats) within the 5′ untranslated region of the FMR1 gene, which codes for the FMRP protein. The repeat expansion leads to gene silencing by methylation resulting in FMRP deficiency. About half of the maternal grandfathers of affected boys, carrying ‘premutation’ repeat numbers from 55 to 200 may manifest a disorder characterized by tremor and ataxia with onset above the age of 50  years. This led to description of FXTAS in permutation carriers of FMRP gene. FXTAS occurs in approximately 40–​45% of male and 8–​16% of female permutation carriers over the age of 50. The prevalence of the FMR1 premutation has been described as 1 in 113 to 259 females and 1 in 260 to 813 males in the general population. Thus, about 1 in 3000 men and about 1 in 6000 women in the general population may be suffering from FXTAS, making it one on the common neurodegenerative genetic disease. The molecular mechanism of FXTAS is different from that of Fragile X syndrome with full mutations: FXTAS permutation syndrome shows normal or almost normal FMRP levels, but increased FMR1 mRNA levels and develops RNA inclusions. As the repeat number increases, particularly more than 110 CGG repeats, the level of FMR1 mRNA increases and the levels of FMRP start to decline. Pathological mechanisms under investigation include ‘RNA toxicity’, toxic sequestration of crucial transcriptional proteins, a non​canonical translation of the CGG repeats which may result in the expression of toxic polyglycine products and antisense FMR1 transcription which may lead to toxicity by antisense transcripts product. Pathologic hallmarks are eosinophilic and ubiquitin-​ positive intranuclear inclusions in neurons and astrocytes throughout the brain, peripheral nervous system, and other organs such as the adrenals, thyroid, heart, Leydig cells, and pancreas. Also associated is mild brain atrophy and involvement of the cerebellum with loss of Purkinje neuronal cells, spongiosis of the deep cerebellar white matter, Bergman gliosis, and swollen axons.

Clinical presentation is often after the age of 50, with mean age of onset of 62 years. Men are more frequently diagnosed with a definite diagnosis of FXTAS compared to women, who may have a milder presentation due to presence of an additional normal X-​chromosome. 75% of males above the age of 80 may be affected. Presenting features are tremor and ataxia, followed a decade later by cognitive, typically executive impairment including working memory, inhibitory control, and visuospatial processing. Parkinsonism is common, and may occasionally dominate the clinical picture. Neuropathy and/​or autonomic dysfunction may also be seen as minor features. Psychiatric features such as anxiety, depression, and apathy are also described, which can worsen before the appearance of tremor and ataxia. Some other symptoms seen in females but not males with FXTAS include thyroid disorders, fibromyalgia, migraine, chronic muscle pain, and immune medicated disorders. Table 24.17.11 outlines the diagnostic criteria for FXTAS. Cardinal radiologic clue to the diagnosis, although npt specific for FXTAS, is the middle cerebellar peduncle sign of T2 hyperintensity on MRI, seen in approximately 60% of patients. Additional features are global brain atrophy, ventricular dilatation, nonspecific white matter disease and T2 hyperintensities in corpus callosum. There are as yet no effective targeted therapies for FXTAS; however symptomatic therapy is warranted. In a randomized, double-​ blind, placebo-​controlled trail of 94 individuals with FXTAS using Memantine, showed no improvement with respect to intention tremor severity nor BDS scores. However, the treatment may have benefits on verbal memory. Selective serotonin and selective norepinephrine reuptake inhibitors are effective along with psychotherapy for anxiety and depression. Atypical antipsychotics are used for psychosis and agitation. As with essential tremor, propranolol and primidone may offer benefit. Deep brain stimulation has Table 24.17.11  Diagnostic criteria for FXTAS Molecular

FMR1 CGG Repeat Size 55–​200

Clinical Major signs

Intention tremor Gait ataxia

Minor signs

Parkinsonism Moderate-​to-​severe short-​term memory deficits Executive function deficits

Radiologic Major signs

MRI white matter lesions in the middle cerebellar peduncle (MCP sign)

Minor signs

MRI white matter lesions in cerebral white matter Moderate-​to-​severe generalized atrophy

Diagnostic Categories Definite

Presence of one major radiologic sign plus 1 major clinical symptom

Probable

Presence of either one major radiologic sign plus 1 minor clinical symptom or has two major clinical symptoms

Possible

Presence of one minor radiologic sign plus 1 major clinical symptom

Adapted from Jacquemont S, Hagerman RJ, Leehey M, et al. Fragile X premutation tremor/​ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet 2003; 72(4): 869.

24.17  Inherited neurodegenerative diseases

shown a general poor outcome for FXTAS patients for tremor and/​ or ataxia.

atrophy of the corticospinal tracts. Within the cerebellum there is atrophy of the dentate nucleus, which results in the loss of cerebellar outputs. There is variable loss of Purkinje’s cells in the cerebellum. Recessive ataxias Heart disorder starts with early hypertrophy of cardiac myocytes, Autosomal recessive cerebellar ataxias (ARCA) are a complex group followed by loss of myocytes and progressive replacement by conof over 55 recessive disorders in which ataxia is a major or the nective tissue. Eventually heart failure sets in with ventricular dilatamajor feature, and genes are known for approximately 45 of these. tion. Iron deposits are seen in surviving myocardial cells. Clinical phenotypes vary from predominantly cerebellar syndromes The cardinal presenting features are progressive gait instability to sensorimotor neuropathy, ophthalmological disturbances, invol- and ataxia most often presenting in adolescence, ranging from beuntary movements, seizures, cognitive dysfunction, skeletal anom- tween 7 and 25 years, resulting in loss of ambulation within 10 to alies, and cutaneous disorders. Here the ‘big five’ recessive ataxias 15 years after onset of symptoms, in most patients by late 20s. The are reviewed: FRDA (Friedreich ataxia), AT (ataxia-​telangiectasia), initial symptom is almost invariably ataxia of gait, although foot or ARSACS (autosomal recessive spastic ataxia of Charlevoix-​ spinal deformity may antedate this. At first it is noted that the child Saguenay), AOA1 and AOA2 (ataxia-​ocular motor apraxia types 1 walks awkwardly with a tendency to stumble and fall readily; in cases and 2), POLG-​related disorders are reviewed under mitochondrial of early onset, walking may never have been normal. As the disease disorders. progresses, the gait slowly becomes more irregular and clumsy. The patient walks on a broad base and tends to lurch from side to side. Friedreich ataxia Involvement of the upper limbs develops later, at first giving rise Friedreich ataxia is the most common autosomal recessive ataxia to clumsiness of fine movements, subsequently for all movements. in white populations, accounting for about one-​third of recessive A coarse intention tremor becomes obvious. The trunk is also afataxias with a frequency of approximately 1 in 40 000. Carrier fre- fected, leading to oscillation of the body when standing or sitting quency of the expanded allele is about 1 in 100 in white people due unsupported. A regular tremor of the head (titubation) occasionally to a founder effect. It is caused by homozygous triplet-​repeat ex- appears. Dysarthria of cerebellar type develops and may become sepansions in the first intron of the frataxin gene, FXN, located on vere enough to make speech almost unintelligible. chromosome 9q13 in humans in 95% to 98% of affected individuals. Nystagmus is present in about a quarter of the cases. Eye moveThe remaining 2% to 5% are compound heterozygotes with one ex- ments may show macrosaccadic oscillations superimposed on panded allele and a second allele containing a point mutation or de- smooth pursuit and saccadic eye movements. The pupils are unletion. FXN contains five exons that encode a 210 amino acid highly affected. Optic atrophy is present in about a third of cases and 10% conserved mitochondrial matrix protein, frataxin. develop sensorineural deafness with particular difficulty in speech In humans, normal alleles contain 8 to approximately 38 repeats of discrimination. the GAA TTC tract. The critical pathologic triplet-​repeat threshold Initially weakness is not obtrusive, but this develops as the disis approximately 90 repeats; however, most patients carry between ease advances, starting in the legs and later involving the upper between 600 and 900 repeats. The repeats are unstable; when trans- limbs. It results from degeneration in the corticospinal pathways mitted from the mother they can expand or contract with equal fre- and tends to vary in severity between cases. The plantar responses quency, whereas inheritance from the father more often results in become extensor, but tone is not usually increased because of the contractions. The expanded triplet repeat is unstable within somatic accompanying disturbance of the afferent fibres from muscle spincells, including postmitotic cells. This may account for the selective dles. There may be mild wasting of the anterior tibial and small vulnerability of specific cell types, such as the dorsal root ganglia hand muscles related to loss of anterior horn cells. Bladder and sensory neurons and motor cortex neurons. bowel function is usually unaffected. The repeat expansion causes partial gene silencing through Loss of the larger dorsal root ganglion cells leads to impairment blockage of transcription elongation and/​or pre-​mRNA stability and of the sense of joint position, of vibration, and to some extent of processing resulting in loss of frataxin. Severity of loss of function touch–​pressure sensibility, initially distally in the limbs. The impairis inversely correlated with the number of expanded triplet repeats. ment of proprioception superimposes a sensory element on the The smaller allele determines the age of onset but not severity of dis- cerebellar ataxia. The tendon reflexes are depressed or absent. ease. In contrast, missense or null alleles are result in non​functional Associated skeletal deformities are common, in particular foot or only partially functional frataxin. deformities (pes cavus and pes equinovarus) and kyphoscoliosis. Frataxin has an important role in the biogenesis of iron-​sulfur Contractures of the knees may develop in the later stages. Essential clusters. In Friedreich ataxia, because of the deficiency of iron-​sulfur criteria for classical FRDA are age of onset before 25  years, proclusters, mitochondrial respiratory chain complexes I, II, and III gressive ataxia of gait and limbs, absent lower-​limb reflexes, posicannot function adequately. Free radical formation damages a host tive Babinski signs, and diminished or absent upper limb sensory of intracellular proteins, lipids, and DNA, as well as lead to stimu- nerve action potentials with normal motor conduction velocities lation of stress responses, resulting in cellular injury and ultimately (>40 m/​s) within the first 5 years of symptom onset; and dysarthria cell death through apoptosis. The sensory neurons of the dorsal after at least 5  years of symptoms. Systemic involvement includes root ganglia conveying proprioceptive information degenerate early abnormal EKG, cardiomyopathy, diabetes mellitus, or impaired gluin the disease process, with consequent loss of the larger myelin- cose tolerance in about one-​third of patients. ECG demonstrates ated fibres in the peripheral nerves and degeneration in the dorsal widespread T-​wave inversion and ventricular hypertrophy in almost columns. Degeneration is also evident in Clarke’s column and the 70% of patients. Commonest cause of death in FRDA is myocardial spinocerebellar tracts. Degeneration of motor neurons results in failure in their 30s, mean age of death is 37 years.

6261

6262

section 24  Neurological disorders

Variant syndromes include Friedreich ataxia with retained reflexes where spasticity and even hyperreflexia may be seen. Late-​ onset Friedreich ataxia and very late-​onset Friedreich ataxia are described in patients with onset of first symptoms at more than 25 and more than 40 years, respectively. Heart disease is often mild or absent. Acadian FA found in the Cajun (French) population in North America is milder and rarely accompanied by cardiomyopathy. MRI brain shows relatively spared cerebellar volume, especially early in the course of the disease, with an atrophic spinal cervical cord and superior cerebellar peduncle. and ECG-​repolarization abnormalities (T-​wave inversion) in approximately 70%. Electrocardiography is more sensitive to cardiac involvement than echocardiography, although the latter can demonstrate the evolution from concentric hypertrophy to dilatation. Friedreich ataxia should be suspected in any individual with apparent sporadic or autosomal recessive progressive ataxia. As late-​ onset forms are known, age should not necessarily preclude the diagnosis. Testing can be initiated with triplet-​repeat expansions in the first intron of the FXN gene, followed by sequencing the gene for missense mutations, if this is non​diagnostic because of the presence of only one expanded allele. The Friedreich’s Ataxia Rating Scale is a useful tool to follow progression. Supportive treatment is the most important aspect of care for an individual with Friedreich ataxia. Moderate exercise and physical therapy is advisable for all patients with Friedreich’s ataxia. Attention needs to be paid to swallowing disorder, scoliosis, sleep apnoea, and urinary urgency or incontinence. Annual monitoring with echocardiogram to evaluate for left ventricular and septal hypertrophy for the development of cardiomyopathy is recommended. Electrocardiogram is performed annually to evaluate for repolarization abnormalities that could cause to arrhythmias. Screening for diabetes mellitus annually and appropriate management of diabetes in affected individuals is necessary. Vision and hearing should be monitored on a regular basis. Rationally based treatment with aim to counter the effects of oxidative stress using free radical scavengers such as idebenone appeared promising in phase 2 trials, but unfortunately failed in phase 3. Histone hypoacetylation is shown to be associated with heterochromatin formation and transcriptional silencing in expanded FXN alleles. Histone deactylase (HDAC) inhibitors are being actively investigated as a mechanismto induce an active chromatin conformation, and thereby increase frataxin expression. Ataxia-​telangiectasia Ataxia-​telangiectasia (AT) is reviewed previously in neurocutaneous syndromes. Autosomal recessive spastic ataxia of charlevoix-​saguenay Autosomal recessive spastic ataxia of charlevoix-​saguenay (ARSACS) was first described in the 1970s among inhabitants of the Charlevoix-​ Saguenay region of northeastern Quebec in Canada with a carrier prevalence estimated to 1/​22. It has since been described all over the world including in Europe, North Africa, and Japan. The ARSACS gene is located on chromosome 13q12.12 and encodes the large protein sacsin, which may be involved in chaperone activity through its interaction with Hsp70 chaperone machinery. The gene was initially described as a large gene with 11 487 bp encoded by a single gigantic exon. Subsequently, 11 different exons and several transcripts of the

gene have been identified. Most Quebec patients have a single mutation due to founder effect, a single nucleotide deletion (6594delT). Few compound heterozygous patients, have na associated nonsense mutation (5254C > T). More than 70 different mutations, in the form of frameshift or nonsense point mutations, have been identified worldwide with no evidence of founder effect. The gene is highly expressed in the brain especially the Purkinje cells. Patients with ARSACS exhibit early onset signs of spasticity in the lower limbs between the ages of 12 and 24 months; spasticity observed in infancy is considered specific for ARSACS. Slower motor development may be seen observed in preschoolers but there is no intellectual impairment. Dysarthria is reported in all ARSACS patients; slurred in childhood and explosive in adulthood. Non​progressive signs on examination are nystagmus, bilateral abnormal plantar responses, saccadic alteration of smooth ocular pursuit and fundoscopic finding of prominent myelinated fibres radiating from the optic disc and embedding the retinal vessels. Progressive pyramidal involvement in teens leads to progressive increase in muscle tone and in deep tendon reflexes. Discrete to marked distal amyotrophy which manifests as wasting of intrinsic hand and foot muscles is seen later with subsequent loss of reflexes by age 25. Irreducible bony pes cavus and hammer toes are common. By late twenties, electromyography generally shows signs of severe denervation in the distal muscles indicative of axonal degeneration. Nerve conduction studies show signs of severe to moderate axonal neuropathy. Sensory action potentials are absent in all four limbs in the Quebec patients. Sural nerve biopsy reveals severe axonal degeneration with loss of large myelinated fibres, associated with regenerating axonal clusters and rare demyelinating aspects. Brain MRI shows cerebellar atrophy more marked in the upper cerebellar vermis and associated with spinal atrophy. Biochemical findings originally described include impaired pyruvate oxidation, hyperbilirubinaemia, and low serum β-​lipoproteins and HDL lipoproteins; however, these are not reliable for diagnosis. Diagnosis is confirmed by genetic testing, which may still be time consuming and expensive given the size of the gene. Ataxia-​oculomotor apraxia type 1 Ataxia-​oculomotor apraxia type 1 (AOA1) is the commonest form of recessive ataxia in Japan (where FRDA is virtually non​existent). Ataxia-​oculomotor apraxia type 1 is caused by mutations in the APTX gene-​encoding aprataxin. First symptoms of ataxia are noticed between ages two and ten years following normal initial motor development. Dysarthria and upper-​ limb dysmetria with mild intention tremor ensue. Oculomotor apraxia is usually noticed a few years after the onset of ataxia, which then progresses to external ophthalmoplegia. Individuals with oculomotor apraxia care unable to fixate on objects. When asked to look to one side, they turn their heads and their eyes follow to the same side in several slow saccades and head thrusts. Blinking is exaggerated. Eye movements are not possible if the head is immobilized. Oculocephalic reflexes are spared until advanced stages of the disease. Later in the course, about 7–​10 years after onset, there is generalized areflexia due aperipheral neuropathy and quadriplegia with loss of ambulation. Likely secondary to early onset of disease, hands and feet are short and atrophic. Chorea and upper-​limb dystonia are

24.17  Inherited neurodegenerative diseases

common in about 80% of cases, which may later subside. Intellect remains normal in some individuals. Brain MRI shows cerebellar atrophy in all affected individuals with occasional brain stem atrophy. Signs of axonal neuropathy are found in 100% of individuals with AOA1. After 10–​15 years of disease duration, a low albumin (G). mtDNA mutations are the major cause of visual loss in young adult males. About one-​ half of all males who harbour one of three point mutations of mtDNA (m.11778G>A, m.14484T>C, m.3460G>A) develop bilateral sequential visual loss in the second or third decade—​a disorder known as Leber hereditary optic neuropathy. Most individuals with these mutations are homoplasmic, harbouring only mutated mtDNA. It is not clear why the disease only affects approximately one-​half of the males and only 10% of females

who inherit the primary mtDNA defect. Clinical penetrance is increased by cigarette smoking and a high alcohol intake. Additional, as yet unknown, nuclear genetic factors may also be important in modulating the phenotype. Leigh’s syndrome (subacute necrotizing encephalomyopathy) is a relapsing encephalopathy with prominent cerebellar and brainstem signs that usually presents in childhood and is associated with characteristic neuroimaging abnormalities involving the basal ganglia. Leigh’s syndrome can be due to an X-​linked pyruvate dehydrogenase deficiency or a defect of the mitochondrial respiratory chain. Complex I deficiency or cytochrome c oxidase deficiency are common findings in Leigh’s syndrome. In these patients it may be possible to identify recessive mutations in nuclear complex I genes, or genes involved in the assembly of the respiratory chain complexes (e.g. SURF1). Point mutations at position m.8993 in the ATPase 6 gene of mtDNA may cause neurogenic weakness with ataxia and retinitis pigmentosa. These particular mutations are also associated with some forms of childhood Leigh’s syndrome. Alpers–​Huttenlocher syndrome is a severe autosomal recessive hepatoencephalopathy with intractable seizures and visual failure which presents in early childhood and is associated with depletion (loss) of mtDNA in affected tissues. Mutations in POLG are a major cause of Alpers–​Huttenlocher syndrome. Sodium valproate precipitates fulminant liver failure in these patients and should not be used. Other causes of mtDNA depletion include mutations in MPV also cause liver disease, TK2 (encoding thymine kinase) which presents with a progressive childhood myopathy or spinal muscular atrophy, DGUOK (encoding dexyguanosine kinase) which presents in childhood with a myopathy and liver failure, and SUCLA2 (coding for ADP-​forming succinyl-​CoA synthase) which presents in early childhood with an encephalomyopathy. Cytochrome c oxidase deficiency may also present in childhood with an infantile myopathy and a severe lactic acidosis, which may also be associated with a cardiomyopathy and the Toni–​Fanconi–​ Debre syndrome. Despite maximal supportive intervention, this is usually a fatal disorder and a severe depletion of mtDNA occurs in a proportion of these cases. It is important to recognize that isolated myopathy and lactic acidosis may be self-​limiting, often with a significant improvement by 1 year of age and complete resolution by the age of 3 years. This is associated with the homoplasmic m.14674T>C mtDNA mutation. Other homoplasmic mtDNA mutations known to cause disease include m.1555A>G which causes non​syndromic deafness that may be precipitated by aminoglycosides; and m.1624T>C which can cause Leigh’s syndrome. Coenzyme Q10 deficiency can present in childhood with recurrent myoglobinuria, myopathy, and seizures. In some families it presents with an infantile encephalomyopathy with renal tubular defects. Finally, it may also present with ataxia and variable involvement of other regions of the central nervous system, peripheral nerve, and muscle. Mutations in genes coding for enzymes involved in the biosynthesis of coenzyme Q10 have been found in some families (e.g. COQ2, ADCK3).

Non​specific clinical presentations Many patients do not present with a characteristic phenotype. Children may present in the neonatal period with a metabolic encephalopathy and systemic lactic acidosis, often associated with

24.19.5  Mitochondrial disease

Central nervous system Encephalopathy Stroke-like episodes Seizures and dementia Psychosis and depression Ataxia Migraine Cardiac Hypertrophic cardiomyopathy Dilated cardiomyopathy Heart block Pre-excitation syndrome Renal Renal tubular defects Toni-Fancomi Debre syndrome

Gastrointestinal Dysphagia Pseudo-obstruction Constipation Hepatic failure

Eye External ophthalmoplegia Ptosis Cateract Pigmentary retinopathy Optic atrophy

D-LOOP mtDNA subunits

12SrRNA 16SrRNA

I II III Hearing Bilateral sensorineural deafness

IV

ND1

V

I

Nuclear subunits CELL

M ND2 W

Nucleus

CYT b

P

L (UUR)

OH

E ND6

ND5

Q A N C Y

OL Endocrine and diabetes Diabetes mellitus Hypoparathyroidism Hypothyroidism Gonadal failure Peripheral nervous system Myopathy Axonal sensorimotor neuropathy

T

F

V

COX I

L (CUN) S (AGY) H ND4 S (UCN) D

K

COX II

ATPase8

G

R

ND4L

ND3 COX III ATPase6

The mitochondrial genome Mitochondrion

Fig. 24.19.5.1  The clinical features and biochemical and molecular genetic basis of mitochondrial disease.

hepatic and cardiac failure. This may be associated with depletion in the total amount of mtDNA within affected tissues (see earlier). This syndrome may be fatal. Childhood presentations may be even less specific, with neonatal hypotonia, feeding and respiratory difficulties, and failure to thrive. A respiratory chain defect should be considered in any patient who has a disease with multiple organ involvement, particularly if there are central neurological features (such as seizures and dementia), a myopathy, cardiomyopathy, and endocrine abnormalities such as diabetes mellitus (Fig. 24.19.5.1). Bilateral sensorineural deafness and ocular features (retinopathy, optic atrophy, ptosis, and ophthalmoparesis) are common. Renal tubular defects, gastrointestinal hypomotility, cervical lipomatosis, and psychiatric features are also well described in patients with respiratory chain disease. Patients with biochemical defects affecting multiple respiratory chain enzymes are common. These disorders can present from floppy infants with poor feeding at birth to myopathy and ophthalmoplegia in old age. Many are caused by mutations of mtDNA, but a vast array of autosomal recessive nuclear gene defects are also implicated, causing defective intramitochondrial protein synthesis.

Investigation of respiratory chain disease The investigation of patients with a suspected mitochondrial encephalomyopathy involves the careful assimilation of clinical and laboratory data. In a significant proportion of cases (such as Leber’s hereditary optic neuropathy), it is possible to identify a specific clinical syndrome with a clear maternal family history. Under these circumstances it is appropriate to carry out a molecular genetic test on a blood sample. In many situations, particularly in sporadic cases, this is not appropriate because the clinical features overlap with those of many other disorders. Even if the patient has a mitochondrial disorder, numerous different genetic defects may be responsible, some of which will not be detectable by analysis of blood samples. Investigations fall into two main groups:  clinical investigations used to characterize the pattern and nature of the different organs

involved, and specific investigations to identify the biochemical or genetic abnormality.

General clinical investigations It is essential to search for the more common features of respiratory chain disease, especially those which are potentially treatable. This includes cardiac assessment (ECG, echocardiography, and MRI) and endocrine assessment (oral glucose tolerance test, HbA1c, thyroid function tests, alkaline phosphatase, fasting calcium, and parathyroid hormone levels). The organic and amino acids in urine may be abnormal even in the absence of overt tubular disease. Measuring blood and cerebrospinal fluid lactate levels is more helpful in the investigation of children than adults. These measurements must be interpreted with caution because there are many causes of blood and cerebrospinal fluid lactic acidosis, including fever, sepsis, dehydration, seizures, and stroke. The cerebrospinal fluid protein may be elevated. The serum creatine kinase level may be raised but is often normal. Neurophysiological studies may identify a myopathy or neuropathy. Electroencephalography may reveal diffuse slow-​wave activity consistent with a subacute encephalopathy, or evidence of seizure activity. Cerebral imaging may be abnormal, showing lesions of the basal ganglia, high signal in the white matter on MRI or generalized cerebral atrophy.

Specific investigations A skeletal muscle biopsy is invaluable in the investigation of respiratory chain disease. Histochemical and biochemical investigations, in conjunction with the clinical assessment, often indicate where the underlying genetic abnormality must lie. Other clinically affected tissues may also be biopsied, and cultured skin fibroblasts may be investigated particularly in children. Histochemistry and biochemistry Histochemical analysis may reveal subsarcolemmal accumulation of mitochondria (so-​called ‘ragged-​red’ fibres), or cytochrome c oxidase deficiency. A mosaic of cytochrome c oxidase-​positive and

6347

6348

section 24  Neurological disorders

cytochrome c oxidase-​negative muscle fibres suggests an underlying primary mtDNA defect or a secondary defect of mtDNA as seen in patients with POLG mutations. Patients who have cytochrome c oxidase deficiency due to a nuclear genetic defect usually have a global deficiency of this enzyme affecting all muscle fibres. Electron microscopy may identify paracrystalline inclusions in the intermembrane space, but these are non​specific and may be seen in other non-​ mitochondrial disorders. Respiratory chain complex assays can be carried out on various tissues. Measurement of the individual respiratory chain complexes determines whether an individual has multiple complex defects that would suggest an underlying mtDNA defect, involving either a tRNA gene or a large deletion, or a nuclear genetic defect affecting protein translation within mitochondria. Isolated complex defects may be due to mutations in either mitochondrial or nuclear genes. Co-​enzyme Q10 can be measured directly in affected tissues. Molecular genetic investigations Under certain circumstances, the clinical and/​ or biochemical features may point towards a specific genetic defect detected by targeted molecular genetic analysis in a blood sample (e.g. Leber hereditary optic neuropathy, or POLG diseases), or urinary epithelium for some mtDNA defects (e.g. m.3243A>G). In other patients, the first step is to exclude a defect of mtDNA, testing for mtDNA deletions, depletion or point mutations by sequencing in an affected tissue (see next). In patients where the clinical and biochemical features implicate a nuclear genetic diagnosis (e.g. paternal transmission, or multiple deletions of mtDNA), or the mtDNA is normal, then nuclear genetic analysis is carried out. If there is one obvious candidate gene known to be a common cause of the clinical and biochemical phenotype (e.g. SURF1 in isolated COX deficiency), then it is appropriate to sequence a specific gene. In other patients, a long list of genes may be implicated. These may form part of a panel tested using next generation sequencing (e.g. in patients with complex I deficiency). If an obvious panel of genes is not indicated, then exome or whole genome sequencing should be performed. For some mtDNA defects (particularly mtDNA deletions and depletion) the abnormality is not detectable in a DNA sample extracted from blood, and the analysis of DNA extracted from muscle is essential to establish the diagnosis. Urinary epithelium can also be used in some circumstances. Many patients with mitochondrial disease have a previously unrecognized mtDNA defect and it is necessary to sequence directly the mitochondrial genome. Interpretation of the sequence data can be extremely difficult. mtDNA is highly polymorphic and any two normal individuals may differ by up to 60 base pairs. In the strictest sense, a mutation can only be considered to be pathogenic if it has arisen independently several times in the population, it is not seen in controls and it is associated with a potential disease mechanism. These stringent criteria depend upon a good knowledge of polymorphic sites in the background population. If a novel base change is heteroplasmic, this suggests that it is of relatively recent onset. Family, tissue segregation and single cell studies may show that higher levels of the mutation are associated with mitochondrial dysfunction and disease, which strongly suggests that the mutation is causing the disease.

Management There is currently no definitive treatment for patients with mitochondrial disease, except for patients with deficiency of coenzyme Q10. Management is aimed at minimizing disability, preventing complications and genetic counselling.

Supportive care and surveillance Many patients with mitochondrial disorders require follow-​ up over many decades. An integrated approach is essential involving the primary physician, other specialist physicians (ophthalmology, diabetes, and cardiology), specialist nurses, physiotherapists, and speech therapists. Vigilant clinical monitoring over many years can prevent the development of complications, such as those secondary to cardiac and endocrine involvement. Specific procedures may be indicated at various stages of disease. These include cardiac pacing, ptosis correction, cataract surgery, percutaneous gastrostomy, and even transplantation for organ limited disease.

Genetic counselling The detailed investigation of patients with respiratory chain disease usually leads to a specific molecular genetic diagnosis. This has profound implications on the counselling given to patients and their families. Similar clinical phenotypes can have very different genetic causes. For example, PEO can be maternally inherited (due to m.3243A>G), autosomal dominant (due to OPA1) or autosomal recessive (e.g. due to POLG). If it is possible to identify the causative mutations in both the offspring and parents, then this will allow confident genetic counselling for the whole family. If, as in some cases, it is not possible to identify the underlying gene defect, or the genetic defect in the affected child cannot be traced back to the parents, then counselling is less straightforward. If a causative primary mtDNA defect is identified, then the implications for counselling are distinctly different. Males cannot transmit pathogenic mtDNA defects. Patients who carry mtDNA deletions rarely have a family history suggestive of mtDNA disease, and there is low risk that they will transmit the mtDNA defect to any offspring. Women harbouring heteroplasmic pathogenic mtDNA point mutations may transmit the genetic defect to their offspring. The mitochondrial genetic ‘bottleneck’ leads to a variation in the proportion of mutated mtDNA that is transmitted to any offspring (see earlier). It is therefore possible for a female to have mildly affected as well as severely affected children. The risk of having affected offspring varies from mutation to mutation, and although there does appear to be a relationship between the level of mutated mtDNA in the mother and the risk of affected offspring, there are insufficient data from prospective studies to allow accurate risk prediction. Nuclear genetic defects follow well described inheritance patterns, but the clinical penetrance of many recently identified nuclear gene defects has yet to be established, creating uncertainty in the clinic.

Prognosis In general, the prognosis depends upon the extent of central neurological involvement. Patients with Leber’s hereditary optic neuropathy

24.19.5  Mitochondrial disease

rarely have significant central neurological features and have a normal lifespan. The prospect for visual recovery varies. After the initial nadir, individuals harbouring the m.11778G >A mutation are the least likely to regain functional vision, while those harbouring the m.14484T >C mutation are the most likely to regain their sight. Children presenting with an encephalopathy have a poor prognosis. Although residual neurological deficits are common after repeated childhood encephalopathic episodes, the disease may enter a more stable ‘chronic’ phase during teenage years and adulthood. A similar course may be seen in adults presenting with a relapsing encephalopathy. In contrast, a large proportion of adults with mtDNA defects and chronic progressive external ophthalmoplegia have very mild disease that may remain limited to the extraocular muscles for many decades. For specific mtDNA mutations, there also appears to be a relationship between the proportion of mutated mtDNA in skeletal muscle and the severity of the disease. Although the proportion of mutated mtDNA in muscle may give some guide to prognosis, there is insufficient information available to allow accurate prognostic counselling based upon these determinations. A significant proportion of patients have distinct phenotypes associated with unique genetic defects and the prognosis must be guarded in these families.

Pharmacological treatments and novel approaches under development No medicines are licenced for the treatment of mitochondrial diseases, and there is no objective evidence that any treatment is effective. Anecdotal reports describe benefits from ubiquinone (coenzyme Q10) in patients with disorders of coenzyme Q10 biogenesis, and some patients have a riboflavin-​responsive disorder. Several clinical trials are currently evaluating the effects of novel treatment approaches in patients with mitochondrial disease (https://​ClinicalTrials.gov), and idebenone shows promise as the first treatment for Leber hereditary optic neuropathy. Bone marrow transplantation is effective in patients with very rare autosomal recessive enzyme defects (caused my mutations in TP). Dichloracetate can be used to reduce lactic acid

levels but may cause an irreversible toxic neuropathy and is therefore not used in adults. Exercise is important for patients with mtDNA disease, and isometric muscle contraction may lead to an improvement in muscle strength. Finally, several centres are investigating methods for correcting the underlying mtDNA defect using targeted antigenomic molecules and gene therapy, and new approaches are being developed to prevent the transmission of mtDNA mutations through mitochondrial donation.

FURTHER READING Anderson S, et  al. (1981). Sequence and organization of the human mitochondrial genome. Nature, 290, 457–​65. Chinnery PF, et al. (2014). The challenges of mitochondrial replacement. PLoS Genet, 10, e1004315. Di Mauro S, et al. (2013). The clinical maze of mitochondrial neurology. Nat Rev Neurol, 9, 429–​44. Gorman GS, et  al. (2015). Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Annals of Neurology, 77, 753–​9. Klopstock T, et  al. (2011). A randomized placebo-​controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain, 134, 2677–​86. Klopstock T, et  al. (2013). Persistence of the treatment effect of idebenone in Leber’s hereditary optic neuropathy. Brain, 136, e230. Koopman WJ, Willems PH, Smeitink JA (2012). Monogenic mitochondrial disorders. N Engl J Med, 366, 1132–​41. Pfeffer G, et  al. (2012). Treatment for mitochondrial disorders. Cochrane Database Syst Rev, 4, CD004426. Pfeffer G, et al. (2013). New treatments for mitochondrial disease—​no time to drop our standards. Nat Rev Neurol, 9, 474–​81. Stewart JB, Chinnery PF (2015). The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease. Nat Rev Genet, 16, 530–​42. Taylor RW, et al. (2014). Use of whole-​exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies. JAMA, 312, 68–​77. Vafai SB, Mootha VK (2013). Medicine: a common pathway for a rare disease? Science, 342, 1453–​4.

6349

24.20

Developmental abnormalities of the central nervous system Chris M. Verity, Jane A. Hurst, and Helen V. Firth

ESSENTIALS The brain and spinal cord arise from a sheet of cells that develop through a series of distinct transformations into the final complex structure. Congenital abnormalities of the central nervous system are considered in the context of this process, which may fail at distinct stages of development.

General clinical approach A rigorous approach to the diagnosis of and counselling for developmental abnormalities of the central nervous system is required. Referral for specialist advice is recommended because of the far-​ reaching consequences of misdiagnosis. Many abnormalities can be identified by detailed ultrasonography, and magnetic resonance imaging in utero is proving to be particularly useful for accurate investigation of the fetal brain. Prenatal diagnosis is available for some conditions, with non​invasive prenatal diagnosis (and preimplantation diagnosis) becoming available for some conditions where a precise genetic diagnosis is possible. In the absence of a specific diagnosis genetic advice is usually limited and empirical, but where a specific gene is implicated parental questions can often be accurately addressed. Where there are strong environmental factors, it is imperative to reduce the risk to future pregnancies by taking appropriate measures (e.g. folic acid or iodide supplementation before conception).

A. Malformations resulting from abnormalities in the major steps of central nervous system formation Neural tube defects Clinical features and epidemiology—​neural tube defects such as spina bifida and anencephaly reflect a failure of closure of the ectoderm folds that normally fuse 18–​26 days after ovulation. Prevalence rates vary greatly by geographical area but worldwide they remain among the most frequent and the most devastating congenital anomalies. Most cases are caused by interactions between genes and environmental factors such as nutritional folic acid, but in the presence of additional features, they may be part of a genetic disorder. Screening—​many serious (open) neural tube defects lead to an increased concentration of α-​fetoprotein in maternal serum, and at-​ risk women with this elevated biomarker on screening—​or those with a history of an affected pregnancy—​are recommended to have fetal ultrasonography from 12 weeks onwards.

Prevention—​the incidence of neural tube defects can be markedly reduced at a population level by preconceptual supplementation of folic acid (400 μg daily), which has been effectively introduced in some countries by fortification of foods with folic acid. Where possible, avoidance of drugs periconceptually and in pregnancy that impair folate metabolism (eg. folate antagonists, anticonvulsants such as sodium valproate). Treatment and prognosis—​the major focus is on prevention, but neurosurgical procedures are employed for closure and for relief of hydrocephalus by diversion of cerebrospinal fluid through shunt procedures. The outcomes and prognosis of affected children vary greatly and surgical management remains controversial, except for those with mild abnormalities. Other developmental abnormalities of the spinal cord—​these include syringomyelia, which usually presents in later life and is associated with the Chiari malformation and hydrocephalus. Agenesis of the sacrum with abnormalities of the distal cord is associated with maternal diabetes mellitus.

Disorders of regionalization of the fully formed neural tube Numerous genes, including those encoding signalling molecules that induce the expression of homeotic genes involved throughout evolution in regional and segmental development, are implicated in the complex process of regionalization of the neural tube. Disorders affecting these pathways often involve gene–​environment interactions and give rise to abnormalities of the specification of cells in the forebrain, midbrain, hindbrain, and spinal cord (e.g. holoprosencephaly).

Disorders of cortical development Numerous genetic determinants have been identified for disorders of cortical development such as microcephaly and lissencephaly, which reflect abnormalities of proliferation and cellular migration (respectively). Microcephaly may also be caused by environmental influences in pregnancy, including radiation, drugs, infections and maternal hyperphenylalaninemia (a preventable factor of importance in the management of women with phenylketonuria).

Malformations of posterior fossa structures Hindbrain development is disturbed in the Chiari II malformations and the Dandy–​Walker syndrome (agenesis of the vermis, with dilatation of the fourth ventricle and enlargement of the posterior fossa).

24.20  Developmental abnormalities of the central nervous system

Complex malformations of the brain and cord Many types are recognized, including agenesis of the corpus callosum and porencephaly. These disorders are rare, but are increased in children with other developmental abnormalities. Agenesis or hypogenesis of the corpus callosum may be caused by mutations in a single highly penetrant gene (e.g. ARID1B; Coffin-​Siris syndrome), chromosomal imbalance, and some rare metabolic syndromes (e.g. non​ketotic hyperglycinaemia). Porencephaly may be a prenatal manifestation of mutations in COL4A1/​2.

three-​dimensional structure. A range of abnormalities results from failures at distinct stages of development. This chapter uses the normal development of the human CNS as a framework to discuss these disorders. Only structural abnormalities of the CNS that are present at birth have been included, not the numerous metabolic and degenerative disorders that can affect the infant brain. During intrauterine life the brain develops from a plate of ectodermal cells into the complex structure seen in the full-​term infant as is shown in Fig. 24.20.1.

Vascular developmental abnormalities These include Sturge–​Weber syndrome (where a vascular birthmark on the face is associated with an angioma involving the meninges overlying the cerebral cortex) cerebral cavernomas, capillary and venous malformations resulting from somatic mosaicism.

B. Clinical problems associated with abnormalities of central nervous system development Enlargement of the cerebral ventricles (ventriculomegaly) Ventriculomegaly may be discovered on antenatal scanning and may be isolated or associated with other cerebral developmental abnormalities. Sometimes it is an early sign of hydrocephalus—​this results from expansion of the ventricles secondary to a block in the normal flow pathway of cerebrospinal fluid. Intellectual disability can result from both the damage associated with ventricular expansion and other abnormalities associated with the underlying cause of the problem.

Disorders of the developing brain caused by external factors Alcohol—​fetal alcohol syndrome may cause microcephaly, structural anomalies of the brain such as partial or complete agenesis of the corpus callosum, cerebellar hypoplasia, and a dysmorphic appearance. Fetal alcohol spectrum disorders are much more common than fetal alcohol syndrome. Drugs of abuse—​there is emerging evidence that prenatal exposure to stimulants such as cocaine and methylamphetamine can affect brain development and function Congenital infections—​for example, toxoplasmosis, herpes simplex, cytomegalovirus, rubella, and syphilis. Primary maternal infection is implicated in most instances; hence measures to prevent these infections are important.

The cerebral palsies These are an important but heterogeneous group of non​progressive disorders of the immature brain that cause defects of movement and posture that may have associated manifestations such as deafness, seizures, and learning difficulties. Several clear genetic factors have been identified, and environmental exposure to toxins such as carbon monoxide, alcohol, and methyl mercury may also be responsible. Although cerebral palsy has in the past been attributed to ‘asphyxia’ at birth, this view is now changing; premature infants are at a greatly increased risk.

Normal development of the human central nervous system The human central nervous system (CNS), like that of all vertebrates, develops from a two-​dimensional sheet of cells into a complex

A. Malformations resulting from abnormalities in the major steps of CNS formation Disorders of neural tube formation The nervous system develops from a tube formed when part of the embryonic ectoderm folds and separates from the remaining ectoderm (Fig. 24.20.2). Closure of this tube starts at a level corresponding to the future hindbrain/​spinal cord junction and then proceeds towards both the head (rostrally) and the tail (caudally). This process generates the entire neural tube except for the most caudal part, which is formed by thickening of the neural plate and the subsequent formation of a cavity. A population of cells (the neural crest) then migrates out of the dorsal part of this tube to form the peripheral nervous system, while those that remain in the tube form the CNS. The neural tube usually fuses completely between 18 and 26 days after ovulation (32 and 40 days, respectively, after the first day of the last menstrual period). Failure of closure leads to malformations that include anencephaly, encephalocele, spina bifida, and spina bifida occulta. They are malformations of the neuroectoderm, which are associated to a variable extent with abnormalities of the surrounding mesodermal structures. The term ‘dysraphism’ is used when there is continuity between the posterior neuroectoderm and cutaneous ectoderm. Craniorachischisis is the most severe type of neural tube defect, in which almost the entire brain and spinal cord are open.

Epidemiology The prevalence of neural tube defects varies according to geography and race. High rates (more than 8 per 1000 births) have been reported in Northern Ireland, Egypt, India, and China. There are worldwide reports of decreasing prevalence. In England and Wales there was a substantial decline in the birth prevalence which started in the early 1970s—​in 1964 the rate was 3.6/​1000 births and this fell 93% to 0.3/​1000 in 2004. It was estimated that 59% of the fall was due to an underlying decrease in the prevalence of neural tube defects and 34% to antenatal screening and termination of pregnancy. During this period there was an increase in dietary folate and there is evidence of a protective effect of adequate folate consumption, however some of the decreased prevalence remains unexplained. In England and Wales anencephaly and spina bifida have been of approximately equal prevalence, together making up 95% of all neural tube defects.

Aetiology Genetic factors Most neural tube defects result from a complex interaction between several genes and environmental factors, but a minority occur as part of a Mendelian disorder (e.g. Meckel’s syndrome). If one

6351

6352

section 24  Neurological disorders

5 WEEKS

11 WEEKS TELENCEPHALON

HINDBRAIN (RHOMBENCEPHALON)

MIDBRAIN (MESENCEPHALON) CEREBELLUM

SPINAL CORD

MEDULLA OBLONGATA DIENCEPHALON

DIENCEPHALON TELENCEPHALON FOREBRAIN (PROSENCEPHALON)

PONS

9 MONTHS CEREBRUM

CEREBELLUM MEDULLA OBLONGATA PONS

Fig. 24.20.1  Diagram showing some of the key stages in normal brain development.

member of a family is affected by an isolated (i.e. non​syndromic defect), there is a small increased risk in their first-​degree relatives of c.3% for all types of neural tube defect. Major genes have been identified that cause neural tube defects in the mouse, but their relevance to human defects is still not clear. Some genes have been shown to alter risk modestly (e.g. mutations in the methylene tetrahydrofolate reductase gene are associated with elevated blood homocysteine levels in pregnant women and a twofold increased risk of neural tube defects). At this time, however, genetic investigations offer little in the management of families with one member having an isolated neural tube defect. Environmental factors Periconceptual multiple vitamin supplements containing folic acid have been shown to reduce substantially the incidence of neural tube defects. In England it is currently recommended that women who are planning pregnancy should take 400 µg folic acid daily before conception and during the first 12 weeks of pregnancy. To prevent recurrence of neural tube defects a higher dose of 4–​5 mg/​day is recommended. In the United Kingdom, the Food Standards Agency has recommended the mandatory addition of folic acid to bread or flour. In North America fortification of certain foodstuffs with folic acid has been mandatory since 1998. Since many pregnancies are unplanned, countries that have instituted folic acid fortification policies have seen reductions in neural tube defects of 27–​50%. Some drugs taken during pregnancy may increase the risk of neural tube defects in the fetus, including sodium valproate and folic acid antagonists such as trimethoprim, triamterene, carbamazepine, phenytoin, phenobarbitone, and primidone.

Prenatal diagnosis Ultrasonography This is recommended for all at-​risk women—​those who have had one or more affected child and those taking drugs associated with neural tube defects in the fetus. Anencephaly can be detected by ultrasonography from week 12 of gestation and spina bifida from 16 to 20 weeks (Fig. 24.20.3a, b), although even the best ultrasonographers may occasionally miss spina bifida, particularly in the L5-​S2 region. The recent marked improvement in the resolution of fetal ultrasonography has meant that direct sampling of the amniotic fluid (mniocentesis) is no longer performed. However, when adequate ultrasound images cannot be obtained, amniocentesis with measurement of α-​fetoprotein and assay of neuronal acetylcholinesterase does provide an alternative method of prenatal diagnosis. α-​fetoprotein levels in maternal serum The fetal liver is the main source of α-​fetoprotein, which leaks through open neural tube defects into the amniotic fluid and then into maternal blood. The consequent abnormal increase in maternal serum α-​fetoprotein is best detected at 16–​18 weeks of pregnancy. Maternal serum screening does not detect closed defects (those covered by skin). The widespread use of prenatal ultrasound for fetal anomaly screening has superseded maternal serum α-​fetoprotein as a screening measure in pregnancy in many countries.

Cranial abnormalities of neural tube closure Anencephaly This is a lethal defect that results from failure of fusion of the rostral folds of the neural tube. The cranial vault is absent and an

24.20  Developmental abnormalities of the central nervous system

of posterior defects below the tentorium, cerebellar defects. They may be part of a recognized syndrome such as frontonasal dysplasia. Posterior encephaloceles may be a feature of an underlying ciliopathy such as Meckel syndrome.

Anencephaly Rostral neuropore 0 Closure 3 Caudal/ posterior neuropore

Spinal abnormalities of neural tube closure

Closure 1

Spina bifida

Open spina bifida

This can be divided into spina bifida occulta, which consists of failure of closure of the vertebral arches without an external lesion, and spina bifida cystica in which there is a cystic lesion on the back. The lesion may be either a meningocele without neural tissue or a myelomeningocele in which the spinal cord is a component of the cyst wall. The term ‘rachischisis’ is used for the most severe defect, which is a widely patent dorsal opening of the spine, often associated with anencephaly.

Craniorachischisis

Neural plate

Notochord Neural groove

Myelomeningocele This spinal defect represents the abnormality found in 80–​90% of children with spina bifida cystica. It is lumbosacral in about 80% of cases and consists of a sac covered with a thin membrane that may leak cerebrospinal fluid (Fig. 24.20.3c). Neurological abnormalities depend on the level of the lesion. There is usually a mixture of upper

Epidermis

(a)

Neural tube

(b)

Neural crest cells

Fig. 24.20.2  The upper part of the diagram shows neural tube defects arising from errors in the multisite closure of the neural tube. The coloured section shows how the embryonic ectoderm separates, folds, and closes to form the neural tube.

(e)

(c) (d)

angiomatous membranous mass lies on the floor of the cranium. The eyes are protuberant as a result of shallow orbits and there is variable involvement of the spinal cord. Before the advent of prenatal diagnosis by ultrasonography most anencephalic babies were liveborn; now an increasing number of such pregnancies are terminated. In liveborn anencephalic babies, the initial neurological examination may be surprisingly normal if brainstem structures are reasonably intact. However, the infants usually die in hours or days. Cephaloceles A cephalocele is a herniation of the cranial contents through a skull defect. There are several subtypes: a cranial meningocele contains only meninges, an encephalocele contains brain tissue, and a ventriculocele contains part of the ventricle within the herniated portion of the brain. Cephaloceles are less common than anencephaly or spina bifida, occurring in 1 to 3 per 10 000 live births. Posterior cephaloceles are the most common group in Western countries and most are occipital encephaloceles, whereas anterior cephaloceles are more common in some parts of Asia. Anterior cephaloceles are associated with other brain abnormalities such as agenesis of the corpus callosum, abnormal gyration, or, in the case

Fig. 24.20.3  (a) Prenatal ultrasonography of a child with a neural tube defect, showing the ‘lemon sign’ resulting from the change in shape of the back of the skull (on the left-​hand side in the image) which is associated with the Chiari II malformation described in the text. (b) Prenatal ultrasonography of a child with a neural tube defect, showing a cystic lumbar meningomyelocele in the caudal neural tube. (c) Lumbar meningomyelocele: photograph of a newborn infant. (d) Chiari I malformation and syringomyelia in an asymptomatic girl aged 11 years. Photograph of tuft of hair seen over the lumbar region at birth. The associated central nervous system malformations are shown in (e). (e) Chiari I malformation and syringomyelia. T1-​weighted sagittal MRI shows that there is herniation of the cerebellar tonsils through the foramen magnum (arrow) and a syrinx of the lower cervical spinal cord (C5–​7) (arrow head). The associated tuft of lumbar hair is shown in (d).

6353

6354

section 24  Neurological disorders

and lower motor neuron signs, disturbance of bladder and bowel sphincters, and bladder detrusor dysfunction. The sensory level correlates with the severity of abnormalities in the urinary tract and has prognostic significance regarding long-​term disability. Higher lesions of the cord are associated with bladder outlet obstruction, dilatation of the upper urinary tract, and chronic pyelonephritis. Hydrocephalus complicates about 90% of cases of lumbosacral meningomyelocele. Usually it is associated with the Chiari II malformation, where there is downward displacement of the cerebellar vermis or tonsils through the foramen magnum to overlap the spinal cord. The fourth ventricle is elongated and the midbrain distorted, causing palsies from involvement of the lower cranial nerves and central apnoea (which may be misdiagnosed as epilepsy in older children). Hydrocephalus may also be due to aqueduct stenosis or have no clear structural cause. If there is evidence of progressive ventricular dilatation (often detected by ultrasonography) or signs of increasing intracranial pressure, insertion of a ventriculoperitoneal shunt is usually necessary. Meningocele Here there is protrusion of the meninges outside the spinal canal: the sac does not contain any neural tissue. Meningoceles account for about 5% of cases of spina bifida cystica. There is no associated hydrocephalus and the neurological examination is usually normal. They must be distinguished from meningomyeloceles because the prognosis is so different.

Management of neural tube defects The major emphasis is on primary prevention. It is recommended that women planning to conceive supplement their diet with folic acid, which reduces the risk of neural tube defects. Screening of maternal serum for α-​fetoprotein is possible and prenatal diagnosis by ultrasonography is available. This is discussed above. Treatment of infants with meningomyeloceles became possible with the development of ventriculoatrial and ventriculoperitoneal shunts. In the early 1960s, it was argued that closure of the defect within 24 h of birth reduced mortality and morbidity by avoiding infection and reducing trauma to the exposed neural tissue. A selective approach to the surgical management of affected infants was proposed but this has been controversial. Lorber reported four adverse criteria that he thought were contraindications to treatment: a high level of paraplegia, clinically evident hydrocephalus at birth, lumbar kyphosis, and the presence of other major malformations. However, even using these criteria, the outcome was uncertain; many infants survived even though they did not have closure of the defect within 24 h, and some children with a supposedly good prognosis were left with major disabilities after surgery.

Other developmental abnormalities of  the spinal cord

Spina bifida occulta

Syringomyelia

This term is often applied to a defect of the posterior arch of one or more lumbar or sacral vertebrae (usually L5 and S1). It is found incidentally by radiography in 25% of children admitted to hospital and may be a normal variant. However, if examination of the skin over the spine reveals a naevus, hairy patch (Fig. 24.20.3d), dimple, sinus, or subcutaneous mass, further evaluation including magnetic resonance imaging (MRI) of the spinal cord is indicated. Several clinical abnormalities may be found on examination. Spinal cord malformation may cause an asymmetrical lower motor neuron weakness with wasting, deformity, and diminished reflexes in the lower limb, or progressive gait disturbance with spasticity. Either presentation may be associated with disturbed bladder control. Dorsal dermal sinuses may connect the skin surface to the dura or an intradural dermoid cyst. An open sinus tract can cause recurrent meningitis so ideally it should be explored and excised before infections occur. Lipomyelomeningoceles present as a bulge in the lumbosacral region, usually lateral to the midline. They consist of a lipoma or lipofibroma attached to a low-​lying abnormal spinal cord. Diastematomyelia is the presence of a sagittal cleft that divides the spinal cord into two halves, each surrounded by its own pia mater. A bony or cartilaginous spur may transfix the cord, fixing it in a low position as the child grows. The cleft is usually in the low thoracic or lumbar region, but cervical clefts have been reported. If any abnormality involving the cord or nerve roots is found there may be a good case for neurosurgical intervention. The aim is to free the spinal cord from its abnormal attachments to allow for growth and prevent further damage. Early intervention may prevent worsening motor deficits and urological complications, but the indications for intervention are controversial.

This is a tubular cavitation of the spinal cord that is often associated with the Chiari I malformation and hydrocephalus (Fig. 24.20.3e). It tends to be in the cervical region but may involve the whole cord. It rarely becomes symptomatic in children. Treatment is controversial. Shunting of the abnormal cavity is sometimes performed and posterior fossa exploration may be undertaken if there is a Chiari I malformation.

Sacral agenesis This is strongly associated with maternal diabetes mellitus. Absence of the sacrum and coccyx is usually associated with abnormalities of the lumbosacral cord. There may be arthrogryposis at birth (defined as a fixed deformity of one or more joints). A flaccid neurogenic bladder causes incontinence and there are sensory and motor deficits in the legs. Sacral agenesis may also occur as part of the single gene disorder Currarino syndrome due to heterozygous mutation of the homeobox gene HLXB9.

Disorders of regionalization Once the neural tube has developed, specification of different regions and individual cells within these regions occurs. This patterning occurs in both the rostrocaudal and dorsoventral axes. The three basic regions of the CNS (forebrain, midbrain, and hindbrain) develop at the rostral end of the tube, with the spinal cord more caudally. Within the developing cord the specification of the different populations of neural precursors (neural crest, sensory neurons, interneurons, glial cells, and motor neurons) is observed in progressively more ventral locations. This process reflects the interaction between

24.20  Developmental abnormalities of the central nervous system

genes whose expression defines individual territories or cell types and diffusible signalling molecules secreted by adjacent areas of the embryo. Of particular importance are the extracellular signalling molecules such as sonic hedgehog required for ventral induction, and a family of genes called homoeotic genes. Most of these encode proteins containing a conserved homeodomain motif that binds DNA sequences involved in the regulation of expression of other genes, so controlling cell differentiation. Failure of normal development of the most rostral portion of the neural tube (the mediobasal prosencephalon) and associated structures caused by disturbances in the process of ventral induction may result in various abnormalities of the brain and face. The most severe CNS abnormality is holoprosencephaly in which there is failure of the prosencephalon to separate into two cerebral hemispheres. The mildest is olfactory aplasia with no other cerebral malformations. The severity of the associated facial abnormalities tends to parallel those in the brain. In the most severe facial abnormality there is anophthalmia and absence of the nose. However, there may be just mild hypotelorism (closely set eyes) or a single central incisor tooth, or the face appear normal.

Holoprosencephaly (prosencephaly) This occurs with a frequency of approximately 1 in 250 conceptuses and c.1 in 10 000 births. There is failure of formation of the two cerebral hemispheres, resulting in abnormalities of varying severity. There are many possible causes that act within a short vulnerable period, because ventral induction probably occurs before 23 days. Environmental factors are important and it is at least 20 times more common in the infants of mothers with diabetes than in the general population. In addition, there are several genetic causes, with at least 12 genetic loci and 9 holoprosencephaly (HPE) genes identified in humans. One (HPE3 on chromosome 7q36) is the sonic hedgehog gene, and mutations in PTCH, the receptor for sonic hedgehog, have also been found in some individuals with holoprosencephaly. Many other genes are implicated in the pathogenesis of holoprosencephaly and it is associated with chromosomal abnormalities that include trisomy and other abnormalities of chromosome 13, partial deletion of the short arm of chromosome 18, ring chromosome 18, and partial trisomy of chromosome 7. In alobar holoprosencephaly, the completely undivided forebrain is in the shape of a horseshoe surrounding a single cavity. The thalami are fused but the brain stem and cerebellum are well developed. The associated facial abnormalities are severe—​ there may be anophthalmia or cyclopia in which there is a single orbit. In holoprosencephaly with median cleft lip there is marked hypotelorism. In semilobar holoprosencephaly the brain is divided into two hemispheres posteriorly but anteriorly the two hemispheres are fused (Fig. 24.20.4). In lobar holoprosencephaly there is almost complete separation of the hemispheres and the face may be normal. The head is usually microcephalic unless there is associated hydrocephalus. In some families in which the condition is inherited in autosomal dominant pattern, the severity can be variable, with some family members having only minor features such as a single central incisor, and others with severe holoprosencephaly. When providing genetic counselling it is therefore important to look for minor signs in both parents of an affected child. The signs include orbital hypotelorism, median cleft lip, flat nose with or without a single nostril, anosmia,

(a)

(b)

Fig. 24.20.4  (a) Semilobar holoprosencephaly in a girl aged 2 years imaged with T1-​weighted sagittal MRI. This midline view shows absence of the corpus callosum and fusion of the frontal lobes. (b) Semilobar holoprosencephaly in the same patient using T2-​weighted axial MRI. There is fusion of the frontal lobes of both cerebral hemispheres and a common central ventricle.

and a single central incisor. Prenatal diagnosis can be made by ultrasonography from week 16 of pregnancy, with orbital hypotelorism an important feature for antenatal diagnosis. The most severely affected infants die in the neonatal period. Less severely affected patients may live for months or years. The survivors often develop infantile spasms or other seizures. Some patients with significant structural abnormalities may survive to adulthood but usually there are severe learning difficulties. Associated anomalies suggest a syndromic cause (e.g. Trisomy 13) and include congenital heart disease, scalp defects, and polydactyly.

Disorders of cortical development Modern brain imaging, in particular MRI, has resulted in the identification of many previously unrecognized developmental abnormalities of the cerebral cortex. The best characterized of these arise from defects in one of two basic processes in cortical development. The first is the proliferation of the stem cell population which generates all the neurons required for the cortex. This occurs throughout fetal development in the region next to the ventricle (germinal layer). The second is the migration of the newly formed neurons away from this ventricular region into the overlying cortex to form appropriate connections with other neurons. Abnormalities in migration are shown schematically in Fig. 24.20.5.

Disorders of proliferation Microcephaly A failure of proliferation results in a reduced number of cells, causing a head that is disproportionately small (less than the 0.4th centile) in relation to the rest of the body. This microcephaly is often associated with significant additional abnormalities of the nervous system such as pyramidal tract signs and learning difficulties. Microcephaly is a feature of many genetically determined developmental disorders/​syndromes. Autosomal recessive primary microcephaly is the term used to describe a genetically determined form of microcephaly previously known as ‘microcephaly vera’, with a severe and non​progressive reduction in head circumference (more that four standard deviations

6355

6356

section 24  Neurological disorders

below the mean for age) associated with mild-​to-​moderate learning disability but normal height, weight, and appearance. Many of the genes identified encode centrosomal proteins that are crucial for cell division. In many types of genetic microcephaly the head size may not become abnormal until as late as 32–​34 weeks of gestation or even after birth. Severe microcephaly may also be a feature of a more generalized disorder of growth (e.g. microcephalic primordial dwarfism where birth weight is typically cytoplasm (all neurones)

HuD, HuC

SCLC, neuroblastoma,, prostate

PEM, PSN, PCD, gastrointestinal pseudo-​obstruction

Yo

Cytoplasm, Purkinje cells

CDR34, CDR62

Ovary, breast,

PCD

Ri

Nucleus>cytoplasm (CNS neurones)

Nova

Breast, gynaecological cancer, lung, bladder

Brainstem encephalitis, opsoclonus–​myoclonus

Tr

Cytoplasm, Purkinje cells

Not known

Hodgkin’s disease

PCD

VGCC

Presynaptic neuromuscular junction

P/​Q-​type VGCC

SCLC

LEMS, PCD

VGKC-​complex

Presynaptic: neuromuscular junction and CNS neurones

LGI1 (non​paraneoplastic) and CASPR2 (paraneoplastic)

Thymoma, SCLC

Neuromyotonia, antonomic, limbic encephalitis or combinations of these (Morvan’s syndrome)

Retinal

Photoreceptor, ganglion cells

Recoverin and others

SCLC, melanoma, gynaecological

CAR, MAR

Amphiphysin

Presynaptic

Amphiphysin

Breast, SCLC

Stiff person syndrome, PEM, myelopathy, and myoclonus

CV2 (CRMP5)

Oligodendrocytes cytoplasm

CRMP5 (POP66)

SCLC, thymoma

PEM, PCD, chorea, sensory neuropathy, myelopathy, gastrointestinal pseudo-​obstruction

Ma1

Neurones (subnucleus)

Ma1

Lung, others

Brainstem, PCD

Ma2

Neurones (subnucleus)

Ma2

Testis

Limbic/​brainstem encephalitis

NMDAR

Surface membrane of hippocampal and other neurones

NR1 subunit

Ovarian teratoma

Limbic encephalitis with prominent neuropsychiatric features progressing to movement disorders, fall in consciousness and autonomic instability

AMPA receptor

Surface of hippocampal and other neurones

GluR1/​2

SCLC, breast, thymoma

Limbic Encephalitis

GABA(B) receptor

Surface of hippocampal and other neurones

GABA(B1) or GABA(B2)

SCLC

Limbic Encephalitis

Glycine receptor

Inhibitory synapses on neurones

GlyRα1 and others

Thymoma, lymphomas

Stiff Person Syndrome often with dysautonomia and brainstem involvement

mGluR5

Neuronal cell surface

Metabotropic glutamate receptor

Hodgkins disease (2 cases reported)

Limbic encephalitis

Ganglionic form of nAChR

Ganglionic synapses

Ganglionic AChR

SCLC, thymoma

autoimmune dysautonomia

AChR, acetylcholine receptor; CAR, cancer-​associated retinopathy; CNS, central nervous system; PCD, paraneoplastic cerebellar degeneration; SCLC, small-​cell lung cancer; VGCC, voltage-​gated calcium channels; VGKC, voltage-​gated potassium channels; CRMP5 (collapsin response mediator protein). For other abbreviations, see text.

6385

6386

section 24  Neurological disorders

(both Hodgkin’s Disease and Non-​Hodgkin’s Lymphoma) and testis. In a recent European survey, other tumours were also identified suggesting that whole-​body scanning is appropriate in the diagnostic work-​up of patients with suspected PNS. 35–40 kDa

Fig. 24.23.1  Anti-​Hu antibodies: serum immunoreactivity with rat brainstem counterstained showing strong nuclear staining (solid arrow) and weaker cytoplasmic staining (dashed arrow) typical of anti-​Hu (anti ANNA 1) antibodies (DAB-​peroxidase counterstained with haematoxylin and eosin). Western blot shows a ‘ladder’ pattern of bands between 35 and 40 kDa. The patient was a woman with paraneoplastic cerebellar degeneration who was subsequently found to have lung cancer. Courtesy of Elizabeth Amyes Msc, University of Oxford.

(e.g. voltage-​ gated calcium channels and N-​methyl-​D-​aspartate (NMDA) receptors). Certain autoantibodies are associated with specific tumours but widely varying paraneoplastic syndromes. For example, the anti-​ Hu antibody (Fig. 24.23.1) is almost always associated with SCLC (occasionally neuroblastoma or prostate cancer), but may be found in several different clinical syndromes usually encompassed by the term ‘encephalomyelitis’. The clinical abnormalities include limbic encephalitis, paraneoplastic cerebellar degeneration, brainstem encephalitis, sensory neuronopathy, and autonomic failure. Some or all of these clinical abnormalities may be found in the same patient. Not all patients with a classical syndrome and associated tumour have onconeural antibodies. Thus, the absence of positive detectable antibodies should not be taken as evidence that the patient has a non​paraneoplastic form of disease. In some conditions, there are no identified antibodies. A good example is opsoclonus–​myoclonus associated with neuroblastoma in children. This paraneoplastic disorder is probably immune-​ mediated. The failure to find a disease-​or tumour-​specific antibody does not mean that one is not present, only that current techniques have not identified it. As techniques improve, new antibodies are regularly being reported; of particular interest is the discovery of antibodies directed against N-​methyl-​D-​aspartate receptors (NMDAR) on hippocampal neurones in young female patients and children with a progressive encephalitis, many of which are associated with ovarian teratomas (see ‘Further reading’).

Tumours associated with PNS The most common tumours associated with PNS are found in lung (both SCLC and non-​SCLC), ovary, breast, thymus, lymph nodes

Diagnosis Certain clinical clues suggest that a neurological disorder may be a PNS. The onset is subacute or even acute; in some cases, the symptoms develop over a few days so that a stroke is initially suspected. Most PNS are progressive initially then stabilize after weeks to months, although more slowly progressive syndromes may occur. Recovery is rare in most of the central nervous system syndromes, probably because of irreversible neuronal loss and degeneration, although improvement after oncological treatment have been reported. The neurological disorders are usually moderate or severe. Most patients have substantial disability by the time they first come to medical attention. Mild or waxing and waning neurological symptoms are rarely paraneoplastic. For example, the patient with paraneoplastic cerebellar degeneration is usually unable to walk or sit unsupported because of truncal ataxia, unable to write and, sometimes, unable to read because of oscillopsia. The neurological findings are often characteristic. A subacutely developing pancerebellar disorder, the rapid development of opsoclonus, or the development of LEMS strongly suggests cancer as the underlying cause. However, none of these syndromes, even the most characteristic, is invariably associated with cancer. Thus, only about two-​thirds of patients with LEMS have cancer and only about 10% of patients with myasthenia gravis have a tumour (almost always thymoma). Probably about one-​half of the patients with subacute cerebellar degeneration have cancer. Limbic encephalitis can present as both a paraneoplastic and a more common non-​ paraneoplastic form (Chapter 24.24). Imaging in suspected PNS is often normal or non​specific. Indeed, one of the clues to the presence of a PNS is the relative normality of imaging in a patient with such severe clinical symptoms and signs. Occasionally MRI may show high signal within one or both medial temporal lobes (limbic encephalitis) or brainstem (brainstem encephalitis), and very rarely diffuse oedema of the cerebellum (paraneoplastic cerebellar degeneration). The cerebrospinal fluid may show pleocytosis (30–​40 cells), elevated protein, increased IgG, and oligoclonal bands, particularly early on in the course of disease, which then settles within a few weeks of onset. The immunoglobulin abnormalities usually persist. In a patient with a known cancer, the diagnosis of PNS should usually only be made after exclusion of the more common neurological complications of cancer, particularly malignant meningitis or treatment toxicity (e.g. chemotherapy-​ induced peripheral neuropathy). In a patient without a known cancer, particularly when conventional imaging studies (radiography, CT, ultrasonography, and mammography) are negative, the appropriate use of whole-​body fluorodeoxyglucose positron emission tomography (FDG-​ PET) may show a FDG-​avid ‘hot spot’ suggestive of an occult malignancy (Fig. 24.23.2). Blood tumour markers are rarely helpful in this clinical context. If an onconeural antibody is present and the search for an underlying cancer is negative, the physician is obliged to follow

24.23  Paraneoplastic neurological syndromes

antineuronal antibodies and (4) exclusion of other possible causes of a similar neurological syndrome. On the basis of combinations of these criteria, the diagnosis of a PND is now either ‘definite’ or ‘possible’. (See ‘Further reading’.)

Pathogenesis

Fig. 24.23.2  Axial T2W MRI brain of patient with limbic encephalitis showing high signal in left medial temporal lobe (arrow).

the patient carefully, searching periodically for a cancer. The recommended time for follow-​up is five years from presentation, except for LEMS which is 18 months. The difficulties of defining and hence diagnosing PND have been carefully considered by an international panel of neurological experts who have established guidelines for more rigorous diagnostic criteria. The aim of these guidelines has been to facilitate diagnosis, classification, and collaborative research. They rely on the definition of ‘classical’ paraneoplastic syndromes and ‘well-​characterized’ onconeural autoantibodies. On this basis a condition could be diagnosed as paraneoplastic based on a descending hierarchy of factors: (1) presence or absence of ‘classical’ syndrome; (2) presence or absence of cancer; (3)  presence or absence of ‘well-​characterized’

Current evidence suggests that PNS result from an autoimmune reaction to ‘onconeural’ antigens in the tumour. These antigens are those that are normally restricted to the nervous system (or the testis, which is also an immunologically privileged site). The immune system therefore recognizes the antigen as foreign and some patients mount an immune response. The immune response may have the beneficial effect of slowing tumour growth, but it can also damage those parts of the nervous system that express the antigen. Although many PNS are associated with specific neuronal autoantibodies, there is limited evidence that those directed against cytoplasmic or nuclear antigens are pathogenic. T lymphocytes recognizing these or other onconeural antigens, and other cellular immune mechanisms, are the likely pathogenic agents in these conditions. In contrast, antibodies directed against membrane ion channels or receptors for neurotransmitters (e.g. voltage-​gated calcium and potassium channels, NMDA and AMPA forms of glutamate receptors) are pathogenic but are also often present in non​paraneoplastic forms of the disease. These antibodies recognize epitopes located at presynaptic or postsynaptic sites.

Treatment Those PNS which are associated with antibodies to the neuronal surface proteins (NMDAR, AMPAR, GABA(B)R, CASPR2), such as LEMS, MG, and NMDAR encephalitis respond to immunosuppression or to treatment of the underlying cancer (Table 24.23.3). Some syndromes, such as opsoclonus–​myoclonus, may remit spontaneously, but for most PNS associated with antibodies to intracellular

Table 24.23.3  Treatable paraneoplastic neurological syndromes Syndrome

Treatment

Completely responsive Lambert–​Eaton myasthenic syndrome (LEMS)

Tumour therapy, plasma exchange, intravenous immunoglobulin, 3,4 diaminopyridine

Myasthenia gravis

Tumour therapy, plasma exchange, intravenous immunoglobulin, steroids, immunosuppressants, thymectomy, anticholinesterases

Dermatomyositis

Steroids, immunosuppressants, intravenous immunoglobulin

Opsoclonus–​myoclonus (children)

Steroids, ACTH, tumour therapy

Limbic encephalitis or other syndromes with antibodies to cell-​surface antigens, e.g. VGKC, NMDAR, AMPAR, GABA(B)R, GlyR

Tumour therapy, plasma exchange, intravenous immunoglobulin, immunosuppressants

Neuromyotonia

Antiepileptics, steroids, plasma exchange, tumour therapy

Demyelinating neuropathy (osteosclerotic myeloma)

Tumour therapy, radiation, bevacizumab

Partially responsive Opsoclonus–​myoclonus (adults)

Steroids, tumour therapy, clonazepam, diazepam, baclofen

Paraneoplastic cerebellar ataxia (Hodgkin’s disease)

Tumour therapy

Opsoclonus/​ataxia (anti-​Ri)

Steroids, cyclophosphamide

6387

6388

section 24  Neurological disorders

antigens, treatment is unrewarding, and the patient remains severely disabled even if the cancer is cured. Treatments usually involve immunosuppression with plasma exchange, intravenous immunoglobulin, steroids, or cytotoxic agents (e.g. cyclophosphamide), particularly for those syndromes associated with onconeural autoantibodies. It is possible that the rapid onset of the syndromes does not allow sufficient time for accurate early diagnosis and for treatment to begin before irreversible neuronal damage has occurred. With earlier diagnosis, therapy may be more successful. However, as mentioned already, several of the ‘classical’ paraneoplastic conditions appear to exist in non​paraneoplastic forms (e.g. limbic encephalitis with potassium channel antibodies) and may respond to immunotherapies; therefore, if onconeural antibodies are absent, and no cancer is found, a trial of immunotherapy should be considered. There has been interest in rituximab (anti-​CD20 monoclonal Ab) which has shown modest benefit in a small open trial of patients with PNS.

Specific syndromes Brain and cranial nerves (See Box 24.23.1.) Paraneoplastic cerebellar degeneration Paraneoplastic cerebellar degeneration may complicate any malignant tumour but is most common with lung cancer (especially SCLC), breast and gynaecological cancer, and Hodgkin’s disease. Males and females are both affected, and the age incidence reflects the age distribution of the underlying cancer. Neurological manifestations precede detection of the associated tumour in over one-​ half of patients, rarely by more than five years, or paraneoplastic cerebellar degeneration may develop after diagnosis of the tumour. In some instances, the tumour is not found until autopsy. Typically, the disorder begins as gait ataxia that progresses over a few days to weeks to severe truncal and appendicular ataxia with dysarthria and nystagmus. The nystagmus is frequently downbeating. Vertigo with or without nausea and vomiting is common and many patients complain of diplopia. The cerebellar signs are bilateral but may be asymmetrical. The cerebellar deficit usually stabilizes but, by then, the patient is often incapacitated. Spontaneous improvement sometimes occurs, particularly when associated with Hodgkin’s disease. Some patients will also be found to be mildly cognitively impaired and demonstrate extensor plantar reflexes or sensory changes suggesting a more widespread encephalomyelitis. The cerebrospinal fluid may be normal, but there is usually a pleocytosis within the first few months, and raised protein and oligoclonal bands may also be present. Cytological examination of the cerebrospinal fluid and contrast-​enhanced MRI of the brain are essential to rule out leptomeningeal metastases. MRI scans typically

Box 24.23.1  Paraneoplastic syndromes affecting the brain • Subacute cerebellar degeneration • Opsoclonus–​myoclonus • Limbic encephalitis • Brainstem encephalitis

are normal early, but later show signs of progressive cerebellar atrophy with prominent cerebellar folia and a dilated fourth ventricle. The pathological hallmark of paraneoplastic cerebellar degeneration is loss of Purkinje cells, affecting all parts of the cerebellum. Less striking changes in the cerebellar cortex may include thinning of the molecular layer with microglial proliferation and astrocytic gliosis, proliferation of Bergmann glia, and slight thinning of the granular layer with decreased numbers of granule cells. When typical, the clinical picture of paraneoplastic cerebellar degeneration is almost pathognomonic. When atypical, the disorder must be distinguished from a cerebellar tumour (primary or metastatic) and from leptomeningeal metastases (by MRI and cerebrospinal fluid examination, respectively), from late-​ onset, non​ paraneoplastic cerebellar degenerations, cerebellar haemorrhage and infarction; prion diseases, cerebellar ataxia related to 5-​ fluorouracil, capecitabine or high-​dose cytarabine, and metabolic disorders, especially alcoholic cerebellar degeneration. There have been occasional reports of a partial or near-​complete remission of paraneoplastic cerebellar degeneration following treatment of the primary tumour. This is very unusual, however, and most patients do not improve even when treatment is begun early in the illness, before Purkinje cells are irreversibly damaged. Plasmapheresis, corticosteroids, immunosuppressive drugs, intravenous immunoglobulin, and rituximab have all been tried and may lead to mild symptomatic improvement in the ataxia. Paraneoplastic cerebellar degeneration may occasionally be associated with LEMS, both associated with SCLC and antivoltage-​ gated calcium channels antibodies. Recognition and treatment of the peripheral symptoms can lead to overall clinical benefits. In the future, non​paraneoplastic potentially treatable forms may be identified. Opsoclonus–​myoclonus Opsoclonus is a disorder of eye movements consisting of almost continuous chaotic, multidirectional, involuntary, high-​amplitude conjugate saccades that are often accompanied by synchronous blinking of the lids. It is usually considered to be a paraneoplastic syndrome complicating 2% of childhood neuroblastoma (dancing eyes syndrome) or a variety of tumours in adults, particularly breast cancer and SCLC, but there are cases that are non​paraneoplastic and self-​limiting (see next). Opsoclonus may be an isolated neurological sign, but is often accompanied by myoclonus of the trunk, limbs, head, diaphragm, larynx, pharynx, and palate, and ataxia, hence the term opsoclonus–​ myoclonus or opsoclonus–​myoclonus ataxia. Neurological symptoms precede identification of the neuroblastoma in at least 50% of patients, and the tumour may be missed by abdominal examination; thus, recognition of the neurological syndrome is an important clue to the presence of a neuroblastoma. There are reports of antibodies to neuroblastoma cell lines but no specific antigen has been defined. When a neuroblastoma is associated with opsoclonus–​myoclonus, there is a higher than expected incidence of intrathoracic tumours and of tumours with a benign histology. The prognosis of the neuroblastoma is better if opsoclonus–​myoclonus is associated than when there is no neurological complication, an observation not explained by earlier diagnosis when neurological symptoms are present. The neurological disorder responds to adrenocorticotropic hormone (ACTH) and to intravenous immunoglobulin but not to prednisone.

24.23  Paraneoplastic neurological syndromes

However, most patients suffer residual neurological damage, usually cognitive. Opsoclonus–​myoclonus is less common in adults, and in younger adults is often non​paraneoplastic. Nevertheless, about 20% of adult patients reported with opsoclonus–​myoclonus have an underlying cancer. The neurological symptoms usually precede diagnosis of the tumour and commonly progress over several weeks, although more rapid or slower progression may be observed. The cerebrospinal fluid may show a mild pleocytosis and an elevated protein. The MRI is usually normal. Neuropathological findings have been variable. In some patients there are no identifiable abnormalities. In others, the changes resembled those of paraneoplastic cerebellar degeneration with a loss of Purkinje cells, inflammatory infiltrates in the brainstem, Bergmann gliosis, and loss of cells from the granular layer of the cerebellum. The prognosis for recovery or partial remission of the neurological disorder is better for opsoclonus–​myoclonus than it is for paraneoplastic cerebellar degeneration. Improvement may follow treatment of the underlying tumour, and spontaneous partial remissions occur. Differential diagnosis includes non​paraneoplastic conditions such as viral infections, postinfectious encephalitis, hydrocephalus, thalamic haemorrhage, and toxic encephalopathies from thallium or lithium, amitriptyline overdose, and diabetic hyperosmolar coma. Limbic encephalitis Limbic encephalitis may occur as an isolated finding initially, but the paraneoplastic forms frequently progress to a more extensive encephalomyelitis. The neurological symptoms often precede diagnosis of the tumour by up to 2 years; sometimes the cancer is not detected until autopsy. Symptoms usually progress over several weeks, but the course may be more insidious. Anxiety and depression are common early symptoms, but the most striking feature is a severe impairment of episodic memory. Other manifestations include agitation, confusion, hallucinations, and partial or generalized seizures. The symptoms may spread to include other brain functions (e.g. the hypothalamus), with changes in appetite or sleep (e.g. hypersomnia). Dementia usually occurs, but occasionally there may be a spontaneous remission; an increasing number of these cases are now known to be associated with antibodies to voltage-​gated potassium channel complex proteins. Indeed, this test should now be sent off in any patient presenting with a rapidly progressive amnesic syndrome, as it is treatable. The cerebrospinal fluid commonly shows a pleocytosis and an elevated protein concentration in PNS cases. MR scans are usually normal but medial temporal abnormalities have been reported (Fig. 24.23.3). Inflammatory pathological changes affect the grey matter of the hippocampus, cingulate gyrus, pyriform cortex, orbital surfaces of the frontal lobes, insula, and the amygdala. No treatment has proved uniformly beneficial although spontaneous remissions have been reported and some patients have improved after treatment of the underlying tumour. If onconeural antibodies are negative and there is no evidence of a tumour, immunosuppression should be considered as recent studies have identified antibodies against novel cell-​ surface antigens (voltage-​ gated potassium channel complex proteins, LGI1, CASPR2, or NMDARs) which are associated with a favourable prognosis.

Fig. 24.23.3  Whole-​body FDG-​PET scan showing two hot spots in right middle lobe (arrow) from patient with cerebellar degeneration and anti-​Hu antibodies in whom chest radiography and CT of the thorax were both negative. Subsequent biopsy confirmed small-​cell lung cancer.

NMDAR antibody encephalitis This condition, relatively recently described, has proved to be common, particularly in younger adults and children. Patients present with neuropsychiatric features, sometimes following a viral illness, and progress rapidly to a severe encephalopathy with seizures, movement disorders, autonomic instability, and reduced consciousness. Despite the severity of the disease, the MRI is often normal or changes non​specific, but the cerebrospinal fluid often shows pleocytosis during the first days. Oligoclonal bands tend to appear later. Ovarian teratomas or cysts are found in up to 50% of the adult females, but tumours are less common in males or the increasing number of children identified, even within the first year of life. Removal of the ovary(s) and multiple symptomatic treatments are required, combined with immunotherapies with steroids, plasma exchange, and intravenous immunoglobulins; benefits may be evident within a few weeks but if not, rituximab and cyclophosphamide are recommended (see ‘Further reading’). Although many patients require intensive care for weeks or months, the long-​term prognosis is positive with a proportion returning to normal life particularly if identified and treated early. The ovarian tumours express NMDARs. Experimental results suggest that the antibodies reduce the number of hippocampal NMDARs in a reversible manner.

6389

6390

section 24  Neurological disorders

Brainstem encephalitis Paraneoplastic brainstem encephalitis is often associated with clinical and pathological evidence of encephalomyelitis elsewhere within the central and peripheral nervous systems, but may occur as the dominant or an isolated clinical finding. It is commonly associated with SCLC, but an identical clinicopathological syndrome may be seen in the absence of a malignancy. The clinical features vary according to the brainstem structures involved in the pathological process. Common manifestations include vertigo, ataxia, nystagmus, vomiting, bulbar palsy, oculomotor disorders, and corticospinal tract dysfunction. Less common clinical features include deafness, myoclonus of the palate, central alveolar hypoventilation presenting with respiratory failure and jaw dystonia. Basal ganglia involvement produces movement disorders including chorea or Parkinson’s syndrome, these being more commonly seen in patients with anti-​CV2 antibodies. Neurological symptoms may develop before or after discovery of the malignancy. The pathological changes are identical to those observed in other forms of paraneoplastic encephalomyelitis. Visual loss PNS can affect retinal photoreceptors, either rods or cones or both. They can cause a retinal vasculitis or optic neuropathy. Paraneoplastic retinal degeneration, also called cancer-​associated retinopathy, usually occurs in association with SCLC, melanoma, and gynaecological tumours. Typically, the visual symptoms include episodic visual obscurations, night blindness, light-​induced glare, photosensitivity, and impaired colour vision. Visual symptoms usually precede the diagnosis of cancer. The symptoms progress to painless visual loss. They may begin unilaterally but usually become bilateral. Visual testing demonstrates peripheral and ring scotomas and loss of acuity. Fundoscopic examination may reveal arteriolar narrowing and abnormal mottling of the retinal pigment epithelium. The electroretinogram is abnormal. Cerebrospinal fluid is typically normal, although elevated immunoglobulin levels have been reported. Inflammatory cells are sometimes seen in the vitreous by slit-​lamp examination. Retinal antibodies (e.g. recoverin), although well recognized, are not routinely available in most countries. Pathologically, cancer-​associated retinopathy is associated with a loss of photoreceptors and ganglion cells with inflammatory infiltrates and macrophages. The other parts of the optic pathway are preserved, although a loss of myelin and lymphocytic infiltration of the optic nerve may occur. Treatment of cancer-​ associated retinopathy is usually unsuccessful although a recent report describes improvement in some patients with the use of intravenous immunoglobulin. The condition is not recognized very frequently, and there may be non​paraneoplastic forms that are difficult to distinguish.

Spinal cord and dorsal root ganglia (See Box 24.23.2.) Necrotizing myelopathy This is an extremely rare PNS. The initial symptoms of muscle weakness and sensory loss in the arms and legs may be asymmetrical, but eventually signs become bilateral and symmetrical. Back or radicular pain may precede other neurological signs. Cerebrospinal fluid abnormalities may include an elevated level of protein and a

Box 24.23.2  Paraneoplastic syndromes affecting spinal cord and dorsal root ganglia • Sensory neuronopathy • Necrotizing myelopathy • Subacute motor neuronopathy • Motor neuron disease (primary lateral sclerosis) • Myelitis (as part of encephalomyelitis)

mild pleocytosis. Swelling of the spinal cord may be apparent on MRI. Typically, the neurological deficit progresses rapidly over days or a few weeks, ultimately leading to respiratory failure and death. There is no effective treatment. Pathologically, there is widespread necrosis of the spinal cord, often most marked in the thoracic segments. The necrosis involves all components of the spinal cord with white matter usually more affected than grey matter. Motor neuron disease (amyotrophic lateral sclerosis) There is controversy as to whether motor neuron disease can be regarded as a classical PNS. It is likely to be paraneoplastic in three distinct groups of patients; the first with a rapidly progressive amyotrophic lateral sclerosis picture associated with anti-​Hu antibodies; the second with primary lateral sclerosis and breast cancer; and the third with a subacute motor neuronopathy associated with lymphoma. Classical motor neuron disease in a patient with a previous history of cancer is probably not paraneoplastic, merely reflecting the occurrence of two reasonably common diseases of older age in the same patient separated in time. Myelitis Paraneoplastic myelitis is usually a part of the encephalomyelitis syndrome with inflammatory lesions elsewhere in the brain and dorsal root ganglia as well as the spinal cord. The clinical picture is dominated by the radicular element of a myeloradiculitis and is characterized by patchy wasting and weakness of muscles, sometimes combined with fasciculations. The upper extremities are often more severely affected than the legs, reflecting predominant involvement of the cervical spinal cord. There may be striking weakness of neck and intercostal muscles, resulting in respiratory failure. Sensory symptoms and autonomic dysfunction may be present. Sensory neuronopathy Paraneoplastic sensory neuronopathy is most commonly associated with SCLC. Symptoms typically begin before the cancer is identified, with dysaesthetic pain and numbness in the legs or occasionally in the arm(s), face, or trunk. The symptoms may be asymmetrical at onset but progress over days to several weeks to involve the limbs, trunk, and sometimes the face, causing a severe sensory ataxia. All sensory modalities are affected. Deep tendon reflexes are lost but motor function is preserved. Occasional patients have a mild and indolent neuropathy. The cerebrospinal fluid is typically inflammatory. Early pathological changes are limited mostly to the dorsal root ganglia, in which both a loss of neurones and the presence of lymphocytic inflammatory infiltrates are noted (Fig. 24.23.4). About 50% of patients with paraneoplastic sensory neuronopathy have pathological changes that may be clinically inapparent in other

24.23  Paraneoplastic neurological syndromes

A relatively pure sensory neuropathy, a mononeuritis multiplex due to microvasculitis, an acute polyradiculopathy, a focal neuropathy such as brachial neuritis, or an autonomic neuropathy may also be paraneoplastic. Most of these neuropathies are not associated with autoantibodies and the diagnosis is often one of exclusion.

Neuromuscular junction and muscle (See Box 24.23.4.) Paraneoplastic disorders of the neuromuscular junction include the Lambert–​Eaton myasthenic syndrome, myasthenia gravis, and acquired neuromyotonia. These disorders have a common pathogenetic mechanism—​they are caused by antibodies against ion channels and, whether paraneoplastic or not, they respond to immunological treatment. They are described in more detail in Chapter 24.18. Finally, because of its similarity to neuromyotonia, the stiff person syndrome is also included in this section. Whereas the more common non​paraneoplastic form is associated with antibodies to glutamic acid decarboxylase, the presence of amphiphysin or other onconeural antibodies should raise the suspicion of a tumour. Lambert–​Eaton myasthenic syndrome

(See Box 24.23.3.)

Lambert–​Eaton myasthenic syndrome (LEMS) results from a reduced release of acetylcholine at presynaptic nerve terminals. The same P/​Q-​type voltage-​gated calcium channels are found in small-​cell lung cancers. Interestingly, the richest source of P/​Q-​ type voltage-​gated calcium channels is the cerebellum, perhaps explaining the occasional relationship of paraneoplastic cerebellar degeneration and LEMS. LEMS can be treated either by immune suppression or by treatment of the underlying cancer when present. Patients with SCLC associated with LEMS have a better prognosis than patients with SCLC who do not develop a paraneoplastic disorder, but this could be partly due to earlier diagnosis.

Sensory and sensorimotor neuropathy

Myasthenia gravis

Peripheral neuropathies, particularly mild distal sensorimotor neuropathies, are common in patients with cancer and may be due to the metabolic or nutritional effects of late cancer, or associated with certain drugs (e.g. cisplatin). Some patients not known to have cancer, and who are not evidently systemically ill, present to the neurologist with a peripheral neuropathy that may be quite severe and disabling. It is estimated that about 10% of those patients whose initial evaluations do not reveal an obvious cause (such as vitamin B12 deficiency, alcohol, or diabetes), will eventually prove to have cancer as the underlying reason for the peripheral neuropathy. Paraneoplastic peripheral neuropathy may take several clinical and pathological forms. The most common is the distal, symmetrical, subacutely developing, sensory neuropathy which may be either axonal or demyelinating.

Myasthenia gravis occurs in 30% of patients with thymomas, and approximately 10% of patients with myasthenia gravis are found to have a thymoma. Usually the two are diagnosed synchronously but rarely myasthenia may develop many years after the thymoma, sometimes in association with other autoimmune diseases (e.g. red-​ cell aplasia).

Fig. 24.23.4  Sensory ganglionitis: dorsal root ganglion with hypercellular nodules marking the site of ganglion cell degeneration. Another ganglion cell (dashed arrow) is in the process of degenerating. A healthy ganglion cell is shown in the bottom left-​hand corner of the plate.

regions of the nervous system. As with other PND, this disorder rarely responds to treatment.

Peripheral nerves

Box 24.23.3  Paraneoplastic syndromes affecting peripheral nerves • Subacute or chronic sensorimotor peripheral neuropathy • Mononeuritis multiplex and microvasculitis of peripheral nerve • Brachial neuritis • Autonomic neuropathy (as part of anti-​Hu syndrome) • Demyelinating peripheral neuropathy (myeloma or plasmacytoma)

Polymyositis and dermatomyositis Only a minority of patients, usually older people, with polymyositis or dermatomyositis have an underlying malignancy as the cause. Dermatomyositis with typical cutaneous changes is more likely to be paraneoplastic than polymyositis. Females and males are affected in approximately equal numbers. Symptoms of proximal muscle weakness, with pain and high creatine kinase levels, generally precede

Box 24.23.4  Paraneoplastic syndromes affecting neuromuscular junction and muscle • Lambert–​Eaton myasthenic syndrome • Myasthenia gravis • Dermatomyositis, polymyositis, acute necrotizing myopathy • Neuromyotonia

6391

6392

section 24  Neurological disorders

identification of the cancer. The tumour may be at any site, but breast, lung, ovarian, and gastric malignancies are the most common. Corticosteroids, cyclosporin, and other immunosuppressants have been used successfully. Other reports suggest that high-​dose intravenous immunoglobulin is useful in patients unresponsive to other forms of immunosuppression. Neuromyotonia and stiff person syndrome Muscle cramps are a common complication of cancer, sometimes related to electrolyte imbalance or induced by chemotherapy. A much rarer but clinically significant PNS is acquired neuromyotonia. The disorder is characterized by muscle stiffness, cramps, and obvious rippling and twitching of muscles, sometimes leading to sustained abnormal postures. Relaxation after voluntary contraction is delayed. Symptoms persist during sleep (and are abolished by curare). Sudden prolonged bursts of high-​frequency, involuntary, repetitive muscle action potentials are seen on electromyography. The muscle spasms and rigidity are sometimes precipitated by activity, forcing patients to become sedentary. The disorder arises from peripheral nerves and is sometimes a part of the encephalomyelitis syndrome. The disorder is usually non​paraneoplastic, but may be associated with cancer including thymomas and SCLC. Antibodies against voltage-​gated potassium channels are often positive (Chapter 24.24). Plasma exchange improves the patient’s condition; but they often respond to anticonvulsants alone. Injection of IgG from affected patients into experimental animals can reproduce evidence of peripheral nerve hyperexcitability. Stiff person syndrome may superficially resemble neuromyotonia, but has a central origin and is usually not paraneoplastic. This rare disorder is clinically characterized by stiffness and rigidity, with episodic spasms of axial muscles. A variant of the syndrome affects the limbs. Painful reflex spasms can occur in response to tactile stimuli or startle. Muscle action potentials are normal on electromyography

but the activity is continuous and excessive and increased by voluntary activity. The disorder is usually autoimmune, associated with antibodies against glutamic acid dehydroxylase; since this antibody is also important in type 1 diabetes, the assay is widely available. When paraneoplastic, it can be associated with lung or breast tumours, often with the appropriate onconeural antibody. Recently antibodies to glycine receptors have been recognized in patients with stiff person syndrome or a form of progressive encephalomyelitis with rigidity and myoclonus.

FURTHER READING Candler PM, et  al. (2004). A follow up study of patients with paraneoplastic neurological disease in the United Kingdom. J Neurol Neurosurg Psychiatry, 75, 1411–​15. Dalmau J, et  al. (2011). Clinical experience and laboratory investigations in patients with anti-​NMDAR encephalitis. Lancet Neurol, 10, 63–​74. Giometto B, et al. (2010). Paraneoplastic neurologic syndromes in the PNS Euronetwork database: a European study from 20 centers. Arch Neurol, 67, 330–​35. Graus F, et  al. (2004). Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry, 75, 1135–​40. Höftberger R, Rosenfeld MR, Dalmau J (2015). Update on neurological paraneoplastic syndromes. Curr Opin Oncol, 27, 489–​95. Kayser MS, et al. (2010). Psychiatric manifestations of paraneoplastic disorders. Am J Psychiatry, 167, 1039–​50. Rees JH (2004). Paraneoplastic syndromes: when to suspect, how to confirm and how to manage. J Neurol Neurosurg Psychiatry, 75 Suppl 2, ii43–​50. Vedeler CA, et al. (2006). Management of paraneoplastic neurological syndromes: report of an EFNS Task Force. Eur J Neurol, 13, 682–​90.

24.24

Autoimmune encephalitis and Morvan’s syndrome Camilla Buckley and Angela Vincent

ESSENTIALS Autoimmune limbic encephalitis—​typical presentation is with acute or subacute onset of short-​term memory loss, seizures, and disorientation. MRI characteristically shows striking abnormalities in the hippocampus. Antibodies against cell-​surface proteins that are components of voltage-​gated potassium channel complexes are found in a high proportion and are probably pathogenic. Aside from supportive care, treatment is with immunosuppression, often comprising corticosteroids with intravenous immunoglobulin and/​ or plasma exchange. Morvan’s syndrome—​a very rare condition presenting with varying degrees of neuromyotonia, memory loss, confusion, sleep disturbance, and autonomic features, also with antibodies to voltage-​gated potassium channel-​complex proteins, in about 90% of patients. Autoimmune encephalopathy with antibodies to N-​ methyl-​ D-​ aspartate receptor (NMDAR)—​ a neuropsychiatric illness, often affecting young women who may have an associated ovarian teratoma. Prompt treatment with immunosuppression can lead to good outcomes but there is a 5% mortality rate and delayed diagnosis is common in patients with less typical presentations.

Autoimmune limbic encephalitis with VGKC-​complex antibodies Epidemiology Since its first recognition in 2001, hundreds of patients have been identified with autoimmune limbic encephalitis (LE) associated with antibodies that immunoprecipitate voltage-​gated potassium channel (VGKC)-​complex proteins. Preliminary epidemiology suggests that it is more common in men (2:1) and that the median age at onset is 65 years. The phenotype has been recognized mainly in patients over the age of 18 years at onset.

Clinical features The classic presentation is with subacute onset of short-​ term memory loss, seizures, disorientation, with psychological disturbance or hallucinations. Additional features that may occur are sleep

disturbance, autonomic dysfunction, and neuromyotonia, but these would be more typical of Morvan’s syndrome (see next). The most striking feature on examination is the profound disorientation and memory loss, leading to poor performance on bedside cognitive tests such as the Mini-​Mental State Examination. Neuromyotonia (see Chapter 24.19.3) may be evident, but often the examination is otherwise unremarkable. Some patients develop only one aspect of the syndrome (e.g. isolated memory loss or isolated temporal or frontal seizures), but are otherwise similar to those with the full syndrome. Some patients report an influenza-​like illness one to two weeks earlier. Recently, an increasing number of patients with immunotherapy-​responsive brief frequent dystonic seizures (termed faciobrachial dystonic seizures), that often precede the limbic disturbance by days to months, have been recognized.

Investigations Hyponatraemia is present in 80% of patients, usually accompanied by a low plasma and urine osmolarity. Other routine blood tests are normal. The cerebrospinal fluid is often normal but may show a mild pleocytosis. VGKC-​complex antibody titres are characteristically very high in these patients (more than 400 pmol/​litre and often more than 1000 pmol/​litre (normal range less than 100 pmol/​ litre)), and higher than the titres commonly found in patients with neuromyotonia (usually less than 400 pmol/​litre) (Fig.  24.24.1b). MRI shows striking abnormalities in 70% of patients and it is often these that lead the clinician to suspect the diagnosis and request the confirmatory serological test (Fig. 24.24.1a). The most classic change is high signal restricted to the hippocampus (either unilaterally or bilaterally), best seen on T2-​weighted or FLAIR (fluid-​ attenuated inversion recovery) sequences, with associated swelling of the affected area. A few patients have more widespread areas of increased signal in the medial temporal lobes and amygdala. LE associated with VGKC antibodies can occasionally (4000

3000 VGKC antibody

6394

2000 1000 400 300 200 100 0 −100

NMT

LE

Fig. 24.24.1 (a) T2-​weighted coronal MRI of the brain with the red circles highlighting the abnormal high signal bilaterally in the hippocampi of a patient with limbic encephalitis (LE) associated with voltage-​gated potassium channel (VGKC) complex antibodies. (b) VGKC-​complex antibody levels in patients with LE compared with those in patients with neuromyotonia. The horizontal line denotes the cut-​off for healthy individuals. LE patients with these antibodies usually have values more than 400 pmol/​litre, these are common and up to 1000 pM/​litre in the rare Morvan’s syndrome (not shown), whereas they tend to be lower titre and absent in >60% of patients with neuromyotonia.

immunoprecipitation of VGKC-​complexes, or by binding to the individual proteins by cell-​based assays. In LE and faciobrachial dystonic seizures, they are most often directed to LGI1; CASPR2 antibodies are found in neuromyotonia and Morvan’s syndrome. However, VGKC-​complex antibodies without LGI1 or CASPR2 reactivity may not be helpful in achieving a diagnosis, and their significance needs further research.

Treatment Initially patients often require fluid restriction to manage the hyponatraemia, antiepileptic drugs for their seizures, antipsychotic drugs to control paranoid ideation, and corticosteroids with plasma exchange or intravenous immunoglobulin for acute immunosuppression. The choice of antiepileptics is complicated by the hyponatraemia, which can be profound. Often the seizures do not respond well to antiepileptics alone and do not start to reduce in frequency until immunosuppression has been established. There have been no randomized controlled trials to determine the most effective immunosuppressive regimens in these patients and currently the protocols are similar to those used to treat patients with autoimmune disorders of the neuromuscular junction (see Chapter 24.18). Corticosteroids appear to be a particularly important component because longer-​term follow-​up suggests that those treated with intravenous immunoglobulin alone respond less well than those treated with intravenous immunoglobulin and steroids. Although early treatment is recommended, as it appears to be associated with improved prognosis, even late introduction of steroids and other immunosuppression can be beneficial.

Differential diagnosis Acutely, the differential diagnosis lies mainly with infectious causes of LE, the most common being herpes simplex encephalitis (HSE), and most patients will have a cerebrospinal fluid polymerase chain reaction for HSE performed on admission, particularly if they have

a high fever and severe headache. Korsakoff ’s pyschosis can present similarly and so an accurate alcohol history and suggestive blood tests, such as liver function tests and mean cell volume, should be performed. The other main differential lies with paraneoplastic LE, so all patients need imaging to detect associated tumours and, in the right context, it may be appropriate to look for the particular antibodies seen with these disorders (see Chapter 24.23). Other forms of potentially immunotherapy-​responsive LE are now being recognized, some of which are associated with antibodies to other neuronal surface antigens (e.g. N-​methyl-​D-​aspartate receptor, see next and Chapter 24.23) and can be non​paraneoplastic. Table 24.24.1 summarizes the most useful antibodies and associated syndromes. Morvan’s syndrome, although very rare, can present similarly to LE but requires sleep disturbance (mainly insomnia) and is also distinguished by additional peripheral and autonomic features (see next), that can go unrecognized. In addition (as with the autoimmune disorders of the neuromuscular junction), there are patients with a similar clinical phenotype who respond to immunomodulatory therapies, but in whom no antibody is detectable by current methods, although new diagnostic tests will undoubtedly emerge.

Pathogenesis VGKC-​complex LE is probably an immune-​mediated disorder given the time course of patients’ clinical, serological, and radiological responses to immunosuppression. VGKC is a transmembrane protein that is densely expressed in the hippocampus and elsewhere in the brain, where it is complexed with LGI1, CASPR2, and other proteins. Genetic mutations in VGKC can cause seizures both in mice and in humans and, as the channel is involved in stabilizing the membrane potential, its dysfunction will result in neuronal hyperexcitability. There is evidence that LGI1 antibodies are pathogenic; they disrupt the role of LGI1 in modulating VGKC function in hippocampal cultures. Less is known about CASPR2 antibodies.

24.24  Autoimmune encephalitis and Morvan’s syndrome

Table 24.24.1  The most useful antibodies and their associated syndromes Antigen

Demographics

Most common clinical phenotypes/​tumours

N-​methyl-​D-​Aspartate receptor (NMDAR)

80% females Age range: 50% males Age range: wide

Progressive encephalomyelitis with rigidity and myoclonus, stiff person syndrome, or related features; thymoma, lymphomas, breast