Oxford Textbook of Medicine, 6e (May 6, 2020)_(0198746695)_(Oxford University Press).pdf 9780198746690, 9780198815334, 9780198815358, 9780198815372, 9780198847410

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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

1

SECTIONS 1-9

Firth Conlon Cox ISBN 978-0-19-885344-2

9 780198 853442

INTERNATIONAL EDITION

Oxford Textbook of

SIXTH EDITION

1

2

2

Medicine SIXTH EDITION VOLUME 1

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 F O R 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 1: Sections 1–9

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

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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

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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

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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.

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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.

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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.

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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

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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.

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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.

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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.

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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 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 Anonymous 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

1.1

On being a patient Christopher Booth†

ESSENTIALS Those who practise medicine should remember that we are all patients at some time, most likely at the beginning and end of our lives. We therefore begin this textbook with an account of encounters with the medical and nursing professions, written by an outstanding doctor, medical historian, and leading clinical scientist. After a highly distinguished and eventful career which spanned the introduction of the British National Health Service in 1948, Christopher Booth died in 2012, aged 87 years. Latterly, he experienced the protracted misery of illness punctuated by repeated surgery; but to the end he retained his intellect and penetrating wit. His piquant observations are a challenge to us all as we try to provide care for our patients, as is his parting shot: ‘If you are a physician, no matter how important you may think that you are, you should, so far as your own illnesses are concerned, consider yourself a layman.’

Introduction We are all patients sooner or later, but particularly at the beginning and end of our lives. A general practitioner brought me into the world, a second twin, by manual removal when my mother was suffering from uterine inertia. Later, as a four-​year-​old, I can recall being injected against some form of infectious disease and passing out cold on the floor. There were then many infections to which my generation was susceptible. Chickenpox, mumps, and measles were frequent. During the misery of measles I remember seeing the flag on our nearby church flying at half-​mast for the death of King George V. Our doctor, the one who had delivered me, was a tall, distinguished man, smelling, as they all did in those far-​off days, of ether. Later I contracted scarlet fever, a streptococcal illness of importance in those days before antibiotics. I was kept in strict isolation at home, with a resident nurse to care for me and daily visits from our general practitioner. Between those childhood days and the years of maturity, I was but rarely a patient. There was a hazardous episode during training as a naval diver when I had an alarming allergic reaction to the sting of a jellyfish (Portuguese man-​of-​war). The main symptoms were caused by severe oedema of the throat, and breathing became difficult. I had †

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

no idea then, long before I became a physician myself, that the large dose of morphine given by the naval doctor might well have exacerbated the respiratory distress. Beyond that, as a young man I was only a patient for a brief period with glandular fever. I have been fortunate to escape those chronic conditions such as multiple sclerosis, Crohn’s disease, or rheumatoid arthritis that blight young lives so terribly. It was not until I was in my fifties that I developed any significant illnesses. I had intermittent atrial fibrillation, which usually subsided with antiarrhythmic drugs. My blood pressure was normal and has remained so. There were repeated electrocardiograms, but no attempts at cardioversion by DC electric shock. For the first time I began to make visits to hospital outpatient clinics or enter the sumptuous rooms of those who undertook private practice. It was this experience that made me realize that the particular feature of being a patient means having patience. One came to accept that so much time is spent waiting—​for an appointment, for a blood test, or an X-​ray, for a consultation, or for drugs from the hospital pharmacy. As the years go by, you should realize that, like your patients, you are more liable to afflictions which may be truly frightening and threaten your life over prolonged periods. My next encounter with medicine in practice came about entirely by chance. I had been retired for some years when my partner encouraged me to have a ‘check-​up’. The excellent lady general practitioner was not one of those many who spend more time staring at a computer screen than they do looking at you. She examined me carefully, found nothing amiss but despatched some blood tests. These too were normal with one exception, a test with which I  was then unfamiliar. The blood concentration of prostate-​specific antigen (PSA) was 15 µg/​litre and thus above the healthy range. I was informed that this suggested the presence of a symptomless cancer of the prostate and although I was reassured that the significance of the finding was uncertain, a subsequent prostate biopsy revealed that there was indeed cancer of the prostate, apparently localized to the gland. The question therefore arose as to what should be done. Much today is made about choice; perhaps this has value when there can be truly an informed discussion, as subsequent events in my case show. So far as I was concerned, I had no interest in where I should be referred for treatment. My doctor could advise me about that. Nor had I much interest in choosing between the options available—​ surgery, radiotherapy, or hormonal treatment. It was for my advisers to recommend what they thought was best. It was only in later years that I realized that

4

SECTION 1  Patients and their treatment

the choice of radiotherapy was unfortunate. At the time, daily treatment as an outpatient for more than six weeks was a tormenting experience since the resulting radiation cystitis caused excruciating pain. I was constantly reminded during those days of the urologist who prayed nightly to his maker: ‘Lord, when thou takest me, take me not through my bladder.’ In the end the symptoms subsided. The PSA level returned to normal and has remained so. Mercifully, the cancer had been eradicated. I soon developed severe muscle pain—​diagnosed by a rheumatologist as polymyalgia rheumatica and which required treatment with steroids. Nothing will ever convince me that these symptoms were not the result of the radiotherapy. These events took place during my 70th year. A few years later, while in manifest good health, illness suddenly struck again. One evening, out of the blue, I developed severe upper abdominal pain. In the absence of an out-​of-​hours service from the local general practice, at midnight we attempted to obtain medical advice from NHS Direct on the telephone—​this was a fruitless task made very trying by ‘language difficulties’. I finished up in the accident and emergency department of our local hospital. There, a very competent Asian doctor treated me with pethidine: and there too I first experienced lying on a trolley for the rest of the night. Lying on a trolley is no great problem for a patient blissfully enjoying the delight of repeated injections of pethidine but it is extremely dispiriting for one’s partner. Deeply troubled by my illness, seated in a small and uncomfortable plastic chair, my wife had nothing to do but watch and wait hopefully for the dawn. A week in hospital taught me how to manage my life while attached to an intravenous drip, which had to accompany me at all times. It turned out that I had acute pancreatitis, possibly associated with a gallstone. The pain soon subsided and, apart from one other minor event, has not recurred. All remained well for four or five months. Then, attending a clinic for a follow-​up appointment, I found out why, for a little while my wife had noticed that I was thirsty and polyuric. She, of course, had made the right diagnosis, which my medical adviser at once recognized when he smelt the acetone on my breath and found my blood sugar to be in excess of 30 mM. I was immediately admitted and the diabetes was brought under control by intravenous therapy. On this occasion I was admitted to a geriatric ward where the noises at night generally made sleep no more than an aspiration. One particularly unfortunate man, suffering from expressive dysphasia caused by a stroke, kept shouting in frustrated attempts to make himself understood. Becoming a diabetic at once changes your lifestyle. You find out how to control your blood sugar, initially on oral medication. But soon, as is so often the case, you require subcutaneous insulin and you now have to learn how to inject yourself as well as keeping to a strict diet. You also have to ensure that you avoid the unpleasantness and fear of hypoglycaemic attacks. In addition, you may require visits to the foot clinic to ensure you neither develop ulcers nor infected toe-​nails. If, in the case of that illness, it was a matter of one thing following another, my next and most serious medical encounter was even more Odyssean. By my 82nd year, I had thought that the prostate cancer, 12 years after radiotherapy, could safely be forgotten. The PSA concentrations had remained within the normal range and I seemed in good health. But then haematuria developed. Cystoscopy as an outpatient failed to identify a source for the bleeding and while waiting for an appointment for an inpatient cystoscopy, I suddenly developed clot retention. It is no pleasant experience driving through metropolitan rush-​hour traffic during an attack of acute retention. Nor was attention at once forthcoming in an accident and emergency department, dealing as usual with the overwhelming evening intake of drunks and dropouts. Finally installed once more on a trolley, a

junior house officer attempted the necessary catheterization. Only after repeated and painful efforts is a more experienced registrar sent for; he at last blissfully relieved the obstruction. Then again, the long wait—​and finally, admission to a high-​dependency ward. I remained in hospital for treatment over the next three and a half months. The events of that first week in a high-​dependency ward set the scene for what was to happen during the next months. A regime of constant bladder washouts was instituted in the hope that the haematuria would subside. Several drugs were tried, all to no avail. There was obvious reluctance to undertake surgery in an elderly patient for a condition which showed no sign of being malignant. So in due course I was transferred to a single room in a urological ward where the haematuria persisted despite continuous bladder washouts. Maintaining the flow of fluid from two large containers hanging on a drip stand became one’s constant concern, nurses not always leaving enough fluid supplies, particularly at night. If the flow ceased, clot retention would recur. For a brief period I was sent home in the hope that the symptoms would subside. But it was to no avail—​as was the search for the cause of the bleeding. Two careful cystoscopies under general anaesthesia failed to identify a bleeding point, another reason why there was reluctance to consider surgery at that time. One soon became used to a ward routine that scarcely varied from day to day, with the exception that at weekends nothing ever seemed to happen. You might be gently woken by a kind nurse from the Philippines wanting to give you something but whose command of English might not be fully up to the task. You would be increasingly less surprised to see the unfamiliar blank wall that had been there when you drifted off to sleep. You would at once be aware of noise, trolleys being pushed along corridors, the clatter of metal containers, and sometimes the cries of the afflicted. You have breakfast, the same cereal most days, sometimes porridge. You are given the morning’s drugs. A venesector takes your blood every day, the veins becoming progressively less easy to find. Your blood pressure, oxygen saturation, and pulse rate are measured on a machine every four hours or so and it may be necessary for a drip to be inserted, a task undertaken better by some than others. Your insulin dosage has to be adjusted, depending on the results of your blood sugar obtained by pinprick. Your bed is made, your body washed. You sometimes see the intern who has the care of you, but they change frequently. Then there is the consultants’ ward round. Instead of a single individual taking care of you, you find that up to five consultants, and their acolytes, visit together. Invariably courteous and considerate, you learn to hang on every word. There are those who find the recumbent position of the patient in bed, in the presence of massed ranks of consultants, to be demeaning. I have preferred not to acknowledge my obvious inferiority but to imagine myself a mediaeval potentate receiving his courtiers. Then, at last, another surgeon is brought to see me. The waiting is now over. Briskly and unhesitatingly, he decides to operate within three days. I am lucky—​he is one of the best in the country. The operation is to be a total cystectomy and prostatectomy, the creation of an intestinal pouch to replace the bladder and transplantation of the ureters into this pouch. One can easily understand why my advisers had been so hesitant to inflict such a procedure on an individual in his 82nd year, irrespective of my status as a former Professor of Medicine. Fortunately the surgery is brilliantly successful and we now have a diagnosis. The pathologist reports that there are no specific bleeding points in the bladder but that there are signs of widespread radiation damage. As with my diabetes, one thing has again led to another: the diffuse pathological bleeding was caused by that course of radiotherapy given so long ago. Surgical success depends on the support you receive before and after the operation. Languishing in hospital, I had lost a considerable amount

1.1  On being a patient

of weight and nutritional advice from a gastroenterologist was needed for recovery. There were other complications. My thumbs became septic because of a faulty technique in obtaining blood for sugar estimations and both were later shown to be infected with the near-​ubiquitous methicillin-​resistant Staphylococcus aureus (MRSA)—​as was a small unhealed focus in my abdominal scar. More drugs—​this time, antibiotics to control the MRSA. Still feeling weak and scarcely able to walk the distance from the kerb to my front door, I was sent home. I felt terrible that day and by evening had developed severe dysphagia. Back in hospital I was soon drifting dreamingly in and out of consciousness; little did I know that my wife had been told by my advisers to expect the worst. By the next morning, however, the gastroenterologists had done an oesophagoscopy and identified oesophageal candidiasis. I was treated with nystatin and soon recovered. Although the appetite took time to recover, I was able to eat again and returned home to convalesce. But it was to be a year or more before my strength fully recovered and for some months my voice was weak and husky. Certain memories of life as a hospital patient persist. I encountered so many consultants during that time: seven urologists, a gastroenterologist, a cardiologist to check whether my heart would stand up to surgery, a diabetologist, a rheumatologist to check my steroid dosage and the status of my polymyalgia rheumatica, as well as a dermatologist when a presumed drug eruption occurred. There was also the infectious diseases expert who treated the MRSA infection. Throughout, the international nature of the team who contributed to my care was impressive. Among doctors, nurses, porters, radiographers, and other staff, I counted members of 38 nationalities, including many nurses from sub-​Saharan Africa and the Philippines—​clearly countries favoured for recruitment to the United Kingdom and one wonders about their loss of national skills. Despite laudable attempts to make it tempting, hospital food was generally unappetizing and I depended largely on my wife for sustenance: she brought in dinner with a small bottle of red wine most evenings, and on this I survived. Yet above all, a patient depends on the support of friends and family, upon whom a greater burden lies than is often realized: my wife visited on every day of my incarceration—​a task that she undertook despite her commitment to our household and her own affairs, when travel was not always easy and when, having arrived at the hospital, parking might be difficult. It is the doctors and nurses whom you meet every day who can do most to sustain your spirits. As a medical student in Scotland I was taught to treat a duchess or a dustman just the same. The patient should, of course, always be treated with respect: I am convinced that this starts with their being addressed naturally using their surname (given name) rather than the all-​too-​prevalent belief that use of their first name would be preferred from the outset. Clearly this familiarity may come later—​by invitation-​and when desired by the name-​holder. It is astonishing to see how frequently patients are offended by the presumption of first-​name familiarity, at least in hospitals in the United Kingdom; it is a behaviour perceived as institutionally controlling by adults of all ages and status—​and not only by elderly professionals. But if the staff genuinely sympathize with your lot, spending time answering your questions and those of your family, you are greatly encouraged. It is so often the little things which count. I recall being much moved and heartened by a young Zimbabwean nurse, who had cared for me during one of my hospital admissions and who later took the trouble to visit me in a far-​off part of the hospital to see how I fared. Continuity of care is also important. Being under the care of an intern or nurse whom you get to know and who understands your illness is essential for morale. Having to explain your problems to a stranger

who drops in for a brief uncomprehending visit after hours or at a weekend does nothing for confidence. There are also practical matters which may be overlooked. Whereas major interventions involving surgery, for example, may be explained scrupulously, staff doing apparently simple procedures such as venesection, cannula insertion, arterial puncture for blood gas determination or catheterization and the like, often forget that these activities also require explanation since they may distress anxious or confused patients—​to whom the slightest invasion of their person rapidly becomes anathema. Anxious despondency also mounts when there is unaccountable delay in carrying out procedures that have been arranged: timely explanation can often mollify this distress but when it comes to the relief of pain, there is no excuse for delay—​diagnostic or otherwise. The failure immediately to catheterize a patient with acute retention of urine is clearly unforgivable but as I learnt, is still regrettably common. Practical and important though many procedures are, requiring both skill and experience—​for the patient, nothing can replace the compassion and sympathy that the caring professions owe the afflicted. So many aspects of excellent practice stem from these simple human qualities, which thankfully survive despite the strong business ethic that pervades medicine in many countries today. Of the lessons that I have learnt, however, perhaps the most important is that to be a patient entails, as the Oxford English Dictionary puts it, ‘enduring pain, affliction, inconvenience, etc, calmly, without discontent or complaint’. It is equally necessary to be ‘able to wait calmly’. In our later years, it easier to agree with this advice. After all, as a man reaches his eighties, he has little choice but to accept with equanimity the world of Shakespeare’s sixth age, when he shifts Into the lean v and slipper’d pantaloon, With spectacles on nose and pouch on side His youthful hose, well sav’d, a world too wide For his shrunk shank; and his big manly voice, Turning again towards childish treble  . . . 

That passage accurately describes me in the immediate postoperative period, even to the urostomy pouch—​but my voice has now recovered. I do not, however, wish to survive into the last of Shakespeare’s seven ages when we are doomed to ‘mere oblivion; sans teeth, sans eyes, sans taste, sans everything’. While I have so far benefited from the courageous decisions of those who did not give up when the end looked inevitable but who saw that there was a ‘quality of life’ worth striving for, I only hope that common sense, compassion, and proper conference with my nearest and dearest will be brought to bear when the seventh age draws nigh. One does wonder if such a perspective truly holds today—​especially in wards for older people in modern Western hospitals. One other lesson remains. If you are a physician, no matter how important you may think that you are, you should, so far as your own illnesses are concerned, consider yourself a layman.

FURTHER READING Booth CC (1987). Doctors in Science and Society. Essays of a Clinical Scientist. Cambridge University Press, Cambridge. Cox TM, Tansley EM (2012). Sir Christopher Charles (Sir) Booth. Royal College of Physicians of London, Munk’s Roll, Volume XII (2005-) http://munksroll.rcplondon.ac.uk/Biography/VolumeXII. Lock SP (2012). Christopher Booth. BMJ, 345, e5768.

5

1.2

A young person’​s experience of chronic disease Anonymous

ESSENTIALS For as long as I can remember, my life has involved hospital care, both as an inpatient and as an outpatient. I’ve never really thought of myself as having a chronic condition, but I have three of them— haemophilia A, hepatitis C and HIV—and have had innumerable medical interactions. Over the years there have been many changes in my treatments, and although these have been to my benefit I have found that they can be unsettling, as are changes in the medical team looking after me, and some changes in the ways that doctors have tried to communicate with me, a notable ­example being reluctance to give clear recommendation about the best course of action. What remains constant is the trust and communication you can share with the medical team.

The Collins dictionary defines chronic as something continuing for a long time; constantly recurring or (of a disease) developing slowly, or of long duration. I’ve never really thought of myself as having a chronic condition. I recently turned 39 but it never really struck me. I was diagnosed with severe haemophilia A at the age of about 14 months. Later, I remember having hepatitis (when I was older this was confirmed as hepatitis C) and later still, I remember being told I was HIV positive. It wasn’t until recently that these infections have been referred to as chronic conditions and it feels strange writing the words as they seem to add a sense of permanence to my illnesses. For as long as I can remember, my life has involved hospital care, both as an inpatient and as an outpatient, under the care of many different departments of the National Health Service. There have been numerous medical interactions, too many to recount here. However, as time has progressed there have been underlying broader themes that affect the level of care I have received and I think are very relevant to anyone who is receiving ongoing medical care. These themes are Trust and Communication, the cornerstones of relationships. ‘Learning to trust is one of life’s most difficult tasks’—​Isaac Watts

A trip to the hospital or to see the doctor for a single issue doesn’t require an advanced level of trust. A chronic condition requires the patient to develop a bond of trust with their care provider to make

decisions that will maintain or, ideally, improve the condition. Vice versa, the care provider, be it doctor or nurse, needs to be able to trust the patient to take on board their advice and be sure any medical plan will be followed, whether it is a set of exercises or a rigid treatment regime. This is a process that occurs over time and, with a chronic condition, time is something that can be afforded. I was diagnosed with haemophilia A as an infant. This was when my family and I were introduced to my first doctors. These were the doctors who explained what haemophilia was, how to treat the condition, and how best to manage the condition and its consequences. They taught my mother, and then me, how to infuse factor VIII. These were the doctors who I grew up with. I learnt their mannerisms, I grew accustomed to their tones of voice, and how these would change depending on what they needed to tell me. The trust was solidified by their consistent approach to treatment and, for want of a better word, the safety and assurance they provided. When they retired in my early teens, this process had to begin again with new doctors and a change in treatment procedures (something I will touch on later). Not only is trust important, but familiarity also plays a part in the feeling of safety within healthcare. My haemophilia clinic has been in the same place for 39 years. It has had a facelift and been made slightly bigger, but it is still the same place. My HIV clinic was built alongside it. For all my check-​ups and appointments I  have been going to the same place. For years there were the same staff, medical, nursing, clerical; everyone knew my name and who I was. It is like a home from home (I even refer to it as mine without conscious thought). But this familiarity and trust can cause problems for both the patient and medical staff. I have never really liked change. It could be argued that my conditions are always there and, to a point, are stable now anyway. Previously they were changeable, be it the development of antibodies to factor VIII, a reduction in my CD4 count, or the need to change my HIV medication. There is always the anxiety when I go to the hospital that something might have changed for the worse. Changing doctors and locations immediately makes me uneasy. A prime example would be going to university. I went away to university to study when I  was 18. While most freshers were finding their feet with new friends, housemates, and experiences I was also having to meet new doctors, which for me

1.2  A young person’s experience of chronic disease

was one of the most uneasy experiences of my life. During the three years at university I can count on one hand how many times I visited the local haemophilia clinic in the university city. It was hard to develop trust, especially as I knew my time there would be temporary. This is not to say I was unsure of the care I would receive, it was more that I  couldn’t get used to their systems of working. I  didn’t have any shared experiences with the staff and no one knew my name, knew my foibles, or knew my family. I never felt at ease, to the point I made sure all my haemophilia check-​ups were at a time when I was home from university so I  could have them close to home in my usual clinic. Even during times of bleeding (unless it was an emergency) my parents would pick me up and take me to my regular haemophilia centre. My HIV experiences were very similar. I tried to make my check-​ up appointments at my usual clinic when I was home, but sometimes this was not always feasible. Also, in my second year it was decided that that I needed to start taking HIV medication. The decision was made by my regular clinic doctor but, due to the regularity of check-​ ups to monitor me on the new regime, these had to be conducted while at university. I never felt at ease there. I had spent years with my regular doctor and, again, a relationship of trust had been built up. I knew when he was going to tell me good news and bad. This wasn’t the case when I was at university. Every dip in CD4, or rise in viral load, or the need to change my regime was a shock. I couldn’t pre-​empt how my appointment would go. I no longer had that split second of preparation because I couldn’t read the tone of voice or body language easily. This was not an ideal situation for the doctor, and I believe I came across as defensive or cagey. I didn’t feel I could be open with him, which can only have made his job harder. This affected my care to the point I left it probably longer than I should have done to notify my doctor when I noticed I was having side effects to a new triple therapy regime (one of several during my time at university). Trust is vital for both sides when dealing with chronic conditions. Linked to this is the topic of communication. I’ve already touched on this; my failure to communicate a change in condition and the ability, once a relationship has been established, to communicate without speaking. Over the years, I have noticed the change in the way patients are spoken to. As an inpatient, as a child, I was spoken to softly with a high degree of empathy, everything was explained clearly in plain language. As I got older and moved to an adult ward,

I noticed that the language became more clinical. The empathy is not lessened but it is different, almost as if there is an assumption that now you are older you have more ability to cope. But any change in condition, any increase in pain will always be scary, no matter how old you are. As time goes by, medical practices change. I  imagine as a healthcare professional this is all part of the ongoing professional development, be it training courses or conferences. New practices, new treatments are taught. As a patient who only sees a doctor/​ nurse once in a while, these changes can go unnoticed. However, I  generally see one of my doctors/​nurses/​physiotherapists every 4 months, and I notice differences in protocols, which can be unsettling. Over time one gets used to a certain way of doing things and suddenly things change, with little or no time to adjust to the changes. A prime example is during consultations. It used to be that you were told the treatment options and the clinician would see what you thought about each option and then it would be made clear which option the clinician believed to be best. In some cases, they would decide for you on the best course of action. However, during a consultation for a surgical procedure, protocols seemed to change. All options were outlined and then I was asked ‘What do you want to do?’. It took a lot of questioning to get a suggestion from the doctor about what the best option was likely to be. There is a lot of pressure on the individual, as the patient, to make this decision. I felt once the options were outlined, communication stopped. While one knows how the condition feels and affects your day to day being, the decision for ongoing treatment/​surgery cannot be made without medical knowledge and input. The communication of this knowledge, not just what the options are, but what each one means and which would be the most viable option, remains a vital part of the consultation. With a chronic condition the patient stays with the care team for a long time; longer than some of their own personal relationships. I’ve seen young house officers develop into renowned surgeons. I’ve seen doctors and nurses come and go. I’ve seen changes to buildings and to treatments. The only real constant in the life of a patient with a chronic condition is the patient themselves. Everything seems to change around you but you stay, perhaps a little older, a little greyer and, hopefully, with little fluctuation in your condition(s). What remains constant is the trust and communication you can share with the medical team.

7

1.3

What patients wish you understood Rosamund Snow†

ESSENTIALS If I have an acute curable condition, it is likely that your aims as a doctor and mine as a patient are aligned:  we both want the problem to go away. But more people are now like me, living with disease rather than dying of it, and that change means that your role becomes less healer and curer, and more an advisor and supporter. A good model of care would be for you to see me, a patient with a long-​term condition, as a full-​time colleague on a job where you are only working part-​time. Please understand that I am the primary caregiver, part of the healthcare team, in fact I am leading that team most of the time. I  am very likely to access patient-​ sourced information (support groups, online forums, crowd-​ sourced information) and find this valuable, and you should not feel threatened by this. If you see me as a full-​time worker with local practical knowledge, and yourself as an advisor to our project rather than leader, that may help us work together. Where we can, let’s learn from each other.

Introduction I’m a patient. I have lived with a demanding long-​term condition for more than 25 years. I also teach medical students with the help of other patient tutors and carers, and I am the BMJ’s Patient Editor. This means, first of all, that I have had to change the way I interact with the world, because my condition makes me different from healthy people. It means I have to spend a lot more time with doctors and other healthcare staff than most people of my age. But it also means that I have been given the chance to work with patients and carers from all kinds of backgrounds to ensure their experience and expertise is shared with readers of the BMJ, working with them to create educational articles that doctors can use to improve their practice. At the University of Oxford, I  collaborate with medical

†

It is with great regret that we report that Rosamund Snow died on 2 February, 2017.

educators to incorporate different patients’ and carers’ priorities in course design and lesson plans. I have also been lucky enough to be asked, as a patient, to introduce this book. I can’t represent every patient, carer, parent, or layperson you will meet; but I can offer some insights into our world. Before I share what patients say they want you to know, here is some context.

Healthcare is changing Learning medicine has traditionally meant a strong focus on acute medicine—​diagnosing, treating, curing, and concentrating on one part of the body at a time. Traditionally, the doctor has always been the expert, the person we come to when something is wrong, so you can help make our bodies healthy again. Those skills are still vital, but things are changing in several key ways.

What happens after diagnosis We have done so well in treating and managing communicable diseases that acute care does not dominate medicine in the way it used to (Fig. 1.3.1). Helping patients manage chronic conditions requires a different set of skills from those used in acute medicine. Diagnosis becomes only a tiny part of the story, because people can live with a long-​term condition for a lifetime, and restoring people to full health is often impossible. Dividing the body up into textbook chapters becomes less and less relevant because chronic illnesses can impact on many body parts at once.

What happens after the patient leaves the clinic The other major change is the way laypeople can now interact with each other about their illness experience, and learn for themselves about their bodies. Patients themselves have changed the way they communicate, their willingness and ability to seek out and share information, and the opportunity to connect online in ways that the traditional medical model has never had to address before. We look things up, we ask each others’ advice, we help each other when doctors cannot be there.

1.3  What patients wish you understood

Global deaths, both sexes, all ages 100%

Noncommunicable diseases Communicable, maternal, neonatal, and nutritional disease

90%

80%

70%

60%

50%

40%

30%

20%

10%

0% 1990

1995

2000

2005

2010

2013

Fig. 1.3.1  Global deaths due to communicable and non​communicable diseases. Data from Institute of Health Metrics and Evaluation (http://​www.healthdata.org/​results/​data-​visualizations).

There are more and more people living with conditions that stay with them for life, that demand their attention and management at varying levels. Some of us have illnesses that require daily work, some may be reminded of our ill health only when our chronic condition flares up, but we cannot be simply treated and cured as in the acute model of care. For many of us this means a different kind of relationship with our doctors than our parents and grandparents had.

What patients want to teach When I ask people to identify the things we wish our doctors were taught, what do they say? What do they ask to be included on the medical curriculum?

Rethink what you mean by listening to the patient Among people who submit patient-​authored articles to the BMJ, one of the most common things they want to teach is listening: ‘Read my notes. Take what I am saying seriously. Take my time and emotions seriously. Find out what matters to me, and address that.’ All of this more or less adds up to: ‘Listen to me.’ Many authors say exactly that, in their suggested key messages, in the proposed title of their article, or both. I have to ask them to change the titles, or so many of them would be the same: Listen to me. Listen to the patient. Listen to the patient’s family. Yet when I talk to doctors and medical students outside the clinical setting, they say they feel as if they are already listening. They

know they ought to take patients’ concerns and ideas seriously, even probe us for what we are feeling if we haven’t volunteered it. In short, many doctors are trying hard to listen, but many patients still don’t feel listened to. Why is there such a communication mismatch? I  don’t know the answer, but here are some thoughts for discussion by both sides. The clash of worlds A lot of medical training focuses on deciding which elements of the patient’s story are key to diagnosis and treatment. Determining which elements have priority is usually left to the clinician. This can lead to problems, as can be seen by comparing the columns in Fig. 1.3.2. On the left, the priorities one might expect a doctor to choose when writing medical notes on a miscarriage. On the right, answers from women who had personally experienced miscarriage, when we asked ‘what would you most like us to prioritize when teaching student doctors about pregnancy loss?’. Most of what is important to the women, and what they remember for the rest of their lives, is left out in the clinical record: it is unrecorded in the medical notes, not prioritized in service delivery, and not counted as part of patient safety. The medical notes are vital, but they are not the only things that need recording. The clash of agendas In teaching doctors I’ve found that one of the hardest things for them to take on board is the way patients feel when offered information they didn’t ask for. Some patients who talk about communication

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SECTION 1  Patients and their treatment

What patients said they wanted doctors to know:

The antenatal unit is not the right place for care: ‘My god that screwed me up seeing mums with little newborn and knowing full well my situation would end so badly’

What medicine records: Parity-0+0 Gestation-?12/40

Remember the rest of the family : ‘My partner had asked if he should stay in the room during the examination but no one bothered to answer him; I was left trying to talk him through what was happening whilst I was very frightened and upset’

Symptoms—bleeding, pain Scan result: 11 weeks, No Fetal heart Otherwise fit and well Diagnosis: missed miscarriage. Treatment options discussed —medical, surgical, conservative. Risks explained.

Remember what miscarriage can mean: ‘[My GP] was amazing. She let me cry and then told me the two most important things—that this is a bereavement and I must allow myself time to grieve and that it was nothing I had done and there was nothing I could have done to prevent it. I will never be able to thank her enough for this as it was far more important than anything medical she could have told me’

Fig. 1.3.2  A woman has had a miscarriage: what medicine records, and what patients said they wanted doctors to know.

problems have asked their doctor for help on one topic, but were given information on something else entirely, because the healthcare professional felt the patient ought to have it. Often it is something the patient is told by every doctor, whether it is useful or not. If you have a patient who you consider to be overweight, but they are coming to see you about something else, giving them information about the benefits of losing weight can feel as if you are not listening to what they are saying. If you have a patient who has a long-​term condition with risks of complications, and you insist on reminding them of these complications at every encounter, it feels as if you are seeing them as a disease rather than a person. Ask yourself: What is this person already likely to know? What did they come in for? Have I understood and answered that? ‘That can’t be true’ Sometimes patients don’t feel listened to because the doctor just doesn’t seem to believe them. If a patient tells you about something that has happened in their body—​the interaction of one disease with another, the unusual reaction of their body to a particular drug, the fact that they feel ill even when a blood test says they ought to feel

well—​be very careful not to dismiss what they have to say. Evidence-​ based medicine has improved many aspects of care, but there are still a great many areas where evidence has not yet been collected, where patients themselves are collecting that evidence, or where your patient may be in a minority that responds in a way that a large-​scale trial cannot pick up. In short, it may not be what you are expecting to hear, it may not be in this book, but that doesn’t mean it isn’t true. You as a doctor can ignore a symptom that you think can’t be real, but we as patients have to go home and continue to manage it. You have enormous power over many of us, because you control access to the drugs and equipment that keep us alive and well. We need you to keep on working with us to find a solution. What does this mean for the way you communicate with patients? In general, when I have talked to doctors and patients who feel they have got this relationship right, the doctor is not asking him or herself ‘what is wrong with this patient?’ or ‘what can I do for this patient?’, but ‘what is this patient asking me for?’ and ‘what does this problem mean to this patient?’ These seem simple changes to the way you listen and the nature of your questions, but if done correctly could transform the way you hear and act.

1.3  What patients wish you understood

We don’t all share your interests or agree with your priorities When I was diagnosed with a serious illness, I had to become an expert in biomedicine, drug interactions, nutrition, and healthcare systems: I had to become ‘health literate’. The difference is that, unlike you, I was not interested in finding out more about it, I did not choose this life path, and nor am I paid to develop my skills in it; it’s something that was forced on me. Imagine the situation the other way around. You have a full day ahead of you doing your job as a doctor. In your spare time, if you can get any, you would also like to see family or friends. Now think of the thing you’d hate the most to have to spend your life learning about—​stamp collecting, a children’s TV programme, fashion, cars, whatever you find tedious. Imagine that you have to expend a lot of effort working on this in order to function. You have to do it in addition to your job, even if it gets in the way and your colleagues get frustrated with the amount of time it takes up. You can’t even leave the subject alone at the end of the day, you have to work on it even when you’d rather be talking to your children. You have to take time off from your job or in your own time to go to clinics where experts in your hated topic test you on your skills (just as people like me have blood tests that show whether we’ve been ‘compliant’ with treatment). And this will never go away, as long as you live. Managing a long-​term condition, particularly one where the healthcare system demands many interactions, is like having a second unpaid job on top of the one you do to pay the bills. What does this mean for the way you deliver care, particularly for people who are living with long-​term illness? Firstly, the more doctors can do to understand and relieve those pressures, practising ‘minimally disruptive medicine’ where possible, the better (see ‘Further reading’). Are there ways for us to get the things we need—​results, advice—​at times and in ways that don’t disrupt the things we love or need to do? Secondly, if we don’t share your priorities when it comes to treatment and self-​management, can you find a way to respect that? Ultimately, we are responsible for our own bodies. For example, if I choose a behaviour you believe to be noncompliant, risky, or that you simply disagree with, it is me, not you, who lives with that choice every day. I cannot walk away from it, my illness comes with me. In fact, perfect compliance with a recommended treatment is sometimes impossible in the real world, especially if you are asking someone to do it for the rest of his or her life. When you talk about doctors and patients reaching ‘concordance’ over treatment or practising ‘shared decision-​making’, there

is still an underlying assumption that at the end of our discussion, we will agree with each other—​perhaps most likely, that you as a doctor will get us as patients to agree with you. But not all your patients will agree with you, though, and that is not a terrible thing. We may even prefer to hand some of the decision-​making back to you, and that is not a terrible thing either. It’s not your job to make us think like you, or even to make us share your decisions and your enthusiasm for medicine, but we need you to help us live the lives we choose.

We are still doing healthcare when you’ve gone home In the traditional patient/​doctor model, the doctor is seen as doing the ‘work’, deciding what is wrong and what should be done about it, and the patient is the passive recipient of care. But once that patient is diagnosed with type 1 diabetes, or Crohn’s disease, or Parkinson’s, or thyroid disease, or has chronic pelvic pain, or another condition that changes life on a permanent basis, that model stops being effective. As patients we are having to do our own healthcare work, not just while we wait to get well, not just during working hours, but all the time. In many situations, a carer may also be doing a lot of that work, and their life choices are affected too. My condition is a particularly good example of this. In the last year I had to make over 2000 decisions about the dosage and timing of the dangerous drug I need to keep alive, and then followed up those decisions with action. I have also made at least another 2000 decisions about monitoring the effects of that drug, as well as monitoring other related aspects of my health. Some of those actions have been in the middle of the night, in the middle of important workplace meetings, on planes and trains and buses; doctors were not present for any one of those. On 2 days out of 365, doctors helped me discuss a few of my decisions and supported me to get further tests that I needed. I am very glad of their help, but however good my doctors are, their work is only a part of the story of my illness. People like me are making healthcare decisions when you are not there, because we have to (Fig. 1.3.3). What does that mean for the way you work with patients? Well, a good model might be to see us, particularly those with long-​term conditions, as full-​time colleagues on a job where you are only working part-​ time. Please understand that we are in fact the primary caregivers, part of the healthcare team, in fact we are leading that team most of the time. We will know less than you about particular topics and may need your help in new or difficult situations, but that is true of your coworkers too. We will certainly know more than you about the way our disease affects

Medication delivery Decisions about dose/timing Discussion with doctors

Healthcare access work Decisions made alone (99.8% of time)

Ad-hoc adjustments

Selfmonitoring

Nutrition management

Fig. 1.3.3  Hours of healthcare work done in a year. Data approximated from the author’s personal experience, diaries, and medical data in a typical year of living with a complex chronic condition.

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SECTION 1  Patients and their treatment

us and how feasible it is to incorporate your suggestions into our lives. After years with a chronic illness, we may well know a great deal more of the biomedical facts about our condition than you do. Just as you would take advice and gain knowledge from a colleague on something you aren’t an expert in, you can take our advice too. If you see us as a full-​time worker with local practical knowledge, and yourself as an advisor to our project rather than leader, that may help us work together. And just as you would ensure a good handover of care to the healthcare professional taking over from you at the end of a shift, you also need to ensure good handover of any changes to our care to us. This means explaining what has changed and why, what needs to happen next, and where we can look for support and training in areas we are not yet familiar with. If you don’t, we can’t do our work safely.

We look for information just like you do If you are ill, what do you do? You probably do one or more of the following: 1. Think about what you already know about the possible causes and management of your illness 2. Ask colleagues or friends who might have more information 3. Look information up 4. Make a decision about whether you need to get more formal advice and tests

Everyone does a version of this, although how far each of us takes it depends on how scared we are or how difficult it is for us to gather the information. In the past, patients had to be particularly educated or motivated to access medical facts and penetrate doctors’ jargon. Now it is becoming far easier for all of us, if we want to find out how to cope with an illness, to go online to find what we need. For some doctors, that has in the past been seen as a source of annoyance or a threat. When I teach medical students, I often show them social media and online forum discussions between patients, with no doctor moderating the information. It is interesting to watch the students’ unease shift, after spending time on those forums, as they realize that crowd-​ sourced patient advice is transforming people’s lives for the better. Peer support is particularly valuable for those of us with conditions that need constant work. Often we encourage each other online, share the rationale for our decisions, offer advice and help in the middle of the night, when you cannot be there to advise us. Sometimes, we correct inaccurate advice given by well-​meaning health professionals whose knowledge is too general to be helpful. In an era when people can connect so easily with others in similar situations, patient-​ sourced information (support groups, online forums, crowd-​sourced info) is at least as valuable as the information in your textbooks, if not more so (Fig. 1.3.4). Don’t be afraid of it. Learn from it. Don’t be worried if your patient has gone to the internet for more information—​isn’t that what you do, if you can’t

Fig. 1.3.4  Many patient communities have been set up by and for those living with a particular condition, such as #GBDOC. They are not moderated by the medical profession. Regular tweetchats share information about treatment and technology, as well as offering emotional support.

1.3  What patients wish you understood

get it from colleagues and the books around you? And if patients are seeking out more information about their condition, it means they are interested and engaged. What does this mean for the doctor’s role? Again, this means a change in medical thinking: if we know things you don’t know, if patients help each other and seek information in other places than your clinic or surgery, then work with us, add your expertise to ours rather than being threatened by it. Where we can, let’s learn from each other.

The future of good care In my work in medical education I have met many clinicians who are already practising these different working relationships with their patients and finding it rewarding. There is no need to be afraid of patients who know more than you, who think differently from you, or who challenge the traditional doctor/​patient relationship. For doctors who have learnt to focus purely on diagnosis and treatment, perhaps it is a question of using your knowledge and skills in a slightly different way. Thanks to modern medicine, more people are living with disease rather than dying of it, but that change means that the doctors’ role becomes less healer and curer, and more an advisor and supporter. If I have an acute curable condition, it’s likely that your aims and mine are aligned. We both want the problem to go away. If I have a more complex issue, or a lifetime of living with a condition, I may challenge your ideas of the best outcome: I may need to define myself as something other than just my disease. I may need to compromise on your medical goals in order to live the life I  want to live. I may disagree with the outcomes you have set for me. I may be doing nearly all the healthcare work my condition demands, and

I appreciate it when you notice and respect that, but I do still need you. Let’s work together.

Acknowledgements My sincere thanks go to the authors in the BMJ’s What Your Patient Is Thinking series, and to those patients, carers, and doctors who have advised me while writing this chapter. In particular I  would like to acknowledge the help of Ruth Bender-​Atik, Mary Cheetham, Jo Crocker, Sally Crowe, David Griffiths, Abi McNiven, Rajiv Mehta, Jane Moore, Tessa Richards, Sara Riggare, and Michael Seres for their input and support.

FURTHER READING DeBronkart D, Sands D (2013). Let patients help. Create Space Independent Publishing, New Hampshire. Entwistle VA, et  al. (2011). How information about other people’s personal experiences can help with healthcare decision-​making: a qualitative study. Patient Education and Counseling, 85, e291–​8. Greenhalgh T, et al. (2015). Six ‘biases’ against patients and carers in evidence-​based medicine. BMC Med, 13, 200. May C, Montori VM, Mair FS (2009). We need minimally disruptive medicine. BMJ, 339, b2803. Miscarriage Association. What women and their partners think student doctors should learn about pregnancy loss. https://​www. miscarriageassociation.org.uk/​information/​for-​health-​professionals/.​ Patients Like Me. https://​www.patientslikeme.com/​ What Your Patient Is Thinking, a monthly BMJ series written by patients and carers, with learning outcomes for healthcare professionals. http://​www.bmj.com/​specialties/​what-​your-​patient-​thinking

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1.4

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

ESSENTIALS It is the job of doctors to know about disease and how to diagnose and treat it, and textbooks such as this are part of that endeavour. However, proportionally little actual physical disease remains in resource-​rich countries of today, yet the demand is for more and more medicine. This prompts the conclusion that other forces determine the demand for contemporary healthcare. A counterculture view of the traditional medical model is offered here in which the reasons why patients consult their doctors is explored. In countries with developed healthcare, the traditional medical model of illness is dead or at least dying. A simplistic and reductionist approach to medicine is insufficient and signally fails to recognize or integrate the complexities of illness behaviour, and why it is that patients seek medical advice today. Contrary to traditional thinking and teaching, it is not illness that dictates the health-​seeking behaviour of a population but the healthcare system itself, and—​most importantly—​our actions as healthcare professionals. A scourge affecting clinical practice in the developed world today is the medicalization of all interactions, accompanied by overinvestigation, overdiagnosis, and overtreatment. Our profession retains its traditional duty, wherever possible, to diagnose disease and treat or cure illness appropriately, also to comfort the sick, irrespective of the ability to cure. At the same time, a long-​held principle of medicine at all levels is to do no harm, while at the same time supporting the maintenance of health and protecting those who are well. Maintaining the balance between these apparent conflicting precepts is a scarce skill that needs to be taught by example during the education and training of the modern doctor.

the foundation of our professional status and the basis of the professional fees charged. But the concrete is beginning to crumble. Clinical knowledge is no longer the preserve of the profession; anyone with a smart (mobile) phone can access global medical knowledge in a matter of seconds. In a lifetime, illness has changed out of recognition. In the developed world there is no rheumatic fever or diphtheria and finally with the introduction of new vaccines, even bacterial meningitis is being eradicated. Infectious disease as we know it, the great scourge of humanity a century ago, has gone. Tuberculosis is still present but occurs principally in recent immigrants. Similarly, we are witnessing the end of smoking-​related conditions with premature ischaemic heart disease and stroke rapidly disappearing, and lung cancer in decline. For other common cancers we offer screening programmes that detect cancers long before they become symptomatic and drive the traditional medical consultation (screening is discussed later). In resource-​rich countries of today, proportionally little actual physical disease remains. Predicted health spending should fall but in reality health costs are burgeoning: figures from the World Bank show that in the United States almost one in every five dollars is consumed by healthcare and figures published by the US Center for Disease Control in 2014 provide compelling evidence for this trend. This prompts the conclusion that other forces determine the costs of contemporary healthcare as it is provided as well as utilized. A  counterculture view of the traditional medical model is offered here in which the reasons why patients consult their doctors is explored.

Importance of clinical communication Introduction In the traditional ‘medical model’ we assume that the reason for the consultation is self-​evident:  patients have symptoms, a history is taken, an examination is conducted, and the diagnosis is made—​treatment is then offered. It is a process perfected by countless generations of doctors through the ages:  concrete, familiar, and certain. Knowledge of clinical signs and symptoms is

Communication skills are often maligned as ‘soft skills’; indeed, the old idea of ‘bedside manner’ is a pejorative term representing a mode of practise seen as increasingly irrelevant to the gleaming scientific new world of medicine. But the art and craft of communicating with patients in the new world of disappearing diseases is far more powerful than any machine or investigation. If we truly seek to establish ‘why’ the patient has consulted us, we need to listen and converse.

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

Every time a person, or a parent or guardian calls, and takes time out of their day to do so—​often after an unconscionable wait and an even more punishing internal debate—​they always have a specific reason. This reason—​the so-​called ‘patient agenda’—​is frequently overlooked, even though its crucial importance is a fundamental principle which applies across all healthcare settings. The traditional mechanistic approach, a tick list of questions, frequently fails since the ‘agenda’, either through fear or simple embarrassment, is so often ‘hidden’. It is worth reflecting on own experiences as a patient: Did the doctor really discover what our concerns were? A simplistic guide which helps us to elicit this agenda is not a ‘tick box’ exercise, rather it is a more general and analytical way to understand the person who has become a patient by exploring their ideas, concerns, and expectations. Ask the patient if they have any ‘idea’ what might be causing their symptoms, what ‘concerns’ they might have about the symptoms, and what ‘expectations’ they have of the consultation. This may appear obvious, but doctors constantly and spectacularly fail to explore these aspects of their patients’ motivation. Among many other disadvantages, this failure leads to overinvestigation, unnecessary referral and, ultimately, dissatisfaction. If we were to supplement the clinical approach with improved non​verbal communication which notes eye contact, posture, and facial expression, the chances of establishing why the patient has attended and of addressing what they seek from the consultation would be greatly enhanced. Development of skilful communication is important in life generally, but it is a crucial part of clinical education and clearly best reinforced by instruction and self-​critical evaluation throughout one’s entire professional career.

Health beliefs We all have health beliefs. These may not be based on commonly accepted scientific precepts, but often defy scientific reasoning despite being held with absolute conviction. Many patients (and some doctors) for example, passionately believe in homeopathy—​this, despite the counterintuitive nature of the science (in homeopathy the more dilute a treatment, the stronger it is alleged to become). We may berate these ideas, but for the patient the effectiveness of homeopathy is a fixed ‘health belief ’ held in the face of accepted scientific concepts and evidence. Strong health beliefs concern the benefit of other alternative medicines and medical interventions such as chiropractice, osteopathy, acupuncture, Reiki, and many others—​despite little or no obvious scientific basis for their clinical use. As with many believers in matters requiring a large element of faith and trust, a challenge to these beliefs is frequently met by anger and defensiveness. However, it is not just those who pursue alternative treatment who have unscientific health beliefs. Does removing tonsils reduce the rates of sore throat? Do annual physician examinations offer any value to health? Do screening programmes cause more harm than good? Indeed, individual doctors strongly disagree over much of the foundation of what may be termed medical science. A fascinating aspect of health beliefs is that they seem to be inherited, passed down through the family. If your parents have certain health beliefs, you are likely to share them. For example, patients

who attend doctors frequently often belong to family clusters. In one study conducted by the author, members of families classified as frequent attenders constituted about 10% of the population but accounted for 50% of consultations.

Health culture Consider what shapes and influences health beliefs that differ radically between people and populations. Why should otherwise apparently similar populations have wide variation in consultation rates across the world? How can health costs vary about twofold between countries such as the United Kingdom and the United States? In the United Kingdom most doctors are salaried and are not generally paid according to their activity. In most systems, however, ‘fee for service’ is payable. This remunerates doctors for activity and encourages more testing, more prescribing, and more consumption of healthcare. The simple truth is that many doctors consciously or subconsciously have vested financial interests in ensuring that patients return for care, even for minor illness. A cynical view would be that many have a vested financial interest in rendering patients doctor-​dependent and health-​anxious. Making those who are well, worried, can certainly be a great business model. Doctors often blame patients for needless health-​seeking behaviour, but in truth, doctors and their medical health systems forge this health culture. The wide variation in health-​seeking behaviour between different nationalities owes much to the health system that operates in the countries of origin.

Changing health beliefs An important principle to reduce health-​seeking behaviour is based on the concept of Numbers Needed Not to Treat—​the number of patients we need not to treat, to prevent one patient returning with the next episode of illness. Intervene more, and more patients will return:  intervene less and less patients return. So health systems should seek to intervene less. A  simple illustration is the use of antibiotics for sore throat. Declining to prescribe antibiotics might lead initially to conflict with patients. In time, however, as shown by Little and colleagues in a study involving nearly 800 patients from 11 primary care centres of general practice in the United Kingdom, the patients will realize that they will not be prescribed an antibiotic, and will appreciate the natural course of many types of sore throat, which improve without this treatment. Their health belief changes and gratuitous attendance decreases. This is better clinical practice and frees up access, thus reducing pressure on the medical system. While the complications of sore throat may not be rare and can be severe (with some requiring intravenous antibiotic treatment, management of fluid balance, and sometimes surgical intervention due to lack of treatment or inadequate antimicrobial therapy), correctly applied, the principle offers a way to reduce demand in all healthcare services. Changing the clinical practice of doctors, changes the behaviour of patients. This facile idea is one that is beyond the comprehension of many with responsibility for healthcare. We must not conflate more medicine as better medicine: generally less medicine is better medicine.

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The i-​patient effect Two doctors working in the same healthcare system, same area, and serving patients with similar demographic characteristics can vary their referral rates—​in a recent study by the author—​by as much as 10-​fold, with highly divergent investigations and prescribing patterns. How can this be explained? Like all of us, doctors are hostage to their own health beliefs: those who take antibiotics for coughs and colds will duly dispense antibiotics to patients for similar indications. Doctors anxious about their own cardiovascular health will prescribe more statins and antihypertensive drugs. Doctors worried about their own pigmented lesions will refer patients with skin lesions more frequently. Simply put:  doctors’ personal beliefs affect their clinical practice. This is what I and others have termed the ‘i-​patient’ effect. Doctors who are anxious and who struggle with uncertainty and risk, practise very differently from the those who do not. We cannot prevent doctors bringing their individual health bias into the consulting room, but understanding and acknowledging our own health beliefs allows us to control its influence. While this may appear to be an obvious concept, it is one that is scarcely acknowledged and little studied. One might ask whether there is an argument that universities should select medical students who have low personal anxiety about their own health anxiety.

Medical reviews—​the problem of ‘bring backs’ How often do patients need to be invited to return for review? Every week, every month, every year, or perhaps never. Intervals recommended for medical ‘check-​ups’ have a limited scientific basis and are frequently found to be a mere thoughtless habit. It is appropriate to reflect on how much time is dedicated to reviewing appointments for raised cholesterol, hypertension, routine blood tests and the remaining justifications for such ‘bring backs’. In most systems of healthcare, these review appointments are highly lucrative activities driven simply by financial interest. But in systems with limited budgets, access for the sick is restricted because of this factor. Many medical systems are busy, often with numerous pointless, unscientific but easy recall appointments, rather than busy serving the sick. The so-​called ‘inverse care law’ dictates that most healthcare is consumed by those least at risk, rather than those with the most medical need. In financial terms, ‘contact time’ with medical professionals represents the greatest expenditure, yet many healthcare systems appear to be devoid of any reflection on how this costly resource is used. Simply changing the interval between reviews would free up numerous appointments, but this important aspect of healthcare practice has attracted very little attention for research.

Particular difficult issues Medically unexplained symptoms The medical model has a familiar simplicity that is accessible to doctors, but the classic description of disease is unravelling in developed

countries because many diseases are themselves in terminal decline. The patterns and frequency of vascular or infectious diseases are changing rapidly, some cancers are in decline, and there is even an end in sight for smoking-​related disease. Patients now more frequently present with nebulous symptoms such as tiredness, weakness, numbness, dizziness, headaches, bladder symptoms and, most commonly, unexplained or bizarre forms of pain. Such patients are often the majority of those attending primary care and in several hospital settings. Clearly, because such symptoms could represent a more serious condition, those who complain of them generate a whirlwind of uncertainty in doctors weaned on the traditional medical model. This uncertainty precipitates testing and the prescription of medications. These patients are the frequent attenders: they accumulate thick medical files and report persistent, and ever-​changing patterns of symptoms which constitute a chronic illness. Despite endless investigations these symptoms remain ‘medically unexplained’:  this term is not used here to dismiss these patients, because their symptoms are real to them, but there is no underlying pathological process. Estimates indicate that a quarter of consultations are for unexplained symptoms, but experience suggests that in reality the proportion might be even higher. So, medically unexplained symptoms should hold a priority position in every medical textbook (see Chapter 26.3.3), and this author contends that every medical school should have an academic group devoted to their study, although clearly this is not the case. Current medical teaching usually suggests that symptoms equate to the presence pathology, and accordingly many doctors are simply unable to recognize patients with symptoms that will defy understanding in straightforward pathological terms. Doctors should reassure these patients, and their failure to do so is the cause of ever-​increasing use of investigations, polypharmacy (most notably analgesics and psychoactive agents), interventions, and hospital admissions, thereby employing vast resources. In the United States, the epidemic of deaths from the use of prescription drugs is in part caused by the fact that pain has been treated as a simple symptom, and not a subjective, complex, and often medically unexplained process. Moreover, in a private healthcare system, patients presenting with medically unexplained symptoms are at a particular risk of being exploited cynically for profit. As our insights into many medically unexplained symptoms are not likely to be rapidly enhanced by innovative research, we would do well to consider the views of a few wise physicians, often with experience in primary care, that while this may not be the science of medicine, it more accurately reflects the art of medicine. Some of these views are epitomized in the following cautionary statements, some of which may appear cynical or might prove to be inappropriate in individual cases: ‘If the symptoms don’t make any sense then there is nothing wrong with them.’ ‘Remember, frequency of attendance is inversely proportional to likelihood of pathology.’ ‘Referring the anxious only makes them more anxious.’ ‘Medicine is just magic and misdirection.’ ‘Everything you were taught in medical school is wrong.’ ‘Look for normality, not pathology.’ ‘Do nothing, but with style.’

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

The sick role and conversion syndromes Many forces encourage patients to attend a doctor, but sometimes we should remember that there may be a personal gain from being ‘sick’. There is a range of illness behaviours: at its most basic, it can generate a spontaneous day off work, the ‘sickie’; but more destructive behaviour can be seen in which the patient appears completely wheel-​chair bound. The sick role affords attention, sympathy, and even status within family and society. The role can excuse us from work and responsibility, and may be rewarded with financial benefits. Such patients typically complain of medically unexplained symptoms and often have no insight into their illness behaviour. It not as simple as ‘just pretending’ but much more complex: family members, either consciously or subconsciously, often collude in maintaining this sick role by acting as advocates. In addition, extreme sickness behaviour can be expressed through a proxy, such as a child or older person, who is offered up as having an illness which is fabricated: ‘Munchhausen disease by proxy’. Tackling extreme sickness behaviour is very challenging, if not impossible, for doctors:  patients and families alike can become very hostile and angry at any suggestion that symptoms might be psychologically based. Doctors need to be taught and made aware of the extremes of sickness behaviour.

Drug-​seeking and manipulative behaviours Doctors have replaced the gruff paternalism of the past with ‘patient-​ centredness’:  we are encouraged to use expressions like ‘choice’, ‘patient power’, and to adopt a ‘non​judgemental’ stance. This is a seismic shift in the doctor-​patient relationship. Today, it is hard to say ‘no’ to the patient; indeed, even challenging patients’ views or requests for particular treatment is difficult in our complaint-​driven culture, hence a form of consumerism is the new norm of medicine. However, giving patients what they ‘want’ can lead to very bad medicine, which is harmful to the recipient. Sometimes patients wilfully seek to deceive doctors—​a statement that is not cynicism but realism, and perhaps best illustrated by those seeking psychoactive medications, such as opioids, benzodiazepines, and the antiemetic, cyclizine; more recently gabapentin and related drugs are implicated. Patients can either sell these medications or personally abuse them (often both) in what is overt deception. Often pain or anxiety symptoms are reported at the time of presentation. Doctors accept this history in good faith and prescribe psychoactive medication. Soon there are stories of mislaid or lost medications and dose escalation. In countries where healthcare is poorly integrated, patients may go ‘doctor shopping’, attending multiple doctors from each of whom they are independently prescribed medication. Active deceit of this kind is signalled by inconsistent accounts and aggressive or tearful reactions to any form of challenge. Lack of ability to address or recognize manipulative behaviour is in part responsible for the epidemic of drug-​related deaths in North America. The Centers for Disease control report data from the National Vital Statistics System 2013 that in the United States, 44 people die every day from overdose of prescription opioid painkillers, and many more become addicted. More than twice as many residents die annually from unintended prescription drug overdoses than the total number of US soldiers killed in Iraq. Drug-​seeking places a huge pressure on practising doctors. Trust in medicine has

great power to heal; but mistrust and manipulation of medicine exerts a huge power and harm.

Welfare benefits In many countries, doctors act as gatekeepers to welfare benefits. If you could receive more income would there not be a strong incentive to overplay and invent symptoms? Many people cheat on claims for expenses or seek to minimize or avoid income tax, and so there are well-​known parallel behaviours. Some would ask, if you were injured in a road traffic accident, where is the harm in overstating your neck pain to improve your pay out? There are huge variations in reported sickness rates across countries and regions that simply cannot be accounted for by illness prevalence, and it is a statement of fact that patients will attend doctors seeking to manipulate insurance and benefit systems.

External forces There are, of course, the individual reasons why patients attend doctors. However, other major environmental forces are in play, which constantly effect health-​seeking behaviour and health beliefs. These are not always predictable and are often beyond intervention and thus largely outside the remit of medical control.

Medical charities and advocacy groups Patient advocacy groups and charities are considered to be important and legitimate to healthcare. Charities also offer important photo opportunities for politicians and are a constant source of human-​interest stories for the media; they have real grass roots support. So charities sponsor campaigns advertising disease awareness that encourage patients to seek medical advice. But we should ask the question: Is the role of charities always positive? Advocacy pressure groups can dominate agendas, potentially distorting resource allocation. Health messages promulgated by charities are often in effect simplistic sound bites that are factually flawed and couched in emotionally charged language. Often, despite there being a lack of evidence of benefit, they call for more screening, testing, and treatment. There are nefarious interests at work, too. Charities are sometimes exploited by the corporate medicine and pharmaceutical companies in an activity colloquially known as, ‘astroturfing’. In this activity, companies provide large sums of money to charities, who unwittingly act as proxy advocates of these companies. For a charity, promoting a disease is also promoting the treatment, and this might be one of several competing medications. Not cynicism, but again merely good business sense. It is always worth exploring the reported sources of funding of medical charities, for the distorting effect of corporate money is widespread.

Direct-​to-​consumer advertising There has been an explosion of prescribing in the last few decades, such that today lifelong polypharmacy is the norm and not the exception. Coprescription of several drug classes is frequent, including statins, antihypertensives, bisphosphonates, antidiabetic agents, non​steroidal analgesics, opioids, proton-​pump inhibitors, and ever-​mushrooming mental health medication. For ‘chronic disease’ is the golden goose that provides most of the revenue for Big

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Pharma. So how better to promote your medication (sometimes for dubious conditions, especially in relation to sexual ‘performance’ in women and men) than directly to patients? In the United States (one of only two countries to allow public advertising), flashing logos, tear-​jerking stories, and smiling celebrities paid to offer personal endorsements (e.g. a famous sportsman in the promotion of sildenafil) fill the airways. For example, in 2011 it was reported that one company (Pfizer) had spent $220 million on advertising its top-​selling cholesterol drug in the previous year, which was almost 25% of its overall $900  million in direct-​to-​consumer (DTC) spending. And as the internet is poorly regulated, companies are advertising the world over: after all, who knows who is behind online blogs and medical forums. There seems to be little we can do to resist the power of marketing and advertising. The patient is reduced to the status of a health ‘consumer’ (where the customer is always right), thus disturbing the equilibrium in the doctor–​patient relationship forever. Money shapes the reason and outcome of our consultations, and it is a telling fact that despite competition in the free market of the United States, not only the charges for branded drugs are up to twice those in other countries, but the expenditure per capita is the highest of any country.

Internal forces Paid experts and ‘disease creep’ Despite the essentially egalitarian nature of science and scientific enquiry, medicine remains a deeply hierarchical and deferential profession. The professional medical agenda is set by a few international specialists and opinion leaders, often cultivated by companies and referred to as KOLs, or key opinion leaders. Small groups of specialists define conditions, control guidelines, and sit on national governmental advisory boards. An example of the influence is provided by national recommendations which change the boundaries of treatment for raised serum cholesterol concentrations, thus encircling ever more people who become patients receiving lifelong treatment. It has been suggested that 25% of people in the United States have a ‘mental illness’, a simply incredible figure which reflects a pervasive ‘disease creep’ observed in numerous definitions and conditions. This softening and blurring of boundaries has the effect of ensnaring people into the world of unmet medical needs. Defining the ‘unmet medical need’ is a critical point for meaningful interactions. Despite a strong backlash and the recent Sunshine Act in the United States, with tight controls in Europe, some medical opinion leaders are still found to be on the take, and over past years, some have been paid very large sums of money by pharmaceutical companies to work as their paid advisers and advocates. It is an uncomfortable truth that everywhere in the world there are undisclosed payments to practising doctors. Indeed, in relation to the generous figures for mental illness cited earlier, the author noted in 2012 that about three-​quarters of the contributors to the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders published by the American Psychiatric Association report conflicts of interest and links to pharmaceutical corporations. Other countries are belatedly introducing Sunshine legislation which forces companies and doctors to disclose payments and links, but in many ways this has been too little and too late.

Evidence-​based medicine In the mid-​1990s, evidence-​based medicine arrived to save medicine from the vagaries of opinion and bring ‘best clinical evidence’ to the care of the individual patient. Naturally, the explicit articulation of the previously arcane process of therapeutic decision-​making was a source of wide-​ranging reflection and has undoubtedly rid medicine of much poor practice. But evidence-​based medicine has itself become a shackle, a vehicle of judgement, a new source of deference, and spurious virtue. Where rigorous evidence is unobtainable or simply lacking, the approach has replaced the deferential behaviour and unquestioned practices of the past with another parody of the Emperor with no clothes. Emperors were tyrants and so doctors mutter: ‘better not go against the evidence’. Thus, clinical care is increasing proscriptive, and ‘clinical guidelines’ have become an instrument of pervasive political control. The problem is much of the evidence is not what it seems. There is an inherent commissioning bias, for pharmaceutical companies own and commission most of the available ‘evidence’. Thus the evidence-​based agenda is dominated by a commercial therapeutic mindset. Also the available research is riven with surrogate end points which are required by regulatory authorities for licensing and approval of drugs for reimbursement. Often these have been arrived at and agreed in the absence of a true clinical perspective of the disease as experienced by patients and seen by their doctors: achieving the predetermined outcomes with endpoints that maybe statistically significant is of little use if the outcomes are clinically irrelevant. Moreover, research data from high-​risk populations often recruited into clinical trials are usually wide off the mark but sometimes cynically extrapolated to patients with low risk present in unselected general populations. Unfortunately, the temptation to cheat, and opportunities for cheating in research are legion. In research involving clinical trials, there are incentives to err because there are literally billions of dollars to be made. One US researcher faked research leading to billion-​ dollar sales. Research fraud related to pharmaceutical activity and clinical trials remains even now an important matter. Corrupt researchers affiliated to the pharmaceutical industry face little by way of punishment other than the indirect reputational damage cast onto their employing organization. The importance of good clinical practice and rigorous monitoring of clinical trial results should not be overemphasized. Evidence-​based medicine has become the principal marketing tool of the pharmaceutical industry: naturally, this is a scientifically persuasive and appropriate stance, but it requires ceaseless vigilance to ensure that those who engage in evidence-​ laundering to sell their medication are in a tiny minority and that they are punished rigorously for misdemeanours.

Screening Medical screening consumes increasing amounts of professional effort, especially in primary care. The intuitive principle is extremely attractive at first glance: catch a condition early and the better the outcome—​or so it appears. Thus, even questioning the value of screening generates angry defensiveness. But the issues at stake are not simple. Detecting a condition earlier may merely mean you know about a cancer earlier, rather than live longer. Also, detecting cancer early might give an artificial appearance of better outcome, if the outcome is determined by the ‘5-​year survival ’. This is known as

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

‘lead time bias’ and confounds attempts to compare survival statistics between countries. However, the major issue for all screening is the effect of ‘overdiagnosis’. Cancer screening programmes provide illustrative examples. They may often identify tiny non​progressive tumours, as a result of which we witness a rapid increase in cancer prevalence, such as has been noted in melanoma, breast, and bowel cancers. Since the detection by screening includes non​progressive cancers, screening tends to produce a better relative overall survival rate but, depending on the type of tumour screened for, the change in absolute death rate is often very limited. There is then an epidemiologic pattern of overdiagnosis generated by screening. Screening is often hailed as the equivalent of Mao’s Great Leap Forward for Medicine, and while it may lead to absolute benefit in terms of health, such benefits tend to be less than expected. Moreover, they must be balanced against the certain costs of real harm:  it is highly disingenuous to trumpet clinical success if millions of people are ‘diagnosed’ with a cancer that is not progressive but who then undergo unnecessary chemotherapy and surgery with consequential loss of well-​being and independence. How not to harm the healthy is a sophisticated challenge for the authentic success of many contemporary, and superficially attractive, screening programmes.

The need for change Given that the traditional medical model of illness is moribund, the scope, as well as style of medical education must adapt at all levels. The current reductionist approach to medicine classically fails to recognize or integrate the complexities of illness behaviour and often ignores the factors which drive patients to seek medical advice. It is now clear that it is not illness that dictates the health-​ seeking behaviour of a population but the healthcare system itself, and importantly the actions of healthcare professionals. A key principle of medicine, that the most important intervention is non-​ intervention, is linked strongly to the notion that our most potent medicine is reassurance. If, through enlightened teaching and research, we were able to enhance understanding of why patients attend health services, then we might be able to at least contain the burgeoning scourge of contemporary medicine:  medicalization. Medicalization of all clinical interactions leads to overinvestiga­ tion, overdiagnosis, and overtreatment. Our profession retains its

traditional duty, wherever possible, to diagnose disease and treat or cure illness appropriately, also to comfort the sick, irrespective of the ability to cure. At the same time, a long-​held principle of medicine at all levels is to do no harm, while at the same time supporting the maintenance of health and protecting those who are well. Maintaining the balance between these apparent conflicting precepts is a scarce skill that needs to be taught by example during the education and training of the modern doctor.

FURTHER READING Centers for Disease Control and Prevention (2014). Health, United States http://​www.cdc.gov/​nchs/​data/​hus/​hus14.pdf#103 Centers for Disease Control and Prevention (2015). National Vital Statistics System Mortality Data. http://​www.cdc.gov/​nchs/​deaths.htm Hatcher S, Arroll B (2008). Assessment and management of medically unexplained symptoms. BMJ, 336, 1124–​8. Kanavos P, et al. (2013). Higher US branded drug prices and spending compared to other countries may stem partly from quick uptake of new drugs. Health Affairs, 32, 753–​61. Little P, et al. (1997). Reattendance and complications in a randomised trial of prescribing strategies for sore throat: the medicalising effect of antibiotics. BMJ, 315, 350–​2. Moynihan R, Doust J, Henry D (2012). Preventing overdiagnosis: how to stop harming the healthy. BMJ, 344, e3502. Spence D (2008). The i-​patient. BMJ, 337, a1919. Spence D (2011). Explaining the unexplainable. BMJ, 342, d1039. Spence D (2011). The painful truth: deaths and misuse of prescribed drugs. BMJ, 343, d7403. Spence D (2012). The psychiatric oligarchs who medicalise normality. BMJ, 344, e3135. Spence D (2013). The art of deception. BMJ, 347, f5889. Spence D (2013). The cause of clinical variance. BMJ, 346, f1122. Spence D (2013). The power of doing nothing. BMJ, 347, f4409. Spence D (2013). Why I worry about large international studies. BMJ, 347, f6510. Spence D (2014). Evidence based medicine is broken. BMJ, 348, g22. Spence D (2014). Frequent attenders are getting poor care. BMJ, 348, g208. Staton T (2012). Lilly takes the lead in DTC ad spending, surpassing Pfizer. FiercePharma, 16 August 2012. http://​www.fiercepharma. com/​story/​lilly-​t akes-​lead-​dtc-​ad-​spending-​surpassing-​pfizer/​ 2012-​08-​16

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1.5

Medical ethics Mike Parker, Mehrunisha Suleman, and Tony Hope

ESSENTIALS Medicine is both a scientific and a moral enterprise. It is as important to give reasons for the ethical aspects of clinical decisions as it is for the scientific aspects. The corollary of evidence-​based medicine is reason-​based ethics. Two concepts central to many ethical aspects of clinical practice are autonomy and best interests. Autonomy—​Mill argued that society has no right to exercise its power over individuals against their will purely for their own good. In the medical context, a competent adult has the right to refuse any, even life-​saving, treatment. Some conceptions of autonomy focus on competent choice; others emphasize the importance of reasons that relate to a person’s long-​term interests and goals. The requirement to respect patient autonomy can be problematic when it harms the patient, or others, or when a patient lacks capacity. Best interests—​when patients lack capacity to make their own choices they should generally be treated in their own best interests. But what does this mean? Philosophers have given three broad answers:  maximizing positive states of mind, such as pleasure; maximizing the fulfilment of desires; and maximizing aspects of life that are objectively valuable. The legal concept of best interests is a composite of all these. Three of the most common issues for which doctors seek ethics support are consent, end of life, and confidentiality. Consent—​a crucial issue if a patient is refusing beneficial treatment is whether he or she is competent to do so. The assessment of competence involves three steps. First, identify the key information relevant to the decision. Second, assess the patient’s cognitive ability: Can the patient understand, retain, and weigh the key information to come to a decision? Third, assess other factors that may interfere with decision-​making, such as delusions. When a patient lacks capacity doctors must consider the patients’ best interests, whether there is a proxy decision-​maker, and whether the patient has made any relevant advance directive. End-​of-​life decisions—​ different ethical approaches disagree over the significance of two distinctions:  that between acts and omissions; and that between intending and foreseeing an outcome. These distinctions are important in considerations of mercy killing; the moral difference between withholding life-​extending

treatment and killing; and in giving treatments that relieve distress but might shorten life. The law varies on these issues in different countries. Confidentiality—​when should doctors breach confidentiality, either for the good of the patient or to prevent harm to someone else? There are differing accounts of the most important reason for medical confidentiality: respect for patient autonomy; keeping an implied promise; and bringing about the best consequences. These different accounts can have different implications for when it is right to breach confidentiality in problematic situations.

Introduction Evidence-​based medicine emphasizes the importance of critical assessment: interventions should be evaluated on the basis of evidence, not tradition. Critical skills are therefore crucial to modern scientific medicine. Importantly, medicine is a moral enterprise as well as a scientific one. Many clinical decisions involve a combination of factual and ethical aspects. It is as important to be able to give good reasons for the ethical aspects of clinical decisions as it is for the science. Society increasingly expects this from doctors as part of transparent decision-​ making. Doctors’ reasoning about ethical aspects of care will need to stand up to scrutiny—​in a court if necessary—​just as much as will the scientific aspects. The corollary of evidence-​based medicine is reason-​based ethics. Two concepts central to many ethical aspects of clinical practice are autonomy and best interests.

Two concepts: Autonomy and best interests Autonomy John Stuart Mill’s essay, On Liberty, is one of the great statements of liberal thinking. Mill wrote: ‘  . . .    the only purpose for which power can be rightfully exercised over any member of a civilised community, against his will, is to prevent harm to others. His own good, either physical or moral, is not

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a sufficient warrant. He cannot rightfully be compelled to do or forbear . . . because, in the opinion of others, to do so would not be wise, or even right’. (Mill 1859, Chapter 1)

This principle imposes strict limits on the interference of the state into individual’s lives. Mill articulates at its most general level a principle that in the medical setting is known as the principle of respect for (patient) autonomy. This principle has had an enormous effect in changing attitudes to the doctor–​patient relationship over the last 40 years. It has been used to criticize medical paternalism, and has informed the development of ‘patient-​centred’ medicine. It has led to an emphasis on providing patients with information, and to the development of the concept of informed consent. It is one of the main grounds for the importance of patient confidentiality. In situations where a competent adult patient refuses treatment that is, in the doctor’s considered view, good for the patient, a conflict arises between respecting the patient’s wishes, and doing what is best for him or her. This is widely seen as a conflict between the principle of respect for patient autonomy and the principle of acting in patients’ best interests (often called the principle of beneficence). The concept of autonomy, however, is not straightforward, and respecting what a patient says (e.g. his refusal of treatment) and respecting his autonomy may, on some views of autonomy, be different. Some aspects of autonomy The term autonomy has no clear single meaning. As Dworkin wrote (Dworkin, 1988, p. 6): ‘It is sometimes used as an equivalent of liberty  . . .  , sometimes as equivalent to self-​rule or sovereignty, sometimes as identical with freedom of the will. . . . It is identified with qualities of self-​assertion, with critical reflection, with freedom from obligation, with absence of external causation, with knowledge of one’s own interests.  . . .  It is related to actions, to beliefs, to reasons for acting, to rules, to the will of other persons, to thoughts and to principles.’ In the ideal of autonomy decisions should be rational, consistent with the person’s life plans and based on critical reflection. If a desire, or choice, is not based on a rational evaluation then, on some views, it is not autonomous. This is one reason why respecting a person’s autonomy is not necessarily the same as respecting her choice. Respecting patient autonomy can be problematic for doctors in at least three situations: 1. when to do so harms the patient herself; 2. when to do so harms others; and 3. when the patient lacks the capacity to make choices for herself. With regard to the first situation patients sometimes refuse treatment that doctors believe is strongly in their best interests. This became a legal matter in England when an adult patient with motor neurone disease and who had capacity wanted to have her life support removed. Her doctors refused because they thought this was tantamount to killing her. The court, consistently with Mill’s principle and English common law, said that her wishes must be complied with: ‘The doctors must not allow their emotional reaction to or strong disagreement with the decision of the patient to cloud their judgement in answering the primary question whether the patient has mental capacity to make the decision’ (Re B, 2002). The conflict between respecting autonomy and harm to the patient or to others can also arise in the context of confidentiality (see next).

In the third situation, when a patient lacks capacity to make decisions for himself, is it possible to respect the patient’s autonomy. Consider the following case (Hope et al., 2007).

Case example: Alzheimer’s disease Mr D always valued academic and artistic pursuits. ‘If I  develop Alzheimer’s disease allow me to die if given the chance,’ he says. Mr D subsequently develops Alzheimer’s disease. He no longer recognizes his family, but he remains physically fit. He is looked after in a nursing home and appears to enjoy a simple life: flowers, food, TV. Mr D gets a chest infection. This could be treated with antibiotics. Without curative treatment he could be kept comfortable and would probably soon die.

On a straightforward view it would seem that we respect Mr D’s autonomy by withholding antibiotic treatment and allowing him to die. This is consistent with the wishes that he expressed when he had the capacity to do so. But there are at least three concerns that we might have even if our only ethical value were to respect autonomy. First, do we know that when he expressed his view about being allowed to die he had taken into account all the relevant facts of his current situation? For example, at what stage in Alzheimer’s disease did he want to be allowed to die; was he meaning to refuse even a simple treatment like giving antibiotics; and did he take into account the possibility that he would generally be enjoying life? Second, he might have changed his mind after he had made the statement about being allowed to die and before he lost capacity, but no one knows of this change of mind. Third, is it possible for a person when healthy to imagine sufficiently the state of having Alzheimer’s? When we allow a person with capacity to refuse beneficial treatment we can take care to ensure that this is what the person really wants, and that he understands all the relevant issues. Even if it is possible in this case to respect the patient’s autonomy, in many (probably most) situations where a patient lacks capacity there will not be sufficient information about his previous views and values to make a decision about what to do based only, or even mainly, on this principle. The more useful principle in such situations is the principle of beneficence that is treating people in their best interests.

Best interests In many situations judging a patient’s best interests is straightforward but this is by no means always the case. Consider again Mr D. What is in his best interests? The answer may differ depending on your conception of best interests. The philosophical discussion relevant to best interests has been conducted mainly in terms of the concept of well-​being. There are three main theoretical approaches to well-​being. Mental state theories According to these theories, well-​being is defined in terms of mental states. At its simplest (hedonism) it is the view that happiness or pleasure is the only intrinsic good, and unhappiness or pain the only intrinsic bad. If Mr D with Alzheimer’s disease is generally enjoying the ‘simple’ pleasures then, on this view, it will be in his best interests to continue to live by treating the infection. The fact that he might

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previously have despised enjoying the TV soaps he now enjoys is irrelevant. Desire-​fulfilment theories According to desire-​fulfilment theories, well-​being consists in having one’s desires fulfilled. If desire-​fulfilment theories are to provide a plausible account of well-​being it is necessary to restrict the relevant set of desires. In one view, only those desires pertaining to life as a whole count as relevant in the analysis of well-​being. These are desires that relate to a person’s life plans. According to this view Mr D’s prior intellectual values would be relevant. Withholding antibiotic treatment would be fulfilling his previous desires and these are the desires that fit with his long-​term values. Desire-​fulfilment theories of well-​being have much in common with respecting autonomy, but they are not the same. In the case of Mr D, desire-​fulfilment theories highlight the question of whether Mr D, at the time of deciding whether to give antibiotics, has relevant desires. From the perspective of autonomy, the issue is whether he has capacity. Objective list theories According to objective list theories of well-​being certain things can be good or bad for a person and can contribute to her well-​being, whether or not they are desired, and whether or not they lead to pleasurable mental states. Examples of the kind of thing that have been given as intrinsically good in this way are engaging in deep personal relationships, rational activity, and the development of one’s abilities. Examples of things that are bad might include being betrayed or deceived, or gaining pleasure from cruelty. An objective list theory does not give an unequivocal answer to what is in Mr D’s best interests. On most lists—​although not all—​ the pursuit of worthwhile life goals would normally take precedence over very simple pleasures. But that is not the choice that faces the carers of Mr D. The question is whether it is in Mr D’s best interests to be dead, given that he can only enjoy these simple pleasures. Composite theories Each of the three theories of well-​being outlined earlier identifies something of importance, but none seems adequate. Because of this, we might opt for a composite theory in which well-​being is seen as requiring aspects of all the theories. A composite theory has some practical implications for medical practice. The main implication is that when considering what is in a patient’s best interests, particularly when these are not clear, it may be relevant to consider the aspects of well-​being that are highlighted by each of the three theories. This does not tell us how to balance these considerations but it does suggest that in coming to a decision about Mr D’s best interests it is relevant to take into account all of the following factors: his previous values and wishes, his current experiences (of enjoyment, for example), and any current desires.

Three issues in medical ethics Doctors who seek help with ethical issues in their clinical practice often do so with regard to three types of issue: consent, end of life, and confidentiality—​each of which presents questions relating to autonomy and best interests. We will discuss each in turn.

Consent The philosophical basis of informed consent rests on the principle of patient autonomy. Valid consent is widely regarded as requiring three main criteria: that the patient be informed and competent (or having capacity); and that the consent is voluntary. In the legal and ethical analysis of treating people against their will, a great deal depends on whether the patient is competent (or has capacity) to make the relevant decision. The approach to competence endorsed by both law and most ethical analyses is what is known as the functional approach. This focuses on the process by which the person comes to the particular decision. One implication of this approach is that competence is specific to a particular decision. A person may, at one time, be competent to make one decision (e.g. whether to take a particular medication) but not a different decision (e.g. whether she is capable of living alone). When patients are making decisions (e.g. refusing treatment) that appear to be (significantly) contrary to their best interests, then doctors must carefully assess the capacity of that patient to make that decision. In broad terms, if patients have the capacity, then their decision must be respected, although the doctor must make sure that the implications of the decision have been fully understood. The law in the United Kingdom and North America gives competent adult patients the right to refuse any, even life-​saving, treatment. If, on the other hand, patients lack capacity to consent to (or refuse) treatment then they should be treated, generally, in their best interests (but see next). Assessing competence There are three main steps in assessing competence. Step 1: Identify the information relevant to the decision The critically relevant information includes the likely consequences of different decisions (e.g. different possible treatments, or treatment versus non​treatment) and including both wanted and unwanted effects; and understanding in broad terms what would be involved in carrying out a decision. Step 2: Assess cognitive ability The Mental Capacity Act (2005) which is the key legislation in England and Wales states that a person is unable to make a decision (i.e. lacks capacity) if he is unable to understand the information relevant to the decision; to retain that information; to use or weigh that information as part of the process of making the decision; or to communicate his decision (whether by talking, using sign language or any other means). Step 3: Assess other factors that may interfere with competence Cognitive impairment is only one factor that may interfere with the elements of information processing just outlined. It may also be important to assess whether there is such interference due to a mental illness. A delusion, for example, may interfere with believing the information. An affective illness (depression or mania) may interfere with the weighing-​up of information and coming to a decision. Making decisions for people who lack competence There are four theoretically possible approaches to making decisions about the healthcare of incompetent patients (Buchanan and Brock, 1989).

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Best interests

Mercy killing

One approach for a doctor faced with an incompetent patient is to ask which plan of management serves the patient’s best interests. We have already outlined some different approaches to the question of what is in a person’s best interests (see the case example on Alzheimer’s disease earlier).

Lillian Boyes was an English patient with very severe rheumatoid arthritis, so severe that she was expected to die within a few weeks. She was in so much distress that she wanted to be killed, but she retained full decision-​making capacity. Painkillers did not overcome her distress. Her caring relatives also wanted her to be killed. If the doctor caring for Mrs Boyes were to apply the principle of autonomy and respect her competent wishes, should he not kill her? If every day of continued life was for her a burden, and there was no prospect of significant change until she died naturally, was it not in her best interests to be killed? The principles of autonomy and of beneficence point to the same action: to kill Lillian Boyes. In the United Kingdom, and North America, however, a doctor who killed such a patient would commit murder. In some counties, the Netherlands, for example, such a mercy killing (active voluntary euthanasia) can be legally carried out under carefully controlled conditions.

Proxy An alternative approach is for a proxy to make decisions on behalf of an incompetent patient. Such an approach raises the question of why the proxy has such a right. The most obvious answer is that the patient had nominated the proxy at a time when she was competent to do so. The proxy of course is left with the question of the basis on which the decision should be made. English law, under the Mental Capacity Act [2005] allows a competent person to nominate someone else (‘Lasting Power of Attorney’) as proxy in the case of loss of capacity. The proxy (rather like a parent of a young child) must act in the person’s best interests. If doctors believe a proxy is refusing highly beneficial treatment, then they may need to seek a court ruling. Substituted judgement The criterion of substituted judgement asks the hypothetical question: suppose the patient were (magically) able to become competent, what treatment would he choose? In order to try and answer this question, the doctor could use a range of evidence: reports of what the patient has said about this kind of situation in the past; the kind of general values the patient held; and experience with other patients. This criterion is problematic, not only in practice, but also theoretically since it is unclear precisely what are the person’s abilities and beliefs in this magical state. Advance directives Advance directives (or advance decisions as they are called in the English Mental Capacity Act [2005]) are statements made by people at a time when they are competent, about how they want to be treated in the future were they to become ill and at the same time incompetent to give consent for treatment. The central justification for advance directives is that they extend patient autonomy to include situations in which a person is no longer competent. One problem with advance directives is that they need to be interpreted when applied to the specific situation and this can be difficult. More fundamentally is the concern that when completing the advance directive, the person may not have been able to sufficiently imagine the situation at the time a decision needs to be made (see the earlier discussion of Mr D).

End of life Killing someone is of course morally wrong. Doctors often care for patients who are near the end of life and perhaps who are suffering. Modern medicine can in many circumstances prolong life. Paradoxically it is the very fact that doctors care for patients that can make the general moral ban on killing ethically problematic. It is problematic in at least two ways. First killing can, to some at least, appear merciful. Second, there is some ambiguity around what counts as killing.

The principle of the sanctity of life One reason why mercy killing might be wrong is because of an additional relevant principle: the principle of the sanctity of life. There are differing versions of this principle. The most extreme form is called vitalism: human life is of absolute value. Whenever possible, human life should be maintained; and it is always wrong to take human life. A less extreme form is one that sees life as a basic but not an absolute good. Preserving life on this view does not necessarily outweigh all other goods but the value of life cannot be completely accounted for in terms of a person’s experiences and beliefs. In English law, and in that of many other countries, there are two components to the act of killing. First, the death results from a positive action on behalf of the killer, and second that the killer intends to cause the death. In a clinical setting this means that omitting to do something, such as withholding life-​extending treatment (IV fluids, mechanical ventilation, for example) on the grounds that it is kinder to the patient to ‘let nature take its course’ is not considered to be a positive action, and is not killing. Such withholding of treatment is not only perfectly legal but might be seen as good clinical practice, and morally required. Furthermore, in English law, withdrawing treatment (taking down the IV line; switching off the ventilator) is seen as equivalent to withholding treatment. The intention too is crucial, at least legally. Sometimes a treatment for unpleasant symptoms can shorten life. This might be the case when large doses of morphine are given to very ill patients in order to control pain, because morphine can reduce respiratory drive. Giving morphine in such a situation is not killing and would normally be perfectly legal because the shortening of life is not intended, but is only foreseen. If killing is wrong but these two examples are not killing and not generally wrong, a lot of ethical weight rests on two distinctions: that between acts and omissions and that between intending and foreseeing. Those who believe that what is of primary importance in judging the morality of an act is the foreseeable consequences will not find any significant moral difference in either of these distinctions. If we foresee, for example, that giving morphine will shorten life, then this has the same moral weight as if we intend the shortening of life. We cannot close our eyes, on this view, to the foreseen consequences of

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our actions by claiming that although we foresaw them, we did not intend them. An alternative framework sees the nature of the choices and not only the foreseeable consequences as of moral significance. One idea within such a framework is known as the Doctrine of Double Effect. At the core of this doctrine is the claim that there is a moral distinction between foreseeing a result and intending a result. Thus, it may be forbidden on moral grounds to bring about a bad result if that result is intended (even if as a means to a better overall outcome), but not forbidden to bring about the same result if the result is foreseen but not intended.

Confidentiality Much of the information that a doctor gains about a patient in her professional duties is confidential. By this it is meant that there is an expectation that the doctor will not divulge that information to another person without the agreement (possibly implied) of the patient. What is the basis for medical confidentiality? There are at least three different grounds. On all three approaches doctors should normally keep information about patients confidential. The ethically problematic situations are generally those in which breaching confidentiality will reduce a risk of harm either to the patient himself, or to someone else. The professional guidelines for UK doctors emphasize the importance of confidentiality but state that: ‘Disclosure of personal information about a patient without consent may be justified in the public interest if failure to disclose may expose others to a risk of death or serious harm’ (General Medical Council, 2009). Such guidelines need interpretation in applying to particular circumstances, and the interpretation will sometimes be affected by one’s views about what underpins the importance of confidentiality. Three different answers to this question are: respect for patient autonomy; keeping an implied promise; and bringing about the best consequences. Respect for patient autonomy This principle implies that a person has the right, by and large, to decide who should have access to personal information about himself. If respect for patient autonomy is considered an important ethical principle, then any breach of confidentiality is potentially serious and only the prevention of serious harm would justify it. Furthermore, on this approach, it might be argued that, contra to the General Medical Council (GMC) guidelines, if a competent patient refuses to give consent for a doctor to inform a third party, where failure to inform risks serious harm to that patient only, breaching confidentiality is wrong. After all, we allow a competent patient to refuse even life-​saving treatment. Can there be a serious breach of confidentiality if the patient never knows about the breach? On the view of confidentiality which considers that respect for patient autonomy is of key importance, the answer is yes. Keeping an implied promise Some views of the doctor–​patient relationship see it as having elements of an implied contract. Such a contract may include an implied promise that doctors keep information about their patients confidential. Patients generally expect doctors to treat information confidentially, and professional guidelines emphasize the importance of high standards of confidentiality.

This view of confidentiality is different from that of patient autonomy. It does not ultimately depend on what the patient would want or believes. It depends on a concept of the doctor–​patient relationship that is independent of what a specific patient believes. There are, however, two problems with this view: first, there has been no explicit promise, so the issue of an implied promise is to some extent a fiction; second, it raises the whole issue of why it is important to keep promises. The reason for the importance of keeping promises is likely to be grounded either in autonomy or consequences. Bringing about the best consequences From the perspective of a consequentialist ethical perspective it is the (foreseeable) consequences of the breach of confidentiality that determine the seriousness of the breach, and indeed that underlie whether breaching confidentiality is wrong in the first place. There are several different types of consequence that could be relevant, and the analysis of the situation depends in part on how these are viewed. If respect for autonomy is the principal basis for confidentiality, then when maintaining confidentiality puts others at risk of harm there is a clash of two incommensurable values:  respecting the patient’s autonomy and preventing harm to others. From the consequentialist perspective, the judgement is conceptually simpler. There is only one question: Which action (breaching or maintaining confidentiality) has the better overall consequences? At first sight it might seem that on this consequentialist view risk of even modest harm to others justifies a breach since we have to balance the harm to others against only the patient’s emotional response to the breach. But this is too simplistic. Unless doctors are trusted to maintain high levels of confidentiality patients in general may lose trust and not seek healthcare. The issue is not just about ill health: there are other consequences of untreated illness. For example, if people with uncontrolled epilepsy drive they may kill other road users. There is a public interest in ensuring that such people receive good healthcare in order to maximize control of the epilepsy. Even where the harm to others is potentially great, as in the example of epilepsy, it could be the case that more lives will be lost if doctors do breach confidentiality because fewer people with fits will seek medical help. So although the consequentialist approach can deal with difficult cases in a conceptually clear way, in practice the lack of evidence and complexity can make such judgements difficult. From a consequentialist perspective, as opposed to the perspective of respect for patient autonomy, if a patient never finds out that a doctor has breached confidentiality and no harm comes to the patient as a result, that breach is trivial, even if it concerned something that the patient would strongly wish to keep confidential.

Conclusion Ethics, like science, is at root a rational enterprise. For those of us who are concerned to do the right thing, and this includes most medical students and doctors, the questions arise:  How can we examine our own moral standards and behaviour in specific situations; how can we develop these standards; and how can we ensure that our views stand up to scrutiny? We believe that rational enquiry is central to an answer to these questions. Such enquiry involves arguing with others, facing counterarguments, and seeing how good our own arguments are. If the counterarguments are stronger, we

1.5  Medical ethics

need to change our views. If there is a contradiction between what we thought our principles were and what we think is right in a specific situation, then we need to resolve that contradiction. There may be no final grounding of morality in nature but from that it does not follow that our personal moral system and our decisions in specific situations should be irrational or arbitrary.

FURTHER READING Ashcroft R, Draper H, Dawson A, McMillan J (eds) (2007). Principles of health care ethics, 2nd edition. John Wiley & Sons, Chichester. Beauchamp TL, Childress JF (2008). Principles of biomedical ethics, 6th edition. Oxford University Press, New York. Buchanan AE, Brock DW (1989). Deciding for others: the ethics of surrogate decision making. Cambridge University Press, Cambridge.

Dworkin G (1988). The theory and practice of autonomy. Cambridge University Press, Cambridge. General Medical Council (2009). Confidentiality: protecting and providing information. GMC, London. https://​www.gmc-​uk.org Hope T (2004). Medical ethics:  a very short introduction. Oxford University Press, Oxford. Hope T, Savulescu J, Hendrick J (2007). Medical ethics:  the core curriculum, 2nd edition. Churchill Livingstone (Elsevier), Edinburgh. Mill JS (1859). On liberty. Many modern editions, including: Harmon dsworth: Penguin Books, 1982. Parker M (2012). Ethical problems and genetics practice. Cambridge University Press, Cambridge. Re B (2002). Adult: refusal of medical treatment. All England Reports 449 at 445. Shakespeare T (2006). Disability rights and wrongs. Routledge, London.

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1.6

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

ESSENTIALS Clinicians make decisions at every stage of the patient pathway. In routine practice complex decisions are often made rapidly using ‘intuition’ or common sense, but this can lead to suboptimal management plans. Clinical decision analysis is a way of formalizing the logical process behind decision-​making, and when combined with evidence from medical research is described as the practice of evidence-​based medicine. Clinical decision analysis consists of five discrete steps: (1) constructing the ‘decision tree’—​structuring the problem so that alternative courses are defined; (2) estimating the probability of each possible outcome; (3) assigning a relative value or utility to each potential outcome; (4)  calculating the best alternative using the decision tree model; (5)  performing a set of sensitivity analyses, which provides insight into which values are the most critical to a decision. In practice, most clinicians do not have the time, intellectual energy, or training to perform a formal clinical decision analysis and they tend to use short cuts and go for the ‘safe’ decision which is suitable for the ‘average patient’ and often in keeping with guidelines for local practice. However, clinicians who follow the logical process of clinical decision analysis find it easier to live with the uncertainty of an inexact science and subjective wishes of the patient. Good understanding of the decision tree and use of sensitivity analyses allow clear documentation of the reasoning behind each decision that is made. This approach provides the tools to help make the right decision for each patient, free from the artificial constraints of clinical guidelines.

Introduction Clinical decision-​making is an essential skill required to practice medicine, yet the process of clinical decision-​making is often rushed. Complex decisions can be made rapidly using ‘intuition’ or common sense, based on a combination of information derived from theoretical knowledge and personal experience. This intuitive approach alone, although it saves the busy clinician valuable time, may lead

to suboptimal treatment plans. The discipline of ‘clinical decision analysis’ has, therefore, evolved to formalize the logical process behind decision-​making. When combined with evidence from medical research to make decisions, this is described as the practice of ‘evidence-​based medicine’. Clinical decision analysis is used by national clinical and public health services. In practice, this mean that clinical decision aids are widely available as guidelines, both national and local. Government guidelines often also include cost-​benefit or economic analysis to decide which treatments to fund. However, as every patient is different, it is helpful to understand how guidelines should be adapted to tailor treatment for individual patient needs. Ideally the patient should also play an active role in decision-​making. This is called ‘shared decision-​making’. In this chapter we set out the principles of clinical decision-​ making and give guidance as to how it can be applied by the busy clinician in routine practice.

Clinical context Clinicians make decisions at every stage of the patient pathway. Typical decisions made for a patient attending a hospital emergency department are summarized in Table 1.6.1. Table 1.6.1  Typical decisions made for a patient attending a hospital emergency department Decision node

Choice

Decision to admit to hospital

Admit or send home?

Medical Investigations

Which tests?

Diagnosis

Which diagnosis?

Treatment plan

Which treatment?

Resuscitation plan

For cardio-pulmonary resuscitation?

Management of incidental findings

To investigate further or not?

Discharge plan

When and where to?

Discussion with relatives

How much do you tell them?

These points are called ‘decision nodes’ in decision theory. The most critical decisions are made at points on the pathway where some of the consequences may be irreversible.

1.6  Clinical decision-making

Analysis Clinical decision analysis consists of five discrete steps which can be performed at each decision node (see Fig. 1.6.1):

Table 1.6.2  Examples of common unfavourable outcomes Adverse outcome to patient

Examples

Death Significant adverse events

Stroke Amputation Unnecessary surgical intervention End stage renal failure Seizure ITU admission Readmission to hospital Prolonged hospital stay

Psychological distress

Fear of possible future morbidity Hypochondria Unnecessary frequent emergency department attendance

Drug side effects

Bleeding Anaphylaxis Immunosuppression

2. Estimating the probability of each possible outcome

Public health implications

Spread of TB Road accident

For each possible outcome, the probability of that outcome needs to be estimated. While past experience and the expert opinion of colleagues may be an attractive source of information, a systematic review of the evidence produces a more unbiased estimate of probabilities. Where little evidence is available, a range of plausible probabilities using expert opinion should be made which will allow a sensitivity analysis to be made for the final decision. These might be available in published guidelines and the uncertainty can be captured by the level of evidence quoted.

Pregnancy outcome

Fetal or maternal death Fetal or maternal morbidity

Social consequences

Loss of job Loss of driving licence Breakdown of trust within a family

3. Assigning a relative value or utility to each potential outcome

Loss of professional reputation

The most challenging, and more subjective step, is to assign utility to each outcome. The purpose is an attempt to compare the relative importance of different outcomes. A variety of different metrics have been proposed including quality adjusted life years, disability adjusted life years or monetary value of health cost. All such metrics will provide a numeric value for each outcome that are then easily compared to show the optimum outcome. For example, death is usually awarded value 0, disease free life awarded 1, and morbidity such as side effects from chemotherapy would be awarded a value between 0 to 1, depending on perceived severity. To create an individualized decision analysis requires the patient to express their personal views about different outcomes. This is ‘shared decision-​making’. For guidelines which have been constructed nationally, or for cost-​effective analyses, groups of patient representatives are asked to provide the patient’s perspective. One problem with this approach is that the relative utility assigned by doctors may be different from that assigned by a particular patient. The patient’s views may also be in conflict with their own family. In addition, personal views may change with time as the understanding of each outcome changes and anxieties are allayed or fuelled. The decision to discuss every outcome with a patient is in itself a decision. Judgement is required to decide whether the psychological distress that may be caused by such a discussion is justified by the benefit of assigning a personalized utility to each outcome. For instance, the discussion of resuscitation with a relatively well patient for whom cardiorespiratory arrest is an unlikely event might in itself cause unnecessary distress.

Loss or fear loss of licence to practice

1. Constructing the ‘decision tree’; structuring the problem so that alternative courses are defined The different possible management choices need to be defined and the different possible outcomes, good and bad, need to be listed for each. In decision analysis terminology, this is referred to as constructing a ‘decision tree’. To busy clinicians, this may seem trivial but is critical because the omission of important treatment options or outcomes may lead to a suboptimal management plan. For instance, for any clinical treatment decision, failure to consider a ‘no intervention’ option could result in an unnecessary poor outcome for the patient.

Adverse outcome to doctor

Guilt Complaint from angry patient Litigation or fear of litigation

Table 1.6.2 shows examples of common unfavourable outcomes. These outcomes may be differently valued by doctor and patient, resulting in differing assumptions of the relative utility of each. 4. Calculating the best alternative using the decision tree model For each management plan chosen, the probability and utilities chosen are used to produce a combined numerical value. The values can then be easily compared to determine the best possible outcome for that patient. In some cases, the utilities assigned by the medical practitioner may be so different from those chosen by the patient that the practitioner is unwilling to proceed with the identified management plan. Sometimes a change in clinician might be required before a decision can be made which will be acceptable to the patient (see Fig 1.6.1a). 5. Performing a set of sensitivity analyses A sensitivity analysis explores how outcomes vary depending on making changes to the probability or utility values. This is particularly helpful when there is uncertainty over the probabilities of different outcomes or when there are differing views on the utilities, such as where the patient is themselves unsure as to their own views. Sensitivity analysis provides insight into which values are the most critical to a decision. Sometimes it is found that a particular decision is robust even when there are major differences of opinion on a particular probability or utility (see Fig 1.6.1b). For example, the precise probability of bleeding makes little difference to the

27

SECTION 1  Patients and their treatment

(a)

Foot saved 0.5 Antibiotics Infected fractured ankle

Infection not controlled 0.5

BKA

Full recovery 0.8 Recovery with limp 0.2 Death 0.1 AKA 0.8 BKA 0.1

Utility

Expected value Overall (Probability x utility value for for each outcome) each decision

1

0.5 x 0.8 x 1 = 0.4

0.98

0.5 x 0.2 x 0.98 = 0.098

0

0.5 x 0.1 x 0 = 0

0.6

0.5 x 0.8 x 0.6 = 0.24

0.7

0.5 x 0.1 x 0.7 = 0.035

0.7

0.7

Total for ‘give antibiotics’ 0.773

Total for ‘amputate’ 0.7

BKA – Below knee amputation Decision node: amputate or give antibiotics (b)

0.9

AKA – Above knee amputation

Sensitivity analysis

1 Overall value of utilities

28

Immediate amputation better

Antibiotics better

0.8 0.7 0.6 0.5 0

0.2 0.4 0.6 Probability of antibiotics saving leg BKA

0.8

1

antibiotics

Fig. 1.6.1  (a) Decision tree showing the possible outcomes of a case of a seriously infected compound fracture of the ankle following a decision to either amputate immediately or give antibiotics with the hope of saving the leg but with the risk of mortality from infection. Blue square represents the decision node; green circles show different possible outcomes following the decision with the assigned probability of the outcome documented on the branches. The triangles represent the final outcomes with the utility shown alongside. The calculations showing the expected values for each outcome and the overall values for each decision is also shown. (b) Sensitivity analysis showing how changes in the assigned probability of antibiotics saving the leg affects the overall values of amputation versus antibiotics. The original calculation estimated that antibiotics would prevent amputation in 50% of cases. The red line shows that amputation is the preferred option only if antibiotics prevents fewer than 33% of cases. The sensitivity analysis can also be altered to reflect changes in utility awarded to each outcome which could also impact on the decision. Adapted from Lee A, et al. for the EBM Teaching Scripts Working Group (2009). Tips for Teachers of Evidence-​based Medicine: Making Sense of Decision Analysis Using a Decision Tree. J Gen Intern Med, 24,  642–​8.

decision to anticoagulate a patient following a life-​threatening pulmonary embolus.

Decision-​making in clinical practice In practice, clinicians do not have the time, intellectual energy, or training to perform a formal clinical decision analysis and they tend

to use short cuts and go for the ‘safe’ decision, which is suitable for the ‘average patient’ and often in keeping with guidelines for local practice. Clinical decisions are often made heuristically, using ‘intuition’ which is a combination of pattern recognition and personal experience, to come to a rapid conclusion regarding the most likely best outcome. Unfortunately, intution is not reliable and can lead to suboptimal outcomes.

1.6  Clinical decision-making

Most clinicians informally use the ‘decision tree’ but often without being aware that they are doing so, and can easily be swayed by personal bias which may distort their perception of probabilities. For example, a physician who has recently seen a patient die from an undiagnosed subarachnoid haemorrhage is much more likely to perform a diagnostic lumbar puncture even when the clinical indication is negligible. To introduce a more systematic approach, ensuring use of best available evidence, guidelines are widely available. National guidelines summarize best available evidence to clarify the probabilities for common clinical outcomes. Local guidelines are then created to ensure that local clinicians are also aware of the subjective utility value for each outcome to the department. In order to make the best possible decision for an individual patient, the clinician needs to be aware that the utility to the department may be at odds with the utility to the patient. This is where shared decision-​making is critical. Shared decision-​making, where the doctor and patient are both involved in making the decision, is well documented to lead to the best patient outcomes and greater patient satisfaction. There are two main reasons why the departmental guideline might not be followed: 1. Objective factors which alter the assumed probabilities for each outcome: a. Diagnostic uncertainty b. Specific physical factors for a particular patient c. No relevant guideline or limited evidence base 2. Subjective factors altering the utility allocated for each outcome. a. Patient would like to be supported not to follow guideline for personal reason Clearly, if the physician has a personal reason to fear a particular outcome, this can affect their own assignment of utility, but this must be recognized as subjective and should not be allowed to influence the final clinical decision.

Case studies Comparison of two possible treatments A 60-​year-​old man presents with a badly infected compound fracture of the left ankle. The infection is not only threatening to destroy the ankle itself, but is spreading proximally and the septic complications are potentially life-​threatening. The options are either to perform a below-​knee amputation immediately or to perform surgical debridement followed by antibiotic treatment to save the leg. Although the second option offers a chance of complete recovery, it is associated with a substantial risk of infection that spreads leading to below-​knee amputation or possible an above-​knee amputation, or even death. Even if conservative management with debridement plus antibiotics is successful, there is still a chance of minor long-​term disability. A decision tree is drawn and, after discussion with the patient, utilities are assigned to each of the possible outcomes (see Fig 1.6.1a). A sensitivity analysis is performed (see Fig 1.6.1b) which shows that immediate amputation is only indicated if the chance of antibiotics working is less than 33%. After discussion with colleagues it was decided that antibiotics had a better than 33% chance of working and therefore the patient was treated conservatively.

(Case study based from A.  Lee et  al. for the EBM Teaching Scripts Working Group (2009). Tips for Teachers of Evidence-​based Medicine:  Making Sense of Decision Analysis Using a Decision Tree. J Gen Intern Med, 24(5), 642–​8.)

Variations in utility a. A  70-​ year-​ old man, living alone since the death of his wife 6  months ago, is admitted at 7  pm with acute onset of haematemesis and melaena and blood pressure 160/​100, pulse 140 bpm, and haemoglobin 82. He is resuscitated with IV fluids and given 4 units of blood after which his haemoglobin is 102 and his pulse rate settles to 88 bpm. ECG showed sinus tachycardia and chest X-​ray and all other blood tests were normal including clotting. He is usually well with no past medical history but has recently taken non​steroidal anti-​inflammatory medication for knee pain. He regularly exercises by walking his dog. The following morning, he is haemo-​dynamically stable but the medical team plan for him to stay in hospital for a repeat blood test and endoscopy to reduce the risk of further bleeding. The patient becomes very agitated and states that he feels perfectly all right now and needs to go home immediately. The consultant’s view is that the patient is at high risk for further bleeding with possible life-​threatening complications and local hospital policy is that severe gastrointestinal bleeds require inpatient endoscopy with at least 24 h observation as an inpatient in order to reduce the hospital readmission rates. On discussion, the consultant establishes that the patient’s main concern is to get home to look after his elderly dog who requires daily medication with regular painkillers and will be suffering without his owner. Finally, a compromise is reached as the patient agrees to come in to hospital daily for review and blood tests with clear understanding of the risks to his own health if he bleeds again while alone at home. The patient did not want to die but was prepared to take a moderate risk in order to look after his dog. The main risks and the patient’s views were clearly recorded in the notes to explain the rationale behind the decision. This case illustrates the different utility accorded by each party to a particular outcome, in this case rapid discharge home. Clear communication can help make a decision that both doctor and patient are happy with. b. A  60-​year-​old woman is referred with a new diagnosis of acute myeloid leukaemia. She has successfully gone into remission following chemotherapy and is told that the median life expectancy is 5 years. She is given the option to have a bone marrow transplant from her sister which will give her a 50% chance of total cure but a 15% chance of dying immediately as a consequence of the transplant. Her daughter is due to give birth next month. The doctors advise immediate transplantation, with enforced 6-​week hospital stay to maximize her overall chance of survival. However, the patient values short-​term life as she wants to see her new grandchild and therefore decides not to go ahead with the transplant immediately but requests a six month delay, despite the risk that the leukaemia will progress.

Variation in probability of clinical events A 32-​year-​old woman presents with rapidly deteriorating kidney function. Her estimated glomerular filtration rate is now down

29

30

SECTION 1  Patients and their treatment

to 14, from baseline more than 60, one month before. She has a history of systemic lupus erythematosus (SLE) for which she takes regular painkillers and low-​level immunosuppression. The differential diagnosis includes analgesic nephropathy or lupus nephritis requiring immediate immunosuppression. Standard procedure would be to stop the non​steroidal anti-​inflammatory drugs (NSAIDs) and perform a renal biopsy to confirm the diagnosis. However, the patient announces that she is a lifelong Jehovah’s witness and would decline blood transfusion under any circumstances. The possible adverse events following a kidney biopsy include bleeding requiring transfusion and possible death. In this case, because the patient is not willing to have the routine treatment for bleeding, the probability of more serious consequences of bleeding, such as death, is much higher. It is essential, therefore, to perform a new decision analysis reflecting the uncertainties of the diagnosis and the increased risks of performing the renal biopsy, in order to make a rational management plan.

Conclusion Clinicians who follow the logical process of clinical decision analysis find it easier to live with the uncertainty of an inexact science and subjective wishes of the patient. Good understanding of the decision tree and use of sensitivity analyses allow clear documentation of the

reasoning behind each decision. This approach provides the tools to help make the right decision for each patient, free from the artificial constraints of clinical guidelines.

FURTHER READING Barry MJ, Edgman-​ Levitan S (2012). Shared decision making—​ pinnacle of patient-​centered care. N Engl J Med, 366,  780–​1. Charles C, Whelan T, Gafni A (1999). What do we mean by partnership in making decisions about treatment? BMJ, 319,  780–​2. Cooper N, Frain J (eds) (2016). ABC of clinical reasoning. Wiley Blackwell BMJ Books, Oxford. Croskerry P (2013). From mindless to mindful practice—​cognitive bias and clinical decision making. N Engl J Med, 368, 2445–​8. Elstein AS, Schwartz A (2002). Clinical problem solving and diagnostic decision making: selective review of the cognitive literature. BMJ, 324, 729–​32. Elwyn G, et al. (1999). Towards a feasible model for shared decision making:  focus group study with general practice registrars. BMJ, 319,  753–​6. Rodriguez-​Osorio CA, Dominguez-​Cherit G (2008). Medical decision making:  paternalism versus patient-​centered (autonomous) care. Curr Opin Crit Care, 14, 708–​13. Sondhi M, et al. (2005). DEALE-​ing with lung cancer and heart failure. Med Decis Making, 25,  82–​94. Weinstein MC, Feinberg HV (1980). Clinical decision analysis. Saunders, Philadelphia, PA.

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

2.2 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 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

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

2.14 Deprivation and health  157 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 Jeremy Farrar

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

2.19 Regulation versus innovation in medicine  185 Michael Rawlins

2.20 Human disasters  188 Amartya Sen

2.21 Humanitarian medicine  193 Amy S. Kravitz

2.22 Complementary and alternative medicine  201 Edzard Ernst

2.1

Science in medicine: When, how, and what William F. Bynum

ESSENTIALS Science has always been part of Western medicine, although what counts as scientific has changed over the centuries, as have the content of medical knowledge, the tools of medical investigation, and the details of medical treatments. This brief overview develops a historical typology of medicine since antiquity. It divides the ‘kinds’ of medicine into five sections: (1) Bedside medicine, developed by the Hippocratic doctors in classical times, has its modern counterpart in primary care. (2) Library medicine, associated with the scholastic mentality of the Middle Ages, still surfaces in the problems of information storage and retrieval in the computer age. (3) Hospital medicine, central to French medicine of the early 19th century, placed the diagnostic and therapeutic functions of the modern hospital centre stage in care and teaching. (4) Social medicine is about prevention, both communal and individual, and is especially visible in our notion of ‘lifestyle’ and its impact on health. (5) Laboratory medicine has its natural home in the research establishment and is a critical site for the creation of medical knowledge, setting the standards for both medical science and scientific medicine.

Introduction At least since the Hippocratic era, Western medicine has always aspired to be scientific. What has changed is not so much the aspirations but what it has meant to be ‘scientific’. ‘Science is the father of knowledge, but opinion breeds ignorance’, opined the Hippocratic treatise The Canon, and Hippocratic practitioners developed an approach to health, disease, and its treatment based on systematic observation and cumulative experience. Even the word ‘physic’, whence physician as well as physicist, derives from the Greek for ‘nature’. Further, Hippocratic medicine was experimental, that word stemming from the same classical roots which gave us ‘experience’.

Words, however, can be slippery, as philosophers as divergent as Francis Bacon and Ludwig Wittgenstein have stressed. The science and experiment of the Hippocratics can still inspire, but they are not our science and experiment. During the past two or three centuries, an armoury of sciences and technologies has come to underpin medical practice. This essay briefly describes these, within the context of distinctive and perennial features of medical practice (i.e. suffering individuals whose problems and diseases demand attention).

A historical typology of Western medicine The history of Western medicine can be divided into five ‘kinds’ of medicine: bedside, library, hospital, social, and laboratory, with the latter extended to include technology (Table 2.1.1). Each approach to medical care and knowledge emerged at a particular historical period, but each still has relevance to us today.

Bedside medicine Bedside medicine can be equated with the vision of the Hippocratics, with its emphasis on the individual patient, a tendency towards holism, and an abiding concern with the patient within his or her own unique environment. These are some of the reasons why Hippocrates (Fig. 2.1.1) is still claimed as the dominant father figure by both orthodox and alternative medical practitioners.

Library medicine What can be called ‘library’ medicine dominated in the Middle Ages, when learned medicine retreated into the universities and scholars sometimes assumed that everything worth discovering had been uncovered by the ancients, and everything worth being revealed could be found in the Bible. The millennium between the sacking of Rome and the discovery of the New World is often dismissed as a sterile period scientifically, but the physicians of the period, linguistically erudite and philosophically inclined, would have been surprised to be described as unscientific. They simply believed that the road to knowledge was through the book, and—​were they able to—​would point out that this so-​ called sterile period gave us the hospital and university.

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SECTION 2  Background to medicine

Table 2.1.1  A historical typology of Western medicine CHARACTERISTICS

T Y P E S

Object of inquiry

Form and site of education

Goal

Example

Bedside

Whole patient

Apprenticeship

Therapy

Hippocrates (c.460–​370 bce)

Library

Text

Scholastic, linguistic, University

Preservation, recovery, commentary

Constantine the African (d. before 1098)

Hospital

Patient, organ, lesion

Hospital

Diagnosis

R. T. H. Laennec (1781–​1826)

Social

Population, statistic

Community

Prevent

John Simon (1816–​1904)

Laboratory

Animal model

Laboratory

Understand

Claude Bernard (1813–​1878)

Technology

Molecule

Automated laboratory

The above + profit

Kary Mullis (b. 1944)

Adapted from W. F. Bynum, History of Medicine: a very short introduction, OUP, 2008.

These medical men also sometimes engaged with nature, although it is undeniable that nature rather than words became an increasing source of truth and knowledge during the Scientific Revolution, a period stretching roughly from just before Andreas Vesalius (1514–​ 1564) to Isaac Newton (1642–​1727). Around 1600, it was becoming apparent to many that the Greeks had not left behind a complete and accurate account of the nature of the world, and that scientific knowledge was cumulative. This ‘Battle of the Books’, the debate over whether the ancients or the moderns knew more, was decided in favour of the moderns.

Many of the outstanding scientific achievements of the era were in astronomy and physics, but medicine, both in its theory and its practice, was also affected. Theory has always been easier to change than practice, of course, and it was famously remarked that William Harvey’s discovery of the circulation of the blood had no impact on therapeutics. Harvey (1578–​1657) also notoriously lamented that his practice fell off mightily following the discovery, his patients fearing that he was ‘crack-​brained’. The fear that too close an identification with science was detrimental to patient confidence recurs in medical history, and is still part of the delicate negotiations between the profession and its public, and to the status of academic medicine. Within the discipline of medicine itself there have always been individuals—​some of them, like Thomas Sydenham (1624–​1689), eminently successful—​who believed that experimental science had little to offer to patient care. But these ‘artists’ of medicine could still invoke the authority of Hippocrates, with its older connotations of knowledge and experience. Sydenham himself did not demur from his being dubbed ‘the English Hippocrates’. During the early modern period, the whole spectrum of the sciences—​mathematics, physics, chemistry, the life sciences (not yet called biology)—​made their ways into formulations of health and disease. Iatrophysics, iatromathematics, and iatrochemistry all had their advocates in the 17th and 18th centuries as approaches to medical theory and practice. That these systems tended to encourage speculation to run ahead of evidence was recognized at the time, and this was part of the reason why ‘hospital medicine’ had little recourse to those disciplines we now call ‘basic medical sciences’. The founders of French hospital medicine, Xavier Bichat (1771–​ 1802), J.  N. Corvisart (1755–​1821), and R. T. H. Laennec (1781–​1826), often referred to chemistry, physiology, and the like as sciences that were ‘accessory’ to medicine.

Hospital medicine

Fig. 2.1.1  A statue of Hippocrates, originally from Kos Odeion but now in the Archaeological Museum of Kos. This is a late Hellenistic period copy of a classical prototype. No contemporary likeness of Hippocrates exists, but several busts and statues were created later on in the classical period. Copyright © D. A. Warrell.

The medicine that developed in the Paris hospitals, after the reopening in 1794 of the medical schools closed by the Revolution a couple of years earlier, emphasized above all the study of disease in the sick patient. In a sense, this was Hippocratic medicine writ large, but with some significant differences. First, the hospital offered the curious doctor a vast arena for observing disease. The equivalent of a lifetime’s experience of a lone practitioner in the community could be experienced in a few

2.1  Science in medicine: When, how, and what

months of hospital work. Hospitals offered the possibility of defining disease on the basis of hundreds of cases. Secondly, Hippocratic humoralism gradually disappeared as the dominant explanatory framework of health and disease, replaced by the primacy of the lesion, located in the solids: the organs and tissues, and by the mid-​19th century, cells. In this new orientation, disease was literally palpable, its lesions to be discovered in life by the systematic use of physical examination—​Corvisart rediscovered percussion, Laennec invented the stethoscope—​and these findings to be correlated after death by routine autopsy. French high priests of hospital medicine brought diagnosis to a new stage and replaced the older symptom-​based nosologies with a more objective, demonstrable one of lesions. The third feature of hospital medicine was what Pierre Louis (1787–​1872) called the numerical method, the use of numbers to guide both disease classification and therapeutic evaluation. The philosophy underlying early 19th-​century French medicine was most systematically expounded by one of the many American students who studied in Paris, Elisha Bartlett, in his Philosophy of Medical Science (1844). The medical science whose philosophy he chronicled was one of facts. Bartlett argued that all systems of medicine, past and present, were speculative, vague, and useless. Cullen, Brown, Broussais, and Hahnemann were all consigned to the historical dustbin. The new medicine was one of systematic observation and collection of facts, which, when properly compared and organized, could provide an objective understanding of disease and a rational basis for its treatment. Bartlett’s philosophy was essentially undiluted Baconian inductivism applied to medicine. Unsurprisingly, he counted Hippocrates as well as Pierre Louis among his heroes. One consequence of the lesion-​based medicine was the recognition that not much of what doctors did actually altered the natural history of disease. Therapeutic scepticism, or even nihilism, flourished among doctors whose lives were spent, as Laennec put it, ‘among the dead and dying’. It was less likely to be expressed among doctors concerned with earning a living treating private, paying patients, but the concern with medicine’s therapeutic impotency also fuelled the movement to prevent disease.

Social medicine The fourth kind of medicine, social, also flourished in the 19th century. Just as hospitals existed long before ‘hospital medicine’, so epidemics and preventive measures were not invented by the public health movement of the 1830s. Nevertheless, the preventive infrastructures developed partly in response to the cholera pandemics still exist, although of course much changed. The chief architect of the British public health movement, Edwin Chadwick (1800–​1890), was a lawyer who thought that, on the whole, doctors were overrated (he was neither the first nor the last lawyer to hold that opinion). He held that filth spread via the foul smells (miasma) of rotting organic matter caused epidemic diseases. His solutions were engineering ones—​clean water and efficient waste disposal—​which he argued would leave the world an altogether more pleasant and healthier place. His ideas were formed during the 1830s and early 1840s, and they remained more or less fixed for the rest of his long life, which extended well into the bacteriological age. Nevertheless, Chadwick also invoked science in his public health reform programme, above all the science of statistical

investigation. His use of statistics can easily be shown to have been naive, but it was ardent. In his own sphere of enquiry, Chadwick was as much in awe of the unadorned ‘fact’ as was his contemporary Bartlett. A later generation of Medical Officers of Health and others concerned with disease prevention (or containment) would develop new investigative techniques, more sophisticated statistics and, especially, new theories of disease causation and transmission. But the early public health movement was firmly based on the science of its time.

Laboratory medicine The final locus of medicine, the laboratory, was also largely a product of the 19th century, though of course laboratories (a place where one worked, especially to mutate lead into gold) had existed for much longer. A  leading exponent of the laboratory, and one of its most thoughtful philosophers, had experienced Paris hospital medicine as a medical student. Claude Bernard’s Introduction to the Study of Experimental Medicine (1865) is at once an intriguing account of his own brilliant career and a sophisticated analysis of the philosophy of experimentation within the life sciences (Fig. 2.1.2). Hospitals, he argued, are merely the gateways to medical knowledge, and bedside clinicians can be no more than natural historians of disease. To understand the causes and mechanisms of disease, it is necessary to go into the sanctuary of the laboratory, where experimental conditions can be better controlled. There are in nature no uncaused causes:  determinism is the iron law of the universe, extending equally to living systems and inorganic ones. However, organisms present special experimental problems, and it is only through isolating particular features, and holding other parameters as constant as possible, that reliability and reproducibility can be achieved. Bernard identified three primary branches of experimental medicine:  physiology, pathology, and therapeutics. His own research programme touched all three pillars:  his research on the roles of the liver and pancreas in sugar metabolism contributed to understanding normal physiology as well as diseases such as diabetes; his investigations of the sites of action of agents such as curare and carbon monoxide foreshadowed structural pharmacology and drug receptor theory; his work on the functions of the sympathetic nerves buttressed his own more general notion of the constancy of milieu interieur as the precondition to vital action (and freedom), a precursor of Walter Cannon’s concept of homeostasis. Bernard stands supreme as the quintessential advocate of the laboratory.

Who was the first modern medical experimentalist? When Bernard wrote, experimental medical science was still a fledgling activity, best developed in the universities of the German states and principalities. The German university ideal of medical education was to be extolled by the American educational reformer Abraham Flexner (1866–​1959) in the early 20th century. It was in the reformed and newly created German universities that the forms of modern scientific research were established. Research careers were created; copublication in specialist journals became common; scientific societies flourished. The microscope became the symbol of the medical scientist even as the stethoscope was becoming the hallmark of the forward-​looking clinician. In the

35

36

SECTION 2  Background to medicine

Fig. 2.1.2  Claude Bernard and his pupils. Oil painting, 1889 by Léon Augustin Lhermitte. Courtesy of the Wellcome Collection, Creative Commons Attribution (CC BY 4.0).

hands of scientists like Schwann, Virchow, and Weismann, the modern cell theory was developed and applied to medicine and biology more generally. These researchers established the drive to push units of analysis further and further. Eduard Buchner’s identification of cell-​free ferments in 1897 firmly established the importance of subcellular functions. Pasteur, Koch, Ehrlich, von Behring, and others advanced new notions of the causes of disease, the body’s response to infection, and the possibilities of new drugs to combat disease. Any of these scientists might arguably be the answer to the parlour-​game question: Who was the first modern medical scientist? The German-​speaking lands perfected the modern forms of scientific research, but a good case can be made for a Frenchman to be crowned the first thoroughly modern experimentalist within medicine. François Magendie (1783–​1855) (Fig. 2.1.3) was a child of the Enlightenment and product of the French Revolution. One of several eminent individuals (Thomas Malthus was another) raised according to the anarchic principles espoused by Jean-​ Jacques Rousseau, Magendie did not learn to read or write until he was 10. His subsequent precocity was such that he was ready for medical studies by the age of 16, learned anatomy and surgery as an apprentice, and made his way through the Paris hospital system. Although he never lost interest in practical medical issues, his reputation was established primarily within the laboratory.

Fig. 2.1.3  François Magendie. Lithograph by N. E. Maurin. From Burgess R (1973). Portraits of doctors and scientists in the Wellcome Institute, London, no. 1870.2, by courtesy of the Wellcome Library, London.

2.1  Science in medicine: When, how, and what

His monographs on physiology and pharmacology marked new beginnings, and his life manifests three emblematic qualities which make him one of us. First, he valued facts above theories, evidence above rhetoric. However, he went beyond Bartlett and the high priests of hospital medicine in insisting that in experiment, and not simply observation, lay the real future of medical knowledge. Like his pupil Claude Bernard, Magendie was a deft experimentalist. He used animals (and occasionally patients) to probe into a whole range of problems in physiology, pathology, and pharmacology:  the functions of the spinal nerves, the physiology of vomiting, important facets of absorption, digestion, circulation, nutrition, and the actions of drugs and poisons. He described anaphylaxis a century before it was named. He was as philosophically naive as Bernard was sophisticated: of course he had theories, but his image of himself as a rag-​ picker with a spiked stick, gathering isolated experimental facts where he found them, is a telling one. Secondly, he was modern in sometimes backing the wrong horses. He judged cholera and yellow fever to be non​contagious, was suspicious of anaesthesia, and sometimes claimed more than we might for his newly introduced therapeutic substances, such as strychnine and veratrine. Magendie could often be mistaken in his beliefs; so can we. Thirdly, Magendie was the scientist who first expunged the double-​faced Janus from the medical mentality. William Harvey worshipped Aristotle, Albrecht von Haller was steeped in history, and Isaac Newton popularized the pious conceit of pygmies standing on the shoulders of giants. Until the 19th century, doctors routinely looked to the past, not simply for inspiration but for useful information. Magendie looked only in one direction: the future. He had no sense of history and no use for it. He meant what he said when he insisted that most physiological ‘facts’ had to be verified by new experiments, and he undertook to provide a beginning. He made the laboratory the bedrock of medicine. With Magendie, the history of medicine became an antiquarian discipline.

What happened next? Like everyone, Magendie was of his time. Nevertheless, his values were symptomatic of important themes within 19th-​century medicine and medical science. By the beginning of the First World War, most of the structures and the fundamental concepts of modern medicine were in place. Of course, both medical science and medical practice have been utterly transformed since. But the impulse of experimentation and its variable translation into practice were there. We have gone far beyond the cell in our analytical procedures, and our medical, surgical, and therapeutic armamentaria are vastly more sophisticated and powerful.

Technological medicine Our medicine is fundamentally different in one important respect, even if the trend was already evident in the 19th century:  the fusion of science and technology. Science and technology have become so intertwined that the older distinctions between them

Fig. 2.1.4  Photograph of a radiograph (x-ray negative) taken on 22 December 1895 by Wilhelm Röntgen, the discover of x-rays. It shows his wife’s left hand; she wears a large ring on her 4th digit. Courtesy of the Science Museum, London, Creative Commons Attribution (CC BY 4.0).

are blurred. Technology made a real but minimal impact on 19th-​century medicine. Some instruments, such as Helmholtz’s ophthalmoscope, came into clinical medicine through the laboratory; and German experimental scientists were eager to exploit the latest equipment such as kymographs, sphygmographs, and the profusion of artefacts (Petri dishes, autoclaves, and so on), which Koch and his colleagues devised for the bacteriological laboratory. Most important of all was probably X-​rays, discovered by Roentgen in late 1895. This made an immediate impact on medical diagnosis, and the associated science of radioactivity soon was felt within therapeutics (Fig. 2.1.4). Significantly, perhaps, the pioneers of the radioactive phenomena—​Roentgen, Becquerel, the Curies—​got their Nobel Prizes in physics or chemistry. Hounsfield and Cormack got theirs for computer-​assisted tomography in medicine or physiology. More recently, Kary Mullis’s Nobel Prize was for a technological development within molecular biology. Both medical science and medical practice are now inseparably rooted in technology. So is modern life, another reflection of a perennial historical truth: medical knowledge and medical practice are products of wider social forces with unique historical individualities.

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SECTION 2  Background to medicine

FURTHER READING Ackerknecht EH (1967). Medicine at the Paris hospital, 1784–​1848. Johns Hopkins University Press, Baltimore, MD. Bynum WF (1994). Science and the practice of medicine in the nineteenth century. Cambridge University Press, Cambridge. Bynum WF (2008). History of medicine:  a very short introduction. Oxford University Press, Oxford. Bynum WF, Bynum H (eds) (2007). Dictionary of medical biography. Greenwood, Westport, CT. Bynum WF, Porter R (eds) (1993). Companion encyclopedia of the history of medicine. Routledge, London.

Bynum WF, et al. (2006). The Western medical tradition, 1800 to 2000. Cambridge University Press, Cambridge. Conrad LI, et al. (1995). The Western medical tradition, 800 bc to ad 1800. Cambridge University Press, Cambridge. Cooter R, Pickstone J (eds) (2000). Medicine in the 20th century. Harwood Academic Publishers, Amsterdam. King LS (1982). Medical thinking:  a historical preface. Princeton University Press, Princeton, NJ. Reiser SJ (1978). Medicine and the reign of technology. Cambridge University Press, Cambridge. Weatherall DJ (1995). Science and the quiet art: medical research and patient care. Oxford University Press, Oxford.

2.2

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

ESSENTIALS The role of evolutionary biology as a basic science for medicine is expanding rapidly. Some evolutionary methods are already widely applied in medicine, such as population genetics and methods for analysing phylogenetic trees. Newer applications come from seeking evolutionary as well as proximate explanations for disease. Traditional medical research is restricted to proximate studies of the body’s mechanism, but separate evolutionary explanations are needed for why natural selection has left many aspects of the body vulnerable to disease. There are six main possibilities:  mismatch, infection, constraints, trade-​offs, reproduction at the cost of health, and adaptive defences. Like other basic sciences, evolutionary biology has limited direct clinical implications, but it provides essential research methods, encourages asking new questions that foster a deeper understanding of disease, and provides a framework that organizes the facts of medicine. Physicians who understand evolution recognize that bodies are not designed machines but jury-​rigged products of millions of years of natural selection that work remarkably well, given that no trait can be perfect, and that selection maximizes reproduction, not health.

Introduction This medical textbook is, as far as we know, the first to offer a chapter on evolutionary biology. The occasion of the 160th anniversary of the publication of The Origin of Species makes it fitting, albeit somewhat delayed. Medical students are taught how the human body is (anatomy), and how it works (physiology), but seldom are they taught why it works (natural selection) or whence it comes (evolution). It is as though car mechanics were taught how a car works, and how to fix breakdowns, but never where it came from (factories

Acknowledgement: Thanks to the Berlin Institute for Advanced Study for providing a fellowship to RMN that made preparation of this chapter possible.

and designers’ drawing boards) nor the purpose for which it was designed (transport along roads). Things are beginning to improve. The past 15 years have seen a series of books, articles, and meetings that report new applications of evolutionary biology to medicine. Evolution is as fundamental to medicine as physics or chemistry. This chapter cannot review its whole scope. We can only illustrate a few core principles in hopes of encouraging further reading.

Core evolutionary principles for medicine Natural selection and adaptation When individuals in a population vary in ways that influence their genetic contribution to future populations, the average characteristics of the population will change. This is not a theory; it is necessarily true. Natural selection involves no design, no planning, and no goal. The word ‘evolution’ refers more generally to any changes over time in a population, whether from selection, mutation, genetic drift, or migration. Notwithstanding his most famous title, Darwin’s greatest contribution was not his explanation of speciation, but his explanation of adaptation. Recent research on the Galapagos finches known as ‘Darwin’s finches’ illustrates the point. During drought, only larger seeds are available, so individuals with larger beaks get more food and have more offspring. In just a few generations, the average beak in the population became significantly larger after a drought. When the rains came, and small seeds again became plentiful, selection switched to favouring smaller beaks. No trait is adaptive except in relation to a specific environment.

Levels of selection Non​specialists often assume that natural selection should shape traits to benefit groups. After all, if a species goes extinct, all the individuals and their genes are lost. This ‘group selection’ fallacy was unmasked over 40 years ago, but it continues to cause confusion in medicine. For instance, one might expect pathogens to evolve low virulence: killing off the host is surely not good for the group! However, even long association of a host and pathogen does not necessarily decrease virulence. People who are out of bed transmit a rhinovirus

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SECTION 2  Background to medicine

faster; this selects for low virulence. The story is very different for insect-​borne diseases. Plasmodium is transmitted faster from patients who are too sick to slap mosquitoes, so virulence is high for malaria in humans (infected mosquitoes feel just fine). Ageing can be similarly misunderstood. One might think that senescence could speed the evolution of the species by making room for new individuals. The species, however, is not the level at which selection acts. Consider a lethal or deleterious gene that is expressed only late in life. Many carriers will have passed on the gene before it kills them. The same gene would be quickly selected out if it killed individuals before they reproduced. We are all descended from individuals who died after having children. Not one of our direct ancestors ever died in childhood! Moreover, a pleiotropic gene that gives a benefit early in life may be favoured, even if it causes deleterious effects later, when selection is weaker. This evolutionary explanation for senescence is now confronting remarkable new evidence that single-​gene effects in the insulin signalling pathways can have huge effects. The reasons why selection has not incorporated such changes will prove most interesting.

Established applications Some methods from evolutionary biology have long been applied to medicine. Population genetics describes how natural selection, mutation, migration, and drift account for shifting gene frequencies. This body of knowledge has been a foundation for medicine since the middle of the twentieth century, so we will only note a few new applications. It is now clear that the ability to digest lactose as an adult is the exception, rather than the rule. In our ancestors, milk was a food for babies only. New analyses show that the ability to digest lactose as an adult has emerged on at least three separate occasions in human prehistory, always in dairying cultures. Remarkably, the selective advantage in these cultures has been huge, of the order of 5 to 15%. The exact benefits remain to be fully understood but calcium and vitamin D may be important, as well as getting more calories. Another example is the prevalence of mutations influencing the acetaldehyde dehydrogenase genes in some populations (especially in southeast Asia). Carriers get sick when they drink alcohol. Is the prevalence of this mutation a result of random genetic drift, or does it give some advantage, perhaps by decreasing the risk of alcoholism? New data show that it does protect against alcoholism and that strong selection has acted at this locus; it is at the centre of one of the largest haplotypes in some populations. This supports the role of alcohol, but the geographical distribution suggests that diet or other cultural variations may be responsible. Genetic methods for tracing phylogenies of pathogens have long been available. Influenza strains are tracked so assiduously that it is possible now to predict some characteristics of likely future epidemic strains—​invaluable information for vaccine design. Epidemics of pathogen-​contaminated food are now routinely traced back to the source using genetic data. It has even been possible to trace specific cases of HIV back to a specific source, because rapid mutations leave a clear trail. Evolutionary methods also can also be applied to somatic cell lines within a body, for instance, to determine if the cells in a tumour

are all identical or if subclones are competing in the tumour. The implications for customizing chemotherapy are substantial.

Evolutionary aetiology Most medical research provides proximate explanations based on the anatomical and chemical details of the body’s mechanisms. However, even knowing every detail about a trait offers only one half of a complete biological explanation. The other half is provided by an evolutionary explanation of how that trait came to exist in the first place. There are two kinds of evolutionary explanations: the first is a phylogenetic explanation based on the sequence of prior traits across evolutionary history; the other is an explanation of what evolutionary forces account for the changes across time. Most often, this requires an understanding of how the trait gives a selective advantage.

Explain vulnerabilities, not diseases Evolution can explain why aspects of the body have been left vulnerable to disease. Why do we have wisdom teeth, and a small birth canal? Why do we so often develop lower back pain and hip problems? Why hasn’t selection shaped our immune systems to better eliminate pathogens and cancer cells? Answering such questions in an evolutionary way is often challenging. A framework can help to organize the effort. There are six main reasons why bodies have vulnerabilities to disease despite the actions of natural selection (Box 2.2.1).

Mismatch Chronic ‘diseases of civilization’ such as obesity, hypertension, and diabetes are now pandemic. The motivations that make us eat too much and exercise too little were shaped for an environment where sweet, fatty, or salty foods were good for us, and excess exercise could be fatal. Recognizing the origins of our unhealthy preferences does not change them, but it illuminates the source of the problem and possible solutions. Similarly, allergies and autoimmune disorders are more common in developed societies. Our immune systems evolved when people were routinely exposed to intestinal parasites and pathogens. In their absence, inhibitory immune cells are not stimulated, leaving the system overactive and responsive to self. An attempt to recreate the original intestinal environment by administering whipworm ova has proved remarkably effective as a treatment for Crohn’s disease.

Coevolution We remain vulnerable to infections because pathogens evolve faster than us. Just how fast is demonstrated by the rapid rise of resistance

Box 2.2.1  Six kinds of evolutionary explanations for vulnerability Mismatch between aspects of our bodies and novel environments • • Pathogens that evolve faster than we do, and resulting costly defences that cause harm themselves • Constraints on what natural selection can do • Trade-​offs that keep any trait from being truly perfect • Traits that increase reproduction at the cost of health • Protective defences such as pain and fever

2.2  Evolution: Medicine’s most basic science

to every antibiotic. Evolutionary analysis of the phenomenon shows that initial intuitions may not be right. For instance, rotating the first-​choice antibiotic in a hospital every few months does little to decrease multidrug resistance, and taking all of an antibiotic prescription may not prevent resistance. Most of our antibiotics are products of natural selection sifting through a vast range of molecules during a billion years of competition between microbes. Pathogens also have strong selection effects on hosts, particularly in shaping defences such as fever, vomiting, diarrhoea, cough, and the many manifestations of inflammation. These adaptive responses often have harmful effects because they are products of an evolutionary arms race. Every defence creates selection for ways to escape it, and this shapes yet more expensive and dangerous defences. At equilibrium, we would expect the defences to become nearly as dangerous as the pathogens (natural selection would be expected to amplify them until they approach the danger level), a principle that should inform studies of anti-​inflammatory agents in infection.

Constraints Many of the body’s limitations reflect the limits on what natural selection can do. It cannot maintain an information code without errors, nor can it start afresh to correct a poor ‘design’. For instance, the eye’s nerves and vessels are between the light and the retina, and their exit causes a blind spot. Such constraints can never be fixed, because intermediate stages do not work. Human engineers can, literally, go back to the drawing board, evolution cannot (imagine if the jet engine had had to ‘evolve’ from the propeller engine, step by step).

Trade-​offs Not only does selection result in many suboptimal ‘designs’, but it cannot make any trait perfect. All traits involve trade-​offs. Thicker wrist bones would break less easily, but they would inhibit free wrist rotation. Muscles fatigue, but careless use of a new drug that blocks fatigue may reveal just what damage fatigue prevents. Bilirubin is, according to some medical teaching, a waste product from haem metabolism. However, an intermediate molecule, biliverdin, is relatively water soluble. Why not excrete biliverdin? Because bilirubin is an effective antioxidant. If there are no such specific trade-​offs to be seen, economics always furnishes an ultimate trade-​off. Individuals could be built with thickened bones that never break, but they would spend extra energy moving those big bones while individuals with thinner bones would have more offspring because they divert the economic goods saved (e.g. calcium and energy) elsewhere in the economy of the body (e.g. milk) where they can do more good. Engineers know this as the principle of ‘overdesign’, in which risks of failure are minimized within available budgets. But whereas engineering budgets are arbitrary—​civilian aviation standards are more risk averse than military, for example—​evolutionary budgets are set by the competition. Individuals whose bones are ‘too good’ will end up having fewer children than rivals whose ‘spending policy’ accepts the increased risk of breakage.

Reproduction at the expense of health A related point explains the differences in mortality between the sexes. A trait that increases reproduction will tend to spread, even if it harms health. Investments in competitive ability give greater

reproductive pay-​offs for males than for females, so men have been shaped to take more risks and to invest less in bodily repair. Data from developed societies shows that mortality rates for men at the age of sexual maturity are about three times higher than that for women.

Defences The final explanation is not really a reason for vulnerability, but it is on the list because defences against disease are so often inadequately distinguished from direct manifestations of disease. Pain, fever, nausea, and vomiting are adaptations useful in certain situations. Unfortunately, they are often expressed as ‘false alarms’ when they are not essential. From a physician’s point of view, it seems that selection has done a poor job. After all, much of general medicine involves of blocking normal defence reactions such as pain, fever, vomiting, and anxiety, and few patients expire as a result. However, selection has not made a mistake. The costs of not expressing a response when it is needed are so huge relative to the costs of false alarms that the optimal threshold allows for many false alarms. This ‘smoke detector principle’ explains why blocking a defence is usually safe: the doctor can judge if the response is necessary. Nonetheless, we should expect that defences have been shaped to be expressed when they were needed on the average, in the long run.

Utility In the clinic Upon hearing about new evolutionary approaches to medicine, most journalists and many doctors ask how it can improve treatment in the clinic today. This is the wrong question. There are some direct clinical applications, such as hesitating before blocking a defensive response such as a raised temperature or vomiting. However, theory should not change practice directly. Instead, evolution offers established methods such as population genetics, new questions about why the body is vulnerable, strategies for answering them, and a scientific foundation for an integrative understanding of the body.

Research implications Revisions and extensions of evolutionary methods will make them even more valuable. As extensions of the Human Genome Project move us towards individualized genetic medicine, an evolutionary view of genetic variations can get us beyond simply labelling some ‘defective’ and others ‘normal’. There is, after all, no normal genome. There are just genes that construct phenotypes that result in more or fewer offspring in a given environment. As outlined above, an evolutionary approach also suggests a new class of questions about the aetiology of disease. Research to answer these questions should eventually allow a book like this to provide an additional evolutionary section for each disease. The chapter on gout will describe comparative data which tests the hypothesis that uric acid’s benefits as an antioxidant in a long-​lived species justify its raised levels, despite the pain to some individuals. The chapter on jaundice will mention the costs, benefits, and evolution of bilirubin. The chapter on infectious disease will describe the arms races that shape pathogens and defences, and the costs and benefits of blocking defensive responses. The chapter on anxiety and depression will not

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SECTION 2  Background to medicine

treat them simply as pathological states, but as potentially useful responses, prone to dysregulation. So far, however, the benefits of seeking the evolutionary aetiology for every disease is only beginning to be recognized.

who understand the body in evolutionary terms will make better decisions for their patients because they will have a better sense of what it is that they are actually doing.

Teaching implications

Interested physicians will want to be in touch with The International Society for Evolution, Medicine & Public Health (https://​isemph. org/​). It sponsors an annual meeting, an Oxford University Press Journal (Evolution, Medicine, & Public Health), The Evolution and Medicine Review, and an email list and network to connect clinicians and researchers interested in evolutionary approaches to medicine.

There is more to teach than can be taught, so medical educators try to provide students with core facts, general understanding, and critical skills that allow them to learn more. Evolutionary knowledge is invaluable not only for itself, but because it offers a framework that can organize and relate the thousands of facts. It helps students realize why bodies fail, and therefore what disease really is. Evolution also offers opportunities for designing courses that provide deeper understanding. For example, a biochemistry course could emphasize the origins of certain pathways, and how adaptation is constrained by the limits of natural selection. Students in physiology would learn the evolutionary reason why the respiratory system relies on carbon dioxide, not oxygen, to regulate respiration.

A deeper understanding of the body Physicians are increasingly being educated as if they are technicians, identifying problems and applying officially approved solutions. This makes very poor use of medicine’s most valuable resource. We select medical students carefully because we want—​or should want—​doctors who think. Providing them with a deep evolutionary understanding of the body will foster clear thinking. Instead of viewing the body as a designed machine, they will see it as a product of natural selection with traits more exquisite than in any machine, some of which nonetheless leave us vulnerable to diseases. Doctors

Opportunities

FURTHER READING Evolution, Medicine, and Public Health. https://academic.oup.com/emph Gluckman D, et al. (2011). How evolutionary principles improve the understanding of human health and disease. Evol Appl, 4, 249–​63. International Society for Evolution, Medicine, and Public Health. http://isemph.org Nesse RM (2011). Ten questions for evolutionary studies of disease vulnerability. Evol Appl, 4, 264–​77. Nesse RM, Stearns SC (2008). The great opportunity: evolutionary applications to medicine and public health. Evol Appl, 1,  28–​48. Nesse RM, Williams GC (1994). Why we get sick: the new science of Darwinian medicine. Vintage Books, New York. Perlman, R (2013). Evolution and medicine. Oxford University Press, Oxford. Stearns SC, Medzhitov R (2016). Evolutionary medicine. Sinauer Associates, Sunderland, MA.

2.3

The Global Burden of Disease: Measuring the health of populations Theo Vos, Alan Lopez, and Christopher Murray

ESSENTIALS To make the best decisions to improve health, policymakers need reliable, up-​to-​date information on the major challenges facing their country. The Global Burden of Disease study facilitates this by providing comprehensive and scientifically rigorous estimates of the causes of death and illness across the globe. It examines a total of 84 risk factors and the amount of health loss attributable to each or combinations of them. Analysis over time reveals a shift from disease burden dominated by communicable, maternal, neonatal, and nutritional causes to a burden increasingly made up of non​communicable diseases and injuries. By making comparisons between countries or subnational units like states or counties, the Global Burden of Disease can highlight areas of particular success or challenge, providing opportunities to examine what is working, or what is not.

Introduction To improve health by making the best decisions, policymakers need reliable, up-​to-​date information on the major challenges facing their country. The Global Burden of Disease (GBD) is a large-​scale enterprise dedicated to expanding the quantitative evidence base for health by producing estimates of deaths, prevalence, and incidence by disease for all countries and by identifying the major risks that impinge on population health. The GBD study was created to provide comparable, comprehensive, and scientifically rigorous estimates of the causes of death and illness across the globe and aims to answer the following questions:  What are the world’s major health problems? How well is society addressing these problems? Additionally, how do we best dedicate resources to get the maximum impact in improving population health in the future? In the early 1990s, when the World Bank commissioned the original GBD study, researchers were surprised to discover that the answers to these questions were elusive. For some parts of the world, data were sparse or non​existent. In summing disease-​specific mortality estimates by organizations whose mission was to combat a

given disease, GBD researchers found a total that was considerably greater than the number of people, globally, who had actually died in a particular year. The GBD approach not only makes sure that deaths attributed to different causes sum to the total number of deaths—​it goes beyond mortality estimates and looks at causes of disability, or non​fatal conditions. Increasingly, around the world, people are living longer and are exposed to disease risks that are more common with increasing age. Examining disabling conditions, such as back pain, dementia, or diabetes is therefore more important than ever. With the diversity of health conditions facing different populations, having comparable measurements is essential. The GBD approach allows policymakers to directly compare the public health impact of diseases that often are fatal, such as cancers, and conditions that primarily disable, such as depression or anaemia. Underlying some of these conditions are risk factors including alcohol and tobacco use, dietary factors, occupational exposures, and air pollution. The GBD 2017 study examined 84 risk factors and the amount of health loss attributable to each or combinations of them. This information can help decision-​makers to identify opportunities to promote population health by preventive measures. After the original GBD study, disease burden estimates by world regions were produced on a regular basis in the 2000s by the World Health Organization. In 2007 the Institute for Health Metrics and Evaluation (IHME) was established at the University of Washington in Seattle with funding from the Bill & Melinda Gates Foundation to make these estimates by country and to regularly update estimates. IHME published a comprehensive update, the Global Burden of Diseases, Injuries, and Risk Factors Study 2010, in December 2012 in a dedicated issue of The Lancet. Since then, IHME has committed to producing annual updates of these results for the whole time period from 1990s onward and for an increasing number of countries and subnational units such as the provinces of China and the states of India, Mexico, Brazil, and the United States. New risks, diseases, and their disabling outcomes are added based on policy interest. For instance, the GBD 2017 includes new estimates for type 1 and type 2 diabetes mellitus, and bullying victimization as a risk factor for depression and anxiety. Governments and funding partners want to maximize the impact of their healthcare spending. By pinpointing the leading causes

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of health loss, including risk factors for diseases, GBD can guide how health services are planned and how resources are directed to diseases and risks. By making comparisons between countries or subnational units like states or provinces, GBD can highlight areas of particular success or challenge, providing opportunities to examine what is working, or what is not.

Methods GBD quantifies health loss from hundreds of diseases, injuries, and risk factors. In order to achieve this, a large effort is made to collect all available data on deaths and the epidemiology of more than 300 diseases and injuries in 195 countries and territories, by age and sex, from 1990 to the present. This large-​scale effort is coordinated by IHME. Health data for many countries are sparse, and they are often messy. Researchers at IHME with guidance from a global consortium of researchers—​more than 3300 in over 140 countries—​ identify every possible source of data for a country or condition and work to gain access to them. Once in hand, the data are often adjusted to account for known differences in measurements between data sources. The next step is synthesizing the data—​taking what is known and making sense of it. Sophisticated statistical modelling approaches are used to estimate health loss for every disease and country. Every estimate in GBD is estimated 1000 times over to account for the impact of uncertainty from sampling errors, measurement errors, and the choice of models. Causes of health loss are classified at a first level into three broad categories in the GBD:  communicable, maternal, neonatal, and nutritional diseases; non​ communicable diseases; and injuries. The first of these encompasses diseases like HIV, tuberculosis, malaria, diarrhoea, lower respiratory infections, iron-​deficiency anaemia, and preterm birth complications. Non​communicable diseases include heart disease, stroke, diabetes, cancer, depression, and asthma. Injuries range from self-​harm (suicide) to road injuries to animal bites. In order to account for death and disease, GBD uses the disability-​ adjusted life year (DALY). DALYs equal the sum of years of life lost to premature mortality and years lived with disability. To calculate years of life lost, a choice was made to set a norm for long life. This norm was set by looking at the lowest observed mortality rates at any given age in any population greater than five million. Years of life lost are computed as the remaining life expectancy if an individual had not died but continued to live at low risk of dying. This works out as almost 88 years of remaining ‘ideal’ life expectancy for an infant that has died, 39 years for someone who died at age 50, and still another 2.2 years for someone dying at age 100. It reflects an assumption that everyone, all over the world, deserves to live a long life in full health. Years lived with disability take into account the prevalence of disability in a population as well as its severity. To make more than 2500 disabling outcomes of diseases and injuries included in the GBD comparable, researchers mapped these into 234 homogenous ‘health states’ for which they wrote short lay descriptions of the main symptoms and functional limitations such as pain, inability to move, see, or hear, or changes in mood. These lay descriptions were put to over 60 000 respondents in country and internet surveys, each

time in a randomly chosen pair, followed by the question ‘who is the healthier’. From over half a million of these judgements, disability weights were derived that indicate the relative severity of a health state as a number between 0 and 1. The disability weights in GBD vary from 0.003 for mild vision loss to 0.778 for a person with schizophrenia with fulminant psychosis. As we combine years of life lost (YLLs) and years lived with disability (YLDs) into the DALY measure by simple addition, it means that we equate the health loss experienced by 333 cases of mild vision loss and a little more than one person with schizophrenia in a year to a year of life lost due to a death. Another factor that is considered in creating GBD estimates is that the world’s population is growing. An increase in the number of deaths from a particular disease, then, might simply be explained by the fact that there are more people alive who may then contract the disease. One way to account for these changes in population is to calculate rates of each condition, usually expressed as deaths or DALYs per 100 000 people. In some cases, an apparent increase is revealed as a decrease when considered this way. For example, in the Democratic Republic of Congo between 1990 and 2017, the number of deaths from tuberculosis increased by 45% but the rate of tuberculosis deaths per 100 000 actually decreased by 32% over the same period. While the absolute burden in terms of number of people suffering from TB increased, the proportion of people in the population who are suffering actually decreased. The increase in the number of deaths from TB indicates to health service planners that they need to expand tuberculosis treatment resources even though the decline in rates indicates that the existing TB control measures may be having success. Age-​ standardizing also allows for more accurate comparison across countries and time frames. This technique applies observed age-​specific rates of a condition to a standard age distribution and avoids distortion when one population is older or younger than another.

Results GBD 2017 generated 38 billion data points. In order to make these results more accessible to researchers, policymakers, students, health workers, journalists, and others, IHME created a group of interactive data visualization tools that allow people to explore health trends for different countries and regions. One of these, GBD Compare, shows numbers and rates of deaths, YLLs, YLDs, and DALYs by diseases and risk factors. The main view is a ‘tree map’, which is basically a square pie chart showing the proportional distribution of the overall burden by underlying causes. Additional views can be added showing a map of the world, time plots, age plots, and ranking lists. Each can interactively be explored by country, age, sex, year, cause, or risk factor. They can be found at https://vizhub.healthdata.org/ gbd-compare/. Looking at global patterns in causes of death and disability over time reveals a shift from disease burden dominated by communicable, maternal, neonatal, and nutritional causes (shown in red) to a burden increasingly made up of non​communicable diseases (blue) and injuries (green, Fig. 2.3.1). This pattern has been partly driven by improvements in healthcare and greater access to vaccines and life-​saving medical interventions that contributed to healthcare

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

Leading causes 1990

Leading causes 2017

1 Lower respiratory infections

1 Ischaemic heart disease

2 Diarrhoeal diseases

2 Lower respiratory infections

3 Preterm birth complications

3 COPD

4 Ischaemic heart disease

4 Diarrhoeal diseases

5 Neonatal encephalopathy

5 Preterm birth complications

6 COPD

6 Low back pain

7 Drug-susceptible tuberculosis

7 Intracerebral haemorrhage

8 Measles

8 Diabetes type 2

9 Malaria

9 Neonatal encephalopathy

10 Intracerebral haemorrhage

10 Ischaemic stroke

11 Other neonatal disorders

11 Migraine

12 Low back pain

12 Malaria

13 Protein-energy malnutrition

13 HIV/AIDS other

14 Drowning

14 Lung cancer

15 Ischaemic stroke

15 Drug-susceptible tuberculosis

16 Congenital heart anomalies

16 Falls

17 Self-harm by other means

17 Age-related hearing loss

18 Dietary iron deficiency

18 Major depression

19 Migraine

19 Other neonatal disorders

20 Pedestrian road injuries

20 Self-harm by other means

22 Falls

23 Dietary iron deficiency

23 Lung cancer

27 Pedestrian road injuries

26 Diabetes type 2

29 Congenital heart anomalies

28 Major depression

36 Drowning

30 Age-related hearing loss

38 Protein-energy malnutrition

38 HIV/AIDS other

73 Measles Cause type: Communicable, maternal, neonatal, and nutritional Noncommunicable Injuries

Fig. 2.3.1  Top 20 causes of DALYs per 100 000 globally, both sexes, all ages, 1990 and 2017.

successes, such as the nearly 90% decrease in health loss from measles and tetanus globally between 1990 and 2017. Meanwhile, heart disease, stroke (intracerebral haemorrhage and ischaemic stroke), type 2 diabetes, low back pain, and chronic obstructive pulmonary disease (COPD) climbed in ranking over this period to occupy 6 of the top-​10 slots for causes of DALYs (per 100 000). The rise in non​communicable diseases can be explained by several factors. Economic development has propelled some countries from low-​to middle-​income status, often bringing improvements in healthcare, water quality and sanitation, and living conditions. At the same time, as countries gain higher economic status, air pollution may increase, and changes in diet and levels of physical activity typically occur. Factors like these have led to an epidemiologic transition away from communicable, maternal, neonatal, and nutritional disorders and towards a much greater burden of non​communicable diseases. The exception to this trend has been the HIV/​AIDS epidemic: in 1990, HIV/​AIDS caused the 39th-​highest rate of deaths (per 100 000) globally. In 2005, at the peak of the epidemic, this rank had jumped to fifth place, and by 2017 it had dropped to 13th due to increased access to antiretroviral treatment.

Greater economic development has also led to a demographic transition, meaning that birth and death rates, typically high in low-​ income countries, decreased as industrialization occurred. This results in population growth, as death rates decrease faster than birth rates, and later, population ageing. Policymakers must plan for the results of these changes by expanding health services and anticipating the need to care for the changing spectrum of prevalent diseases and comorbidities that are more common at older ages. At the regional and country levels, more variation can be seen. High-​ income countries, including the United States, Australia, Western Europe, and Japan, exhibit a disease burden dominated by non​communicable diseases. Life expectancy in these countries is typically high: between 78 and 84 years for both sexes combined in 2017 (Fig. 2.3.2), and the leading causes of health loss are all non-​ communicable diseases:  ischaemic heart disease, low back pain, lung cancer, COPD, and Alzheimer’s disease and other dementias are the top five. By contrast, life expectancy in sub-​Saharan Africa ranged from 52 to 71 years; this region also has the greatest burden of communicable diseases including malaria, diarrheal diseases, HIV/​AIDS, and tuberculosis among the top ten causes of DALYs

45

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FJI

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Fig. 2.3.2  Life expectancy at birth, both sexes, 2017. (ATG, Antigua and Barbuda; VCT, St Vincent and the Grenadines; BRB, Barbados; COM, the Comoros; DMA, Dominica; E Med, Eastern Mediterranean; FJI, Fiji; FSM, Federated States of Micronesia; GRD, Grenada; KIR, Kirbati; MDV, Maldives; MHL, Marshall Islands; MLT, Malta; MUS, Mauritius; LCA, St Lucia; SGP, Singapore; SLB, Solomon Islands; SYC, Seychelles; TON, Tonga; TTO, Trinidad and Tobago; TLS, Timor Leste; VUT, Vanuatu; W Afr, West Africa; WSM; Western Samoa.)

T) in DNA, particularly at dipyrimidine sites when two cytosines are adjacent (CC>TT). This specific base-​change was confirmed by the demonstration of a huge predominance of C>T mutations in squamous cell carcinomas of the skin. Other DNA mutational signatures were C>A

C>G

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20% Signature 1

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discovered by aggregating patterns of transition and transversion mutations (Fig. 5.2.5) discovered in the TP53 gene across many cancer types. Importantly, these signatures could also be shown to be induced in experimental systems using relevant chemical exposures. For example, the TP53 mutational spectrum in lung cancer is dominated by C>A substitutions, which were shown to be the result of misrepair of bulky DNA adducts formed by carcinogenic components of tobacco smoke. In hepatocellular carcinoma, C>A transversions were shown to be induced by environmental aflatoxin exposure. T>A

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Fig. 5.2.5  Patterns of mutational signatures. Bar plots show proportions of each substitution in each trinucleotide context (labelling not shown). Courtesy of the Catalogue of Somatic Mutations in Cancer (COSMIC).

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SECTION 5  Principles of clinical oncology

These early discoveries of the links between exposures and somatic mutation were extremely important but had several limitations. First, they were only able to elucidate the dominant mutational signature in a cancer and could not distinguish between multiple signals from different mutagenic processes. Secondly, the use of a single gene (usually TP53) to catalogue mutational signatures can bias the statistical analysis, owing to strong selection for particular driver mutations in cancer development. For example, the commonest mutations in BRAF in melanoma are T to A transversions, which are not characteristic of UV crosslinking, but nevertheless are likely to have arisen from UV induced mutation. The availability of detailed catalogues of whole exome-​and whole genome sequencing from multiple cancer types has resulted in the discovery of many other mutational signatures, by providing thousands of passenger mutations for analysis instead of a limited number of mutations found in driver genes. Whole genome sequencing is superior to whole exome sequencing for analysing signatures because it includes non​coding sequences that comprises 99% of the normal genome, offering many more mutations for analysis. In addition, the application of signal analysis methods to whole genome data can identify many signatures in a single cancer by deconvoluting the imprints of multiple mutational processes. Although there are six possible DNA substitutions based on Watson–​Crick changes in DNA (Fig. 5.2.5), mutational signatures are described as trinucleotide sequences by

including the 5′-​and 3′-​base at each site of mutation. By including the sequence context for the mutation, different mutational processes can be unambiguously discriminated. For example, a UV light-​induced C>T transversion at a dipyrimidine site (NpCpC) can be distinguished from the same C>T change arising from deamination of 5-​methyl cytosine at a NpCpG site (where N indicates any nucleotide). Currently, detailed analysis of 7000 genomes from 30 cancer types has identified 30 distinct mutational signatures (Figs. 5.2.5 and 5.2.6). This number is likely to increase as other mutational data, including deletions and large structural variants, are integrated into pattern-​recognition methods. Several of these signatures already provide strong candidate biomarkers for therapy, and it is to be expected that the rapid uptake of whole exome and whole genome methods in clinical genomics will soon lead to precise characterization of tumours as they occur in routine oncological practice. The two most common signatures found across all cancer types arise from deamination of 5-​methyl-​cytosine and are related to ageing and carcinogenesis. Other signatures reveal specific exposures and mutational processes. Liver, uterine, and stomach cancer can have up to six distinct signatures, suggesting complex DNA damage and repair phenotypes in their aetiology. Mutational signatures can now provide strong diagnostic and aetiological information for cancer research. Whole genome

a om an el ma lm o ea arc a Uv nos om i rc cin a ca ar m e e c ino in er rin arc id Ut Ute l c yro lia Th ch he a ot om Ur St tate os Pr ma to cy a tro om as gli s tic an ea cy ag ncr lo ar Pi P Pa ary v O a m co ar s os ou ste m O qua us l s ag ca ph a uc so m -b Oe asto a vo bl gi ro om in eu in a lg N carc om ra l O l ea ye a ng M om ry an ha el ma M sto op a in as N bl lo gk ul od ed H ell M ma B-c o a s ph m ou m ho m Ly mp ua ll Ly g sq ll ce a n Lu sm eno ng ad Lu g ver n Lu Li y r lla pi pa ell ey ar c dn le e Ki y c hob e p k dn o Ki om nec r ch nd de ey d a gra dn ea a Ki H low om t a m as io bl tum Gl io Gl rec L lo CL Co a m co ar ix os rv dr Ce t s on ea Ch Br r de ad Bl ML A L AL a

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Signature 3 Signature 4 Signature 5 Signature 6 Signature 7 Signature 8 Signature 9 Signature 10 Signature 11 Signature 12 Signature 13 Signature 14 Signature 15 Signature 16 Signature 17 Signature 18 Signature 19 Signature 20 Signature 21

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Signature 22 2 Signature 23 1 Signature 24 1 Signature 25 1 Signature 26 4 Signature 27 1 Signature 28 1 Signature 29 1 Signature 30 2 Other signatures Mutational signature present

Total validated mutational signatures in a cancer type

Fig. 5.2.6  Occurrence of mutational signatures by cancer type. Courtesy of the Catalogue of Somatic Mutations in Cancer (COSMIC).

Total cancer types in which a signature is operative

5.2  The nature and development of cancer

sequencing studies have revealed distinct patterns of smoking-​ related signatures by analysing 5000 tobacco-​associated cancers from smokers and non​smokers. Cancers from smokers had significantly higher numbers of base substitutions and lung cancers in smokers had higher numbers of copy number aberrations. Signature 4, which represents exposure to the tobacco carcinogen benzo[a] pyrene, was most prominent in lung and laryngeal cancers, where epithelia are directly exposed to tobacco smoke but was also found in lung cancer from non​smokers, suggesting contributions from secondary smoke inhalation. Studies on radiation-​associated cancers show that the additional induced burden of mutations is relatively low, but in contrast to other mutational signatures, the distribution of mutations is evenly distributed across the genome, and does not show bias with replication timing, sequence complexity, or GC base content. Radiation-​induced tumours also show a very rare aberration of balanced inversions which may uniquely identify these cancers. These data show that the stochastic nature of radiation is not affected by the chromatin context of DNA but induces relatively infrequent additional mutations, which may explain the low absolute risk of radiation-​induced cancer. Cancers with microsatellite instability can be identified by a strong preponderance of signature 6 (Fig. 5.2.6), which reflects very high numbers of substitutions and 1-​base pair indels in nucleotide repeats. This signature is most commonly seen in colorectal, uterine, and stomach cancer and is strongly associated with loss of mismatch repair genes. Detection of this signature has important therapeutic implications as it indicates patients who are likely to benefit from with immune checkpoint inhibitors, owing to increased frequency of expressed neoantigens in the tumour microenvironment. Signature 3 is frequent in breast, ovarian, and pancreatic cancers and

is strongly correlated with homologous recombination deficiency (HRD) and is commonly caused by mutation in BRCA1 and BRCA2. Cancers with HRD can also be identified by different signatures based on the pattern of structural variants as they characteristically have large indels (≤50 bp) with overlapping microhomology at breakpoint junctions. Patients with HRD show increased sensitivity to platinum-​based chemotherapy and poly (adenosine diphosphate [ADP]) ribose polymerase inhibitor (PARPi) therapy. Sequencing for germline and somatic mutations in BRCA1 or BRCA2 (and other less frequent mutations in homologous recombination genes) cannot identify all patients with HRD, whereas the finding of a dominant signature 3 is strongly suggestive of possible benefit from PARPi therapy. The analysis of signature 3 across 32 cancer types has shown that 7–​12% of cases of gastric cancer have features of HRD. As gastric cancer is the second commonest cancer worldwide, there may be significant benefits from routine profiling for mutational signatures of HRD or MSI.

Mutations offer targets for personalized therapies Most targeted therapies currently in the clinic are designed to disrupt gain-​of-​function properties in cancer cells and these commonly overlap with the hallmarks of cancer. These effects are often mediated by oncogenic mutations that induce constituent activity of the respective protein. They are often driver mutations, and the term ‘oncogene addiction’ is used to describe the dependency of the cancer cell on the induced gain of function, hence targeting of these mutations may have dramatic effects on cancer growth (Table 5.2.2). This is exemplified by the development of therapeutics against BRAF mutations in malignant melanoma. The BRAF gene encodes a serine threonine kinase and is a member of the Raf family of growth

Table 5.2.2  Overview of relationships between cancer genotypes and their predicted responses to targeted therapy

a

Cancer type

Genotype

Therapy

Colorectal cancer

Mutant KRAS

Cetuximab/​Panitumimab (no response)

Chronic eosinophilic leukaemia (CEL)

PDGFR translocations

Imatinib

Chronic myeloid leukaemia (CML)

BCR-​ABL translocation

Imatinib

Resistant CML

Mutant BCR-​ABL translocation

Dasatinib Ponatinib Bosutinib

Gastrointestinal stromal tumour (GIST)

Mutant KIT

Imatinib

Breast cancer

HER2 amplification

Trastuzumaba Pertuzumaba ado-​trastuzumab emtansinea

Melanoma

Mutant BRAF

Vemurafenib Dabrafenib Trametinib Dabrafenib/​Trametinib

Myelofibrosis

Mutant JAK2

Ruxolitinib

Non-​small cell lung cancer

Mutant EGFR

Erlotinib Gefitinib Afatinib

Non-​small cell lung cancer

ALK translocation

Crizotinib Ceritinib

Non-​small cell lung cancer

ROS1 translocation

Crizotinib

Eligibility is not strictly on genomic amplification of HER2, as strong HER2-​positivity by immunohistochemistry is also an eligibility criterion for treatment. Reprinted from Tursz T and Bernards R (2015). Hurdles on the road to personalized medicine. Molecular Oncology, 9(5), 935–​9. Published under a Creative Commons Attribution (CC BY) License.

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SECTION 5  Principles of clinical oncology

promoting proteins. Activating mutations in BRAF were first identified by the Cancer Genome Anatomy Project from melanoma cell lines. Sequencing studies on clinical specimens showed that 50–​70% of malignant melanoma cases have the V600E BRAF mutation, and this is also found in 8–​12% of colorectal cancers and less commonly in other cancers. The V600E mutation induces constitutive activation of the BRAF kinase, while successful pharmacological targeting of the kinase CP-​pocket was achieved with the clinical development of the drug vemurafenib. Use of vemurafenib in patients with metastatic melanoma has shown dramatic responses in over 70% of patients treated, but resistance to single agent therapy develops by activation or mutation of other pathways that circumvent BRAF inhibition, the implications of which are discussed later.

Mutational analysis measures cancer evolution Genomic studies carried out over the past 20  years have revealed considerable intratumoural genetic heterogeneity and strong evidence of evolutionary selection of subclonal tumour populations during treatment, as well as during metastasis. These studies were initially carried out in paediatric acute lymphoblastic leukaemia, but similar processes of clonal evolution and selection have now been confirmed in many epithelial tumours. This has led to the clinical realization that profiling a single sample of an individual’s cancer may not represent a comprehensive depiction of all driver genes. In addition, reliance on the original diagnostic cancer sample cannot provide accurate information about subsequent somatic changes contributing to therapy resistance. Optimal decision-​making for personalized medicine now requires contemporaneous genomic information from repeat or sequential biopsies. The use of image-​guided biopsies, particularly using ultrasound with 14 G or 16 G cutting needles, can provide high-​ quality samples for next-​ generation sequencing. However, biopsy may be difficult at metastatic sites such as bone or abdominal lymph nodes, and the expense and discomfort for the patient may limit repeatability over their treatment. Mutational profiling of cell-​free DNA in blood offers an alternative ‘liquid biopsy’ and is

being rapidly developed for clinical use in many cancer types and for different applications, from diagnostic information to detection of emerging resistance mechanisms. Detecting cancer mutations in cell-​free DNA Cell-​free DNA was first demonstrated in blood in 1948 and shown to be increased in the serum of cancer patients in 1977. The possibility that it could be used as a cancer biomarker was established in the early 1990s by the detection of cancer mutations in plasma, stool, and sputum as well as other body fluids. Most cell-​free DNA in plasma originates from normal haemopoietic cells and in healthy individuals the concentration of plasma DNA concentrations range between 1 and 10 ng/​ml. However, these levels are dynamic and may be altered by disease processes causing tissue injury such as trauma or stroke, as well as physiological changes during pregnancy and physical exercise. Cell-​free DNA in blood is fragmented into short fragments of approximately 166 base pairs, which likely reflect the length of DNA strands in close contact with the nucleosome proteins in chromatin. Deep sequencing of cell-​free DNA can also predict likely gene expression in the parental cells by predicting sites of DNA localization to nucleosomes. Cancer circulating tumour DNA (ctDNA) molecules are typically shorter than normal DNA at around 140 base pairs, although the reasons for this are unknown. The mechanisms determining how DNA enters the bloodstream as ctDNA have not been fully defined, but are most likely caused by apoptosis of tumour cells. The half-​life of ctDNA is between 16 minutes and 2.5 hours and this, together with the wide dynamic range and relatively low cost of ctDNA assays, make cell-​free DNA a highly attractive diagnostic and tumour response indicator. By contrast, the detection of circulating tumour cells is more difficult and has higher expense. Critically, often only low numbers of circulating tumour cells can be detected from a blood sample which limits potential diagnostic and prognostic information. Clinical evidence that ctDNA can indeed be used as a ‘liquid’ biopsy that can replace tissue biopsy has emerged from improvements in the diagnostic pathway for lung cancer (Fig. 5.2.7). Lung

(a)

(b) Serial liquid biopsies

Cancer detection: Molecular Detection screening or profiling or of residual earlier diagnosis prognostication disease

Monitoring response

Quantitative analysis • Disease staging • Response monitoring • Prognostication

Monitoring clonal evolution

Clone 1 Clone 2 Clone 3 Size of clone

454

Time

Genomic analysis • Mutation profiling • Treatment selection • Monitoring clonal evolution Surgery (or other)

Treatment 1

Treatment 2

Treatment selection

Fig. 5.2.7  Applications of circulating tumour DNA for cancer diagnosis, prognostication, detection of minimal residual disease and monitoring clonal evolution. Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Cancer (Wan JCM, et al., 2017, Liquid biopsies come of age: towards implementation of circulating tumour DNA, Nature Reviews Cancer, 17, 223–​38), copyright © 2017.

5.2  The nature and development of cancer

cancer is an important exemplar for development of ctDNA assays owing to the need to identify patients who can benefit from targeted therapy and the relative difficulty of obtaining tissue biopsies. Existing CT-​ guided and bronchoscopic biopsy have a comparatively high failure rate and costs. The first FDA and EMA approvals for the use of ctDNA in lung cancer are for assays based on real-​time polymerase chain reaction (rtPCR) to detect common oncogenic mutations in EGFR. These assays depend upon allele-​ specific primers that generate different fluorescent PCR products that discriminate between mutations (deletion of exon 19, L858R, or T790M) from wild-​type sequences and can be used for tumour specimens or ctDNA. These assays are now in clinical use for the selection of gefitinib, erlotinib, and osimertinib therapy and regulatory approval now allows a therapeutic decision to be made based solely on a ctDNA result if a tumour sample is not available. These advances widen the availability of therapy to lung cancer patients who may be too frail for biopsy or who have a tumour that is not easily accessible. The rapid uptake of ctDNA assays in lung cancer trials has also provided strong evidence for utility in the clinic that will be relevant to other cancer types. Over 4000 patients have had ctDNA results in lung cancer trials, and meta-​analysis of these data show an overall sensitivity of 60% and specificity of 94% for detection of EGFR mutation. Direct comparison between plasma ctDNA and lung cancer biopsies in over 650 patients showed a sensitivity of 66% and a specificity of 100%. A key question now is how effective ctDNA assays will be for the detection of secondary resistance mutations during therapy and on follow-​up. Perhaps not surprisingly, the sensitivity of detecting the classical EGFR resistance mutation T790M is less good, reflecting lower abundance of revertant mutations and the effects of tumour heterogeneity. In colorectal cancer the presence of KRAS mutation is a strong predictor of resistance to the EGFR inhibitor cetuximab. Use of sequential ctDNA assays for KRAS has shown the emergence of clonal populations marked by KRAS mutations that are resistant to cetuximab therapy. In addition, these low-​frequency populations can be demonstrated at diagnosis in some patients, which are selected to become the predominant population with therapy. There are now intensive efforts to improve the sensitivity of next-​generation sequencing methods for ctDNA and to widen the number of genes included in these assays. These advances are likely to overcome current sensitivity limitations by better discriminating between early driver mutations (sometimes called ‘stem mutations’), which have higher abundance in plasma and the rarer revertant mutations. Clinical trials are now needed to address whether outcomes and response rates are different for patients treated on the basis of ctDNA and tumour monitoring. These impacts may further change therapeutic approaches. A key challenge will be the ability to detect ctDNA in patients with early stage disease as ctDNA strongly correlates with tumour volume and can vary by 100–​640-​fold between stage I and stage IV disease. See Chapter 3.10 for broader discussion of the development and uses of circulating DNA for molecular diagnostics.

Conclusion The development of precision medicine using DNA sequencing has had several dramatic successes in the past decade, notably with the targeting of BRAF and EGFR. There are grounds for considerable optimism about the wider applicability of sequencing technology in clinical practice. An absolute requirement for the wider development of clinical sequencing will be the need to use fresh or frozen specimens from biopsy and surgical procedures because—​although current technology can provide high-​quality sequencing data for multiple genes using DNA extracted from formalin-​fixed paraffin-​embedded tissues—​the DNA from these tissues is degraded and not suitable for whole genome sequencing. As whole genome sequencing becomes cheaper and the utility of integrative genomic signatures becomes established, the routine pathological processing of fresh or frozen material will be essential. The second main challenge will require clear recognition that resistance to conventional and targeted therapies often reflects evolutionary or selective pressure, which induces expansion of new clonal populations of tumour cells. This observation immediately prompts investment in suitable infrastructure for sequential or repeat biopsy of patients undergoing routine standard of care treatment, and the wider use of non​invasive methods such as circulating tumour DNA. Finally, despite the impending arrival of thousands of cancer genomes, we are faced with major challenges for data interpretation, sharing of the data with patients, and more widely for increased knowledge and the training of healthcare staff to interpret the clinical meaning of genomic change. These challenges will, in part, be addressed by an increasing focus on clinical trials based on the molecular targeting of patients harbouring particular mutations in genes implicated in cancer development, and also the rapid dissemination of positive or negative results of such trials. It is difficult, however, to conceive how even dedicated oncology specialists will be able to keep abreast of all potential mutations, functional changes, and therapy. One solution to this challenge may be wider data sharing and the use of computerized decision support tools. At the same time, it will be critically important to have high-​level clinicians working in molecular pathology, as these individuals with specialized knowledge will be at the nodal point of most clinical decisions based on tumour mutation analysis.

FURTHER READING Alexandrov LB, et  al. (2013). Signatures of mutational processes in human cancer. Nature, 500, 415–​21. Diaz LA, Jr., et al. (2012). The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature, 486, 537–​40. Hanahan D, Weinberg RA (2011). Hallmarks of cancer: the next generation. Cell, 144, 646–​74. Helleday T, Eshtad S, Nik-Zainal S (2014). Mechanisms underlying mutational signatures in human cancers. Nat Rev Genet, 15, 585–98. Kucab JE, et al. (2019). A compendium of mutational signatures of environmental agents. Cell, 177, 821–36. Misale S, et al. (2014). Resistance to anti-​EGFR therapy in colorectal cancer: from heterogeneity to convergent evolution. Cancer Discov, 4, 1269–​80.

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5.3

The genetics of inherited cancers Rosalind A. Eeles

ESSENTIALS All cancer can be termed ‘genetic’ as the disease is caused by somatic cell mutations (alterations in the DNA code), which result in abnormal cellular growth and/​or proliferation. Most of these mutations are sporadic (only occurring in the cancer cell), but some are due to the inheritance of a germline mutation in a cancer predisposition gene. Cancer predisposition genes can be rare and confer a high cancer risk (about 10-​fold lifetime relative risk), or common and confer a low to moderately increased risk (from just over onefold, up to two-​to threefold). They have been shown to be involved in causing some of the most common cancers, as well as some rare cancers.

Mechanisms of inherited cancers Cancer predisposition genes are usually (1)  tumour suppressor genes—​for example, retinoblastoma caused by mutations in RB1—​ when, although the mutations are recessively inherited at the cellular level, they tend to manifest with a dominant inheritance pattern because the chance of a mutation being inherited by the offspring is 50%, and a sporadic mutation of the remaining normal allele occurs in a somatic cell during the lifetime of the germline mutation ­carrier to lead to cancer development; (2) oncogenes—​for ­example, the RET oncogene in the multiple endocrine neoplasia type 2A syndrome—​when gain-​of-​function mutations act in a dominant manner; (3)  mismatch repair genes—​for example, causing genetic instability leading to the hereditary non​polyposis colorectal cancer (Lynch) syndrome.

Clinical features Genetic predisposition to cancer should be suspected when cancers: (1) occur at a younger age than is seen in the general population; (2) occur in more than one site or at multiple times at the same site in an individual (multiple primary tumours); or when (3)  rare cancers are seen in clusters in a family; or (4) common cancers are seen in clusters in a family, often at a young age or with multiple primaries. Genetic predisposition to common cancers—​ this includes (1) breast—​BRCA1 and BRCA2 mutations confer 80–​85% lifetime risk of breast cancer by 80 years (and also a significantly increased risk of ovarian cancer); TP53 (Li–​Fraumeni syndrome) mutations confer

90% risk of breast cancer by 60 years; (2)  colon—​mutations in the APC gene cause familial adenomatous polyposis and a virtually 100% risk of colon cancer by the age of 40 years; hereditary non​polyposis colorectal cancer, which is also associated with other cancers in addition to colon cancer, particularly endometrial cancer (15–​60% lifetime risk) and ovarian cancer (9–​12% lifetime risk). Rare inherited cancer syndromes—​there are many of these, including hereditary retinoblastoma, neurofibromatosis type 1 (optic nerve glioma, sarcoma, phaeochromocytoma), neurofibromatosis type 2 (acoustic neuroma and other tumours of the central nervous system), multiple endocrine neoplasia type 1 (parathyroid adenomas, pancreatic islet tumours and anterior pituitary tumours), multiple endocrine neoplasia, type 2A and 2B (medullary thyroid cancer, phaeochromocytoma, parathyroid adenomas), Cowden’s syndrome (breast and other cancers), tuberous sclerosis (childhood brain tumours, cardiac rhabdomyomas), Gorlin’s syndrome (multiple basal cell naevi/​ carcinomas), Von Hippel–​Lindau syndrome (cerebellar and spinal haemangioblastomata, renal cell carcinoma, phaeochromocytoma, pancreatic tumours).

Clinical management Patients and/​or families known or suspected to carry cancer predisposition gene mutations require genetic counselling and risk assessment, which may lead on to (1) cancer screening—​for example, colonoscopy for some individuals at increased risk of colon cancer; (2)  lifestyle changes—​ for example, avoidance of known cancer-​ causing factors such as sunlight in Gorlin’s syndrome; (3)  prevention strategies—​for example, prophylactic total colectomy in the familial adenomatous polyposis syndrome; (4)  cancer treatment considerations—​for example, tumours with a particular genetic abnormality may respond to particular treatments; and (5)  genetic testing—​which may either be diagnostic (the detection of a mutation in an individual affected by cancer) or predictive (the detection of a mutation in a clinically unaffected individual). Future prospects—​gene alterations that predispose to cancer affect prognosis and treatment, hence genetic information is increasingly recognized as important in oncological practice. Cancer genetics will become part of mainstream clinical pathways for cancer care in the next decade and is likely to contribute to healthcare that is tailored to individual patients.

5.3  The genetics of inherited cancers

Introduction Cancer is a common disease; it affects up to one-​half of the population during their lifetime. All cancer can be termed ‘genetic’ as cancer is caused by somatic cell mutations (alterations in the DNA code), which result in abnormal cellular growth and/​or proliferation. Most of these mutations are sporadic (occurring only in the cancer cell) and only a proportion of these cases is due to the inheritance of a germline mutation in a cancer predisposition gene. In these latter cases, the genetic alteration is in all cells of the body with the exception of the gametes where, on average, the genetic alterations are in one-​half of the gametes. It used to be thought that such alterations were rare, but each conferred a high cancer risk (about 10-​fold lifetime). However, recent studies have shown that there are also more frequent alterations in cancer predisposition genes with each of such mutations conferring a slightly increased risk (with just over a onefold, up to a two-​to threefold relative risk). This has implications for the role of genetic predisposition to cancer in general medical and oncological practice, as a larger proportion of cancer cases may harbour these latter alterations in the genetic code. Identification of such alterations will become important in the genetic profiling of the population to aid targeted cancer screening and prevention. There is emerging evidence that gene alterations that predispose to cancer affect prognosis and treatment and thus their significance is becoming incorporated into the clinical pathway for cancer care. Cancer genetics will become part of mainstream cancer care in the next decade and is likely to contribute to healthcare that is tailored to individual patients.

Historical perspective Since Roman times, cancer has been known to run in families. In some families, the pattern of cancer incidence among family members is consistent with the inheritance of a mutated gene and carriers of this mutated gene have a high risk of cancer. The chance that cancer will develop if an individual has a mutation in a cancer predisposition gene is called the penetrance. Most cancer predisposition genes have incomplete penetrance (i.e. the cancer risk is =64 years. Am J Clin Nutr, 89, 1366–​74. Butterworth RF (1982). Neurotransmitter function in thiamine deficiency. Neurochem Int, 4, 449–​65. Carmel R (2000). Current concepts in cobalamin deficiency. Annu Rev Med, 51, 357–​75. Cashman KD, et al. (2008). Estimation of the dietary requirement for vitamin D in healthy adults. Am J Clin Nutr, 88, 1535–​42. Dakshinamurti K, Chauhan J (1989). Biotin. Vitam Horm, 45, 337–​84. Englard S, Seifter S (1986). The biochemical functions of ascorbic acid. Annu Rev Nutr, 6, 365–​406. European Food Safety Authority (EFSA) (2006). Tolerable upper intake levels: vitamins and minerals. Scientific Panel on Dietetic Products, Nutrition and Allergies. European Food Safety Authority (EFSA) (2012). Tolerable upper intake levels for vitamins and minerals. Scientific Committee on Food, Scientific Panel on Dietetic Products, Nutrition and Allergies. Ferland G (2001). Vitamin K. In:  Bowman BA, Russel RM (eds) Present knowledge in nutrition, 8th edition, pp. 164–​72. ILSI Press, Washington, DC. Froese DS, Fowler B, Baumgartner MR (2019). Vitamin B12, folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation. J Inherit Metab Dis, 42, 673–85. Henderson L, et al. (2000). The national diet & nutrition survey: adults aged 19 to 64 years. Vitamin and mineral intake and urinary analytes. HMSO, London. Holick MF (1994). McCollum award lecture: vitamin D—​new horizons for the 21st century. Am J Clin Nutr, 60, 619–​30. Hommes FA (1986). Biotin. World Rev Nutr Diet, 48,  34–​84. Huemer M, Baumgartner MR (2019). The clinical presentation of cobalamin-related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways. J Inherit Metab Dis, 42, 686–705. Institute of Medicine (2000). Dietary reference intakes for vitamin C, vitamin E, selenium and carotenoids. National Academy Press, Washington, DC. Jiang Q, et al. (2001). γ-​Tocopherol, the major form of vitamin E in the US diet, deserves move attention. Am J Clin Nutr, 74, 712–​22. Kril JJ (1996). Neuropathology of thiamine deficiency disorders. Metab Brain Dis, 11,  9–​17. Lal H, Pandey R, Aggarwal SK (1999). Vitamin D: non-​skeletal actions and effects on growth. Nutr Res, 19, 1683–​718. Leon del-rio A (2019). Biotin in metabolism, gene exression and human disease. J Inherit Metab Dis, 42, 647–54. Marcé-Grau A, Martí-Sánchez L, Baide-Mairena H, Ortigoza-Escobar JD, Pérez-Dueñas B (2019). Genetic defects of thiamine transport and metabolism: A review of clinical phenotypes, genetics, and functional studies. J Inherit Metab Dis, 42, 581–97. Merrill AH, Jr., Henderson JM (1987). Diseases associated with defects in vitamin B6 metabolism or utilization. Annu Rev Nutr, 7, 137–​56. Morrissey P, Hill TR (2009). Fat soluble vitamins and vitamin C in milk and milk products. In: Fox PF, McSweeney P (eds) Advanced dairy chemistry-​3. lactose, water, salts and minor constituents, pp. 527–​89. Springer, New York. Neuzil J, Weber C, Kontush A (2001). The role of vitamin E in atherogenesis: linking the chemical, biological and clinical aspects to the disease. Atherosclerosis, 157, 257–​83. O’Callaghan B, Bosch AM, Houlden H (2019). An update on the genetics, clinical presentation, and pathomechanisms of human riboflavin transporter deficiency. J Inherot Metab Inherit Dis, 42, 598–607. Pellagra (2000). Prevention and Cure of Review 32 pages. Wolrd Health Organization. https://www.who.int/nutrition/publications/ en/pellagra_prevention_control.pdf

Pope S, Artuch R, Heales, Rahman S (2019). Cerebral folate deficiency: analytical tests and differential diagnosis. J Inherit Met Diseases, 42, 655–72. Prentice A, Goldberg G, Schoenmakers I (2008). Vitamin D across the lifecycle: physiology and biomarkers. Am J Clin Nutr, 88, 500S–​505S. Pryor WA (2000). Vitamin E and heart disease: basic science to clinical intervention trials. Free Radical Biology and Medicine, 28, 141–​64. Rahman S, Baumgartner M (editors) (2019). B Vitamins; Small Molecules, big effects. J Inherit Metabol Dis, 42, 579–80. Ross C, et al. (2010). Dietary reference intakes for calcium and vitamin D. Institute of Medicine, Washington, USA. Scientific Advisory Committee on Nutrition. Vitamin D and Health Report. Crown copyright. Available online: https://www.gov.uk/ government/publications/sacn-vitamin-d-and-health-report (accessed on 14 April 2019). Scott J, Weir D (1994). Folate/​vitamin B12 inter-​relationships. Essays Biochem, 28,  63–​72. Shea MK, Booth SL (2008). Update on the role of vitamin K in skeletal health. Nutr Rev, 66, 549–​57. Shearer MJ (2000). Role of vitamin K and Gla proteins in the pathophysiology of osteoporosis and vascular calcification. Curr Opin Clin Nutr Metab Care, 3,  433–​8. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine (1998). Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin and choline. National Academy Press, Washington, DC. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine (2000). Dietary reference intakes for vitamin C, vitamin E, selenium and carotenoids. National Academy Press, Washington, DC. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine (2001). Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium and zinc. National Academy Press, Washington, DC. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine (2001). Dietary reference intakes for calcium and vitamin D. National Academy Press, Washington, DC. Tahiliani AG, Beinlich CJ (1991). Pantothenic acid in health and disease. Vitam Horm, 46, 165–​228. Tucker JM, Townsend DM (2005). Alpha-​tocopheropl: roles in prevention and therapy of human disease. Biomed Pharmacother, 59,  380–​7. Vallerand IA, Lewinson RT, Farris MS, et al. (2018). Efficiency and ­adverse events of oral isotretinoin for acne: a systematic review. Br J Dermatol, 178, 76–85. Various authors (1999). Symposium proceedings: nutrition, biochemistry and molecular biology of biotin. J Nutr, 129, 476s–​503s. Wagner KH, Kamal-​Eldin A, Elmadfa I (2004). Gamma-​tocopherol-​ an underestimated vitamin? Ann Nutr Metab, 48, 169–​88. Wang S (2009). Epidemiology of vitamin D in health and disease. Nutr Res Rev, 22, 188–​203. Wang ZY, Chen Z (2000). Differentiation and apoptosis induction theraphy in acute promyelocytic leukaemia. Lancet Oncology, 1, 101–6. Wilson MP, Plecko B, Mills PB, Clayton PT (2019). Diseases affecting Vitamin B6 metabolism. J Inherit Metab Dis, 42, 629–641. Ziegler M (2000). New functions of a long-​known molecule. Emerging roles of NAD in cellular signaling. Eur J Biochem, 267, 1550–​64. Zubaran C, Fernandes JG, Rodnight R (1997). Wernicke-​Korsakoff syndrome. Postgrad Med J, 73,  27–​31.

11.3

Minerals and trace elements Katherine Younger

ESSENTIALS The essential minerals, calcium, phosphorus, potassium, sulphur, sodium, chlorine, and magnesium (macrominerals) and trace elements chromium, copper, fluorine, iodine, magnesium, manganese, molybdenum, phosphorus, selenium, and zinc, have diverse and critical functions in human metabolism. Dietary sources and the intake requirements for macrominerals and trace elements for optimal physiological well-​being have been established, and the upper range of intake has been also been set so that unwanted or even toxic effects can be avoided. Deficiency of certain trace elements contributes importantly to the global burden of illness and mortality, especially in infants under the age of five years. Latterly also, especially in high-​and middle-​ income regions, there has been burgeoning public and commercial interest in the role of, and requirements for, minerals and trace elements in health and disease. An up-​to-​date familiarity with the scientific basis of mineral and trace element physiology is therefore critical for maintaining good standards of clinical practice and to inform the best standards of nutritional advice, especially in the treatment of severe illnesses associated with deficiency or toxic excess of one or more macrominerals or trace elements.

Introduction Around 4% of body weight is made up of mineral elements, of which seven are required in larger amounts: calcium, phosphorus, potassium, sulphur, sodium, chlorine, and magnesium. In health these are required in amounts of g/​day and may be referred to as the macrominerals. They are present principally in body fluids (typically as electrolytes) and as structural components of tissues. The remaining element are required in amounts less than 100 mg/​day and are termed trace minerals/​elements: iron, zinc, copper, iodine, manganese, molybdenum, selenium, and chromium. Cobalt is required only as preformed vitamin B12. Fluorine is not essential but is beneficial as fluoride. Lithium is used to treat bipolar disorder. Some other elements may prove to be essential to humans (based on their role in other organisms):  aluminium, arsenic, boron,

bromine, cadmium, germanium, lead, nickel, rubidium, silicon, tin, and vanadium. They would be required in amounts less than 1 mg/​day and are therefore sometimes referred to as ultratrace elements. Most of the other elements may be found in the human body, in amounts that depend on the environment, but have no known function and may be toxic (e.g. mercury). The essential trace elements function as part of enzyme reactions, either as a constituent part of the enzyme, the metalloenzymes, or as activators of enzyme systems (where they are more loosely bound). They have a structural and catalytic role in gene expression. Other functions include the storage and transport of substrates as metalloproteins (e.g. zinc + insulin in secretory vesicles in the β cells of the pancreas). Their essentiality arises from their individual chemistry, which determines their specific roles. In general, the more soluble the mineral or trace element, the better it is absorbed in the gut. Uptake is usually controlled (i.e. via transport proteins), except when intakes are very high. All elements may be toxic in excess; intake may be via the gut, skin, or lungs. Excretion is usually minimal when the element is present in the body bound to protein(s), hence the risk of toxicity. Normal loss of these elements is mainly via desquamation (and bile), though chelating agents can be administered in the case of copper toxicity (e.g. in Wilson’s disease) in order to promote excretion in the urine (and phlebotomy is used to deplete the body of excess iron in hemochromatosis). Primary deficiencies occur widely in the cases of iron and iodine, and, in some groups, zinc and selenium. Secondary deficiencies may occur due to excess losses from the body (urine, blood, diarrhoea), or due to malabsorption, gut surgery, alcohol abuse, and other clinical conditions. It is possible that suboptimal status of minerals and trace elements could be involved in the development of degenerative diseases such as coronary heart disease, cancer, and osteoporosis. However, it is currently difficult to investigate this due to the lack of good methods for assessing status and hence determining requirements of some minerals and trace elements, and the complex interactions possible between them and other minerals, nutrients, and non-​ nutrients in the diet.

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Chromium Chromium exists in nature in several valence states, trivalent (reducing) being the most stable in biological systems. Hexavalent chromium is a strong oxidizing agent and is carcinogenic. Trivalent chromium was established as an essential nutrient in 1977 when the diabetic signs of a patient on TPN were reversed by supplemental chromium. Chromium’s main role appears to be the regulation of insulin, normalizing its secretion in both hyper-​and hypoglycaemia such that blood glucose concentrations are normalized, and having no effect where glucose tolerance is normal. Lipid profiles are also improved following normalization of insulin function. Supplemental chromium increases insulin binding and increased numbers of insulin receptors, and may be involved in the phosphorylation and dephosphorylation of insulin receptor proteins. Deficiency in humans is rare; the clinical signs and symptoms include impaired plasma glucose utilization and increased insulin requirements, weight loss, neuropathy, elevated plasma fatty acids, and abnormalities in nitrogen metabolism. The richest dietary sources of chromium are brewer’s yeast, spices such as black pepper, mushrooms, prunes, raisins, nuts, asparagus, beer, and wine. Stainless steel vessels can contribute chromium to acidic foods. Absorption of chromium is inversely related to dietary intake at normal intakes of 10–​40 µg/​day, via a saturable passive diffusion process in the small intestine; absorption is promoted by ascorbic acid. It is transported in the blood mainly bound to transferring, and excreted mainly in the urine. There is no satisfactory measure of chromium status, thus setting recommended dietary intakes is problematic. The UK dietary reference value (DRV) merely recommends safe and adequate intakes of more than 25 µg/​day for adults and 0.1–​0.2 µg/​kg/​day for children and adolescents. The US Institute of Medicine (IOM) has set adequate intakes (AI) ranging from 0.2 µg/​day in infants up to 35 µg/​day in adult men, 25 µg/​day in adult women, 35 and 45 µg/​ day in pregnant and lactating women, respectively. In contrast, the European Food Safety Authority (EFSA) has not set any recommendations due to lack of evidence. Similarly, there is insufficient evidence on which to base upper intake levels (UL), though there is World Health Organization (WHO) guidance that chromium supplementation should not exceed 250 µg/​day.

Copper This essential transition metal can switch between redox states (cuprous, Cu1+, and predominant cupric, Cu2+) forming a catalytic centre in several enzymes, notably cytochrome oxidase in the inner mitochondrial membrane, dopamine β-​hydroxylase required for the synthesis of noradrenaline, Cu/​Zn superoxide dismutase which protects cells from oxidative damage, and lysyl oxidase which hydroxylates some of the ε-​amino groups of elastin thereby enabling crosslinking which is essential for the integrity of connective tissue. Copper is therefore required for infant growth, immune function, bone strength, red and white blood cell maturation, and iron, cholesterol, and glucose metabolism. The human body contains between 50 and 150 mg, mostly bound to proteins. Liver stores are

particularly important in newborn babies (being 5–​10-​fold more concentrated than in adults), in order to provide copper for growth while intakes are low. Preterm infants are therefore at risk of copper deficiency since their liver stores are inadequate, and cow’s milk is a poor source of copper. In the plasma, more than 60% of copper is bound to caeruloplasmin, which functions as a ferroxidase enzyme. Iron crosses cell membranes in the Fe 2+ (ferrous) form and is oxidized by caeruloplasmin to the Fe 3+ (ferric) form in order to bind to its transport protein, transferrin. Copper deficiency (rare) therefore causes hypochromic anaemia; other symptoms include neutropenia and bone abnormalities (and in an inherited copper deficiency disease, Menkes syndrome, characteristic hypopigmentation, and pili torti). In adults, copper deficiency also causes myelopathy and hence spastic gait and peripheral neuropathy similar to that seen in vitamin B12 deficiency (subacute combined degeneration of the spinal cord). High levels of dietary zinc are known to adversely affect copper absorption and bioavailability via the induction of the protein metallothionein in the intestinal epithelial cells, which inhibits uptake into the blood. Copper absorption may also be inhibited by dietary ferrous iron, sucrose, fructose, animal proteins, S-​amino acids, and histidine. High dietary amounts of ascorbic acid supplements, molybdenum, calcium, and/​ or phosphorus and cadmium have been shown to adversely affect copper absorption and bioavailability. The richest dietary sources of copper are organ meats, seafood, nuts, seeds, and whole grains. Drinking water distributed via copper piping can add 1.0 mg/​day to intakes in acid and soft water areas. Absorption of copper depends on dietary intake, shown to range from 56% at low intakes (0.78 mg/​day) to 12% at high intakes (7.53 mg/​day); on typical EU diets, average absorption is 30–​40%. Copper balance can therefore be achieved over a broad range of intakes, mainly by regulating excretion in bile (the major route of excretion). Recommended intakes for copper have been set: for adult males and females the UK DRV reference nutrient intake (RNI) is 1.2 mg/​day, and the IOM recommended daily allowance (RDA) is 900 µg/​day. Chronic copper toxicity can arise due to high levels in drinking water, and causes liver, kidney, and brain damage, probably due to oxidation. Acute copper toxicity causes gastrointestinal disturbances. The IOM have set the UL for adults at 10 mg/​day, whereas the EFSA figure is 5 mg/​day. People with Wilson’s disease (an autosomal recessive disease of copper storage, incidence 1 in 30 000 worldwide), if untreated (with a chelating agent), accumulate copper in the liver, the cornea (Fig. 11.3.1) and the central nervous system, leading ultimately to hepatic failure and death (Chapter 12.7.2). There may also be a genetic component in many cases of Indian childhood cirrhosis, arising from consumption of milk that has been boiled and stored in copper and brass containers. Neurodegenerative diseases such as Alzheimer’s and human prion disease have been associated with disruptions in copper metabolism. Mutations in the Cu/​Zn superoxide dismutase gene are seen in 20% of familial cases of motor neurone disease, though it is not clear how this causes the progressive muscle weakness and atrophy; ditto in Down’s syndrome, where there is an extra copy of this enzyme on the extra chromosome 21.

11.3  Minerals and trace elements

and it should be noted that there is a narrow margin between beneficial intakes and the levels that cause fluorosis.

Iodine

Fig. 11.3.1  Kayser–​Fleischer ring: deposit of copper (brown, golden, or reddish-​green) in Descemet’s membrane of the cornea. Reproduced from Bloom S, Webster G, Marks D (2011). Oxford handbook of gastroenterology and hepatology, 2nd edition with permission from Oxford University Press.

Fluorine Fluorine, as the highly soluble fluoride ion, has gained notoriety in recent years as a public health issue. It is beneficial in bones and teeth, forming calcium fluorapatite, and in teeth also fluorhydroxyapatite, which together with fluoride’s bacteriostatic effect, helps prevent dental caries. However, fluoride is toxic in excess, causing fluorosis, hence public concern. Fluorosis is dose-​related, the effects ranging from mere mottling of the teeth (endemic in areas such as parts of Africa, China, and India where fluoride levels in water are naturally high, i.e. over 10 mg/​litre; see Fig. 11.3.2), through to calcification of the ligaments and tendons causing crippling skeletal fluorosis (extremely rare in the developed world, seen only when excess intakes, i.e. over 10 mg/​day are consumed over at least 10 years, or in cases of industrial poisoning; see Fig. 11.3.3). Both EFSA and IOM have derived an AI for fluoride. The EFSA AI for adult males is 3.4 mg/​day and 2.9 mg/​day for adult females (with a UL for adults of 0.12 mg/​kg body weight/​day); the corresponding IOM AIs are 4.0 and 3.0 mg/​day (UL 10 mg/​day). If fluoridated, the public water supply is generally fluoridated at levels up to 1 mg/​litre,

Iodine, I2, is a non​metallic blue-​black solid halogen that sublimes to form a violet gas. Iodine can exist in various oxidation states, the commonest being  –​1 (iodide), +5 (iodates) and + 7 (periodates). Iodine is the only mineral element that is an essential component of hormones, that is, the thyroid hormones thyroxine (T4) and the more active triiodothyronine (T3). These appear to bind to nuclear receptors in cells, affecting gene expression in brain cells, pituitary, liver, heart, and kidney cells, stimulating enzyme synthesis, oxygen consumption, and hence metabolic rate overall. Heart rate, respiratory rate, substrate mobilization, and oxidation, and other physiological activities are all involved. Hypothyroidism and hyperthyroidism are the terms used to describe under-​and overproduction of thyroid hormones, respectively. Iodine probably also has other functions since it is concentrated from the blood by the salivary glands, the gastric mucosa, the choroid plexus (brain) and the lactating mammary gland. Iodine is required for the development of the nervous system during the first trimester of pregnancy. Iodine may also have antibiotic and anticancer roles. Functional indicators of iodine status are provided by serum levels of thyroid stimulating hormone (TSH, most sensitive), T4, and T3. Iodine deficiency disorders (IDD) are some of the most prevalent nutritional deficiencies worldwide. In the fetus it causes severe brain damage (cretinism: IQ as low as 20, hearing and speech defects, characteristic physical abnormalities) or hypothyroidism with less severe brain damage, both with stunted growth. In young children and adolescents, iodine deficiency causes hypothyroidism (high TSH with very low T3 and T4, causing lethargy, weakness, weight gain, poor concentration, oedema, myalgia, myxoedema, delayed tendon reflexes, slow heart rate) and intellectual and growth retardation, while in adolescents and adults it causes goitre and hypothyroidism. The hypothyroidism is also associated with other mineral deficiencies: zinc, iron, copper, and the metabolic disruption caused by IDDs affects the metabolism of many other nutrients, notably vitamin A.

(a)

Fig. 11.3.2  Dental fluorosis: (a) mild and (b) severe. (a) By Dozenist (CC BY-​SA 3.0, https://​creativecommons.org/​licenses/​by-​sa/​3.0).

(b)

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Fig. 11.3.3  Skeletal fluorosis. Reprinted from Indian Journal of Medical Specialties, Vol. 8, Gupta L, Zanwar A, Agarwal V, Skeletal fluorosis mimicking Diffuse Idiopathic Skeletal Hyperostosis, Pages 213–​4, Copyright © 2017, with permission from Elsevier.

Goitre is an enlargement of the thyroid gland, due to hyperplasia and an excess of colloid in the follicles (the gland is stimulated to grow by TSH in an attempt to extract iodide from the blood; see Fig. 11.3.4). Goitre is ultimately harmful since, if large enough, the thyroid gland presses on the windpipe and gullet. Iodine deficiency

Fig. 11.3.4 Goitre. From Wass JAH, Stewart PM, Amiel SA, Davies MJ (eds) (2011). Oxford textbook of endocrinology and diabetes, 2nd edn. By permission of Oxford University Press.

is also associated with decreased fertility, increased rates of stillbirth and spontaneous abortion, perinatal and infant mortality. It has been estimated that over 1 billion live in iodine-​deficient areas, mostly in Africa and Asia. The WHO has identified iodine deficiency as the main cause of preventable brain damage worldwide. Iodine supplementation in the form of iodized salt or iodized oil injections can reverse many of the deficiency symptoms in adults and older children, including goitre and mental deficiency (to some extent) and hypothyroidism. However, cretinism is irreversible. Goitrogens are another factor associated with iodine deficiency. They are organic substances (glucosides) containing sulphur (thiocyanates, isothiocyanates) which interfere with the uptake of iodide by the tissues, causing goitre. Active goitrogens may be released from progoitrogens by plant enzymes, or in animal tissues. Foods containing goitrogens or progoitrogens include cassava (a staple in much of Africa, the progoitrogen hydrogen cyanide is removed by soaking in water), bamboo shoots, maize, sweet potatoes, lima beans, brassica vegetables (e.g. cabbage). Tobacco smoke contains thiocyanate and other antithyroid compounds. In addition, the amounts of Ca, F, Mg, and Mn ions in hard water may be goitrogenic. The best sources of iodine are seafoods (fish, shellfish, seaweed); milk is now a major source of iodine (though seasonal) since the introduction of iodine-​supplemented cattle feed and salt licks, iodinated casein (a lactation promoter), and teat dip containing iodophors (sterilization agents). Organic milk has been found to be lower in iodine content than conventional milk due to the restrictions of organic farming. The iodine content of cereals and grains is variable as the level is dependent on the iodine content of the soil (iodine is leached out of soil by high rainfall, glaciations, or soil erosion, hence inland/​upland areas most deficient). In most European countries and the United States and Canada, iodine intake is maintained by the use of iodized table salt; without it, low intakes are of concern, particularly among young women.

11.3  Minerals and trace elements

Iodine is usually present in food and water as iodide or iodate (soluble), is rapidly absorbed in the intestine and circulates in the blood; excess is excreted in the urine (hence urinary levels are a useful indicator of recent iodine intake). Approximately 80% of circulating iodide is taken up by the thyroid glands; depending on the activity of the gland. Here, the iodide is oxidized to iodine which is then bound to tyrosine in thyroglobulin proteins to form monoiodotyrosine and diiodotyrosine, catalysed by thyroid peroxidase. These iodinated compounds are converted to triiodothyronine, T3, and thyroxine, T4 in the epithelial cells of the gland. T4, thyroxine, is then bound to a globulin to form thyroglobulin, for storage in the follicles of the gland until released into the blood (Chapter 13.3.1). Flavonoids (from many plants) and phenol derivatives (from soil) inhibit thyroid peroxidase and are therefore antithyroid. The enzymes responsible for forming T3 from T4 (in the liver, kidney, muscle, and pituitary) are the selenium-​dependant deiodinases, and selenium and iodine deficiencies overlap in various places (e.g. China, Tibet, Zaire). Recommended intakes have been set for iodine: for adult men and women the UK DRV RNI for adults is 140 µg/​day, the IOM RDA is 150 µg/​day, rising to 220 µg/​day in pregnancy and the EFSA have set an AI for adults at 150 µg/​day, and 200 µg/​day in pregnancy. Excess iodine intakes (>2 mg/​day) can cause elevated TSH levels, possibly leading to hypothyroidism (Chapter 13.3.1). Consequently, ULs have been set, at 600 µg/​day by the EFSA, 1.0 mg/​day in the United Kingdom and 1.1 mg/​day by the IOM. In contrast, those with IDDs can develop hyperthyroidism when exposed to moderate doses of iodine. Some individuals are sensitive to iodine and may develop mild skin symptoms (at relatively low doses), in severe cases, leading to cardiovascular collapse, convulsions, and death.

Magnesium Magnesium is unusual among the minerals in that, because it is an essential component of chlorophyll, the best dietary sources are plant-​based (green vegetables, whole grains, and pulses). Processing reduces the magnesium content, so highly refined diets are low in magnesium. Fish and shellfish are intermediate sources and tap and bottled water also contribute (variable). The body contains approximately 25 g (1000  mmol) of magnesium, mostly (50–​60%) in bone, in combination with phosphate and bicarbonate. The rest is in the soft tissues where it is mostly in combination with protein. Serum magnesium (Mg2+) is normally strictly maintained between 0.75 and 0.95  mmol/​litre; it is involved with acid/​base balance. Intracellular magnesium concentration is much higher, approximately 10  mmol/​litre (maintained against a concentration gradient). Mg2+ plays a role as cofactor in over 300 enzymic steps in intermediary metabolism: ATP synthesis, Coenzyme A, DNA replication, RNA transcription, protein synthesis, β-​ oxidation, and glycolysis. Mg2+ is an integral part of mitochondrial superoxide dismutase. Mg2+ is also involved with the maintenance of the potential difference across the membranes of nerves and muscles. Parathyroid hormone (PTH) release requires Mg2+, hence calcium homeostasis depends on it; also K and Na homeostasis. Hypomagnesaemia is defined as a serum Mg2+ below 0.75 mmol/​ litre and is often accompanied by hypocalcaemia. Magnesium homeostasis is maintained by control (of the active component) of absorption in the small intestine (efficiency is

20–​70%) and excretion via the kidney (the principal regulator). Vitamin D may regulate absorption, phosphate (free and/​or phosphate groups in phytate) may inhibit absorption, and protein and fructose may enhance it. Frank magnesium deficiency only occurs secondary to other diseases (including endocrine disorders such as hyperparathyroidism and hyperthyroidism) which cause malabsorption or excess losses of Mg via muscle wasting, diarrhoea, vomiting, or urinary losses due to renal dysfunction. Prolonged fasting can also cause magnesium deficiency, as can proton pump inhibitors when used in combination with diuretics. Hypomagnesaemia is particularly common in patients with alcoholism admitted to hospital, with causes including poor dietary intake, diarrhoea, acute pancreatitis, and urinary wasting due to tubular toxicity of alcohol. There are several rare genetic abnormalities of Mg status which lead to Mg deficiency, with features including reduced serum Mg2+ and red cell magnesium, hypocalcaemia, and hypocalciuria, hypokalaemia caused by excess potassium excretion, neuromuscular dysfunction, muscle weakness, tachycardia, ventricular fibrillation, and death. Suboptimal magnesium status has been associated with chronic diseases including cardiovascular disease, hypertension, eclampsia, pre-​eclampsia, and osteoporosis, though this is controversial due partly to the lack of sensitive and reliable tools for assessing magnesium status. However, there is concern that magnesium intakes (in the United States and Europe) are suboptimal, thus the IOM have raised the RDA for magnesium for adult men and women to 420 mg/​day and 320 mg/​day, respectively; the EFSA have set AIs of 320 and 300 mg/​day for men and women, respectively, while the corresponding UK DRV RNIs are 300 and 270 mg/​day. Magnesium salts have a laxative effect, and ULs have been set for supplemental magnesium (only) at 250 mg/​day for adults by the EFSA and 350 mg/​day by the IOM.

Manganese Manganese is a transition element which can exist in 11 oxidation states, Mn2+ being the predominant form in biological systems. The human body contains about 15 mg of manganese, 25% of which is in the skeleton; relatively high concentrations are also present in the liver, pancreas, and intestine. Manganese is an essential catalytic cofactor for mitochondrial superoxide dismutase, arginase, and pyruvate carboxylase; it is also an activator of several other enzymes. It is therefore essential for amino acid, lipid, and carbohydrate metabolism. Primary deficiency has not been reported in humans, probably due to the relative abundance of Mn in the food supply (whole-​ grain cereals, legumes, nuts, fruits, and dried tea are good sources, depending on the soil, also crustaceans and molluscs, while animal products are less good). One case of an individual fed a purified diet (accidentally) deficient in Mn has been reported, which caused weight loss, dermatitis, reduced growth of hair and nails, reddening of black hair, and lowered blood lipids. However, it is possible that deficiency may occur more widely in infants since breast (and formula) milks are low in manganese. Absorption (both active, hence regulated, and passive) occurs in the small intestine and is relatively inefficient (50 µmol/​litre after the newborn period) is caused by increased production (e.g. by intestinal urease-​producing bacteria) or decreased detoxification of ammonia. Decreased detoxification results from inherited or acquired deficiency of key enzymes and transporters of the urea cycle, or bypassing of the liver (e.g. open hepatic duct). Secondary impairment of ammonia detoxification results from conditions where glutamate or acetyl-​CoA are decreased,

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3'

6 7 8 4.8 0.8 0.7

cDNA Exons: Exon size (bp):

1

2

3

4

1613

152

117

288

5

6

7

145 131 158

8 155

DNA-binding

RECEPTOR PROTEIN Transcription-regulation

Domains NH2-

Hinge Zn++

Steroid-binding -COOH

Zn++

Fig. 13.6.2.5  Structure of androgen receptor. The gene is made up of 8 exons, the mRNA encoding 910 amino acids. The zinc finger configuration is characteristic of all steroid hormones.

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Table 13.6.2.2  Consequences of androgen deficiency before and after the onset of puberty. Hypogonadism occurring at the time of expected puberty results in a different phenotype to that acquired postpubertally Physiological action of androgen

Onset of androgen deficiency before puberty

Onset of androgen deficiency after puberty

Increase bone mass and density

Osteoporosis

Osteoporosis, female fat distribution

Fusion of long bone epiphyses

Tall, eunuchoid habits

Decrease subcutaneous/​visceral fat

Female fat distribution

Laryngeal enlargement

Unbroken, high pitched voice

Secondary sexual hair development

Lack of pubic, axillary, and facial hair, no temporal recession

Decrease facial and pubic hair, no temporal recession

Increase pilosebaceous activity

Lack of sebum, pale smooth skin

Atrophy, fine wrinkles, pallor

Stimulation of erythropoiesis

Moderate anaemia

Moderate anaemia

Increase in muscle mass

Underdeveloped, poor physical stamina

Decrease strength and physical stamina

Penile growth

Infantile

Prostate and seminal vesicle growth

Underdeveloped, no ejaculate

Atrophy, low volume, or absence of ejaculate

Stimulation of spermatogenesis

Not initiated, very small testes

Regression, small testes

Stimulation of sexual interest

Not developed

Decrease

Stimulation of erectile function

Low/​absent spontaneous erection

Decrease erection

Effect on mood and behaviour

Placid

Low moods, unassertiveness, tiredness

that are found in the promoter regions of androgen sensitive genes. The transcriptional activity of the androgen receptor is modulated by numerous coactivators, including SRC 1/​NCoA-​1, SRC2/​GRIP1-​ TIF2 and SRC3/​ACTR/​AIB1, and negatively regulated by AP-​1, NFκB, TR4, HBO1, and AES. A defective androgen receptor may lead to variable phenotypes of androgen insensitivity in humans. Physiological effects of testosterone The functions of T are age-​related (Table 13.6.2.2). In the embryo, androgens are responsible for sexual differentiation (i.e. virilizing the external and internal genitalia). Thus, during the sexual differentiation phase, development, and growth of the Wolffian duct, epididymis, vas deferens, and seminal vesicles are promoted by testosterone. The enzyme 5 α-​reductase, which converts T to DHT, is expressed in scrotal skin, the penile shaft, and the prostate. These tissues depend on DHT for their development (Fig. 13.6.2.6). Failure of 5 α-​reductase activity leads to micropenis

Female fat distribution

and incomplete/​deficient labioscrotal fusion giving rise to ambiguous genitalia. At puberty, androgens, acting with growth hormone, are responsible for the adolescent growth spurt, in particular for vertebral (i.e. upper segment) growth. It also induces promotion of secondary sexual characteristics. In adulthood, it maintains the male phenotype, sexual function as well as mediating anabolic effects. The endocrine (androgen synthesis) and gametogenic (spermatogenesis) functions of the testis are interlinked. Although testosterone is important as the principal circulating androgen, its local paracrine action within the testis is crucial, together with FSH, for the initiation and maintenance of normal spermatogenesis and hence fertility. Since germ cells do not possess AR, these hormones signals are transduced through the Sertoli cells and peritubular cells. Sertoli cells create an insular microenvironment in the seminiferous tubules by providing the physical framework and elaborating a chemical myriad of growth

TESTOSTERONE Aromatase

5-α reductase

Oestradiol

Dihydrotestosterone Sexual differentiation Secondary sexual hair growth Production of sebum Prostatic growth

Sexual differentiation Muscle growth Increase in bone mass Erythropoiesis Erythropoietin synthesis Sexual potency and libido Psychotropic effects

Bone mass Epiphyseal fusion Psychotropic effects Negative feedback modulation of gonadotrophin secretion Prostate growth (complex effects)

Fig. 13.6.2.6  Testosterone is metabolized to dihydrotestosterone by the enzyme 5-​α reductase and to oestradiol via the aromatase enzyme. These hormones exert different effects to testosterone.

13.6.2  Disorders of male reproduction and male hypogonadism

factors and cytokines for the developing germ cells. Sertoli cells also secrete inhibin B, a glycoprotein hormone which inhibits FSH secretion by the pituitary.

Male hypogonadism Male hypogonadism is a descriptive term for the clinical complex associated with androgen deficiency due to failure of Leydig cell function. Concomitant impairment of spermatogenesis is likely since the seminiferous tubules will also be androgen deficient or directly involved by the same pathological process. However,

infertility is usually an isolated abnormality of spermatogenesis where patients seldom show any clinical of androgen deficiency. In the past several years, an increasing number of specific genetic defects have been identified by genomic DNA mapping to be associated with abnormal gonadal function and development. New light has been shed on the pathogenesis of these conditions.

Aetiologies There are a large number of pathological conditions that can lead to destruction or malfunction of the hypothalamo-​pituitary-​testicular axis (Tables 13.6.2.3 and 13.6.2.4). It is important to identify the underlying cause of hypogonadism and distinguish between pituitary/​hypothalamic

Table 13.6.2.3  Classification and aetiologies of male reproductive disorders Site of lesion

Clinical picture

Androgen deficiency

Infertility

Hypothalamus and pituitary (hypogonadotropic hypogonadism) Isolated GnRH deficiency

Congenital GnRH deficiency

+

+

Kallmann syndrome

Anosmia and GnRH deficiency

+

+

GnRH insensitivity

GnRH receptor gene mutation

+

+

Fertile eunuch (Pasqualini syndrome)

Partial GnRH deficiency, low LH

+

-

Hypogonadotropic hypogonadism/​adrenal hypoplasia

DAX-​1 gene mutation

+

+

Constitutional delayed puberty

Self-​limiting

+

+

Male anorexia nervosa

Weight-​related, reversible GnRH deficiency

+

+

Hyperprolactinaemia

Pituitary tumour, drug induced

+

+

Congenital hypopituitarism

PROP 1 gene mutation, hypogonadotropic hypogonadism prolactin, GH, ACTH deficiencies

+

+

Acquired hypopituitarism

Pituitary tumour, craniopharyngioma, haemachromatosis irradiation, hypophysitis, transfusion haemosiderosis, sarcoidosis, tuberculosis, histiocytosis X

+

+

Biologically inactive LH

LH β gene mutation

+

+

Isolated FSH deficiency

FSH β gene mutation

?

+

Klinefelter’s syndrome

47XXY, 48XXXY,47XXY/​46XY mosaic, and so on

+

+

46XX male

SRY gene translocation to X chromosome

+

+

Sex chromosome/​autosomal abnormalities

Translocation, deletion

+

–​

Mixed gonadal dysgenesis

XY/​XO, true hermaphroditism

+

+

Testicular agenesis

Absence of testes postnasally

+

+

Testicular torsion

Destruction of testicular tissue

+

+

Surgical orchidectomy, testicular trauma, tumour orchitis

Destruction of testicular tissue

+

+

Sickle cell disease

Microinfarcts of the testes

+

+

Noonan–​Leopard syndrome

12q22 gene defect, autosomal-​dominant cryptorchidism, Turner’s stigmata, with short stature, webbed neck, pectus excavatum hypertelorism, ptosis, right sided congenital heart disease

Persistent Müllerian duct syndrome

AMH gene or AMR receptor type II gene mutation, Fallopian tube, and uterus present with cryptorchidism

+/​-​

+

Congenital steroidogenic enzyme deficiencies

10q.24.3 CYP17 17,20-​desmolase, 9q22 HDD17b3, 17OH-​steroid DH gene mutation

+

+

Testicular (hypergonadotropic hypogonadism)

(continued)

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Table 13.6.2.3 Continued Site of lesion

Clinical picture

Androgen deficiency

Infertility

LH insensitivity

LH receptor mutation, pseudohermaphroditism

+

+

Idiopathic infertility

Defective spermatogenesis of uncertain aetiology

–​

+

Varicocele

Reflux in spermatic vein

–​

+

Microdeletions Yq

Deletion of azoospermic factor

–​

+

Cryptorchidism

Congenital deficiency of testosterone or AMH action, dysgenetic gonads

+/​–​

+

Immotile cilia syndrome

Absent dynein arms of sperm tail microtubules

–​

+

Globozoospermia

Absence of acrosome cap on sperm head

–​

+

FSH insensitivity

2q21 FSH receptor gene mutation

?

+

Immunological

Sperm antibodies

–​

+

Immotile cilia

Dynein arms absent in sperm tail

–​

+

Young’s syndrome

Mercury poisoning?

–​

+

Congenital bilateral absence of vas deferens

CFTR gene mutation and intronic variant

–​

+

Genital tract infection

Postinfection, postvasectomy, herniorrhaphy

–​

+

Accessory gland/​prostate infection

Bacterial, chlamydia, abnormal seminal fluid

–​

+

Retrograde ejaculation

Autonomic neuropathy, postprostatectomy

–​

+

Coital insufficiency

Defective vaginal insemination

–​

+

Androgen insensitivity syndromes

Xq11-​12 androgen receptor gene mutation

+

+

Androgen receptor defects

Xq11-​12 androgen receptor gene CAG repeat expansion

+

+

5-​α reductase deficiency

2p23 5 α reductase 2 gene mutation

+

+

Oestrogen insensitivity

ER α gene mutation

–​

?

Aromatase

CYP19 gene mutation

–​

?

Acute critical illness

Cytokine or cortisol-​induced multilevel dysfunction

+

–​

Chronic illness: congestive cardiac failure, neoplasia, uncontrolled diabetes mellitus

Cytokine or caloric deprivation induced multilevel dysfunction in HPT axis

+

+

Liver cirrhosis

Primary testicular failure, followed by gonadotrophin deficiency

+

+

Chronic renal failure

Hypogonadotropic hypogonadism

+

+

Thyrotoxicosis

Increased SHBG, gonadotrophins, oestradiol

+

+

Cushing’s syndrome

Multilevel dysfunction in HPT axis

+

+

Haemochromatosis

Hypogonadotropic

+

+

HIV infection

Hypogonadotropic

+

+

Morbid obesity

Hypogonadotropic, low SHBG, total, free T

+

+

Obstructive sleep apnoea

Hypogonadotropic

+

+

Rheumatoid arthritis

Suppression of testosterone during flare up

+

?

Acute febrile illness

Temporary suppression of spermatogenesis

–​

+

Untreated congenital adrenal hyperplasia

Suppression of gonadotrophin

–​

+

Dystrophia

Myotonin protein kinase (MT-​PK) gene CTG repeat expansion

+

+

Prader–​Willi syndrome

Deletion/​mutation of imprinting centre in paternal 15q11-​13, hypogonadotropic, mental retardation hypotonia, hyperphagia, obesity, short stature

+

+

Laurence–​Moon syndrome

Hypogonadotropic, retinitis pigmentosa, mental retardation, obesity, polydactyly

+

+

Post-​testicular

Target tissues

Systemic diseases

Neurological diseases

13.6.2  Disorders of male reproduction and male hypogonadism

Table 13.6.2.3 Continued Site of lesion

Clinical picture

Androgen deficiency

Infertility

Bardet–​Biedl syndrome

Defects in BBS loci 16q11, 15q23.3, or 3p12 hypogonadotropic, retinitis pigmentosa, mental retardation, polydactyly

+

+

Familial spinocerebellar degeneration

9p frataxin gene GAA repeat expansion, hypogonadotropic, progressive ataxia

+

+

Kennedy syndrome

X911-​12 androgen receptor gene CAG repeats expansion, late-​onset androgen resistance, progressive spinobulbar muscular atrophy

+

+

Temporal lobe epilepsy

Unknown

+

–​

Spinal cord injury

Abnormal thermoregulation or neuroregulation of testes

–​

+

Fragile X syndrome

FMR 1 gene CCG repeats expansion, mental retardation, macro-​orchidism

–​

–​

Digitalis, spironolactone, cyproterone acetate, flutamide, bicalutamide, cimetidine

Antiandrogenic

+

+

Corticosteroids

Multilevel dysfunction in HPT axis

+

+

Ketoconazole

Inhibits steroidogenesis

+

+

Antipsychotics, sedatives

Hyperprolactinaemia, gonadotrophin suppression

+

+

Anticonvulsants

Increase SHBG, decreased free testosterone

+

+

Ethanol

Direct suppression of testicular function, hepatotoxic

+

+

Opiate, cocaine, cannabis abuse

Suppression of gonadotrophin

+

+

Cytotoxic drug

Agent specific, dose-​related germ cell loss

–​

+

Ionizing radiation

Dose-​dependent loss of spermatogenesis, spermatocytes

–​

+

Sulfasalazine

Abnormal sperm morphology and motility

–​

+

Nitrofurantoin

Direct suppression or antiandrogenic

–​

+

Anabolic steroids, oestrogens, progestins

Gonadotrophin suppression or antiandrogenic

(+)

+

Lead, mercury, cadmium

Adverse effects on spermatogenesis

–​

+

Pesticides, fungicides, amoebicides

Direct toxic effects on spermatogonia

–​

+

Drugs/​chemical or physical agents

Aminoglutethimide

HPT, hypothalamic–​pituitary–​thyroid  axis.

(secondary or hypogonadotropic hypogonadism), and testicular (primary or hypergonadotropic hypogonadism) disorders. The causal lesion may require specific treatment (e.g. as in the case of a prolactin secreting pituitary tumour and haemochromatosis). Hypogonadotropic conditions are amenable to treatment aimed at inducing or restoring spermatogenesis, while in primary testicular failure—which is usually irreversible—only testosterone replacement therapy is possible.

Clinical features General clinical features of hypogonadism The age of onset of androgen deficiency critically influences the manifestations of hypogonadism (Table 13.6.2.2). Prepubertal onset of testosterone deficiency gives rise to sexual infantilism and patients present with delayed puberty. Eunuchoid body proportions (arm span greater than height and heel to pubis exceeding crown to pubis lengths by at least 5 cm) develop due to the continued growth of long bones (growth hormone mediated, allowed by the delayed closure of epiphyses due to lack of testosterone/​oestradiol-​induced spinal growth in late puberty).

Postpubertal onset of testosterone deficiency leads to regression of spermatogenesis, low libido, erectile malfunction, loss of ejaculation, sarcopenia, poor stamina, and decreased secondary sexual hair and shaving frequency. However, no change is observed in body and penile proportions nor voice. Symptoms and signs of hypogonadism usually develop and progress insidiously. It is therefore common for patients to present many years following the onset of hypogonadism. Furthermore, younger patients who have never been adequately androgenized may not be aware, or even deny, that sexual function is subnormal. By contrast, after surgical or traumatic/​inflammatory castration, adults may experience hot flushes from acute withdrawal of androgens. Fetal onset of defective androgen action due to androgen receptor abnormalities or defects of steroidogenic enzymes, will cause failure of masculinization of the genitalia resulting in intersexual states. Clinical findings associated with hypogonadism Hypothalamo-​pituitary tumours should be considered in the presence of headache, defects of visual acuity or visual field loss, polyuria and polydipsia suggesting diabetes insipidus, or clinical /​biochemical

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Table 13.6.2.4  Phenotypic characteristics associated with genes that cause hypogonadotropic hypogonadism (HH) Gene

Gene product

Inheritance

Clinical phenotype

GnRH

GnRH

Autosomal recessive

Normosmic HH

GnRHR

Gonadotrophin releasing hormone receptor

Autosomal recessive

Normosmic HH

LH β

Luteinizing hormone β chain

Autosomal recessive

Normosmic HH

SEMA3A

Semaphorin-​3A

Autosomal dominant

IHH and anosmia

SOX10

SOX10

Autosomal dominant

IHH and anosmia, Waardenburg syndrome

NR0B1

DAX-​1

X-​linked

X-​linked adrenal hypoplasia and HH

KAL-​1

Anosmin-​1

X-​linked

IHH and anosmia, synkinesis, solitary kidney

FGFR1

FGF receptor 1

Autosomal dominant

Normosmic HH, craniofacial defects, digital anomalies of toes, dental agenesis

FGF8

Fibroblast factor 8

Autosomal dominant

Normosmic HH

FGF17

Fibroblast growth factor 17

Single allelic defect insufficient

Normosmic HH

HS6ST1

Heparan-​sulphate 6-​0-​sulphotransferase

Non​mendelian

HH +/​-​ anosmia

IL17RD

Interleukin 17 receptor D

Single allelic defect insufficiency

IHH and anosmia, hearing loss

DUSP6

Dual-​specific phosphatase 6

Single allelic defect insufficient

HH

SPRY4

Sprouty homologue 4

Single allelic defect insufficient

HH

FLTR3

Fibronectin leucine-​rich transmembrane protein 3

Single allelic defect insufficient

HH

NELF

Nasal embryonic LHRH factor

Single allelic defect insufficient

HH+/​-​ anosmia

CHD7

Chromodomain helicase DNA-​binding protein-​7

Autosomal dominant

HH+/​-​anosmia, CHARGE syndrome

PROK2

Ligand for G protein coupled prokinecitin receptor-​2

Heterozygous mutations, oligogenic inheritance

HH +/​-​ anosmia

PROKR2

G-​protein-​coupled prokineticin receptor-​2

Heterozygous mutations, oligogenic inheritance

HH +/​-​ anosmia

WRD11

WD repeat containing protein-​2

Heterozygous missense mutations

HH+/​-​ anosmia

GPR54

KISS1-​derived peptide receptor

Recessive mutations

HH

KISS1

Metastin or kisspeptin

Recessive mutations

HH

TACR3

Neurokinin B receptor

Recessive mutations

HH

TAC3

Neurokinin B

Recessive mutations

HH

LEP

Leptin

Recessive mutations

HH

LEPR

Leptin receptor

Recessive mutations

HH

IHH, ‘isolated’ or ‘idiopathic’ HH; LHRH, luteinizing hormone-​releasing hormone.

evidence of pituitary hormone excess such as that found in Cushing’s disease, acromegaly, and hyperprolactinaemia. Hyperprolactinaemia causes loss of libido even in the presence of apparently normal testosterone concentrations. Primary testicular failure is suggested by a history of orchitis, torsion, testicular trauma, surgery, chemotherapy, irradiation. An increasing number of chronic systemic diseases (Table 13.6.2.3) are associated with compromised hypothalamo-​ pituitary-​testicular function. With improved survival resulting from specific treatments, the role of gonadal dysfunction in the quality of life of these patients is becoming increasingly recognized. A history of excess alcohol consumption, use of recreational drugs and consumption of medications that interfere with pituitary-​ testicular function or androgen action should be specifically elucidated. Ethanol causes a lowering of plasma testosterone through a direct toxic effect on Leydig cell steroidogenesis. Testicular atrophy and gynaecomastia, found in 50% of men with liver cirrhosis, are due to disordered androgen steroid metabolism, an increase in sex hormone binding globulin, coupled with an increased oestrogen production. These changes are usually irreversible.

Neurological diseases can be associated with hypogonadism. Postpubertal atrophy of the seminiferous tubules occurs in 80% of patients with dystrophia myotonica, an autosomal-​ dominant disorder characterized by myotonia, distal muscle atrophy, lens opacification, and premature frontal balding. Variable degrees of androgen deficiency also coexist. Hypogonadotropic hypogonadism is associated with familial cerebellar ataxia, Gordon Holmes ataxia, Lawrence Moon, Bardet–​ Biedl, and Prader–​ Willi syndromes. Defective spermatogenesis is common in paraplegia or quadriplegia following spinal cord injury, perhaps due to the inability to maintain a low scrotal temperature.

Specific conditions Primary gonadal failure Klinefelter’s syndrome Klinefelter’s syndrome is the commonest cause of male hypogonadism with an incidence of 2 per 1000 live births. It is a developmental disorder of the testes resulting from the presence of an

13.6.2  Disorders of male reproduction and male hypogonadism

additional X chromosome derived from non​disjunction of parental (maternal origin in two-​thirds of cases) germ cells during meiosis. In fewer than 5% of patients, the non​disjunction occurs during mitosis of the zygote. Such postfertilization mitotic non​disjunction will result in mosaicism. The most common karyotype is 47XXY (80 to 90%), but rarer variants include 46XY/​47XXY mosaic, multiple X+Y, and the so-​called XX male syndrome. Unlike many other numeral aberrations of chromosomes, KS is not associated with an increased rate of miscarriage. The risk of having a child with KS increases with both increasing maternal and paternal age. The signs of Klinefelter’s syndrome are almost unnoticeable in childhood. Accelerated atrophy of germ cells before puberty and hyalinization of the seminiferous tubules give rise to very few intact gametes, and the usual outcome is sterility and small firm (around 4 ml) testes. Individual tubules with intact spermatogenesis are seen in patients with the mosaic form 46,XY/​47,XXY and very occasionally motile sperms are found in the semen. Leydig cells appear relatively hyperplastic, although Leydig cell mass is in fact normal. The degree and impact of the Leydig cell steroidogenic defect (of uncertain aetiology) is very variable, ranging from the virilized adult male presenting with infertility, to the eunuchoid youth who fails to complete sexual maturation. In KS, the extra X chromosome carrying the androgen receptor with a short CAG repeat length in Exon 1 (i.e. greater AR activity) undergoes activation preferentially. Thus, the skewed inactivation of the X chromosome resulting in the preferential activity of the long CAG repeat may contribute to the phenotypic severity and variability of KS. In adults, libido and potency are initially normal, but decrease between the ages of 25 and 35, reflecting an increasing insufficiency of Leydig cells. In mid-​adulthood, 80% of patients have reduced testosterone with elevated LH/​FSH and oestradiol levels. Other clinical features include gynaecomastia, reduced body hair, long legs, tall stature (eunuchoid proportions), and learning (verbal and cognitive) difficulties, poor school performance, behavioural disturbances, and autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and Sjogren’s syndrome, as well as type 2 diabetes mellitus. Infants with KS may manifest with micropenis, hypospadias, cryptorchidism, or developmental delay. In addition to relatively tall stature, some patients have clinodactyly, hypertelorism, elbow dysplasia, high arched palate, hypotonia, language delay or reading and learning disabilities requiring therapy occurs in up to 70%. Character and personality disorders and behavioural problems occur commonly, possibly in part because of the psychosocial consequences of androgen deficiency. IQ scores may be reduced by 10–​15%, though not into the intellectual disability range. There is also an increased incidence of osteopenia, mitral valve prolapse, breast tumours (3–​5%:  the risk increases if there is a family history of breast cancer among female relatives), testicular and extratesticular germ-​cell tumours (especially mediastinal and retroperitoneal), varicose veins, and leg ulcers. Taurodontism, characterized by enlarged molar teeth resulting from enlargement and extension of the pulp chamber, is present in 40% of men with KS. Mental retardation is associated with higher order X chromosome polysomy. Diagnosis and laboratory findings Testicular volumes of less than 4 ml should always lead to a suspicion of KS. Serum testosterone (T) is often reduced or lies in the lower reference range (40% patients), and free T is more frequently reduced than total T as the SHBG level tends to be increased. As LH stimulation is increased,

Leydig cells produce relatively more oestradiol, with increase in free E2 to free T ratios. The Barr chromatin body test is a rapid investigation used to determine a chromosomal abnormality in a swab of cheek mucosa, but the definitive diagnosis rests on karyotyping of lymphocytes. Therapy  Androgen deficiency, as evidenced by a rise in LH, should prompt replacement therapy with testosterone. Androgen treatment should start early in the adolescent as this significantly promotes psychosocial development, and may prevent the development of gynaecomastia and reduce the risk of breast cancer. It is important also for adequate development of secondary sexual characteristics, attainment of peak bone mass and bone mineral density and strength, energy, motivation, mood, and behaviour. If gynaecomastia is cosmetically unacceptable, mastectomy may be indicated. Infants with micropenis may benefit from topical testosterone, and early intervention with speech and language therapy is important if speech delay and dyslexia are present. Dystrophia myotonica This is an autosomal-​dominant inherited condition, characterized by delayed muscle relaxation after contraction, dystrophy of the distal musculature and pharyngeal muscles, cataracts, hyperacusis, and frontotemporal hair loss. 80% of affected males develop a progressive untreatable primary hypogonadism with testosterone deficiency and damage to the germinal epithelium, with accompanying reduced testicular volumes, and hyalinization of the seminiferous tubules and vacuolation of Sertoli cells. 60% of affected males have testosterone deficiency, with loss of libido and impotence. Gonadotrophins are increased, particularly FSH. Tuberculosis Tuberculous orchitis is rare, but should be included in the differential diagnosis of testicular tumours. The scrotal mass is usually painless, and haematospermia, sterile pyuria, hydrocele, and oligoasthenoteratozoospermia may be present. Leprosy This can cause a granulomatous infiltration of the testes and up to 60% of affected males are hypogonadal, particularly with lepromatous leprosy, though rarely with the tuberculoid form. Gynaecomastia may be present, and testosterone levels are low with increased gonadotrophin. Transverse section of the spinal cord Severe trauma to the spinal cord often leads to exocrine testicular insufficiency. Testosterone secretion often returns to normal spontaneously, but spermatogenesis is usually permanently impaired in paraplegics and tetraplegics. This is thought to occur as a consequence of disorders of thermoregulation and circulation. Secondary gonadal failure This can result from absent or defective GnRH secretion, or failure of the anterior pituitary to respond to GnRH released from the median eminence, leading to hypogonadotropic hypogonadism (HH). Kallmann syndrome and other forms of inherited HH This has an incidence of 1 in 7500 males, and is a sporadic or familial (X-​ linked or autosomal) form of congenital hypogonadotropic

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section 13  Endocrine disorders

hypogonadism associated with several somatic congenital abnormalities including anosmia or hyposmia (defective smell sense), hereditary bimanual synkinesis (mirror hand movements), nerve deafness, cleft lip or palate, renal malformations, and dental abnormalities. There are now over 20 genes whose mutations have been incriminated in the pathogenesis of congenital hypogonadotropic hypogonadism. One of the most severe phenotypes is seen in X-​linked Kallmann syndrome, caused by mutations or deletions within the KAL-​1 gene, located in the Xp22.3 region, encoding the cell adhesion protein anosmin-​1. This is associated with faulty embryonic migration of GnRH secreting neurons from their site of origin in the medial olfactory placode into the hypothalamus, thereby preventing normal neurosecretion of GnRH (gonadotrophin releasing hormone) into the median eminence capillary circulation such that it does not reach the gonadotrophs of the anterior pituitary, resulting in hypogonadotropic hypogonadism. Associated maldevelopment of the olfactory bulb is responsible for anosmia. Patients present with delayed puberty, but the diagnosis may be suspected when neonatal males have undescended testes. Several additional genes are mutated in Kallmann syndrome that affect the fate and migration of GnRH neurons. Some of these will be associated with ‘isolated’ or ‘idiopathic’ hypogonadotropic hypogonadism (IHH) and anosmia, while others are associated with IHH alone (normosmic forms of IHH) (Table 13.6.2.4). Genes encoding fibroblast growth factor 8 (FGF8) signalling pathway proteins, chromodomain helicase DNA-​binding protein 7 (CHD7) and sex determining region Y-​Box 10 (SOX10) affect the neurogenic niche in the nasal area and craniofacial development. Prokineticin-​2 and prokineticin receptor 2 (encoded by PROK2 and PROKR2, respectively), WD repeat domain 11 (encoded by WDR11), semaphorin 3A (encoded by SEMA3A) and FEZ family zinc finger 1 (encoded by FEZF1) influence the migration of GnRH neurons. Postmigratory GnRH neurons are embedded in a complex neuronal network of afferents that send information about permissive reproductive cues such as steroid and metabolic hormones to these cells (Fig. 13.6.2.2). Individual components of the underlying neural circuits are increasingly recognized, and some key molecules have been discovered through the study of the genetics of isolated hypogonadotropic hypogonadism. Inactivating mutations in genes encoding kisspeptin-​1 (KISS1) and its receptor (KISS1R) arrest pubertal development in humans. Extensive experimental studies in various species have demonstrated that kisspeptin-​producing neurons are major afferents to GnRH neurons and essential for different aspects of GnRH function, ranging from the tonic feedback control of GnRH and/​or gonadotropin secretion to generation of the preovulatory surge responsible for ovulation. Although kisspeptins are not essential for GnRH neuron migration, experimental data has documented that populations of kisspeptin neurons undergo a dynamic process of prenatal and postnatal maturation enabling them to establish connections with GnRH neurons early in development (under the control of steroid hormones). Similarly, identification of mutations in TAC3 (encoding tachykinin-​3, cleaved to form neurokinin B) and TACR3 (encoding tachykinin receptor 3; also known as neuromedin-​K receptor or NKR) in patients with IHH have underlined the importance of the tachykinin family in the

control of GnRH neurons. These findings led to the identification of a subpopulation of afferent neurons in the arcuate and/​or infundibular hypothalamic region, coexpressing kisspeptins and neurokinin B (NKB), and it appears that the actual number of kisspeptin and/​or NKB neurons change during development. Mutations in proteins that regulate ubiquitination such as OTU domain-​containing protein 4 (encoded by OTUD4) and E3 ubiquitin-​protein ligase RNF216 (also known as ring finger protein 216; encoded by RNF216), as well as in proteins involved in lipid metabolism such as neuropathy target esterase (also known as patatin-​like phospholipase domain-​ containing protein 6; encoded by PNPLA6), have been identified in patients with Gordon Holmes syndrome (with associated IHH and ataxia). Thus, mutations in these three genes give rise to a broad and progressive neurodegenerative syndrome that includes IHH. Haploinsufficiency of DMXL2, which encodes synaptic protein DmX-​like protein 2, has been shown to cause a complex new syndrome associating IHH with polyendocrine deficiencies and polyneuropathies. Peripheral signals that convey information about metabolic status indirectly modulate GnRH neurosecretion as evidenced by the reproductive phenotype of absent pubertal development and hypogonadotropic hypogonadism in patients with inactivating mutations in the genes encoding leptin (LEP) or its receptor (LEPR). Experimental data suggest that kisspeptin neurons are sensitive to changes in leptin concentrations and metabolic conditions by an indirect mechanism. Mutations of the GnRH locus and in the GnRH receptor cause IHH with normal olfactory function. This also occurs in patients with LH β-​gene mutations (Table 13.6.2.4). Oligogenicity and reversibility in IHH  Recent evidence suggests that in a few cases the coexistence of mutations in several genes incriminated in IHH may be necessary for full phenotypic expression. This may explain why phenotypic penetrance can be variable with an identical genotype at one locus shared by several members of a kindred. It has also been shown that the HH phenotype is potentially reversible in up to 10% of patients with IHH. Late-​onset hypogonadism Total and free testosterone decline gradually and in varying degrees in men from the age of 40 onwards. This is amplified by the age-​ related increase in SHBG levels exacerbated by concomitant systemic diseases and the use of some medications. Differentiation of non​specific symptoms of ageing such as frailty, decreased muscle strength, lack of stamina and vitality, decline in libido, from those of mild classical hypogonadism can be difficult. A significant percentage of men over 60 years of age have serum testosterone levels below the lower limits of normal for young male adults (20 to 30 years), and some longitudinal studies have suggested that as many as 20% of men in their 60s and approximately 50% of men in their 80s have serum total testosterone (TT) levels significantly below those of normal young men. However, the European Male Ageing Study (EMAS) estimated a much lower prevalence (2.1%) of symptomatic late-​onset hypogonadism in the population. It is evident that the clinical symptoms/​manifestations in this age group may be more difficult to recognize because of masking by comorbid illnesses. There is controversy as to the significance of falling testosterone levels with age, some believing that it is a

13.6.2  Disorders of male reproduction and male hypogonadism

medically significant condition resulting in significant detriment to the quality of life and adversely affecting the function of multiple organ systems, while others suggest that it is a chemical marker of generalized illness. Although significant advances have been made in improving the understanding of the pathophysiology of the hypogonadism, the diagnostic methods used to diagnose low testosterone levels, and testosterone replacement therapy, a great deal of confusion and misunderstanding still exists among clinicians and patients about the diagnosis of hypogonadism in ageing men, and benefits and risks associated with testosterone therapy. The important questions as yet unanswered questions are:  (1) How to diagnose late-onset hypogonadism in ageing males? (2) What are the best treatment options for late-onset hypogonadism? (3)  Will older hypogonadal men benefit from testosterone treatment? (4) What are the risks associated with such interventions?

Investigation Confirmation of hypogonadism The clinical suspicion or diagnosis of hypogonadism must be confirmed by demonstration of low circulating testosterone before replacement therapy can be envisaged. It is recommended that blood samples be obtained between 8 to 9 AM, avoiding the circadian fall in levels of testosterone seen later in the day. The interpretation of total testosterone requires measurements of SHBG, which can alter in ageing, obesity, with the use of anticonvulsive medications, diabetes, iron overload, and liver disease. The free testosterone can be calculated from the total testosterone, SHBG and albumin concentrations using the Vermeulen formula (see http://​www.issam.ch/​ freetesto.htm for calculator). Assessment of the hypothalamo-​pituitary-​testicular axis and the target tissue androgen resistance Measurement of LH, FSH, and testosterone are required to distinguish between primary and secondary hypogonadism. In primary gonadal failure, LH and FSH levels are elevated and testosterone levels low, whereas in secondary gonadal failure low testosterone levels are associated with inappropriately low gonadotrophins. Causes of hypo and hypergonadotropic hypogonadism are listed in Table 13.6.2.3, as are other conditions that can impair fertility. Pathologies in the hypothalamus and pituitary give rise to low or low normal gonadotrophins and low testosterone (hypogonadotropic hypogonadism or secondary testicular failure), where the potential for stimulating testicular function by exogenous gonadotrophin or GnRH replacement is maintained. Conditions affecting the testes will interrupt normal testicular negative feedback. This results in elevated gonadotrophin levels with a low testosterone, characteristics of a hypergonadotropic hypogonadal state (primary testicular failure). Failure of spermatogenesis with reduced testicular size is commonly associated with a rise in FSH alone. The value of estimation of circulating inhibin B and Müllerian inhibiting hormone (MIH) for diagnostic purposes is currently being assessed. Patients with androgen insensitivity syndromes have elevated testosterone with high LH, but normal to low FSH. Increased LH or FSH is associated with a very rare LH and FSH resistance syndromes.

Human chorionic gonadotropin (HCG) stimulates Leydig cell steroidogenesis and increases plasma testosterone level over 4 to 7 days. Administration of HCG is useful for detecting the presence of functional testicular tissue in patients with impalpable testes, and to assess functional reserve of the testes prior to treatment with exogenous gonadotrophin or GnRH, and in differentiating hypergonadotropic hypogonadism from rare causes who produce immunologically detectable but biologically inactive LH excess. Stimulation tests of gonadotrophin secretory reserve using clomiphene and GnRH seldom give additional information and have become largely obsolete, especially with the improved sensitivity and range of modern gonadotrophin assays. Assessment of the pituitary Patients with hypogonadotropic hypogonadism without the stigmata of Kallmann syndrome should undergo full anterior pituitary functional evaluation and an anatomical basis sought for their gonadotrophin deficiency (e.g. a mass lesion in the hypothalamo-​ pituitary region). They require pharmacological tests of growth hormone and ACTH reserve, thyroid function tests, visual field charting, and MR or CT scanning of the hypothalamus-​pituitary region. Other investigations Ultrasound and MR scanning are useful in locating ectopic or intra-​ abdominal testes. DNA analysis can help confirm the diagnosis of androgen resistant syndromes and an increasing number of rare causes of hypogonadism such as haemochromatosis.

Treatment objectives The treatment objectives are to: 1. Relieve the symptoms of androgen deficiency 2. Prevent the long-​term consequences of androgen deficiency such as osteopenia 3. Reproduce physiological circulating and tissue levels of plasma testosterone, dihydrotestosterone, and oestradiol 4. Induce fertility if required in hypogonadotropic patients 5. Treat any specific underlying disorder The mainstay of treatment of the hypogonadal male is androgen replacement therapy. Although hypogonadotropic patients have the potential for fertility, gonadotrophin and pulsatile GnRH therapy should only be employed where there is a requirement for fertility because of the expense and complexity of these regimens. Previous testosterone exposure does not jeopardize response to gonadotrophins, hence younger hypogonadal subjects should be treated by testosterone in the same manner as hypergonadotropic patients to initiate and maintain virilization and sexual function.

Modalities of androgen replacement therapy The circulating half-​life of free testosterone is around 10 minutes due to rapid metabolism by the liver. To achieve sustained physiological circulating concentrations, testosterone must be administered in a modified form or by a parenteral route so that its rate of metabolism or absorption is retarded. Injectable testosterone esters are the commonest first-​line androgen preparations. A  mixture of four different testosterone

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esters (propionate, phenylpropionate, isocaproate, and decanoate) (Sustanon, 250 mg 2 to 3 weekly) and testosterone enanthate (Primoteston Depot) are the most popular. While undoubtedly effective, these preparations inevitably give rise to high supraphysiological peak testosterone levels within the first week, which then fall sharply to the lower limit of normal before the next dose. Some patients are disturbed by fluctuations in libido, mood and stamina associated with the repeated rise and fall of testosterone levels, as well as by the painful deep intramuscular injections. Crystalline testosterone compressed into cylindrical palates, surgically implanted subcutaneously under local anaesthesia, provide a depot source of testosterone which last 6 to 8 months. Peak testosterone levels are achieved after 2 to 4 weeks followed by a gradual decline over the subsequent months. A total dose of 800 mg can maintain physiological concentrations of testosterone for between 6 to 8 months, which some patients find more convenient than more frequent injections. The implantation procedure can be conducted as an outpatient, although rarely can be complicated by haemorrhage or infection, and in inexperienced hands 10% of implanted pellets may be extruded, often quite late. Implants should only be used as maintenance therapy in patients who have already shown satisfactory tolerance to the androgen effects of shorter acting preparations. Testosterone undecanoate is administered orally, but low bioavailability (150 pmol/​ litre) in the context of a relevant clinical history and the presence of a pancreatic mass. Multiple molecular weight forms of somatostatin may be demonstrated by column chromatography of plasma or tumour extracts, and these may explain unusual clinical features. Localization is rarely a problem due to the large size at presentation. Pancreatic and duodenal somatostatinomas appear to have similar rates of metastases and malignancy. The overall 5-​year survival rate is 75%, or 60% if metastases are present.

Somatostatinoma

Other functional peptides can present with characteristic syndromes such as:

Somatostatinomas are extremely rare, with an estimated annual incidence of about 1 in 40 million per year. Fifty per cent of these tumours are pancreatic, the remainder arising in the duodenum. Unlike other functional pancreatic neuroendocrine tumours, somatostatinomas are rarely associated with MEN-​1. Pancreatic somatostatinomas are usually large, more than 2 cm at diagnosis, and thus present with local symptoms, biliary obstruction, or features relating to excess somatostatin secretion. Somatostatin has pan-​ inhibitory effects on gut motility, transit and absorption, gallbladder contraction and secretion, and endocrine and exocrine pancreatic functions. The so-​called somatostatin syndrome resulting from somatostatin hypersecretion therefore consists of steatorrhoea (due to inhibition of pancreatic exocrine function), cholelithiasis (due to reduction of cholecystokinin secretion and inhibition of gallbladder contraction), hyperglycaemia (due to suppression of insulin secretion), and hypochlorhydria (due to suppression of gastrin secretion). Hypoglycaemia has occasionally been described, possibly due to larger molecular forms of somatostatin having a greater inhibitory effect on counterregulatory hormones such as glucagon than on insulin. In comparison to pancreatic somatostatinomas, duodenal somatostatinomas are smaller, frequently associated with neurofibromatosis type 1, seldom associated with a recognizable ‘somatostatin syndrome’ and often containing psammoma bodies (a round concretion of calcium said to originate from the calcification of abnormal collagen produced by the neoplastic cells). Duodenal somatostatinomas usually present with

GLP-​1omas Neuroendocrine tumours that cosecrete GLP-​1 together with other bioactive peptides have been described. In one case, an ovarian neuroendocrine cosecreting GLP-​1 and somatostatin was associated with diabetes mellitus during oral and IV glucose tolerance tests followed by a profound reactive hypoglycaemia, due to the subsequent glucose-​ dependent potentiation of insulin secretion by GLP-​1. In a second case, a patient with a pancreatic neuroendocrine tumour cosecreting glucagon and GLP-​1 manifested diabetes mellitus (due to the hyperglucagonaemia) together with a fasting hyperinsulinaemic hypoglycaemia, attributed to chronic hypertrophy of β cells and autonomous secretion of insulin. In two other cases, cosecretion of GLP-​1 and the related peptide glucagon-​like peptide-​2 (GLP-​2) caused hyperplasia of the small intestinal mucosa (due to the excess GLP-​2), prolonged intestinal transit time, intractable constipation, and recurrent vomiting. Other rare pancreatic neuroendocrine tumour syndromes

• Ectopic ACTH production by pancreatic neuroendocrine tumours, resulting in Cushing’s syndrome, is well documented in the literature and virtually all cases are highly malignant with a poor prognosis. These patients can develop a pseudo-​Nelson’s syndrome which is due to the evolution of α-​MSH from the tumour, stimulating skin pigmentation. • Secretion of parathyroid hormone-​related peptide (PTHrP) by pancreatic neuroendocrine tumours can manifest with intractable hypercalcaemia. • Neurotensinomas are rare and truly difficult to separate from the symptom complex produced by VIP excess. • Patients can present with a secondary acromegaly and gigantism as a result of ectopic GHRH secretion by pancreatic neuroendocrine tumours. • Arginine vasopressin (AVP) leading to hyponatraemia due to the syndrome of inappropriate antidiuresis. • Calcitonin, which can be released by neuroendocrine tumours other than medullary thyroid carcinoma, and which leads to a syndrome of flushing and diarrhoea. • Insulin-​like growth factor-​II (IGF-​2) causing hypoglycaemia. Other peptides produced by islet-​cell tumours include neuropeptide Y, neuromedin B, calcitonin gene-​related peptide, bombesin, and motilin, but these are not associated with recognized clinical syndromes.

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Pancreatic polypeptide-​secreting tumours (PPomas) PP is secreted by up to 75% of pancreatic neuroendocrine tumours, and as noted above PP appears to be secreted in many cases as an epiphenomenon of an otherwise non​functioning neuroendocrine tumour. Where the tumour is secreting PP as its primary secretion, PPomas may present with either watery diarrhoea or weight loss, due to the known appetite-​suppressive effects of PP. Non​functioning pancreatic neuroendocrine tumours Non​functional tumours represent 15 to 30% of pancreatic neuroendocrine tumours. These most frequently arise in the pancreatic head and are most often diagnosed in the fifth to sixth decades of life. Twenty to thirty per cent (20–​30%) of these tumours are associated with MEN-​1. They usually present late with symptoms attributable to either tumour bulk, such as anorexia and weight loss, or to effects on local structures, such as obstructive jaundice or intestinal obstruction. The clinical silence of these non​functioning pancreatic neuroendocrine tumours may also reflect secretion of neuropeptides at low circulating concentrations, biologically inactive molecular forms, downregulation of peripheral receptors, or simultaneous production of an inhibitor such as somatostatin. Non​functioning pancreatic neuroendocrine tumours are often mistakenly diagnosed as adenocarcinomas, but the presence of elevated circulating markers such as chromogranins A and B, CART, pancreatic polypeptide, or neurotensin, uptake on somatostatin receptor imaging and the presence of neuroendocrine markers on biopsy samples can establish the correct diagnosis. The overall 5-​year survival is about 50%.

Management of pancreatic neuroendocrine tumours As can be seen from the following sections, the treatment of pancreatic neuroendocrine tumour runs the entire gamut of modalities including gastroenterology, endocrinology, surgery, nuclear medicine, interventional radiology, and oncology. Treatment decisions must essentially be taken in a suitably constituted multidisciplinary meeting so that all suitable modalities are considered. Surgical treatment Surgery is the only curative treatment for pancreatic neuroendocrine tumours and should be considered for tumours of G1 or G2 grade. Generally, tumours less than 2 cm have a low propensity to metastasize with only 6% being malignant when discovered. These can be surveyed with cross-​sectional imaging without the necessity for surgery. Localized pancreatic NETs less than 2 cm, or those causing significant hormonal syndromes may be considered for curative resection, for example, enucleation for lesions close to the surface, pancreaticoduodenectomy for head of pancreas lesions, a distal pancreatectomy ± splenectomy for lesions in the body and head of pancreas. The question as to whether the primary tumour should be resected in the presence of unresectable liver metastases is not yet answered. Although there is some evidence that suggests some improvement in median overall survival with resection of the primary tumour under these circumstances, this should be taken with caution as the quality of evidence in this area is relatively poor. The surgical management of pancreatoduodenal neuroendocrine tumours in MEN-​1 remains controversial because of the multifocal nature of the associated pancreatic disease. In cases where patients present with functional syndromes such as

insulinomas or Zollinger–​Ellison syndrome, detailed investigation (e.g. with exendin-​4 imaging or ASVS) is sometimes necessary to distinguish those tumours which are secretory from those that are non​functional, so that the right procedure may be planned. In patients with MEN-​1, surgical cure rates are high for insulinomas, but are significantly lower for gastrinomas, as gastrinomas are frequently multifocal and situated in the duodenum. Even so, resection of gastrinomas can reduce the rate of subsequent liver metastases, thus improving their overall prognosis, and this option should be seriously considered where there is no evidence of extrapancreaticoduodenal spread. Some centres advocate an aggressive surgical approach to MEN-​1-​associated pancreatoduodenal neuroendocrine tumours, including the choices of total pancreaticoduodenectomy or distal subtotal pancreatectomy combined with preservation of the pancreatic head, enucleation of any neuroendocrine tumours remaining in the pancreatic head and in the duodenal wall. This approach may significantly reduce the morbidity and mortality associated with pancreatic neuroendocrine tumours in MEN-​1 patients, but comes at the cost of perioperative morbidity and mortality, as well as the morbidity associated with endocrine and exocrine pancreatic insufficiency, particularly brittle diabetes mellitus. Somatostatin analogues Somatostatin analogues such as octreotide and lanreotide are the standard of care in the medical treatment of neuroendocrine tumours. Octreotide and lanreotide bind most avidly to SSTR-​2 and -​5 with a lower affinity for SSTR-​3. A newer SSTA, pasireotide, possesses a different affinity for SSTR-​1, -​3, and -​5 and is still being studied for its effects in neuroendocrine tumour therapy. SSTR-​2 is believed to mediate the biochemical responses to somatostatin analogues, whereas both SSTR-​2 and -​5 subtypes are believed to mediate their antiproliferative effects. Somatostatin analogues have two principal effects:  (1) antisecretory, leading to relief of functional syndromes. This is particularly useful for glucagonomas and VIPomas, although analogues are markedly less reliable for suppressing insulinomas (50% effectiveness) and gastrinomas (see next); (2) antiproliferative, supported by the results of the CLARINET study in patients with pancreatic, jejeuno-​ileal, colonic, and rectal NETs of grades G1 and G2, which demonstrated that lanreotide Autogel therapy was capable of significantly extending progression-​free survival. Octreotide has a half-​life of several hours in the circulation and requires frequent subcutaneous injected administration three times a day. Depot injection preparations of somatostatin analogues such as octreotide LAR or lanreotide Autogel are more commonly used since these allow sustained release, typically necessitating an intramuscular or deep subcutaneous injection every 4 weeks. Patients are often initially stabilized on short acting subcutaneous octreotide to ensure that treatment is tolerated well and that there are no adverse reactions, before converting to longer acting depot preparations. Tachyphylaxis is said to occur with time, but this is not a frequent issue. Peptide-​receptor radionuclide therapy (PRRT) Following the binding of labelled somatostatin analogues to SSTRs, neuroendocrine tumour cells internalize and retain the analogues, leading to the retention of tracer. By binding high-​energy ß-​particle

13.8  Pancreatic endocrine disorders and multiple endocrine neoplasia

emitting radionuclides such as 177Lu and 90Y to somatostatin analogues such as lanreotide and DOTATATE, tumour cells can be selectively exposed to high-​energy ß-​radiation, leading to cell apoptosis. Such PRRT acts systemically and is a particularly useful palliative option for patients with inoperable or multisite disease. A key prerequisite prior to treatment is to demonstrate that there is high tumour uptake of the SSTA relative to non​target tissues on quantitative somatostatin receptor imaging, preferably with the same peptide (e.g. DOTATATE) that will be used for therapy. Patients must also have stable haematological and renal function. In uncontrolled case series, PRRT is associated with favourable partial responses or tumour stabilization, with relatively mild adverse reactions—​acute nausea, bone marrow suppression, and renal toxicity being the chief problems. The results from a randomized controlled trial in mid-​gut neuroendocrine tumours (NETTER-​1) show that 177Lu DOTATATE therapy is capable of increasing progression-​ free survival and overall survival compared to treatment with highdose somatostatin analogue therapy. Definitive randomized controlled trials in patients with pancreatic neuroendocrine tumours are currently lacking, but it should be noted that 177Lu DOTATATE therapy for pancreatic NETs is now approved by cost-effectiveness bodies such as the UK National Institute for Health and Care Excellence based on appraised data from single-arm studies. Systemic chemotherapy Traditional antiproliferative chemotherapy has a relatively limited role in the treatment of neuroendocrine tumours. It is more effective against high-​grade G3 tumours, those exhibiting high-​grade FDG uptake or biologically aggressive behaviour. Typical chemotherapeutic regimens include combinations of etoposide and cisplatin, fluorouracil with streptozocin, fluorouracil with doxorubicin, or fluorouracil with streptozocin and cisplatin. Temozolomide ± capecitabine has also been advocated for the treatment of pancreatic NETs. Temozolomide is a cytotoxic alkylating agent, with comparable antitumour activity to streptozotocin, and is particularly effective in neuroendocrine tumours expressing low levels of the DNA repair enzyme O6-​ methylguanine DNA methyltransferase (MGMT). Capecitabine with streptozocin has also recently been shown to be reasonably effective in the Phase II NET-​01 trial, producing a radiological response or stabilization in 74%, a median progression-​free survival of 9.7 months and median overall survival of 27.5 months. The addition of cisplatin to the regimen did not improve outcomes. Targeted molecular therapy Targeted molecular therapies, for example the tyrosine kinase inhibitor sunitinib (inhibiting VEGFR, PDGFR, c-​KIT, and FLT3) and everolimus (inhibiting mTOR), have been shown to be active against pancreatic neuroendocrine tumours in recent Phase III trials. In a placebo-​controlled randomized controlled trial in 171 patients with advanced and non​resectable pancreatic neuroendocrine tumours, sunitinib therapy was shown to double median progression-​free survival compared to placebo. Overall survival was improved. The main adverse effects were diarrhoea, nausea, and vomiting, tiredness, hypertension, and neutropenia. The RADIANT-​3 Phase III randomized controlled trial showed that everolimus was also capable of doubling median progression-​free survival in patients with progressive and metastatic pancreatic neuroendocrine tumours. Unlike sunitinib, no benefit on overall survival was noted. The most common adverse effects noted were stomatitis/​

aphthous ulceration, rash, diarrhoea, fatigue, neutropenia, and an increased rate of infections. The latter side effect is due to its activity as an immunosuppressant. Everolimus also induces some metabolic adverse effects:  hypertriglyceridaemia and diabetes mellitus. The metabolic effects are controllable with insulin and hypolipidaemic treatment. Indeed, its hyperglycaemic effect is sometimes advantageous in the case of metastatic insulinomas. The main dose-​limiting adverse effect of everolimus is pneumonitis, interstitial lung disease, and sometimes lung fibrosis. This can be potentially very serious and may require steroid treatment and withdrawal or dose reduction of everolimus. Other angiogenesis inhibitors such as sorafenib (a tyrosine kinase inhibitor of VEGFR2, PDGFRB, FGFR1 and FLT3), pazopanib (targeting VEGFR-1, -2 and -3, PDGFRα and β, FGFGR-1, -2 and -3, c-Kit, Itk, Lck, c-Fms and B-Raf) and bevacizumab (a monoclonal antibody against VEGF-​A) have shown some promising activity in smaller trials but are not currently in routine use. Pazopanib, brivanib, cabozantinib, sulfatinib, famitinib and lenvatinib are newer tyrosine kinase inhibitors also targeting VEGFR which are currently under evaluation. External beam radiotherapy This may be effective in relieving pain from bone metastases and, in a small number of cases, has been curative in patients with locally unresectable pancreatic neuroendocrine tumours. Orthotopic liver transplantation Because of the generally less aggressive biological behaviour of neuroendocrine tumours, orthotopic liver transplantation (OLT) is an accepted, if uncommon, treatment of disease limited to liver metastases. The 5-​year survival after OLT has been shown in various series to vary between 36% and 90%. Contraindications include high-​grade tumours (G3), extrahepatic disease, or disease draining to the systemic circulation. As the experience of OLT for this indication is limited, there remains considerable uncertainty about the true benefit of OLT and this treatment is usually recommended only on a case-​by-​case basis. Interferon alpha Interferon alpha (IFN-α) exhibits an antiproliferative activity and has been used for the treatment of gastrointestinal and pancreatic neuroendocrine tumours, with an overall response rate of 20% and a biochemical response rate of 63% (26). However, its adverse effects—​flu-​like symptoms, myelotoxicity, weight loss, and fatigue, depression, and on occasion, suicidal ideation—​limit the dose and duration of treatment, making this usually a third-​line therapy. Local ablation Ablation of liver metastases may be considered if the number of lesions is small ( young

Obesity

Unusual

++ (Almost invariable in white people)

Family history

±

+

Clinical insulin dependence (weight loss and hyperglycaemia without insulin replacement)

+

–​

C-​peptide

Low, especially 5 years after diagnosis

Normal or raised

HLA DR3 or DR4

++

–​

Islet cell antibodies: ICA, GAD, IA-​2, ZNT8

++

–​

Special investigations:

GAD, glutamic acid decarboxylase; HLA, human leukocyte antigen; ICA, islet cell antibodies; IA-​2, insulinoma associated antigen-​2, ZnT8 –​zinc transporter-​8

of stress hormones. Genital candida infections, causing recurrent pruritus vulvae in women and balanitis in men, are frequent and should always prompt testing for diabetes. Pyogenic skin infections and urinary tract infections, sometimes complicated by severe renal damage, are also common, and certain rare infections have a particular predilection for diabetic people (see next). Diabetic ketoacidosis presents with hyperglycaemic symptoms, which are usually severe, together with nausea and vomiting, acidotic (Kussmaul) breathing, the smell of acetone on the breath, and, especially in children, altered mood and clouding of consciousness that may progress to coma. Diabetic ketoacidosis is described in detail later. Unlike type 2 diabetes, which is often present for several years before diagnosis, hyperglycaemia in newly presenting type 1 patients develops too acutely for chronic diabetic complications to appear. Because obvious symptoms appear quickly, very few cases are picked up fortuitously, although doctors who have forgotten to think of diabetes in their differential diagnosis of weight loss or hyperventilation may be surprised when hyperglycaemia is detected by routine screening. With the rising incidence and awareness of diabetes in the general population (due to rising rates of type 2 diabetes), an increasing number of cases of type 1 diabetes are detected before ketosis develops—​giving rise, especially in adults, to confusion over whether the diagnosis is type 1 or type 2 diabetes. Prognosis of type 1 diabetes Before the introduction of insulin during the early 1920s, type 1 diabetes was invariably fatal, usually within months. With various semistarvation diets, hyperglycaemic symptoms could be improved somewhat and life extended by a few miserable months. Over the last 20 years the mortality rate from diabetic ketoacidosis has fallen from 8% to 0.67%, although one-​third of deaths in diabetic children and young adults are still due to metabolic emergencies, notably ketoacidosis. The main threat to survival with type 1 diabetes is now chronic tissue damage, particularly renal failure from nephropathy, and vascular disease, notably myocardial infarction and stroke. Throughout

adult life, the overall risk of dying within 10  years is about fourfold higher for patients with type 1 diabetes than for their non​diabetic peers. Life expectancy There is encouraging evidence from Europe and the United States of America that the outlook for type 1 diabetes has improved over the last 10 to 20 years, with definite declines in the incidence of microvascular complications and extended survival—​at least in countries able to afford effective diabetes care. This is partly attributable to tighter control of hyperglycaemia, which can reduce by 30 to 40% the risks of nephropathy and retinopathy developing or progressing to a clinically significant degree (see next). Other measures have undoubtedly contributed, including better treatment of raised blood pressure and blood lipids. Tragically, however, in many parts of the world patients with type 1 diabetes still die today as they did a century ago, simply because insulin is not available or is not affordable.

Type 2 diabetes Type 2 diabetes is a heterogeneous condition, diagnosed empirically by the absence of features suggesting type 1 diabetes (see Table 13.9.1.2) and of the many other conditions that cause hyperglycaemia (see Table 13.9.1.1). Diagnostic accuracy may depend on the thoroughness of investigation; for example, up to 10% of subjects with presumed type 2 diabetes show evidence of autoimmune β-​cell damage and thus probably have slowly evolving type 1 diabetes (so-​called latent autoimmune diabetes in adults, LADA) and a further 1% will have monogenic diabetes. The term ‘type 2’ replaces ‘non-​insulin-​dependent’ and ‘maturity-​ onset’ which were both clumsy and misleading: many type 2 patients require insulin to control hyperglycaemia and increasingly type 2 diabetes is being diagnosed in (overweight) children. Epidemiology and demographic features Type 2 diabetes accounts for 85 to 90% of diabetes worldwide. It is very common, affecting at least 3 to 4% of the white populations in

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most countries, with rates rising to between 8 and 11% in Eastern Europe and North America. The prevalence rises with age to well over 10% of those over 70 years. It is substantially more common in certain immigrant populations living in more affluent countries (e.g. 10–​15% of adults in some Asian or Afro-​Caribbean groups in the United Kingdom are affected, compared with a prevalence of 4% in the white population). Type 2 diabetes is most commonly diagnosed in those over 40 years of age and the incidence rises to a peak at 45 to 64 years. However, much younger people are now presenting with type 2 diabetes, following the rapid rise in childhood obesity. Up to one-​third of North Americans diagnosed as diabetic under 20 years of age have type 2 diabetes, with Afro-​Caribbean and Hispanic populations being at particular risk. Monogenic diabetes or maturity-​onset diabetes of the young (MODY) due to single-​gene defects, commonly presents before 25 years of age in more than one generation, and is now classified separately (read on for more details). The prevalence of type 2 diabetes shows striking geographical variation—​entirely different from that of type 1—​and ranges from less than 1% in rural China to 50% in the Pima Indians of New Mexico. Prevalence is also rising rapidly, especially in developing countries and, worldwide, will increase by at least 50% within 10 to 15 years. This pandemic can be largely explained by Westernization, and is following in the wake of the obesity that is spreading throughout the world. The Pima Indians illustrate this process especially vividly; most developed and developing countries are now showing the same phenomenon, albeit more slowly. Diabetes was rare while the Pima tribes led a frugal existence in desert conditions and were lean and physically active. Following urban resettlement and exposure to overnutrition and inactivity, there were rapid increases in the prevalence of obesity (currently 80% of adult Pima Indians have a BMI of over 30  kg/​m2) and later of type 2 diabetes. There is a 3:2 male preponderance among subjects with type 2 diabetes in Western countries although worldwide there is a 10% excess of females. Aetiology Type 2 diabetes is due to the combination of insulin resistance and β-​ cell failure, the latter preventing sufficient insulin secretion to overcome insulin resistance. These two components vary in importance between different individuals, who may be clinically quite similar, and each has numerous possible causes. Susceptibility is determined by the interactions between genes and environment. The steeply rising prevalence of type 2 diabetes suggests that diabetogenic genes are common and are now enjoying an unparalleled opportunity to express themselves through the global spread of Westernized lifestyle and obesity. Genetic factors Overall genetic susceptibility to type 2 diabetes is probably 60 to 90%, rather less than was previously deduced from twin studies. Generally, transmission does not follow simple mendelian rules, and this polygenic pattern reflects the inheritance of a critical mass of minor diabetogenic polymorphisms which interfere with insulin action and/​or insulin secretion. Having a first-​order relative with the disease increases an individual’s chances of developing it fivefold, representing a lifetime risk in white people of about 40%. However, this figure will be strongly influenced by modifiable factors, notably the BMI and physical activity of the at-​risk individual.

Much progress has been made recently in identifying the gene loci predisposing to type 2 diabetes by using genome-​wide scanning in large population databases. Importantly, these findings have been verified by repeat analyses in other data sets to exclude spurious statistical findings arising from the very large number of statistical comparisons performed. At least 30 loci have been confirmed, with predicted effects on insulin resistance (PPARG) and obesity (FTO), but interestingly, a greater number of confirmed loci seem to relate to pancreas development and/​or insulin secretion (TCF7L2, KCNJ11, HHEX–​IDE, CDKAL1, CDKN2, IGF2BP2, and SLC30A8)—​see Fig. 13.9.1.8. Although confirmed, the influence of each locus is relatively weak: the strongest association is with TCF7L2 (odds ratio for diabetes of high-​risk polymorphism is 1.5) with the remaining loci conferring odds ratios of 1.1 to 1.25. Taken together, the known loci still only explain a small proportion of the inheritance of type 2 diabetes, indicating that there are many more minor loci to be identified. Interestingly, only three of the defined loci for common polygenic type 2 diabetes are the same as those identified to cause the much rarer monogenic diabetes syndromes of maturity-​onset diabetes of the young (MODY, see next—​glucokinase, HNF-α, HNF-​1 β). Environmental factors These clearly play a critical part, because obesity and type 2 diabetes are spreading too rapidly to be explicable by changes in the genome; environmental factors are also important in practice because they may be modified to treat and prevent the disease. Known environmental diabetogenic factors mostly induce insulin resistance (e.g. obesity, pregnancy, intercurrent illness, certain drugs). Hyperglycaemia per se can both impair insulin sensitivity and inhibit insulin secretion (glucotoxicity). Specific risk factors for type 2 diabetes Obesity, itself determined by both genes and environment, is one of the most important risk factors, apparently due to aggravation of insulin resistance (see earlier). The diabetogenic properties of excess fat depend not only on its bulk but also on its anatomical distribution and the time of life at which it is laid down. The risks of developing type 2 diabetes begin to increase steeply once the BMI exceeds 28 kg/​ m2; some studies estimate the risk at a BMI over 35 kg/​m2 to be 80-​ fold higher than for individuals with a BMI of less than 22 kg/​m2—​a lifetime risk of about 50%. Fat in the truncal (central) distribution is more diabetogenic than that deposited around the hips and thighs, and the visceral (intra-​abdominal) depot is strongly associated with insulin resistance. Increasing adiposity after the early twenties, especially around the waist, aggravates the risk of a high BMI. Physical inactivity, especially from the twenties onwards, is an independent predictor of diabetes in middle age, the risk increasing by about threefold for sedentary people as compared with regular athletes. This is due to worsening insulin resistance, which can be improved by physical training and may in part be due to changes in activity of the enzyme AMP kinase in skeletal muscle. The Barker–​Hales hypothesis suggests that poor fetal growth can programme enduring metabolic and vascular abnormalities that are manifested in adult life, especially in people who were underweight at birth but then become obese. These abnormalities include key features of the metabolic syndrome (hyperglycaemia, hypertension, dyslipidaemia), resulting in atheroma formation, myocardial infarction, and stroke (see earlier). Evidence, mainly

13.9.1 Diabetes

CDKALI, CDKN2A CDKN2B

MTNR1B, TCF7L2, KCNJ11

FTO

IRS1, PPARG

Reduced β-cell mass

β-cell dysfunction

Obesity

Insulin resistance not due to obesity

Reduced insulin secretion

Insulin resistance

Predisposition to type 2 diabetes

Fig. 13.9.1.8  Pathways to type 2 diabetes implicated by identified common variant associations. Type 2 diabetes results when pancreatic β cells are unable to secrete sufficient insulin to maintain normoglycemia, typically in the context of increasing peripheral insulin resistance. The β-​cell abnormalities fundamental to type 2 diabetes are thought to include both reduced β-​cell mass and disruptions of β-​cell function. Insulin resistance can be the consequence of obesity or of obesity-​ independent abnormalities in the responses of muscle, fat, or liver to insulin. Examples of susceptibility variants that, given current evidence, are likely to influence predisposition to type 2 diabetes by means of each of these mechanisms are shown. Reproduced from McCarthy MI (2010). Genomics, type 2 diabetes, and obesity. N Engl J Med, 363, 2339–​50. Copyright © 2010 Massachusetts Medical Society.

from animals, suggests that maternal and therefore fetal malnutrition during a critical early phase of fetal development can reduce β-​cell mass and permanently impair insulin secretory reserve; deficiencies of sulphur-​containing amino acids may be responsible in experimental animals but the relevance to humans is unknown. Other studies suggest that insulin sensitivity may also be reduced into adult life. β-​Cell failure in type 2 diabetes β-​Cell failure is an obligatory defect in the pathogenesis of type 2 diabetes:  near normoglycaemia can be maintained even in severe insulin resistance (e.g. due to mutations in the insulin receptor), as long as the β cell can respond to the challenge and secrete enough insulin to overcome the resistance. Subtle abnormalities of insulin secretion, including loss of the physiological pulses and of the first-​phase response to intravenous glucose injection, are seen in normoglycaemic subjects who later develop the disease. These defects presumably indicate that the β cell is already stressed in trying to produce enough insulin to overcome insulin resistance. Normoglycaemic first-​order relatives of type 2 diabetic subjects also show loss of pulsatility of insulin secretion which might indicate an inherited tendency to β-​cell failure. The key role of β-​cell failure in predisposing to type 2 diabetes has recently been underlined by the finding that most of the confirmed genetic susceptibility loci for type 2 diabetes relate to islet cell function or development rather than insulin resistance (see earlier and Fig. 13.9.1.8). The mechanism of β-​cell failure in human type 2 diabetes is not known. Histologically, the islets in type 2 diabetes show no features

of type 1 autoimmune insulitis, and β-​cell mass is not so dramatically reduced. Animal models of the disease suggest various causes, including synchronized β-​cell apoptosis (possibly mediated by nitric oxide) in the Zucker diabetic fatty rat, and the deposition of amyloid fibrils (see earlier) in the rhesus monkey. Amyloid deposits are also prominent in the islets of some type 2 diabetic patients but may merely be due to dysfunctional β-​cell hypersecretion rather than the cause of β-​cell damage. Once hyperglycaemia is established, glucotoxicity per se may further worsen both insulin secretion and insulin resistance. Elevated free fatty acid levels resulting from insulin resistance have also been proposed to impair β-​cell function—​so-​called lipotoxicity—​but this remains controversial. In established type 2 diabetes, insulin secretion is unequivocally subnormal and tends to decline progressively with time, as illustrated by the long-​term follow-​up data from the United Kingdom Prospective Diabetes Study. Initially, plasma insulin levels may be higher than in non​diabetic subjects but are still inappropriately low, as the normal pancreas would produce much higher insulin concentrations in response to diabetic levels of blood glucose. Conventional radioimmunoassays may overestimate insulin levels in type 2 diabetic patients because of cross-​reaction with incompletely processed insulin precursors (proinsulin and its split products) released by the constitutive pathway which operates in the malfunctioning β cell (see earlier). Many type 2 patients ultimately need insulin replacement; this indicates relatively severe insulin deficiency, although still not as profound as in type 1 diabetes. Some type 2 patients who require insulin early have autoimmune markers characteristic of type 1 diabetes, suggesting that they in

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fact have an indolent variant of the disease. Although patients with type 1 diabetes have significantly lower insulin C-​peptide levels at diagnosis than in type 2, there remains overlap in the ranges (see Fig. 13.9.1.6) such that C-​peptide alone only has a sensitivity of 83% in diagnosing type 2 diabetes even in children. Natural history Longitudinal and cross-​sectional studies indicate that insulin resistance develops first and that compensatory increases in insulin secretion can initially maintain near normoglycaemia. Worsening insulin resistance is thought to drive the β cells towards maximal insulin output, a metastable stage that probably corresponds to impaired glucose tolerance (see earlier). Rescue is still possible if insulin resistance is decreased (e.g. through weight loss or insulin-​ sensitizing drugs):  about 25% of subjects with impaired glucose tolerance return to normoglycaemia within 5  years. However, if insulin resistance persists or worsens, the β cells fail and insulin production falls. At this point, the brake-​limiting hyperglycaemia is released and blood glucose rises into the diabetic range. The bell-​ shaped response of insulin secretion, initially increasing to compensate but ultimately failing, has been termed the ‘Starling curve’ of the β cells because it recalls the classical plot of cardiac output against preload in heart failure. In common type 2 diabetes, these events usually take many years, and significant hyperglycaemia may have been present for several years at the time of diagnosis. The whole process can be greatly accelerated by acute increases in insulin resistance as those induced by steroid treatment or pregnancy, to give just two examples. Metabolic disturbances in type 2 diabetes Hyperglycaemia is the most obvious abnormality, the extreme case being the hyperosmolar non​ketotic state. Lipid metabolism is also disturbed but true ketoacidosis occurs only exceptionally and is usually provoked by intercurrent events such as infections or myocardial infarction. Blood glucose concentrations are raised both in the basal (fasting) state and after eating. This reflects the impairment of insulin action in both liver and skeletal muscle, where insulin respectively shuts off hepatic glucose production and stimulates glucose uptake after meals. Hepatic glucose output is increased, due mainly to unsuppressed gluconeogenesis, and this is largely responsible for hyperglycaemia overnight and before meals. In muscle, GLUT-​4 activity and glycogen synthesis are especially decreased; this reduces insulin-​stimulated glucose uptake into muscle after meals, although basal glucose uptake (non-​insulin-​mediated glucose uptake; see earlier) is higher than in normal subjects because of the mass action effect of hyperglycaemia. The degree of hyperglycaemia varies widely: many patients have fasting plasma glucose levels of 8 to 13 mmol/​litre with postprandial peaks of up to 20 mmol/​litre, while values exceeding 60 mmol/​litre are not uncommon in the hyperosmolar non​ ketotic state. Insulin deficiency is less profound than in type 1 diabetes, so mobilization of triglyceride (loss of body fat, ketoacidosis) and catabolism of protein (muscle breakdown) are not usually pronounced. Diabetic ketoacidosis may develop in patients with apparently typical type 2 diabetes who can subsequently be controlled by oral hypoglycaemic agents rather than insulin (see ‘Flatbush or ketone-​ prone diabetes’ next). Diabetic ketoacidosis is usually precipitated by severe intercurrent illness (e.g. myocardial infarction, stroke, or

pneumonia) in which excessive secretion of counterregulatory stress hormones exacerbates the metabolic disturbance caused by relative insulin deficiency. Clinical features Many cases present with classical symptoms of osmotic diuresis, blurred vision due to hyperglycaemia-​related refractive changes in the lens, and genital candidiasis (see Table 13.9.1.2). Weight loss may occur but is generally less dramatic than with newly presenting type 1 diabetes and may not be obvious because many type 2 patients—​over two-​thirds in the United Kingdom—​are obese. Rapid or severe weight loss in patients who otherwise appear to have type 2 diabetes should be regarded with suspicion as it may point to an early need for insulin replacement (and possibly type 1 diabetes itself) or to coexisting illness: a well-​recognized but unexplained association with recent onset type 2 diabetes is carcinoma of the pancreas. The hyperosmolar non​ketotic state can present with confusion or coma (see next); as mentioned earlier, diabetic ketoacidosis is rare. Chronic diabetic complications may be a presenting feature, because hyperglycaemia severe enough to cause tissue damage may already have been present for several years. Extrapolating the numbers of microaneurysms (which only develop at diabetic glucose concentrations) in type 2 patients at various intervals after diagnosis suggests that significant hyperglycaemia is present for an average of 5 to 7 years before diagnosis. Common problems are arterial disease (myocardial infarction, stroke, and peripheral vascular disease), cataracts—​which are especially common in the older population—​ and retinopathy, especially maculopathy, which can damage central vision, and foot ulceration. Increasing numbers of people with diabetes are detected by screening, either in high-​risk groups such as the obese and those with cardiovascular disease, or at routine health checks. Many of these are nominally asymptomatic but will admit to symptoms such as nocturia or perineal irritation if asked directly. Prognosis of type 2 diabetes A long-​held and prevalent misconception is that type 2 diabetes is mild. Some patients do have relatively unexciting or asymptomatic hyperglycaemia, but this can still be enough to cause complications which wreck the patient’s life just as much as in type 1 diabetes. Moreover, hyperglycaemia can be as hard to control (even with insulin) as in type 1 patients. Overall, life expectancy is shortened by up to a quarter in patients with type 2 diabetes presenting in their forties, with vascular disease (myocardial infarction and stroke) being the main cause of premature death. Renal failure from diabetic nephropathy is becoming more common in type 2 patients as their survival from vascular complications improves, and the disease is now the most frequent pathology among people waiting for renal replacement therapy in the United States of America and some European countries. Type 2 diabetes is therefore an important threat to the patient’s health and survival, and must be taken seriously by patients and their medical attendants, even if the blood glucose concentrations are not dramatically raised. Accordingly, treatment guidelines for the disease are rigorous (see Table 13.9.1.3 and discussion later in this chapter).

13.9.1 Diabetes

Table 13.9.1.3  Treatment targets for patients with diabetes

HbA1c

Blood pressure

Lipids

BMI

Patient sub-group

Source of Specific goal recommendation of therapy

Notes

Most

EASD and ADA

150 µmol/​l) • Coagulopathy (PT >14 s or APTT >34 s) • Microvesicular steatosis on liver biopsy Reproduced from CL Ch’ng, et al. (2002). Prospective study of liver dysfunction in pregnancy in Southwest Wales. Gut, 51, 876–​880, with permission from BMJ Publishing Group Ltd.

Fig. 14.9.1  Typical appearance of the skin in a woman with intrahepatic cholestasis of pregnancy. Dermatological changes include scratch marks with skin discolouration and more generalized skin lesions.

14.9  Liver and gastrointestinal diseases of pregnancy

and stillbirth. Several studies have shown that these adverse outcomes occur more commonly in pregnancies where the maternal serum bile acid concentration is ≥40 µmol/litre, and a recent metaanalysis reported that stillbirth occurs more commonly if the maternal serum bile acid concentration is ≥100 µol/litre.

biochemical hyperthyroidism. These typically resolve on resolution of vomiting. Ongoing elevation in liver enzymes should trigger consideration of alternative diagnoses. There is no role for liver biopsy, as this is non​specific.

Treatment

Treatment of hyperemesis gravidarum is supportive and includes intravenous re-​hydration, electrolyte replacement, antiemetics, and gradual re-​introduction of oral intake. Vitamin supplementation especially thiamine is mandatory to prevent Wernicke’s encephalopathy. Most patients will require day case treatment or hospital admission, but relapse is common. Recurrence in subsequent pregnancies is common.

Women with intrahepatic cholestasis of pregnancy should have regular liver function tests and serum bile acids performed, and investigations should be performed to exclude hepatitis C, autoimmune hepatitis, or primary biliary cholangitis. Women with severe cholestasis or steatorrhoea should have a coagulation screen performed. An abdominal ultrasound will evaluate whether there are gallstones or another hepatobiliary cause of cholestasis. The drug most commonly used to treat intrahepatic cholestasis of pregnancy is ursodeoxycholic acid (UDCA), typically at a starting dose of 500 mg BD, rising to a maximum of 2 g daily. This reduces maternal pruritus and biochemical abnormalities in approximately 75% of cases, but it is not known whether it also protects against adverse fetal outcome. Otherwise, aqueous cream with 1–​2% menthol may improve the sensation of pruritus and vitamin K 10 mg OD is advisable for women with steatorrhoea. Other drugs that have been used with varying success are S-​adenosyl methionine, cholestyramine, and activated charcoal. Rifampicin has been used in conjunction with UDCA for women with a limited response to the latter drug, as the drugs have synergistic actions to induce hepatic biliary transport proteins that enhance excretion of bile acids. Delivery and post-​partum Many clinicians choose to induce labour in women with intrahepatic cholestasis of pregnancy between 37–​38 weeks’ gestation as stillbirth in this condition typically occurs at later gestational weeks. This practice is not associated with an increase in operative delivery. Symptoms and hepatic dysfunction typically resolve rapidly after delivery of the fetus, and therefore UDCA and other drugs can usually be stopped within a small number of days. It is important to ensure that liver function tests return to normal by three months post-​partum, and if not then further investigation should be performed to exclude other hepatic pathology. Women should be advised to avoid oestrogen-​containing contraception, and that the condition has a high rate of recurrence in subsequent pregnancies.

Hyperemesis gravidarum Nausea and vomiting is common in pregnancy. In contrast, hyperemesis gravidarum, characterized by intractable vomiting, resulting in dehydration, ketosis, and ≥5% weight loss, is seen in 0.3–​ 2% of all pregnancies. Its exact cause is unclear, but a combination of hormonal factors, abnormal gastric motility, and changes in the autonomic nervous system are thought to play a role. Risk factors include pre-​existing diabetes and multiple pregnancies, increased body mass index, previous psychiatric illness, and molar pregnancy. Clinical features and diagnosis Hyperemesis gravidarum may begin as early as the fourth week of gestation and typically resolves by the eighteenth week. Serum AST and ALT may be markedly raised (Table 14.9.3). Other findings include elevated serum urea and creatinine levels, hypophosphataemia, hypomagnesaemia, hypokalaemia, and

Management

Liver diseases incidental to pregnancy Viral hepatitis in pregnancy Viral hepatitis is probably the most commonly recognized cause of jaundice occurring during pregnancy worldwide. There is no specific change in the presentation, clinical features, or general outcome for hepatitis A  virus, hepatitis B, hepatitis C, cytomegalovirus, or Epstein–​Barr virus infection in pregnancy. Hepatitis B virus can present in an acute or chronic form. For patients with acute hepatitis B, transmission of the virus to the child occurs in 50% of cases with 70% of children infected if acute viral hepatitis B occurs in the third trimester. For patients with chronic hepatitis B, transmission of virus is dependent on the degree of viral replication and the quantity of HBV DNA detectable in the serum of the mother. Transmission rates above 90% have been reported from mothers who are HBV DNA positive and these are typically hepatitis B E antigen positive. Vaccination programmes throughout Southeast Asia and in the developed world have reduced transmission rates dramatically. Following transmission, up to 80% of children become chronic hepatitis B carriers. Therefore, strategies exist to limit this transmission rate. Firstly, the use of antiviral therapy such as tenofovir disoproxil fumarate 245 mg daily to reduce the HBV DNA level in the third trimester for appropriate patients reduces viral load, and transmission rate. Secondly the use of hepatitis B immunoglobulin with hepatitis B vaccination in the neonate within seven days of birth and at 1, 2, and 12 months of age also reduces the transmission rate significantly. Mother-​to-​child transmission (MTCT) of hepatitis C virus has become the leading cause of paediatric infection, at an approximate rate of 5%. Maternal HIV co-​infection is a significant risk factor for MTCT and anti-​HIV therapy during pregnancy can reduce the transmission rate of both viruses. A high maternal viral load is an important, but unpreventable risk factor since no antihepatitis C virus treatment can be given in pregnancy. Obstetric procedures, such as amniocentesis or invasive fetal monitoring, should be used with caution as they could expose the fetus to maternal blood, although evidence is lacking on the real risk of these obstetric practices. Mode of delivery and type of feeding do not represent significant risk factors for MTCT. Therefore, there is no reason to offer elective caesarean section or discourage breastfeeding to hepatitis C virus-​infected patients. Antibody conversion of infants following transmission may take 6–​12 months, although measurement of hepatitis C virus RNA levels will allow for early diagnosis.

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Hepatitis E virus is problematic in pregnancy typically occurring in epidemic form in Southeast Asia, the Indian subcontinent, and the Middle East. The development of acute liver failure in the third trimester can be associated with a mortality of up to 20%.

Pregnancy in patients with cirrhosis Many patients with chronic liver disease and cirrhosis are infertile. However, patients with autoimmune liver diseases such as autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cholangitis may become pregnant. Patients with autoimmune hepatitis should be maintained on baseline immunosuppression throughout pregnancy (azathioprine plus/​minus prednisolone). For patients treated with mycophenolate mofetil pre-​pregnancy, they should be converted to an alternative immunosuppressant such as azathioprine, tacrolimus, or cyclosporine prior to planned pregnancy. A 20–​25% risk of flare in autoimmune hepatitis occurs following delivery in the first three months post-​partum, and this is reduced if immunosuppressive treatment is maintained. Patients with established cirrhosis should be screened for varices in the second trimester. This is to facilitate and guide appropriate peri-​ partum care. The presence of small varices in otherwise well compensated cirrhotic patients should not preclude against a vaginal delivery. Variceal bleeding in pregnancy Even in normal patients without liver disease, varices develop during pregnancy. This is related to changes in cardiac output, azygos blood flow, increased circulating blood volume and changes in splanchnic haemodynamics. For patients with non​cirrhotic portal hypertension, a bleeding rate in pregnancy of 13% has been reported. In cirrhotic patients contemplating pregnancy, pre-​pregnancy screening and appropriate treatment of large varices should be undertaken. Propranolol is not contraindicated in pregnancy and episodes of variceal bleeding should be treated with normal endoscopic approaches including endoscopic band ligation, histoacryl glue, whereas transjugular intrahepatic shunts should be reserved for rescue therapy and field endoscopic treatment. There are limited safety data for vasoconstrictors such as terlipressin, but they may be used in women with life-​threatening haemorrhage.

Pregnancy following Liver Transplantation Successful pregnancy following liver transplantation has been widely reported and fertility will return typically within six months of transplant. Best outcomes are reported for pregnancies undertaken greater than one year following the transplant operation since this reduces the risk of acute cellular rejection and other infective complications. Tacrolimus, cyclosporine, azathioprine, and corticosteroid therapy are widely and safely used in pregnancy. Specific complications in pregnancy related to a higher prevalence of hypertension/​pre-​eclampsia and preterm delivery have been reported. Patients on mycophenolate should be converted to an alternative immunosuppressant prior to pursuing pregnancy.

Gastrointestinal diseases of pregnancy Inflammatory bowel disease The respective incidence of Crohn’s disease and ulcerative colitis is 10.7 and 12.2 per 100 000. Both disorders typically affect women at

Box 14.9.2  Relationship between disease activity at the time of conception and the risk of flare of inflammatory bowel disease in pregnancy If active disease at the time of conception: Ulcerative colitis •​ 45% will have flare •​ 30% will have stable disease •​ 25% will improve Crohn’s disease •​ 33% will have a flare •​ 34% will have stable disease •​ 33% will improve

reproductive age. While fertility is reduced in women with active disease, or if there is scarring or inflammation affecting reproductive tissues, for most women there is no major impact on the ability to conceive. Clinical presentation Women with inflammatory bowel disease should have pre-​ pregnancy counselling as this will enable evidence-​based decisions to be made about drug treatment. Ideally women should have been in remission for several months, as disease activity at conception does influence the risk of flare in pregnancy (Box 14.9.2). The pre-​pregnancy period is a good time to ensure there are no deficiencies of vitamins D, B12, or iron, and women should be encouraged to take folic acid supplementation. Most drugs used to treat inflammatory bowel disease can be taken in pregnancy (Table 14.9.5) and women should be informed that the greatest risk of flare occurs in those that discontinue treatment. There is an increased risk of spontaneous miscarriage, preterm labour and small for gestational age infants, and the risk of low birth weight increases further in women with disease flares. If women continue their medication, the risk of disease flare is the same as in non​pregnant women. Treatment Most drugs used to treat inflammatory bowel disease, including biological therapies, are safe in pregnancy and lactation (Table 14.9.5). The only drug that is contraindicated is methotrexate as this causes congenital abnormalities and spontaneous miscarriage. Some studies have found increased rates of small for gestational age and preterm infants in women treated with thiopurines or cyclosporine, but it is difficult to establish whether this is related to severity of the underlying disease or due to use of the drug. Overall, the benefits of treatment with these drugs, and with glucocorticoids, outweighs the possible association with preterm or small infants, and women should be encouraged to continue to take drugs that maintain disease remission, particularly given the clearly documented increase in these complications in women with disease flares. Biologic therapy is well tolerated in pregnancy and there are accumulating data to support the use of these drugs in pregnancy and during breastfeeding. Ideally, IgG1 antibody therapies (infliximab, adalimumab, and golimumab) should be avoided in the third trimester as they are transported across the placenta, and levels of these drugs are higher in fetal than maternal blood in late pregnancy. However, some women have severe flares, necessitating treatment. The infants of

14.9  Liver and gastrointestinal diseases of pregnancy

Table 14.9.5  Drugs used to treat inflammatory bowel disease in pregnancy Drug name

High or low risk in pregnancy

High or low risk in breastfeeding

Methotrexate

High •​ teratogenicity and fetal loss

High •​ transferred in breast milk

Corticosteroids (budesonide and prednisolone)

Low •​ possible slight increase in the risk of cleft lip/​palate, but benefits for women with flares outweigh risks

Low

Aminosalicylates (sulfasalazine and mesalazine)

Low •​ sulphasalazine interferes with folate metabolism so essential to give high-​dose folic acid (5 mg OD)

Low

Thiopurines (azathioprine and 6-​mercaptopurine)

Low •​ no increase in congenital abnormalities, but care with starting during pregnancy due to associated low risk of pancreatitis, hepatic impairment, or bone marrow suppression

Low

Cyclosporine

Low

Medium •​ transferred to breast milk

Anti TNFα agents (IgG1 antibodies—​infliximab, adalimumab, golimumab)

Low •​ but ideally avoid in 3rd trimester due to risk of immune suppression in neonatea

Low

Anti TNFα agents (pegylated Fab fragment—​certolizumab)

Low •​ not actively transported across the placenta, therefore less concern about treatment in the 3rd trimester

Likely low, but limited data

IgG1—​immunoglobulin G1; TNFα—​tumour necrosis factor alpha a If a woman has severe disease the clinical need for these agents may necessitate treatment. All neonates of women treated with Anti-​TNFα agents in pregnancy should not receive live vaccines for the first six months of life.

women treated with biologic agents should not receive live vaccines for the first six months of life. If a woman has a flare in pregnancy, the treatment is the same as for non​pregnant women. Clostridium difficile infection is more common in pregnant women with inflammatory bowel disease and stool samples should be tested in women with new diarrhoea. If imaging is required, magnetic resonance imaging is preferred as this avoids radiation exposure. Flexible sigmoidoscopy and colonoscopy can be performed if indicated, with appropriate sedation. The indications for surgery are the same as for non​pregnant individuals. Delivery and post-​partum Women with inflammatory bowel disease have higher rates of caesarean section than the background population. However, for most women with inactive disease there is no contraindication to vaginal delivery, and caesarean section should be performed only for obstetric reasons. There are two groups of women where decisions about mode of delivery should be made on a case-​by-​case basis. For women with active perianal disease there is a risk of perineal trauma, and caesarean section should be considered. For women with an ileal pouch-​anal anastomosis, it is important to avoid anal sphincter damage to preserve continence. It is advisable to have a multidisciplinary discussion, including the colorectal surgeon, to decide about mode of delivery in this group of women. There is some evidence that vaginal delivery does not significantly affect pouch function, but the opinion of the surgical and gastrointestinal team will be invaluable to individualized decision-​making in this context.

Gallstones and acute cholecystitis Gallstones and gallbladder sludge occur more commonly in pregnant women. Several prospective studies have reported rates of

8–​10% in the third trimester and puerperium. Affected women more commonly have a raised body mass index, and gallstones are also more commonly diagnosed in women with intrahepatic cholestasis of pregnancy. Most pregnant women with gallstones are asymptomatic, and this group should be managed conservatively. If a woman develops symptoms of acute cholescystitis, she should be given intravenous fluids, antibiotics, and feeding should be stopped. Surgical management is usually preferred, as 40% of women treated medically have relapse. If surgery is required, a laparoscopic approach is usually preferred as this is associated with lower rates of complication and shorter operative recovery than open surgery.

Appendicitis The commonest presenting symptoms of appendicitis in pregnancy are right lower quadrant pain, although retrocaecal appendicitis may result in flank or back pain. Other characteristic symptoms are anorexia, vomiting, abdominal guarding or rebound, but they may be absent. The white blood cell count and C-​reactive protein are usually raised. Graded abdominal ultrasound imaging usually achieves a diagnosis in the first two trimesters, but may be difficult in late pregnancy. Magnetic resonance imaging is safe in pregnancy and increasing data support its use due to high sensitivity and specificity in pregnant women. As with acute cholecystitis, laparoscopic removal is associated with lower complication rates than open surgery.

Pancreatitis Acute pancreatitis is rare, affecting approximately 1 in 10 000 pregnant women. The commonest cause is gallstones, but it may also be caused by hypertriglyceridaemia, alcohol abuse, hyperparathyroidism, or drugs (e.g. thiazide diuretics), and approximately 10% of cases are idiopathic. The most valuable tests for diagnosis are

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serum amylase or lipase. Treatment is the same as for non​pregnant women, in addition to surgical or medical management of the underlying cause.

Gastro-​oesophageal reflux and peptic ulcer Gastro-​oesophageal reflux disease affects approximately 40% of pregnant women. Most women have a benign course and symptoms resolve after delivery. Simple treatments are often effective, including lifestyle modification and use of antacids, alginates, or sucralfate. If required both H2-​antagonists and proton pump inhibitors have good safety data for use in pregnancy. Peptic ulcer disease is considerably less common and typically presents with epigastric pain, postprandial nausea, vomiting and anorexia. If suspected, endoscopic investigation can be performed in pregnant women. It is advisable to also screen for Helicobacter Pylori. Peptic ulcer can be treated with the same drugs that are used for gastro-​oesophageal reflux disease and the commonest treatment regimens used for Helicobacter Pylori can be used in pregnancy (proton pump inhibitor, amoxicillin, clarithromycin).

Coeliac disease Coeliac disease is an autoimmune disorder of the small intestine. It should be considered in pregnant women presenting with diarrhoea or unexplained abdominal pain. Serology for anti-​ endomysial, antigliadin, and antitissue transglutamase antibodies is reliable in pregnancy, and endoscopy can be performed for a definitive diagnosis if indicated. Affected women should be referred for dietary advice, and compliance can be assessed using serial serological measurements. This is important as inadequately controlled women are at risk of deficiency of fat soluble vitamins, calcium malabsorption, and oxalate kidney stone formation. There is evidence for an increased risk of intrauterine growth restriction and preterm birth in undiagnosed disease.

Gastrointestinal cancer Malignancies affecting the gastrointestinal tract are rare women of reproductive age. However, they should be considered in women with unexplained, severe symptoms of weight loss, abdominal pain, anorexia, nausea, vomiting, constipation, or rectal bleeding. Many of these symptoms are common in pregnancy, but gastric or colon cancer may be present if they are ongoing or severe. If suspected, endoscopic investigation should be pursued. Pregnancy does not affect the serum concentration of carcinoembryonic antigen, so this can be used as a prognostic or monitoring test for women with known colorectal cancer.

FURTHER READING Ch’ng CL, et al. (2002). Prospective study of liver dysfunction in pregnancy in Southwest Wales. Gut, 51, 876–​80. Geenes V, et al. (2013). Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes:  a prospective population-​based case-​control study. Hepatology, 59, 1482–​91. Ibdah JA, et al. (1999). A fetal fatty-​acid oxidation disorder as a cause of liver disease in pregnant women. N Engl J Med, 340, 1723–​31. Knight M, et al. (2008). A prospective national study of acute fatty liver of pregnancy in the UK. Gut, 57, 951–​6. Mahadevan U, Matro R (2015). Care of the pregnant patient with inflammatory bowel disease. Obstet Gynecol, 126, 401–​12. Walker I, Chappell LC, Williamson C (2013). Abnormal liver function tests in pregnancy. BMJ, 347, f6055. Westbrook RH, et al. (2012). Outcomes of pregnancy in women with autoimmune hepatitis. J Autoimmun, 38, J239–​44. Westbrook RH, et al. (2015). Outcomes of pregnancy following liver transplantation:  the King’s College Hospital experience. Liver Transpl, 21, 1153–​9. Williamson C, Geenes V (2014). Intrahepatic cholestasis of pregnancy. Obstet Gynecol, 124, 120–​33.

14.10

Diabetes in pregnancy Bryony Jones and Anne Dornhorst

ESSENTIALS Diabetes in pregnancy is predominantly either pre-​existing type 1 or type 2 diabetes mellitus, or gestational diabetes, the latter defined as diabetes or glucose intolerance first diagnosed during the pregnancy. Gestational diabetes usually arises in the late second trimester and is common, affecting from 2–​6% to 15–​20% of pregnant women depending on diagnostic criteria and country of origin. Gestational diabetes is most commonly diagnosed on the basis of an oral glucose tolerance test performed at 24–​28 weeks’ gestation by a plasma glucose at 0 minutes of more than 5.1 (or >5.6, depending on the authority) mmol/​litre, or at 120 minutes of more than 8.5 (or >7.8) mmol/​litre. Diabetes affects fertilization, implantation, embryogenesis, organogenesis, fetal growth and development, and neonatal and perinatal morbidity and mortality. Preconception counselling is associated with improved pregnancy outcomes. Key aspects of periconceptional and pregnancy management include optimization of glycaemic control, stopping of medications contra-​indicated in pregnancy, avoidance of hypoglycaemia and diabetic ketoacidosis, and screening and management of diabetic complications. Risks to the fetus of maternal diabetes include congenital malformations, fetal macrosomia, intrauterine growth restriction, and those from the increased incidence of maternal pre-​eclampsia. Long-​term adverse effects such as increased susceptibility to metabolic disease later in life are also recognized. Once pregnancy is confirmed, women with pre-​existing diabetes should be encouraged to book early in the pregnancy for management by a hospital-​based multidisciplinary team. Optimal blood glucose targets are a fasting capillary glucose of 5.3 mmol/​litre, a one hour after meal value below 7.8  mmol/​litre, or a two-​hours after meal value below 6.4 mmol/​litre. In some women with gestational diabetes this may be achieved with diet and exercise, but oral hypoglycaemic agents (typically metformin or glibenclamide) and/​or insulin are often required. Women with diabetes should give birth in hospitals where 24 hour-​ a-​ day advanced neonatal resuscitation skills are available. Induction of labour or an elective caesarean section before 38 + 6 weeks of pregnancy is recommended if spontaneous labour has not occurred before then because of the increased risk of stillbirth.

The effect of pregnancy on maternal glycaemic control ceases very quickly post-​partum, hence women with pre-​existing diabetes taking insulin should immediately revert to their pre-​pregnancy regimen after birth, but with a lower insulin dose.

Introduction Diabetes mellitus (DM), whether pre-​existing, or new onset in pregnancy has major long-​term implications for both maternal and fetal health. The overall incidence of diabetes in women of childbearing age has increased over the last decade and is anticipated to continue to rise. One of the underlying causes of this is the rising prevalence of obesity, and this is impacting on the type of diabetes as well as the demographic factors of pregnant women with diabetes. Understanding the type of diabetes a woman has and the associated risk factors is key to the management of diabetes in pregnancy, as well as the implication for success or failure of potential intervention strategies. In addition, as the number of pregnant women with diabetes rises, there is a substantial impact on healthcare costs and resource utilization, emphasizing the need for the implementation of the best evidence-​based cost-​efficient treatment strategies.

The physiology of glucose homeostasis during pregnancy In normal early pregnancy there is an increase in insulin sensitivity and a fall in fasting plasma glucose in non​obese women. This increase in insulin sensitivity accounts for the fall in insulin requirements seen in women with type 1 DM and their susceptibility to hypoglycaemia during the first trimester. Insulin sensitivity continues to increase at the beginning of the second trimester, after which there is a progressive reduction in insulin sensitivity until term, and by late pregnancy insulin sensitivity will have fallen by 40–​60%. The underlying mechanisms for these changes are complex and due in part to maternal and placental adipokines and cytokines, as well as to the upregulation of the growth hormone/​insulin-​like growth factor axis by high circulating concentration of placental

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Section 14  Medical disorders in pregnancy

growth hormone. The contributions of the early increase in corpus luteal and then placental progesterone and 17β-​oestrogen by 10-​and 30-​fold, respectively, on insulin resistance is unclear. The physiological reduction in insulin sensitivity in later pregnancy facilitates the maternal-​fetal transfer of glucose and other nutrients across the placenta. Decreased insulin sensitivity decreases the glucose uptake in maternal muscle, the principal site of whole-​body glucose disposal, thereby redirecting glucose to the fetus where it is the principal fetal substrate. This transfer of glucose is facilitated by GLUT-​1, a specific placental glucose transporter protein, and by the maternal-​fetal glucose concentration gradient. By late pregnancy the degree of maternal hepatic and peripheral insulin resistance results in an increased hepatic glucose output and free fatty acid release from maternal adipose stores that increase during early pregnancy due to the relative insulin resistance. This normal physiological fall in insulin sensitivity in pregnancy is greater in obese women and those with gestational diabetes mellitus (GDM). Maternal insulin secretion increases in response to the fall in insulin sensitivity, such that post-​prandial insulin secretion is increased 200–​250% from baseline levels by late pregnancy. This is accompanied by an adaptive increase in the numbers of β cells in small islets, implying β-​cell neogenesis rather than duplication of β cells in existing islets. The increase in maternal insulin secretion helps promote maternal lipogenesis in early pregnancy and the deposition of adipose stores. If the maternal insulin response to pregnancy is inadequate, maternal hyperglycaemia will develop, leading to the development of gestational diabetes mellitus. While most women who become hyperglycaemic are at risk of future type 2 DM, and start pregnancy with increased insulin resistance such that their insulin demands to maintain euglycaemia in pregnancy are extremely high, a smaller proportion of women are in the early preclinical phases of type 1 DM. The increased insulin demands of pregnancy account for the observation that there is a threefold increase in the new presentation of type 1 DM in pregnancy. Identifying this small group of women is important as early insulin treatment and close antenatal surveillance is important.

Epidemiology and classification Diabetes in pregnancy is predominantly either pre-​existing type 1 or type 2 diabetes mellitus, or gestational diabetes, the latter defined as diabetes or glucose intolerance first diagnosed during the pregnancy. There are other rarer forms of pre-​existing diabetes, including monogenetic diabetes, recognition of which in pregnancy will increase as awareness and the ability to diagnose them increases. While the overall incidence of women with diabetes of any type is increasing, the largest proportional rise is seen in women with pre-​existing type 2 diabetes mellitus and gestational diabetes. In 2012, overall prevalence of gestational diabetes across Europe was reported as between 2 to 6%, but this is dependent on the diagnostic criteria used and the ethnic and demographic mix of the antenatal population, and higher values will be reported as more universal screening and testing for gestational diabetes is introduced (see later).

Maternal gestational diabetes and obesity are both independently associated with adverse pregnancy outcomes, and their combination has a greater impact than either one alone. Obesity and gestational diabetes are also associated with adverse long-​term cardiovascular health in both the mother and the child in later life. In 2015 it was estimated that in England and Wales around 35 000 pregnant women annually would have either pre-​existing diabetes (20%) or gestational diabetes mellitus (80%). Gestational diabetes usually arises in the late second trimester as a consequence of the pregnancy-​induced changes in maternal carbohydrate metabolism. However, undiagnosed type 2 diabetes mellitus is increasingly seen, and it is essential to identify these women as their clinical management needs to be similar to those with pre-​ existing recognized type 2 and optimized as early in pregnancy as possible.

The diagnosis of diabetes and type of diabetes in pregnancy The criteria for the diagnosis of diabetes outside of pregnancy can be made by any of the following; • a fasting plasma glucose of 7.0 mmol/​litre or above; • a two-​hour plasma glucose of 11.1 mmol/​litre or above during a 75 g oral glucose tolerance test taken as anhydrous glucose dissolved in water; • a glycosylated haemoglobin (HbA1c) of 6.5% (48  mmol/​mol) or above; • a random plasma glucose of 11.1 mmol/​litre or above in the presence of hyperglycaemic symptoms. The distinction between type 1 and type 2 diabetes mellitus can usually be made on the basis of clinical risk factors. Both types 1 and 2 are heterogeneous diseases in which the clinical presentation and disease progression in adults may vary considerably and can appear to overlap. The diagnosis of type 1 diabetes mellitus, an autoimmune disease characterized by β-​cell destruction, can if necessary usually be confirmed by the presence of islet specific autoantibodies and low circulating or undetectable concentration of serum C-​peptide, a measure of endogenous insulin secretion. These islet cell autoantibodies include those directed against insulin, glutamic acid decarboxylase (GAD) (GAD65), the tyrosine phosphatases IA-​2 and IA-​2b, and ZnT8. The diagnosis of type 2 diabetes mellitus remains a clinical diagnosis. Other than hyperglycaemia, including elevated HbA1c levels, there are no specific clinical diagnostic tests for type 2 diabetes mellitus. The lack of β-​cell autoimmunity, other autoimmune diseases, or other known causes for hyperglycaemia all favour a diagnosis of type 2. Most, but not all, patients with type 2 are overweight or obese, and many will have a family history of type 2 diabetes mellitus or other metabolic risk factors. See Chapter  13.9.1 for further discussion. In pregnancy, if the diagnosis of pre-​existing type 1 diabetes mellitus is uncertain, the presence of GAD antibodies would be expected to confirm the diagnosis in around 80% of cases, and the decision to undertake further testing for antibodies will depend on risk assessment (Fig. 14.10.1).

14.10  Diabetes in pregnancy

Test for Type 1 DM using GAD* antibodies

No need to test for type 1 DM

Strong fam

ily history

No risk fact

of type 2 D

M

Two or mo re ri BMI > 27kg 2sk factors for type 2 DM/m , family history of DM, age > type 2 40 yrs., no nwhite, pre vious GDM

ors for typ

e 2 DM

1 st or 2 nd degree rela tive DM or oth er autoimm with type 1 une disease s Autoimmu ne thyroid disease disease, A ddison’s vi , coeliac ti myasthen ia gravis, p ligo, ernicious anaemia. au toimmune hepatitis,

Fig. 14.10.1  Factors affecting the decision to test for GAD antibodies in a patient with diabetes in pregnancy.

Gestational diabetes mellitus Definition and diagnosis Gestational diabetes mellitus is defined as a new diagnosis of diabetes during pregnancy. There remains some controversy as how best to diagnose it. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study was designed to establish internationally agreed diagnostic criteria. In this landmark observational study more than 25 000 non​diabetic pregnant women were recruited between 2000 and 2006 from nine different countries. All women underwent a 75 gram, two-​hour OGTT between 24 and 32 weeks’ gestation, with healthcare providers blinded to the results unless suggestive of overt diabetes (fasting plasma glucose above 5.8 mmol/​l (105 mg/​dl), or the 2-​hour value above 11.1 mmol/​l (200 mg/​dl), or a random plasma glucose at 34–​37 weeks above 8.9 mmol/​l (160 mg/​ dl)). The fasting, 1-​and 2-​hour plasma glucose results of the OGTT were analysed from 23 316 mother-​newborn pairs for their association with four primary outcomes: macrosomia (corrected birth weight >90th centile), primary caesarean delivery, clinical neonatal hypoglycaemia, and hyperinsulinemia (as assessed by cord serum c-​peptide >90th centile for the study group as a whole). The analysis of the data showed the associations between the OGTT results at different time points and the four primary outcomes were continuous, with no clear inflection points. The results of the HAPO analysis formed the basis of the International Association of the Diabetes and Pregnancy Study Groups (IAPDSG) 2014 criteria for gestational diabetes. The new criteria for gestational diabetes were based on the threshold of glucose value at each time point that gave a 1.75 likelihood of an adverse outcome when compared with the mean reference value at the three separate time points. The American Diabetes Association (ADA), World Health Organization, and International Diabetes Federation

all subsequently endorsed the IAPDSG diagnostic criteria for gestational diabetes, which included a 75 gm OGTT performed between 24 to 28 weeks. In contrast to the HAPO-​ derived criteria, following a cost-​ effectiveness analysis of published intervention studies the National Institute for Health and Care Excellence (NICE) 2015 Diabetes and Pregnancy update proposed a higher fasting value and a lower two-​ hour oral glucose tolerance test value, with no one-​hour value for the diagnosis of gestational diabetes (Table 14.10.1). The NICE criteria also advocate the use of universal screening of five risk factors identified at the initial antenatal visit, with a 75 gm OGTT between 26 to 28 weeks performed on only those women with one or more risk factors, these being a body mass index (BMI) above 30 kg/​m2, a previous macrosomic baby weighing 4.5 kg or above, previous gestational diabetes, a first-​degree relative with diabetes, and belonging to an ethnic family origin with a high background prevalence of diabetes. An earlier diagnostic OGTT (at 16 weeks) is recommended for women with a history of previous gestational diabetes, with repeat at 24–​28 weeks if the first test was normal. The five risk factors recommended by NICE is not exhaustive and leaves out other recognized risk factors, including increasing age and a history of polycystic ovary syndrome. The NICE-​recommended screening at booking potentially may miss up to 25% of women with gestational diabetes. Applying the new IAPDSG criteria to the original HAPO cohort diagnosed between 15 to 20% of parturients as having gestational diabetes, depending on country of origin. Gestational diabetes mellitus in early pregnancy There is currently no agreed strategy for identifying women not known to have diabetes who have significant hyperglycaemia in early pregnancy. Glycosylated haemoglobin (HbA1c) is less reliable

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Table 14.10.1  Recommendations for screening and oral glucose tolerance testing in pregnancy IAPDSG criteria

NICE 2015 criteria

Screening

None

Risk factors at 1st antenatal clinic 1. BMI >30 kg/​m2 2. Previous history of GDM 3. Previous macrosomic birth, ≥ 4.5 kg 4. Family history 5. Minority ethnic family origin with a high prevalence of diabetes

75 gm OGTT

Universal at 24–​28 weeks

Selective testing 26–​28 weeks Based on the presence of risk factors

Plasma glucose

IAPDSG criteria one or more of the following thresholds be met or exceeded:

NICE 2015 criteria one or more of the following thresholds be met or exceeded

0 minute

5.1 mmol/​litre (92 mg/​dl)

5.6 mmol/litre (100 mg/​dl)

60 minute

10 mmol/​litre (180 mg/​dl)

120 minute

8.5 mmol/​litre (153 mg/​dl)

7.8 mmol/​litre (140 mg/​dl)

GDM, gestational diabetes mellitus.

in pregnancy due to the higher turnover of erythrocytes, and fasting blood glucose falls in early pregnancy. However, an HbA1c measurement of ≥5.9% (≥41 mmol/​mol) at the initial antenatal clinic appears to be a good discriminator for women who have significant glucose intolerance on a subsequent OGTT performed at around 20 weeks’ gestation, and with an increased risk of adverse pregnancy outcomes. This HbA1c value is lower than the diagnostic value for diabetes outside pregnancy (HbA1c 6.5% (48 mmol/​mol). Aetiology As described, pregnancy induces a state of relative decreased insulin sensitivity due to both maternal and placental factors. High circulating levels of maternal free fatty acids, adipokines, and cytokines may be factors contributing to this. Women who are obese and those who have gestational diabetes have increased levels of many of the adipokines and inflammatory cytokines associated with decreased insulin sensitivity, including leptin, tumour necrosis factor-​α (TNF​α) and interleukin-​6, while the insulin sensitizing adipocyte cytokine adiponectin is reduced. The placenta is a major source of these cytokines, hormones, and inflammatory mediators, as well as of human placental lactogen and placental growth hormone. Pregnancy is a physiologically leptin-​resistant state and results in a significant upregulation of leptin, which in turn leads to hyperglycaemia. The human growth hormone (GH) gene cluster contains a single gene expressed solely in the anterior pituitary (GH1), plus four genes expressed in the placenta (SHL1, CSH1, GH2, CSH2). GH1 encodes solely pituitary GH, which is also a ligand for the maternal GH receptor and stimulates the insulin-​like growth factor (IGF)-​1 axis. In pregnancy the 6–​8-​fold increase in placental growth hormone increases and replaces normal circulating pituitary growth hormone by 20 weeks’ gestation, and this is thought to decrease insulin sensitivity by inhibiting key components of the insulin-​signalling pathway.

The other members of the GH gene cluster, CSH1 and CSH2, encode for human placental lactogen which is a ligand for the maternal prolactin receptors. This can be detected in the maternal circulation by six weeks’ gestation and has been implemented in augmenting maternal insulin resistance and promoting the supply of fatty acids and glucose to the placenta. Changes in the placental microcirculation and placental dysfunction leading to increased fetal complications have been attributed to the adverse diabetic metabolic milieu resulting from hyperglycaemia, hyperinsulinism, dyslipidaemia, and secretion of adipokines and inflammatory cytokines, causing increased oxidative stress and protein glycosylation.

Rarer forms of diabetes Monogenic β-​cell diabetes is thought to be responsible for approximately 2% of all diabetes diagnosed before the age of 45 years, about 80% of such patients being misdiagnosed as either type 1 or type 2 diabetes, reflecting lack of clinical awareness and limited clinical access to genetic testing. Clues to the diagnosis of monogenic forms of diabetes include lack of typical characteristics of type 1 diabetes (no islet cell autoantibodies, low or no insulin requirement five years after diagnosis, persistence of measurable stimulated C-​peptide, absence of diabetic ketoacidosis), or type 2 diabetes (lack of obesity, hypertension, dyslipidaemia), in the presence of a strong family history of diabetes. An autosomal dominant family history of diabetes may be caused by monogenic disruption of glucokinase (GCK), hepatic nuclear factor (HNF)-​1A, HNF-​4A, or HNF-​1B gene expression. The molecular diagnosis of such forms of diabetes is important because it enables genetic counselling, predictive genetic testing in affected families, personalized tailoring of medication, and provides patient information regarding prognosis. GCK-​related diabetes Making the diagnosis of GCK-​related diabetes is important as it allows patients to be reassured that they have an inherited tendency to mild hyperglycaemia, which requires no specific glucose-​lowering treatment or self-​monitoring of blood glucose (outside of pregnancy), because the condition is not associated with microvascular or macrovascular complications. It also has important implications for management of pregnancy, because in parturients with GCK-​ related diabetes the risk of fetal macrosomia depends upon the fetal GCK genotype. If the fetus has not inherited the GCK mutation it will respond to maternal hyperglycaemia with increased insulin production, leading to excess fetal growth (adding an additional approximately 550–​700 g by term). Alternatively, if the fetus does inherit the GCK abnormality, it will sense the maternal hyperglycaemia as normal, produce normal amounts of insulin and have normal growth, and in this context the aggressive lowering of maternal glucose into the normal range may adversely affect fetal growth. As it is not currently possible to determine the fetal genotype non​invasively during pregnancy, the decision on whether to treat maternal hyperglycaemia in parturients with GCK-​related diabetes is made on the basis of monitoring fetal abdominal circumference, with a reading above the 75th percentile being the recommended threshold to start insulin and normalize maternal glycaemia. In the future, fetal genotyping using cell-​free fetal DNA from maternal plasma sampling during early pregnancy may assist in this context.

14.10  Diabetes in pregnancy

The impact of diabetes on the mother and fetus during pregnancy Diabetes affects all aspects of a woman’s reproductive life, including pregnancy. Diabetes, specifically maternal hyperglycaemia, affects fertilization, implantation, embryogenesis, organogenesis, fetal growth, and development and neonatal and perinatal morbidity and mortality. Women with pre-​existing diabetes or those who develop diabetes during the pregnancy are at added risk of maternal and fetal complications during pregnancy. Maternal diabetes and obesity also influence the risk of future obesity and diabetes in the child, through epigenetic factors and fetal programming in utero. Preconception planning, surveillance, and screening throughout pregnancy by a multidisciplinary specialist team can lessen the risks for both mother and fetus.

Preconception counselling for women with diabetes Preconception counselling is associated with improved pregnancy outcomes. Uptake is highly dependent on sociodemographic factors, and women with the greatest social deprivation scores, those with type 2 diabetes mellitus, and those from ethnic minority groups are less likely to access these services. As half of all pregnancies are unplanned, counselling women about pregnancy should form part of the ongoing care pathway for all women of childbearing age with diabetes. When any potentially teratogenic medication is prescribed as part of a woman’s routine diabetes care (such as an angiotensin converting enzyme (ACE)-​ inhibitor or a statin (HMG-​CoA reductase inhibitor)) women need to be counselled on the need to stop this prior to or as soon as pregnancy is confirmed in an unplanned pregnancy. In addition, advice should be given on the need to take high dose folic acid (5 mg daily) three months prior to pregnancy and continued for the first 12 weeks in pregnancy to reduce the risk of fetal neural tube defects. The key elements of preconception counselling and assessment are shown in Table 14.10.2.

Table 14.10.2  Key elements of preconception counselling Optimizing glycaemic control Medication review Screening and management of diabetes complications Advice regarding diet and weight Information on pregnancy risk to the mother, including particular risks of hypoglycaemia and DKA Increased risk of hypertensive disease in pregnancy Information on pregnancy risk to the baby—​risk of congenital abnormalities, preterm birth, and risk of macrosomia and growth restriction Importance of pregnancy planning and accessing multidisciplinary care in early pregnancy DKA, diabetic ketoacidosis.

Management of diabetes peri-​conceptionally and in pregnancy Optimizing glycaemic control Women need to be supported to achieve optimal glycaemic control peri-​conceptionally and throughout pregnancy to reduce the risk of miscarriage, congenital malformation, stillbirth, and neonatal death. Improved control prior to pregnancy also reduces the risk of deterioration of diabetic retinopathy and nephropathy during the pregnancy. Providing women with structured education around insulin management and dose adjustment of their rapid acting insulin to match their carbohydrate intake improves glycaemic control and lessens the risk of hypoglycaemia. Meta-​analysis of large data sets shows that congenital malformations, preterm delivery and maternal hyperglycaemia in the first trimester of pregnancy are all reduced in women who receive preconception counselling. There is a strong positive association of fasting glucose or glycated haemoglobin in women with type 1 diabetes mellitus and type 2 diabetes mellitus and major fetal anomalies, with multiple organ anomalies associated with the poorest glycaemic control. This association is so strong that 2015 NICE guidance is that women with an HbA1c above 86 mmol/​mol (10%) be strongly advised not to get pregnant. 2015 NICE guidance is to aim for an HbA1c below 48 mmol/​mol (6.5%) if this is achievable without causing problematic hypoglycaemia. Plasma glucose targets are fasting levels of 5–​7 mmol/​l on waking for women with type 1 diabetes mellitus and a plasma glucose level of 4–​7 mmol/​l before meals at other times of the day. To achieve this level of glycaemic control women with type 1 diabetes mellitus will require the use of a multiple dose insulin regime consisting of 4 or 5 insulin injections a day given as 1 or 2 basal insulin injections and 3 bolus rapid acting insulin injections to cover the main meals, or a continuous subcutaneous insulin infusion (CSII) pump. Recent technological advances around insulin pumps, continuous glucose monitoring, and automated bolus insulin calculators that help calculate pre-​meal insulin dosing depending on the amount of carbohydrate eaten, are all available to help women to achieve these targets. In the future, closed-​loop insulin delivery technologies, combining real-​time continuous glucose monitoring with CSII using a computer algorithm, will also be available, and early work in this field holds great promise that lower HbA1c levels will be achievable with less risk of hypoglycaemia. For women with type 2 diabetes mellitus, achieving an HbA1c below 48  mmol/​mol (6.5%) prior to pregnancy is easier, as these women will be at less risk of hypoglycaemia due to their relatively short history of diabetes and less dependency on insulin therapies. However, many such women will need to be started on an insulin prior to a planned pregnancy as all oral agents other than metformin will need to be stopped.

Medication review Some antihypertensive and lipid lowering agents routinely used in the management of diabetes have been associated with an increased risk of congenital malformations when used in the first trimester. These include ACE-​inhibitors, angiotensin II receptor blockers, and the HMG-​CoA reductase inhibitors known collectively as statins. NICE guidance cautions against the use of thiazides and related

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Section 14  Medical disorders in pregnancy

diuretics in pregnancy. Daily 5  mg of folic acid is recommended three months prior to any planned pregnancy.

Screening and management of diabetic complications During preconception counselling women need to be informed of how a pregnancy may affect their own health, including the impact on pre-​existing micro and macrovascular disease. It is important to ensure that a retinal and renal assessment has been performed within the previous year, and to seek information on symptoms of peripheral and autonomic neuropathy, and all cardiovascular risk factors including hypertension and hypercholesterolaemia. Retinopathy Pregnancy can lead to new onset diabetic retinopathy or worsening of pre-​existing disease. Sight-​threatening diabetic retinopathy in pregnancy is rare, but proliferative diabetic retinopathy which accelerates during pregnancy may not regress post-​partum. Screening for retinopathy is therefore recommended prior to pregnancy, during early pregnancy, and again at 28 weeks’ gestation. Any retinopathy detected requires treatment as it may deteriorate during pregnancy, and ongoing follow-​up during pregnancy and postnatally will be required. Diabetic retinopathy is not a contraindication to rapid optimization of blood glucose control in women who present with a high HbA1c, nor is it a contraindication to pregnancy or vaginal birth. Renal function Physiological changes occur in renal function in pregnancy. Glomerular filtration rate, creatinine clearance, and protein excretion all increase. Renal function is usually preserved in women with diabetes who start pregnancy with normal renal function. Women with diabetic nephropathy (serum creatinine >1.5  mg/​dl or proteinuria of more than 3 g protein/​24 hours) have an increased risk of preeclampsia, preterm delivery, fetal growth restriction, perinatal death, and a permanent deterioration in renal function (see Chapter 14.5). Assessment of renal function at the outset of pregnancy is important as optimization of blood glucose as well as blood

pressure before pregnancy may improve maternal and fetal outcomes. Furthermore, knowing baseline renal function (serum creatinine and urinary microalbumin excretion or urinary albumin/​ protein creatinine ratio) is essential for later comparison in case preeclampsia is suspected. Autonomic neuropathy Pre-​existing autonomic neuropathy is an important risk factor for poor glucose control, increased glucose variability and hypoglycaemia. It is also associated with gastroparesis. Although pregnancy does not worsen autonomic neuropathy, it can worsen the symptoms of gastroparesis due to the hormonal and mechanical effects of pregnancy that independently slow intestinal motility. Patients with gastroparesis may develop severe nausea and vomiting, as well as malabsorption, that complicate the timing of insulin administration and contribute to high levels of glucose variability and post-​prandial hypoglycaemia. Women with autonomic neuropathy should have an anaesthetic assessment in the third trimester of pregnancy due to the associated increased anaesthetic risk.

Maternal complications of diabetes in pregnancy Hypoglycaemia Hypoglycaemia in pregnancy is a significant problem, affecting up to 70% of women with pre-​existing diabetes and associated with excess mortality. Undoubtedly the strict glycaemic targets women are expected to achieve before and during pregnancy are an important factor. Awareness of hypoglycaemic symptoms is reduced in pregnancy and women require assessment and education around hypoglycaemia avoidance. This is particularly important for those with initial poor glycaemic control who undergo rapid intensification of their insulin management. Hypoglycaemia is particularly prevalent in the first half of pregnancy, when insulin requirements actually fall, and the first few weeks post-​partum (Fig. 14.10.2). Women who have frequent

16 14 12 Number of events

2632

10 8 6 4 2

4

6

8

10

12

14

16

18

20

22

24

26

28

30

32

34

36

38

Gestational week

Fig. 14.10.2  Hypoglycaemic episodes during pregnancy in women with type 1 diabetes. Reproduced from Nielsen LR et al. (2008). Hypoglycemia in pregnant women with type I diabetes. Diabetes Care, 31(1), 9–​14. Copyright © 2008, American Diabetes Association.

14.10  Diabetes in pregnancy

hypoglycaemic events may benefit from “smart” diabetes technologies, including insulin pumps with continuous glucose monitoring that allows the glucose monitor to temporarily switch off the insulin pump.

Diabetic ketoacidosis Diabetic ketoacidosis is a rare but serious complication in pregnancy and has an associated fetal mortality of up to 10%. All women with type 1 diabetes mellitus should be provided with blood ketone testing strips and a meter, instructed on their use, and advised to test for ketonaemia if they become hyperglycaemic or unwell, and be aware of the indications to seek urgent medical advice. Diabetic ketoacidosis can occur at near normal blood glucose levels during pregnancy, hence it should be excluded in any pregnant woman with pre-​gestational diabetes and persistent nausea and vomiting. The risk of diabetic ketoacidosis increases in late pregnancy due to increased insulin demands and enhanced lipolysis. The treatment of diabetic ketoacidosis in pregnancy is the same as for non​pregnant patients. Fetal assessment should occur following maternal stabilization, noting that fetal heart rate abnormalities usually correct with maternal treatment.

and neuropathy, both peripheral and autonomic, are all more common in women with type 1 diabetes mellitus. Women with type 2 diabetes mellitus are more likely to have a duration of diabetes of less than 10 years and usually less than 5 years, but this may change in the future due to the increasing prevalence of type 2 diabetes mellitus among younger women. All women with diabetes, particularly those with longstanding type 1diabetes mellitus and older obese women with type 2 diabetes mellitus and gestational diabetes, are at an increased risk of diabetic macrovascular disease, including coronary heart disease. Diabetic macrovascular disease remains uncommon in pregnancy, but when it precedes or occurs for the first time in pregnancy, both maternal and fetal outcomes are poor. As the prevalence of macrovascular complications increases with duration of diabetes mellitus, and the numbers of women choosing to delay childbirth into their thirties and forties increases, the prevalence of macrovascular complications in the pregnant population are likely to increase.

Other maternal complications The potential maternal complications from conception to the post-​ partum period are listed in Table 14.10.3.

Pre-​existing diabetic complications Pre-​existing complications differ in women with type 1 or type 2 diabetes mellitus, or gestational diabetes. Women with type 1 diabetes mellitus are likely to have had diabetes for longer than those with type 2 diabetes mellitus, and established diabetic microvascular disease increases with diabetes duration. Retinopathy, nephropathy,

Risks to the fetus Although maternal glucose crosses the placental barrier, insulin does not and, consequently, increases in maternal glucose stimulate fetal insulin production and result in hyperplasia of fetal insulin

Table 14.10.3  Maternal complications of diabetes from conception to the post-​partum period Time

Issue

Type 1 DM

Type 2 DM

GDM

Conception

Fertility

Subfertility due to poor control Delayed menarche Early menopause Autoimmune ovarian failure Increased prevalence of weight related amenorrhoea (anorexia)

Subfertility if associated with polycystic ovarian syndrome

1st trimester 0–​12 wks

Miscarriage

Increased Poor glycaemic control

Hypoglycaemia

High risk of severe recurrent hypoglycaemia

Increased if due to PCO

Loss of hypoglycaemic awareness 2nd trimester 13–​28 wks

Retinopathy

Worsening retinopathy

Hypoglycaemia

High risk of severe recurrent hypoglycaemia

Autonomic neuropathy

Gastroparesis

Nephropathy

Worsening renal function Increased proteinuria

3rd trimester 29–​40 wks

Preeclampsia Pregnancy-​induced hypertension Operative birth Birth trauma

Failed induction of labour Operative birth including caesarean section Birth trauma

Post-​partum

Post-​partum haemorrhage

Increased risk

Long term, 1–​10 years

Expected improvement of any pregnancy related deterioration in retinopathy and nephropathy

CVD, cardiovascular disease; DM, diabetes mellitus; GDM, gestational diabetes mellitus.

Long-​term risk of coronary vascular disease, and diabetic microvascular complications

Recurrent GDM Future type 2 DM Increased risk of CVD

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Section 14  Medical disorders in pregnancy

sensitive tissues. Maternal hyperglycaemia also enhances production of hPG, fetal IGF, and TNF​α. Like insulin, these act as fetal growth factors and result in accelerated fetal growth, macrosomia, and enlargement of the heart and liver.

Congenital malformations As previously discussed, diabetes mellitus is also associated with an increased risk of congenital malformation which is dependent upon glycaemic control (Fig. 14.10.3). When women with diabetes have a normal HbA1c in early pregnancy, congenital malformation rates approach that of the background population (risk of around 2%), but as HbA1c values increase from two to eight standard deviations above the normal range the malformation risk rises from 3 to 10% respectively. Diabetes mellitus is associated with a wide variety of malformations involving the cardiovascular system (e.g. transposition of the great vessels, ventricular septal defect), the central nervous system (e.g. anencephaly, spina bifida, hydrocephaly and holoprosencephaly), the genitourinary system, and the skeleton. The exact mechanism of the embryopathy remains uncertain, but there is evidence for contributions from increased oxidative stress due to elevated superoxide dismutase activity, reduced levels of myoinositol and arachidonic acid, and inhibition of the pentose phosphate shunt pathway.

Fetal macrosomia Maternal weight gain, even without diabetes, predisposes to fetal macrosomia, hence obese pregnant women are advised to avoid unnecessary weight gain during pregnancy. The causes of macrosomia are not fully understood. The Freinkel hypothesis attributes excessive fetal insulin to increased transport of maternal fuel to the conceptus as the predominant cause of fetal macrosomia. However, fetal growth is complex and influenced by maternal, paternal, and fetal genes and factors, uterine environment, and maternal and fetal hormonal status. Infants of diabetic mothers have an additional influence of maternal fluctuations in glycaemia, as a hyperinsulinized fetus can cause a glucose steal phenomenon in late pregnancy, reducing maternal insulin requirements and precipitating maternal hypoglycaemia. Macrosomia is associated with risks for birth for both the fetus and the mother. It is a risk factor for shoulder dystocia which can be difficult to predict but may occur more commonly in fetuses of 30 Congenital malformation (%)

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25 20 15 10 5 0

Women without diabetes

6.1–7.7

7.8–10.0

>10.0

HbA1c (%)

Fig. 14.10.3  Risk of congenital malformation dependent upon glycaemic control. Reproduced from BMJ, Taylor and Davison, 334: 742–​745, copyright © 2007, with permission from BMJ Publishing Group Ltd.

diabetic mothers with an estimated weight of more than 4 kg, and up to 50% in fetuses weighing 4.5 kg or more. Operative delivery and caesarean section are increased in both preexisting and gestational diabetes, independent of the effect of birth weight, potentially related to placental dysfunction leading to fetal distress in labour.

Intrauterine growth restriction Pre-​existing diabetes is also associated with intrauterine growth restriction (IUGR), which is diagnosed when ultrasound-​estimated fetal weight is below the 10th percentile for gestational age, implying a possible pathological process causing the low fetal weight. IUGR in pregnancy complicated by pre-​existing diabetes is usually caused by placental dysfunction related to maternal vasculopathy. Prevention of IUGR should ideally start before pregnancy. Strict glycaemic control and intensive treatment of nephropathy and hypertension are essential. Low-​dose aspirin initiated before 16 gestational weeks may also reduce IUGR risk in women with vasculopathy. Umbilical and other fetal Doppler studies can guide diagnosis and surveillance of fetuses with IUGR as these may reflect placental resistance and function.

Pre-​eclampsia There is an increased risk of pre-​eclampsia in women with pre-​ existing diabetes, especially in those with diabetic nephropathy. Preterm delivery may be required, balancing the risks of delivery and neonatal short term and long-​ term effects of prematurity. Delivery management and the timing of delivery is made according to maternal well-​being, the degree of glycaemic control, the presence of diabetic complications, growth of the fetus, evidence of uteroplacental insufficiency, and the results of fetal surveillance. Perinatal mortality remains high among infants of mothers with type 1 and type 2 diabetes mellitus. Although high glucose levels have been implicated, the exact mechanism remains unclear.

Neonatal and longer-​term effects The impact of maternal hyperglycaemia persists into the neonatal period with an increased risk of neonatal hypoglycaemia, respiratory distress, polycythaemia, hypocalcaemia, and hyperbilirubinaemia. The severity of these fetal metabolic problems correlates with levels of C-​peptide, insulin, and erthyropoietin in amniotic fluid and fetal cord blood, but these are not measured routinely. There is also a growing body of evidence suggesting a longer-​term effect of poor glycaemic control on neonatal outcome. Fetal pancreatic islet cells subjected to hyperglycaemia in utero appear to contribute to an increased susceptibility to metabolic disease later in life, such as obesity, type 2 diabetes mellitus, and the metabolic syndrome. The risks of developing type 2 diabetes mellitus are complex and poorly understood, but infants with both decreased and increased birth weight are at increased risk of developing type 2 diabetes mellitus when compared to those born with a normal birth weight.

Management of diabetes in pregnancy Pre-​existing diabetes Once pregnancy is confirmed, women with pre-​existing diabetes should be encouraged to book early in the pregnancy with an early dating scan at 11–13 weeks. Multidisciplinary, consultant-​ led,

14.10  Diabetes in pregnancy

hospital-​based care is usually the most appropriate level of care, with the multidisciplinary team (MDT) comprising of endocrinologists, diabetes nurses, dieticians, specialist midwives, and obstetricians. In addition to routine antenatal care and screening tests, regular surveillance (usually every two weeks) is suggested to assess blood glucose levels, screen for fetal anomaly, and assess fetal growth (Table 14.10.4). All women should have contact details and telephone access between clinic visits with a member of the MDT team. The optimal blood glucose targets remain the same throughout pregnancy and are similar regardless of the type of diabetes, namely a fasting capillary glucose of 5.3 mmol/​litre, a one hour after meal value below 7.8 mmol/​litre, or a two-​hours after meal value below 6.4 mmol/​litre. However, these targets may need to be individualized and increased for women at risk of hypoglycaemia. Women with type 1, type 2, or gestational diabetes on multiple dose insulin regimen or pump therapy are advised to perform home glucose monitoring fasting, one hour pre-​meals, one to two hours post-​meal, and before bed. Women with gestational diabetes managed with diet and exercise alone, or oral therapy, only need to test fasting and one to two hours post-​meals.

Gestational diabetes Women with gestational diabetes should be taught home glucose monitoring to ensure that their glycaemic targets are met throughout the duration of pregnancy. The aim of treatment is to achieve euglycaemia (while avoiding hypoglycaemia), as this has been shown to benefit both maternal and fetal outcomes. The primary intervention for women diagnosed with gestational diabetes but with a fasting blood glucose below 6 mmol/​l is dietary counselling in combination with physical activity and self-​ monitoring of blood glucose. In women who have a fasting blood

glucose on OGTT above 7.0 mmol/​l, diet and exercise alone would not be expected to lower this value to 5.3 mmol/​litre within an acceptable time period, and therefore the prompt initiation of insulin therapy, with or without metformin, is advised. For women with a fasting blood glucose on OGTT between 6.0 to 7.0 mmol/​l, immediate treatment with insulin therapy, with or without metformin, should be considered if there is clinical evidence of macrosomia or polyhydramnios. Dietary advice All patients with gestational diabetes should be referred to specialist dieticians, the key elements of dietary advice being to substitute complex for simple carbohydrates and increase dietary fibre. The need for pharmacological therapy for gestational diabetes depends entirely on the severity of the glucose intolerance, in addition to fetal growth as assessed on prenatal ultrasound. Diet alone will maintain the fasting and postprandial blood glucose values within the target range in approximately half of women with gestational diabetes. Exercise The role of exercise in gestational diabetes may be even more important than in women with pre-​existing diabetes, given that exercise in some women may lessen the need for medical therapy. Moderate exercise in women with gestational diabetes is well tolerated and has been shown to lower maternal glucose levels. Using exercise after a meal in the form of a brisk walk may blunt the postprandial glucose excursions sufficiently to avoid the need of medical therapy. Establishing a regular routine of modest exercise during pregnancy may also have long-​lasting benefits for women with gestational diabetes due to their appreciable risk of developing type 2 diabetes in the future. Pharmacological treatments

Table 14.10.4  Management plan for diabetes in pregnancy Early pregnancy 8–​9 weeks

Booking visit Dating scan at 11–13 weeks HbA1C, renal profile, assessment of proteinuria Baseline BP Referral for retinopathy screen

12 weeks

Diabetes review First trimester ultrasound scan

14–​16 weeks

Routine antenatal care

18–​20 weeks

Anomaly scan including fetal echocardiography

22 weeks

Diabetes review

24 weeks

Ultrasound fetal growth

26 weeks 28 weeks

Ultrasound fetal growth

30 weeks 32 weeks

Ultrasound fetal growth

34 weeks 36 weeks

Ultrasound fetal growth

37 weeks 38 weeks

Aim for delivery of women with pre-​existing diabetes Consider delivery of women with complex gestational diabetes

40 weeks

Offer induction of labour in women with gestational diabetes

If diet and exercise are insufficient, oral hypoglycaemic agents and/​ or insulin will be required. Insulin does not cross the placenta, but is more difficult to administer, and the risk of hypoglycaemia and weight gain is greater than with oral hypoglycaemic agents. Oral hypoglycaemics, particularly metformin and glibenclamide, have been demonstrated to be safe and efficacious in pregnancy. The advantages of metformin include ease of use, low risk of hypoglycaemia, and limitation of maternal weight gain and weight retention post-​partum. Although there is a theoretical concern that metformin crosses the placenta, recent evidence has demonstrated acceptable short-​term outcomes, with longer term outcomes yet to be clearly defined. Use of metformin was recommended by NICE in 2015, but it does not currently have a UK licence for use in diabetes in pregnancy. Glibenclamide is the only sulfonylurea that has been studied in a large randomized control trial performed in women with gestational diabetes. Maternal glycaemic control, macrosomia, neonatal hypoglycaemia, and neonatal outcomes were not different between women managed with glibenclamide or insulin. There is either very limited or no safety or outcome data on women with gestational diabetes being treated with other oral agents, including pioglitazone, metglitinides, acarbose, and incretins. If blood glucose control remains above target following treatment with the oral agents, then a recombinant human insulin should be considered. It is common to add a short and medium duration acting insulin to achieve better 24-​hour control while continuing the

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Section 14  Medical disorders in pregnancy

metformin therapy. Glibenclamide is usually discontinued once insulin is required. There is evidence suggesting an association between vitamin D deficiency/​insufficiency and gestational diabetes, although the molecular or cellular mechanisms for this association is unclear. It is currently not known whether vitamin D supplementation can reduce the risk of developing gestational diabetes and/​or improve glycaemic control in diabetic pregnant women with vitamin D deficiency/​insufficiency.

Obstetric matters Timing, mode, and place of birth Women with diabetes should give birth in hospitals where 24 hours-​ a-​day advanced neonatal resuscitation skills are available. Women with type 1 or type 2 diabetes mellitus and no other complications should be advised that birth between 37 + 0 weeks and 38 + 6 weeks of pregnancy lessens their heightened risk of stillbirth. Induction of labour or an elective caesarean section before 38 + 6 weeks of pregnancy is recommended if spontaneous labour has not occurred before then. Birth before 37 + 0 weeks may be advisable if there are metabolic or maternal or fetal indications. Antenatal steroids for fetal lung maturation can be used if a preterm delivery is anticipated, but close glycaemic monitoring is required alongside careful insulin titration.

Management of diabetes in labour During labour and delivery, most women with pre-​existing diabetes should be managed with a sliding scale of intravenous insulin and dextrose infusion to maintain capillary plasma glucose between 4 and 7  mmol/​litre to lessen the risk of neonatal hypoglycaemia. Hourly capillary plasma glucose should be performed. Women with gestational diabetes using diet, oral hypoglycaemic agents, or small doses of insulin can cease the medications in labour, with continued regular assessment of maternal capillary glucose. Women with gestational diabetes requiring large doses of insulin may require an insulin sliding scale in labour.

Post-​partum care The effect of pregnancy on maternal glycaemic control ceases very quickly post-​partum, hence women with pre-​existing diabetes taking insulin should immediately revert to their pre-​pregnancy regimen after birth, but with a lower insulin dose. It is important for women and healthcare staff to be prepared for the potential increased risk of hypoglycaemia in the immediate post-​partum period. Breastfeeding, lack of sleep, and the need for maternal adjustment to not requiring ‘tight glycaemic’ control as during the pregnancy, all contribute to this increased risk, which can be reduced if post-​partum women take 25–​30% less than their pre-​pregnancy insulin dose. Women taking insulin who breastfeed should test their blood glucose before and after breastfeeding and be encouraged to have a snack before and have one available when feeding. Due to the heightened risk of hypoglycaemia when breastfeeding, women need

to be warned of the potential dangers to the newborn when breastfeeding in bed. Healthcare staff and patients should be trained to monitor for both neonatal and maternal hypoglycaemia. Women with type 2 diabetes mellitus on metformin prior to and during pregnancy can safely continue this post-​partum and during breastfeeding. The concentration of metformin in breast milk is low, and infant exposure to metformin has been reported to range between 0.3 to 1.1% of the weight-​normalized maternal dose. Breastfeeding appears to confer an advantage to all women, reducing incidence of developing type 2 diabetes mellitus in those with and those without gestational diabetes. Breastfeeding has also been linked to a decreased risk of the infant developing obesity and impaired glucose tolerance in later life. Women with gestational diabetes can usually cease all diabetes medication post-​partum, with most reverting to normal glucose levels soon after birth, although 5–​10% will fulfil the criteria for type 2 diabetes. Although screening women with prior gestational diabetes for subsequent type 2 is accepted, there is a lack of consensus as to how and when this should be done. The ADA recommends using a 75 gm OGTT to screen for persistent diabetes 6–​12 weeks’ post-​partum, and lifelong screening for development of diabetes or pre-​diabetes at least every three years. In the United Kingdom, the 2015 NICE guidelines recommend a laboratory glucose prior to discharge, and a fasting glucose 6–​13 weeks post-​partum or a HbA1C after 13 weeks, with an annual fasting plasma glucose or HbA1C thereafter. All women with prior gestational diabetes remain at risk of diabetes in the future, with up to half developing type 2 diabetes mellitus within 10 years. A programme of diet and exercise can improve this risk, hence dietary and lifestyle modifications, including regular exercise, should be advocated in the long term. Post-​partum care should include advise on family planning and the need for contraception that allows women time to optimize their health prior to any future pregnancy.

Areas of uncertainty, controversy, and future developments The maternal and neonatal obstetric outcomes in women with pre-​ existing diabetes have the potential to improve with continuing advances in diabetes management, fetal surveillance, and neonatal care. However, a significant improvement in pregnancy outcomes will require more women with pre-​existing diabetes to plan their pregnancy and participate in preconception counselling to optimize their glycaemic control and identify and manage proactively any diabetic complications prior to pregnancy. Preconception counselling improves both maternal and fetal short-​and long-​term outcomes. It will become increasingly important to identify women with gestational diabetes, not only to minimize the impact of gestational diabetes on the pregnancy, but also for the future health of the child. Women with gestational diabetes represent the future population of parous women with diabetes, mostly type 2. This potential provides an opportunity for targeted prevention strategies to curb the current rise in obesity and type 2 diabetes. The association

14.10  Diabetes in pregnancy

of obesity and glucose intolerance in the offspring of women with pre-​ existing diabetes mellitus or gestational diabetes provides an opportunity for intergenerational risk prevention for future obesity and diabetes.

FURTHER READING Bellamy L, et al. (2009). Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-​analysis. Lancet, 373, 1773–​9. Confidential Enquiry into Maternal and Child Health (2005). Pregnancy in women with type 1 and type 2 diabetes in 2002–​03, England, Wales and Northern Ireland. London, CEMACH. Crowther CA, et al. (2005). Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med, 352, 2477–​86. Garcia-​Patterson A, et  al. (2010). Insulin requirements throughout pregnancy in women with type 1 diabetes mellitus: three changes of direction. Diabetologia, 53, 446–​51. Guerin A, Nisenbaum R, Ray JG (2007). Use of maternal GHb concentration to estimate the risk of congenital anomalies in the offspring of women with prepregnancy diabetes. Diabetes Care, 30, 1920–​5. Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study Group (2008). Hyperglycemia and adverse pregnancy outcomes. N Engl J Med, 358, 1991–​2002. International association of diabetes and pregnancy study groups (2010). International association of diabetes and pregnancy study

groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care, 33, 676–​82. Macintosh MC, et  al. (2006). Perinatal mortality and congenital anomalies in babies of women with type 1 or type 2 diabetes in England, Wales, and Northern Ireland:  population-​based study. BMJ, 333, 177. National Institute for Health and Care Excellence (NICE) (2015). Diabetes in Pregnancy:  Management from Preconception to the Postnatal Period. https://​www.nice.org.uk/​guidance/​ng3 Rowan JA, et al. (2008). Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med, 358, 2003–​15. Secher AL, et  al. (2013). The effect of real-​time continuous glucose monitoring in pregnant women with diabetes: a randomized controlled trial. Diabetes Care, 36, 1877–​83. Stewart ZA, et al. (2016). Closed-​loop insulin delivery during pregnancy in women with type 1 diabetes. N Engl J Med, 375, 644–​54. Tennant PW, et  al. (2014). Pre-​existing diabetes, maternal glycated haemoglobin, and the risks of fetal and infant death: a population-​ based study. Diabetologia, 57, 285–​94. Tripathi, A., et al. (2010). Preconception counseling in women with diabetes: a population-​based study in the north of England. Diabetes Care, 33, 586–​8. Zhao P, et  al. (2016). Maternal gestational diabetes and childhood obesity at age 9–​11: results of a multinational study. Diabetologia, 59, 2339–​48.

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14.11

Endocrine disease in pregnancy David Carty

ESSENTIALS Thyroid Many pregnant women will develop goitre. Gestational thyrotoxicosis needs to be differentiated from Graves’ disease, which requires treatment with propylthiouracil in early pregnancy and carbimazole in later pregnancy. Overt hypothyroidism is associated with adverse maternal and fetal outcomes and should be treated to maintain thyroid-​ stimulating hormone within the trimester-​ specific reference range.

Adrenal The diagnosis of both Addison’s disease and Cushing’s syndrome can be challenging in pregnancy. Patients with adrenal insufficiency may require higher replacement steroid doses, particularly in the third trimester.

Pituitary Prolactinomas are commonly encountered in pregnancy. Women with macroprolactinomas should have visual field monitoring throughout pregnancy. Lymphocytic hypophysitis is increasingly recognized as a cause of hypopituitarism arising in late pregnancy and in the post-​partum period.

Thyroid disease Thyroid physiology in pregnancy Pregnancy has a significant impact on thyroid physiology. The fetal thyroid does not secrete active thyroid hormone until 18–​20 weeks of gestation, hence maternal thyroid hormone production must increase by up to 50% in order to provide enough thyroid hormone for the developing fetus. As a result, many pregnant women, particularly in iodine deficient areas, will develop goitre. Interpretation of thyroid tests is also affected by pregnancy. Thyroid-​stimulating hormone (TSH) closely resembles β-​HCG at a molecular level, and due to cross-​reactivity in pregnancy normal TSH ranges are lower. Trimester-​specific reference ranges for use in pregnancy have been developed in many laboratories: these should

be used wherever possible, since TSH ranges will depend upon the population and ethnicity of the women studied.

Gestational thyrotoxicosis In early pregnancy, particularly in those with excessive vomiting or with twin pregnancies, excessively high β-​HCG levels can lead to apparent thyrotoxicosis. Most women with gestational thyrotoxicosis can be managed conservatively with fluids and antiemetics, although it is important to differentiate from Graves’ disease presenting in pregnancy: several clinical features can help to discriminate (Table 14.11.1).

Treatment of Graves’ disease in pregnancy Graves’ disease affects around 0.2% of pregnancies. Carbimazole (methimazole) is the most commonly used drug for thyrotoxicosis. Case reports (although not larger studies) have associated this drug with rare congenital malformations including aplasia cutis and oesophageal atresia, and so propylthiouracil has traditionally been recommended for use pre-​pregnancy. Propylthiouracil, however, has been associated with hepatotoxicity in late pregnancy, so a balance between the small risks associated with these two medications is required. Treatment, which can usually be down-​titrated, should be continued throughout pregnancy and into the early post-​ partum period to reduce the risk of early recurrence post-​partum (see Box 14.11.1). Block and replace regimes should be avoided in pregnancy. If antithyroid medications are ineffective or not tolerated, then surgical treatment should be considered; the use of radioactive iodine is contra-​indicated in pregnancy and while breastfeeding.

Table 14.11.1  Differentiation of Graves’ disease from gestational thyrotoxicosis Graves’ disease

Gestational thyrotoxicosis

Goitre

√

X

Thyroid receptor antibodies

√

X

Symptoms prior to pregnancy

√

X

Eye signs

√

X

14.11  Endocrine disease in pregnancy

Box 14.11.1  Management of Graves’ disease in pregnancy • Confirm diagnosis • Treat with propylthiouracil if diagnosed prior to planned pregnancy or in first trimester • Consider switch to carbimazole in second trimester — Aim to continue treatment until delivery • Monitor thyroid function tests 4–​6 weekly — Titrate dose where necessary • Check thyroid receptor antibodies (TRAB) in third trimester — Inform neonatologist if positive (risk of fetal thyrotoxicosis) • Review post-​partum — Check for recurrence

up to 15%. Although associated with adverse fetal and maternal outcomes in some studies, evidence that thyroxine treatment leads to an improvement in these outcomes is limited and conflicting. Recent guidelines from US and European Societies advocate treatment with thyroxine of women found to have subclinical hypothyroidism, although definitions differ between guidelines.

Fetal and neonatal thyroid dysfunction

Women are at risk of recurrence of Graves’ disease in the post-​ partum period, and thyroid function tests should be monitored regularly after delivery. Loss of ability to breast-​feed can be an early sign of recurrence. Both carbimazole and propylthiouracil are detectable in breast milk, although there is no evidence of harm to the baby: in general, if further pregnancy is desired then propylthiouracil is preferable.

In women with uncontrolled thyrotoxicosis or high thyroid receptor antibody (TRAB) titres, additional fetal ultrasound monitoring of fetal heart rate, growth, amniotic fluid volume, and assessment for fetal goitre should be undertaken. The diagnosis of fetal thyrotoxicosis can be confirmed if necessary by fetal blood sampling. Treatment is by maternal administration of high-​dose propylthiouracil (300–​450 mg/​day) together with thyroxine during gestation to prevent maternal hypothyroidism. Involvement of fetal medicine specialists is required. Neonatal hypothyroidism may very rarely occur at birth due to maternal TSH receptor blocking antibodies, maternal antithyroid drug administration, iodine deficiency, and maternal goitrogen ingestion. All these conditions are transient, and the mother can be reassured.

Hypothyroidism in pregnancy

Post-​partum thyroid dysfunction

Overt hypothyroidism is associated with several adverse maternal and fetal outcomes, including pre-​eclampsia, intrauterine growth restriction, preterm delivery, and reduced intelligence quotient (IQ) in the offspring. Treatment of overt hypothyroidism leads to an improvement in these outcomes and for this reason many clinicians advocate the universal screening of thyroid function in pregnant women. The aim in pregnancy is to maintain TSH within the trimester-​specific reference range. Some women with hypothyroidism will require an increase in daily dose of thyroxine of 25–​50 mcg to attain this: those with no thyroid gland because of previous radio iodine or surgical treatment are more likely to need a dose increase than those with autoimmune hypothyroidism. T3 does not cross the placenta, and its use should be avoided in pregnancy. Subclinical hypothyroidism describes TSH above the trimester-​ specific reference range, but with a normal fT4. Depending on the population studied, rates of this condition are reported to be

Up to 15% of women in the general population have positive thyroid peroxidase antibodies; of these 50% will develop a degree of post-​ partum thyroid dysfunction. The condition is thought to be caused by autoimmune-​associated release of preformed hormone from the thyroid. In general, the disease is characterized by transient thyrotoxicosis, followed by hypothyroidism, and then a return to normal (Fig. 14.11.1) The thyrotoxic phase is usually asymptomatic; in contrast the hypothyroid phase will often be associated with symptoms and require thyroxine treatment. There is a high risk of recurrence in future pregnancies, and up to 65% of women will develop permanent hypothyroidism during long-​term follow-​up. TSH should be measured annually in affected women.

Thyroid nodules in pregnancy Thyroid nodules occur in up to 10% of pregnant women, and in general these should be dealt with in a similar manner to outwith

fT4 and T3 levels

Reference range

TSH levels

Thyrotoxic phase 2–6 months

Hypothyroid phase 3–12 months

Recovery

Fig. 14.11.1  Pattern of thyroid dysfunction in post-​partum thyroid dysfunction.

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Section 14  Medical disorders in pregnancy

Thyroid nodule detected in pregnancy

History and examination TFTs Ultrasound reveals nodule >1cm

Benign ultrasound appearances

Ultrasound suspicious for malignancy

Compressive symptoms

Defer further investigation until after pregnancy

Consider FNA

Refer for surgery

Fig. 14.11.2  Investigation algorithm for thyroid nodules.

pregnancy. A  suggested algorithm for investigation is shown in Fig. 14.11.2. Surgery, if required, should be undertaken in the second trimester. Investigation of nodules identified in late pregnancy can be deferred until the post-​partum period.

Parathyroid disease Diseases of the parathyroid glands are uncommon in women of childbearing age, but hyperparathyroidism during pregnancy can lead to acute pancreatitis or severe hypercalcaemia. There is an increased incidence of prematurity and neonatal hypocalcaemia and tetany if maternal calcium levels are high. The high maternal calcium levels suppress fetal parathyroid hormone causing the neonatal calcium to fall following cord clamping at delivery. Surgical management can be undertaken safely in pregnancy and ideally in the second trimester. Hypoparathyroidism is treated with vitamin D analogues, with dosage often needing to be increased during pregnancy to maintain normocalcaemia, hence calcium levels should be monitored regularly throughout pregnancy, at least once in each trimester.

Adrenal disease Addison’s disease Addison’s disease can rarely present in pregnancy. Diagnosis can be difficult, but should be considered in women with unexplained hypotension, hyponatraemia/​hyperkalaemia, or pigmentation. In women already known to have the condition, many will require an increase in steroid dose particularly in the third trimester, if hyperemesis develops, or during any intercurrent infection. Higher doses of intravenous hydrocortisone are required for labour or operative delivery, and anaesthetists should be informed of the patient’s condition.

Cushing’s syndrome Cushing’s syndrome is associated with several adverse pregnancy outcomes, including diabetes, pre-​eclampsia, and wound healing problems. The presentation of Cushing’s syndrome in pregnancy

is similar to outwith pregnancy, but diagnosis can be challenging: elevated cortisol levels are seen in the second and third trimesters in normal pregnancy, dexamethasone suppression testing is less reliable in pregnancy, and reference ranges for urinary free cortisol in pregnancy have not been established. Unlike the general population, where adrenocorticotropic hormone-​dependent Cushing’s is more common, the proportion of Cushing’s syndrome due to adrenal lesions is higher in pregnancy than in the non​pregnant population. Since ongoing cortisol excess is associated with significant maternal and fetal morbidity, a surgical cure should be pursued.

Adrenal tumours Adrenal tumours in pregnancy are rare, but as with other tumours there is a risk of enlargement in pregnancy. Phaeochromocytoma can be mistaken for pre-​eclampsia, and should be considered in women with episodic hypertension, associated symptoms of headache or palpitations, or a family history. Diagnosis involves measurement of 24-​hour urinary or plasma metanephrines. In general, the lesion should be removed laparoscopically if identified in the first or second trimester; if the lesion is identified in the third trimester then adrenalectomy is usually deferred until a few weeks later. Women should be adequately α-​blocked (and then, if ­necessary, β-​blocked) prior to surgery and/​or delivery.

Congenital adrenal hyperplasia Congenital adrenal hyperplasia is a group of autosomal recessive conditions characterized by impaired cortisol synthesis. 21-​Hydroxylase deficiency is the most common cause, present in over 95% of cases. Fertility in women with the more severe variant (classical) congenital adrenal hyperplasia is reduced, owing to androgen excess, oligoanovulation, and chronically elevated levels of adrenal-​derived progesterone. Although androgen levels are often elevated in pregnancy, placental aromatase production prevents virilization of unaffected female fetuses. Fertility is less likely to be affected in women with the less severe (non​classical) form of the disease. Management of congenital adrenal hyperplasia in pregnancy involves adequate steroid replacement and adrenal androgen suppression. In women with classical congenital adrenal hyperplasia, hydrocortisone should be used in pregnancy; dexamethasone, which can cross the placenta, should be avoided. Genetic counselling may be considered for an index case desiring pregnancy, or in families with a previously affected infant.

Pituitary Prolactinomas Prolactinomas are the most common type of functioning pituitary lesion and since they have a peak incidence in women during childbearing years they are commonly encountered in pregnancy. Monitoring of prolactin levels in pregnancy is unhelpful: the normal pituitary expands by 30% in pregnancy, largely due to lactotroph expansion, and so normal pregnancy is associated with a 10-​fold increase in prolactin levels. Medical therapy with dopamine agonists is the treatment of choice for prolactinoma:  these reduce tumour bulk and

14.11  Endocrine disease in pregnancy

normalize prolactin levels in most patients. Women with lesions that are resistant to dopamine agonists or who are intolerant should be counselled regarding the benefits of surgery prior to pregnancy. Women with microprolactinomas should, in general, stop dopamine agonists when they find out they are pregnant, since the risk of enlargement causing visual field impairment is less than 1%. In women with macroprolactinomas, however, the risk is much higher, and such women may require to stay on their dopamine agonist therapy. After careful counselling they may wish to discontinue treatment in the last month of pregnancy to facilitate breast-feeding. Women with macroprolactinomas should have visual field monitoring throughout pregnancy, particularly if dopamine agonists are discontinued or if they develop symptoms. Symptoms indicative of expansion include headache, visual field deterioration, and cranial nerve palsies. If a lesion enlarges in pregnancy, then restarting or increasing dose of dopamine agonist therapy should be considered; there are now extensive safety data available for both cabergoline and bromocriptine in pregnancy.

Diabetes insipidus Central diabetes insipidus may present during pregnancy. It is seen in women with lymphocytic hypophysitis (see next) and in women with infiltrative disorders such as Langerhans’ cell histiocytosis. Synthetic desmopressin is normally used in the management of diabetes insipidus and can be given orally or intranasally. Use during pregnancy seems to be safe for both mother and baby:  synthetic desmopressin does not affect delivery and has no adverse effects on the neonate. Diabetes insipidus may be seen transiently at the end of otherwise normal pregnancy and in women with acute fatty liver of pregnancy. This is related to production of vasopressinase by the placenta, the breakdown of which is delayed in acute fatty liver.

Lymphocytic hypophysitis

Lymphocytic hypophysitis is increasingly recognized as a cause of hypopituitarism arising in late pregnancy and in the post-​partum period. The underlying aetiology is thought to be autoimmune, and pathology is characterized by dense infiltration of lymphocytes. Women may present with a pituitary mass lesion, headache, or visual field disturbance, and imaging resembles a pituitary adenoma in 80% of patients. Affected women will commonly have parAcromegaly tial hypopituitarism, with adrenocorticotropic hormone and TSH Fertility is reduced in women with acromegaly because of co-​ the most common deficiencies, and relative sparing of luteinizing secretion of prolactin along with growth hormone, and because of hormone (LH) and follicle-​stimulating hormone. Treatment is usudecreased gonadotrophin reserves due to the tumour expansion. In ally with corticosteroids. It has been speculated that many cases of affected women wishing to conceive, growth hormone and prolactin Sheehans’s syndrome, a now rare condition characterized by hypopituitarism associated with post-​partum haemorrhage, may in fact levels should be normalized prior to conception. In general, women with microadenomas should discontinue have been caused by lymphocytic hyophysitis. medical therapy in pregnancy and be assessed at each trimester. Women with macroadenomas should be monitored closely, with FURTHER READING visual field monitoring in each trimester and MRI scan when Casey BM, et al. (2017). Treatment of subclinical hypothyroidism or necessary. hypothyroxinemia in pregnancy. N Engl J Med, 376(9), 815–25. There are limited safety data for the use of somatostatin analogues de Groot L, et al. (2012). Management of thyroid dysfunction during in pregnancy, and if necessary use of dopamine agonists can be conpregnancy and postpartum: an Endocrine Society clinical practice sidered instead. guideline. J Clin Endocrinol Metab, 97, 2543–​65.

Non​functioning pituitary adenomas Although non​functioning pituitary adenomas represent 30% of pituitary adenomas overall, they tend to present in older age and are associated with reduced fertility, hence they are rarely encountered in pregnancy. Non​functioning lesions do not usually increase in size in pregnancy,s but monitoring of visual fields is recommended for women with macroadenomas. If symptomatic enlargement occurs, medical treatment with dopamine agonists or trans-​sphenoidal surgery can be considered.

Frise CJ, Williamson C (2013). Endocrine disease in pregnancy. Clin Med, 13, 176–​81. Lazarus J, et al. (2014). 2014 European thyroid association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J, 3, 76–​94. Lindsay JR, Nieman LK (2006). Adrenal disorders in pregnancy. Endocrinol Metab Clin North Am, 35, 1–​20, v. Stagnaro-​Green A, et al. (2011). Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid, 21, 1081–​125.

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14.12

Neurological conditions in pregnancy Pooja Dassan

ESSENTIALS Pregnancy can influence the clinical course of an underlying neurological problem or precipitate the first presentation of a neurological disease. Epilepsy—​sodium valproate is associated with higher risk of major congenital malformations and impaired neuropsychological development than other antiepileptic drugs: lamotrigine or levetiracetam are preferred. Women taking antiepileptic drugs can breastfeed. Multiple sclerosis—​ relapse rate is reduced in pregnancy but substantially increased for three months post-​partum. Cerebrovascular disease—​stroke syndromes specific to pregnancy include pre-​eclampsia, which can lead to posterior reversible vasoconstriction syndrome. Reversible cerebral vasoconstriction syndrome presents after delivery and has many similarities to posterior reversible vasoconstriction syndrome. Cerebral venous thrombosis accounts for approximately 20% of all strokes occurring in pregnancy and puerperium. There are conflicting opinions as to whether pregnancy or delivery increases the risk of cerebral aneurysm or arteriovenous malformation rupture.

Computed tomography Computed tomography (CT) can be performed in pregnancy. The fetal exposure dose from a head CT scan is less than 0.1 mGy, which is low. The patient should be informed that no association has been proven between radiation exposure of less than 50 mGy and risk of spontaneous miscarriage or developmental malformations. Iodinated contrast should only be given if required in pregnancy:  it does cross the placenta, but no teratogenic effects have been described.

Magnetic resonance imaging This is the modality of choice in pregnancy. Despite theoretical concerns, there is no evidence to suggest that magnetic resonance imaging (MRI) exposure, irrespective of trimester, is associated with fetal harm. Contrast agents such as gadolinium are avoided in pregnancy because of an increased risk of harm; including stillbirth and neonatal death.

Headaches Introduction Neurological conditions in pregnancy are an important cause of mortality and morbidity in the United Kingdom. From 2010 to 2015, there were 50 maternal deaths in the United Kingdom related to diseases of the central nervous system. The commonest causes identified were subarachnoid haemorrhage, intracerebral haemorrhage, and epilepsy. During pregnancy, a range of haemodynamic and biochemical changes occur in the mother, and these can significantly impact and influence the natural history of an underlying neurological problem or precipitate the first presentation of neurological disease in pregnancy. This chapter will cover the management of common neurological diseases during pregnancy.

Headaches are common in women of childbearing age and pregnancy is no exception to this. The commonest headache presentations encountered in pregnancy include, tension headaches, and migraines. However, it is important to always be mindful of any red flag features, suggestive of a more sinister pathology, necessitating urgent evaluation (Box 14.12.1).

Migraine Migraines usually improve during pregnancy and 60–​70% of women report fewer migrainous attacks during pregnancy. In women who are troubled by headaches in pregnancy, non​pharmacological steps

Box 14.12.1  Red flags in headache presentation

Imaging in pregnancy This causes safety concern during pregnancy, but the clinician should put maternal well-​being at the centre of all decision-​making.

• Headaches of sudden onset • Headaches associated with neck stiffness • Patient reports worst headache ever • Headache with abnormal neurological signs

14.12  Neurological conditions in pregnancy

are usually advocated as part of the first line management. This includes advising patients to improve hydration, reduce consumption of caffeinated drinks, avoid sleep deprivation, and adopt regular eating patterns. Approaches to drug treatment should involve using non​opioid ­analgesics, such as paracetamol and non​steroidal anti-​inflammatory drugs, although the latter should be avoided after 30 weeks’ gestation. A prokinetic agent such as domperidone is a helpful adjunct to these abortive medications. Opiates, although safe to use during pregnancy, are usually avoided in migrainous patients as they can exacerbate nausea and, if anything, worsen gastric motility problems. If despite these initial measures the headaches are still troublesome, then a preventative medication is usually prescribed. Both propranolol and amitriptyline are reasonable first line options and should be used at the lowest effective dose.

Epilepsy An important aspect of the consultation with any female patient of childbearing age with epilepsy is preconception counselling (see Box 14.12.2). As approximately 50% of pregnancies are unplanned, clinicians must approach this subject at the earliest opportunity to ensure that the patient’s therapy has been optimized and folic acid 5  mg per day has been initiated for at least three months preconception.

Antiepileptic drugs Lamotrigine Lamotrigine’s teratogenic profile is more favourable than other antiepileptic drugs, in particular when compared with valproate. However, one drawback with lamotrigine use in pregnancy is that the apparent clearance increases steadily through pregnancy Box 14.12.2  Pre-​pregnancy counselling issues • Reassure the patient that most women with epilepsy give birth to a healthy child. • Aim to maintain the mother pre-​pregnancy on a single agent, at the lowest effective dose. Higher risk of malformations with polytherapy and dose-​ related effects are likely to be observed with most antiepileptic drugs (e.g. valproate). • Teratogenicity is defined in the following categories: — Structural malformations and these can be either major or minor; — Impaired neuropsychological development; — Reduced intrauterine growth. • Sodium valproate—The MHRA (Medicines and Healthcare products Regulatory Agency) recently updated their guidance in March 2018 recommending that valproate must no longer be used in any woman of childbearing age, unless she has a pregnancy prevention programme in place. This is designed to make sure patients are fully aware of the risks and the need to avoid becoming pregnant. If valproate is taken during pregnancy, up to 4 in 10 babies are at risk of developmental disorders, and approximately 1 in 10 are at risk of birth defects. • The magnitude of the risk of maternal seizures on the fetus is difficult to quantify. Overall, women with epilepsy who are having generalized seizures during pregnancy should be informed that the fetus may be at risk of harm with multiple or prolonged seizures, but the actual absolute risk—​particularly of a single seizure—​is probably low.

and notably peaks at 32 weeks, when it can be as high as 330% as compared with non​pregnant baseline. This can result in quite a significant fall in lamotrigine levels in the third trimester, with deterioration in seizure control as a consequence. This change in lamotrigine’s pharmacokinetics during pregnancy does revert back to pre-​pregnancy conditions within a few days of delivery. In our practice, we advocate checking serum lamotrigine level either pre-​pregnancy or in very early pregnancy and treating this as the mother’s baseline. Thereafter, the clinician should consider increasing the lamotrigine dose to prevent significant reduction of levels from baseline. Whether such increases should be based on clinical assessment or therapeutic drug monitoring is currently the subject of a multicentre randomized trial. Levetiracetam Levetiracetam is a newer generation antiepileptic mediation with a favourable side effect profile and is widely used to treat seizures. The emerging data suggest that the risk of major congenital malformation for mother’s taking levetiracetam is between 2 to 3%, which is comparable to the background risk. In addition, current evidence suggests that taking levetiracetam during pregnancy does not have a negative impact on the child’s cognitive and language development. Levetiracetam metabolism also increases in pregnancy and in our practice, we advocate checking drug levels once every trimester.

Management of pregnancy and labour Several antiepileptic drugs, including phenytoin and carbamazepine, are hepatic enzyme inducers and thus lead to a reduction in vitamin K-​dependent clotting factors in the fetus. Previously oral vitamin K was prescribed for women taking hepatic enzymeinducing antiepileptic drugs from 36 weeks’ gestation until delivery, to prevent hemorrhagic disease of the newborn. This is no longer necessary as all babies receive intramuscular (IM) vitamin K after birth. Women with epilepsy should be encouraged to deliver in hospital as it is recognized that 3% will have a seizure within 24 hours of delivery. The reasons behind this include fatigue and sleep deprivation, failure to adhere to usual antiepileptic drug regime during labour, and impaired absorption. If a mother is felt to be at particular risk of seizures during this period, then short-​term clobazam (a benzodiazepine derivative) can be used as an effective adjunct to her usual medication.

Breastfeeding All antiepileptic drugs are excreted in varying degrees into breast milk. Despite this, it is the opinion of experts to support breastfeeding in women using antiepileptic drugs, as the benefits of breastfeeding are likely to outweigh any theoretical risks.

Multiple sclerosis Most women with multiple sclerosis (MS) can safely conceive, give birth, and breastfeed without any significant ill-​ effects to the mother or baby. Important aspects to discuss during pre-​pregnancy counselling in women with MS are detailed in Box 14.12.3. Use of disease-​modifying drugs in pregnancy is described in Table 14.12.1.

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Box 14.12.3  Key issues to discuss during pre-​pregnancy counselling in women with multiple sclerosis • Fertility is not affected in multiple sclerosis (MS). • There is no single genetic cause of MS. The risk of MS in the general population is 0.13%. However, when a parent has MS, risk to the child is 2–​2.5%. • Safety of disease-​modifying drugs (DMDs)—​see Table 14.12.1 • Relapse rate is reduced by up to 70% in pregnancy, especially during the third trimester. • This is followed by a substantial increase in risk of relapses in the immediate post-​partum period and for up to three months thereafter. • Vitamin D supplementation (up to 4000 IU/day) can be used safely during pregnancy to reduce the relapse rate. • Mild relapses during pregnancy can be managed conservatively, but significant relapses leading to new disability can be treated with either intravenous methylprednisolone or oral prednisolone. Less than 10% of the maternal dose of methylprednisolone or prednisolone reaches the fetus as a result of metabolism to the inactive form by the placenta. • Mode of delivery should be guided by obstetric reasons and there is no documented adverse effect of regional anaesthesia.

Myasthenia gravis Myasthenia gravis affects skeletal muscles and does not affect the smooth muscles of the myometrium, thus uterine contractions are not impaired. The key to managing myasthenia gravis in pregnancy is the same as with any other autoimmune condition; to optimize control pre-​pregnancy. It is important to remember that several of the drugs used to treat myasthenia gravis (see Table 14.12.2) are safe in pregnancy and it is imperative that women are reassured of this. The issues pertaining to the management of myasthenia in the preconception stage, during pregnancy, and thereafter are covered in Table 14.12.3.

Cerebrovascular disease

of pregnancy-​related ischaemic strokes are cardioembolism, pre-​ eclampsia/​eclampsia and cerebral venous thrombosis. If a stroke is suspected, urgent imaging should be carried out, as in non​pregnant patients (see Fig. 14.12.1). In non​pregnant individuals, intravenous recombinant tissue plasminogen activator (t-​PA) is the recommended treatment for an acute ischaemic stroke presenting within 4.5 hours of onset. There is very little evidence relating to the use of this treatment in pregnant women but, overall, the evidence suggests that treatment with t-​PA should be considered in all pregnant patients with disabling strokes.

Stroke syndromes specific to pregnancy Pre-​eclampsia This is a multisystem disorder, primarily thought to be a disorder of placental implantation and presents with a constellation of symptoms including pregnancy-​induced hypertension and proteinuria. In approximately one-​third of cases of stroke diagnosed in pregnancy or the puerperium, pre-​eclampsia/​eclampsia is also concomitantly diagnosed. Haemorrhagic strokes occur most commonly. The pathophysiology underpinning this is complex but appears to be related to impaired endothelial function. In addition, pre-​eclampsia can lead to posterior reversible vasoconstriction syndrome, which is radiologically characterized with bilateral, symmetrical subcortical changes, often seen predominantly in the occipital and parietal areas (see Fig. 14.12.2). The imaging characteristics of this condition are of vasogenic oedema, although in a few patients areas of cytotoxic oedema have been identified, suggestive of irreversible ischaemic damage. It classically presents with a severe, often thunderclap, headache. Other clinical features include seizures, cortical blindness, fixed neurological deficits, and alteration in level of consciousness with eventual stupor. Urgent identification of these patients is paramount. Management entails adequate control of seizures (primarily with IV magnesium sulphate in patients with eclampsia), control of blood pressure and, on occasions, urgent delivery of the fetus is required. Reversible cerebral vasoconstriction syndrome

Ischaemic strokes The estimated incidence of stroke in pregnancy is 4–​7 cases per 100 000. The three common aetiologies accounting for most cases

This condition, like posterior reversible vasoconstriction syndrome, is recognized as a self-​limiting condition, occurring within the first week after delivery, often following an uncomplicated pregnancy and delivery. This condition characteristically presents with

Table 14.12.1  Use in pregnancy of disease-​modifying drugs for multiple sclerosis (MS) Disease-​modifying drugs (DMDs)

FDA pregnancy category

Advice in pregnancy

β-​interferon

C—​animal studies have shown adverse fetal effects; there are no adequate studies in humans; benefits of treatment may outweigh risks

• Large molecule, does not cross placenta • Emerging data suggest, it is safe to continue until at least

B—​animal studies have not shown adverse fetal effects; there are no adequate studies in pregnant women

• Large molecule, does not cross placenta • Emerging data suggest, it is safe to continue until at least

C—​animal studies have shown adverse fetal effects; there are no adequate studies in humans; benefits of treatment may outweigh risks

• Large molecule which crosses placenta via active transport

Glatiramer acetate

Natalizumab

conception and that the benefits of breastfeeding outweigh any associated risks.

conception and that the benefits of breastfeeding outweigh any associated risks. after first trimester

• During pre-conception counseling, the MS team should

discuss the pros and cons of stopping vs continuing on this treatment during pregnancy. Evidence shows that women who stop Nataizumab can experience a rebound of their MS (severe relapse) during pregnancy.

14.12  Neurological conditions in pregnancy

Table 14.12.2  Use in pregnancy and when breast feeding of drugs for myasthenia Drug

Pregnancy

Breastfeeding

Pyridostigmine

• Very little crosses the placenta, no reports of fetal harm

•​ 7.5 mg/​day, the consensus is to give a stress dose of hydrocortisone 100 mg TDS intravenously in labour • Care with anaesthetic agents which can precipitate myasthenia gravis Baby

• Transient neonatal myasthenia gravis is a well-​

• • •

•

recognized consequence of maternal myasthenia gravis and is independent of the severity of maternal myasthenia gravis Presents within the first week of life Occurs due to transplacental transfer of anticholinesterase receptor (AChR) antibodies Presents with hypotonia, poor sucking, or even respiratory muscle weakness. Treatment is usually supportive, but some may need pyridostigmine or even intravenous immunoglobulin Its presentation does not correlate with the onset of myasthenia gravis later in life

Fig. 14.12.2  Magnetic resonance imaging (MRI) of the brain showing symmetrical bilateral hyperintense lesions in the posterior cerebral hemispheres, typically seen in posterior reversible vasoconstriction syndrome.

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(a)

(b)

Fig. 14.12.3  MRI brain and magnetic resonance angiogram (MRA) showing changes compatible with reversible cerebral vasoconstriction syndrome. Top row (left to right) shows MRI brain scan (coronal section) with hyperintensity in the sulci of the frontal lobes compatible with subarachnoid haemorrhage (solid arrow) and MRA reveals multifocal beading of the cerebral arteries (dashed arrows). The bottom row shows resolution of both these changes.

Cerebral venous thrombosis Cerebral venous thrombosis accounts for approximately 20% of all strokes occurring in pregnancy and puerperium. It commonly presents with headaches (can be thunderclap), focal neurological deficit, low Glasgow Coma Scale, and seizures. Cerebral venous thrombosis can be diagnosed with an unenhanced CT (see Fig. 14.12.4), but MRI with magnetic resonance venography is the modality of choice during pregnancy as it can provide a detailed view of the cerebral venous system without any X-​ray exposure and does not require administration of contrast. The treatment of cerebral venous thrombosis involves anticoagulation, even if there is evidence of haemorrhage on the scan. Anticoagulation should be continued for a minimum of six months. Vascular malformations There are conflicting opinions as to whether pregnancy or delivery increases the risk of cerebral aneurysm or arteriovenous malformation rupture. This is primarily due to paucity of evidence. Cerebral aneurysm In patients diagnosed with a ruptured aneurysm during pregnancy, acute treatment should be offered during pregnancy as this

Fig. 14.12.4  (a) Unenhanced CT head scan showing a hyperdensity in the superior sagittal sinus, suggestive of a thrombosis (solid arrow) with fragmented parenchymal haemorrhage seen in the left posterior temporal lobe (dashed line). (b) CT venogram showing a filling defect in the superior sagittal sinus, known as the ‘empty delta sign’ (arrow).

leads to better outcomes. In pregnant patients with an unruptured aneurysm, the evidence suggests that there is not an increased risk of rupture during pregnancy or delivery. Recommendations regarding delivery are difficult and decisions should be made on an individual patient basis. A caesarean section is not mandatory in patients with unruptured aneurysm. In our clinical practice, we would routinely avoid a prolonged second stage of labour in this group of patients and recommend assisted delivery, should the need arise. Similarly, pregnant women with treated cerebral aneurysms should be encouraged to deliver vaginally without any specific considerations.

14.12  Neurological conditions in pregnancy

Table 14.12.4  Common peripheral nerve disorders associated with pregnancy Neuropathy

Clinical presentation

Treatment

Bell’s palsy (facial nerve)

Asymmetrical facial droop (lower motor neurone)

Short course prednisolone treatment, eye protection, and artificial tears

Carpal tunnel syndrome (median nerve)

Paraesthesia and pain in lateral side of hand and wrist, especially at night

Overnight wrist splints. Some require local steroid injections or even decompression

Meralgia parasthetica (lateral cutaneous nerve of the thigh)

Numbness and pain over anterior, lateral aspect of the thigh. Improves with sitting and lying down

Usually improves spontaneously but treatment options can include lidocaine patch or capsaicin cream

Femoral neuropathy

Weakness of the quadriceps (i.e. knee extension) and sensory loss anterior thigh and medial calf. Common mechanism of injury is excessive flexion of hip in lithotomy position

Conservative management with physiotherapy and analgesia Recovery usually within three to four months

Common peroneal nerve

Foot drop, foot eversion weakness compared with inversion and sensory loss over the dorsum of foot and lateral aspect of shin. Can be precipitated by prolonged squatting or stirrups

See treatment of femoral neuropathy

Obturator nerve

Weakness of hip adduction and sensory loss medial aspect of thigh. Usually precipitated during assisted delivery

See treatment of femoral neuropathy

Arteriovenous malformations Intracranial arteriovenous malformations are relatively uncommon but a recognized cause of catastrophic intracerebral haemorrhages. The evidence suggests that the risk of rupture in pregnancy is not increased. Furthermore, there are identified predictors of haemorrhage, such as age, location, and deep venous drainage, and these can be useful for evaluating risk. Treatment of unruptured arteriovenous malformations should largely be restricted to outside of pregnancy. Treatment options include endovascular embolization, surgery, or stereotactic radiotherapy. In terms of the issues surrounding labour, these are similar to those mentioned in the management of cerebral aneurysms, and decisions should be made on an individual patient basis.

Peripheral nerve disorders The most frequent examples of peripheral nerve disorders encountered during pregnancy, labour, and the post-​partum period are listed in Table 14.12.4.

FURTHER READING Bove R, et al. (2014). Management of multiple sclerosis during pregnancy and the reproductive years. Obstet Gynecol, 124, 1157–​68. Bove RM, Kleim JP (2014). Neuroradiology in women of childbearing age. Continuum, 20, 23–​41. Knight M, et al. on behalf of MBRRACE-UK (2017). Saving lives, improving mothers’ care - lessons learned to inform maternity care from the UK and Ireland confidential enquiries into maternal deaths and morbidity 2013–15. National Perinatal Epidemiology Unit, University of Oxford, Oxford. Harden CL (2014). Pregnancy and epilepsy. Continuum, 20, 60–​79. Macgregor EA (2014). Headaches in pregnancy. Continuum, 20, 128–​47. Marsh MS, Nashef LAM, Brex PA (2012). Neurology and pregnancy. Informa Healthcare, London. Norwood F, et al. (2014). Myasthenia in pregnancy: best practice guidelines from a UK multispecialty working group. J Neurol Neurosurg Psychiatry, 85, 538–​43. Powrie RO, Greene MF, Camman W (2010). De Swiet’s medical disorders in obstetric practice. Blackwell Publishing, Chichester. Wiles KS, et al. (2015). Reversible cerebral vasoconstriction syndrome: a rare cause of postpartum headaches. Pract Neurol, 15, 141–​4.

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The skin in pregnancy Gudula Kirtschig and Fenella Wojnarowska

ESSENTIALS Dermatoses in pregnancy are common, they may be very itchy and may impact the life of a pregnant woman dramatically. There are four classical dermatoses of pregnancy. It is particularly important to recognize these as they may have serious health implications for mother and child. Intrahepatic cholestasis of pregnancy—​occurs in 1/​40 to 1/​500 pregnancies and is the most serious cause of itch in pregnancy, with potentially substantial effects on mother and fetus. Treatment is with ursodeoxycholic acid. Atopic eruption of pregnancy—​affects 1/​300 pregnancies, typically with an eczematous eruption over abdomen and limbs. Treatment is with topical steroids. Polymorphic eruption of pregnancy—​a ffects about 1/​240 pregnancies, usually beginning with red papules and plaques on the abdomen and thighs before spreading more widely. Treatment is with reassurance and emollients, with topical steroids if neccessary. Pemphigoid gestationis—​ occurs in 1/​ 50 000 pregnancies and is due to circulating antibodies against the skin basement membrane zone. The eruption often begins around the umbilicus and spreads to the whole trunk, limbs, hands, and feet. If potent topical steroids fail systemic steroids are required. Transplacental transmission to the fetus may occur. Recurrence in future pregnancies is to be expected.

Common skin changes in pregnancy Vascular changes and lesions There is increased skin blood flow during pregnancy, possibly resulting in oedema (e.g. manifest as tightening of rings and shoes), erythema, and itch. Spider naevi and palmar erythema are common, and there maybe erythema of the gums (with gingivitis) and the vulvovaginal area. Unilateral telangiectasia may appear for the first time, as may haemangiomas. Varicose veins may develop during pregnancy. Swollen skin around the ankles may be a first sign, worsening during the day and improving over night when lying down. Supportive stockings or flight socks should be worn: special pregnancy types are available. If there is a family or personal history of the development of varicose veins or thrombophlebitis/​phlebothombosis, further risk assessment for venous thromboembolism is required. Pyogenic granuloma, a benign tumour with a tendency to ulcerate and bleed, may develop on the skin or oral cavity, where they are known as pregnancy tumours (Fig. 14.13.1). They are

Introduction The skin undergoes profound alterations during pregnancy as a result of endocrine, metabolic, and physiological changes. Some of these are trivial and chiefly cosmetic, producing no or minor symptoms; some will improve during or after pregnancy and others can be distressing and/​or of major medical importance. Pregnancy will profoundly modify expression of pre-​ existing skin disease, and there are dermatoses that are specific Fig. 14.13.1  Pyogenic granuloma on the finger. to pregnancy. Courtesy of Dr Jonathan Bowling, Oxford Radcliffe Hospital NHS Trust, UK.

14.13  The skin in pregnancy

shedding after parturition gives rise to the distressing post-​partum telogen effluvium three months after delivery. This is completed 6–​12 months later and treatment is not needed. Hirsutism may begin or worsen in pregnancy, driven by an increase in androgens and usually resolving a few months after delivery.

Pilosebaceous changes/​acne The development of acne during pregnancy is unpredictable. Skin in pregnancy is often more greasy, termed ‘pregnancy glow’. The increase in oestrogens usually improves acne, but there may be worsening of acne in some unfortunate patients. Acne treatment in pregnancy may be tricky as topical and oral vitamin A derivatives must be avoided because they are teratogenic. Topical treatment with benzoyl peroxide and clindamycin for limited areas (most commonly the face) are the treatments of choice in pregnancy.

Striae gravidarum

Fig. 14.13.2 Melasma. Courtesy of Dr Christina Ambros-​Rudolph, University of Graz, Austria.

sometimes confused with melanoma and often recur after local destruction.

Striae gravidarum (stretch marks) are common in pregnancy, affecting about 50% of women. They are more frequently seen in young women, in women with a raised body mass index, and those who have large babies. They are familial in about 50% of cases and are more likely if a woman has had them previously. The breasts and sides and lower areas of the abdomen are the typical sites, but thighs and arms can be affected. They start as linear depressed purple lines and fade to pale, atrophic, scar-​like lesions. They may be itchy. There is an association with subsequent tendency to prolapse. There is no good treatment. Olive oil massage, castor oil, cocoa butter, glycolic or fruit acids, homeopathic creams and/​or oils are used, but the benefit of these is not proven.

Pruritus

Pigmentary changes and pigmented lesions

Itching occurs in about 20% of pregnancies, frequently in associIncreased skin pigmentation is common, particularly in dark-​ ation with an inflammatory dermatosis such as atopic eczema, polyskinned women, up to 90% of whom may be affected. There is morphic eruption of pregnancy, allergic reactions, or infectious darkening of the nipples, genitalia, and linea alba. In some women diseases. The underlying dermatosis must be treated. Oral antihistarecent scars will darken. The unsightly and sometimes psychologic- mines such as loratadine are safe to be used in pregnancy and can be ally distressing facial pigmentation of melasma (chloasma, formerly used for symptomatic relief (see Table 14.13.1). Pruritus may occur known as the ‘mask of pregnancy’) affects many women. It gets without physical signs, other than scratch marks. The most serious worse with sunlight and can be reduced by using high protection cause is intrahepatic cholostasis of pregnancy, which is diagnosed in factor (SPF 50) UVB and UVA sunscreens (Fig. 14.13.2). Melasma about 3% of itchy pregnant women (see below and Chapter 14.9). If often disappears spontaneously after delivery, but treatment with no underlying dermatosis exists emollients and antihistamines may topical vitamin A  derivatives and hydrochinon may be indicated be useful. after pregnancy in some women. Urticaria Pigmented naevi can increase in size, in particular around the abdomen due to the increased body circumference, and pigmenta- Urticaria (hives) and dermographism (wealing in response to prestion during pregnancy. Any asymmetrical change is suspicious of sure, e.g. scratching) may be precipitated by pregnancy and are very malignant change. Melanoma may occur and is not associated with itchy conditions. Urticaria has been attributed by some authors to a poorer prognosis in pregnant women. Any rapidly changing, ir- physiological changes in vascular reactivity. Physical factors such as regularly shaped, or irregularly pigmented lesion larger than 6 mm in diameter should be excised under local anaesthesia to exclude a dysplastic naevus or melanoma. Risk factors for developing a mel- Table 14.13.1  Antihistamines safe to be used in pregnancy anoma are fair skin, high density of freckles, red hair, more than 50 Group Generic name moles, the presence of more than five atypical moles (irregular shape Sedating Chlopheniramine, chlorphenamine and colour), a history of severe sunburns during childhood, espeuseful at night if pruritus prevents cially with blistering, and a family history of melanoma. Clemastine sleep

Dimetinden

Hair changes There is diminished shedding of hair due to prolongation of the anagen phase. This is perceived as thickening of the hair. The synchronized

Non​sedating treatment of choice

Cetirizine Loratadine

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Section 14  Medical disorders in pregnancy

pressure and heat may evoke it. Particular drugs or foods may be the cause in some patients and must be avoided in such cases. Treatment with a non​sedating antihistamine such as loratidine, cetirizine or sedating chlopheniramine is safe.

Cutaneous infections Candida of the vulva as well as the vagina is common and occurs in about 15% of pregnant women, causing itching, burning, and discharge. During pregnancy, treatment with miconazole or clotrimoxazole cream or vaginal pessaries is preferred and may need to be repeated several times or preventative treatment may be necessary. Oral antiyeast treatments must not be used for vulvo-​vaginal yeast infection during pregnancy. Dermatophyte infections (tinea/​ ringworm) are common and may affect pregnant women. They typically manifest interdigitally (athlete’s foot) or in the groin, but can affect any body site including the nails. In uncomplicated cases tinea is usually treated with topical antifungals; in pregnancy, clotrimazole and miconazole are preferred. Oral antifungals must be avoided in pregnancy and treatment for onychomycosis postponed until after delivery. Cutaneous and genital warts thrive in pregnancy, often commencing, proliferating, or enlarging. Treatment for genital warts should be started as soon as possible. However, in the last eight weeks of pregnancy methods that destroy the warts and harm the skin over large areas should be avoided so there is no damage to the skin before delivery. The choice of the therapy is dependent on the type, the extent, and the location of the warts. Localized lesions can be treated with freezing (cryotherapy), electro surgery or with trichloracetic acid (TCA, 33–​50%), which is a liquid that ‘burns’ or ‘peels’ the warts away and can be applied to the lesions with a cotton tip by a physician once every one to three weeks. Imiquimod has been used in pregnancy without observed adverse effects, but it is not licensed for use in pregnancy. Podophyllin or 5-​Fluorouracil must not be used in pregnancy. Genital herpes simplex infections during pregnancy can affect the unborn child. The baby can catch the virus by transmission from the mother via the placenta or during delivery. If the baby is infected before delivery it is at risk of abnormalities, mainly of the brain and the eyes, but herpes virus transmission predominantly occurs during delivery and not during pregnancy. The risk for infection depends mainly on the severity and timing of the mother’s infection (highest if the mother is very ill with herpes, or the baby is premature). If the baby is infected by the virus during delivery or as a newborn the infection may be restricted to the skin, mucosa, and/​or the eyes (45%), the infection may involve the brain (30%), or the infection may be wide spread involving many organs including lungs, liver, and the brain (25%). The risk of transmission from the mother to the baby at delivery is highest (30–​50%) among women who acquire genital herpes (primary herpes infection) near the time of delivery (within six weeks). In a primary infection during the first or the second trimester of pregnancy aciclovir or valaciclovir may be used, depending on the severity of the disease. Antiviral treatment may be used for four weeks before delivery to prevent recurrences and viral shedding around delivery; a caesarean section is usually not indicated. Primary herpes infection during the third trimester must be treated with aciclovir or valaciclovir. A caesarean section

in pregnant women developing a primary infection in the six weeks preceding delivery and in women with recurrent disease if they have lesions at the time of delivery is controversially discussed, but there is no certain reduction of the infectious risk for the baby. Lice may be seen as head lice or pubic/​crab lice. A very safe and effective treatment for head lice is combing with dimeticon or, alternatively, coconut oil or vinegar water. For easier combing, conditioner (possibly containing tea tree oil) may be used. Malathion (lice resistance is reported) or pyrethrum extract and synthetic pyrethroids (permethrin topical 5% cream/​scalp treatment) are the treatment of second choice. Pump sprays should be avoided because of the danger of systemic intake through the air. Pubic lice may be treated with malathion or permethrin 5% cream applied to the affected site. Scabies is a common and very itchy skin condition caused by human scabies mites. It can affect people of any age but is most common in the young. Itching is the main symptom, usually starting about a month after the mites were picked up. The itching affects the body and limbs but usually spares the head and neck, except in infants. The rash of scabies is a mixture of scratch marks and red scaly areas; later it can become superinfected. This itchy rash covers much of the skin, but the mites themselves show up mainly where they burrow, typically on the sides of the fingers and hands, and around the wrists, ankles, feet, breasts, and genitals. Usually several members of a family are affected and need to be treated. Permethrin seems more effective than other treatments, but there are no studies that prove absolute safety in pregnancy. Permethrin 5% cream is applied all over the body, except the head, and washed off after about 12 hours; re-​treatment of hands if washed with soap in between is recommended. Taking a bath or shower before treatment is not recommended. The treatment should be repeated after seven days. Benzyl benzoate, malathion, and crotamiton seem less effective but are considered safe. Oral Ivermectin (200 microgr/kg body weight in one dose) is not recommended during pregnancy, however, harm to the baby after accidental use is not reported.

The pregnancy dermatoses Historical perspective The striking blistering eruption known as ‘pemphigoid gestationis’ was described in 1867 by Wilson and named by Milton in 1872 as ‘herpes gestationis’. During the 1980s it was characterized as an autoimmune blistering disease by Black, Charles-​Holmes, and Shornick, and renamed as ‘pemphigoid gestationis’ to emphasize the close relationship to the commoner autoimmune blistering disease bullous pemphigoid and to prevent confusion with viral herpes disease. Further skin diseases that arise in pregnancy have been confusing in their nomenclature and clinical descriptions, but recently Ambros-​ Rudolph and colleagues proposed a new and much simpler classification (Table 14.13.2).

Intrahepatic cholestatis of pregnancy It is particularly important to recognize itch/​ pruritus due to intrahepatic cholestasis of pregnancy (obstetric cholestasis, cholestasis of pregnancy, and pruritus/​prurigo gravidarum), which has important implications for the health of both mother and fetus (see Chapter 14.9). It is the most serious cause of itch in pregnancy.

14.13  The skin in pregnancy

Table 14.13.2  Four major pregnancy dermatoses (numbers are based on 505 pregnant patients with skin problems; Ambros-​Rudolph et al. 2006)

a

Pregnancy dermatosis

Frequency (%)

Effect on fetus

Effect on mother

Intrahepatic cholestatis of pregnancy

 3

Can be substantial (see Chapter 14.9)

Can be substantial (see Chapter 14.9)

Atopic eruption of pregnancy

50

None described

Usually improves after delivery

Polymorphic eruption of pregnancy

22

None described

Pemphigoid gestationis

 4a

Small for dates

May be major, usually resolves months after delivery

Raised frequency as tertiary referral centre.

In Europe about 0.2–​2.4% of pregnant women will get the condition; in Scandinavia and South America intrahepatic cholestatis of pregnancy is more common and it may also occur in women on the oral contraceptive pill. The itching begins typically in the third trimester and affects the abdomen, palms, and soles. The longer the itch persists, the more skin changes due to scratching may be present. Excoriations and prurigo nodules typically involve the shins, arms, and buttocks. Apart from these changes, there is usually no rash associated with intrahepatic cholestatis of pregnancy. Loss of sleep, loss of appetite, and an inability to perform normal daily tasks can be a result of the intense itching. Less common symptoms include dark urine and/​or pale stools, jaundice, abdominal pain, and nausea. Liver function tests may be normal, but bile salts are typically raised. Other causes for itchy skin such as hepatitis, iron deficiency, specific dermatoses of pregnancy, or infectious causes should be excluded. The condition resolves post-​partum but will recur in subsequent pregnancies. Reducing the bile acids is essential. Ursodeoxycholic acid (UDCA—​a naturally occurring bile acid) is currently the best treatment for intrahepatic cholestatis of pregnancy. It is not licensed for use in pregnancy but may be prescribed on an individual basis. It improves liver function and helps to reduce the toxic bile acid concentration, and it is the only treatment that has been shown to reduce fetal risks in intrahepatic cholestatis of pregnancy. UDCA tablets, 15 mg/​kg/​day or simply 1 g daily, are given either as a single dose or divided into two to three doses and continued until delivery, when treatment can usually be stopped. Symptomatic management is with emollients and sometimes antihistamines.

Atopic eruption of pregnancy

Fig. 14.13.3  Atopic eruption of pregnancy in a 24-​year-​old gravida 2 at 19 weeks’ gestation: small red pruritic papules and eczematous features on the trunk (and limbs).

This condition includes entities formerly known as prurigo of pregnancy and pruritic folliculitis. It may affect 1 in 300 pregnancies. It occurs in women with an atopic background (personal or family history), of whom about 20% have had previous eczema. The immunological changes of pregnancy and the tendency to pruritus may both contribute to the worsening of atopic eczema or its first occurrence with pregnancy. Atopic eruption of pregnancy thus affects women who already have atopic eczema but experience a flare-​up of the disease, and women with their first occurrence of eczema during pregnancy (80%). It can be severe and life-​ruining, and life-​threatening if secondary infection with herpes simplex (eczema herpeticum) or streptococci occurs. Atopic eruption of pregnancy commences early, in three-​quarters of women before the beginning of the third trimester. There is intense pruritus, it typically presents with an eczematous eruption over abdomen and limbs (Fig. 14.13.3). The lesions can be chiefly eczematous with red, dry, and scaly skin, with areas of excoriation and thickening or lichenification. Pre-​existing atopic eczema

often deteriorates becoming more widespread and may result in erythroderma in the most severe cases. Another presentation is with excoriated papules and nodules (prurigo of pregnancy). The least common form is follicular pruritic papules and pustules (pruritic folliculitis), which may present in the third trimester and in a small series was associated with male infants and low birth weight. Secondary infection with Staphylococcus aureus and streptococci is a frequent complication. Histopathology is usually non​specific, but may show a perivascular infiltrate with thickened epidermis. Direct and indirect immunofluorescence are negative. Treatment is with moderate to potent topical steroids that although absorbed do not adversely affect the fetus. The use of emollients may lessen the requirements for topical steroids, and steroids should be used in the minimum quantities and strengths necessary to control the disease (see Table 14.13.3). Many topical

Courtesy of Dr Christina Ambros-​Rudolph, University of Graz, Austria.

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Table 14.13.3  Examples of topical steroids. Prolonged treatment with very potent topical steroids may lead to fetal growth restriction; see guidelines for the use of topical steroids in pregnancy Group

Generic name

Mild

Hydrocortisone 1%

Moderately potent

Hydrocortisone 1% with urea Clobetasone butyrate 0.05% Flurandrolone

Potent

Betamethasone valerate 0.025%/​0.1% Betamethasone dipropionate Hydrocortisone 17-​butyrate Fluticasone propionate Mometasone furoate

Very potent

Clobetasol propionate 0.05%

steroids contain antiseptics and antibiotics that will be absorbed, and some may be contraindicated in pregnancy. The sedating antihistamine chlorpheniramine may help with sleep. Secondary infection often requires systemic antibiotics such as oral penicillins or erythromycin. The condition resolves in days to weeks after delivery. It may recur in one-​third of pregnancies.

Polymorphic eruption of pregnancy Polymorphic eruption of pregnancy was formerly known as ‘pruritic urticated papules and plaques of pregnancy’ or ‘toxic erythema of pregnancy’. Its aetiology is unknown, but there is an association with a low serum cortisol. It affects 1 in 240 singleton pregnancies, being most common in first pregnancies, with multiple births (hence following in vitro fertilization)—​perhaps related to the mechanical effect of the abdominal stretching or to an increased immune complex load—​and with a male fetus. This condition usually begins in the third trimester and occasionally post-​partum. Red papules and plaques typically begin in striae on the abdomen and thighs and then spread to the whole trunk and limbs, including the hands and feet. They are very itchy, and the itching can be so severe as to prevent sleep. Initially the lesions are raised red papules (Fig. 14.13.4) and plaques; with time they become more diverse in morphology, occasionally polycyclic or blistering. The histopathology shows oedema, perivascular lymphocytes, and eosinophils. Immunofluorescence does not demonstrate any circulating or bound immunoreactants. Treatment is with reassurance and emollients (e.g. cold cream containing 1–​2% menthol). This is helpful, but not always sufficient. Antihistamines and moderate to very potent topical steroids, which may be absorbed through the skin (see Table 14.13.3), may be required, and occasionally systemic steroids for induction of remission. The condition resolves over days to weeks after delivery. It does not usually recur. The outcome of the pregnancy is not adversely affected.

Pemphigoid gestationis Pemphigoid gestationis, formerly herpes gestationis (a name best abandoned as ‘herpes’ refers to the herpetiform grouping of the blisters rather than herpes infection), is an autoimmune blistering disease

Fig. 14.13.4  Polymorphic eruption of pregnancy: urticated papules and plaques on the thigh.

characteristically occurring in pregnancy. Pemphigoid gestationis is the most severe of the pregnancy dermatoses. It is due to circulating antibodies against adhesion molecules of the skin basement membrane zone. Very potent topical or systemic steroids are usually required. Transplacental transmission to the fetus may occur. Recurrence in future pregnancies is to be expected. The aetiology is only partially understood. The pathogenicity of the circulating basement membrane zone antibodies is demonstrated by transplacental transmission of the disease. The major target antigen is BP180/​collagen XVII (chief epitope being the transmembrane NC16A domain); BP230 is a less common antigen. Both antigens are present in skin, mucosa, and amnion, associated with the hemidesmosome and adhesion complex linking epithelium to dermis/​mesenchyme, which are targets in other autoimmune blistering diseases. The placenta shows increased expression of antigen-​ presenting cells, but it is unclear why breakdown of tolerance occurs, and why normal components of amnion and stratified squamous epithelium become antigenic. The mothers have the HLA DR 3, 4, haplotype and are C4 null, and there is an association with thyroid and less commonly other autoimmune disease. Pemphigoid gestationis occurs in approximately 1 of 50 000 pregnancies. It commences from the second trimester onwards and quite often in the first week post-​partum (range from five weeks of gestation to four weeks post-​partum). It usually occurs in the first and subsequent pregnancies, although 8% of pregnancies are skipped. The eruption typically begins around the umbilicus and spreads to the whole trunk, limbs, hands, and feet, including the palms and soles, and rarely the face. The mouth and vulva may be involved showing blisters or erosions. Vesicles and blisters are characteristic, but lesions comprise annular lesions, papules, and plaques (Fig. 14.13.5). Pruritus is severe and sleep often impaired.

14.13  The skin in pregnancy

Fig. 14.13.5  Pemphigoid gestationis: urticated papules and blisters. From Charles-​Holmes R, Black MM (1990). Herpes gestationis. In: Wojnarowska F, Briggaman RA (eds) Management of blistering disease, pp. 93–​104. Chapman & Hall, London, with permission.

Transplacental transmission of antibodies to the fetus occurs in about 3% of affected pregnancies, the neonate developing transient self-​limiting blistering (Fig. 14.13.6). Histopathology demonstrates an eosinophilic infiltrate, papillary oedema, and subepidermal blisters. Direct immunofluorescence demonstrates that C3 component of complement and IgG1 are bound at the basement membrane zone of the dermoepidermal junction. The patient’s serum has circulating IgG1 basement membrane zone antibodies that bind C3. These immunoreactants are also found at the basement membrane zone of the amnion (Fig. 14.13.7). Treatment with potent or very potent topical steroids and chlorpheniramine is recommended, however, systemic steroids (e.g. prednisolone 0.3–0.5 mg/kg body weight daily) may be required, the dose adjusted according to disease activity. There is usually a post-​ partum flare, necessitating increased steroids. Azathioprine and Ciclosporin may reduce steroid requirement in selected cases. The disease slowly resolves post-​partum, but may persist for several months. Recurrence in subsequent pregnancies is usual, only about 8% being spared. The classical teaching is that it recurs earlier and is more severe in subsequent pregnancies, but this has not always been our experience. Onset of pemphigoid gestationis in the first or second trimester and presence of blisters may lead to adverse pregnancy outcomes, including decreased gestational age at delivery,

Fig. 14.13.7  Pemphigoid gestationis: linear deposition of C3 at the amnion basement membrane zone as demonstrated by immunofluorescence. The nuclei are counterstained with propidium iodide. Courtesy of B.S. Bhogal and M.M. Black, St John’s Institute of Dermatology, St Thomas’s Hospital, London.

preterm birth, and children with low birth weight. Such pregnancies should be considered high risk and appropriate obstetric care should be provided. Systemic corticosteroid treatment, in contrast, does not substantially affect pregnancy outcomes, and its use for pemphigoid gestationis in pregnant women is justified.

Classical dermatoses affecting pregnant women Psoriasis Psoriasis improves in most women during pregnancy, but can deteriorate. Therapy poses special problems as most systemic treatments are contraindicated. Methotrexate is a folic acid antagonist and can cause miscarriage; acitretin is teratogenic; fumaric acid causes leukopenia (whether this affects the fetus is unknown, but case reports have shown no harm). Oral psoralens with UVA (PUVA) are still not proven to be safe, but topical PUVA and UVB light treatment is safe. Ciclosporin and tumour necrosis factor (TNF) α inhibitors are reserved for severe cases. Topical therapy with steroids can be used if needed. Coal tars and dithranol have been widely used in pregnancy but are not proven to be safe. The new vitamin D analogues are not licensed for use in pregnancy, but there is no hint from case reports that indicate harm if used in usual doses. The ideal is minimum treatment, encouraging emollient use and if necessary UVB. A severe form of pustular psoriasis, impetigo herpetiformis, may occur in pregnancy and is best managed with bed rest, emollients, and moderate potent topical steroids or low doses of oral prednisolone. In severe cases topical PUVA or oral Ciclosporin are used, and induction of labour may be indicated if the mother is at risk.

Cutaneous lupus erythematosus Fig. 14.13.6  Pemphigoid gestationis: urticated papules in the neonate. From Charles-​Holmes R, Black MM (1990). Herpes gestationis. In: Wojnarowska F, Briggaman RA (eds) Management of blistering disease, pp. 93–​104. Chapman & Hall, London, with permission.

Cutaneous lupus erythematosus may be adversely affected or improved or unchanged by pregnancy. However, such patients should be screened for anti-​Ro and anticardiolipin antibodies, preferably prior to conception, to identify at-​risk pregnancies (see Chapter  14.14).

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Autoimmune bullous diseases Linear IgA disease, an autoimmune blistering disease with linear IgA basement membrane zone antibodies, usually improves with pregnancy, such that some patients can discontinue their therapy, usually dapsone. Despite the deposition of immunoreactants in the amnion basement membrane zone, the fetus is not adversely affected. There is usually an exacerbation three months post-​partum. Pemphigus vulgaris is an autoimmune blistering disease with widespread mucosal and/​or cutaneous erosions caused by IgG antibodies to desmosomal components of the epithelium. The desmosomal antibodies are directed at desmoglein 3, a major adhesion molecule in mucosa and neonatal skin, and can be transmitted across the placenta, causing severe neonatal pemphigus with devastating results to the fetus. This does not occur in the related pemphigus foliaceus, which is endemic in Brazil, characterized by superficial cutaneous erosions and mediated by desmoglein 1 antibodies that do not cause oral lesions or affect neonatal skin. Both forms of pemphigus may worsen in pregnancy and treatment may require systemic steroids and immunosuppressants like azathioprine. Spontaneous remission after pregnancy is described.

Vulval dermatoses Many dermatoses may affect the vulval skin, and this may be particularly distressing in pregnancy as concerns regarding delivery may arise. A disease commonly seen at the vulva is lichen sclerosus, a chronic inflammatory condition of unknown cause. This is usually treated with very potent topical steroids. Their use should be limited during pregnancy to a minimum, but the disease may improve during pregnancy and does not inhibit vaginal delivery, although episiotomy may be required and should be anticipated.

FURTHER READING Ambros-​Rudolph CM, et al. (2006). The specific dermatoses of pregnancy revisited and reclassified:  results of a retrospective two-​ center study on 505 pregnant patients. J Am Acad Dermatol, 54, 395–​404. Chi CC, et al. (2009). Pemphigoid gestationis: early onset and blister formation are associated with adverse pregnancy outcomes. Br J Dermatol, 160, 1222–​8. Chi CC, et al. (2015). Safety of topical corticosteroids in pregnancy. Cochrane Database Syst Rev. Oct 26;(10):CD007346. doi:10.1002/14651858.CD007346.pub3. Review. European Academy of Dermatology and Venereology. Patient Information Leaflets. http://​www.eadv.org/​patient-​corner/​leaflets/​ Jenkins RE, Hern S, Black MM (1999). Clinical features and management of 87 patients with pemphigoid gestationis. Clin Exp Dermatol, 24, 255–​9. Kirtschig G, Cooper S (2016). Gynaecologic dermatology: symptoms, signs and clinical management. Jaypee Brothers, New Delhi. Kirtschig G, Schäfer C (2015). Dermatological medications and local therapeutics. In: Schaefer C, Peters P, Miller RK (eds) Drugs during pregnancy and lactation, 3rd edition. Elsevier, London, pp. 467–​510. Muller S, Stanley JR (1990). Pemphigus: pemphigus vulgaris and pemphigus foliaceus. In: Wojnarowska F, Briggaman RA (eds) Management of blistering disease, Chapman & Hall, London, pp. 43–​62. Vaughan Jones S, Ambros-​Rudolph C, Nelson-​Piercy C (2014). Skin disease in pregnancy. BMJ, 348, g3489. Vaughan Jones SA, et al. (1999). A prospective study of 200 women with dermatoses of pregnancy correlating clinical findings with hormonal and immunopathological profiles. Br J Dermatol, 141, 71–​81. Zhang Y, et al. (2016). Ursodeoxycholic acid and S-adenosylmethionine for the treatment of intrahepatic cholestasis of pregnancy: a meta-analysis. Hepatitis Monthly, 16(8), e38558. doi:10.5812/hepatmon.38558.

14.14

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

ESSENTIALS Autoimmune diseases affect 5–​7% of people, are more common in women of childbearing age, and are frequently encountered in pregnancy. They may remit or improve during pregnancy, but can flare or present in pregnancy or post partum.

Systemic lupus erythematosus The mother—​ pregnancy probably exacerbates systemic lupus erythematosus and increases the likelihood of a flare, which can be difficult to diagnose since many clinical features also occur in normal pregnancy. Differentiation of active renal lupus from pre-​eclampsia is notoriously difficult:  renal flares are more common if disease is active within six months of conception, in particular in women with hypertension, heavy proteinuria, or high baseline serum creatinine. There is an increased risk of maternal thrombosis and premature atherosclerosis. The fetus—​systemic lupus erythematosus is associated with increased risks of adverse pregnancy outcome including fetal death and intrauterine growth restriction. Most fetal losses occur in association with secondary antiphospholipid syndrome or active disease, particularly renal. For women with systemic lupus erythematosus in remission and without hypertension, renal involvement, or the antiphospholipid syndrome, the risk of problems in pregnancy is similar to that of the general population. Management—​flares of systemic lupus erythematosus must be actively managed, pre-​pregnancy counselling should be encouraged with treatment depending on both organ involvement and severity. Mild cases can be managed with analgesics alone (paracetamol); rash and arthritis will usually respond to non​steroidal anti-​inflammatory drugs, low-​dose prednisolone and/​or hydroxycholorquine; more severe disease may require introduction of a disease-​modifying agent (e.g. azathioprine or higher steroid dose). Steroids remain first-​line treatment for severe lupus flares in pregnancy (and treatment of other autoimmune conditions). The baby—​neonatal lupus syndromes are caused by transplacental passage of autoantibodies directed against cytoplasmic ribonucleoproteins Ro and La. Cutaneous neonatal lupus is the most common manifestation (5%) and congenital heart block the most serious (20% mortality).

Antiphospholipid syndrome Clinical features—​antiphospholipid antibodies include anticardiolipin antibodies (IgG and/​ or IgM), lupus anticoagulant, and anti-​ β2-​ glycoprotein-​ I antibody. Antiphospholipid syndrome is the combination of any of these with one or both of the following clinical features:  (1) thrombosis—​arterial, venous, or small vessel; (2) specific pregnancy morbidity. Women with isolated but persistent antiphospholipid antibodies without clinical features of antiphospholipid syndrome have obstetric outcomes similar to the general population. Management—​aim is to improve pregnancy outcome and prevent maternal thrombosis. This requires low-​dose aspirin from early pregnancy for prevention of pre-​eclampsia ± low-​molecular-​ weight heparin. Close fetal and maternal surveillance are required.

Rheumatoid arthritis Rheumatoid arthritis improves with pregnancy in some women. Methotrexate is teratogenic, but with the advent of treatment with biologics, more women with rheumatoid arthritis are now attempting pregnancy. Birth outcomes of women on anti-​TNFα agents are reassuring and there is no link with teratogenicity, but concern about immunosuppression of the fetus through transplacental transfer means treatment with some agents should be discontinued in later pregnancy. Overall the risk of adverse obstetric outcomes remains minimal and similar to the normal population. Post-​partum flares of rheumatoid arthritis are common.

Introduction Autoimmune diseases affect 5–​7% of the population and are more common in women of childbearing age. Many women with autoimmune rheumatic diseases have been advised against pregnancy in the past, but this is no longer appropriate with a new generation of pregnancy-​friendly disease-​modifying antirheumatic drugs and biological agents that afford excellent disease control without compromising fertility. Nevertheless, many women with autoimmune rheumatic diseases are older and have more comorbidities (i.e. hypertension, obesity, diabetes, cardiovascular disease, and so on) when they do attempt pregnancy.

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Section 14  Medical disorders in pregnancy

The importance of planned pregnancies with good preconception advice from clinicians knowledgeable in both the disease process and its effects on pregnancy (and lactation), and vice versa, cannot be overemphasized. Pregnancy is associated with suppressed cell-​mediated immunity (Th1) and enhanced humoral immunity (Th2), but these changes revert post-​partum accompanied by rapid reductions of oestrogen, progesterone, and cortisol levels. The post-​partum period is therefore a time of susceptibility to autoimmune disorders; and women who already have an autoimmune disorder may suffer disease exacerbation following pregnancy. Conversely, some autoimmune diseases may remit or improve during pregnancy, but this is not a universal rule. Flares in pregnancy are often accompanied by adverse obstetric outcomes for both mother and fetus. This chapter considers the relationship between pregnancy and systemic lupus erythematosus, antiphospholipid syndrome, rheumatoid arthritis, vasculitides, and scleroderma, and how pregnancy affects treatment of these conditions.

Systemic lupus erythematosus Systemic lupus erythematosus is much more common in women than men (ratio 9:1), with peak onset during the childbearing years. A  recent extensive review of published epidemiological studies demonstrated that the prevalence ranges from 0.07/​1000 in Caucasian Americans to 1.59/​1000 in a British Afro-​Caribbean population.

Effect of pregnancy on systemic lupus erythematosus Flares of systemic lupus erythematosus may be difficult to diagnose during pregnancy since many features such as hair loss, oedema, facial erythema, fatigue, musculoskeletal pain, anaemia, and raised erythrocyte sedimentation rate (ESR) also occur in normal pregnancy. Several disease activity scores are being validated for use in pregnancy. Active systemic lupus erythematosus in the four to six months preceding conception increases the likelihood of a flare during pregnancy. Several case–​control studies have addressed this issue, but differ in patient ethnicity, criteria for flare and systemic lupus erythematosus activity scales employed. The type of flare usually follows previous disease pattern. Hydroxychloroquine has been linked with better disease control and improved obstetric outcomes, and therefore should be continued in pregnancy. Conversely, steroids do not prevent flares, hence it is not appropriate to prescribe or increase the dose of steroids prophylactically during pregnancy or during the post-​partum period. Ideally, pregnancy should be planned when systemic lupus erythematosus is in remission, while on drugs that are suitable to be continued in pregnancy. Renal flares are more common if disease is active within six months of conception. There is a risk of deterioration of renal function in pregnancy, particularly if the patients are hypertensive, have pre-​existing heavy proteinuria, or a high baseline serum creatinine. A recent meta-​analysis reported that the incidence of renal lupus flares during pregnancy was 11–​69% and renal impairment occurred in 3–​27%, which was irreversible in up to 10%. Tacrolimus is being increasingly used as a treatment for lupus nephritis. De novo presentations of lupus nephritis

during pregnancy are not uncommon, particularly in those who are not treated. Women with systemic lupus erythematosus and secondary antiphospholipid syndrome have an increased risk of maternal thrombosis, especially in the puerperium. There should be a low threshold for empiric treatment with low-​molecular weight heparin pending appropriate diagnostic imaging. Young women with systemic lupus erythematosus are also at risk of premature atherosclerosis, even in the relative paucity of cardiovascular risk factors. It is possible the pregnancy and its associated complications accelerate this process. Hence, myocardial infarction should be considered as a differential if she presents with chest pain or shortness of breath. Pulmonary hypertension present in up to 14% of patients. It carries a significant risk of maternal death. Idiopathic pulmonary hypertension is associated with an up to 25% risk of maternal mortality, and this risk is even higher in women with underlying connective tissue disorders. Women who have pulmonary hypertension should be advised against pregnancy and when pregnant, offered the option of termination on the basis of life-​threatening maternal disease. Nevertheless, the most common cause of maternal death in women with systemic lupus erythematosus is infection.

Effect of systemic lupus erythematosus on pregnancy Women with systemic lupus erythematosus remain fertile, except during severe flares or after exposure to prolonged high doses of cyclophosphamide, which results in premature ovarian failure. However, systemic lupus erythematosus is associated with increased risk of early pregnancy losses and the later adverse pregnancy outcome as a result of placental insufficiency, and manifest as pre-​eclampsia, fetal growth restriction, or small for gestational age infants, placental abruption, and stillbirth—​collectively known as maternal-​placental syndrome. These complications often lead to preterm deliveries. The main factors influencing pregnancy outcomes in women with systemic lupus erythematosus are disease activity (especially at time of conception), hypertension, renal involvement, secondary antiphospholipid syndrome, and anti-​Ro/​La antibodies (see next). Pregnancy outcomes in women with systemic lupus erythematosus have greatly improved in recent years due to continuation of hydroxychloroquine in pregnancy, fetal surveillance in women who are Ro and La positive, improved disease control even in the non-​ pregnant cohort, likely milder disease course as diagnostic latency is shortened and clinicians are now more comfortable with the management of systemic lupus erythematosus in pregnancy thereby reducing the rate of iatrogenic preterm delivery. Presence of renal disease is closely associated with pregnancy outcomes in women with systemic lupus erythematosus. In a meta-​ analysis active nephritis at conception was associated with 25–​50% rate of fetal loss as compared to 8–​12% if the disease was inactive. One case–​control study showed that 28% of patients with class III or IV lupus nephritis developed pre-​eclampsia, 35% had a preterm delivery, and a significantly lower birth weight compared to the women with systemic lupus erythematosus without nephritis. A higher baseline creatinine is also associated with poor pregnancy outcomes. Women with systemic lupus erythematosus in clinical remission but with persistently low complement levels or positive anti-​double

14.14  Autoimmune rheumatic disorders and vasculitis in pregnancy

Box 14.14.1  Baseline investigations to assess risk of pregnancy in patients with systemic lupus erythematosus • Blood pressure • Urinalysis and quantification of proteinuria (albumin/​ protein creatinine ratio and/​or 24 h urinary protein) • Full blood count, ESR • Urea, creatinine, and electrolytes • Liver function tests • Uric acid • Serology—​ antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies, anti-​β2glycoprotein I antibodies), ENA (esp. Ro and La antibodies), ANA, ds-​DNA • Complements: C3 and C4

stranded DNA (anti ds-​DNA) in the second trimester have worse pregnancy outcomes than seen in women with normal complement or negative anti ds-​DNA. However, it is women with both serological and clinically active disease who have the highest rates of pregnancy loss and preterm delivery. Positive anti ds-​DNA was more closely associated with high clinical systemic lupus erythematosus activity in pregnancy, but low complement alone was not.

Management of systemic lupus erythematosus in pregnancy Preconception counselling When possible, management should begin with preconception counselling. Baseline renal function, blood pressure, and the anti­ phospholipid and anti-​Ro/​La antibody status allow prediction of the risks to the woman and her baby (see later). Appropriate baseline investigations are listed in Box 14.14.1. A decision should be made as to whether to start aspirin and/​or low-​molecular weight heparin if the woman is at risk of thromboses. The outlook is better if conception occurs during remission, and women should be advised to avoid pregnancy for at least 6 months post-​flare, especially if there is renal involvement. Her medications should be reviewed and changed to pregnancy-​friendly drugs (if possible). It is important to ensure clinical stability on this regime for at least six months preconception. Maternal surveillance Pregnancy care is best undertaken in multidisciplinary, combined clinics where physicians and obstetricians can monitor disease activity, fetal growth, and uterine and umbilical artery Doppler blood flow. Women will need to be regularly reviewed for any signs of pre-​ eclampsia or a flare. Frequency of visits depends on gestation and maternal disease activity. As a rule of thumb, the visits increase in frequency towards and during the third trimester—​when superimposed pre-​eclampsia is commonest. Diagnosis of flare Differentiation of active renal lupus from pre-​eclampsia is notoriously difficult, and the two conditions may co-​exist. Table 14.14.1 lists features to help to distinguish them. The gold standard is a renal biopsy to differentiate a renal lupus flare from pre-​eclampsia. Renal biopsies can be performed in pregnancy, but there is an increased risk of bleeding and haematoma formation due to increased vascular perfusion to kidneys during pregnancy. Renal biopsies are performed rarely in pregnancy and only before 24 weeks’ gestation. Other useful markers for

Table 14.14.1  Features to help distinguish lupus nephritis flare and pre-​eclampsia Pre-​eclampsia

Flare of SLE

Hypertension

Yes

Often present

Other organs

No

Malar rash, photosensitive rash, or arthritis

Seizures

If eclampsia

Only if there is neurological involvement

Proteinuria

++ ≥0.3 g/​day or PCR ≥30

++ (in lupus nephritis)

Urinary casts

Absent

Present (if lupus nephritis)

RBC in urine

Absent

Present (if nephritic)

Urate

Elevated

Not elevated unless CKD

Albumin

Low

Very low if nephrotic syndrome

LFT

May be deranged

Rarely deranged in a flare of SLE

C3 and C4

Unchanged from baseline in early pregnancy

Low compared to baseline in early pregnancy

Anti-​ds-​DNA

Unchanged

Elevated

CKD, chronic kidney disease; LFT, liver function test; RBC, red blood count; SLE, systemic lupus erythematosus.

a flare of lupus nephritis include a raised ds-​DNA and active urinary sediment or the presence of casts in the urine. Management of flare Disease flares must be actively managed. Delivery is seldom the sole management of choice as post-​partum flares are common and severe. Treatment will depend on the organ involvement and severity (see the later section in this chapter, ‘The use of antirheumatic drugs, immunosuppressive agents, and biologics in pregnancy’ for a summary of the therapeutic options available). Most drugs can be used in pregnancy. Teratogenic agents such as cyclophosphamide should be avoided in the first 12 weeks during which organogenesis occurs. There are long-​term safety data on the use of cyclophosphamide later in pregnancy with a cohort of children exposed in utero showing no signs of neurodevelopmental delay or other adverse effects when followed up to adolescence. Due to the prolonged action of rituximab, it is best avoided for six months prior to delivery. However, its use in pregnancy (for other indications, e.g. idiopathic thrombocytopenic purpura or as part of a chemotherapy regimen) has not been associated with adverse neonatal effects, and the exposed infants are able to mount an adequate response to vaccination despite the reduction of lymphoid B cells in the reticuloendothelial system seen in the offspring of exposed primates. Corticosteroids are the most widely prescribed drug for a flare in pregnancy as they have a well-​established safety profile. Non-​ fluorinated steroids (e.g. prednisolone), are metabolized by the placenta, and the fetus also inactivates steroids by way of sulphate conjugation, hence very little (7.5 mg/​day for >2 weeks) require parenteral steroids to cover the stress of labour and delivery. Prednisolone is safe in breastfeeding mothers since less than 10% of active drug is secreted into breast milk. Notwithstanding the above risks, steroids remain first-​line treatment for severe lupus flares in pregnancy (and treatment of other autoimmune conditions), as the benefits of rapid disease control outweigh the risks. Disease-​modifying antirheumatic drugs are discussed later in this chapter, in the section ‘The use of antirheumatic drugs, immunosuppressive agents, and biologics in pregnancy’.

Neonatal lupus syndromes About 30% of patients with systemic lupus erythematosus are anti-​ Ro positive. In such women the risk of transient cutaneous lupus is about 5% and the risk of congenital heart block about 2%, with the two conditions rarely coexisting. Anti-​Ro antibodies are present in 90 to 100% of mothers of affected offspring, and 68 to 91% have anti-​La antibodies. Maternal titres of anti-​Ro antibodies as high as 50 U/​ml or more are more likely to be associated with congenital heart block. There is no relationship between anti-​La titre and neonatal lupus. The risk of neonatal lupus is increased if a previous child has been affected, at 15–​25% if one and 50% if two previous children are affected. Not all anti-​Ro/​La positive mothers of neonates with congenital heart block have systemic lupus erythematosus or Sjögren’s syndrome, some are asymptomatic, but 48% of these developed symptoms of connective tissue disease in a median 3.7 years follow-​up in one study. In mothers who do have systemic lupus erythematosus there is no correlation between the severity of maternal disease and the incidence of neonatal lupus. Cutaneous neonatal lupus usually manifests in the first two weeks of life. The infant develops typical annular skin lesions similar to those of adult subacute cutaneous lupus, usually of the face and scalp, which appear after sun or UV light exposure. The rash disappears spontaneously within six months. Residual hypopigmentation or telangiectasia may persist for up to two years, but scarring is unusual. No specific treatment is required, except topical steroids in severe cases.

Congenital heart block usually appears in utero, around 18–​ 20 weeks and is associated with a structurally normal heart. The mechanism of damage appears to involve binding of the anti-​Ro/​La antibodies to antigens on the fetal cardiocytes, inducing an inflammatory process which leads to tissue damage and fibrosis of the conducting system. In women known to be anti-​Ro/​La positive, the fetal heart rate should be monitored at each visit (from 16 weeks onwards), and fetal cardiology scans offered at approximately 18–​20 weeks’ gestation and again at 28 weeks. Complete heart block causes bradycardia which can be detected on auscultation, but lesser degrees of heart block require Doppler echocardiography. Overall mortality is around 20%, with deaths usually occurring in utero (after developing hydrops, pleural and pericardial effusions) or the neonatal period, but can occur up to three years of age. Most infants who survive the neonatal period do well, although two-​thirds require pacemakers. There is no treatment that reverses complete heart block. In the past, intravenous immunoglobulins, fluorinated glucocorticosteroids, plasmapheresis, salbutamol, and digoxin have all been tried and found to be ineffective. Studies on congenital heart block have been difficult to conduct due to the rarity of the condition. However, a large retrospective study did find an association between maternal hydroxychloroquine use, and a reduction in heart block in the offspring. Its follow-​on study focusing on subsequent pregnancies of women whose offspring were affected found that there was a definite reduction in the incidence of heart block in the offspring of the women who were receiving hydroxychloroquine. Hence, hydroxychloroquine should be used in women who are planning pregnancy (or in early pregnancy) and are Ro or La antibody positive, even if they are asymptomatic.

Antiphospholipid syndrome and antiphospholipid antibodies Antiphospholipid antibodies include anticardiolipin antibodies (IgG and/​or IgM), lupus anticoagulant, and anti-​β2-​glycoprotein-​I antibody. The combination of any of these with one or more of the characteristic clinical features of thrombosis, recurrent pregnancy loss, or adverse pregnancy outcome (as detailed in Table 14.14.2) is known as the antiphospholipid syndrome. antiphospholipid

Table 14.14.2  Revised (2006) classification criteria for the antiphospholipid syndrome Revised classification criteria (Sydney criteria) for antiphospholipid syndrome.

Vascular thrombosis: ≥1 clinical episode of arterial, venous, or small vessel thrombosis. Thrombosis must be objectively confirmed. For histopathologic confirmation, thrombosis must be present without inflammation of the vessel wall. Pregnancy morbidity: a. ≥1 unexplained death of a morphologically normal fetus ≥10 weeks of gestation. b. ≥1 premature delivery of a morphologically normal fetus 99th percentile) of IgG or IgM isoforms c. anti-​ß2 glycoprotein-​I antibody (anti-​ß2GP I) of IgG or IgM present in plasma. Adapted from Miyakis S, et al. (2006). International consensus statement on an update of the classification criteria for definite antiphopholipid syndrome (APS). J Thromb Haemost, 4, 295–​306.

14.14  Autoimmune rheumatic disorders and vasculitis in pregnancy

antibodies are common and are not always associated with a clinical picture of pregnancy losses, obstetric complications, or thrombosis.

The implications of antiphospholipid antibodies and antiphospholipid syndrome in pregnancy Antiphospholipid syndrome is the most commonly acquired thrombophilia. Antiphospholipid antibodies are prevalent in the general population. In a cross-​sectional study of healthy blood donors, lupus anticoagulant was present in 8% and anticardiolipin antibodies in 10%. However, these antibodies were transient and persistence occurred in less than 2%. Antiphospholipid antibodies can be generated after exposure to certain medications, after infection (e.g. with HIV, HTLV-​1, hepatitis A, B, or C, CMV, EBV, VZV, TB, or poststreptococcal rheumatic fever, syphilis, Klebsiella, malaria), following a miscarriage, or in association with certain malignancies. However, these antiphospholipid antibodies—​particularly those generated after infection or following a pregnancy loss—​are transient and are unlikely to be of clinical significance, hence the importance of retesting antiphospholipid antibodies after more than 12 weeks. The presence of antiphospholipid antibodies does not equate to clinical disease. Only 8% of those with primary antiphospholipid syndrome developed systemic lupus erythematosus or 5% a ‘lupus-​like’ disease over a nine-​year follow-​up interval. The association with thrombosis is more robust in lupus anticoagulant than with anticardiolipin antibodies (OR 11.0 vs. 1.6). For those with antiphospholipid antibodies only, several case–​control studies, and a prospective multicentre study have shown the incidence rate of thrombosis is 1.86% per 100 patients per year. In the obstetric setting, women with antiphospholipid syndrome are at increased risk of recurrent early fetal loss, severe early onset pre-​eclampsia, placental abruption, intrauterine fetal death, or fetal growth restriction without hypertension. Recurrent pregnancy loss in women with antiphospholipid syndrome is typically in the second trimester. Fetal death is typically preceded by fetal growth restriction and superimposed pre-​eclampsia. Quantifying the risk is difficult. In a meta-​analysis, lupus anticoagulant in particular was more strongly and consistently associated with fetal loss (OR 7.79; 95% CI:2.3–​26.45). The pathogenesis of fetal loss in these patients is not fully understood, although a variety of mechanisms have been suggested and there appear to be both thrombotic and inflammatory components. Women with obstetric antiphospholipid syndrome have a much higher risk of severe early onset (10 weeks’ gestation, early onset pre-​eclampsia necessitating 250 cells/​mm3 in spontaneous bacterial peritonitis

Cytology

High yield in ovarian cancer

Amylase

Pancreatic duct leak in chronic pancreatitis from pancreatic injury Rarely associated with jaundice from biliary obstruction

It is also useful in mapping the extent of biliary obstruction in bile duct cancers, particularly hilar cholangiocarcinomas, to help in deciding if stenting will improve jaundice and decide between endoscopic and percutaneous approach. MRCP will also identify chronic pancreatitis and swollen pancreas typical of IgG4 disease. Endoscopic retrograde cholangiopancreatography (ERCP) is also used to confirm diagnosis and for therapy. Pancreatic CT is needed before endoscopic stenting to stage/​assess operability of ampullary, pancreatic, or bile duct cancers because further assessment of operability is impossible if post-​ERCP pancreatitis occurs (1 in 20 risk).

Liver biopsy Liver histology is often needed once posthepatic biliary obstruction and acute viral hepatitis have been excluded, to stage the degree of liver injury, to differentiate acute from chronic liver damage, and to aid diagnosis. It is a major component of the diagnostic criteria for autoimmune liver disease and is often needed to make a diagnosis in the presence of a hepatitic liver function test once acute viral hepatitis has been excluded serologically. Percutaneous liver biopsy has a 0.5% risk of bleeding and a small risk of pneumothorax. Other rare complications include intrahepatic arteriovenous fistulae and haemobilia. Transjugular liver biopsy is indicated in the presence of ascites, a platelet count less than 50 × 109/​litre, and a prolonged prothrombin time. Noninvasive markers of liver fibrosis such as FibroScan are less useful in the presence of jaundice as inflammation can increase FibroScan scores, incorrectly suggesting cirrhosis. Ascites also reduces the sensitivity and specificity of FibroScan.

Other tests In a patient with cirrhosis less than 40 years of age and with haemolysis, particularly in the presence of a normal or low ALP, Wilson’s disease should be considered and examination for Kayser–​Fleischer rings with a slit lamp should be performed.

15.22.1  Investigation and management of jaundice

JAUNDICE

Abnormal ALP/ALT

Normal ALT/ALP Normal albumin/platelets*

Ultrasound scan

No evidence of haemolysis Unconjugated bilirubin

Undilated CBD**/*

Dilated CBD Gilbert’s syndrome

High ALT MRCP/ERCP

See Table 15.22.1.5

High ALP

Exclude drugs AMA MRCP to exclude PSC

No cause identified

Liver biopsy (diagnosis/staging) **If pain and gallbladder stones and elevated ALP or ALT 5%, through inflammatory nonalcoholic steatohepatitis (NASH), to fibrosis or cirrhosis, and in some cases hepatocellular carcinoma. Critically, most patients with NAFLD do not progress beyond steatosis, but a substantial minority do progress to cirrhosis and end-​stage liver disease and so experience associated morbidity and mortality. The presence of NAFLD is also an independent risk factor for development of cardiovascular disease and stroke. The key challenge in the management of NAFLD is to identify the patients at greatest risk of disease progression so that treatment may be targeted at those that will benefit most.

Aetiology Hepatic steatosis and steatohepatitis may be attributable to a diverse range of acquired exposures as well as numerous rare monogenic inherited disorders (summarized in Table 15.24.2.1). The

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NAFLD

Steatohepatitis (NASH)

Steatosis (NAFL)

Fat infiltration >5% with or without mild inflammation

Steatosis + necroinflammation (ballooning, Mallory bodies, megamitochondria)

Cirrhosis

Increasing fibrosis, eventually leading to cirrhosis

Fig. 15.24.2.1  NAFLD—​a spectrum of liver disease. Table 15.24.2.1  Aetiology of steatosis and steatohepatitis Aetiological factor

Predominant pattern of histological steatosis

Metabolic syndrome (obesity, insulin resistance/​ type 2 diabetes mellitus)

Macrovesicular

Starvation and cachexia

Macrovesicular

Protein malnutrition (Kwashiorkor, anorexia nervosa)

Macrovesicular

Dietary choline deficiency

Macrovesicular

Total parenteral nutrition

Macrovesicular

Drugs

Macrovesicular

Aspirin

Microvesicular

Chloroquine

Macrovesicular

Corticosteroids

Macrovesicular

Methotrexate

Macrovesicular

NSAIDs (naproxen, ibuprofen, ketoprofen)

Microvesicular

Nucleoside analogues used in HAART (zidovudine, didanosine, zalcitabine, fialuridine, etc.)

Microvesicular

Oestrogens

Macrovesicular

Tamoxifen

Macrovesicular

Tetracycline

Microvesicular

Valproic acid

Microvesicular

Toxins

Amanita phalloides mushroom poisoning Bacillus cereus emetic toxin

Microvesicular

Carbon tetrachloride Ethanol

Macrovesicular

Petrochemicals Toxic shock syndrome

Predominant pattern of histological steatosis

Genetic factors

Acquired metabolic and/​or nutritional disorders

Amiodarone

Aetiological factor

Microvesicular

Abetalipoproteinaemia

Macrovesicular

Alpers’ disease

Microvesicular

Cholesterol ester storage disease

Microvesicular

Familial combined hyperlipidaemia Familial hypobetalipoproteinaemia Glycogen storage disease Inherited defects in fatty acid β-​oxidation

Microvesicular

Lecithin–​cholesterol acyltransferase deficiency

Microvesicular

Lipodystrophy

Macrovesicular

Lysosomal acid lipase deficiency (Wolman’s disease)

Microvesicular

Ornithine transcarbamylase deficiency

Microvesicular

Wilson’s disease

Macrovesicular

Infections

Chronic hepatitis C (genotype 3)

Macrovesicular

Bacterial overgrowth following jejunoileal bypass

Macrovesicular

Others

Acute fatty liver of pregnancy

Microvesicular

Coeliac disease HELLP syndrome

Microvesicular

Reye’s syndrome

Microvesicular

Metals HAART, highly active antiretroviral therapy; NSAIDs, nonsteroidal anti-​inflammatory  drugs.

15.24.2  Nonalcoholic fatty liver disease

Environmental Factors Diet, Microbiome, Xenobiotics

Genetic & Epigenetic Factors Genetic variants in PNPLA3, TM6SF2, MBOAT7, HSD17B13 DNA methylation

lantation

th or Transp

Risk of Dea

Steatosis

Steatosis + Lobular Inflammation

NASH +/–Portal Inflammation

Early fibrosis

F1

F2

F3

F4

Advanced fibrosis & Cirrhosis

Rates of Fibrosis Progression vary between individuals

Steatotic/Steatohepatitic phase

Fibrotic phase

Fig. 15.24.2.2  Natural history of NAFLD.

most common aetiological factors underlying the development of NAFLD are central obesity, insulin resistance/​type 2 diabetes mellitus, hypertension, and dyslipidaemia, a group of chronic conditions indicative of increased cardiovascular risk that together comprise the ‘metabolic syndrome’. NAFLD is also associated with conditions including polycystic ovary syndrome, obstructive sleep apnoea, and small-​bowel bacterial overgrowth. Due to sedentary lifestyles and the increasing consumption of diets enriched in fats and carbohydrates, the metabolic syndrome is now endemic in many developed countries and so the incidence of NAFLD has risen rapidly to become the leading cause of chronic liver disease worldwide.

Epidemiology The true worldwide prevalence of NAFLD is not known as estimates vary between the populations studied due to different ethnicities, dietary patterns, and the sensitivity of the modality used to detect disease. Overall, however, NAFLD is estimated to affect approximately 20 to 30% of the population in Western countries and 5 to 18% in Asia, with about 1 in 10 NAFLD cases exhibiting features of NASH. Studies from the United States of America indicate that the frequency of steatosis varies significantly with ethnicity (45% in Hispanics, 33% in white people, and 24% in black people) and sex (42% white males vs 24% white females). Prevalence increases dramatically when populations with known metabolic syndrome risk factors are selected. Illustrating this, 91% of obese patients (body mass index (BMI) ≥30  kg/​m2), 67% of overweight (BMI 25–​30 kg/​m2), and 25% in normal weight individuals in an unselected European population sample had NAFLD, and 40 to 70% of patients with type 2 diabetes mellitus also have NAFLD. Of concern, while the prevalence of most liver diseases is stable, the prevalence of NAFLD is increasing, placing a greater burden on healthcare resources.

There is an important paradox: most individuals with features of the metabolic syndrome develop steatosis and so NAFLD is highly prevalent in the general population, but only a subgroup progress to advanced liver disease and experience liver-​related morbidity (Fig. 15.24.2.2). During a median 12.6-​year follow-​up period in a cohort of 619 NAFLD patients, an overall 33.2% risk of death or liver transplantation was observed, with liver-​related mortality being the third most common cause of death, after cardiovascular disease and extrahepatic malignancy. Challenging the dogma that ‘simple’ steatosis is a benign condition with no clinical sequelae, serial biopsy studies indicate that patients with either steatosis or NASH may exhibit progressive fibrosis, with approximately 40% showing increased fibrosis, 40% stable disease, and 20% disease regression over a 6-​to 7-​year period. The presence and severity of hepatic fibrosis on liver biopsy (or as assessed by noninvasive testing) appears to be the single most important determinant of long-​term prognosis, with advanced fibrosis/​cirrhosis (fibrosis stages F3–​4) being predictive of liver-​related events, transplantation, and death in patients with NAFLD. Compared with cases without histological evidence of fibrosis, the presence of early [F1–​2] fibrosis conferred an 11.2-​fold risk. This increased to an 85.8-​fold risk in patients with advanced [F3–​4] fibrosis/​cirrhosis. The average age of NASH patients is 40 to 50 years and for NASH cirrhosis is 50 to 60 years, but the emerging epidemic of childhood obesity means that NAFLD is present in increasing numbers of younger patients and so the age that patients develop significant liver disease is likely to fall.

Pathogenesis/​pathology It is generally accepted that the initiating events in NAFLD are dependent on the development of obesity and insulin resistance. Together these lead to increased fatty acid content in the liver due to the combination of de novo lipogenesis and fatty acid import from

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dietary sources and adipose tissue stores. This places hepatocytes under considerable metabolic pressure, promotes lipotoxicity, increases oxidative stress secondary to free radical production during β-​and ω-​fatty acid oxidation, and induces endoplasmic reticulum stress. Hepatocellular triglyceride accumulation (i.e. steatosis) is the histologically visible evidence of these metabolic stressors but is itself unlikely to be directly harmful to the liver, being an adaptive response through which potentially lipotoxic fatty acids are partitioned into relatively inert intracellular stores. Ultimately, these insults combine with the additive effects of endotoxin-​initiated Kupffer cell cytokine release and immune-​mediated hepatocellular injury to induce cellular damage and activate cell death pathways, marking the transition to steatohepatitis. If these processes persist, stellate cell activation, collagen deposition, and hepatic fibrosis occur. Interpatient variation in disease progression and prognosis is thought to be determined by the combined effects of environmental (dietary and intestinal flora) exposures acting on a susceptible polygenic background. Studies implicate single nucleotide polymorphisms in a number of genes including PNPLA3, TM6SF2, MBOAT7 and HSD17B13 as factors that modify development of NAFLD and subsequent progression of fibrosis.

Clinical features NAFLD is frequently asymptomatic although may be associated with nonspecific symptoms such as fatigue and mild right upper quadrant abdominal discomfort due to steatotic hepatomegaly distending the liver capsule. It is most commonly identified as an incidental radiological finding or a mild biochemical abnormality noted during routine blood tests taken for another indication. Alternatively, patients with progressive NAFLD may present late in the course of disease with complications of cirrhosis and portal hypertension such as variceal haemorrhage, or hepatocellular carcinoma (HCC). HCC is a frequent complication of NAFLD (cumulative incidence 2.4–​12.8%) that may occur in both precirrhotic and postcirrhotic patients. Recognized independent risk factors for NAFLD progression and advanced fibrosis include age greater than 45  years, presence of diabetes (or severity of insulin resistance), obesity (BMI >30  kg/​m2), and hypertension (Table 15.24.2.2). These

factors are clinically useful as they assist with identification of ‘high-​risk’ patient groups. There are no specific physical signs to establish a diagnosis of NAFLD. Hepatomegally may be noted, but abdominal adiposity may hamper effective examination. In the absence of advanced disease, where the classical stigmata associated with the presence of chronic liver disease such as jaundice, spider naevi, and ascites may be apparent, clinical examination is frequently unremarkable. In light of the strong association between NAFLD and the metabolic syndrome, height and weight should be recorded, hip/​waist circumference measured, and evidence of end-​organ damage due to insulin resistance and hypertension sought.

Differential diagnosis Key to the diagnosis of NAFLD is recognition that an individual possesses features of metabolic syndrome (central obesity, insulin resistance/​type 2 diabetes mellitus, dyslipidaemia, and hypertension) and therefore is at risk of NAFLD. The more features of the metabolic syndrome that are present, the higher the probability that a patient has underlying NAFLD and the more likely they are to exhibit steatohepatitis and progressive liver disease. There are many causes for steatosis and steatohepatitis and hence a potentially wide differential diagnosis (Table 15.24.2.1). In practice, the principal differential is between metabolic syndrome-​ related NAFLD and alcoholic liver disease. Discriminating these is reliant upon a detailed history and seeking corroboration from family members (where available) to ensure that any history of concealed excessive alcohol consumption is excluded. An arbitrary threshold for ethanol consumption of less than 20 g/​day for women and less than 30 g/​day for men is adopted to sustain a diagnosis of NAFLD. Metabolic syndrome-​related NAFLD sensitizes the liver to the effects of other injurious processes such as alcohol consumption. As obesity and the wider metabolic syndrome become endemic within the population, the distinction between NAFLD and alcohol-​related liver disease can easily become blurred with these apparently mutually exclusive conditions coexisting in some individuals. To avoid this diagnostic oxymoron, the condition may be described as ‘dual-​aetiology fatty liver disease’.

Table 15.24.2.2  Common risk factors for NAFLD Risk factor

Effect

Age

Higher risk of NAFLD and advanced fibrosis aged >45

Metabolic syndrome (obesity, insulin resistance/​type 2 diabetes mellitus, dyslipidaemia, and hypertension)

70–​90% of metabolic syndrome patients have NAFLD. The more features an individual possesses, the greater the likelihood of NASH and severity of fibrosis

Sex

Males >females

Ethnicity

High risk in Hispanics, white individuals intermediate, lower risk in black individuals

Dietary factors

Diets high in cholesterol, saturated fats, and fructose but low in carbohydrate increase risk Caffeine may be protective

Obstructive sleep apnoea

Increased risk of hepatic fibrosis

Genetic factors

Variants in Patatin-​like phospholipase domain-​containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) genes are associated with greater steatosis, NASH, and more advanced liver fibrosis. PNPLA3 mutations also increase the risk of NAFLD-​associated hepatocellular carcinoma

15.24.2  Nonalcoholic fatty liver disease

A detailed drug history including prescribed medication, over-​ the-​counter medication, and traditional/​herbal remedies should be taken.

hepatitis, and haemochromatosis respectively. Raised ferritin levels and the presence of increased IgA levels are indicative but not diagnostic of more advanced fibrosis.

Radiological studies

Clinical investigation Once excessive alcohol consumption has been excluded and other confounding environmental factors discounted, investigation of suspected NAFLD should be directed first towards exclusion of other liver diseases and then confirming the presence of NAFLD: • Exclusion of other liver diseases:  laboratory testing should confirm absence of chronic viral hepatitis (hepatitis B virus surface antigen and hepatitis C virus serology), autoimmune liver disease (antinuclear antibodies, antimitochondrial antibodies, smooth muscle antibodies, liver–​kidney microsomal type 1 antibodies, immunoglobulins) and other treatable metabolic diseases (haemochromatosis, Wilson’s disease, coeliac disease, α1 antitrypsin deficiency). • Confirmation of the presence of NAFLD:  may be obtained radiologically or histologically. • Assessment of underlying liver damage: discriminating steatosis from NASH and determining the extent of hepatic fibrosis present (i.e. grade and stage of disease) is important to assist with individual risk stratification and prognostication. This has traditionally necessitated liver biopsy for histological assessment, but techniques for noninvasive testing to detect significant liver fibrosis are becoming more robust.

Biochemical tests The diagnosis, staging, and long-​term follow-​up of NAFLD is made more complicated as there is no single blood test that is diagnostic for NAFLD or which can be used to accurately determine disease severity and treatment response. Aminotransferases Elevations of serum alanine transaminase (ALT) and aspartate transaminase (AST) are modest and usually less than twice the upper limit of normal. Although many NAFLD cases are first detected due to the incidental finding of a mild transaminitis, these routine biochemical tests are insensitive with approximately 80% of patients having normal-​range ALT levels. Indeed, ALT levels fall as hepatic fibrosis progresses and so the characteristic AST/ALT ratio of less than 1 commonly seen in NAFLD reverses (AST/ALT >1) as fibrosis progresses toward cirrhosis, meaning that fibrosing steatohepatitis and/​or advanced liver disease may be present even in those with normal-​range ALT levels. Other biochemical markers Other laboratory abnormalities that may be present include non­ specific elevations of γ-​glutamyl transferase, low-​titre antinuclear antibodies, and/​or antismooth muscle antibody in 20 to 30% of patients, and elevated ferritin levels despite normal transferrin saturation. These can lead to diagnostic uncertainty as they may be incorrectly ascribed to high alcohol consumption, autoimmune

Steatosis can readily be detected by various imaging modalities. Ultrasonography is widely available and cost-​effective and is therefore most often used. A  steatotic liver appears ‘bright’ due to increased echogenicity, but this finding is subjective and provides only a qualitative assessment of hepatic fat content. Sensitivity of ultrasonography is poor when less than 33% of hepatocytes are steatotic and so significant steatosis can be missed. Alternatives include CT, MRI-derived Proton Density Fat Fraction (MRI-PDFF), or magnetic resonance spectroscopy, which offer greater sensitivity for detecting lesser degrees of steatosis but are resource intensive and not widely used in routine practice. Currently no widely available clinical imaging modality can distinguish steatosis from steatohepatitis or accurately quantify intermediate stages of fibrosis short of cirrhosis.

Assessing the severity of the underlying liver disease In the absence of routinely available ‘standard’ tests to confirm the diagnosis, assess the degree of inflammation, and accurately determine the extent of liver fibrosis to assist prognostication, liver biopsy is commonly used and remains the ‘gold standard’ investigation. However, it is invasive, carries a modest but appreciable risk of complications, and is unsuitable for widespread use outside the secondary care setting. Several noninvasive techniques, both commercial and noncommercial, have been proposed that may be used to predict the presence of NAFLD or the stage of fibrosis. The performance of selected tests that are commonly used are summarized in Table 15.24.2.3. Of these, simple scores like the NAFLD Fibrosis Score and FIB-​4 Score, or specialist panels such as the Enhanced Liver Fibrosis (ELF) Test, offer the ability to rule out significant underlying liver disease (fibrosis stages F3–​4) with a high degree of confidence and so are widely used to assist risk stratification, enabling invasive testing to be reserved for those where it may offer clinically relevant additional information. All three tests have also been shown to be predictive of long-​term disease outcome and mortality. Techniques that measure liver stiffness as a surrogate for fibrosis severity, such as ultrasonography-​based transient elasto­ graphy (Fibroscan), are also widely adopted, although adiposity can interfere with accuracy in some patients. Promising alternatives that are emerging include acoustic radiation force impulse imaging and magnetic resonance elastography. In general, noninvasive techniques have good negative predictive values for advanced fibrosis but more modest specificity and so lower positive predictive values. A suggested algorithm for the assessment and risk stratification of patients with NAFLD is provided in Fig. 15.24.2.3. Histology NAFLD ranges from hepatic steatosis, through inflammatory steatohepatitis, to fibrosis or cirrhosis (Fig. 15.24.2.1). The histological classification of NAFLD, which allows grading of disease

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Table 15.24.2.3  Noninvasive tests for NAFLD and NAFLD fibrosis Test

Formula

Sensitivity and specificity

Fatty Liver Index (FLI) predicts NAFLD

FLI = (e 0.953 × loge (triglycerides) + 0.139 × BMI + 0.718 × loge (γGT) + 0.053 × waist circumference − 15.745)/​(1 + e 0.953 × loge (triglycerides) + 0.139 × BMI + 0.718 × loge (γGT) + 0.053 × waist circumference − 15.745) × 100

High risk (FLI >60) Intermediate (FLI 30–​60) Low risk (FLI 0.676): Se 0.51, Sp 0.98, PPV 0.90, NPV 0.85 Indeterminate (NFS −1.455 to 0.676). Low risk (NFS 2.67): Se 0.33, Sp 0.98, PPV 0.80, NPV 0.83 Indeterminate (1.30–​2.67) Low risk (FIB-​4  0.3576): Se 0.80, Sp 0.90, PPV 0.71, NPV 0.94 Low risk (ELF < 0.3576)

Fibroscan predicts advanced fibrosis [F3–​4]

Ultrasonography-​based transient elastography measures the velocity of an elastic shear wave propagating through the liver to assess liver stiffness. Three probes S, M, and XL are used according to body habitus. Greater adiposity may limit test accuracy

High risk (M >9.6 kPa; XL >9.3 kPa): M/​XL Se 0.75/​0.57, Sp 0.92/​0.90, PPV 0.72/​0.71, NPV 0.93/​0.84 Indeterminate (M 7.9–​9.6; XL 7.2–​9.3) Low risk (M 4 foci per ×20 field

(S) Steatosis score 0–​3 Hepatocyte ballooning

PLUS

2 PLUS Inflammation

PLUS 0 1 2

None < 2 foci per 20× field > 2 foci per 20× field

(A) Total = activity score 0–​4 Fibrosis

Hepatocyte ballooning

0 1a 1b 1c 2 3 4

Inflammation

(NAS) Total = NAFLD activity score 0–​8 No fibrosis Zone 3 mild perisinusoidal Fibrosis Zone 3 moderate Perisinusoidal fibrosis Periportal/​portal fibrosis only Zone 3 plus portal/​periportal fibrosis Bridging fibrosis Cirrhosis

(F) Fibrosis score 0–​4

of thiazolidinediones in patients with diabetes has been associated with congestive heart failure, bladder cancer, and bone fractures. Preliminary data suggests that the glucagon-​like peptide-​1 agonist Liraglutide may be beneficial in slowing NAFLD progression, which effect may be largely through weight loss. Vitamin E (800 IU/​day) has been shown to lower ALT levels and to ameliorate histological steatohepatitis in pre-cirrhotic, nondiabetic patients in the PIVENS and TONIC trials, but a clear benefit on liver fibrosis was not demonstrated. Concern regarding an association with increased all-​cause mortality and prostate cancer mean that its use remains controversial, but it is considered by many to be a first-​ line therapy for selected patients with histologically confirmed NASH without cirrhosis or type 2 diabetes. A Cochrane analysis in 2017 of pharmacological interventions for NAFLD found most of the evidence to be of very low quality and concluded that there was no proven benefit for the majority of agents tested up to that point. However, there is substantial drug development activity in this field with a number of pharmacological agents currently in clinical trials such as FXR agonists, PPARa/d/g agonists and CCR2/5 antagonists. It is therefore likely that additional, liver-​ directed therapies will become available within the next few years.

Prognosis The presence of NAFLD appears to be associated with greater all-​cause mortality, estimated to be 34 to 69% higher than the age and sex-​ matched general population. In most cases it has an indolent course, with patients ultimately succumbing to nonhepatic causes of death (principally cardiovascular disease), but some patients exhibit a more aggressive and rapidly progressive form of disease that leads to cirrhosis.

Fibrosis

0 1a 1b 1c 2 3 4

No fibrosis Zone 3 mild perisinusoidal Fibrosis Zone 3 moderate Perisinusoidal fibrosis Periportal/​portal fibrosis only Zone 3 plus portal/​periportal fibrosis Bridging fibrosis Cirrhosis

Fibrosis score 0–​4

FURTHER READING Natural history Angulo P, et al. (2015). Liver fibrosis, but no other histologic features, is associated with long-​term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology, 149, 389–​97.e10. Anstee QM, Targher G, Day CP (2013). Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol, 10, 330–​44. Ekstedt M, et al. (2015). Fibrosis stage is the strongest predictor for disease-​specific mortality in NAFLD after up to 33 years of follow-​ up. Hepatology, 61, 1547–​54. McPherson S, et al. (2015). Evidence of NAFLD progression from steatosis to fibrosing-​steatohepatitis using paired biopsies: Implications for prognosis and clinical management. J Hepatol, 62, 1148–​55. Musso G, et al. (2011). Meta-​analysis: natural history of non-​alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-​invasive tests for liver disease severity. Ann Med, 43, 617–​49.

Diagnosis and risk-​stratification Angulo P, et al. (2007). The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology, 45, 846–​54. Anstee Q, Day C (2015). The genetics of non-​alcoholic fatty liver disease:  spotlight on PNPLA3  & TM6SF2. Semin Liver Dis, 35, 270–​90. Burt AD, Lackner C, Tiniakos DG (2015). Diagnosis and assessment of NAFLD:  definitions and histopathological classification. Semin Liver Dis, 35, 207–​20. Dyson JK, McPherson S, Anstee QM (2013). Non-​alcoholic fatty liver disease:  non-​invasive investigation and risk stratification. J Clin Pathol, 66, 1033–​45.

15.24.3  Drug-induced liver disease

Therapy Gawrieh S, Chalasani N (2015). Pharmacotherapy for non-​alcoholic fatty liver disease. Semin Liver Dis, 35, 338–​48. Lombardi R, et  al. (2017). Pharmacological interventions for non-​ alcohol related fatty liver disease (NAFLD): an attempted network meta-​analysis. Cochrane Database Syst Rev, 3, CD011640. Nguyen V, George J (2015). Non-​alcoholic fatty liver disease management: dietary & lifestyle modifications. Semin Liver Dis, 35, 318–​37.

15.24.3  Drug-​induced liver disease Guruprasad P. Aithal ESSENTIALS Drug-​induced liver disease encompasses a wide range of pathology including idiosyncratic drug-​induced liver injury (DILI), acute fatty liver, autoimmune hepatitis, sclerosing cholangitis, granulomatous hepatitis, and nodular regenerative hyperplasia, as well as drug-​ associated fatty liver disease, cirrhosis, and liver tumours. The vast majority of commonly used drugs are reported to be associated with DILI, including over-​the-​counter preparations, herbal remedies, and dietary supplements. It is important to consider drug therapy as an aetiology when assessing patients presenting with hepatocellular or cholestatic patterns of liver injury. Systematic evaluation and prompt diagnosis followed by discontinuation of the particular medication is crucial to prevent the development of acute liver failure and to avoid inappropriate investigations. Both candidate gene and genome-​wide association studies have identified the critical role of the adaptive immune system in the pathogenesis of idiosyncratic DILI. Human leucocyte antigen alleles that are strongly associated with DILI have the potential to assist in the clinical investigation of patients suspected to have DILI in particular circumstances.

Introduction The term hepatotoxicity has been used nonspecifically in the literature to describe the pathological process leading to hepatocyte death and liver injury from medications, alcohol, illicit drugs, and environmental toxins as well as overdoses. Drug-​induced liver disease encompasses a wide range of pathologies where drug therapy has been implicated as an underlying aetiology. Over 350 medications have been associated with adverse effects on the liver, which is probably due to the central role of the liver in the metabolism and clearance of most drugs. Idiosyncratic drug-​induced liver injury (DILI) is defined as an adverse hepatic reaction that is unexpected on the basis of the pharmacological action of the drug administered; this includes acute liver injury, the most common form, and should be distinguished from the consequences of drug overdose.

Case definitions and phenotypes Liver biochemical tests are most commonly used in clinical practice to detect liver injury. These generally include serum alanine aminotransferase (ALT), alkaline phosphatase (ALP), bilirubin, and albumin. Case definitions for DILI include one of the following thresholds: (1) fivefold or higher elevation above the upper limit of normal (ULN) for ALT, (2) twofold or higher elevation above the ULN for ALP (particularly with accompanying elevations in concentrations of γ-​glutamyl transferase in the absence of known bone pathology driving the rise in ALP level), or (3) threefold or higher elevation in ALT concentration and simultaneous elevation of bilirubin concentration exceeding twice the ULN. Liver injury is designated ‘hepatocellular’ when there is a fivefold or higher rise in ALT alone, or when the ratio of serum activity (activity is expressed as a multiple of ULN) of ALT to ALP is 5 or more. Liver injury is designated ‘cholestatic’ when there is a twofold or higher rise in ALP alone, or when the ratio of serum activity of ALT to ALP is 2 or less. When the ratio of the serum activity of ALT to ALP is between 2 and 5, liver injury is termed ‘mixed’. Several other distinct phenotypes of drug-​induced liver diseases are discussed in this chapter. Each of these forms is identified using the same characteristic features as used to define the primary condition such as autoimmune hepatitis, primary sclerosing cholangitis, and others.

Epidemiology Standard toxicological studies during the preclinical phase of drug development do not reliably detect potential hepatotoxicity of a novel agent; the concordance between liver toxicity in animals and humans is poor. Hepatic adverse reactions are therefore one of the top three organ toxicities identified in phase I to III trials, and are responsible for 22% of 79 drug candidates being dropped from clinical development. As hepatic adverse reactions are too low in incidence to be detected in clinical trials, the hepatotoxic potential of new medications may only be recognized when a large number of people have been exposed to the drug; therefore, hepatotoxicity has been the second most common reason for withdrawal of approved drugs from the market worldwide, accounting for 32% of 47 such drug withdrawals between 1975 and 2007.

Incidence and prevalence of DILI Idiosyncratic DILI due to commonly used medications continues to be encountered in clinical practice. A prospective population-​based study from Iceland estimated the crude incidence of DILI to be 19 per 100 000 inhabitants per year. The incidence of DILI was similar in women and men, but increased from 9 per 100 000 among 15-​to 29-​year-​olds to 41 per 100 000 among those over 70 years of age. The increase in DILI incidence with age has been attributed to increasing use of medications with age. The incidence of acute serious liver injury requiring hospitalization has been estimated to be 0.7 to 1 per 100 000 population per year. In a recent audit from the United Kingdom, involving 881 consecutive patients presenting with jaundice in whom biliary obstruction had been ruled out by imaging, DILI was the underlying

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aetiology in 15% of cases and the second most common cause of hepatocellular jaundice after alcoholic liver disease, which accounted for 25% of cases. Idiosyncratic DILI contributes to 7 to 22% of cases of acute liver failure worldwide, highlighting the potentially serious consequences of this adverse reaction.

on re-​exposure) were described with over 90% of these agents, and all of these drugs were linked to death. Table 15.24.3.1 includes a list of common agents associated with particular forms of drug-​induced liver disease.

Drugs implicated

In the population-​based cohort, 1% of patients presenting with DILI die, while large registries of idiosyncratic DILI (consisting mainly of cases from secondary care) report that 5 to 10% of patients die or receive liver transplantation in a period of 6 months after DILI onset. Those who present with jaundice are more likely to reach these outcomes compared to those who present with less severe manifestations (13 vs 4%), and a hepatocellular pattern of DILI has a worse prognosis than a cholestatic or mixed pattern. The prognosis of those who develop acute liver failure as a consequence of idiosyncratic DILI is worse than that due to other aetiologies. Once acute liver failure develops in patients with DILI, 50 to 80% either die or require transplantation in contrast to 15 to 40% of those secondary to paracetamol overdose. Acute liver injury due to drugs resolves in those who survive the initial episode, but evidence of persistent liver injury (‘chronicity’) 12 months after the onset of DILI has been observed in a small, yet significant proportion of patients on long-​term follow-​up. Several longitudinal cohorts have reported that 6 to 14% of patients have persistent elevation of liver enzymes. In those who were investigated with liver biopsy, chronic hepatitis, fibrosis, ductopenia (vanishing bile duct syndrome), and cirrhosis have been detected histologically. Among 685 survivors of DILI with jaundice at presentation from one cohort, 3.4% were hospitalized over 10 years of follow-​up for reasons related to their liver disease. Diagnoses of autoimmune

Spontaneous reporting, case reports or series, and more recently hepatotoxicity registries have been the main source of information regarding hepatic adverse reaction due to specific drugs or a class of drugs. In addition to variability of reporting, lack of an accurate denominator (number of people taking the particular medication) means that neither the incidence of DILI due to a particular medication nor its relative contribution to the burden of DILI can be reliably estimated. This issue has been exemplified by the findings of a recent prospective study which estimated that 1 in 2350 taking co-​amoxiclav and 1 in 133 on azathioprine developed DILI when compared to previous estimates of 1 in 10000 and 3.4 in 100, respectively. A systematic evaluation of reports of hepatotoxicity due to drugs compiled at the website LiverTox (established by the National Institutes of Health, Bethesda, Maryland, United States of America) has resulted in the categorization of drugs based on the number of convincing reports in the published literature. This process concluded that 353 drugs (excluding herbal remedies, dietary supplements, and illicit substances) were linked to DILI, of which 48 were implicated in more than 50 cases each and included in the highest category of causes of DILI (the vast majority are listed in Table 15.24.3.1). Over 80% of the drugs included in this category were associated with more than 100 reports of DILI, positive rechallenge (recurrence of DILI

Prognosis

Table 15.24.3.1  Common drugs associated with specific forms of drug-​induced liver diseases Phenotype of liver disease

Drug group

Medications

Idiosyncratic DILI

Antimicrobials

Co-​amoxiclav, erythromycin, flucloxacillin, interferon alpha/​peginterferon, isoniazid, ketoconazole, minocycline, nevirapine, nitrofurantoin, pyrazinamide, rifampicin, co-​trimoxazole, and sulphonamides

Central nervous system

Carbamazepine, chlorpromazine, dantrolene, halothane, phenytoin, and valproate

Cardiovascular

Amiodarone, hydralazine, methyldopa, quinidine, statins (atorvastatin and simvastatin)

Immunomodulatory

Azathioprine/​6-​mercaptopurine, infliximab, interferon beta, methotrexate, and thioguanine

Antineoplastic

Busulfan, floxuridine, and flutamide

Rheumatological

Allopurinol, auranofin/​gold products, diclofenac, ibuprofen, nimesulide, and sulindac

Endocrine

Anabolic androgenic steroids, oestrogens/​progestins, and propylthiouracil

Others

Disulfiram and ticlopidine

Autoimmune hepatitis

Diclofenac, halothane, indomethacin, infliximab, methyldopa, minocycline, nitrofurantoin, and statins

Secondary sclerosing cholangitis

Amiodarone, atorvastatin, co-​amoxiclav, gabapentin, infliximab, 6-​mercaptopurine, sevoflurane, and venlafaxine

Granulomatous hepatitis

Allopurinol, carbamazepine, methyldopa, phenytoin, quinidine, and sulphonamides

Acute fatty liver

Amiodarone, didanosine, stavudine, valproate, and zalcitabine

Drug-​associated fatty liver disease

Methotrexate, 5-​fluorouracil, irinotecan, and tamoxifen

Nodular regenerative hyperplasia

Azathioprine, busulphan, bleomycin, cyclophosphamide, chlorambucil, cysteine arabinoside, carmustine, doxorubicin, 6-​ thioguanine, and oxaliplatin

Ductopenic (vanishing bile duct) syndrome

Azathioprine, androgens, co-​amoxiclav, carbamazepine, chlorpromazine, erythromycin, oestradiol, flucloxacillin, phenytoin, terbinafine, co-​trimoxazole

Liver tumours

Anabolic androgenic steroids and oral contraceptives

15.24.3  Drug-induced liver disease

hepatitis as well as cirrhosis leading to decompensation and death were observed as long-​term outcomes.

Risk factors Pathogenesis of DILI involves interaction of a number of drug and host-​related factors which determine the occurrence of these rare events during entirely appropriate therapeutic use of medications (Fig. 15.24.3.1). There are indications that certain risk factors may also influence the phenotype of the adverse reaction, its severity, or duration.

Nongenetic factors Idiosyncratic DILI is clearly distinct from overdose, but the therapeutic dose of a drug could influence the amount of reactive metabolite formed and hence make further downstream events leading to clinical DILI more likely. Drugs with a daily dose of up to 10 mg are less likely to be associated with DILI than those with a dose of at least 50 mg/​day dose. The latter group of drugs is also associated with severe consequences of DILI, such as acute liver failure, transplantation, and death. Similarly, medications with greater than 50% hepatic metabolism and biliary excretion are more frequently associated with severe DILI. Although there is no clear association between age and sex and susceptibility to DILI, these host factors may influence the phenotype of DILI; while hepatocellular pattern of DILI is more common in women less than 50 years of age, men over 60 years of age develop a predominantly cholestatic pattern of DILI.

Genetic susceptibility Absorption, distribution, metabolism, and excretion genes Since drug absorption, distribution, metabolism, and excretion are the key determinants of variability in drug responses in humans, genes that encode proteins involved in regulating these aspects of drug disposition have been investigated as risk factors for DILI.

Daily dose, hepatic metabolism, biliary excretion

HLA genotypes

Cytochrome P450, UDP-glucuronosyl transferase, Nacetyltransferases, pregnane X receptor, ABC transporters

Fig. 15.24.3.1  Genetic and nongenetic risk factors that contribute to the development of DILI.

Cytochrome P450 Genes from the cytochrome P450 family have potentially a key role in determining susceptibility to DILI due to the involvement of these enzymes in oxidative metabolism of drugs, including the formation of reactive intermediates. One such example is that of bosentan (the endothelin receptor antagonist)-​related DILI with the CYP2C9*2 variant which is associated with decreased enzyme activity. Isoform CYP2B6 has been linked to DILI secondary to ticlopidine and efavirenz; oxidative metabolism of both of these drugs is mediated by CYP2B6 enzyme activity. The alleles CYP2B6*1H and *1J associated with increased CYP2B6 activity have been found to increase the risk of ticlopidine DILI, while the CYP2B6*6 allele, associated with decreased CYP2B6 activity and higher levels of plasma efavirenz, is a risk factor for DILI from this drug. UDP glucuronosyltransferases Conjugation with glucuronic acid is a major pathway of drug metabolism. Drugs which include carboxylic acid groups form acyl glucuronides, and these conjugates may form covalent adducts with cellular proteins leading ultimately to DILI. Other glucuronides such as phenol glucuronides have also been implicated in DILI. Slow metabolism of tolcapone may be associated with hepatotoxicity as polymorphisms in the gene encoding the main tolcapone metabolizing enzyme UGT1A6 are significantly associated with elevated transaminase levels. Another UDP-​glucuronosyltransferase gene UGT2B7 has been linked to liver injury from diclofenac. Possession of UGT2B7*2 is associated with higher glucuronidation and increased hepatic levels of diclofenac acyl glucuronide, hence an increased risk of hepatic adverse reaction. In addition, a recent genome wide association study (GWAS) demonstrated that two intronic single nucleotide polymorphisms (SNPs) in UGT2B7 and another in the adjacent UGT2B4 gene were associated with DILI due to diclofenac. N-​acetyltransferases The N-​acetyltransferases conjugate xenobiotics with acetyl groups; NAT1 and NAT2 are two isoforms. Isoniazid, an essential component of most antituberculosis regimens, is metabolized by genetically polymorphic N-​acetyltransferase 2 (NAT2). NAT2 metabolic activity depends on the number of active alleles (NAT2*4 and *12). A  meta-​analysis of 38 studies involving 2225 patients and 4906 controls concluded that slow acetylators (without any active alleles) develop hepatotoxicity more often than rapid acetylators (with two active alleles); the risk ratio of the association between NAT2 genotype and adverse hepatic reaction varied among different ethnic groups. ATP-​binding cassette transporters ATP-​ binding cassette (ABC) transporter family gene products transport both bile acids and drugs. ABCC2 has a major role in the biliary excretion of many glucuronide conjugates. Carriage of an upstream SNP in ABCC2 (C-​24T) has been associated with the risk of DILI among diclofenac users; this SNP lowers the expression of the ABCC2 protein and leads to cellular accumulation of the reactive diclofenac acyl glucuronide. In a study based in Korea, one SNP in linkage disequilibrium with C-​24T and another in the promoter region of ABCC2 were risk

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factors for DILI caused by a range of drugs. Genotypes of ABCB1 which codes for another transporter have been associated with DILI due to nevirapine. Pregnane xenosensing receptor The nuclear receptor pregnane xenosensing receptor (PXR) is a transcriptional regulator for several genes responsible for metabolism and disposition of both drugs and endogenous factors such as bile acids. Numerous drugs act as PXR agonists. SNPs in the PXR gene (NR1I2) have been associated with an increased risk of DILI due to flucloxacillin and diclofenac. Antioxidant genes It is plausible that an individual’s ability to deal with oxidative stress generated by reactive metabolites is one of the determinants of susceptibility to DILI. Accordingly, genotypes of isoforms of glutathione S-​transferases (GSTM1 and -​T1), glutathione peroxidase I  (GPX1), and mitochondrial manganese-​dependent superoxide dismutase (SOD2) have been investigated as risk factors for DILI. Perspective Overall, it is difficult to draw firm conclusions from the studies discussed previously due to heterogeneity between the cohorts and lack of replication. It is also important to note that most of the evidence related to the role of absorption, distribution, metabolism, and excretion genes in DILI has come from candidate gene case–​control studies with small sample sizes, variable case definitions, and the modest relative risks associated with particular alleles or genotypes. Human leucocyte antigen genetic risk factors Several candidate gene studies and GWAS have found consistent associations between both human leucocyte antigen (HLA) class I as well as class  II alleles and DILI. Strongest of such associations is that between HLA‐B*5701 and flucloxacillin-​induced liver injury, where 84% of patients carried the risk allele (compared to 5% of the population-​based controls) with an 81-​fold increased risk of DILI. HLA class II haplotype DRB1*1501-​DQB1*0602 has been found to be a risk factor for co-​amoxiclav DILI consistently across different ethnic groups; the haplotype is found in 53 to 70% of patients compared to 12 to 33% of controls. Association between DILI due to lapatinib (a kinase inhibitor) and DRB1*07:01-​DQA1*02:01 has also been confirmed in two different cohorts. However, as there is extensive linkage disequilibrium in the major histocompatibility complex (MHC) region, it is difficult to conclude that HLA alleles which have the strongest associations are causally related to particular forms of DILI. In addition to influencing the susceptibility to DILI, specific HLA genotypes have also shown protective associations; an 80% reduction in co-​amoxiclav DILI was seen in those carrying the DRB1*07 allele. In contrast, DRB1*07 is associated with an increased risk of flucloxacillin DILI, while DRB1*15 is associated with a reduced risk. Recently, a GWAS demonstrated an association between the HLA class I allele A*33:01 and DILI in general, and the cholestatic or mixed form of DILI in particular. DILI secondary to a number of structurally dissimilar compounds including terbinafine, fenofibrate, ticlopidine, sertraline, enalapril, and erythromycin contributed to this association, highlighting a crucial role for adaptive immune response in the pathogenesis of DILI.

Pathogenesis It is increasingly clear that the grouping of DILI as metabolic or immunological idiosyncrasy is too simplistic. The rarity of idiosyncratic DILI among those exposed to a drug indicates that combinations of a number of drug-​specific and host-​related factors are involved in its pathogenesis.

Formation of protein reactive molecules (haptens) Drugs (prohaptens) in general are low molecular weight organic chemicals and therefore too small to be antigenic. The liver is central to the biotransformation of most drugs, a process which generally leads to the formation of stable metabolites and their safe excretion. Genetic and environmental factors that influence the expression and activities of the drug metabolizing enzymes (phases I and II), transporters involved in the excretion (phase III) of drug metabolites, and PXRs that regulate a number of these processes, together determine the rate of formation and accumulation of reactive metabolites. Overwhelming oxidative stress induced by reactive metabolites can lead to hepatocellular injury, particularly when cellular defence is impaired or these reactive metabolites covalently bind to cellular proteins interfering with vital cellular function. However, unlike in the case of hepatotoxicity as a result of paracetamol overdose, formation of reactive metabolites alone is insufficient to cause clinically significant idiosyncratic DILI. Instead, development of subclinical hepatocyte injury may underlie asymptomatic elevations of liver enzymes seen more frequently in association with exposure to medications. These initial steps are probably necessary precursors of downstream events in pathogenesis (Fig. 15.24.3.2), hence drug-​ specific factors such as daily dose, lipophilicity, hepatic metabolism, and biliary excretion influence the hepatotoxic potential of a particular compound.

Role of drug-​specific antigens and antibodies The importance of further downstream events in the development of DILI is highlighted by the fact that an increasing number and range of medications such as diclofenac, antibiotics, and antitubercular agents taken in their standard therapeutic doses have been associated with drug metabolite–​protein adducts. Antibodies to drug-​ related adducts have also been found in those taking diclofenac in the absence of DILI, although these adducts have been detected more frequently in patients with DILI. A  wide range of anti-​isoniazid, anticytochrome P450, and autoantibodies have been demonstrated in most of a group of patients with antituberculosis therapy-​induced acute liver failure, although the role of these antibodies in the development of organ damage remains unclear.

Adaptive immune response The observations that there is a period of latency between the exposure to the drug and manifestation of DILI, as well as its recurrence with the re-​exposure to the drug (consistent with the formation of memory T cells) following its initial resolution on drug withdrawal, suggest that the adaptive immune response contributes to underlying mechanisms. Emerging evidence from recent GWASs further establishes a central role of components of the adaptive immune system, especially drug-​specific T cells, in mediating the immune responses in the pathogenesis of DILI.

15.24.3  Drug-induced liver disease

activated T cell destroys hepatocyte

HEPATOCYTE endogenous protein

BILE CANALICULUS

no presentation so no response

processing + HLA

Covalent adduct

DRUG

CD8+ T CELL

self protein gives no response

metabolite

metabolite Covalent adduct

MHC I presentation

DRUG

activates cytotoxic immune response

Hapten pathway TCR

damage ‘danger’ signals

metabolite

DRUG

Covalent adduct

non-covalent

Covalent adduct direct bindin

g

no APC required

pi pathway MHC II presentation

APC

CD4+ T CELL

DRUG

endocytosis

MEMORY B CELL Antibodies

pi pathways proliferation

Covalent adduct

altered peptide repertoire pathways

processing + HLA

activates immune responses

Y Y Y

Y Y

endogenous protein

B CELL

Hapten pathway other endogenous proteins

if costimulation by cytokines/danger signals

Fig. 15.24.3.2  Putative mechanisms underlying the pathogenesis of idiosyncratic DILI. pi, pharmacological interaction.

HLA molecules are central to the activation of T cells responsible for initiating the inappropriate immune response that underlies DILI. Both branches of the highly specific adaptive immune response rely on the selective presentation of antigens to T cells by HLAs, highly polymorphic proteins also known as MHC proteins. MHC class I molecules are expressed by almost all nucleated cells, including hepatocytes as well as biliary epithelial cells, and these are encoded by the HLA-​A, HLA-​B, and HLA-​C loci. MHC class I proteins usually associate with peptide antigens consisting of 9 to 11 amino acids generated by the partial degradation of self-​proteins which could include drug metabolite–​ cellular protein adducts. The MHC I–​antigen complex is then expressed on the cell surface and elicits an immune response if a non-​self antigen is recognized,

causing the activation of CD8+ T cells, which leads to the cell-​ mediated killing of the original cell. The first GWAS involving DILI demonstrated that possession of the HLA-​B*5701 allele was associated with an 81-​fold increased risk of DILI on exposure to flucloxacillin when compared with ancestry-​matched controls. Another GWAS involving co-​amoxiclav DILI described a novel association involving HLA-​A*02:01. Both flucloxacillin and co-​amoxiclav DILI cohorts include a predominantly cholestatic/​ mixed pattern of DILI cases. Most recently, a GWAS demonstrated an association between DILI, treated as a single phenotype, and HLA-​A*33:01; this association was stronger with cholestatic/​mixed pattern of cases and strongest with terbinafine DILI.

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MHC class II proteins are only expressed by specialized antigen-​ presenting cells and are encoded by the HLA-​DP, HLA-​DQ, and HLA-​DR loci within the MHC genetic region. MHC class II proteins have a larger binding cleft that can accommodate 12 to 25 residues of an antigenic peptide often derived from an extracellular, non-​ self protein (processed in the endosome following endocytosis). These MHC class  II–​antigen complexes are recognized by CD4+ T cells, which subsequently elicit an immune response. The association of a single HLA allele with DILI due to several chemically unrelated compounds has been observed in relation to the association of DRB1*15:01 with co-​amoxiclav and lumiracoxib, as well as DRB1*07:01 with DILI from lapatinib and ximelagatran. The associations of A*33:01 with DILI in general and DILI secondary to a number of structurally dissimilar compounds including terbinafine, fenofibrate, ticlopidine, sertraline, enalapril, and erythromycin, together with recent findings from in vitro studies on T-​cell responses to flucloxacillin and amoxicillin–​clavulanate, support the hypothesis that either the parent drug or metabolites bind covalently to cellular or circulating protein to form adducts. The drug metabolite–​protein complex then binds to the peptide binding groove of HLA molecules leading to activation and differentiation of T cells with a consequent adaptive immune response-​mediated liver injury (Fig. 15.24.3.2). Evidence that most drugs showing the A*33:01 association undergo hepatic metabolism and biliary excretion may explain the association of A*33:01 with a cholestatic pattern of DILI and could indicate that metabolites contribute to the mechanism leading to hepatotoxicity. In the case of co-​amoxiclav, neither the amoxicillin nor the clavulanic acid components are subject to P450-​mediated metabolism, and in the case of flucloxacillin, the extent of metabolism is very limited. However, activation of T cells by flucloxacillin requires covalent binding to protein and presentation of the drug by antigen-​ presenting cells expressing HLA-​B*57:01; broadly similar findings have been reported for co-​amoxiclav-​induced T-​cell proliferation. Pharmacological interaction concept The pharmacological interaction concept hypothesizes that drugs act directly via noncovalent interactions with MHC proteins or T-​ cell receptors without the presence of an antigenic peptide. Drugs could also interact with peptides that are already associated with an MHC molecule to activate T cells. In the case of ximelagatran, neither the drug nor its metabolites bind covalently to proteins specifically, hence neoantigen formation required for the hapten pathway does not occur. However, in vitro studies have demonstrated that ximelagatran as well as its intermediate metabolite melagatran-​ethyl can directly bind to an HLA-​DRB1*0701 molecule, indicating that pharmacological interaction may be the underlying mechanism leading to the activation of immune response (Fig. 15.24.3.2). Altered peptide repertoire model According to this model, drugs can noncovalently occupy sites within the peptide binding groove of MHC proteins, hence altering the specificities of the MHC peptide binding. This leads to the presentation of self-​peptide antigens that are different to those normally bound. This has been proposed as the central mechanism mediating the cutaneous hypersensitivity reaction secondary to abacavir. In the experiments that described this mechanism, flucloxacillin did

not modify the affinity of HLA-​B*5701-​binding peptides for HLA, indicating that the particular mechanism may not be involved in DILI.

Danger signal This ‘costimulation or danger hypothesis’ proposes that immune activation requires two signals, first an engagement of the T-​cell receptor with an MHC–​peptide complex presenting the antigen, then a second costimulatory ‘alarm or damage signal’ from injured or distressed cells. Danger signals are released by cells following damage caused by infection, toxins, and sterile inflammation. Immune recognition of danger signals occurs through pattern recognition receptors including Toll-​like receptors expressed by most cells found in the liver. In this context, it is interesting to note that antibiotics—​ even with their short duration of exposure (as prescribed in courses of days to weeks)—​are a group of drugs commonly associated with DILI; it plausible that ongoing sepsis could act as a costimulatory signal. In addition to pathogen-​associated molecular patterns (representing exogenous danger), damage-​associated molecular patterns (representing endogenous damage) can also be recognized by Toll-​ like receptors. Drugs or their reactive metabolites may cause subtle hepatocyte injury or bind to cellular components disrupting their function. Damage-​associated molecular patterns released as a result of subclinical injury may act as the necessary costimulatory signal leading to the activation of antigen-​ presenting cells to trigger an immune-​mediated hepatocyte and/​ or cholangiocyte damage.

Diagnosis Hepatotoxicity shares its manifestations with liver diseases from other aetiologies and therefore has to be considered in the differential diagnosis of all acute presentations of liver disease, including those presenting with what appears to be hepatic manifestations of systemic diseases. Specific drugs could also be risk factors for certain forms of chronic liver diseases. Both misinterpretation of liver biochemistry results and failure to recognize the possibility of specific drug therapy as an underlying reason behind a particular pattern of liver biochemical abnormalities continue to occur. One hospital-​based study found that a proactive system identified a 12-​fold higher incidence of acute drug-​induced liver enzyme elevations compared to that identified in routine clinical practice, hence raising suspicion is the first step in the process of diagnosis of DILI (Fig. 15.24.3.3). Diagnosis of DILI is incorrectly made in half of cases; failure to identify a drug as the cause of clinical manifestation, as well as missing a correct alternative diagnosis, both occur in routine practice. Accuracy of clinical diagnosis of DILI (about 45%) is a problem both in primary care and in hospital settings. Delay in diagnosis can mean continued exposure to the offending medication, with consequent worsening of DILI leading to acute liver failure in some cases. Prolonged exposure to drugs has also been associated with delayed resolution of DILI, even after withdrawal of the drug, and with chronicity in a few cases. Missed diagnoses such as biliary obstruction from gallstones and autoimmune hepatitis due to incorrect attribution of the clinical problem to DILI can

15.24.3  Drug-induced liver disease

Consider DILl Acute rise in liver biochemistry * ALT ≥ 5 × ULN * ALT ≥ 3 × ULN and Bilirubin ≥ 2 × ULN * ALP ≥ 2 × ULN

New-onset manifestations • Jaundice • Acute liver failure

New systemic manifestations • Generalized itching • Skin rash • Eosinophilia

Drug history • • • •

New medication introduced (with in the past 3 months in particular) Course of antibiotics in the past 6 weeks Over-the-counter medications Herbal remedies or complementary medications

Causality assessment • • • •

Temporal relationship with the drug and the manifestation Exclusion of biliary obstruction Evidence to support or refute alternative explanation for the manifestation Tests that support or refute alternative diagnosis

Consider specific tests for DILl • HLA genotyping • Lymphocyte transformation test

Fig. 15.24.3.3  Clinical approach to the diagnosis of DILI.

have serious consequences, hence systematic assessment is the key to an accurate diagnosis.

Causality assessment methods These involve structured evaluation of several factors in relation to the clinical presentation that support or refute the link between the drug and the manifestations. The temporal relationship between intake and discontinuation of the suspected drug and onset and disappearance of the manifestation is one of the important factors to consider in the diagnosis. This requires precise information regarding all the drugs, their doses, and durations, including nonprescription (over-​ the-​ counter), herbal, and complementary medications which patients may not consider as relevant. Most DILI occurs between day 4 and 3 months of initial therapy, although some occur later during the first year of treatment. By contrast, DILI due to some drugs (e.g. nitrofurantoin) typically appears more than a year after initial exposure. Ischaemic hepatitis with its characteristic rapid ALT elevation peaking within the first 72 h following circulatory shock, cardiorespiratory arrest, or exacerbation of heart failure is an important differential diagnosis to consider, especially in secondary care. Similarly, perioperative hypotension manifests with liver injury earlier during the postoperative period than DILI from anaesthetic agents. Different components that form causality assessment have been incorporated into tools that assist in a structured evaluation of cases suspected to have DILI. Two such tools are the Roussel Uclaf Causality Assessment Method, developed by Council for International Organizations of Medical Sciences, and the Clinical Diagnostic Scale. These tools attribute scores (numerical weighting) with regards to specific domains that include the temporal

relationship between drug exposure and clinical features, the course of these manifestation once the drug is discontinued, the recurrence of liver injury on re-​exposure to the drug, rigour of exclusion of alternative diagnoses, the presence or absence of risk factors and extrahepatic features of an adverse liver reaction, as well as the strength of previous reports of a particular type of DILI. These validated tools were developed to facilitate pharmacovigilance of hepatic adverse reactions and have been effectively used to harmonize phenotyping of DILI between international groups of researchers. Although it is unrealistic to apply causality assessment tools routinely in clinical practice, these provide a template on which a reliable process of diagnosis and decision-​making can be based. Acute biliary obstruction (e.g. from gallstones within the common bile duct) accounts for more than half the cases of jaundice, and one-​ quarter of cases presenting with an acute hepatocellular pattern of liver enzyme increase (AST >400 IU/​litre) and 5% of those with ALT greater than 1000 IU/​litre. It is therefore imperative to perform hepatobiliary imaging first to exclude this aetiology. Autoimmune hepatitis has an acute presentation in about 40% of people, and it can have a remitting and relapsing course. Early diagnosis and intervention is crucial to improve outcomes in both DILI and autoimmune hepatitis, hence in-​depth investigations are of paramount importance. Ischaemic hepatitis is associated with greater than 50% in-​hospital mortality and should be distinguished from DILI as comorbidity associated with ischaemic hepatitis precludes the consideration of liver transplantation, even when fulminant liver failure ensues. In about 80% of patients with ischaemic injury, lactate dehydrogenase reaches very high concentrations with an ALT/​lactate dehydrogenase ratio less than 1, a pointer that can be used in the diagnostic

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process. Recently, hepatitis E infection has become a more common cause of acute viral hepatitis than hepatitis A, B, and C infections; cytomegalovirus, Epstein–​Barr virus, and herpes zoster virus also contribute a few cases, all of which resemble DILI in their clinical features. The list of other exclusions to secure a confident diagnosis of DILI is exhaustive: investigations should be tailored to suit the particular clinical context.

HLA genotyping is being carried out regularly in centres with transplantation programmes and these services are readily accessible to other secondary care hospitals. In particular, HLA B*5701 genotyping is routinely performed prior to prescription of abacavir (effectively reducing cutaneous hypersensitivity due to the drug), hence protocols and processes are well established with an ability to perform genotyping within 1 day of receipt of a sample.

Role of liver biopsy

Lymphocyte transformation test

DILI can cause any known pattern of liver pathology, but certain histological features are particularly suggestive of drug-​induced aetiology although there are no specific diagnostic histological features. The benefits of performing a liver biopsy should be weighed against the disadvantages and its limitations. Liver biopsy is worthwhile when (1) autoimmune hepatitis is one of the differential diagnoses under consideration (Fig. 15.24.3.4), (2) the event does not resolve as expected on drug discontinuation, and (3)  in circumstances where the clinical/​laboratory features are atypical, or (4) the patient appears to suffer an as yet unrecognized form of DILI.

This investigation, also called the lymphocyte proliferation or stimulation test, measures the proliferation of T cells from the blood samples of a patient suspected to have suffered DILI in response to that particular drug. Principles underlying this test have been supported by the generation of drug-​specific T-​cell clones from individuals who have had a positive response, and also by the pharmacological interaction concept which states that drugs can directly interact with the T-​cell receptor, without previous metabolism or need to bind to proteins. When applied to a cohort of well-​characterized patients with DILI, results of lymphocyte transformation tests have been variable, ranging from occasional positive cases based on reports from Europe to about a 45% positive rate in cohorts from Japan. In addition, when evaluated in the context of cutaneous hypersensitivity, the test has an estimated 15% false-​positive rate. The lymphocyte transformation test is cumbersome, technically demanding, and hence not widely available.

Genetic tests A strong and consistent association between HLA genotypes and DILI has raised the prospect of the potential use of genetic testing in the risk stratification of patients prior to therapy, but the incidence of DILI is too low to use such testing routinely. However, most HLA alleles associated with DILI have a very high negative predictive value of greater than 0.95; hence, they can be used to rule out adverse hepatic reactions due to particular drugs when the certainty of diagnosis is of paramount importance. Key examples of associations of specific HLA alleles with DILI from particular medications include HLA-​B*5701 with flucloxacillin, HLA-​DRB1*1501 with co-​amoxiclav, and HLA-​A*33:01 with terbinafine and other drugs (fenofibrate, ticlopidine sertraline, enalapril, and erythromycin). A high negative predictive value of a genetic test can also be used to identify the correct agent underlying DILI when the patient has been exposed to two concomitant medications, both with the propensity to cause DILI.

Other forms of drug-​induced liver disease Drug-​induced autoimmune hepatitis Many drugs have been reported to have induced the syndrome that shares many features of idiopathic autoimmune hepatitis. In a cohort of cases with the diagnosis of autoimmune hepatitis, 9% were considered to be induced by drugs, and conversely drug-​induced autoimmune hepatitis accounts for 9% of all DILI. Most of these drugs have appeared in case reports or small case series and include nitrofurantoin, minocycline, diclofenac, statins, and antitumour necrosis factor-​α agents (Table 15.24.3.1). Drug-​induced autoimmune hepatitis is difficult to distinguish from the idiopathic form as both have very similar biochemical, clinical, and liver histological features, hence the causal relationship between the drug and autoimmune hepatitis can be best established only when the manifestations resolve completely on drug withdrawal and do not recur on prolonged follow-​up (over 2 years).

Secondary sclerosing cholangitis

Fig. 15.24.3.4  Liver biopsy showing portal inflammation and interphase hepatitis secondary to diclofenac-​induced autoimmune hepatitis.

Previously, sclerosing cholangitis had been described following transarterial infusion of chemotherapeutic agents, but these are results of ischaemic injury to the biliary tract rather than toxicity from chemotherapeutic agents themselves. However, secondary sclerosing cholangitis with diffuse inflammatory stricturing of the biliary tree on magnetic resonance cholangiopancreatography has more recently been described in a small proportion of patients presenting with acute cholestatic DILI (Fig. 15.24.3.5), over 90% of whom were women, with two-​thirds presenting with jaundice. Drugs implicated were co-​amoxiclav, sevoflurane, amiodarone, infliximab, 6-​ mercaptopurine, gabapentin, venlafaxine, and atorvastatin.

15.24.3  Drug-induced liver disease

in children on combination of multiple drugs. A case–​control study demonstrated an association between variation in the polymerase γ gene, POLG, which codes for the mitochondrial DNA polymerase γ, and valproate-​induced hepatotoxicity. Nucleoside analogue reverse transcriptase inhibitors are one class of drugs which are liable to cause hepatotoxicity by interfering with mitochondrial function. Symptomatic adverse hepatic reactions occur with an incidence of 1.2 times per 1000 person/​year. Stavudine, zalcitabine, and didanosine have higher affinities for mitochondrial DNA polymerase γ, leading to the depletion of mitochondrial DNA, and hence have a higher rate of hepatotoxicity than abacavir, zidovudine, lamivudine, and tenofovir. Early recognition and withdrawal of the drug is the critical step in the management of these potentially life-​threatening adverse events.

Fatty liver disease

Fig. 15.24.3.5  Magnetic resonance cholangiopancreatography showing diffuse structuring of intra-​and extrahepatic bile ducts due to drug-​induced sclerosing cholangitis.

Granulomatous hepatitis Granulomata are circumscribed accumulations of macrophages, some of which may fuse to form multinucleated giant cells, with a surrounding rim consisting of lymphocytes that have developed with stimulation of mononuclear cells from a variety of cytokines. Considering the long list of infectious and immunological conditions associated with hepatic granulomata, the diagnosis of drug-​related granulomatous hepatitis depends upon a temporal relationship between exposure to the drug and the clinical manifestation, ruling out an alternative explanation for histological changes, and previous reports in the literature. Allopurinol, carbamazepine, phenytoin, quinidine, methyldopa, and sulphonamides are some of the medications which have been associated with this form of hepatotoxicity.

Acute fatty liver This is a distinct form of acute hepatotoxicity associated with drugs that affect mitochondrial function. Microvesicular steatosis and the absence of glycogen in the hepatocytes are characteristic histological features as the liver uses glycolysis to compensate for the lack of ATP produced by mitochondria. Impaired mitochondrial function leads to apoptosis and liver failure manifesting with hypoglycaemia, lactic acidosis, hyperammonaemia, and cerebral oedema. Dramatically rapid development of organ failure precedes the clinical syndrome, with an acute rise in liver enzymes and jaundice that follow, hence having a high index of suspicion is crucial in identifying the drug aetiology when approaching a patient with ‘anicteric hepatic encephalopathy’. Described initially as ‘Reye’s syndrome’ in children treated with salicylate, the incidence of this condition has been reduced markedly by restricting the use of aspirin in those under the age of 16 years and the use of parenteral preparations of tetracycline. Sodium valproate is one of the drugs currently used that has been linked to the development of acute fatty liver; idiosyncratic hepatotoxicity occurs 1 in 37 000 people taking the drug, and the risk increases to 1 in 500

Nonalcoholic fatty liver disease (NAFLD) is an entity associated with accumulation of fat in more than 5% of hepatocytes, with or without inflammation and fibrosis, in those who do not consume alcohol over the amount considered moderate (14 units in men and women per week). When the condition is associated with metabolic syndrome or idiopathic it is considered primary NAFLD; drugs are the aetiology behind some secondary NAFLD cases. This entity is different from acute fatty liver described previously. Methotrexate After more than five decades of clinical use, methotrexate is the most frequently used nonsteroidal immunosuppressant  therapy  worldwide, with rheumatoid arthritis and psoriasis being common indications for its use. Reports that long-​term methotrexate therapy is associated with fatty infiltration and fibrosis with a potential to progress to cirrhosis have resulted in a plethora of guidelines recommending intense monitoring regimens, including liver biopsies at regular intervals. The proportion of patients estimated to have any degree of liver fibrosis varies from 6 to 72%; with advanced fibrosis ranges from 0 to 33%, and cirrhosis from 0 to 26%. Such wide ranges of reported pathology are due largely to heterogeneity of cohorts, study designs, methods of evaluating histological changes, and case mix. A recent study highlighted the rarity of decompensated cirrhosis associated with methotrexate therapy; of over 150  000 adults who had been listed for or received liver transplantation during a 24-​year period, only 117 (0.07%) had methotrexate-​associated cirrhosis. Methotrexate polyglutamate within the cell interferes with pyrimidine and purine synthesis, through which it exerts its therapeutic effect. In addition, methotrexate indirectly affects methylenetetrahydrofolate reductase and hence the generation of methionine from homocysteine. Excess homocysteine induces endoplasmic reticulum stress, which, when unresolved, leads to fatty infiltration of the liver. Homocysteine, in addition, can also activate proinflammatory cytokines and activate hepatic stellate cells, leading to liver fibrosis. The development and progression of chronic drug-​associated liver disease is determined by interaction between a number of factors related to the drug (such as cumulative dose), the host (such as SNPs in the methylenetetrahydrofolate reductase gene), and/​or the environment (such as alcohol consumption, obesity, and type 2 diabetes). Caucasian ethnicity and female sex are associated with

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decompensated cirrhosis although it is unclear whether this merely reflects the predominance of women and Caucasians among patients with rheumatoid arthritis and psoriasis respectively. Assessment of the risk:benefit ratio of long-​term methotrexate therapy depends upon the efficacy of the drug in an individual weighed against the rate of progression of hepatic fibrosis. The primary objective of monitoring is to detect hepatic fibrosis that is of clinical significance, yet reversible on withdrawal of the drug. Several clinical algorithms that incorporate noninvasive markers of liver fibrosis such as ‘enhanced liver fibrosis’ panel and transient elastography are currently being evaluated as tools to monitor patients on methotrexate therapy. Tamoxifen Treatment with tamoxifen, an oestrogen-​ receptor antagonist, has been associated with accumulation of fat within the liver. In a multicentre trial involving more than 5000 women, tamoxifen therapy was associated with a twofold risk of developing fatty liver over a 5-​year period, with an incidence of 0.4% per year in the treated group compared with 0.2% in the placebo group. This association was restricted to overweight and obese women, and the increased risk manifested within the first 2 years of treatment. Other factors associated with the development of nonalcoholic fatty liver disease included hypercholesterolaemia and arterial hypertension. Among those who had a liver biopsy, most had mild to moderate nonalcoholic steatohepatitis histologically (Fig. 15.24.3.6), but none progressed to cirrhosis after a median follow-​up of 8.7 years. In a large registry of 810 patients with breast cancer treated with tamoxifen, 16 (2%) developed fatty liver on treatment. Tamoxifen was associated with an eightfold risk of developing fatty liver; age and body mass index were other risk factors. The median time from the start of tamoxifen to the diagnosis of drug-​associated fatty liver disease was 22 months; when tamoxifen was discontinued, liver enzymes improved. Only two patients had biopsy-​documented cirrhosis in this registry, although a few more have been described in case reports. Chemotherapy-​associated steatohepatitis

steatosis; obesity is associated with an increased risk. Drugs commonly associated with steatohepatitis include 5-​fluorouracil and irinotecan. Chemotherapy-​associated steatohepatitis increases the risk of infections, liver failure, and overall mortality following major liver resections (for hepatic metastasis).

Nodular regenerative hyperplasia Some drugs can injure endothelial cells of sinusoids and portal venules with consequent occlusion or dropout of smaller radicles. Widespread vascular changes lead to diffuse nodularity within the hepatic parenchyma. The hepatocytes within the nodule are arranged in plates that are more than one cell in thickness, while hepatocytes are compressed and atrophic into thin, parallel plates between nodules (Fig. 15.24.3.7). Characteristically, the nodules are not separated by fibrosis, although there can be perisinusoidal fibrosis and incomplete fibrous septa. In patients on azathioprine therapy, the cumulative rate of development of nodular regenerative hyperplasia has been estimated to be 0.5% over 5 years and 1.5% in 10 years. Other drugs associated with this form of liver disease are 6-​thioguanine, busulphan, bleomycin, cyclophosphamide, chlorambucil, cysteine arabinoside, carmustine, and doxorubicin. In recent literature, oxaliplatin is the most common drug associated with this pathology. In a large group of patients treated with oxaliplatin, nodular regenerative hyperplasia was found on histology in 25% and features consistent with sinusoidal obstruction syndrome in over 50% of patients.

Liver tumours Liver cell adenoma is a benign neoplasm of the liver with an estimated incidence of 3 per million per year. Among regular users of oral contraceptives, its annual incidence is at 3 to 4 per 100 000 although it may be lower with newer pills. The hormonal dose and duration of medication have been associated with the risk of adenoma development, which is highest in women over 30 years of age after using oral contraceptives for more than 24 months. The morphology of hepatic adenomas, with their extensive proliferation of blood-​filled sinusoids supplied by high-​pressure arterial

Reactive oxygen species generated by chemotherapy and intended to induce tumour cell apoptosis can also lead to the development of steatohepatitis, especially in those with pre-​ existent hepatic

Fig. 15.24.3.6  Liver biopsy showing evidence of fat-​laden hepatocytes and fibrosis due to tamoxifen-​associated fatty liver disease.

Fig. 15.24.3.7  Liver biopsy with reticulin stain demonstrating hypertrophic cell plates surrounded by atrophic cell plates typical of nodular regenerative hyperplasia attributed to azathioprine therapy.

15.24.3  Drug-induced liver disease

flow, makes 20 to 40% of them bleed spontaneously causing right upper quadrant pain; intraperitoneal bleeds and ruptures leading to deaths have been reported. Progression to hepatocellular carcinoma occurs in about 10% of adenomas. Ultrasonographic features of hepatic adenomas are nonspecific, but triple-​phase CT scanning or MRI are able to distinguish them from haemangiomas, fibronodular hyperplasia, and hepatocellular carcinomas in the vast majority of patients. A causal association between oral contraceptives and hepatic tumours has been accepted as there have been several reports of regression or resolution of adenomas after cessation of the drugs, although such regression may be less likely when the exposure to oral contraceptives is prolonged. Hormone receptors have also been found in many hepatic adenomas. However, there have also been reports of progression to hepatocellular carcinoma 3 to 5 years after stopping oral contraceptives; hence, surgical resection should be considered based on the site, size, and number of hepatic tumours, as well as certainty regarding their nature on imaging. An association of liver tumours with androgens was first described in patients with Fanconi’s anaemia on anabolic androgenic steroids. Hepatic adenomas, hepatocellular carcinomas, and others (cholangiocarcinoma and angiosarcoma) occur in those who take androgens for Fanconi’s anaemia and other forms of aplastic anaemia as well as for other reasons (such as body builders, hereditary angio-​oedema, and immune thrombocytopenia). In a large series including 133 cases, hepatocellular carcinomas were associated with oxymetholone and methyltestosterone, while adenomas were associated with danazol. Both oral and parenteral therapies were associated with the development of tumours, which appeared after a median period of 4 to 6 years of exposure to the medications. Male predominance among cases may be related to exposure of males to this medication. The causal association between anabolic androgenic steroids and hepatic tumours has been inferred from observations of regression of hepatic lesions upon discontinuation of the medications, but the occurrence of tumours many years after discontinuation of therapy has been reported.

Management The importance of drug-​induced liver disease and DILI in particular lies not in the overall number of cases alone, but in the severity of some reactions and their potential reversibility on prompt discontinuation of the offending medication. The role of corticosteroids in the treatment of DILI has not been systematically evaluated, but corticosteroid therapy does not improve clinical outcomes in drug-​induced acute liver failure. However, it is difficult to distinguish drug-​induced autoimmune hepatitis from the idiopathic form; hence, in practice, some patients are treated with corticosteroids at the time of acute presentation. Under such circumstances, one should consider withdrawal of all immunosuppressant drugs when clinically appropriate, and then monitor closely. Patients who do not relapse within a period of 24 months of complete withdrawal of immunosuppressive therapy can be considered to have suffered drug-​induced autoimmune hepatitis. There is no clear evidence that ursodeoxycholic acid therapy changes outcome in the cholestatic form of DILI, although the drug has been widely used for all forms of cholestasis.

In 11 to 30% of patients with DILI, re-​exposure to the particular agent will result in the recurrence of the adverse reaction. Recurrent DILI develops more rapidly (generally after days or weeks) than following initial exposure, manifests with jaundice in two-​thirds, requires hospitalization in half of cases, and in 13% leads to death. Inadvertent re-​exposure to the particular drug must therefore be avoided. The only exception to this could be the first line antituberculosis regimen that is highly effective, relatively inexpensive, and yet associated with the well-​recognized risk of DILI. If second-​line antituberculosis medications are entirely unaffordable, then the benefits of reintroduction of the same drugs following resolution of the initial event with careful monitoring should be weighed against the risks of recurrent DILI.

Prevention Recent advances in the understanding of the molecular basis of DILI have highlighted the role of adaptive immunity and the contribution of host susceptibility in the pathogenesis of these adverse reactions. Incorporating these factors into the in vitro models used during preclinical evaluation of new compounds would improve the detection of the hepatotoxic potential of these molecules early during drug development. However, it is unrealistic to expect each and every effective drug to be entirely free from adverse effects. Although preprescription pharmacogenetics testing is currently not cost-​effective, it is foreseeable that both genetic and nongenetic factors are incorporated into refined algorithms which will allow minimizing the risk of a particular medication in an individual under specific circumstance.

FURTHER READING Aithal GP (2011). Hepatotoxicity related to antirheumatic drugs. Nat Rev Rheumatol, 7, 139–​50. Aithal GP (2015). Pharmacogenetic testing in idiosyncratic drug-​ induced liver injury (DILI): current role in clinical practice. Liver Int, 35, 1801–​8. Aithal GP, et al. (2011). Case definition and phenotype standardization in drug-​induced liver injury (DILI). Clin Pharmacol Ther, 89, 806–​15. Bjornsson ES, Aithal GP (2014). Immune-​mediated drug-​induced liver injury. In Gershwin ME, Vierling JM, Manns MP (eds) Liver immunology: principles and practice, 2nd edition, pp. 401–​12. Springer, New York. Björnsson ES, et al. (2013). Incidence, presentation, and outcomes in patients with drug-​induced liver injury in the general population of Iceland. Gastroenterology, 144, 1419–​25. Björnsson ES, Hoofnagle JH (2015). Categorization of drugs implicated in causing liver injury: critical assessment based upon published case reports. Hepatology, 63, 590–​603. Dawwas MF, Aithal GP (2014). End-​stage methotrexate-​related liver disease is rare and associated with features of metabolic syndrome. Aliment Pharmacol Ther, 40, 938–​48. Grove JI, Aithal GP (2015). Human leukocyte antigen genetic risk factors of drug-​induced liver toxicology. Expert Opin Drug Metab Toxicol, 11, 395–​409. Hunt CM (2010). Mitochondrial and immunoallergic injury increase risk of positive drug rechallenge after drug-​induced liver injury: a systematic review. Hepatology, 52, 2216–​22.

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Padda MS, et  al. (2011). Drug-​induced cholestasis. Hepatology, 53, 1377–​87. Ramappa V, Aithal GP (2013). Hepatotoxicity related to anti-​ tuberculosis drugs:  mechanisms and management. J Clin Exp Hepatol, 3,  37–​49. Urban, Daly AK, Aithal GP (2014). Genetic basis of drug-​induced liver injury: present and future. Semin Liver Dis, 34, 123–​33.

15.24.4  Vascular disorders of the liver Alexander Gimson

Other conditions discussed include congestive hepatopathy, ischaemic hepatopathy, hepatic artery aneurysm, and portal vein thrombosis.

Budd–​Chiari syndrome Budd–​Chiari syndrome is caused by obstruction to hepatic venous outflow. It is described as primary when the obstruction is caused by a process arising within the veins (e.g. thrombosis), and secondary when due to another process (e.g. compression or invasion by malignancy). It is a rare condition (incidence about 2 per million in both men and women) that can present at any age (median 50 years). Most cases develop insidiously over months, but about 20% present acutely. An underlying predisposing cause can be found in most patients, often in combination (Table 15.24.4.1).

Clinical features

ESSENTIALS The liver’s complex blood supply and high metabolic activity may be affected in a number of clinical situations when there is reduced splanchnic inflow and impaired hepatic venous outflow. Budd–​Chiari syndrome is caused by obstruction to hepatic venous outflow, usually by thrombosis within the hepatic veins. Causes include myeloproliferative disease, malignancy, and hypercoagulable states. Presentation may be acute, subacute, or chronic, and the diagnosis requires consideration in any patient presenting with acute liver failure, acute hepatitis, or chronic liver disease. Diagnosis is made by Doppler ultrasonography of the hepatic veins and confirmed with CT or MRI scanning. Management depends on the presentation, but involves anticoagulation in all cases, and thrombolysis, measures to decompress the liver, and liver transplantation in some. Survival is about 75% at 5 years.

Acute Budd–​Chiari syndrome, which develops over a few weeks, typically presents with fever, right upper quadrant pain, and tender hepatomegaly, which may be associated with hepatic encephalopathy if there is fulminant liver failure (5% of cases). Jaundice and ascites develop rapidly but may not be evident at presentation. Liver blood tests show elevation of bilirubin, aminotransferases (typically 100–​500 IU/​L), and alkaline phosphatase (typically 300–​400 IU/​L). Subacute Budd–​Chiari syndrome usually presents with vague epigastric or right upper quadrant pain. Ascites and pedal oedema may be present but are not invariable. The latter is thought to be due to hypertrophy of the caudate lobe of the liver causing compression of the inferior vena cava, into which it drains directly, rather than through the hepatic veins. Abnormal venous collaterals may be seen on the abdominal wall. Variceal bleeding can occur. Patients with chronic Budd–​Chiari syndrome develop symptoms as a consequence of cirrhosis. In both subacute and chronic cases,

Table 15.24.4.1  Causes of the Budd–​Chiari syndrome Cause

Example

Myeloproliferative disease (50% cases of Budd–​Chiari syndrome)

Polycythaemia rubra vera Essential thrombocythaemia

Malignancy (10% cases)

Hepatocellular carcinoma

Benign liver lesions (5–​10% cases)

Hepatic cysts and abscesses

Hypercoagulable states

Oral contraceptive use Clotting factor mutations, e.g. factor V Leiden, factor II (G20210A) deficiency, antithrombin III, protein C and S deficiency, antiphospholipid syndrome Paroxysmal nocturnal haemoglobinuria

Anatomical abnormality

Membranous webs of inferior vena cava and/​or hepatic veins

Miscellaneous conditions

Behçet’s disease Inflammatory bowel disease Coeliac disease Other autoimmune conditions

Idiopathic

Notes

Nearly 20% of cases occur in women who are taking the oral contraceptive, are pregnant, or have recently given birth

Some may have undiagnosed myeloproliferative disorder; always check for JAK2 mutations

Note: multiple risk factors may contribute in an individual case, for example, a combination of factor V Leiden mutation with a myeloproliferative disorder or use of the oral contraceptive.

15.24.4  Vascular disorders of the liver

serum bilirubin, aminotransferases, and alkaline phosphatase may be normal or mildly/​moderately elevated, but clinically obvious jaundice is rare.

Diagnosis The very variable presentations of Budd–​Chiari syndrome mean that it should be considered in the differential diagnosis of patients presenting with acute liver failure, acute hepatitis, or chronic liver disease. The diagnosis can usually be made by Doppler ultrasonography of the hepatic veins (Fig. 15.24.4.1) and confirmed with CT or MRI scanning (Fig. 15.24.4.2), which provide additional information required for treatment planning. Venography may be required if uncertainty remains after these tests, looking for the characteristic ‘spider’s web’ pattern in occluded hepatic veins. Liver biopsy is not generally required. Causes listed in Table 15.24.4.1 should be sought.

Management and prognosis Treatment, when possible, should be given for any underlying cause. With regards to the thrombosis within the hepatic veins, the initial priorities are to initiate anticoagulation (usually commencing with low molecular weight heparin), unless there are very strong contraindications, and to deal with any complications of portal hypertension that are present. Thrombolysis may be given, depending on balance of benefits and risks in each case, if imaging reveals an acute (usually regarded as 95% in good hands). The presence of dilated ducts gives evidence of obstruction, and ultrasonography is around 30 to 70% sensitive and 90% specific for common bile duct stones depending on symptoms and blood tests (pretest probability). A normal examination does not, therefore, rule them out, and where suspicion is high, other tests should be used. MRCP or EUS are the usual next steps depending on availability, with sensitivities of around 95% when pretest probability is moderate to high. Each has its advantages and disadvantages. MRCP has no endoscopic or sedation risks, is useful where there is altered anatomy, and allows later independent review of images (Fig. 15.25.7). EUS can often be used where MRCP is not possible due to the presence of a pacemaker/​implanted cardiac defibrillator, mechanical heart valves, intracranial metal clips, morbid obesity, or severe claustrophobia. CT also has a role as it is often used when the cause of pain or sepsis is uncertain and is useful for differential diagnosis. Obstructing disease of the bile ducts is most commonly due to gallstones (Fig. 15.25.8), but a wide range of stricturing disorders both benign and malignant must also be considered.

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injury to a duct within the gallbladder bed, which usually closes with simple drainage or drainage combined with duct decompression by sphincterotomy and stent. Cholecystectomy relieves symptoms of biliary colic and acute cholecystitis, but other nonspecific symptoms often persist after operation. Common bile duct stones Optimal elective management of common bile duct stones is by ERCP. If the gallbladder is in situ this may be either before or soon after laparoscopic cholecystectomy. ERCP during cholecystectomy may be cost-​effective and convenient for patients but is rarely practical. Laparoscopic bile duct exploration with a flexible choledocoscope is another option and is preferred to open duct exploration because of a lower rate of trauma to the duct, increased chance of primary duct closure, and less use of T tubes with a lower risk of biliary strictures in the future. Preoperative imaging or intraoperative cholangiography is recommended for patients with a high pretest probability of stones (principally those with dilated ducts on ultrasound). Fig. 15.25.7  MRCP revealing stones in the distal common bile duct (arrow).

Management Laparoscopic cholecystectomy With the introduction of laparoscopic cholecystectomy, a shift occurred in the balance between benefit of operation and the associated risks and discomfort. Very few patients are now treated by alternative techniques. Laparoscopic surgery allows most patients to be treated as a day case, with return to normal activities within 2 weeks. Complication rates are low, the most serious being injury to the bowel or a bile duct, which occur in less than 1% of cases. About half of those with persistent bile leak after surgery arise from

Endoscopic removal of gallstones ERCP is an evolving technique for the removal of stones and employs increasingly complex therapeutic options. The basic principles of treating stone disease are as follows: (1) gain and then increase access to the common bile duct by cutting (sphincterotomy) (Fig. 15.25.9) with or without stretching (sphincteroplasty) the

CBD stones

Fig. 15.25.8  ERCP cholangiogram demonstrating stones (seen as filling defects) in the common bile duct (CBD).

Fig. 15.25.9  Balloon sphincteroplasty to facilitate removal of large common bile duct stones. Variable sizes of balloon are available, but in general it is wise not to exceed the diameter of the common bile duct above in order to reduce the risk of perforation.

15.25  Diseases of the gallbladder and biliary tree

Fig. 15.25.11  Crushing lithotripter for stone removal.

Open surgery Fig. 15.25.10  Clearance of common bile duct stones with a balloon trawl (black arrow). Note previous cholecystectomy clips (white arrows).

sphincter of Oddi; (2)  obtain a cholangiogram to identify the number and size of the stones; (3) where necessary, reduce the size of stones in order to facilitate their removal, either by crushing (Fig. 15.25.10) or applying direct energy to them; (4) remove the stones by dragging or grasping them from the duct (Fig. 15.25.11); (5) where removal is not possible, ensure biliary drainage is secured with appropriate stenting.

Despite all of these techniques, endoscopic therapy occasionally fails and a surgical solution may be sought. Where the gallbladder is still present, this may involve laparoscopic bile duct exploration at the time of cholecystectomy. Where the gallbladder has (a)

(b)

(c)

(d)

Other methods of treating gallstones Extracorporeal shock wave lithotripsy, oral bile acid therapy, and contact dissolution of gallstones are seldom used in the era of laparoscopic surgery and ERCP. These treatments lost their appeal when laparoscopic surgery became available because they are slow, requiring many months, and cumbersome, with repeated imaging needed to monitor progress. They also leave the gallbladder in situ and the patient is thus at risk of recurrence of gallstones. By contrast, laparoscopic cholecystectomy and ERCP are day-​case treatments that remove the gallbladder, permanently relieve symptoms in most patients, and have a very low complication rate in skilled hands. Direct cholangioscopy-​facilitated electrohydraulic lithotripsy (EHL) or laser lithotripsy Under direct vision at cholangioscopy, energy can be delivered directly to large troublesome stones to cause fragmentation. EHL uses a high-​voltage spark to create rapid thermal expansion of fluid and a subsequent hydraulic pressure wave. Laser lithotripsy (Fig. 15.25.12) uses pulsed energy to create the same effect. Following fragmentation, stones can be removed by traditional methods including balloons and baskets.

Fig. 15.25.12  Laser lithotripsy of difficult common bile duct stones. Gallstones are targeted and fragmented with high-​energy lasers under direct vision using cholangioscopy, thereby allowing extraction with baskets and balloons. Panels (a) and (b), before lithotripsy; panels (c) and (d), after lithotripsy.

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previously been removed, open duct exploration may be required. In rare cases where stones cannot be removed (usually after multiple attempts), hepaticojejunostomy may be required because of the long-​term risk of secondary biliary cirrhosis and recurrent cholangitis. Laparoscopic-​assisted ERCP in altered surgical anatomy Increasing use of bariatric surgery means that it may not be possible to access the bile duct from the duodenum via the mouth. Nevertheless, gallstone disease is very common after bariatric surgery and stones in both the gallbladder and common bile duct represent a difficult problem. This may be overcome by a combined approach of the surgical team using laparoscopic techniques to access the stomach remnant and hence duodenum via the transperitoneal route. The ERCP can then be carried out as normal. Alternatives to cholecystectomy In some very frail, elderly persons, those with significant comorbidi­ ties, and those with advanced cirrhosis, cholecystectomy presents too great a risk. In these situations, ERCP is often undertaken as definitive treatment of bile duct stones, or to prevent recurrence of pancreatitis, with biliary sphincterotomy and ductal clearance. Where stone extraction is not possible, biliary stenting is often used, usually with placement of double-​pigtail stents to ensure that drainage is maintained, although cholangitis is still a common complication. With this approach, regular stent changes every 3 months are associated with much lower rates of cholangitis and mortality than with an ‘on-​demand’ stent change practice.

Most patients with symptoms after cholecystectomy have nonulcer dyspepsia. If the symptoms are troublesome, investigations should aim to exclude other pathology. Liver function and liver ultrasonography will exclude parenchymal disease; upper gastrointestinal endoscopy may be helpful to look for peptic ulceration and gastro-​ oesophageal reflux, and colonoscopy or CT colonography may be considered if there are lower gastrointestinal symptoms. Serology for Helicobacter pylori and for endomysial antibody to exclude coeliac disease may be helpful. Any treatable condition should be managed appropriately. Gastro-​oesophageal  reflux Reflux symptoms occur or are increased after cholecystectomy in at least 10% of patients as a result of disruption of the feedback mechanism that controls release of cholecystokinin (CCK). After cholecystectomy, postprandial and fasting CCK levels in the blood are raised. In addition to causing gallbladder contraction and relaxation of the sphincter of Oddi, CCK also causes relaxation of the gastric cardia and a fall in lower oesophageal sphincter pressure, which facilitates reflux. In most patients these symptoms settle within 12 months, but some will require temporary or long-​term proton pump inhibitors. Bile salt diarrhoea

After cholecystectomy, between 1 and 5% of patients report increased bowel frequency. Stools may be softer than previously but are rarely loose. This occurs in the absence of identifiable bowel pathology and is caused by disruption of circulation of bile salts so that more enter the colon where they are irritant to the mucosa. Normal Complications of management of gallstones enterohepatic circulation of bile salts requires almost complete reComplications of ERCP absorption in the terminal ileum. The absence of the gallbladder reERCP is an invasive surgical procedure and must not be under- duces the capacitance of the biliary system so that bile production taken lightly. The most common complication is pancreatitis, during fasting cannot be accommodated. Some bile enters the duowhich overall occurs in 2 to 3% of cases, even in expert hands. denum as a result. In addition, the raised fasting levels of CCK after Risk factors for pancreatitis include multiple cannulation attempts, cholecystectomy may reduce sphincter pressure, and also favour remultiple cannulations, and injection of contrast into the pancre- lease of bile in the absence of food. The higher concentration of bile atic duct. Perforation may occur in any part of the upper gastro- salts reaching the colon in the absence of luminal residue which usuintestinal tract in relation to passage of the endoscope but is most ally adsorbs some of the bile salts leads to mucosal irritation in the commonly related to sphincterotomy and/​or precut papillotomy. caecum. This impairs water absorption leading to passage of softer, Guide-​wire perforation also occurs. When recognized and treated more frequent stools. The diagnosis can be confirmed with a SeHCAT test. Radiolabelled by keeping the patient nil by mouth and administering antibiotics, most cases of guide-wire perforation settle without the need for bile salt is ingested and 1 week later the amount of retained isotope indicates normal or impaired bile salt absorption. Mild symptoms surgery. Sepsis and bleeding also occur. Rectal indomethacin (100 mg) has been shown to halve the rate may require no treatment other than explanation of the cause. More of post-​ERCP pancreatitis. In difficult cases where access to the pan- severe symptoms often respond to reduction of dietary fibre and/​or creatic duct inadvertently occurs, the placement of a pancreatic duct antidiarrhoeal medication (codeine or loperamide). Cholestyramine which binds intraluminal bile salts is effective, but many patients stent can further reduce incidence of pancreatitis. find it unpalatable and prefer other measures or adjust to their new Postcholecystectomy syndromes bowel habit. There is often improvement in symptoms during the This is a poorly defined group of symptoms which includes some months after operation, but if symptoms are still present after 1 year specific conditions (e.g. bile salt-​ related diarrhoea and gastro-​ they are likely to be permanent. oesophageal reflux) that result from cholecystectomy. However, many patients given this label in fact have some other condition Sphincter of Oddi dysfunction which has not been affected by the removal of the gallbladder. It is self-​evident that, if cholecystectomy has been performed in patients with symptoms unrelated to the gallbladder (whether or not they Sphincter of Oddi dysfunction is an increasingly recognized clinical have typical biliary colic or acute cholecystitis), then these symp- syndrome comprising right upper quadrant pain with or without abnormal liver biochemistry and with or without dilated bile ducts. toms will still be present after operation.

15.25  Diseases of the gallbladder and biliary tree

Table 15.25.3  Milwaukee Classification for sphincter of Oddi dysfunction 1

Biliary pain, abnormal liver function tests (LFTs), dilated bile ducts

2

Biliary pain, abnormal LFTs or dilated ducts

3

Biliary pain

Indeterminate stricture History, examination, CT/MRI/bloods Associated mass? No

The gold standard for diagnosis is biliary manometry. An alternative strategy involves injection of botulinum toxin into the sphincter and clinical assessment of symptoms. When the diagnosis is confirmed, formal sphincterotomy can be performed, often resulting in long-​ lasting relief of pain. Risk of pancreatitis is very high in this group and the patient should be counselled to this effect. This syndrome can be subclassified into types 1, 2, and 3 by the Milwaukee system (Table 15.25.3) with the best results reported in type 1 patients who have abnormal liver function associated with dilated ducts during an attack of pain. See Chapter 15.26.1 for further discussion of sphincter of Oddi dysfunction in the context of acute pancreatitis, including the Rome III diagnostic criteria.

Indeterminate biliary strictures Biliary strictures are a diagnostic challenge because of their wide differential diagnosis, common lack of unequivocal features on imaging, and the need to obtain tissue, which can be difficult to get. The wide range of possible pathologies (Table 15.25.4) have very different outcomes and management.

Table 15.25.4  Aetiology of biliary strictures with key clinical features Pathology

Clinical features

Cholangiocarcinoma

Imaging, cytology/​FISH/​histology

PSC with dominant stricture

Imaging, negative cytology/​histology

Autoimmune (IgG4) cholangitis

Imaging, serology, IgG4 cytology/​histology Involvement of other organs

Mirrizi’s syndrome

History compatible with cholecystitis

Postoperative

History of gallbladder/​bile duct surgery, often with associated complications. History of liver transplant, type of anastomosis

Stone-​related stricture

History, stones on imaging

Trauma

History

Post radiation

History

Ischaemic/​post-​transarterial chemoembolization

History

Vasculitis

History, serology

Infection, e.g. HIV, tuberculosis, worms

History, serology

Extraluminal compression: • Pancreatic cancer • Chronic pancreatitis • Lymph node metastases • Lymphoma • Pancreatic cysts • Retroperitoneal disease

History, imaging

Yes

ERCP +/-Spyglass +cytology/fish/dia/biopsy

EUS/percutaneous biopsy Diagnosis?

No

Yes

Definitive treatment

Re-evaluate

? Trial of steroids

Fig. 15.25.13  Algorithm for investigation of indeterminate biliary strictures.

Pragmatic approaches which assume a cancer diagnosis run the risk of high-​morbidity surgery or inappropriate metal stenting in benign cases. Watchful waiting risks missing cancers when they are potentially curable. This is a common problem in hepatobiliary medicine and the diagnostic algorithms are continuously evolving: a suggested approach to diagnosis is shown in Fig. 15.25.13. With the increasing recognition of IgG4 disease in these difficult cases, a trial of steroids for 4 to 6 weeks may be justified on the grounds that major surgery can be avoided in some. The disadvantage to this approach is that time may be lost where a tumour becomes impossible to resect, and infective complications might be more common.

Obstructive jaundice due to biliary tract disease Regardless of the type of obstruction, effective biliary decompression (either endoscopically or percutaneously) is of benefit to patients. This improves symptoms of cholestasis, improves nutrition, and, in some cases, improves survival. In gallstone-​related disease, removal of the offending stone is usually sufficient to relieve obstruction. In stricturing disease, stenting is usually required. In malignant disease, drainage allows palliative chemotherapy or neoadjuvant chemotherapy to be given. For palliation, stenting has less morbidity than surgical bypass. At least a third of the liver needs to be drained for decompression to be effective. The best mode of decompression therefore depends on the location of the obstruction. Distal disease involving the common bile duct or common hepatic duct can be treated with a single stent, which is best placed endoscopically. Between 75 and 80% of hilar strictures can be successfully decompressed with a single stent, but strictures at the hilum may require multiple stents, which can sometimes be achieved at ERCP although more often PTC is required. For malignant disease, there is increasing use of self-​expanding metal stents which give longer palliation and long-​ term patency (Fig. 15.25.14, Fig. 15.25.15). In malignant disease where strictures are present, there are several novel endoscopic approaches to therapy aimed at maintain­ing longer patency of the stent. These include photodynamic therapy,

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(a)

(b)

Symptomatic strictures warrant endoscopic therapy with ERCP which should also include the acquisition of brush cytology with or without FISH/​DIA where available. Biliary sphincterotomy and balloon dilatation of stricture under antibiotic cover appears to improve survival and reduce the risk of cholangiocarcinoma developing subsequently. The role of placing biliary stents is unclear; there is no evidence of benefit for plastic stents, although fully covered self-​ expanding metal stents may help by slowly dilating the stricture.

IgG4-​related sclerosing cholangitis

Fig. 15.25.14  (a) Hilar stricture with almost complete occlusion of the hepatic duct going into the right hepatic duct and with no filling of left ducts. (b) Placement of an uncovered self-​expanding metal stent with decompression of right-​sided biliary ducts.

radiofrequency ablation, and brachytherapy. All of these techniques need to be combined with self-​expanding metal stents for optimal results.

Specific causes of biliary strictures Primary sclerosing cholangitis Primary sclerosing cholangitis (PSC) is discussed in Chapter 15.23.4. Dominant strictures of the extrahepatic bile ducts are defined as a stenosis of 1.5 mm or less in the common bile duct or 1 mm or less in the hepatic duct. The presence of a dominant stricture in patients with PSC is a common clinical problem and one which carries a worse overall prognosis (especially in the setting of inflammatory bowel disease). They may be present at presentation, when evaluation is as for an indeterminate stricture. If a dominant stricture develops in a patient with known PSC, it is crucial to exclude a cholangiocarcinoma. (a)

(b)

Fig. 15.25.15  Biliary stricture just below the hilum before (a) and after (b) placement of an uncovered self-​expanding metal stent. The stent is traversing the ampulla and extends up into the intrahepatic ducts. Bile in the side branches will drain through the mesh of the stent.

IgG4-​related disease is a multisystem disorder, first described in 2003 as autoimmune pancreatitis. It is now recognized to affect many organs with several clinical phenotypes. IgG4 disease of the bile duct is increasingly recognized as an important cause of indeterminate strictures. Its diagnosis is important as it has a specific treatment, and diagnosis avoids major surgery or problems related to ‘pragmatic’ metal stent placement. Tissue acquisition with direct cholangioscopy and immunostaining of biopsies for IgG4 facilitates diagnosis. The HISORt criteria (histology, imaging, serology, other organ involvement, and response to therapy) (Table 15.25.5) encompass a number of clinical features to assist with diagnosis. There is a male preponderance and it mainly occurs in the fifth and sixth decades of life. The natural history is not yet established and the differential diagnosis includes cholangiocarcinoma, pancreatic carcinoma, and primary and secondary sclerosing cholangitis depending on the location of the strictures. Pathogenesis is poorly understood but differs from many other autoimmune diseases in that there appears to be T helper (Th)-​2 and regulatory T-​cell drivers as opposed to the more normal Th1/​Th17 phenotype. Treatment is typically with steroids, although there are no high-​ quality trials at the time of writing: 30 to 40mg of prednisolone is typically given for 4 weeks, then tapering 5 mg every 2 weeks. Response to steroids helps make the diagnosis, with CT/​ERCP changes seen within 4 to 6 weeks. A nonresponse may indicate the wrong diagnosis but may also result from burnt-​out disease or a more fibrotic phenotype. Relapse is common and, if it occurs, can be retreated with steroids followed by azathioprine. Table 15.25.5  HISORt diagnostic criteria for IgG4-​related sclerosing cholangitis Histology of the bile duct

Lymphoplasmacytic sclerosing cholangitis Lymphoplasmacytic infiltrate with >104 IgG4 positive cells/​high powered field Storiform fibrosis Obliterative phlebitis

Imaging of the bile duct

Axial imaging reveals 1 or more strictures (intrahepatic, proximal extrahepatic, or pancreatic bile duct with thickening and inflammation) Fleeting or migratory strictures

Serology

IgG4 in serum (can be normal in up to 20%, can be elevated in other conditions, e.g. 9% of PSC)

Other organ involvement

Pancreas, kidney, salivary glands (sclerosing sialadenitis), lungs, pericardium, meninges, pituitary and encompasses retroperitoneal fibrosis, Reidel’s thyroiditis and Mikulicz’s disease

Response to steroid therapy

Normalization of liver enzymes or resolution of stricture

15.25  Diseases of the gallbladder and biliary tree

Secondary sclerosing cholangitis Secondary sclerosing cholangitis develops in response to an identifiable process involving biliary obstruction, including chronic obstruction of any cause, stones, parasites, surgical trauma of biliary tree, ischaemic cholangitis (e.g. after transarterial chemoembolization), and recurrent pancreatitis.

Cholangiocarcinoma Cholangiocarcinoma is discussed in Chapter 15.24.6.

Gallbladder cancer Except when discovered incidentally after laparoscopic cholecystectomy, when the cancer is often confined to the gallbladder wall and metastatic spread is minimal, gallbladder cancer often presents at an advanced stage with direct invasion into bile duct, liver, duodenum, or colon, and spread to local nodes, or liver metastases. It is often asymptomatic until obstructive symptoms arise. On imaging, gallbladder cancer appears as irregular thickening of the gallbladder wall or an intraluminal mass with enhancement after intravenous contrast. In patients with symptoms of biliary disease, ultrasonography is often the first test used. This may show the mass and will detect dilated ducts. However, cross-​sectional imaging using CT or MRI is best, obtaining good views of masses, dilated ducts and enlarged lymph nodes. MRI allows excellent views of hepatobiliary anatomy and when combined with an MRCP shows ductal involvement, demonstrates hilar vascular involvement, and is also good for viewing liver metastases. MRI is not as good as CT

TYPE 1

TYPE 3

for identifying distant metastases, and in clinical practice both are commonly used. Treatment is by surgical resection if possible, with extensive lymphadenectomy to clear the hepatoduodenal ligament and resection of the adjacent liver segments (4 and 5). Some surgeons advocate clearance of bile duct and lymph nodes from the hepatoduodenal ligament, to leave only skeletonized hepatic arteries and portal vein. When gallbladder cancer is discovered incidentally after laparoscopic cholecystectomy, the patient should be referred urgently to a hepatobiliary surgeon for consideration of early repeat operation to resect segments 4 and 5 of the liver with lymph node clearance. This policy greatly improves the chance of cure, and the BILCAP trial has also shown survival benefit for adjuvant capecitabine after surgical resection of gallbladder cancer

Congenital disorders of the bile ducts Choledochal cysts These are rare congenital abnormalities of the bile ducts, most commonly diagnosed in children and most prevalent in east Asian populations. They may be found incidentally or as a result of their complications which include malignant transformation, cholangitis, pancreatitis, and cholelithiasis. Adult patients typically present with biliary or pancreatic symptoms such as abdominal pain or jaundice. The cysts represent increased risk for stone disease during biliary stasis, and for biliary malignancy. Anomalous pancreaticobiliary duct union outside of the duodenal wall is present in 30 to 70%, with a long common channel

TYPE 2

TYPE 4

Fig. 15.25.16  Classification of choledochal cysts.

TYPE 5

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Table 15.25.6  Types of choledochal cyst Type

Comment

1

90% of cases. Cystic lesion of the bile duct. May present as a dilated common bile duct . Lacks biliary mucosa

2

Diverticulum of common bile duct

3

Intraduodenal (lined by duodenal mucosa)

4

Intra-​and extrahepatic duct involvement

5

Caroli’s disease. Intrahepatic saccular dilatations, communicating with bile ducts. Can be associated with extensive fibrosis

(>15 mm from the ampulla). This allows reflux of pancreatic juice into the biliary tree. It is thought that the enzymes may then contribute to cyst formation with inflammation of the cyst walls and hyperplasia. Intrahepatic cysts are associated with portal fibrosis and bile duct proliferation as well. Cysts are classified into five types depending on location and shape (Fig. 15.25.16, Table 15.25.6). Cholangiography is the most sensitive way to define ductal anatomy. Associations include double common bile duct, sclerosing cholangitis, hepatic cysts, and annular pancreas. Types 1 and 4 are most associated with cholangiocarcinoma (Fig. 15.25.17). Management of type 1 and 4 cysts is by excision, which depending on cyst involvement may include hepatic or Whipple’s resections. Types 2 and 3 are usually left alone. Type 5 (Caroli’s disease) may require transplantation due to recurrent sepsis and progressive liver failure.

FURTHER READING Johnson CD (2003). Arris & Gale lecture. Regulation and responses of gallbladder muscle activity in health and disease. Ann R Coll Surg Engl, 85, 297–​305. National Institute for Health and Care Excellence (NICE) (2014). Gallstone disease: diagnosis and management of cholelithiasis, cholecystitis and choledocholithiasis. NICE, London. Soares KC, et al. (2014). Choledochal cysts: presentation, clinical differentiation, and management. J Am Coll Surg, 219, 1167–​80.

Fig. 15.25.17  Type 1 choledochal cyst with anomalous pancreaticobiliary duct union (white arrow) complicated by cholangiocarcinoma (blue arrow).

15.26

Diseases of the pancreas

CONTENTS 15.26.1 Acute pancreatitis  3209 R. Carter, Euan J. Dickson, and C.J. McKay

15.26.2 Chronic pancreatitis  3218 Marco J. Bruno and Djuna L. Cahen

15.26.3 Tumours of the pancreas  3227 James R.A. Skipworth and Stephen P. Pereira

15.26.1  Acute pancreatitis R. Carter, Euan J. Dickson, and C.J. McKay ESSENTIALS Acute pancreatitis affects 300 to 600 new patients per million population per year and is most commonly caused by gallstones or alcohol. Careful imaging reveals that most so-​called idiopathic acute pancreatitis is due to small (1–​3-​mm diameter) gallstones. Diagnosis is made by a combination of a typical presentation (upper abdominal pain and vomiting) in conjunction with raised serum amylase (more than three times the upper limit of normal) and/​or lipase (more than twice the upper limit of normal). Several other acute abdominal emergencies can mimic acute pancreatitis and may be associated with a raised serum amylase. In equivocal cases, a CT scan is indicated to exclude other causes and confirm the diagnosis. Initial management is with (1)  analgesia, (2)  ensuring adequate oxygenation, and (3) intravenous fluid administration. The revision of the Atlanta classification separates patients clinically into (1) mild—​ with early resolution without complications, (2)  moderate—​local complications without organ failure, and (3) severe—​complications associated with organ failure. Mild acute pancreatitis responds to analgesia and intravenous fluids. If gallstones have been identified, then cholecystectomy

(or endoscopic retrograde cholangiopancreatography (ERCP) sphincterotomy where clinically appropriate) should be performed during the same admission, or at least within 2 to 4 weeks to prevent recurrent attacks. Severe acute pancreatitis carries a high mortality (up to 20%). Management in the early stages is centred on organ support (respiratory, circulatory, and renal failure). Later management involves surgical or radiological intervention for sepsis, usually within a specialist pancreatic unit. With regard to some specific aspects of management:  (1) there is no indication for a nasogastric tube or starvation:  enteral feeding of patients with prolonged illness is associated with fewer risks and side effects than total parenteral nutrition. (2)  Antibiotics should not be given until and unless a specific indication arises. (3)  ERCP—​occasionally cholangitis may be associated with hyperamylasaemia, in which case urgent biliary decompression at ERCP is indicated. (4) There are no pharmacological agents that benefit any form of acute pancreatitis. (5) The case for decompressive laparotomy for abdominal compartment syndrome remains unproven.

Epidemiology Population studies from Scotland and Finland have shown the incidence of acute pancreatitis is about 400 patients/​million per year. Incidence would appear to be rising, with a 100% increase in the hospitalization rate in the United States of America over the last 20  years, a 75% increase in admissions in the Netherlands, and a 3.1% yearly rise in incidence in the United Kingdom. The mean age at presentation is 53 years with a roughly equal sex distribution, although the largest increase in incidence has been among women under 35  years, which may reflect increasing obesity within the population. The disease was most prevalent in those with poorer socioeconomic status, especially where alcohol was the cause. Overall mortality is from 2.0 to 7.5%, highest in those who are over 70 years, obese individuals, and those with comorbidity at the time of onset. Prospective and retrospective studies record 45 to 50% of deaths as occurring in the initial week of the illness secondary to fulminant multiple organ failure.

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Clinical features Sudden onset of severe upper abdominal pain focused in the epigastrium with vomiting is the most common presentation. This tends to progressively lessen in severity over the first 48 to 72 h, and it is not usually a significant factor beyond this time. There may be upper abdominal tenderness and guarding, but these signs are often less marked than might be suspected from the severity of the pain, and bowel sounds are usually absent in the early stages. Vomiting is prevalent in the first 12 h of illness, contributing to hypovolaemia and hypotension. Clinical jaundice is rare on admission, although minor abnormalities of biochemical liver blood tests occur in 80% of patients with a biliary aetiology. Occasionally, hyperamylasaemia occurs in association with cholangitis, which if overlooked may result in irreversible multiple organ failure. The presence of jaundice and pyrexia on the day of admission is therefore an indication for urgent endoscopic retrograde cholangiopancreatography (ERCP) and biliary decompression.

Pathology The initial phase of acute pancreatitis is characterized by oedema and the development of an acute inflammatory infiltrate, rich in neutrophils, with tiny spots of fatty tissue necrosis, mainly on the surface but also in the intralobular fatty tissue. In mild cases, the changes are most marked in the peripancreatic tissue, but because the initial pancreatic histological change is within the intralobular fat, there is a relationship between extent of necrosis and the amount of fat within the pancreas. In severe disease, intravascular thrombosis and local enzymic necrosis leads to confluent areas of fat necrosis, which extends beyond the pancreas into the peripancreatic fat. Within the pancreas, disseminated ductal and periductal necrosis may be evident.

Diagnosis and assessment of severity The diagnosis is usually made from the clinical presentation of upper abdominal pain and vomiting associated with an elevation of serum amylase or lipase. A CT scan should be performed when the diagnosis is not clear. This often demonstrates pancreatic oedema and peripancreatic inflammatory stranding, fluid collections, and poor contrast enhancement of the gland (Fig. 15.26.1.1). Occasionally, the diagnosis may first be made at laparotomy, when simple washout and closure is all that should be done. The differential diagnosis is that of an acute abdomen (Box 15.26.1.1). A  raised amylase may be associated with several of these conditions, but the (near) universal availability of CT has simplified diagnosis when doubt exists.

Biochemical abnormalities A multitude of biochemical phenomena are found in acute pancreatitis. Various pancreatic enzymes are released that are useful as diagnostic markers. Acinar cell disruption leads to high serum levels of amylase, lipase, trypsin, chymotrypsin, phospholipase, elastase, trypsinogen activation peptide, and phospholipase activation

Fig. 15.26.1.1  CT scan 36 h from onset of pain showing reduced enhancement of neck and body, a perfused pancreatic tail, and peripancreatic stranding.

peptide. These are also elevated in peritoneal and retroperitoneal tissues as well as lymphatic fluid. C-​reactive protein, an acute-​phase reactant, is of most use for longitudinal monitoring of progress. Very high concentrations of circulating cytokines occur in the blood at an early stage in the disease, including tumour necrosis factor-​α, platelet activating factor, and interleukin 6 with maximal levels in those with severe pancreatitis: these are of research interest rather than clinical value.

Grading disease severity Many biochemical scoring systems attempting to objectively grade severity of an attack of acute pancreatitis have been developed, including the Glasgow and Ranson scoring systems. While there is value in directing less experienced clinicians to the multisystem organ dysfunction associated with a severe attack, none are sufficiently accurate to direct treatment, and the utility lies in assessing equipoise within clinical trials, with regard to which the APACHE II system has been shown to be useful in the stratification of severity of acute pancreatitis. CT scanning can be useful in demarcating location and extent of pancreatic injury, and a CT severity index has been developed, although CT is more commonly used to monitor the development of evolving complications. In practice, sequential physiological scoring systems (e.g. NEWS) can assist the

Box 15.26.1.1  Differential diagnosis of acute pancreatitis • Mesenteric ischaemia/​infarction • Small-​bowel obstruction/​perforationa • Renal failure • Macroamylasaemia • Dissecting aortic aneurysm • Diabetic ketoacidosis • Perforated duodenal ulcera • Acute cholangitisa • Acute cholecystitisa • Atypical myocardial infarctiona • Ectopic pregnancya a

Amylase is usually normal.

15.26.1  Acute pancreatitis

identification of clinical deterioration and are in common use in most surgical units.

Other factors affecting prognosis Other factors affecting prognosis include age and obesity. Many studies have shown that those aged over 70 years have a higher mortality. Chronic cardiorespiratory or renal impairment is common in this age group and further increases the risk of death. Acute pancreatitis carries a significantly higher mortality and morbidity in patients with a body mass index of more than 30  kg/​m2, mainly because of an increased risk of hypoxaemia, but also from other associated factors.

Aetiology Aetiological factors and rare associations of acute pancreatitis are listed in Boxes 15.26.1.2 and 15.26.1.3.

Major factors Biliary disease and alcohol abuse together account for over 80% of patients with acute pancreatitis in most prospective studies. Gallstones Gallstones are the predominant cause of acute pancreatitis and all patients should have an abdominal ultrasound examination to identify these, even where there is a history of alcohol excess. Smaller stones pass through the cystic duct more easily and are at increased risk of precipitating acute pancreatitis. Endoscopic ultrasonography (EUS) is more sensitive than transabdominal ultrasonography in identifying small gallstones (microlithiasis). This may be helpful in demonstrating gallstone aetiology in those patients previously labelled ‘idiopathic’.

Box 15.26.1.3  Rare associations with acute pancreatitis • Hypothermia • Coxsackie B virus • Mumps virus • Sclerosing cholangitis • α1-​Antitrypsin deficiency • Virus infection (non-​HIV) • Worm infestationa • Scorpion biteb • Duodenal duplication a

In South-​East Asia. b In Trinidad.

The mechanism by which gallstones induce acute pancreatitis is not certain, but increased back pressure in the pancreatic duct following transient impaction of a migrating gallstone at the ampulla of Vater is considered to be the likely initiating event. Subsequent intracellular events lead to activation of proteases within acinar cells, acinar cell injury, and a local inflammatory response. Alcohol The proportion of patients in whom pancreatitis is due to alcohol abuse is dependent on the population under study:  rates may be as high as 70 to 80% (in New York (United States of America) and Helsinki (Finland)). The risk is highest in young males who drink in excess of 80 g of alcohol per day. Smoking is a cofactor in the development of both acute and chronic pancreatitis. Many patients with a possible alcohol history also have gallstones and the diagnosis of alcohol-​induced acute pancreatitis should be one of exclusion. Alcohol probably causes acute pancreatitis through intracellular lysosomal release modulated by elevations in cytosolic and mitochondrial ionized Ca2+ concentration.

Minor factors Box 15.26.1.2  Aetiological factors in acute pancreatitis (according to frequency) Major • Biliary disease • Alcohol abuse Minor • After ERCP • Sphincter of Oddi dysfunction • Hyperparathyroidism • Hyperlipoproteinaemia • Blunt or surgical trauma • Autoimmune pancreatitis • Drugs • HIV-​associated pancreatitis • Hereditary (trypsinogen gene defects) • Ampullary or pancreatic tumour • Cancers metastatic to pancreas: Renal — — Stomach — Breast — Ovarian — Lung

Drugs The drugs most commonly implicated in causing acute pancreatitis are valproic acid, azathioprine, l-​asparaginase, and corticosteroids. There is equivocal evidence regarding thiazide and other diuretics. However, unless viral titres have been determined, together with adequate biliary investigations including endoscopic examination of the ampulla of Vater, it is unwise to ascribe acute pancreatitis to a particular drug. Repeat exposure to the same drug again causing acute pancreatitis is the strongest evidence of a direct association. Viral infection Viral infection, particularly mumps, Coxsackie B, and viral hepatitis, can cause acute pancreatitis. One clinical feature that may prove useful is prodromal diarrhoea, which is rare in all other types of acute pancreatitis. Of increasing importance are the effects of HIV infection, where acute pancreatitis may be associated with both the primary viral infection and treatment (antiretroviral drugs). Single combination agent therapy (tenofovir, lamivudine, and efavirenz) is considered the most pancreas friendly, but the evidence for favouring one agent over another is weak. Alcohol abuse is common in many HIV-​positive patients, particularly in Africa, and it may be difficult to define a specific causal agent.

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Benign pancreatic duct stricture

Hereditary

A focal area of pancreatic necrosis in a primary attack of acute pancreatitis can cause secondary fibrosis with main duct stricture formation and segmental ‘upstream’ recurrent attacks of pancreatitis as a consequence. Stricture dilatation or occasionally surgical decompression or distal pancreatectomy may be required. Congenital or developmental anatomical abnormalities can present with pancreatitis (choledochal cyst, duodenal duplication, anomalous pancreaticobiliary junction). Pancreas divisum (nonunion of main and accessory ducts) occurs in 3 to 5% of people and is not considered to be a primary cause of pancreatitis.

This condition is increasingly being studied since the discovery of genetic mutations of the cationic trypsinogen gene (PRSS1), which shed light on the mechanism of acute pancreatitis. A Europe-​wide study (EUROPAC) has tracked multiple families in the United Kingdom and Europe, and similar work in Japan and the United States of America is ongoing. The two most common mutations are R122H and N29I. An autosomal dominant pattern of inheritance is seen. Severe acute inflammatory changes are rare and diagnosis is often delayed. Patients usually have a long history of recurrent abdominal pain from childhood or adolescence. Changes of chronic fibrosis may be present at diagnosis. Typically, chronic pancreatitis is evident by the age of 20 to 40 years, and the risk of pancreatic carcinoma in those aged over 60 years is significantly increased. Mutations in the cystic fibrosis transmembrane conductance regulator gene (CTFR) and the pancreatic secretory trypsinogen inhibitor gene (SPINK1) are also linked to pancreatitis.

Periampullary or obstructive pancreatic tumours Periampullary adenoma or carcinoma resulting in upstream obstruction of the main pancreatic duct is an important association. Ampullary tumours are best diagnosed with side-​viewing endoscopic biopsy. With the increase in this approach to diagnosis, tumours at or close to the ampulla have been shown to cause 0.4% of cases of acute pancreatitis. Effective treatment of the tumour abolishes recurrent attacks. This usually involves surgical resection, but endoscopic laser therapy or endoscopic papillectomy can be effective in older and less fit patients. Carcinoma of pancreas can occasionally present with clinical acute pancreatitis and other primary tumours (such as neuroendocrine tumours) or tumours metastasizing to the pancreas (such as renal carcinoma) may present in this way, probably by causing pancreatic duct obstruction. Pancreatitis in association with a side branch intraductal papillary mucinous neoplasm is considered a risk factor for malignant transformation and requires assessment for potential resection following resolution. Hyperparathyroidism Hypercalcaemia secondary to hyperparathyroidism is now recognized to be an uncommon cause of acute pancreatitis. Removal of a parathyroid adenoma usually prevents further acute pancreatitis since persistent hypercalcaemia appears to be the provoking factor. Hyperlipidaemia Patients with type I  and type V hyperlipoproteinaemia may develop acute pancreatitis in the absence of alcohol ingestion when triglyceride levels exceed 11 mmol/​litre. Both subtypes are associated with chylomicrons, of which greater than 90% are triglycerides. Dietary restriction of lipids and various lipid-​lowering drugs are valuable in therapy. Hyperlipidaemia of any cause where triglyceride levels reach in excess of 2000 mg/​dl may cause acute pancreatitis, and acute pancreatitis may rarely complicate hyperlipidaemia of pregnancy or diabetic ketoacidosis. High triglyceride levels may be present during an attack of acute pancreatitis and identifying high fasting lipid levels following resolution is key to confirmation. Hypothermia This is an important association. In younger patients, this may be associated with alcohol abuse, particularly if patients fall asleep out of doors, or in the elderly in an unheated house. Management is directed at gradual warming and supportive measures for organ compromise.

Trauma Hyperamylasaemia may occur after blunt abdominal trauma, usually from a crush injury to the body of the pancreas against the vertebral column. The risk of associated injuries to surrounding organs is high, and in the acute phase these are usually more significant than the pancreatic injury. The identification of a pancreatic injury during a trauma laparotomy should be managed by simple drainage in most cases. When there is transection of the main pancreatic duct, therapeutic options include endoscopic transpapillary stenting and distal pancreatectomy. Late presentation is associated with pseudocyst formation due to leakage from the damaged pancreatic duct. Pancreatic manipulation during surgical mobilization for colonic, gastric, or splenic surgery may result in inflammation. Iatrogenic Surgical or endoscopic procedures involving the ampulla of Vater can induce pancreatitis. In recent years, diagnostic ERCP (2% risk of acute pancreatitis) has largely been replaced by noninvasive imaging modalities (EUS and magnetic resonance cholangiopancreatography). This has reduced the overall incidence of postprocedural acute pancreatitis, but EUS fine needle aspiration of pancreatic lesions, particularly close to the main duct, can itself result in pancreatitis. The risk of acute pancreatitis increases to 4 to 6% where a therapeutic endoscopic sphincterotomy has been performed and may be as high as 20% in high-​risk patients (sphincter of Oddi dysfunction). Iatrogenic perforation should be considered in all patients who develop pancreatitis after therapeutic ERCP, and patients with early organ dysfunction or abdominal signs should undergo a CT without delay if any doubt exists as this will affect management (antibiotics). Autoimmune pancreatitis This is a rare condition, which is considered part of the systemic IgG4-​related autoimmune disease spectrum and is associated with other autoimmune diseases (polyarteritis nodosa, systemic lupus erythematosus, other vasculitides) and inflammatory bowel disease (Crohn’s disease and ulcerative colitis). It may present as abdominal pain with obstructive jaundice more typical of chronic than acute pancreatitis. Other features may include (1)  an increased IgG4/​

15.26.1  Acute pancreatitis

IgG ratio in serum, (2)  homogeneous gland enlargement with a well-​defined halo on CT, (3) characteristic diffuse abnormality on EUS, and (4) periductal lymphoplasmacytic infiltrate on biopsy. The latter may also be associated with abnormalities in the extrahepatic biliary tree resembling sclerosing cholangitis (IgG4-​ associated cholangiopancreatopathy). Focal autoimmune pancreatitis may prove difficult to differentiate from carcinoma. A good response to steroids is diagnostic (HISORt criteria). Worm infestation Ascaris lumbricoides within the ampullary area may manifest as acute pancreatitis clinically, and other worms lodged in this area can produce the same effect.

Table 15.26.1.1  Grades of severity of pancreatitis (based on the clinical parameters of the presence or absence of organ failure and/​or complications Mild acute pancreatitis

• No organ failure • No local or systemic complications

Moderately severe acute pancreatitis

• Organ failure that resolves within 48 h (transient

Severe acute pancreatitis

• Persistent organ failure (>48 h): • Single organ failure • Multiple organ failure

Critical acute pancreatitis

In addition to the other three categories taken from the Atlanta revision, an additional ‘critical’ category (persistent organs failure and sepsis) was proposed by Petrov et al.

organ failure

Sphincter of Oddi dyskinesia Rarely, sphincter of Oddi dyskinesia can present with acute abdominal pain, although the more common presentation is one of chronic relapsing abdominal discomfort. The attacks associated with hyperamylasaemia are usually mild (except where pancreatitis follows an ERCP). With regard to functional gallbladder and sphincter of Oddi disorders (SODs), the Rome III diagnostic criteria for functional gastrointestinal disorders require episodes of pain in the epigastrium or right upper quadrant and all of the following: episodes lasting 30 min or longer; recurrent symptoms occurring at different intervals (not daily); the pain builds up to a steady level and is moderate/​severe enough to interrupt the patient’s daily activities or lead to a visit to the emergency department; the pain is not relieved by bowel movements, postural change, or antacids; and exclusion of other structural disease that would explain the symptoms. If these criteria are satisfied, then Rome III allowed further classification into functional gallbladder disorder (SOD I), where the gallbladder is present and biochemical tests are normal; functional biliary SOD (SOD II), where amylase and lipase are normal, but association of at least two episodes of pain with elevation of serum transaminases, alkaline phosphatase, or conjugated bilirubin is a supportive criterion; and functional pancreatic SOD (SOD III), characterized by elevation of serum amylase and/​or lipase. More recently, Rome IV, recognizing good evidence that sphincterotomy is no better than sham treatment in patients previously classified as having SOD III, discarded the use of this term and renamed SOD II ‘Functional Biliary Sphincter Disorder’. However, whether this exists as a clinical entity remains a matter of debate, and whether it is a potential cause of acute pancreatitis is controversial. Most clinicians would not recommend pancreatic sphincterotomy in the absence of ampullary stenosis.

organ failure) and/​or

• Local or systemic complications without persistent

heavily influenced by the degree of systemic disturbance, and this is reflected in an additional category of ‘moderately severe’ pancreatitis, where collections are present in the absence of organ dysfunction. In addition to disease severity, mortality is strongly associated with age and comorbidity. The significance of infection has been recognized in an addendum adding a category of ‘critical’, recognizing that those patients with sepsis and organ failure have the highest mortality. This classification further separates local complications/​collections on the basis of time from presentation (4 weeks) and on the presence of necrosis, leading to definitions aimed at permitting comparison of case series (Table 15.26.1.2). The ‘early’ phase is characterized by the initial host response to the pancreatitis, the severity being determined by the magnitude of organ disturbance/​ failure, and a ‘late’ phase typified by the persistence of organ dysfunction and the management of local or systemic complications. The vast majority of acute fluid collections without necrosis will resolve within 4 weeks, and a persistent fluid collection with minimal or no necrotic component (‘pseudocyst’) is very rare. Collections may be sterile or infected. Most clinically significant peripancreatic complications are therefore related to either acute necrotic collections (4 weeks). This temporal separation is somewhat arbitrary as the clinical management and surgical approach is determined by multifactorial individual patient factors. However, this does serve to provide a timeline beyond which, if appropriate, intervention should be delayed.

Management Classification of severity The original Atlanta classification of acute pancreatitis dichotomized clinical behaviour into mild or severe acute pancreatitis, and intervention for necrosis was often focused on early removal of sterile or infected necrosis, usually by open necrosectomy. This oversimplification proved inadequate in clinical practice and the Atlanta criteria were revised in 2013 to address the importance of early systemic organ dysfunction in determining disease severity and outcome (Table 15.26.1.1). The outcome following intervention for the management of local fluid or necrotic collections is also

General aspects The principles of organ support in critical illness should be followed, ensuring reversal of hypoxaemia, restoration of circulating volume, and maintenance of tissue perfusion ideally within a critical care environment. Early restoration of circulating blood volume is associated with an improved outcome. The combination of fluid lost from vomiting and loss of capillary integrity can be very substantial. The introduction of vasoconstrictor therapy should only be considered after establishing adequate volume resuscitation. Hypoxaemia reflects disease severity in acute pancreatitis, and while most patients

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Table 15.26.1.2  Local complications in acute pancreatitis (2012 Revised Atlanta Classification) Timescale

Necrosis absent

Necrosis present

4 weeks

Pancreatic pseudocyst (an encapsulated collection of fluid with a well-​defined inflammatory wall usually outside the pancreas with minimal or no necrosis)

Walled-​off necrosis (a mature, encapsulated collection of pancreatic or extrapancreatic necrosis that has developed a well-​defined inflammatory wall)

Infection

Each collection type may be sterile or infected

can be managed with supplemental humidified oxygen, assisted ventilation may be required in more severe cases. For initial resuscitation, Ringer’s lactate is recommended, with goal-​directed intravenous fluid (5–​10 ml/​kg per hour) to produce 0.5 ml/​kg of urine per hour. Renal replacement therapy by haemodialysis or haemofiltration may be required if renal failure becomes established. The more severe cases of acute pancreatitis are characterized by the development and persistence of a systemic inflammatory response syndrome, one aspect being the development of a swinging pyrexia. This is often inappropriately taken as evidence of sepsis but is usually a reflection of the inflammatory cascade and the presence of devitalized tissue in the retroperitoneum rather than bacterial infection.

Specific aspects

nutritional support is cheaper and is associated with fewer side effects than total parenteral nutrition. In addition, there is no difference in outcome with nasogastric compared to nasojejunal feeding. In clinical practice, therefore, the mode of nutritional support does not appear to influence the disease process, and the choice of delivery relates to tolerance and minimizing morbidity associated with the delivery system. Probiotics may be detrimental in acute pancreatitis and specifically supplemented nutrition should only be administered in the context of clinical trials. It has been suggested that nutritional support may help to preserve mucosal function and limit the stimulus to the inflammatory response. The experimental evidence supporting this has not been confirmed in clinical practice and there is no evidence that the mode of feeding alters disease progression.

ERCP

Other approaches

There is no role for early ERCP in mild disease. High fever within the first 24 h is rare and, if associated with jaundice, is suspicious of ascending cholangitis where the cholangitis, rather than any pancreatic inflammation, is driving organ dysfunction. This is the only unequivocal indication for ERCP and biliary decompression. The role of early ERCP remains controversial in all other circumstances. Several randomized studies and cohort series have looked at the role of early ERCP with endoscopic sphincterotomy compared with conservative management in acute gallstone pancreatitis. A  number of meta-​analyses have failed to demonstrate a definite benefit, and early ERCP is difficult to justify in patients who are not jaundiced.

Previous randomized studies have failed to provide sufficient evidence to recommend the use of antiproteases, antisecretory, anti-​ inflammatory agents, or antioxidant therapy in patients with acute pancreatitis. There is therefore no proven pharmacological therapy for the treatment of acute pancreatitis.

Antibiotics The dual peak in mortality in acute pancreatitis is well recognized. The late peak is determined by complications associated with necrosis, including the development of pancreatic or peripancreatic infection. The consensus of the most recent systemic reviews/​meta-​ analyses is that there is no evidence supporting the use of prophylactic antibiotics in either mild or severe acute pancreatitis, and the recommendation is to avoid their use, using targeted antibiotic therapy for episodes of proven infection. It is, however, reasonable to commence antibiotics in the deteriorating patient with radiological and clinical evidence of sepsis while awaiting culture confirmation. Nutrition support There is no benefit from enteral feeding in mild pancreatitis, and these patients need have no dietary restrictions. Assisted feeding may be required in severe acute pancreatitis to provide long-​term nutritional support. Randomized studies have shown that enteral

Intervention for postacute pancreatitis fluid and necrotic collections The definitions surrounding acute fluid-​predominant and acute necrotic collections have been detailed previously in Table 15.26.1.2. Due to the complexity and diversity of an individual patient’s clinical course, it is challenging to define specific triggers for intervention. Delayed intervention where possible, along with planned minimally invasive sepsis control, has become key to management in most pancreatic units. There is no role for early (week 1)  intervention unless vascular complications are suspected. Intervention is most commonly required for suspected or proven sepsis of acute necrotic collections or walled-​off necrosis after resolution of the initial inflammatory phase. Optimal management may involve a number or combination of techniques and require discussion with a specialist regional pancreatic centre. The indication for early (80 g/​day)   Increased (20–​80  g/​day)   Moderate (80 g/​day for some years in men, smaller amounts in women), or 2 History of increased alcohol intake (20–​80 g/​day for some years), or 3 History of moderate alcohol intake (200 μmol/​litre), the patient has biliary sepsis, there is diagnostic uncertainty, or there is likely to be a delay until surgery. In patients with locally advanced or metastatic disease, endoscopic biliary stenting may be required to relieve jaundice and prevent sepsis, and is associated with lower complication rates than percutaneous biliary drainage or surgical biliary bypass. Endoscopic stent insertion can be performed as soon as a treatment strategy is decided. Preoperatively (depending upon local availability and expertise), fully covered self-​expanding metal stents, rather than plastic stents, are preferred in patients who are deeply jaundiced or cholangitic, or in whom there is another reason for delaying surgery more than 1 to 2 weeks. Uncovered self-​expanding metal stents are generally reserved for patients with cytologically/​ histologically confirmed unresectable disease. Endoscopic stents carry a risk of endoscopic retrograde cholangiopancreatography-​ induced acute pancreatitis, stent migration, or later stent occlusion, but overall are associated with a low complication profile. If patients are found to have unresectable disease at operation, a surgical biliary bypass is often the management method of choice and can be combined with gastrojejunostomy for those patients in whom gastric outlet obstruction is suspected or imminent. Gastric outlet obstruction occurs in 10 to 20% of patients with locally advanced disease and those with successful endoscopic or percutaneous biliary drainage can be managed either by surgical bypass (open or laparoscopic) in patients with good performance status or via endoscopic stent insertion.

Fig. 15.26.3.2  Treatment algorithm for patients with pancreatic ductal adenocarcinoma.

15.26.3  Tumours of the pancreas

Surgical resection Most patients with pancreatic ductal adenocarcinoma present with distant metastases or locally advanced disease (involvement of nearby structures that would prevent a clear resection margin), hence only 10–​15% of patients are able to undergo surgical resection. Specific operative strategies depend upon the site and extent of disease: tumours in the head of the pancreas require pancreaticoduodenectomy, either via a classical Whipple’s procedure or via pylorus-​preserving pancreaticoduodenectomy (usually open but occasionally laparoscopic), whereas tumours in the body or tail can be resected via distal pancreatectomy with or without concurrent splenectomy (laparoscopic where possible; involvement of the spleen or splenic vessels is not a contraindication to surgery). All pancreatic surgery carries a potential risk of significant complications and patient selection is therefore crucial. Since the introduction of the National Cancer Plan in 2001 in the United Kingdom, all such resectional pancreatic surgery is now undertaken in regional specialized centres as there is good evidence that centralization of such services results in improved rates of morbidity and mortality (now 1–​2% in high-​volume centres), as well as oncological outcomes. There has been much recent discussion regarding the definitions of operable and locally advanced disease (inoperable but no progression to distant metastases), and the concept of borderline operable disease has recently been introduced (Table 15.26.3.5). The ESPAC-​5 trial (European Study group for Pancreatic Cancer—​ Trial 5F), a multicentre, prospective, randomized, feasibility phase II trial comparing neoadjuvant therapy to immediate surgical exploration in patients with borderline resectable pancreatic cancer, is currently recruiting.

Chemotherapy Advanced disease In patients with advanced disease, chemotherapy improves both survival and quality of life as compared to best supportive care alone. Overall, gemcitabine (a nucleoside analogue) is the most commonly used chemotherapeutic agent. The phase III, multicentre GemCap study randomized patients to receive gemcitabine alone or in combination with capecitabine (an oral prodrug enzymatically degraded to 5-​fluorouracil, a pyrimidine analogue) in 533 patients with advanced pancreatic ductal adenocarcinoma to demonstrate a trend towards improved survival in patients receiving combination therapy (7.1 vs 6.2 months overall survival; 1-​year survival 24.3% vs 22%; p = 0.077). The phase III randomized MPACT study demonstrated a significantly improved overall survival in patients administered

weekly nab-​paclitaxel (a mitotic inhibitor) with gemcitabine, as compared to gemcitabine alone (8.5 vs 6.7  months; p  =  0.0001). Gemcitabine-​based therapy is therefore a common combination regimen and has been shown to significantly improve progression-​ free and overall survival, as well as overall objective response rates, although this can be offset by the greater toxicity profile associated with combination therapy. Trials of biological agents have largely yielded disappointing results, although a Canadian phase III trial did demonstrate a small improvement in overall survival with the addition of erlotinib (an epidermal growth factor receptor inhibitor) to gemcitabine, as compared to gemcitabine alone (6.2 vs 5.9 months; p = 0.038). Other agents are under investigation. In a French multicentre study of FOLFIRINOX (oxaliplatin (platinum-​based chemotherapeutic agent), irinotecan (topoisomerase I  inhibitor), fluorouracil, and leucovorin (folic acid derivative)) or gemcitabine, there was improved survival in the FOLFIRINOX group (11.1 vs 6.8  months; p 15 min), and with increasing duration myocardial infarction is more likely, but the pain rarely lasts more than a few hours. Infarction is more likely to be associated with systemic symptoms (breathlessness, sweating, nausea, and vomiting) and does not respond to glyceryl trinitrate. About one-​half of patients will have a history suggestive of worsening exertional angina, or short-​lived episodes of chest pain at rest before presentation. The pain of an acute coronary syndrome usually discourages the patient from attempting any exertion and does not improve with exercise. Although the history alone cannot definitively rule out myocardial infarction, it can be used to assess the probability of this condition (Box 16.2.1.1). During the examination, the patient should be asked to map out the distribution of the pain. Pain radiation to both arms is suggestive of acute coronary syndrome. Highly localized pain of less than a few centimetres in distribution is unlikely to ischaemic in origin. Tenderness on palpation of the chest wall or pain exacerbated by rotation of the thorax or passive movements of the arms or neck suggest musculoskeletal pain but does not infallibly rule out cardiac ischaemia. Components of the history, the ECG, and markers of myocardial damage are used in non-​ST elevation acute coronary syndromes to determine the risk of subsequent events in the TIMI (Thrombolysis in Myocardial Infarction) risk score (Table 16.2.1.2) and a scoring system based on the GRACE (Global Registry of Acute Coronary Events) registry. Great emphasis has been placed on the use of troponin estimation in determining the risk of subsequent events in these patients and this is undoubtedly a useful tool. However, in the absence of definitive ECG changes or troponin rise, the patient may still score 5 on the TIMI risk score from the history alone, giving

16.2.1  Chest pain, breathlessness, and fatigue

Box 16.2.1.1  Risk stratification for acute myocardial infarction and acute coronary syndrome according to components of the chest pain history Low risk: • Pain that is pleuritic, positional, or reproducible with palpation, or is described as stabbing Probably low risk: • Pain not related to exertion or that occurs in a small inframammary area of the chest Probably high risk: • Pain described as pressure, is similar to that of a prior myocardial infarction or worse than prior anginal pain, or is accompanied by nausea, vomiting, or diaphoresis High risk: • Pain that radiates to one or both shoulders or arms or is related to exertion

a risk of 25% of major cardiovascular adverse events in the next 14 days. For further discussion, see Chapter 16.13.4. There are no specific findings on cardiovascular examination in acute coronary syndromes. In the context of severe coronary disease the patient may present with the clinical features of left ventricular failure (see ‘Particular causes of breathlessness’) or cardiogenic shock. Features of increased sympathetic tone, pallor, tachycardia, and sweating are often present in infarction, but are also features of all causes of severe chest pain. A pansystolic murmur may indicate the development of a ventricular septal defect or papillary muscle rupture and severe mitral regurgitation, complications which are usually associated with haemodynamic compromise and left ventricular failure. The presence of peripheral vascular disease increases the probability of coexistent coronary disease and the patient should be examined for carotid, femoral, and renal bruits and an abdominal aortic aneurysm. The foot pulses should also be assessed. The presence of neck and/​ or chest wall tenderness will point to alternative diagnoses such as cervical spondylopathy, costochondritis, or nerve entrapment. Hypochondrial tenderness suggests a gastrointestinal cause (e.g. peptic ulcer disease, pancreatitis, or gallstones). Table 16.2.1.2  TIMI risk score for non-​ST elevation acute coronary syndromes Clinical feature

Points

Age ≥65 years

1

At least three risk factors for coronary diseasea

1

Prior demonstration of significant coronary artery stenosis

1

ST deviation on ECG

1

Severe anginal symptoms (e.g. ≥2 anginal events in the last 24 h)

1

Use of aspirin in previous 7 days

1

Elevated cardiac markers (e.g. troponin)

1

a Family history, hypertension, hypercholesterolaemia, diabetes, current smoking. From Antman EM et al. (2000). The TIMI risk score for unstable angina/​non-​ST elevation MI: a method for prognostication and therapeutic decision making. JAMA, 284, 835–​42.

Coronary spasm, Prinzmetal’s angina, syndrome X, atypical angina Patients with unpredictable angina due to the occurrence of coronary spasm, either in the context of coronary disease or with normal coronary arteries, have been described. The diagnosis should only be considered in the patient with a classical description of ischaemic chest pain that usually responds rapidly to glyceryl trinitrate, preferably in the context of ECG changes (ST elevation in the case of Prinzmetal’s angina). Cocaine abuse is a frequent cause of this presentation to the emergency department. Syndrome X, as its name suggests, is poorly understood. This label (whether it can properly be called a diagnosis is debatable) is often attached to patients with cardiac-​sounding chest pain and a normal angiogram. This finding is more common in women. The pain often has features atypical of angina. It is often of submammary location or radiation, and precipitating factors are highly variable. This diagnosis should only be considered after other causes of chest pain have been carefully excluded, since it may expose the patient to a lifetime of inappropriate treatment and anxiety. The term ‘atypical chest pain’ is meaningless (especially for the patient) and is best avoided. There are, however, many patients for whom a confident diagnosis cannot be made. Serious pathology can be excluded and the patient reassured that they have an excellent prognosis. It is better to leave the diagnosis at ‘chest pain-​type symptom’ than to inappropriately label the patient as having ‘atypical angina’ or syndrome X.

Aortic dissection Aortic dissection is a rare but important cause of chest pain: up to one-​half of all patients with an untreated proximal aortic dissection die within 48 h. The pain of aortic dissection is very sudden in onset, is usually described as tearing or ripping, and the patient may report that it migrates from the front to the back of the chest. There should be a particularly high index of suspicion when chest pain is associated with neurological features such as hemiplegia or paraplegia due to involvement of the carotid vessels and spinal arteries, but these are present in less than 20% of cases. Risk factors in the history include hypertension, Marfan syndrome, a bicuspid aortic valve, previous aortic valve replacement, cocaine usage, and the third trimester of pregnancy. Of the clinical features (see Box 16.2.1.2) aortic pain (as described earlier), loss of

Box 16.2.1.2  Clinical features associated with aortic dissection • Sudden onset tearing, ripping chest pain that migrates to the back • Loss of peripheral pulses • Blood pressure difference more than 20 mm Hg between arms • Hemiparesis • Paraparesis • Diastolic murmur • Pleural effusion (usually left-​sided) • Hoarseness • Horner’s syndrome • Bilateral testicular tenderness • Pulsatile sternoclavicular joint • Superior vena cava obstruction • Pulsus paradoxus (with pericardial tamponade)

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peripheral pulses, blood pressure difference between the two arms (>20 mm Hg), and mediastinal widening on the chest radiograph are the most helpful. In the absence of these features the incidence of aortic dissection is less than 5%. The absolute level of blood pressure in unhelpful in discriminating aortic dissection from other causes of chest pain. Pericarditis Pericarditis occurs most commonly following a myocardial infarction or viral infection. The patient may describe a preceding viral illness with fever and cough. The pain is usually sharp and precordial. The onset is often sudden. It is characteristically worse on inspiration and relieved by sitting up and leaning forward, and it can be accompanied by classic pleuritic pain. A less typical description occurs when a pericardial effusion has developed and the pain arises from pericardial distension, when the pain may be a dull retrosternal ache or pressure. Radiation of pericarditic pain occurs to all those areas associated with myocardial infarction, but radiation to the trapezius ridges is pathognomonic of the diagnosis. The patient is usually well and not compromised haemodynamically (except where there is pericardial tamponade). Clinical examination may initially be normal. A pericardial friction rub heard over the sternum may be positional and appear and disappear within hours. Repeated examination may be helpful, including auscultation of the patient lying flat in expiration. The ECG finding of concave ST

elevation in multiple lead is helpful, but ECG findings are equivocal or normal in 40–​50% of cases.

Breathlessness and fatigue Breathlessness (or dyspnoea, derived from Greek words meaning painful or difficult breathing) is the endpoint of a variety of pathologies and is mediated by a series of neural pathways, the sensory inputs of which originate in the lungs, chest wall, and peripheral and sensory chemoreceptors (see Fig. 16.2.1.2). Patients may describe the sensation of breathlessness as tightness, wheeze, ‘inability to get enough air’, sighing, choking, or suffocating. Heart failure, asthma, and chronic obstructive airways disease account for about three-​ quarters of hospital admissions with breathlessness in industrialized nations. Symptom clusters have been described for these pathologies, but most patients find it impossible to distinguish between cardiac and pulmonary causes of dyspnoea. The time course of the illness is an important aid to the diagnosis in patients with dyspnoea but must be interpreted in the context of the patient’s day-​to-​day activities. Even when the disease progresses gradually the patient may report a recent onset of symptoms because they have (often subconsciously) adapted their lifestyle over the course of many months. This is particularly true of patients with chronic heart failure.

Afferent signals

Efferent signals Motor cortex

Effort

Chemoreceptors

Sensory cortex Effort?

Air hunger

Upper airway

Brain stem Upper airway

Chest tightness

Ventilatory muscles

Chest wall

Fig. 16.2.1.2  Efferent and afferent signals that contribute to the sensation of dyspnoea. The sense of respiratory effort is believed to arise from a signal transmitted from the motor cortex to the sensory cortex coincidently with the outgoing motor command to the ventilatory muscles. The arrow from the brainstem to the sensory cortex indicates that the motor output of the brainstem may also contribute to the sense of effort. The sense of air hunger is believed to arise, in part, from increased respiratory activity within the brainstem, and the sensation of chest tightness probably results from stimulation of vagal-​irritant receptors. Although afferent information from airway, lung, and chest wall receptors most likely passes through the brainstem before reaching the sensory cortex, the dashed lines indicate uncertainty about whether some afferents bypass the brainstem and project directly to the sensory cortex. From Manning HL, Schwartzstein RM (1995). Pathophysiology of dyspnea. New England Journal of Medicine, 333, 1547–​53. http://​content.nejm.org/​cgi/​content/​extract/​333/​23/​1547.

16.2.1  Chest pain, breathlessness, and fatigue

Table 16.2.1.3  New York Heart Association classification of breathlessness according to severity Class I

No limitation—​ordinary physical activity does not cause undue fatigue, dyspnoea, or palpitation

Class II

Slight limitation of physical activity—​comfortable at rest, but ordinary physical activity results in fatigue, dyspnoea, or palpitation

Class III

Marked limitation of physical activity—​comfortable at rest, but less than normal activity produces symptoms

Class IV

Inability to carry out any physical activity without discomfort

Until relatively recently, symptoms of fatigue and breathlessness in heart failure have been assumed to be due purely to a combination of poor cardiac output and pulmonary congestion. However, in patients with heart failure the correlation between symptoms and left ventricular ejection fraction is very poor. Changes in skeletal and respiratory muscle function appear to contribute significantly to symptoms, a hypothesis that is supported by the response observed to exercise training programmes in patients with chronic heart failure, and which may account for part of the considerable variability in disability in patients with similar haemodynamic and echocardiographic findings. Because of the contribution of fatigue, it is more helpful to ask about a change in exercise tolerance in patients with suspected heart failure, since this may correlate more closely with the underlying pathology. The New York Heart Association (NYHA) classification is used to classify the extent of disability (Table 16.2.1.3). The time course of onset of breathlessness can be particularly useful in determining the underlying pathology (Table 16.2.1.4). Breathlessness of dramatic onset (over minutes) is suggestive of pulmonary embolism, pulmonary oedema, upper airway obstruction, or a pneumothorax. Chronic dyspnoea presents in the context of worsening breathlessness over a period of months or years is typical

of chronic obstructive airways disease, interstitial lung disease, or anaemia, but may also be a feature of heart failure. Acute or chronic dyspnoea indicates an exacerbation of breathlessness in a patient with established disease. Chronic obstructive airways disease, asthma, and heart failure are common in the population of industrialized countries and most elderly patients presenting to the emergency department with breathing difficulties will have a prior history of pulmonary or cardiac disease. However, it is important not to automatically attribute any deterioration in symptoms as being due to progression of their underlying disease process. Alternative causes should be considered, and this situation is often a major diagnostic challenge. A common example is a sudden deterioration in the patient with long-​standing well-​controlled heart failure, which should prompt consideration of further pathology such as a silent myocardial infarction, pulmonary embolism, or arrhythmia. Breathlessness at rest occurs in pulmonary embolism or pulmonary oedema, and with a pneumothorax. Exertional dyspnoea occurs in left ventricular failure and chronic obstructive airways disease. Psychogenic breathlessness is frequently present at rest and is associated with sighing, features of hyperventilation such as perioral or peripheral paraesthesiae, and chest tightness. The presence of breathlessness at rest but not on exertion strongly suggests a functional origin.

Particular causes of breathlessness Left ventricular failure The incidence of left ventricular failure in the community is 1–​2%. It is important to attempt to identify the cause during the initial assessment. A history of ischaemic or valvular heart disease, alcohol abuse, smoking, diabetes, hypertension, and a family history are important. Patients with left ventricular failure commonly present to the outpatient clinic, but may present for the first time to the emergency

Table 16.2.1.4  Conditions causing breathlessness classified by the rate of onset Acute

Acute on chronic

Chronic

Asthma

Infective exacerbation of COPD

COPD

Myocardial infarction

Decompensated chronic heart failure

Cardiac failure

PE

PE complicating congestive cardiac failure or COPD

Anaemia

Cardiogenic pulmonary oedema (secondary to ischaemia, valvular disease, arrhythmias)

Pneumothorax complicating COPD or asthma

Pulmonary vascular disease (PE, pulmonary hypertension)

Pneumonia

Atrial fibrillation/​flutter complicating COPD or cardiac failure

Parenchymal lung disease, e.g. UIP, sarcoid

Non​cardiogenic pulmonary oedema

Chordal rupture in chronic non​rheumatic mitral regurgitation

Pleural disease, e.g. effusion, asbestosis

Pulmonary haemorrhage

Chest wall disease, e.g. kyphosis, ankylosing spondylitis

Spontaneous pneumothorax

Neuromuscular disorders, e.g. muscular dystrophy, polio, myasthenia gravis

Chest trauma

Malignancy

Upper airway obstruction

Obesity/​deconditioning

Hyperventilation syndrome

Sleep apnoea Silent myocardial ischaemia

COPD, chronic obstructive pulmonary disease; PE, pulmonary embolism; UIP, usual interstitial pneumonia.

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department. An acute presentation is more likely when there has been a rapid rise in the left atrial pressure generating pulmonary oedema. In severe cases this is associated with haemoptysis in the form of frothy pink sputum. This type of presentation occurs with myocardial infarction, mitral valve papillary muscle or chordal rupture, malignant hypertension, tachyarrhythmias, and endocarditis with major valve destruction. Where a rise in left atrial pressure occurs over a longer time course, sustained elevated left atrial pressures are compensated for by increased lymphatic drainage and structural changes in the pulmonary capillary and alveolar basement membrane and patients more commonly present with fatigue, exertional breathlessness, and orthopnoea. Prolonged increases in left atrial pressure are associated with pulmonary hypertension and the associated clinical features of right ventricular enlargement, tricuspid regurgitation, and a loud pulmonary second sound. This type of presentation is more frequently a feature of patients with an idiopathic, ischaemic, hypertensive, or alcoholic cardiomyopathy. Clinical findings that help in assessing impaired left ventricular function or elevated left atrial filling pressures are shown in Table 16.2.1.5. The most helpful features in the history are exertional breathlessness, orthopnoea, paroxysmal nocturnal dyspnoea, or a history of myocardial infarction. Breathlessness that is worse on lying flat and relieved promptly on sitting up is characteristic for orthopnoea. Patients with chronic obstructive airways disease may also describe orthopnoea, but this is usually present only in the setting of severe disease and chronic breathlessness at rest. Paroxysmal nocturnal dyspnoea is due to the development of interstitial oedema and typically occurs 2–​4 h after the onset of sleep. The patient usually stands up or sits on the side of the bed and symptoms resolve over the course of 10–​15 min. This is usually a frightening and memorable experience for the patient, and to avoid these symptoms they will sleep propped up on pillows or, in severe cases, in a chair. However, a history of paroxysmal nocturnal dyspnoea or orthopnoea is only present in 20% of patients with heart failure and its absence does not exclude the diagnosis. Ankle oedema is supportive of a diagnosis of heart failure, but dependent oedema is often present in older people and in patients with chronic obstructive airways disease, and the astute physician should avoid the common mistake of assuming that ‘ankle oedema means cardiac failure means diuretic prescription’. The clinical examination findings are used to support a suspected diagnosis of heart failure, but they are not always helpful.

Table 16.2.1.5  Helpful and relatively specific clinical findings for predicting heart failure in patients presenting with dyspnoea History

Examination

Orthopnoea

Elevated jugular venous pressure

Paroxysmal nocturnal dyspnoea

Cardiomegaly

Recent onset peripheral oedema

Third or fourth heart sound

Prior history of heart failure

Basal crepitations

Previous myocardial infarction

Positive hepatojugular reflux Peripheral oedema beyond mid-​calf

Source data from Badgett RG, Lucey CT, Mulrow CD (1997). Can the clinical examination diagnose left-​sided heart failure in adults? JAMA, 277, 1712–​19.

Tachycardia, cyanosis, and an elevated jugular venous pressure are features of heart failure, but they are also features of the major differential diagnoses, pulmonary embolism, and chronic obstructive airways disease. Although jugular venous pressure correlates with left atrial pressure it may be misleading in the presence of isolated right ventricular dysfunction, tricuspid regurgitation, and pulmonary hypertension. A displaced apex on palpation is helpful and relatively specific. Basal inspiratory crackles (rales) are suggestive of pulmonary oedema but can be present in fibrotic lung disease infection and chronic airways disease and have a sensitivity and specificity as low as 13% and 35%, respectively. The third sound is a low-​pitched sound heard in mid-​diastole, best with the bell of the stethoscope placed lightly over the apex. It can be confused with a split second sound but is later in diastole and has a much longer duration. It has a high specificity (90–​97%) but low sensitivity (31–​ 51%) for detecting left ventricular dysfunction. Fever and purulent sputum usually point to a diagnosis of an infective exacerbation of chronic bronchitis or chest infection. In older people, however, a chest infection may precipitate decompensation of heart failure. Left ventricular failure is highly unlikely in the presence of a genuinely normal ECG. Evidence of a previous myocardial infarction on the ECG, in particular the presence of Q waves in the anterior chest leads is highly predictive of left ventricular dysfunction. The most useful finding on chest radiography is cardiomegaly, but heart size may be normal, particularly in diastolic heart failure. Changes of pulmonary venous distension, pulmonary oedema, and pleural effusion are more common in acute presentations, but are frequently absent in patients presenting with chronic breathlessness. Following clinical assessment, including ECG and chest radiography, there may still be considerable uncertainty about the diagnosis of the cause of breathlessness, particularly in patients presenting to the emergency department. Measurement of blood brain natriuretic peptide (BNP) may assist in a more rapid and accurate diagnosis in this circumstance, a level below 100 pg/​ml (>300 pg/​ml for NT-​ proBNP) making the diagnosis of left ventricular failure highly unlikely and alternative diagnoses should be considered. High levels (>500 pg/​ml) are strongly suggestive of heart failure. Intermediate levels are more difficult to interpret as there are certain confounding factors for BNP measurement (Table 16.2.1.6) As with troponin, BNP levels (see Chapter 16.5.3) must be interpreted in the context of the history, clinical findings, and other investigations. Scoring systems have been devised using BNP and other clinical and investigation findings in acute dyspnoea (Fig. 16.2.1.3). Given the relatively poor predictive value of the clinical history and physical signs in the diagnosis of left ventricular failure, open access to echocardiography may appear superior to clinical assessment. However, there are important arguments for careful clinical assessment. Firstly, echocardiography is not always available in the emergency setting. Secondly, cardiac and non​cardiac causes of dyspnoea, particularly chronic obstructive pulmonary disease (COPD), often coexist, and where there is dual pathology, deciding which treatment to escalate is more dependent on the appropriate interpretation of the symptoms, clinical signs, and chest radiographic findings than echocardiographic parameters. Thirdly, heart failure is frequently present in the presence of apparently preserved systolic function on echocardiography.

16.2.1  Chest pain, breathlessness, and fatigue

Table 16.2.1.6  Confounding factors in the interpretation of BNP measurements

be a feature of chronic CO2 retention. Although often cited as a cause of the clinical features of right heart failure in COPD, true right ventricular failure is relatively uncommon, and the mechanism of fluid retention is complex. COPD and heart failure often coexist. The chest radiograph may be unhelpful and patients with emphysema and left ventricular failure may not have any radiological features of pulmonary congestion or oedema. In these situations, systolic heart failure can only be ruled out by echocardiography.

Increased BNP

Decreased BNP

Increasing age

Obesity

Female sex

Cardioactive drugs

Pulmonary disease

ACE inhibitors

Systemic hypertension

Spironolactone

Hyperthyroidism

β-​Blockers (long term)

Pulmonary embolism

Cushing’s syndrome

Diuretics

Pulmonary embolism is a common differential diagnosis in patients with breathlessness and should be considered in any presenting with breathlessness without clinical signs of left ventricular failure. The acute presenting symptoms are of breathlessness (usually of sudden onset), chest pain (classically pleuritic, but central with large pulmonary emboli), and less commonly haemoptysis, cough, and syncope. The differential diagnosis depends on the predominant presenting feature, such as pleuritic pain (chest infection with pleurisy, pericarditis), central chest pain (myocardial infarction), dyspnoea (COPD), or heart failure. Chronic pulmonary embolic disease and pulmonary hypertension present with exertional breathlessness, and patients may complain of central chest pain that is due to right ventricular subendocardial ischaemia. The diagnosis of pulmonary embolism cannot easily be excluded without investigation and the exclusion of an alternative, more likely, cause of breathlessness is crucial to the initial assessment. Most patients with acute pulmonary embolism are breathless or tachypnoeic (respiratory rate >20/​min) and in the absence of these findings, haemoptysis and pleuritic chest pain are usually due to another cause. See Chapter 16.16.1 for further discussion of examination findings and diagnostic strategy in patients with suspected pulmonary embolism.

Glucocorticoid usage Conn’s syndrome Hepatic cirrhosis with ascites Renal failure Paraneoplastic syndrome Subarachnoid haemorrhage

Airways disease The clinical features of heart failure and airways disease are often difficult to distinguish. Patients with lung disease tend to use the terms ‘chest tightness’ or ‘restriction’, whereas the patient with heart failure is more inclined to describe the sensation of ‘not being able to get enough air’. Patients are more likely to have COPD if they have a self-​reported history of COPD, wheezing on examination (although this can be a feature of heart failure), a forced expiratory time of 9 s or more, and laryngeal descent. Clearly COPD is very unlikely in the absence of a smoking history and in patients under 45 years of age. Patients with COPD and left ventricular failure may suffer from a chronic cough, although in the case of heart failure this is usually a dry cough and more prominent at night. Fluid retention giving rise to an elevated jugular venous pressure and ankle oedema can occur in association with hypoxia, but only if saturations are persistently less than 93%. Ankle oedema may also

% of patients with CHF

100

Derivation population Validation population

80 60 40 20 0 4-​week interval), high risk, and recurrent syncope. Tilt testing When the history is suggestive of vasovagal syncope, the tilt test may be of value in confirming the diagnosis, but a negative test does not exclude the diagnosis. Adjuvant provocation (isoprenaline or nitrate) may increase the sensitivity, but the incidence of false positive tests with tilt testing has been reported as 5–​20%. As such, its use is

probably best limited to investigation of recurrent symptoms with an atypical history in patients in whom there are no features to suggest cardiac syncope. Electrophysiological testing Abnormal sinus node function or evidence of atrioventricular conduction disease may be elicited by electrophysiological testing, but demonstrating bradycardia during ambulatory monitoring more reliably makes both of these diagnoses. In patients with structural heart disease in whom arrhythmia is suspected, programmed electrical stimulation of the ventricles can induce sustained monomorphic ventricular tachycardia. This is a relatively specific response which shows that the patient is at risk of recurrent ventricular arrhythmia and makes an arrhythmic origin of syncope likely. However, recent guidelines on device implantation suggest that an electrophysiological study is no longer routinely required in a patient with impaired ventricular function and syncope likely to be cardiac in origin. If there is enough clinical suspicion, then implantable cardioverter defibrillators can be offered to these patients without electrophysiological testing. It is important to note that the diagnostic yield of electrophysiological testing is low in patients with a structurally normal heart. Other investigations Assessment for structural heart disease is important. Physical examination will detect most significant valve disease, but other diagnoses, such as hypertrophic cardiomyopathy or atrial myxoma, may produce little in the way of clinical signs. An echocardiogram is therefore worthwhile in cases where the diagnosis remains unclear. Exercise testing is useful in patients with a history of syncope during or immediately after exercise. Exercise testing is diagnostic if Mobitz II second-​degree or third-​degree atrioventricular block develop during exercise even without syncope. Troponin measurement is not indicated in patients with syncope in the absence of features suggestive of an acute coronary syndrome. Approximately 10% of patients over the age of 60 presenting to the emergency department with syncope will have an elevated troponin, and although this is an independent risk factor for subsequent serious events, the finding rarely changes management appropriately or contributes to the final diagnosis. A strong suspicion of diagnoses other than syncope should lead to other investigations, including electroencephalography and brain imaging, but these have a low diagnostic yield in patients with syncope and should not be routine.

Management Neurocardiogenic syncope may require no treatment other than reassurance and avoidance of provocative factors. Syncope has several effects on lifestyle. Simple lifestyle measures may be employed to improve symptoms in specific situations: for example, increased fluid and salt intake. Where there is warning before syncope occurs this may be used to prevent injury or complete syncope by adopting a position lying down or with feet elevated. It is crucial for those who suffer syncope to avoid situations that might put them at harm, such as swimming alone or bathing (showering is preferred). Management of vasovagal syncope, bradycardia, and cardiac arrhythmia are discussed in Chapters 16.4 and 24.5.4. In up to one-​third

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of patients, the aetiology of syncope may not be found: these patients have a good outcome unless they have underlying heart disease.

Palpitation The symptom of palpitation is defined as an awareness of one’s heart beating. This may be due to an awareness of an abnormal heart rhythm, but it may also be due to an abnormal awareness of normal rhythm. A  careful and detailed history can provide a likely diagnosis. The most important aim in investigation is to correlate symptoms with cardiac rhythm.

History A description of the symptom should include an estimate of heart rate, duration of symptom, regularity of rhythm, suddenness of onset and offset. It may be helpful to ask the patient to tap with their finger to describe their palpitation. Trigger factors, including exercise, and aggravating factors such as alcohol and caffeine should be detailed. The length of history may be of interest. Sinus tachycardia An awareness of a rapid heart rate of gradual onset and offset is often associated with feelings of alarm and panic in patients with anxiety. Premature/​ectopic  beats Symptomatic atrial and ventricular premature or ectopic beats commonly occur in normal individuals, and often generate considerable anxiety resulting in consultation. In the absence of coronary disease, premature ventricular ectopic beats (PVCs) at a frequency of 1 per hour or more were recorded during Holter monitoring in the Framingham study in 33% of men and 32% of women. PVCs have also been recorded in 0.8% of a healthy military population during a standard 12-​lead ECG. These are important factors to remember when discussing their significance with the patient. The patient may describe ‘missed beats’ or forceful beats. These symptoms relate to the pause that follows a premature beat. The premature beat produces a short diastolic filling interval and the low ventricular volume results in reduced ventricular contraction with a small stroke volume. However, the subsequent pause provides a long diastolic filling period and the resultant stretching of the ventricular walls is associated with an increased and forceful systolic contraction. The combination of the diminished premature beat and the enhanced postextrasystolic beat is responsible for the symptoms. Benign ectopy is indicated by the absence of a history of other cardiovascular symptoms or family history of sudden death, their occurrence at rest and resolution with exercise, and a normal clinical cardiovascular examination and resting ECG. Multifocal ventricular ectopy, and PVCs at a frequency of more than 20 000 in 24 h, are more indicative of potentially significant cardiac pathology and require further investigation. Atrial fibrillation This common arrhythmia may produce a variety of symptoms depending on ventricular rate, irregularity, and persistence. Paroxysmal atrial fibrillation is characterized by self-​terminating episodes of atrial fibrillation, when there may be a rapid and irregular ventricular response. The patient is aware of an increased heart rate

and often describes the irregular nature of the symptom. The variations in diastolic interval produce symptoms by similar mechanisms to that described earlier for premature beats, with ‘missed’ and ‘forceful’ beats. Patients with sinoatrial dysfunction may be most symptomatic on termination of the atrial fibrillation, which can be followed by sinus bradycardia or prolonged sinus pauses. Atrial fibrillation may be persistent or permanent, and the severity of symptoms will be related to the ventricular rate and irregularity. Paroxysmal supraventricular tachycardia A history of sudden-​onset, rapid, regular palpitation in a healthy patient with no underlying structural heart disease is suggestive of paroxysmal supraventricular tachycardia. It may stop spontaneously or with vagotonic manoeuvres, or the patient may have had to attend hospital for intravenous therapy. In addition to palpitation, patients commonly report fatigue, malaise, light-​headedness, or dyspnoea, but because they have normal hearts such episodes of tachycardia are usually well tolerated. Polyuria is a common associated symptom, which results from the release of atrial natriuretic peptide secondary to atrial stretch. Ventricular tachycardia Ventricular arrhythmias can present with the symptom of palpitation, but more severe symptoms such as syncope or cardiac arrest also occur. Characteristically the symptom of palpitation would be the sudden onset and offset of a rapid regular heart rhythm. A history of structural heart disease should be sought.

Investigation Electrocardiogram The first aim is to document cardiac rhythm during symptoms. This may be possible with a standard ECG if the arrhythmia is sustained or persistent. Atrial or ventricular premature beats, or evidence of structural heart disease (e.g. myocardial infarction), may be documented. The presence of pre-​ excitation indicates the diagnosis of Wolff–​ Parkinson–​White syndrome and suggests symptoms due to episodes of atrioventricular re-​entry tachycardia. Other ECG signs indicative of primary electrical heart disease are: a corrected QT interval greater than 460 ms or less than 320 ms (long or short QT syndrome); right bundle branch block with ‘coved’ ST elevation (Brugada syndrome); epsilon waves and/​or T wave inversion with QRS duration greater than 100 ms in the right precordial ECG leads (arrhythmogenic right ventricular cardiomyopathy); and high voltages in the precordial leads with Q wave formation and ST changes (hypertrophic cardiomyopathy). Ambulatory monitoring The success of ambulatory monitoring in documenting the rhythm during symptoms will be dependent on the frequency of symptoms. If they occur daily, then a 24 or 48 h Holter recording should suffice. However, palpitation is often infrequent and other patient-​activated devices can be of more value. These include hand-​held, patient-​ activated event recorders that allow the telephonic transmission of recordings. These devices do not allow retrospective recording and require symptoms of sufficient duration to allow their use. However, there are now devices producing high quality single lead ECG recording that can be used with a smartphone and purchased directly by the patient. Shorter episodes may also be captured using loop recorders: the newest devices are the size of a large plaster, are attached

16.2.2  Syncope and palpitation

on the left upper part of the chest, can record for up to 2 weeks, and are waterproof. Ultimately, implantable loop recorders may be helpful where symptoms are infrequent, and they may also be effective in monitoring therapy once implanted for diagnostic purposes. The most recent devices are small enough to be classed as ‘injectable’, and they may even be implanted in the outpatient clinic setting. Other investigations Thyroid function and a full blood count are of particular importance in patients with atrial arrhythmias or sinus tachycardia, respectively. Electrolytes are routinely analysed. In patients with paroxysmal symptoms, a history of hypertension, sweating, and anxiety during attacks, urinary metanephrines for the investigation of phaeochromocytoma are indicated. Echocardiography is performed in most patients with palpitations and documented arrhythmias: in patients with ventricular ectopy, however, it is usually indicated only in those with suspected structural heart disease, a very high burden of ectopy, or those at a high risk of development of serious ventricular arrhythmias or sudden cardiac death. Electrophysiological studies Invasive studies are of most value in determining the mechanism of a previously documented tachyarrhythmia, particularly with a view to treatments such as radiofrequency catheter ablation.

Management Documentation of the cardiac rhythm during palpitation allows appropriate management, with reassurance as the only treatment in those with sinus tachycardia or premature beats. The treatment of other cardiac arrhythmias is discussed in Chapter 16.4. Lifestyle advice Advice regarding lifestyle with palpitations revolves around reassurance where it is felt to be benign and avoiding precipitants

where these can be identified. Although caffeine, other stimulants, alcohol, and stress are often quoted as potential triggers (and this may be true of ectopy, for example), it is much more common for many arrhythmias to occur without any avoidable trigger. Exercise as a trigger for palpitations is unusual and may signify adrenaline-​ dependent arrhythmias such as some forms of ventricular tachycardia (see Chapter 16.4). Driving restrictions may apply for both palpitations and syncope. In the United Kingdom clear guidance is provided by the Driver and Vehicle Licensing Agency (DVLA) as to who can and cannot drive with these symptoms, investigations that are required, and the duration of driving bans for both a normal driving licence and heavy goods/​passenger vehicle licences.

FURTHER READING Benditt DG, Sutton R (2005). Tilt-​table testing in the evaluation of syncope. J Cardiovasc Electrophysiol, 16,  356–​8. Brignole M, et al. (2018). 2018 ESC guidelines for the diagnosis and management of syncope. Eur Heart J, 39, 1883–948. Brignole M, et al. (2018). Practical instructions for the 2018 ESC guidelines for the diagnosis and management of syncope. Eur Heart J, 39, e43–e80. Grubb BP (2005). Neurocardiogenic syncope and related disorders of orthostatic intolerance. Circulation, 111, 2997–​3006. NICE (2010). Transient loss of consciousness. Clinical guideline. https://​ www.nice.org.uk/​guidance/​cg109 Raviele A, et al. (2011). Management of palpitations: a position paper from the European Heart Rhythm Association. Europace, 13, 920–​34. Shen W-​K, et  al. (2017). ACC/​AHA/​HRS Guideline for the evaluation and management of patients with syncope:  a report of the American College of Cardiology/​ American Heart Association Task Force on Clinical Practice Guidelines, and the Heart Rhythm Society. Circulation, 136(5), e60–​e122.

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16.3

Clinical investigation of cardiac disorders

CONTENTS 16.3.1 Electrocardiography  3294 Andrew R. Houghton and David Gray

16.3.2 Echocardiography  3314 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

16.3.1 Electrocardiography Andrew R. Houghton and David Gray ESSENTIALS The resting 12-​lead ECG The ECG has been recognized as a valuable diagnostic tool since the end of the 19th century. The normal ECG waveform consists of P, QRS, and T waves (and sometimes U waves)—​P waves result from atrial depolarization, QRS complexes from ventricular depolarization, and T waves from ventricular repolarization. The standard 12-​ lead ECG utilizes four limb electrodes and six precordial electrodes to generate 12 leads or ‘views’ of the heart’s electrical activity. There are six limb leads (termed I, II, III, aVR, aVL, and aVF) and six precordial leads (termed V1, V2, V3, V4, V5, and V6). Supplementary ‘views’ can be obtained by using additional leads, such as V7, V8, and V9 to assess the posterior aspect of the heart and right-​sided chest leads to look for a right ventricular myocardial infarction. Assessment of the 12-​lead ECG—​this should be done in a methodical manner, working through each aspect in turn. Conventionally, the heart rate, rhythm, and axis are assessed before inspection of each component of the waveform—​the P wave, PR interval, QRS complex, ST segment, T wave, QT interval, and U wave, with each component having its own range of normal attributes.

Myocardial hypertrophy—​the ECG can be a specific but generally insensitive tool for detecting myocardial hypertrophy: (1) left ventricular hypertrophy can be assessed using certain diagnostic criteria, including the Cornell criteria and the Romhilt–​Estes scoring system; (2) right ventricular hypertrophy is indicated by a dominant R wave in lead V1 with right axis deviation; (3) left atrial hypertrophy is indicated by broad, bifid P waves; and (4) right atrial hypertrophy by tall P waves. Conduction blocks—​(1) left anterior hemiblock results from a block of conduction in the anterosuperior fascicle and is a cause of left axis deviation; (2) left posterior hemiblock results from a block of conduction in the posteroinferior fascicle and is a cause of right axis deviation; (3) left and right bundle branch blocks both cause broadening of the QRS complexes by prolonging ventricular depolarization, and both exhibit characteristic diagnostic features. Ventricular pre-​excitation—​causes shortening of the PR interval and can result from Wolff–​Parkinson–​White-​type pre-​excitation, short PR-​type pre-​excitation, or Mahaim-​type pre-​excitation.

Acute coronary syndromes The ECG is the most useful bedside triage tool in acute coronary syndromes, with utility in diagnosis, in location of the site of ischaemia/​ infarction, and as a prognostic indicator. ST elevation myocardial infarction—​the first indication of infarction on the ECG is usually ST segment elevation, which occurs within a few hours. The J point (the origin of the ST segment at its junction with the QRS complex) is elevated by 1 mm or more in two or more limb leads, or by 2 mm in two or more precordial leads. The ST segment returns to the baseline over the next 48–​72 h, during which Q waves and symmetrically inverted T waves appear. Some patients develop left bundle branch block, either transiently or permanently. The ECG of a completed infarct shows new Q waves greater than 2  mm, R waves reduced in size or absent, and inverted T waves. Non-​ST-​elevation myocardial infarction—​ECG changes are more variable than in ST-​elevation myocardial infarction. The ECG may be normal on first presentation and remain unchanged throughout the acute admission; there may be transient ST segment depression indicative of myocardial ischaemia; in 20–​30% the only change will be T-​wave inversion. Difficulties in interpretation of the ECG in acute coronary syndromes—​ the ECG diagnosis of acute myocardial infarction can pose challenges in the setting of right ventricular infarction, atrial infarction, coronary

16.3.1 Electrocardiography

artery spasm, reciprocal changes, ‘stuttering’ infarction, non​infarct ST segment elevation, late presentation, left bundle branch block, prior infarction, pre-​excitation, and T-​wave inversion. Clinical decision-​making—​incorrect interpretation of an ECG can lead to inappropriate patient triage, either missing the opportunity to provide appropriate reperfusion therapy, or leading to inappropriate treatment with attendant risk. Up to 12% of those with a high-​ risk ECG are missed on admission to the emergency department, yet pressure to provide treatment promptly to fulfil audit ‘targets’, for example, door-​to-​balloon time for primary percutaneous coronary intervention, should not replace accuracy in diagnosis. It is sometimes better to repeat the ECG than to make an incorrect diagnosis. It is easy to place too much reliance on minor changes on the ECG; it is gross changes of ST elevation or depression within the parameters just outlined that should determine treatment.

Exercise ECG testing Exercise ECG testing is better as an indicator of prognosis than as a diagnostic tool. The sensitivity of exercise ECG testing, the proportion with coronary disease correctly identified by the test, is 68% (range 23–​100) and specificity, the proportion free of disease correctly identified by the test, is 77% (range 17–​100). In multivessel disease, these figures are 81% (range 40–​100) and 66% (range 17–​100), respectively. This means that exercise testing frequently yields both false-​positive results—​incorrectly diagnosing disease when coronary arteries are normal or minimally diseased—​and false-​negative results—​missing coronary disease when a flow-​limiting, even critical left main stem, coronary stenosis is present. Appearance of symptoms or ECG changes early in an exercise test is generally associated with more severe and extensive coronary disease and a poor prognosis. Changes within the first 3 min usually indicate severe coronary disease affecting the left main stem or the proximal segments of at least one major coronary artery. Multivessel coronary disease is more likely with ST segment down-​sloping, delayed ST normalization after exercise, increased number of leads affected, and lower workload at which ECG changes appear.

The resting 12-​lead ECG

Switzerland, in 1889. Although Einthoven made considerable improvements to the technique of recording ECGs with the capillary electrometer, it was only with his invention of the string galvanometer at the turn of the century that high-​quality ECG recording became possible. Within a decade of Einthoven’s publication of the first string galvanometer ECG recordings in 1902, a commercial ECG machine became available. Manufactured by the Cambridge Scientific Instrument Company, the first machine was delivered to Sir Thomas Lewis, who would play a major role in developing the clinical application of electrocardiography. Einthoven’s invention led to him being awarded the Nobel Prize in 1924. Einthoven was also the first to use the PQRST notation to describe the ECG waveforms. In the early ECG recordings, the waveforms were named ABCD (four deflections were recognized). Mathematical correction, using differential equations, was used to correct and improve ECG recordings, and it was traditional that mathematical notation used letters from the latter half of the alphabet. The letters N and O were already used elsewhere, so it was decided to begin the notation at P. Over the following years further refinements were undertaken, most notably in the 1930s when the use of the chest leads was first described. At around the same time Frank Wilson invented the ‘indifferent electrode’ (also known as the ‘Wilson central terminal’). This led to the development of the ‘unipolar’ limb leads VR, VL, and VF (‘V’ stands for ‘voltage’). In 1942 the American cardiologist Emanuel Goldberger increased the voltage of these leads by 50%, leading to the term ‘augmented’ leads (aVR, aVL, and aVF), and the 12-​lead ECG which remains familiar today finally took shape. Although the format of the 12-​lead ECG has remained essentially unchanged since that time, there have nevertheless been other significant developments in electrocardiography over more recent years. Ambulatory ECG recorders and implantable cardiac monitors have gained a central role in the investigation of patients with suspected arrhythmias, and the use of intracardiac ECG recording has enabled the rapid development and widespread use of electrophysiological studies.

Normal ECG appearances The ECG waveform

History The first electrocardiogram (ECG), of an exposed frog’s heart, was performed by Marey in 1876 using the mercury capillary electrometer that had recently been invented by Gabriel Lippmann. Two years later the British physiologists John Burdon Sanderson and Fredrick Page demonstrated that recordings of the frog heart’s electrical activity consisted of two phases (which were subsequently to become known as the QRS complex and T wave). The first human ECG was published in 1887 by Augustus D Waller, who had worked under Sanderson in the Department of Physiology at the University College of London. While working at St Mary’s Hospital, London, Waller used a capillary electrometer to record the ECG of a laboratory technician, Thomas Goswell. Electrocardiography was developed further by the Dutch physiologist Willem Einthoven, who witnessed a demonstration by Waller at the First International Congress of Physiology in Basle,

The three fundamental deflections on the normal ECG are termed the P wave, the QRS complex, and the T wave (Fig. 16.3.1.1). The origins of each deflection are as follows.

P wave The P wave results from depolarization of the atrial myocardium. Depolarization of the sinoatrial node itself, which triggers normal atrial depolarization, cannot be seen on the surface ECG (although it can be identified in intracardiac recordings). However, the presence of a P wave with normal morphology and orientation is generally taken to infer normal sinoatrial node depolarization. Repolarization of the atrial myocardium is represented on the ECG by the Ta wave (the atrial equivalent of the ventricular T wave). The Ta wave is seen as a small asymmetrical deflection after the P wave, with an opposite polarity to the preceding P wave. The Ta wave is often hidden within the QRS complex and is therefore not easily

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Fig. 16.3.1.1  Basic ECG waveform.

seen—​in fact, it is unusual to be able to appreciate the Ta wave at all. However, it can extend right through to the following ST segment, where it can be mistaken for the ST segment depression of myocardial ischaemia (particularly because the Ta wave is most likely to be seen extending into the ST segment during exercise-​induced sinus tachycardia). There is one case report of a positive Ta wave (after an inverted P wave) giving the erroneous impression of an acute ST segment elevation myocardial infarction.

QRS complex The QRS complex represents depolarization of the ventricular myocardium. Of all the deflections, the QRS complex can exhibit the greatest variability in appearance. As a result, the individual components of the QRS complex can be labelled in upper case (Q, R, or S) or lower case (q, r, or s) to represent the relative size of the component. For example, QRS complexes with a small Q wave deflection can be termed qRS complexes, and those QRS complexes with no Q wave component and a small R wave component can be termed rS complexes.

The augmented unipolar leads measure the voltage between a single positive electrode and a ‘central’ point of reference generated from the other limb electrodes. Thus, aVR uses the right arm electrode as the positive terminal, aVL uses the left arm electrode, and aVF uses the left leg electrode. The three bipolar leads and the three augmented unipolar leads together comprise the six limb leads that view the heart in the frontal plane. The unipolar chest leads measure the voltage between six electrodes placed across the surface of the chest and a central point of reference, providing a view of the heart that is perpendicular to the frontal plane leads. For all 12 ECG leads, it is conventional that a wave of depolarization moving towards a lead generates a positive (upward) deflection on the ECG recording and vice versa.

The six limb leads (frontal plane leads) Because the limbs act as linear conductors, it does not matter whereabouts the limb electrodes are attached on each limb. The six limb leads provide general spatial information (being less localized than the six chest leads). Fig. 16.3.1.2 shows the orientation of the six

T wave The T wave (together with the preceding ST segment) represents repolarization of the ventricular myocardium.

The 12 conventional ECG leads aVR

Lead nomenclature It is important to emphasize that the term ‘lead’ does not refer to the electrode connecting the ECG machine to the patient. For a standard 12-​lead ECG recording, 10 electrodes are used to generate the 12 conventional ECG leads. The 12 leads can be categorized as limb (or frontal plane) leads (I, II, III, aVR, aVL, aVF) and chest (or precordial) leads (V1, V2, V3, V4, V5, V6). The 12 leads can also be categorized as bipolar (I, II, III) or unipolar (aVR, aVL, aVF, V1, V2, V3, V4, V5, V6). The leads aVR, aVL, and aVF can be further described as ‘augmented’ leads, as they are modified versions of the original VR, VL, and VF leads, having a voltage amplification of 50%. The bipolar leads are generated by measuring the potential (voltage) between two electrodes. One electrode acts as a positive terminal and the other as a negative terminal. For instance, lead I measures the potential between the left arm electrode (positive) and right arm electrode (negative). Lead I is obtained by subtracting the right arm vector from the left arm vector. Similarly, lead II measures the potential between the left leg electrode and the right arm electrode, and lead III measures the potential between the left leg electrode and the left arm electrode.

aVL I

Right

III

aVF

Left

II

Fig. 16.3.1.2  The six limb leads and their ‘view’ of the heart. Note that leads II, III, and aVF are inferior to the heart, I and aVL are anterolateral to the heart, and aVR looks into the cavity of the heart.

16.3.1 Electrocardiography

• The V4 electrode is placed at the left midclavicular line in the fifth intercostal space • The V5 electrode is placed at the left anterior axillary line in a horizontal line with V4 • The V6 electrode is placed at the left midaxillary line in a horizontal line with V4 and V5

Reading a normal 12-​lead ECG V1

V2 V3 V4

V6

V5

Fig. 16.3.1.3  Surface positions of the chest electrodes.

limb leads in relation to the heart. In simple terms, one can visualize lead aVR as ‘looking’ at the heart from the right shoulder, lead aVL from the left shoulder, and lead aVF from the feet. Lead I ‘looks’ at the heart from the left horizontal position. Similarly, the ‘views’ of leads II and III are shown in Fig. 16.3.1.2.

The six chest leads (precordial leads) For the chest (precordial) leads, each of the six electrodes is attached to a particular site on the chest wall. The chest electrodes act as positive terminals, and the indifferent terminal is formed from a combination of leads R, L, and F. The location of each electrode is important, in contrast to the limb leads. The surface positions of the chest electrodes are shown in Fig. 16.3.1.3, and the relation between the chest leads and the heart in Fig. 16.3.1.4. The electrodes are placed as follows: • The V1 electrode is placed at the right sternal edge in the fourth intercostal space • The V2 electrode is placed at the left sternal edge in the fourth intercostal space • The V3 electrode is placed midway between the V2 and V4 electrodes

Fig. 16.3.1.5 shows a normal 12-​lead ECG. As is conventional, this shows the leads arranged in four columns, each column containing three leads. In addition, a rhythm strip runs along the bottom of the ECG across its whole width. This is conventionally lead II, but any one of the 12 leads can be used for the rhythm strip as required. The ECG is recorded at a paper speed of 25 mm/​s, and at a sensitivity of 10 mm/​mV. The speed and sensitivity settings can also be adjusted on most ECG machines, if required, and so it is important that the actual recording speed and sensitivity are always noted on the ECG for future reference. In the following paragraphs we will describe the appearances of the normal ECG, looking at each wave, interval, and segment in turn. We will assume that the patient is in normal sinus rhythm, and that a standard paper speed (25  mm/​ s) and calibration (10 mm/​mV) have been used—​this should always be checked before reading any ECG.

Identification details Before reading the ECG, check the patient’s details (the patient’s name and at least one other form of identification, such as date of birth or identification number, should be recorded on the ECG) and the date and time on which the ECG was recorded. It is good practice to note on the ECG any relevant clinical features. For instance, a note that the patient was experiencing chest pain or palpitations at the time the ECG was recorded can prove invaluable later on. Indeed, ECG interpretation should always take into account the appropriate clinical context. For instance, the ECG shown in Fig. 16.3.1.5 can be interpreted as showing normal sinus rhythm in a patient who is well. However, in a patient who is unconscious and pulseless, the same ECG would be interpreted as showing pulseless electrical activity, a cardiac arrest rhythm. Before interpreting any ECG, it is therefore appropriate (and important) to ask, ‘How is the patient?’ Rate

V6

V5

V1

V4 V2

V3

Fig. 16.3.1.4  The chest leads and their anatomical relationship to the heart. Return to the top.

A normal heart rate is between 60 and 100 beats/​min. A rate below 60 beats/​min is termed bradycardia; a rate greater than 100 beats/​ min is termed tachycardia. Heart rate normally applies to the ventricular rate, as shown on the ECG by the rate of QRS complexes. However, the atria have their own rate, as shown by the P wave rate. The atrial and ventricular rates are usually the same, and there is a 1:1 ratio between P waves and QRS complexes. However, the rates can differ; for instance, in complete heart block (Fig. 16.3.1.6), the atrial rate is usually greater than the ventricular rate, and both rates should therefore be quoted. Ventricular rate can be calculated in two different ways. One method necessitates counting the number of large (5 mm) squares between two adjacent QRS complexes. This figure is then divided into 300 to give the ventricular rate per minute. For instance, if there are five large squares between QRS complexes, the ventricular rate is 300/​5 = 60

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Fig. 16.3.1.5  A normal 12-​lead ECG.

beats/​min. The same method can be used to calculate atrial rate, counting the large squares between two consecutive P waves. If the heart rhythm is irregular, the square-​counting method is not so useful. An alternative method is to count the number of QRS complexes in a certain time period, and then multiply the number up to obtain a rate per minute. Traditionally one counts the number of QRS complexes in a period of 30 large squares, which equates to 6 s of recording (a paper speed of 25 mm/​s covers five large squares per second, or 300 large squares per minute). One then multiplies the result by 10 to obtain the rate per minute. Thus, if there are 8 QRS complexes within 30 large squares, then the ventricular rate is 8 × 10 = 80 beats/​min. Once again, the same method can be used to calculate atrial rate. Rhythm A detailed description of arrhythmias can be found in Chapter 16.4. In general terms, the assessment of rhythm on the ECG requires careful attention to the following: • Whether there is ventricular activity (QRS complexes) and what is the ventricular rate; • Whether there is atrial activity (P waves) and what is the atrial rate; • Whether the heart rhythm is regular or irregular; • Whether the QRS complexes are normal or broad (broad complexes indicating either a ventricular origin to the rhythm or aberrant conduction of a supraventricular rhythm); • Whether there is a relationship between P waves and QRS complexes. Assessing the ECG along these lines will provide a basis upon which to describe the rhythm and begin to identify the nature of the arrhythmia.

Axis The concept of axis is often regarded as one of the hardest principles to grasp when learning ECG interpretation. The concept is, nonetheless, straightforward: axis refers to the overall direction in which the wave of depolarization travels. There is a QRS (ventricular) axis, which is what most people refer to when discussing cardiac axis, but the P wave has its own axis too, representing the overall direction of depolarization in the atria. The T wave also has an axis, in this case referring to the overall direction of the wave of repolarization. In this section the discussion is confined to the QRS (ventricular) axis, but the same principles apply to P wave and T wave axes too. As the ventricles depolarize, the wave of depolarization travels through the atrioventricular node, into the bundle of His, and then to the ventricular myocardium via the Purkinje fibres. The overall direction of this depolarization wavefront is usually towards the apex of the heart. If, by convention, we regard the ‘view’ that lead I has of the heart (a horizontal line to the left of the heart) as 0°, and any angle clockwise from that line is positive (and any angle anticlockwise from that line is negative), then the normal ventricular depolarization wavefront travels through the ventricles at an angle of approximately +60° (Fig. 16.3.1.7). As Fig. 16.3.1.7 illustrates, the six limb leads ‘view’ the heart from different angles. Lead I is taken as the horizontal reference point, 0°. Moving in a clockwise (positive) direction, lead II views the heart from an angle of +60°, lead aVF from an angle of +90°, and lead III from an angle of +120°. Moving anticlockwise from lead I, lead aVL views the heart from an angle of −30°, and lead aVR from an angle of −150°. This system of looking at axes, using the six limb leads, is known as the hexaxial reference system. The shaded area in Fig. 16.3.1.7 shows the normal range for the QRS axis, which lies between −30° and +90°. This does vary with

Fig. 16.3.1.6  Complete heart block: complete dissociation of atrial (P waves) and ventricular (QRS complexes) rate.

16.3.1 Electrocardiography

−90 −60

−120 aVR

aVL −150

−30

0

180

I

30

150

60

120 III

90

II

aVF

Fig. 16.3.1.7  The standard convention for describing the orientation of cardiac axis, and the corresponding ‘views’ of each of the six limb leads. The shaded area represents the normal range for the QRS axis.

body morphology—​tall, slim individuals tend to have axes towards the rightward (+ 90°) end of the normal range; short, overweight individuals have axes towards the leftward (−30°) end of the normal range. An axis more negative (anticlockwise) than −30° is abnormal and termed left axis deviation. Similarly, an axis more positive (clockwise) than + 90° is abnormal and termed right axis deviation. Left axis deviation is seen in left anterior hemiblock (see next), inferior myocardial infarction, and also in ostium primum atrial septal defect. Right axis deviation is seen in left posterior hemiblock, right ventricular hypertrophy, lateral myocardial infarction, ostium secundum atrial septal defect, and Wolff–​Parkinson–​White (WPW) syndrome. There are several ways to calculate the QRS axis. One method is to look for which of the six limb leads has a QRS complex in which the R wave and S wave are closest to being equal (i.e. in which the positive and negative deflections cancel each other out). The QRS axis will be at right angles to this ‘equipolar’ lead, but could be pointing in either direction. For instance, if the equipolar lead is lead III (which looks at the heart from + 120°), then the QRS axis will be at right angles to this, namely either + 30° or −150° (refer back to Fig. 16.3.1.7). Next, find which lead is at right angles to the equipolar lead—​in this example, the answer would be lead aVR. Now, if the QRS axis is −150°, then you would expect a positive QRS complex in lead aVR (because the wave of depolarization would be travelling directly towards it). If, however, the QRS complex in lead aVR is negative, the depolarization must be moving away from it and the QRS axis must be therefore be + 30°. This method works whichever limb lead is equipolar, as every limb lead has another lead at right angles to it.

An alternative and quick method of checking whether the QRS axis is within the normal range is simply to look at leads I and II. If the QRS complex in lead I is positive (or at least equipolar), then the QRS axis must lie somewhere in the range of −90° to + 90°. Similarly, if the QRS complex in lead II is positive, then the QRS axis must lie somewhere in the range −30° to + 150°. Therefore, we can say that if the QRS complexes in leads I and II are both positive then the QRS axis must lie somewhere in the range −30° to + 90°. Thus, a positive QRS complex in leads I and II means the QRS axis is within the normal range; a positive QRS complex in lead I and a negative QRS complex in lead II indicate left axis deviation; a negative QRS complex in lead I and a positive QRS complex in lead II indicate right axis deviation. More precise calculations of the QRS axis can be made by measuring the individual R and S waves in each of the limb leads and using vector analysis to plot out the overall direction of depolarization, but this degree of precision is usually unnecessary. P wave The P wave represents atrial depolarization. P waves are usually upright except in leads aVR and V1 (and sometimes V2), where they can be inverted (or biphasic). P waves are seen most clearly in lead II and this is usually the lead of choice for the rhythm strip so that atrial activity can be assessed clearly. P waves can be inverted in other leads, indicating that atrial depolarization has been initiated somewhere other than the sinoatrial node. For instance, an ectopic focus of depolarization near the atrioventricular node will give rise to inverted P waves in the inferior leads (II, III, and aVF) as the wave of atrial depolarization will spread upwards rather than downwards. P waves are normally no broader than three small squares (0.12 s) and no taller than 2.5 mm. The features of atrial hypertrophy are discussed later. PR interval The PR interval is measured from the beginning of the P wave to the beginning of the QRS complex. A  normal PR interval is between 0.12 s and 0.20 s in adults. A long, fixed PR interval is termed first-​degree atrioventricular block and results from a delay in conduction between the atria and ventricles (Fig. 16.3.1.8). In second-​degree atrioventricular block the PR interval may gradually increase with each beat before a P wave is not conducted (Mobitz type I  or Wenckebach phenomenon) or may be fixed and long (or normal) with intermittent non​conduction of P waves (Mobitz type II). In third-​degree atrioventricular block and also in atrioventricular dissociation, the PR interval will vary because of the absence of any association between atrial and ventricular activity. See Chapter 16.4 for further discussion.

Fig. 16.3.1.8  First-​degree atrioventricular block (long PR interval).

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Fig. 16.3.1.9  A prolonged QT interval. Measurement can be difficult since the precise beginning and end of the interval may not be easy to determine, particularly if the end of the T wave is obscured by a superimposed U wave or the following P wave.

A short PR interval is seen in ventricular pre-​excitation (see next) or when the focus of atrial depolarization arises not from the sinoatrial node but from the vicinity of the atrioventricular node. QRS complex The QRS complex represents ventricular depolarization. The first negative deflection of the complex is termed the Q wave and the first positive deflection the R wave (whether or not it follows a Q wave). A negative deflection after an R wave is termed an S wave. If the deflections are small, lower-​case letters (q, r, and s) are used. Thus, it is possible to have QRS complexes, qRS complexes, rS complexes, and so on. Normal ‘physiological’ q waves are usually narrow (no more than 0.04 s in duration) and small (less than 25% the amplitude of the following R wave) and result from the left to right depolarization of the interventricular septum (‘septal q waves’). Larger Q waves may be pathological, although can be normal in leads III and aVR, and may also been seen in lead aVL if the QRS axis is greater than + 60°. The normal QRS complex duration is less than 0.12 s. The amplitude of the QRS complex varies normally from lead to lead and, in the precordial leads, normally increases progressively from lead V1 to V6. At least one R wave in the precordial leads must be at least 8 mm in height, and the tallest R wave should be no more than 27 mm (and the deepest S wave no more than 30 mm), and the sum of the tallest R wave and the deepest S wave should be no more than 40 mm. In the limb leads, the R wave height should be no more than 13 mm in lead aVL and 20 mm in lead aVF. ST segment The ST segment should be horizontal and should not normally deviate by more than 1 mm above or next the isoelectric line (which is the line between end of the T wave and the start of the subsequent P wave). T wave T waves in the limb leads are normally concordant—​if the QRS complex is positive, the subsequent T wave is upright, and vice versa. The T wave is normally inverted in lead aVR and upright in leads I and II. With regard to the precordial leads, normal T waves are always upright in leads V4 to V6. A flat or inverted T wave is found in lead V1 in 20% of adults, and in lead V2 in 5% of adults (in which case, the T wave should be inverted in lead V1 as well). An inverted T wave in lead V3 can, rarely, be found in normal young adults. T waves should not change their orientation—​an inverted T wave is not normal if previous ECGs show that it was previously upright. There are no strict criteria for normal T wave size, so ‘tall’ and ‘small’ T waves are not well defined and deciding on their presence tends to be a subjective judgement. ‘Tall’ T waves can occur in early acute myocardial infarction (‘hyperacute’ T waves) and in hyperkalaemia (‘tented’ T waves). Small T waves can be seen in hypokalaemia.

QT interval The QT interval is measured between the start of the QRS complex and the end of the T wave. The normal range for the QT interval varies according to heart rate. It is therefore convenient to correct the measured QT interval to what it would be if the heart rate were 60 beats/​min. This is done most commonly using Bazett’s formula, in which the measured QT interval (in seconds) is divided by the square root of the RR interval (in seconds), to give the corrected QT interval (QTc). The normal range for the QT interval at a heart rate of 60 beats/​min, and thus for the QTc, is between 0.35 s and 0.45 s (men) or 0.46 s (women) (Fig. 16.3.1.9). U wave The T wave is occasionally followed by a U wave, most clearly seen in the right precordial leads, which has the same orientation as the T wave and is usually no more than one-​third of its size. The physiological origin of the U wave is still debated but is often said to relate to after depolarizations in the ventricles.

Myocardial hypertrophy Left ventricular hypertrophy Evidence of left ventricular hypertrophy on the ECG is a significant risk factor for cardiovascular morbidity and mortality. Several diagnostic ECG criteria for left ventricular hypertrophy have been developed which, in general, are relatively specific (>90%) but not very sensitive (20–​60%). The diagnostic criteria shown in Box 16.3.1.1 are commonly used. The Cornell criteria involve measuring the S wave in lead V3 and the R wave in lead aVL. Left ventricular hypertrophy is indicated by a sum of more than 28 mm in men and more than 20 mm in women. The Romhilt–​Estes scoring system allocates points for the presence of certain criteria, with a score of five indicating left ventricular hypertrophy and a score of 4 indicating probable left ventricular hypertrophy. Points are allocated as follows: • 3 points for (a) R or S wave in limb leads of 20 mm or more; (b) S wave in right precordial leads of 25 mm or more; or (c) R wave in left precordial leads of 25 mm or more; • 3 points for ST segment and T wave changes (‘typical strain’) in a patient not taking digitalis (1 point with digitalis); • 3 points for P-​terminal force in V1 greater than 1 mm deep with a duration greater than 0.04 s; • 2 points for left axis deviation (beyond −15°); • 1 point for QRS complex duration greater than 0.09 s; • 1 point for intrinsicoid deflection (the interval from the start of the QRS complex to the peak of the R wave) in V5 or V6 greater than 0.05 s.

16.3.1 Electrocardiography

Box 16.3.1.1  Diagnostic criteria for left ventricular hypertrophy Limb leads • R wave >11 mm in lead aVL • R wave >20 mm in lead aVF • S wave >14 mm in lead aVR • Sum of R wave in lead I and S wave in lead III >25 mm Precordial leads • R wave of ≥25 mm in the left precordial leads • S wave of ≥25 mm in the right precordial leads • Sum of S wave in lead V1 and R wave in lead V5 or V6  >35  mm (Sokolow–​Lyon criteria) • Sum of tallest R wave and deepest S wave in the precordial leads >45 mm

A left ventricular ‘strain’ pattern (ST-​T wave abnormalities) is associated with around double the risk of myocardial infarction and stroke as left ventricular hypertrophy in the absence of strain. Left ventricular hypertrophy cannot be assessed reliably using the ECG in patients with bundle branch block, previous myocardial infarction, or WPW syndrome; visualization via echocardiography or cardiac MRI is required. An example of left ventricular hypertrophy is shown in Fig. 16.3.1.10.

Right ventricular hypertrophy As with left ventricular hypertrophy, the ECG criteria for right ventricular hypertrophy tend to be relatively specific but not very sensitive. Right ventricular hypertrophy shifts the QRS complex axis rightwards as well as producing higher-​voltage QRS complexes in the right precordial leads. ECG criteria include: • a dominant R wave (R wave ≥ S wave) in lead V1, in the presence of a normal QRS duration; • a QRS complex axis of greater than + 90°. These criteria are supported by: • ST segment depression and T-​wave inversion in the right precordial leads; • deep S waves in the lateral precordial and limb leads.

Fig. 16.3.1.10  Left ventricular hypertrophy.

It is not essential for all these criteria to be present, but the greater the number of features present, the greater the likelihood of right ventricular hypertrophy. It is prudent to remember that a dominant R wave in lead V1 can also be seen in right bundle branch block, WPW syndrome, and a posterior wall myocardial infarction.

Atrial hypertrophy Left atrial hypertrophy Left atrial depolarization is responsible for the terminal portion of the normal P wave. Left atrial hypertrophy increases the voltage and duration of this depolarization, and thus usually evidences itself by abnormalities of the terminal portion of the P wave. The P wave duration is prolonged, and it becomes bifid in lead II and biphasic, with a predominant negative component, in lead V1. So-​called ‘P mitrale’ can be seen in the left atrial enlargement that results from mitral valve stenosis (hence the term) and also in association with conditions that cause left ventricular hypertrophy, such as hypertension (most commonly) and aortic stenosis (Fig. 16.3.1.11).

Right atrial hypertrophy Right atrial hypertrophy increases the voltage, but not the duration, of the P wave, and this is usually best seen in the inferior and right precordial leads. A P wave height greater than 2.5 mm is regarded as abnormal. So-​called ‘P pulmonale’ can result from right ventricular hypertrophy or from tricuspid valve stenosis (Fig. 16.3.1.12).

The hemiblocks The left bundle branch divides into anterosuperior and postero­ inferior fascicles. A block of either fascicle (hemiblock) causes a deviation of the QRS axis.

Left anterior hemiblock A block of the anterosuperior fascicle leads to a left anterior hemiblock. This causes a leftward shift in the QRS axis, as the

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Fig. 16.3.1.11  Left atrial hypertrophy (‘P mitrale’).

These findings may be accompanied by ST segment depression and T-​wave inversion in the lateral precordial and limb leads, broad QS waves in the right precordial leads and broad R waves in the lateral leads, and R wave notching (‘M-​shaped’ QRS complexes). An example of LBBB is shown in Fig. 16.3.1.13. The extensive nature of the ECG changes means that further interpretation of the QRS complexes, ST segments, or T waves cannot be made. The difficulties of diagnosing myocardial infarction in the setting of LBBB are discussed later.

Right bundle branch block right/​inferior region of the left ventricle depolarizes first (via the posteroinferior fascicle) and then the wave of depolarization spreads to the left/​superior region. Although this hemiblock introduces a minor delay in ventricular depolarization, the QRS duration remains within the normal range (up to 120 ms). The QRS axis shifts to the left (beyond −30°). As a similar axis shift can result from an inferior myocardial infarction, the diagnosis of an left anterior hemiblock requires the presence of left axis deviation in the absence of an abnormal q wave in lead aVF.

Left posterior hemiblock Block of the posteroinferior fascicle leads to left posterior hemiblock. This causes a rightward shift in the QRS axis, as the left/​superior region of the left ventricle depolarizes first (via the anterosuperior fascicle) and then the wave of depolarization spreads to the right/​inferior region. As with a left anterior hemiblock, the QRS duration remains within the normal range (up to 120 ms). The QRS axis shifts to the right (beyond + 90°). However, right axis deviation can occur in several conditions (most commonly right ventricular hypertrophy, but also in lateral myocardial infarction and WPW syndrome). It is therefore not possible to diagnose left posterior hemiblock with certainty from the 12-​lead ECG alone.

Bundle branch block Left bundle branch block A left bundle branch block (LBBB) leads to a delay in left ventricular depolarization, as the left ventricle is depolarized via the right-​sided Purkinje system. In addition, the interventricular septum depolarizes from right to left instead of the usual left to right. Thus, in LBBB: • The QRS duration is prolonged (≥120 ms); • The normal ‘septal’ q waves usually seen in the lateral leads are absent; • A secondary r wave is not seen in lead V1 (this distinguishes LBBB from right bundle branch block (RBBB) with clockwise cardiac rotation).

RBBB leads to a delay in right ventricular depolarization, as the right ventricle is depolarized via the left-​sided Purkinje system. However, the normal left to right activation of the interventricular septum is preserved. The ECG changes seen in RBBB are therefore not as extensive as in LBBB. The QRS duration is prolonged (≥120 ms) and the right ventricular leads contain a second positive wave (and, conversely, the left ventricular leads contain a second negative wave). Thus, in RBBB: • the QRS duration is prolonged (≥120 ms); • lead V1 contains a second positive wave (rsR); • lead V6 contains a second negative wave (qRs). These findings may be accompanied by deep slurred S waves in the lateral precordial and limb leads, and abnormal ST-​T wave changes in the right precordial leads. An example of RBBB is shown in Fig. 16.3.1.14.

Ventricular pre-​excitation The normal progression of a wave of depolarization is from the sinoatrial node through the atria to the atrioventricular node, and then through the bundle of His and the Purkinje fibres to the ventricular myocardium. However, approximately 1 in 1000 of the population has an accessory pathway—​an alternative pathway from atria to ventricles that bypasses part of this normal route. Such a pathway initiates depolarization of the ventricles at a slightly earlier stage in the cardiac cycle than would otherwise be the case, hence the term ‘ventricular pre-​excitation’. This is because the accessory pathway lacks the inherent delay to conduction that is normally found in the atrioventricular node, thus allowing faster conduction of the wave of depolarization from atria to ventricles. There are several types of pathway that can give rise to ventricular pre-​excitation.

WPW-​type pre-​excitation WPW-​type pre-​excitation is exemplified by WPW syndrome. In WPW syndrome an accessory pathway, the bundle of Kent, connects

Fig. 16.3.1.12  Right atrial hypertrophy (‘P pulmonale’).

16.3.1 Electrocardiography

Fig. 16.3.1.13  Left bundle branch block.

the atria to the ventricles and bypasses the atrioventricular node altogether. This shortens the time between the onset of atrial depolarization and the onset of ventricular depolarization, and hence one of the ECG features of WPW syndrome is a short PR interval (2 mm

16.3.1 Electrocardiography

Table 16.3.1.1  Location of infarction and affected coronary artery ECG leads affected

Site of infarction

Most likely artery occluded (positive predictive value)

V3 and V4 I, aVL and V1 to V6 (in extensive infarction)

Anterior

Left anterior descending (96%)

V1 and V2

Septal

V1 to V4

Anteroseptal

I, aVL, and V3 to V6

Anterolateral

II, III, and aVF

Inferior

Right coronary (80%) Right or circumflex (94%)

I, aVL and V6 I and aVL (high lateral)

Lateral

Circumflex (75%)

ST depression in V1 and V2 followed by development of prominent R waves in lead V1 or V2

Posterior

Circumflex (75%)

Lateral or posterior

Right or circumflex (94%)

II, III, and aVF with aVL, V5, and V6

Inferolateral

Right coronary (93%)

in two contiguous leads) is associated with an increased risk of death at 1 year. The presenting ECG and probability of acute coronary syndrome New, or presumed new, ST segment deviation greater than 0.1 mV, however transiently, or T-​wave inversion in multiple precordial leads, is highly indicative of ACS. Q waves, ST segment depression of 0.05–​ 0.1 mV, or T-​wave inversion greater than 0.1 mV have an intermediate probability of ACS. T-​wave flattening or inversion less than 0.1 mV (in leads with dominant R waves) or a normal ECG has a low probability of ACS. The likelihood of NSTEMI is increased threefold in chest pain with ST segment depression in three leads or more than 0.2 mV.

Fig. 16.3.1.16  Evolution of STEMI over several days.

The presenting ECG and triage The presenting ECG can be used to triage patients with acute cardiac-​sounding chest pain: • ST elevation present—​immediate reperfusion should be considered, by primary percutaneous coronary intervention (PCI) (or by intravenous thrombolysis if primary PCI unavailable). • ST elevation not evident—​immediate treatment with antiplatelet drugs and anti-​ ischaemic drugs, with consideration of coronary angiography where appropriate. Risk stratification using tools such as GRACE or TIMI scoring, can help identify those most likely to benefit from early coronary angiography and revascularization.

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ST segment elevation myocardial infarction The ECG changes of myocardial infarction, first described in 1920, reflect myocardial ischaemia, injury, and myocyte necrosis. Within an hour or so of occlusion of a coronary artery, the T wave becomes more prominent, exceeding one-​half the height of the preceding R wave in the ECG leads subtending the infarcted area (see Fig. 16.3.1.16). Many patients present later than this, so these changes may pass unnoticed. In up to 50%, the presenting ECG is normal. The first documented indication of infarction is usually ST segment elevation which occurs within a few hours. The J point (the origin of the ST segment at its junction with the QRS complex) is elevated by 1 mm or more in two or more limb leads, or by 2 mm in two or more precordial leads. The ST segment returns to the baseline over the next 48–​72 h, during which Q waves and symmetrically inverted T waves appear. Some patients develop LBBB, either transiently or permanently. The ECG of a completed infarct shows new Q waves greater than 2  mm, R waves reduced in size or absent, and inverted T waves. This classical evolution of STEMI is seen in about 50–​66% of patients.

Reperfusion therapy, by primary PCI (or thrombolysis where primary PCI is unavailable) may alter this natural sequence of changes in the ECG. If treatment is given with thrombolysis, then an ECG performed 90 min after initiation should show that ST elevation has been reduced by at least 50% from pretreatment levels (Fig. 16.3.1.17). If chest pain persists and the ST segments remain elevated, coronary angiography and rescue PCI should be considered. Where available, primary PCI should be offered in preference to thrombolysis. Resolution of ST segment elevation predicts 30-​day mortality. With greater than 70% ST segment resolution, mortality is 2.1%; with 30–​70% ST segment resolution 5.2%; with no ST segment resolution 5.5%; and with worsening ST segment elevation 8.1%. Non-​ST elevation myocardial infarction ECG changes in NSTEMI are more variable than in STEMI. The ECG may be normal on first presentation and remain unchanged throughout the acute admission. There may be transient ST segment depression indicative of myocardial ischaemia. In 20–​30%, the only change will be T-​wave inversion. Risk-​scoring systems have

(a)

(b)

Fig. 16.3.1.17  (a) Acute inferolateral ST segment elevation myocardial infarction. (b) Substantial (but not complete) resolution of ST segment elevation 90 min after the initiation of thrombolysis.

16.3.1 Electrocardiography

been developed, for example, by the Trials In Myocardial Infarction group (http://​www.timi.org), for use in patients with ACS. These are described in Chapter 16.13.4: with regard to NSTEMI, ST segment deviation greater than 0.5 mm is one of the recorded parameters. The extent of ST depression identifies those who are most likely to benefit from early revascularization (FRISC II trial). Mortality with early invasive therapy is 4% with ST segment depression, 2% with no ECG changes, and 0.2% with T-​wave inversion.

Difficult diagnoses in acute myocardial infarction Right ventricular infarction The ECG provides prognostic as well as diagnostic information. An inferior infarction generally carries a good prognosis unless it is associated with a right ventricular infarction, when there is a sixfold increased risk of a major in-​hospital complication, including

ventricular fibrillation, reinfarction, and death. The right ventricle is involved in about 50% of those with an inferior infarction, occurring with occlusion of the right coronary artery, causing a transmural infarct of the inferoposterior wall and the posterior septum. To determine whether the right ventricle is involved in an inferior infarction, an ECG should be recorded with the anterior chest leads placed on the right side of the chest, in equivalent (but mirrored) positions to a standard 12-​lead ECG. The right ventricle is involved if there is greater than 1 mm ST segment elevation in chest lead ‘right V4’ (RV4); this has a sensitivity of 100%, specificity of 87%, and positive predictive value of 92% for occlusion of the right coronary artery proximal to the right ventricular branch. If these changes are absent, the right ventricle has been spared (Fig. 16.3.1.18).

Atrial infarction This occurs in up to 10% of myocardial infarcts in conjunction with ventricular infarction. A  clue to its presence is PR segment

(a)

(b)

Fig. 16.3.1.18  (a) Inferior ST segment elevation myocardial infarction. (b) Inferior ST segment elevation myocardial infarction with right ventricular involvement (note the right ventricular chest leads, with ST segment elevation in lead RV4).

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displacement but there may also be an abnormal P wave. It can cause rupture of the atrial wall and is frequently associated with atrial arrhythmias including atrial fibrillation, atrial flutter, and atrioventricular nodal rhythm.

Coronary artery spasm The pain of Prinzmetal’s or variant angina is not usually triggered by exercise, emotion, cold, or a meal but tends to occur at rest, accompanied by transient, marked ST segment elevation. This rapidly reverts to normal when the pain resolves spontaneously or with glyceryl trinitrate. Atrioventricular block or ventricular arrhythmia may accompany spasm-​induced myocardial ischaemia. Spasm sufficient to cause myocardial ischaemia, myocardial infarction, and sudden death can follow cocaine use.

Reciprocal changes—​septal ischaemia or posterior infarction? ST or ‘reciprocal’ depression may be seen in leads remote from the site of a STEMI. For example, ST depression may be seen in leads V1 to V4 in an inferior STEMI. There are two explanations. First, in a right-​dominant system (70% of the population), the right coronary artery supplies the posterior interventricular septum, which becomes ischaemic with an inferior STEMI; the ischaemia resolves within a few days as septal perforating arteries from the left anterior descending artery dilate in response to ischaemic stress. Second, in a left-​dominant system, the circumflex supplies the posterior interventricular septum; if this occludes, a ‘true posterior infarction’ follows.

Difficulties in diagnosing STEMI ‘Stuttering’ infarction Symptoms of myocardial infarction are usually severe and of sudden onset. Occasionally, the onset of symptoms is not so clear cut and chest pain may resolve but recur at intervals over several hours. The time of arterial occlusion is at best a guess, but for practical purposes is taken as the time that symptoms increase or are at their worst.

Non​infarct causes of ST segment elevation Pericarditis may mimic the pain of myocardial infarction but is usually relieved by sitting forward and is accompanied by a pericardial rub. The ST segments are elevated diffusely, do not fit the usual lead pattern for an inferior or anterior infarction, and, unlike the convexity of STEMI, are concave upwards (Fig. 16.3.1.19). Prinzmetal’s angina, caused by coronary artery spasm, can also mimic myocardial infarction. This usually occurs at rest, with marked ST elevation during pain and a brisk response to glyceryl trinitrate. The ST segment can be elevated chronically in left ventricular aneurysm, left ventricular hypertrophy, LBBB, hypertrophic cardiomyopathy, acute cor pulmonale, hypothermia, and cocaine abuse. A  normal variant is so-​called ‘high take-​off ’ where serial ECGs show consistent ST elevation across most ECG leads; patients should be given a copy of the ECG to show to medical personnel to avoid unnecessary investigations and treatment. Late presentation Patients who present to hospital outside the 12-​h time limit for reperfusion are sometimes diagnosed as ‘missed infarction’. The ECG may show signs characteristically seen later in the infarction process, with ST segments only slightly elevated, with established Q waves and inverted T waves. Over the next few days, the ST segment fully returns to baseline and Q waves and T waves deepen. LBBB Recognition of acute STEMI in pre-​existing LBBB is challenging, but the Sgarbossa criteria help. Five points are scored for ST elevation 1 mm or greater in at least one lead with a positive QRS complex, 3 points for ST depression 1 mm or greater in leads V1–​V3, and 2 points for 5 mm or greater ST elevation in leads with a negative QRS complex. A score of 3 points or greater has a 90% specificity (but a poor sensitivity) for acute myocardial infarction. ECG changes of ‘old’ infarction Q waves, once formed, usually persist indefinitely and so are a reliable indicator of a previous myocardial infarction (Fig. 16.3.1.20).

Fig. 16.3.1.19  Widespread elevation of the ST segments (concave upwards) in a case of pericarditis.

16.3.1 Electrocardiography

Fig. 16.3.1.20  ‘Old’ inferior myocardial infarction: pathological Q waves in leads II, III, and aVF.

However, there are several other causes of a Q wave that may cause confusion, the most common being hypertrophic cardiomyopathy and idiopathic cardiomyopathy. Rarer causes include myocarditis, cardiac amyloid, neuromuscular disorders (e.g. muscular dystrophy, myotonic dystrophy, Friedreich’s ataxia), scleroderma, sarcoidosis, and an anomalous coronary artery. Pre-​excitation WPW syndrome makes interpretation of the ECG more complicated. It may mask a myocardial infarction if conduction via the bypass tract is towards the left ventricle, as a Q wave will not be apparent. WPW may also simulate an infarction due to a negative δ-wave in the inferior leads producing Q waves. Serial or previous ECGs will reveal the true diagnosis. Patients with WPW syndrome should be given a copy of their ECG to avoid confusion and unnecessary future investigations. T-​wave inversion Atypical ECG features are seen in up to half of all infarctions in the early stages. Alone, these changes are not diagnostic. They can occur in ventricular aneurysm, electrolyte abnormalities, myocarditis, and subarachnoid haemorrhage, and with some drugs. Serial ECGs are necessary to establish a firm diagnosis. Deep, symmetrical ‘arrowhead’ T waves developing during an infarction are most often due to proximal occlusion of the left anterior descending coronary artery (Fig. 16.3.1.21).

Where errors occur Incorrect interpretation of an ECG leads to inappropriate patient triage and misses the opportunity to provide reperfusion therapy, whether by angioplasty or thrombolysis. In the worst-​case scenario, inappropriate thrombolysis might lead to a haemorrhagic stroke or ruptured aneurysm. Up to 12% of those with a high-​risk ECG (i.e. ST segment elevation of at least 0.1 mV, ST segment depression of at least 0.05 mV, or T-​wave inversion of at least 0.2 mV in two or more contiguous leads) are missed on admission to the emergency department. The ECG provides a ‘snapshot’ of electrical events within the heart, when the clinician really needs a ‘movie’ to monitor the dynamic changes of an acute coronary syndrome. If a diagnosis cannot be made on the presenting ECG but the history suggests an acute coronary syndrome, the patient should be admitted to a monitored area, a review by a specialist should be arranged, and the ECG should be repeated if symptoms get worse or if ST segment changes are seen on the monitor. This will ensure prompt and appropriate treatment. While it may be important to provide treatment promptly to fulfil audit targets (e.g. door-​to-​balloon time for primary PCI), speed should not replace accuracy in diagnosis. It is sometimes better to repeat the ECG than to make an incorrect diagnosis. It is easy to place too much reliance on minor changes on the ECG; it is clear changes of ST elevation or depression within the aforementioned parameters, that should determine treatment.

Fig. 16.3.1.21  Recent anterior ST segment elevation myocardial infarction with ‘arrowhead’ T-​wave inversion.

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Exercise ECG testing ECG changes on exercise were first reported in patients with chronic stable angina in the early 1900s. Exercise testing was adopted into routine clinical practice soon after a standardized exercise protocol was developed.

Cardiovascular responses to exercise in normal subjects and in coronary disease Normally on treadmill exercise, heart rate increases as a result of diminished vagal and increased sympathetic outflow. Heart rate increases on commencing exercise and reaches a plateau during each stage of the exercise test. A rapid increase may be due to lack of fitness, prolonged bed rest, anaemia, or dehydration. Systolic blood pressure increases in line with increased cardiac output, while diastolic pressure is near constant or falls slightly due to vasodilatation. On stopping the test, heart rate slows within a few minutes to pretest levels and both systolic and diastolic blood pressure falls, often to below pretest levels, as a result of vasodilatation. With cardiac disease, the maximum cardiac rate may be attenuated (even in the absence of a β-​blocker) due to sinus node disease, coronary heart disease, or postinfarction (with or without β-​ blockade). Failure to achieve the maximum predicted heart rate, calculated as 220 minus age, is suggestive of cardiac disease. Brady-​and tachyarrhythmias including atrial fibrillation may occur. Exercise-​induced hypotension, even a transient fall in blood pressure at (near-​)maximum heart rate, is indicative of severe heart disease and increases the risk of ventricular fibrillation. On stopping exercise, systolic pressure falls to resting levels (or lower) within minutes, where it may remain for several hours. In some, venous pooling may cause a precipitous drop in systolic pressure. ECG changes with exercise in normal subjects and in coronary disease In normal subjects, exercise-​induced tachycardia causes shortened PR, QRS, and QT intervals, increased P wave amplitude, and

down-​sloping of the PR segment. R waves and T waves may diminish, and S waves increase at maximum exercise. The J point (the isoelectric point where the S wave reaches the baseline) may become depressed in all leads and the ST segment may become up-​sloping. The most helpful ECG marker of exercise-​induced myocardial ischaemia is the ST segment which becomes depressed with increasing heart rate. This is due to shortening of the action potential due to ischaemia, setting up electrical gradients between endocardium and epicardium. Horizontal or down-​sloping ST depression, measured 60–​80 ms after the J point, of 1 mm (0.10 mV) or more for 80 ms in at least three complexes is considered significant (Fig. 16.3.1.22), but the leads in which ST depression appear do not reliably localize the site of myocardial ischaemia. Other indicators of myocardial ischaemia include: • ST segment elevation—​ this indicates severe ischaemia due to proximal disease or coronary spasm, or an aneurysmal or dyskinetic left ventricle. Unlike exercise-​induced ST segment depression, the ECG site of ST segment elevation is relatively specific for the coronary artery involved. • T-​ wave inversion—​ this may occur with exercise-​ induced hyperventilation. • Normalization of an inverted T wave—​this alone is not indicative of coronary disease. • U wave inversion—​this is relatively specific for coronary artery disease but is relatively insensitive; in precordial leads, it usually indicates left anterior descending coronary artery disease.

Exercise protocols Various protocols have been developed but the most widely used are the following. Bruce protocol This is a multistage test with 3-​min walking periods during which a steady state is reached before the workload is increased by increasing the speed and slope of the treadmill. It is clearly only suitable for

Fig. 16.3.1.22  ECG recorded during an exercise treadmill test, showing anterolateral ST segment depression after 3 min of exercise using the Bruce protocol.

16.3.1 Electrocardiography

Table 16.3.1.2  Table of MET equivalents Occupation

METs

Activity

METs

Receptionist

1–​2

Carrying a suitcase

7

Professional (active)

1.5–​2.5

Cleaning floor

4

Homemaker

1.5–​4

Washing clothes

5

Farm worker

3.5–​7.5

Cooking

3

Construction worker

4–​8.5

Gardening

4

Miner

4–​9

Push mower

5

Postal carrier

2.5–​5

Sex

5

Bed-​making

5–​6

those whose walking is not limited by other considerations (e.g. musculoskeletal or neurological). For older patients or those with limited exercise capacity, the test can be modified to include two stages with lower workload demands. Bicycle ergometry This is often combined with radionuclide imaging (see Chapter 16.3.3), which increases the sensitivity and specificity of the test. Cycling avoids motion artefact, and so ECG recordings are clearer. The patient pedals at a comfortable speed of between 60 and 80 revolutions/​ min; the test is terminated if speed cannot be maintained above 40 revolutions/​min. Exercise workload begins at 25 W and resistance is increased every 2 min in 25-​W increments by applying either an electronic or mechanical brake. The workload achieved during exercise is measured in metabolic equivalents or METs. This allows comparison of different protocols. A MET is 3.5 ml/​min per kg, the resting Vo2 for a 40-​year-​old 70 kg male. METs equivalent to normal daily activities have been estimated (Table 16.3.1.2).

Conducting the exercise test Who should have an exercise test? Deciding who should and who should not undergo an exercise test requires clinical judgement and the test should not be organized as a routine. Exercise testing is used to: • assess functional capacity and estimate prognosis in the evaluation of chest pain; • assess patients with known coronary artery disease; • establish prognosis after myocardial infarction either predischarge (submaximal test) or 4–​6 weeks post-​discharge (symptom-​limited); • assess the effectiveness of coronary revascularization; • assess patients with symptoms of exercise-​ induced cardiac arrhythmia; • risk-​stratify before non​cardiac surgery in patients with or at high risk of coronary disease; • determine the efficacy of rate-​responsive pacemakers.

Exercise testing may also be indicated in selected asymptomatic individuals: • in specific occupations for licensing purposes (e.g. airline pilots, bus, or heavy goods vehicle drivers); • with more than two cardiovascular risk factors for risk stratification; • wishing to commence a strenuous exercise programme; • to assess cardiovascular risk due to prior to major surgery. Who should not have an exercise test? In its 2016 guideline on assessing chest pain of recent onset, the National Institute for Health and Care Excellence (NICE) recommended that exercise testing should no longer be used to diagnose or exclude stable angina in those without known coronary artery disease. Some conditions are considered to be absolute contraindications to exercise testing but even in these patients a submaximal test may be informative. Exercise testing is inappropriate: • in healthy individuals with a low-​risk factor profile—​the false-​ positive rate is increased (see next); • with unstable medical conditions such as unstable angina; severe congestive cardiac failure; uncontrolled ventricular or supraventricular arrhythmia; myocarditis; severe pulmonary hypertension; drug toxicity; haemodynamic instability; symptomatic aortic stenosis; active thromboembolic disease; hypertension with systolic blood pressure more than 200  mm Hg or diastolic blood pressure more than 110 mm Hg; • in extreme obesity; • when taking specific medication—​digoxin depresses the ST segment (Fig. 16.3.1.23); type 1 antiarrhythmics and tricyclic antidepressants may be proarrhythmic; • in vasoregulatory disorders—​pulse and blood pressure changes are unpredictable. Patients with aortic stenosis may fail to report symptoms of angina, breathlessness, and syncope. Although severe symptomatic aortic stenosis is considered an absolute contraindication to exercise testing, a medically supervised symptom-​limited test in those who appear to be asymptomatic during their everyday activities may identify those who warrant cardiac catheterization and valve replacement. Who should supervise an exercise test—​cardiac technician, specialist nurse, or physician? Patients with new or recent-​onset chest pain thought to be angina are often referred to a rapid-​access chest pain clinic for assessment, where a specialist nurse carries out an initial assessment and then an exercise test. Experience shows that this approach is safe, provided a physician is available for consultation and advice. There are some high-​risk situations where the test, if it must be carried out, should

Fig. 16.3.1.23  Depression of the ST segments caused by digoxin.

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be supervised by a physician. These include patients whose symptoms are unstable, aortic stenosis, known severe coronary disease, severe or moderate systemic or pulmonary hypertension, severe left ventricular dysfunction, congestive or hypertrophic cardiomyopathy, or a history of ventricular tachycardia, or second or third-​ degree atrioventricular block.

Risks of exercise testing Exercise testing is generally considered a safe procedure but full resuscitation facilities, including defibrillator, emergency drug kit, airways management equipment, and oxygen are essential. Serious complications are rare. The risk of myocardial infarction and sudden death is less than 1 in 1000, more when testing patients after myocardial infarction or with malignant ventricular arrhythmia. When to stop an exercise test Reasons for stopping a test include: • achieving 90% of the maximum predicted heart rate; • symptoms—​establish if these are typical symptoms of chest pain or breathlessness; exercise may continue provided that symptoms are not distressing or severe; • systolic blood pressure—​if systolic blood pressure falls below baseline levels or if systolic increases to greater 250 mm Hg or diastolic to greater than 115 mm Hg; • change in ECG—​if more than 2 mm ST segment depression or more than 1 mm ST segment elevation; or if LBBB (this may look remarkably like ventricular tachycardia at fast heart rate) or arrhythmia develops; • clinical signs—​if signs of poor peripheral perfusion such as cyanosis appear; • symptoms of central nervous system dysfunction—​dizziness, near syncope, or ataxia; • serious arrhythmia—​ventricular tachycardia, multifocal ectopics, ventricular couplets; • technical difficulties—​failure of blood pressure recording or poor ECG trace; • patient request—​distressing symptoms of fatigue, breathlessness, wheeze, or claudication; maximal patient effort; or inability to maintain speed of treadmill. Recovery period It is important to observe the patient into the recovery period until the pretest heart rate and blood pressure have been restored. Minor ECG abnormalities early in recovery are common but late changes usually indicate myocardial ischaemia.

Interpreting the results of an exercise test Like all medical tests, the exercise test is not a perfect indicator of the presence or absence of disease. Nevertheless, a test is often described as: • positive—​chest pain develops with or without ST displacement; blood pressure falls; arrhythmia occurs; the patient fails to complete the first two stages of the Bruce protocol or reach 90% of predicted maximum heart rate;

• negative—​the patient completes uneventfully three stages of the Bruce protocol or reaches 90% of predicted maximum heart rate; • indeterminate—​90% predicted heart rate is not reached; symptoms occur which are not typical of cardiac pain with a normal ECG throughout. A positive test does not necessarily mean that the patient has coronary disease, nor does a negative test mean the patient has some other, non​cardiac, cause for chest pain. The exercise test has limited use as a diagnostic test for coronary disease.

Limitations and strengths of the exercise test The exercise test as a diagnostic tool The sensitivity of the exercise test, the proportion with coronary disease correctly identified by the test, is 68% (range 23–​100) and specificity, the proportion free of disease correctly identified by the test, is 77% (range 17–​100). In multivessel disease, these figures are 81% (range 40–​100) and 66% (range 17–​100), respectively. This means that exercise testing frequently yields false-​positive results, incorrectly diagnosing disease when coronary arteries are normal or minimally diseased; and false-​negative results, missing coronary disease when a flow-​limiting, even critical left main stem, coronary stenosis is present. Selection of patients for exercise testing is important as a false-​ positive result is more likely when an individual has few predisposing risk factors for coronary disease or the prevalence of coronary disease prevalence in the population is low. Example 1 A positive test in a middle-​aged man with multiple coronary risk factors (smoking, dyslipidaemia, hypertension, diabetes mellitus, and family history) and typical chest pain on exertion (who is highly likely to have coronary disease) is most likely to be correct. Example 2 A positive test in a young woman with atypical chest pain and few or no cardiovascular risk factors is likely to be incorrect and may lead to other, more invasive tests including coronary angiography. The prevalence of coronary disease is lower in women than men and the specificity of exercise testing is lower in women, which means that the test is more likely to be positive in the absence of coronary disease, possibly due to increased catecholamine secretion during exercise contributing to coronary vasoconstriction. The exercise test as an indicator of prognosis Although the exercise test is of limited value as an aid to diagnosis, it is more reliable as a marker of prognosis. Generally, appearance of symptoms or ECG changes early in the test is associated with more severe and extensive coronary disease and a poor prognosis (Table 16.3.1.3). Changes within the first 3 min usually indicate severe coronary disease affecting the left main stem or the proximal segments of at least one major coronary artery. Multivessel coronary disease is more likely with ST segment down-​sloping, delayed ST normalization after exercise, increased number of leads affected, and lower workload at which ECG changes appear.

16.3.1 Electrocardiography

Table 16.3.1.3  Prognostic indicators on treadmill testing

ST segment

Indicators of a good prognosis

Indicators of a poor prognosis

No displacement or up-​sloping

2 mm or more depression in stage 1 Bruce-​within 3 minutes Down-​sloping or horizontal

Duration of exercise

9 minutes (>9 METs)

Unable to complete stage 2 Bruce or equivalent (120/​min off β-​blocker

Systolic BP response

Maintained or increased

Sustained decrease >10 mm Hg or failure to rise with exercise

Changes on exercise

No changes

Ventricular tachycardia U wave inversion T wave normalization

Recovery

Recovers normal heart rate 10 min

Symptoms

None or atypical

Test terminated due to increasing angina on exercise

Difficulties with exercise testing Baseline ECGs that make interpretation of the exercise test difficult ECG patterns that may make exercise-​induced changes hard to recognize include: • ST depression or elevation at rest • Ventricular strain patterns—​left and right ventricular hypertrophy; • T wave changes—​inversion secondary to previous infarction or ‘strain’ • Conduction abnormalities—​LBBB affects ST segment and T wave; RBBB affects ST segment and T wave changes in V1, V2, and V3 • Prolonged QT interval Alternative tests that do not rely on the ECG to identify myocardial ischaemia are dobutamine stress echocardiography, radionuclide thallium, or myocardial perfusion imaging (MIBI) stress test, or cardiac MRI (see Chapters 16.3.2 and 16.3.3). Medication and exercise testing β-​Blockers and rate-​modifying calcium antagonists may mask myocardial ischaemia by limiting exercise-​induced tachycardia and so delay the appearance of ST depression. Blood pressure-​ lowering medication may blunt the normal exercise-​induced rise in pressure. Digoxin may induce or accentuate ST depression on the resting ECG. Medication may be continued if the indication for exercise testing is to assess the efficacy of treatment but should be temporarily stopped in all other circumstances. Specific rules apply if assessing for driving licensing purposes—​always check local rules, but generally, antianginal drugs must be stopped at least 48 h prior to the assessment. ST segment depression in the absence of symptoms Asymptomatic, exercise-​induced ST segment depression, or ‘silent ischaemia’, is seen in 60% of patients with coronary disease but does not increase the risk of cardiac death compared with those who report angina. Technical issues Current ECG machines filter out motion and muscle artefact to facilitate measurement of the ST segment. Because leads placed

on the limbs produce motion artefact, moving these to the torso exaggerates the degree of change and increases the amplitude of the R wave, potentiating exercise-​induced ST segment changes. It can be difficult to identify ST segment depression during exercise. If there is any doubt about the extent of ST segment depression on the running ECG, most automated machines will provide a filtered 12-​lead ECG for comparison with baseline.

Exercise testing in special groups Peri-​and post-​myocardial infarction Exercise testing after myocardial infarction may be performed for risk stratification and selection for revascularization. A submaximal predischarge test to identify residual ischaemia appears to be safe, with 0.05% morbidity and 0.02% mortality. An abnormal blood pressure response or low exercise capacity predicts a poor outcome and is an indication for urgent revascularization. Evidence of myocardial ischaemia, especially at low workload, is an indication for referral for coronary angiography. Elderly patients Advanced age alone is not a contraindication to exercise testing, provided that the individual can walk at a reasonable speed. If mobility is limited, dobutamine stress echocardiography, radionuclide thallium, or MIBI stress test, or cardiac MRI are alternative means of identifying ischaemia (see Chapters  16.3.2 and 16.3.3). Asymptomatic individuals Testing may be undertaken in asymptomatic individuals, generally a low-​risk population, as part of health screening, for insurance purposes, or for risk stratification. Up to 12% of middle-​aged men and up to 30% of women will have an abnormal exercise test in the absence of symptoms; the risk of a cardiac event is low unless the test result indicates a poor prognosis. The presence of cardiovascular risk factors increases the likelihood of coronary disease. Cardiac arrhythmia Exercise testing can be useful in evaluating cardiac arrhythmia, supplementary to ambulatory monitoring and electrophysiological studies. In about 10%, it may provoke an arrhythmia.

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FURTHER READING Bruce, RA, Fisher LD (1987). Exercise-​enhanced assessment of risk factors for coronary heart disease in healthy men. J Electrocardiol, 20 (Suppl. October), 162. Cura FA, et al. (2004). ST segment resolution 60 minutes after combination treatment of abciximab with reteplase or reteplase alone for acute myocardial infarction (30-​day mortality results from the resolution of ST segment after reperfusion therapy substudy). Am J Cardiol, 94, 859–​63. Einthoven W (1912). The different forms of the human electrocardiogram and their signification. Lancet, 1, 853–​61. Gianrossi R, et  al. (1989). Exercise-​ induced ST segment depression in the diagnosis of coronary artery disease:  a meta-​analysis. Circulation, 80,  87–​98. Hancock EW, et  al. (2009). AHA/​ ACCF/​ HRS recommendations for the standardization and interpretation of the electrocardiogram:  part V:  electrocardiogram changes associated with cardiac chamber hypertrophy. J Am Coll Cardiol, 53, 992–​1002. Houghton AR, Gray D (2014). Making sense of the ECG, 4th edition. Hodder Arnold, London. Joint European Society of Cardiology/​American College of Cardiology Committee (2000). Myocardial infarction redefined—​a consensus document of the joint European Society of Cardiology/​American College of Cardiology Committee for the Redefinition of Myocardial Infarction. Eur Heart J, 21, 1502–​13. Kligfield P, et  al. (2007). Recommendations for the standardization and interpretation of the electrocardiogram: part I: the electrocardiogram and its technology. J Am Coll Cardiol, 49, 1109–​27. Knaapen P, van Loon RB, Visser FC (2005). A rare cause of ST segment elevation. Heart, 91, 188. Levy D, et  al. (1990). Determinants of sensitivity and specificity of electrocardiographic criteria for left ventricular hypertrophy. Circulation, 81, 815–​20. Lloyd Jones DM, et al. (1998). Electrocardiographic and clinical predictors of acute myocardial infarction in patients with unstable angina pectoris. Am J Cardiol, 81, 1182–​6. Marey EJ (1876). Des variations électriques des muscles et du coeur en particulier étudiés au moyen de l’electromètre de M Lippman. C R Acad Sci (Paris), 82,  975–​7. Mason JW, et  al. (2007). Recommendations for the standardization and interpretation of the electrocardiogram:  part II: electrocardiography diagnostic statement list. J Am Coll Cardiol, 49, 1128–​35. Mueller C, et  al. (2004). Prognostic value of the admission electrocardiograph in patients with unstable angina/​ST segment elevation myocardial infarction treated with very early revascularisation. Am J Med, 117, 145–​50. National Institute of Health Care Excellence (2016). Chest pain of recent onset. Clinical guideline. https://​ w ww.nice.org.uk/​ guidance/​c g95 Rautaharju PM, et  al. (2009). AHA/​ACCF/​HRS recommendations for the standardization and interpretation of the electrocardiogram: part IV: the ST segment, T and U waves, and the QT interval. J Am Coll Cardiol, 53, 982–​91. Savonitto S, et al. (1999). Prognostic value of the admission electrocardiogram in acute coronary syndromes. JAMA, 281, 707–​13. Sharma S, et al. (2017). International recommendations for electrocardiographic interpretation in athletes. J Am Coll Cardiol, 69, 1057–75.

Surawicz B, et al. (2009). AHA/​ACCF/​HRS recommendations for the standardization and interpretation of the electrocardiogram:  part III: intraventricular conduction disturbances. J Am Coll Cardiol, 53, 976–​81. Wagner GS, et al. (2009). AHA/​ACCF/​HRS recommendations for the standardization and interpretation of the electrocardiogram:  part VI: acute ischemia/​infarction. J Am Coll Cardiol, 53, 1003–​11. Waller AD (1887). A demonstration on man of electromotive changes accompanying the heart’s beat. J Physiol (Lond), 8, 229–​34.

16.3.2 Echocardiography James D. Newton, Adrian P. Banning, and Andrew R. J. Mitchell ESSENTIALS Ease of use, rapid data provision, portability, and safety mean that echocardiography has become the principal investigation for almost all cardiac conditions. A  modern transthoracic echocardiography examination combines real-​time two-​dimensional imaging of the myocardium and valves with information about velocity and direction of blood flow obtained by Doppler and colour-​flow mapping. A complete examination can be performed in most patients in less than 30 min. Valvular heart disease—​echocardiography has revolutionized the diagnosis and follow-​up of patients with these conditions. Serial cardiac catheterization to assess severity and progress of valvular stenosis has been completely superseded by Doppler echocardiography, and the role of invasive investigation is increasingly limited to the assessment of the coronary arteries prior to revascularization. Transoesophageal echocardiography—​this is now a routine investigation in many centres. Under sedation, an ultrasound probe is passed into the oesophagus to a position behind the heart, producing excellent resolution of cardiac structures. It is used diagnostically in many emergency situations, including aortic dissection and suspected prosthetic mechanical valve dysfunction, and as an additional method of monitoring cardiac performance during cardiac and noncardiac surgery. Other technological developments—​ these include (1)  stress echocardiography—​used to detect occult coronary disease and predict cardiac risk; (2) use of contrast agents—​these improve visualization of the endocardium in patients with poor acoustic windows and allow some estimation of myocardial perfusion; and (3)  real-​time three-​dimensional imaging—​this is available on modern platforms and allows detailed assessment of myocardial and valve function. Recent developments in assessing myocardial mechanics by quantifying strain offer new insights into early pathological changes, and progressive miniaturization of platforms including fully portable systems have further increased the utility of echocardiography in the assessment of cardiac structure and function.

16.3.2 Echocardiography

History of echocardiography The timeline of key discoveries and inventions is as follows: • 1842—​Christian Doppler observed that the pitch of a sound varies if the source is moving. • 1880—​first piezoelectric crystals developed. • 1912—​Richardson develops sonar technique using sound waves to detect underwater objects. • 1929—​ Sokolov uses ultrasound to identify flaws in metal components. • 1954—​ heart visualized with ultrasound by Carl Herz and Inge Edler. • 1960s—​ multielement scanners lead to development of two-​ dimensional (2D) echocardiography. • 1970s—​ Doppler colour-​ flow mapping used to evaluate valve disease. • 1970s—​transoesophageal and stress echocardiography developed. • 1980s—​ultrasound contrast agents developed. • 1990s—​intracardiac and intracoronary ultrasound in wider use. • 2000s—​development and refinement of three-​dimensional (3D) echocardiography and advances in myocardial deformation imaging.

Principles of echocardiography The transducer used for most echocardiographic examinations contains piezoelectric crystals that emit ultrasound frequencies of 2.5–​5 MHz. Most of the sound energy is scattered or absorbed, but reflection occurs at interfaces between tissues of different acoustic impedance (e.g. between blood and muscle). The transducer collects these reflections and the time delay between emission and reception is calculated. This allows the depth of the reflection to be derived and its position to be displayed on a screen as a dot (pixel). The brightness of the dot is related to the magnitude of the reflected signal. In general, higher-​frequency transducers allow better discrimination between structures, but the increased attenuation leads to reduced penetration. There are three main echocardiographic techniques:  two-​ dimensional (cross-​sectional), M-​mode, and Doppler.

Fig. 16.3.2.1  Parasternal long-​axis view of the heart using 2D echocardiography. The sector images through the right ventricle (RV) to the left ventricle (LV). In this view, 2D echocardiography provides useful data on the structure and function of the aortic valve (AV) and mitral valve (MV).

reflections from cardiac structures being displayed as horizontal lines, with superficial structures at the top of the screen and the deeper structures at the bottom (Fig. 16.3.2.2). These data are interpretable when one knows which structure each line represents. The technique has excellent spatial resolution and temporal resolution; hence, with the advent of 2D echocardiography and Doppler, M-​mode is now principally used for measurement of cardiac chamber dimensions and observation of the relative movement of cardiac structures to each other; for example, the relationship of the anterior leaflet of the mitral valve to the septum in hypertrophic cardiomyopathy.

Doppler echocardiography The Doppler principle allows the velocity and direction of movement of an object (blood or myocardium in the case of cardiac ultrasonography) to be calculated from the shift in the frequency of a reflected waveform relative to the observer. Cardiac imaging employs pulsed-​ wave, continuous-​ wave, and colour Doppler techniques. Pulsed-​wave Doppler allows information about flow to be obtained from a defined point within the heart. The range of detectable velocities is limited, and the technique is used for sampling normal and low velocities (e.g. mitral valve flow).

Two-​dimensional echocardiography (cross-​sectional) Cross-​sectional images are constructed as the ultrasound beam sweeps across the heart in a sector (Fig. 16.3.2.1). Between 50 and 100 cross-​sections are presented each second, giving the impression of a moving picture. These images are readily interpretable by an observer with knowledge of cardiac anatomy, and this technique is the cornerstone of modern echocardiography.

M-​mode echocardiography M-​mode echocardiography preceded modern 2D imaging. Unlike 2D imaging, which uses a series of sweeps across the heart, M-​mode uses a single static beam of ultrasound pulses at a very high frequency. The narrow beam is analogous to a vertical mineshaft passing through various layers of rock. Displayed in real time, this results in

Fig. 16.3.2.2  M-​Mode view of the left ventricle. The high imaging frequency of M-​mode allows accurate measurements of structures to be made, in this case the diastolic (D) and systolic (S) cavity size.

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Fig. 16.3.2.3  Continuous-​wave Doppler of the aortic valve showing aortic regurgitation (flow towards the probe above the line). Calculations can be performed using on-​machine software to instantly provide useful haemodynamic data.

Continuous-​wave Doppler identifies the peak velocity encountered along the whole of the ultrasound beam and is particularly valuable for measuring high-​velocity jets such as those in aortic valve disease (Fig. 16.3.2.3). It is important to remember, however, that failure to align the transducer exactly parallel to flow results in measurement of artefactual low velocities and potentially an underestimation of valvular stenosis. Colour Doppler allows a dynamic representation of the direction and velocity of flow to be superimposed on to a 2D image of the heart. Velocities towards the transducer are usually coded in red and velocities away in blue (Fig. 16.3.2.4). Turbulent and high-​velocity flow produces variable velocities and results in a mosaic pattern that is ideal for characterization of regurgitant lesions. This technique is now so sensitive that it can detect trivial regurgitation during the closure of many normal heart valves. Tissue Doppler echocardiography uses the same principles but by changing the settings the direction and velocity of the myocardium is encoded rather than the blood pool. Pulse-​wave Doppler can then be used to interrogate a specific part of the myocardium and

Fig. 16.3.2.5  Tissue Doppler of the basal interventricular septum allowing measurement of the systolic contraction (S) and early passive relaxation (E′) phase.

provide detailed information on myocardial mechanics in both systole and diastole (Fig. 16.3.2.5).

Transthoracic echocardiography Imaging is performed using dedicated echocardiography equipment with the patient lying on their left hip in the left lateral position and with their left arm behind their head to open the rib spaces. Ultrasound cannot travel through bone and thus cardiac imaging is performed via intercostal spaces to the left of the sternum and at the apex of the heart in the axillary line. These ‘echo windows’ provide standard views described as the parasternal short and long axis and apical two-​, four-​, and five-​chamber views. Useful additional views can also be obtained from the subcostal and suprasternal approach in some patients. A standard echocardiography examination involves 2D imaging from the parasternal, apical, and subcostal approaches supported by M-​mode measurements, continuous, pulsed, and colour Doppler and tissue Doppler imaging.

Valvular heart disease Transthoracic echocardiography is the investigation of choice for patients with suspected valvular heart disease. All four cardiac valves can be visualized and interrogated by Doppler and 2D echocardiography. Concomitant abnormalities in ventricular performance can be assessed simultaneously. Aortic stenosis

Fig. 16.3.2.4  Colour-​flow mapping of mitral regurgitation. There is high-​velocity flow in systole from the left ventricle into the left atrium through the mitral valve.

Two-​dimensional echocardiography can usually image the aortic valve cusps; if they are thin and freely mobile, it is unlikely that there is significant aortic stenosis. However, if the valve cusps are thickened and calcified, interrogation by continuous-​wave Doppler is mandatory. The severity of aortic stenosis is usually expressed as the peak pressure difference (or gradient) across the valve, and is calculated from the maximum flow velocity (V) using the modified Bernoulli equation (pressure gradient = 4 V2). In patients with normal left ventricular systolic function, a peak gradient measured by Doppler of over 65 mm Hg or a mean gradient of over 40 mm Hg suggests significant aortic stenosis. The aortic valve area can be estimated using the continuity equation which requires measurement of the left ventricular outflow tract diameter on 2D echo and

16.3.2 Echocardiography

Fig. 16.3.2.6  Continuous-​wave Doppler through the aortic valve. The peak velocity is 503 cm/​s. This equates to a peak pressure gradient (A0 max PG) of 101 mm Hg. Previous measurements of the left ventricular outflow tract diameter and velocity allow a calculated aortic valve area to be derived, in this case 0.57 cm2.

the velocity at this point using pulse-​wave Doppler (Fig. 16.3.2.6). Severe stenosis usually equates to a valve area of less than 1.0 cm2 but should be indexed to the patient’s body surface area. When chronic critical outflow obstruction results in declining left ventricular function and reduced cardiac output, the gradient produced by any degree of valve obstruction also falls. Doubt about the severity of the stenosis can usually be resolved by enhancing left ventricular function by administering intravenous dobutamine and evaluating the gradient during increased flow. Aortic regurgitation

Fig. 16.3.2.7  Pulse-​wave Doppler at the mitral valve leaflet tips in a patient with severe mitral valve stenosis. The pressure half-​time is calculated as 368 ms, giving an estimated valve area of 0.6 cm2.

estimating the area of the valve orifice either by direct planimetry on a 2D short-​axis image or from the Doppler pressure half-​time (mitral valve area = 220/​pressure half-​time). A valve area of less than 1.0 cm2 usually indicates severe mitral stenosis (Fig. 16.3.2.7). The mean gradient across the valve can also be measured by Doppler and is typically more than 10 mm Hg in severe stenosis. Transthoracic echocardiography is also used to assess the suitability of the mitral valve for balloon dilation, although transoesophageal imaging is necessary to exclude left atrial thrombus.

Assessment of the mechanism and severity of aortic regurgitation requires a combination of all three echocardiography modalities. M-​mode may demonstrate fluttering of the anterior leaflet of the mitral valve and, in the setting of acute severe aortic regurgitation, may reveal premature closure of the mitral valve. Two-​dimensional echocardiography will occasionally demonstrate prolapse of one more of the aortic cusps, but even severe aortic regurgitation can occur through an aortic valve that appears to be structurally normal. The severity of aortic regurgitation can be estimated using continuous-​ wave and colour Doppler (see Chapter  16.6, Figs. 16.14.1.3 and 16.14.1.4), although assessment can be difficult as it is influenced by left ventricular function and blood pressure. Doppler-​ derived pressure half-​time and measurement of regurgitant fraction and/​or flow convergence zone are valuable when there is uncertainty over lesion severity. M-​mode and colour Doppler can be combined and, when the regurgitant jet fills more than 50% of the left ventricular outflow tract, the regurgitation is classified as severe. Flow within the descending thoracic aorta can be measured using pulse-​ wave Doppler and in severe aortic regurgitation there is typically holodiastolic flow reversal—​analogous to the collapsing pulse. In patients with severe asymptomatic aortic regurgitation, serial increase in left ventricular dimensions or a progressive fall in ejection fraction are indications for surgery. However, any increase in ventricular dimension should be at least 0.5 cm before it is regarded as significant, given the limited reproducibility of echocardiographic parameters.

Mitral regurgitation

Mitral stenosis

Fig. 16.3.2.8  Apical four-​chamber view with colour-​flow demonstrating an eccentric jet of mitral regurgitation from the left ventricle (LV) to the left atrium (LA). In this case, the leak is due to prolapse of the posterior mitral valve leaflet.

Mitral valve stenosis is well visualized using either M-​mode or cross-​sectional echocardiography. Its severity can be determined by

Transthoracic echocardiography will usually demonstrate the mechanism and severity of mitral regurgitation. Two-​dimensional imaging identifies abnormalities of the valve leaflets and colour-​ flow shows jet direction and area (Fig. 16.3.2.8). Severe mitral regurgitation is suggested by increased left ventricular end-​diastolic dimension and hyperdynamic function due to volume overload.

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Table 16.3.2.1  Classification of mitral regurgitation Mild

Severe

Specific signs of severity Vena contracta Jet size PISA radius

0.7 cm

1.2 m/​s)

CW trace

Soft and parabolic

Dense and triangular

LV and LA

Normal size LV if chronic MR

Enlarged LV and LA if no other cause

CW, continuous wave; LA, left atrium; LV, left ventricle; PISA, proximal isovelocity surface area.

Precise quantification of the amount of regurgitation is demanding as it is influenced by left ventricular function, the direction of the jet, and left atrial size. Various algorithms have been devised to improve quantification of mitral regurgitation, including measurement of the flow convergence zone and the proximal isovelocity surface area (PISA) method, but most centres simply classify the extent of regurgitation as mild, moderate, or severe (Table 16.3.2.1). Pulmonary and tricuspid valve disease In adults, 2D imaging of the pulmonary valve may be difficult, particularly if there is lung disease. Despite this, accurate Doppler information is usually obtainable. Tricuspid stenosis is very uncommon, but some degree of tricuspid regurgitation is detectable even in healthy individuals. Measurement of the peak velocity of tricuspid regurgitation (V) is valuable as, in the absence of pulmonary valve disease, it can be used to estimate pulmonary artery (PA) systolic pressure: PA systolic pressure (mm Hg) = 4V2 + right atrial pressure    (usually 5−10 mm  Hg). Prosthetic valves Transthoracic echocardiography is commonly performed as part of the routine follow-​up of prosthetic valves. It is usually able to assess biological valves accurately, but for mechanical mitral valve prostheses, attenuation artefact produced by the metal may be problematic. Transoesophageal imaging is recommended when transthoracic imaging is suboptimal or if improved resolution is required, for example, in patients with suspected prosthetic valve endocarditis.

Haemodynamic assessment Using Doppler to evaluate flow across all four cardiac valves and the great vessels, the pressure within each cardiac chamber can be estimated and a comprehensive description of the current haemodynamic status provided (Fig. 16.3.2.9). This can be extremely helpful in the setting of intensive cardiorespiratory support,

although obtaining clear and accurate images in critically ill patients can be very challenging.

Abnormal left ventricular function In most patients, a full transthoracic echocardiography study will confirm or refute a clinical suspicion of left ventricular dysfunction and identify the likely aetiology of any abnormality. Systolic and diastolic left ventricular function can be assessed, and a variety of methods can be used to derive an estimate of left ventricular ejection fraction. The most accurate methods use imaging in two orthogonal planes or a 3D technique to model the whole left ventricle (Fig. 16.3.2.10). The normal ejection fraction (calculated from the end-​diastolic and end-​systolic volumes) is greater than 55%. An ejection fraction of 45–​54% equates to mild left ventricular dysfunction, 30–​44% to moderate dysfunction, and less than 30% to severe dysfunction. However, ejection fraction as a single measure of systolic function can be misleading as it is influenced by both preload and afterload, and can be preserved even with significant myocardial pathology. Advances in image processing have facilitated the advent of speckle tracking, whereby unique patterns of ultrasound reflections within the myocardium are tracked frame by frame and used to derive measures of myocardial deformation. The most robust of these is global longitudinal strain, with a value of  –​20% being considered normal and abnormal values being closer to 0%. There is emerging evidence that this parameter changes before ejection fraction and is more reproducible. In patients with ischaemic heart disease, assessment of regional wall motion is valuable. Segments may be described as normokinetic, hypokinetic, akinetic, dyskinetic, or aneurysmal. Detection of a regional wall motion abnormality in patients presenting with left ventricular systolic dysfunction supports an ischaemic aetiology. The echocardiographic assessment of diastolic dysfunction is complex, but increasingly important in the assessment of patients with heart failure presenting with a normal ejection fraction. Impaired diastolic filling is indicated by a combination of echocardiographic findings routinely measured. Measurements of early

16.3.2 Echocardiography

Fig. 16.3.2.9  An example of the haemodynamic parameters that can be estimated with a standard transthoracic echocardiography data set.

Fig. 16.3.2.10  Apical four-​chamber and two-​chamber views in end diastole and end systole with an overall ejection fraction derived from the change in volume.

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diastolic filling E (the peak early diastolic flow velocity) compared to that associated with atrial filling (A) giving an E/​A ratio greater than 1.0 are often used as an indicator of diastolic dysfunction but rely on the patient being in sinus rhythm and can be misleading in severe diastolic dysfunction where pseudo normalization may occur. The ratio of tissue Doppler measurement of peak early diastolic mitral annular tissue velocities (e′) in combination with peak early diastolic filling (E) providing a ratio (E/​e′) is also used as an indicator of diastolic dysfunction. A ratio greater than 15 is strongly supportive of diastolic dysfunction. The presence of an enlarged left atrium is an important discriminator as left atrial size is rarely normal in the presence of significant diastolic dysfunction. These parameters are often abnormal in older people and only support a diagnosis of diastolic heart failure in conjunction with appropriate clinical features. Pulmonary artery pressure Estimation of pulmonary artery pressure from a tricuspid regurgitant jet is possible in most echocardiographic examinations (see earlier). Causes of an elevated pulmonary artery systolic pressure (>35 mm Hg) include left heart failure, valvular disease (particularly mitral valve disease), pulmonary embolic disease, chronic obstructive airways disease, and pulmonary vascular disease. Left ventricular hypertrophy Left ventricular hypertrophy is detected by echocardiography and a measurement of left ventricular mass can also be derived. Transthoracic echocardiography may also detect intracardiac thrombus, particularly in patients with impaired systolic ventricular function (Fig. 16.3.2.11). Minor concentric left ventricular hypertrophy is common in patients with hypertension. In hypertrophic cardiomyopathy, 2D imaging may demonstrate asymmetrical septal hypertrophy with disproportionate thickening of the interventricular septum compared with the left ventricular free wall, or dramatic concentric hypertrophy with left ventricular cavity obliteration. Other characteristic features of hypertrophic cardiomyopathy include systolic anterior motion of the mitral valve and partial midsystolic closure

Fig. 16.3.2.11  Apical four-​chamber view showing the left ventricle (LV), left atrium (LA), right ventricle (RV), and right atrium (RA). There is a large thrombus attached to the left ventricular apical septum.

of the aortic valve, which usually correlates with the presence of outflow tract obstruction. In the absence of conditions that may induce ventricular hypertrophy (e.g. aortic stenosis), these findings are diagnostic of hypertrophic cardiomyopathy. Colour Doppler can demonstrate turbulence in the outflow tract and continuous-​ wave Doppler may detect characteristic ‘dynamic’ gradients that increase in severity as systole progresses. Other associated echocardiographic abnormalities in hypertrophic cardiomyopathy include mitral regurgitation and severe diastolic dysfunction.

Atrial fibrillation Most patients with atrial fibrillation should undergo echocardiography as it excludes a structural cause for atrial fibrillation (e.g. mitral stenosis) and facilitates thromboembolic risk stratification. It also allows measurement of left atrial dimensions, which can guide treatment as the success of cardioversion falls as the left atrium enlarges. Identification of left ventricular hypertrophy can guide the choice of antiarrhythmic drug therapy. Transoesophageal echocardiography can be useful to facilitate cardioversion in patients with atrial fibrillation of unknown duration by excluding intracardiac thrombus, particularly in the left atrial appendage (Fig. 16.3.2.12).

Following an embolic event or stroke Echocardiography is the investigation of choice when a cardiac source of an embolus is suspected. It should be considered in all patients presenting with embolic occlusion of a peripheral artery, or thromboembolic episodes in more than one vascular territory. Echocardiography should not, however, be performed in circumstances when the result is unlikely to influence patient management. In patients with ischaemic stroke and a low likelihood of atheromatous arterial disease, an echocardiogram can be considered as, occasionally, it will detect occult abnormalities such as a cardiac thrombus or atrial myxoma (Fig. 16.3.2.13). Enhancement of the right heart with non​transpulmonary contrast such as agitated saline should be considered to exclude paradoxical embolism through a cardiac shunt, and include Valsalva manoeuvres

Fig. 16.3.2.12  Transoesophageal echocardiography of a patient with atrial fibrillation. There is a large thrombus filling (and extending from) the left atrial appendage (LAA). LA, left atrium; LV, left ventricle.

16.3.2 Echocardiography

and have subtle abnormalities on mitral and tricuspid valve inflow Doppler patterns.

Pulmonary embolism Echocardiography can be useful in patients with pulmonary embolism as it can demonstrate right ventricular dilation and/​or impaired right ventricular systolic function. Tricuspid regurgitant velocity can be used to estimate pulmonary artery systolic pressure, although it is unusual for this to be more than 70 mm Hg acutely. Exceptionally, 2D imaging may show a thrombus within the right heart or the proximal pulmonary arteries. Although echocardiography is diagnostically useful when it demonstrates features consistent with pulmonary embolism, it cannot exclude the diagnosis.

Infective endocarditis Fig. 16.3.2.13  Transoesophageal echocardiography revealing a large myxoma in the left atrium (LA) and close to the mitral valve.

to augment any right to left shunt. In patients with a high clinical suspicion of a cardiac source of embolus, in whom transthoracic echocardiography is normal, transoesophageal echocardiography is recommended.

Pericardial disease Echocardiography is not routinely indicated in patients with uncomplicated pericarditis. It can, however, diagnose the presence of pericardial fluid and is useful when a pericardial effusion is suspected and percutaneous drainage is being considered. Echocardiographic signs of pericardial tamponade include exaggerated respiratory variation in the mitral valve Doppler, presystolic closure of the aortic valve, and (particularly) right atrial and right ventricular diastolic collapse (Fig. 16.3.2.14). Constrictive pericarditis is a difficult diagnosis to make using standard echocardiographic techniques. Patients may complain of episodic breathlessness and fluid retention, have characteristic abnormalities of the venous pressure,

Fig. 16.3.2.14  Apical four-​chamber view demonstrating a large pericardial effusion. There is collapse of the right ventricle, suggesting cardiac tamponade.

Echocardiography cannot be used to exclude endocarditis but is valuable when endocarditis is suspected clinically while there is insufficient data to make a formal diagnosis. Under these circumstances, a typical vegetation (Fig. 16.3.2.15) detected by an experienced observer is regarded as a major criterion in the Duke diagnostic classification, and this may facilitate appropriate management. Transoesophageal echocardiography should be performed when there is a suspicion of aortic root abscess, if prosthetic endocarditis is suspected, or occasionally, in cases where there is persistent diagnostic doubt and the additional sensitivity and spatial resolution of transoesophageal echocardiography might be valuable.

Congenital heart disease Echocardiography is the diagnostic modality of choice for patients with suspected congenital heart disease. Detailed transthoracic cardiac imaging is possible in cooperative infants and children, but occasionally sedation or a short anaesthetic may be required. Rates of cardiac catheterization have been reduced by miniaturization of transoesophageal probes that facilitate diagnosis and follow-​up of complex congenital heart disease. Fetal echocardiography is performed when surveillance obstetric ultrasound is abnormal, or in cases where previous history suggests a possible cardiac problem.

Fig. 16.3.2.15  Apical four-​chamber view demonstrating a large vegetation involving the mitral valve.

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Transoesophageal echocardiography Transoesophageal echocardiography is now available in many centres (Fig. 16.3.2.16). The ultrasound probe is like an endoscope used for upper gastrointestinal investigation, except that there are no optical fibres. Transoesophageal echocardiography is an invasive procedure for which the patient’s written consent is (usually) required. After fasting for a minimum of 4 h, a local anaesthetic spray (10% lidocaine) is applied to the upper pharynx and the patient is usually sedated, typically with a short-​acting intravenous benzodiazepine (e.g. midazolam 2 mg). The probe is manipulated into the oesophagus where its position behind the heart produces excellent resolution, particularly of posterior cardiac structures. Blood pressure and oxygen saturation are monitored throughout, and both resuscitation equipment and the benzodiazepine antagonist flumazenil should be readily available. Even though transoesophageal echocardiography is commonly performed in high-​risk, haemodynamically unstable patients, the rate of serious complications (aspiration and oesophageal rupture/​ tears) is less than 1%. Absolute contraindications to transoesophageal echocardiography include oesophageal tumours, strictures, diverticula, and varices.

Who should have a transoesophageal echocardiogram? The indications for transoesophageal echocardiography are listed in Box 16.3.2.1. The principal advantages over transthoracic imaging are improved spatial resolution and the ability to image posterior structures such as the left atrium and descending aorta. It is valuable in many emergency situations, including suspected aortic dissection, prosthetic mechanical valve failure, and possible endocarditis. Transoesophageal echocardiography may be used to image the heart in patients in whom data from transthoracic imaging is unsatisfactory due to obesity, lung disease, or chest deformity. Other indications include screening for left atrial thrombus before cardioversion of atrial fibrillation, and monitoring cardiac performance during cardiac and some non-​ cardiac surgery.

Box 16.3.2.1  Principal indications for transoesophageal echocardiography Valve disease • Mitral stenosis—​ to assess suitability for percutaneous balloon commisurotomy and exclude left atrial thrombus • Mitral regurgitation—​to assess anatomy, severity, and suitability for surgical repair • Prosthetic valves—​particularly to assess prosthetic mitral regurgitation Infective endocarditis • Possible aortic root abscess • Failure to respond to antibiotics, or recurrent fever in a patient with endocarditis • High clinical suspicion of endocarditis with no diagnostic abnormality on transthoracic imaging • Possible prosthetic valve endocarditis Aortic disease • Possible acute aortic dissection • Follow-​up of patients with known aortic pathology • Imaging aortic atheroma before surgery or patients with possible cholesterol embolization Potential cardiac source of embolism • Before elective cardioversion of atrial fibrillation • Patients with valvular heart disease and a definite embolic episode despite anticoagulation • Patients with a definite embolic episode and a ‘normal heart’ on transthoracic imaging Incomplete or impractical transthoracic imaging • Chest deformity or pulmonary disease • Patients undergoing mechanical ventilation • Congenital heart disease • Perioperative imaging of cardiac function and surgical procedures

Valve disease Patients with mitral stenosis are at increased risk of thromboembolism, and transthoracic echocardiography has limited sensitivity for the detection of left atrial thrombus. Transoesophageal echocardiography is recommended in those patients with mitral stenosis if embolic events occur despite therapeutic anticoagulation, and may demonstrate spontaneous echocardiography contrast (smoke-​like echoes produced by the interaction of erythrocytes and plasma proteins under conditions of stasis). This is an independent predictor of left atrial thrombus and cardiac thromboembolic events. Transoesophageal echocardiography is also used to assess anatomy and exclude left atrial thrombus before balloon valvuloplasty in patients with mitral stenosis and to assess anatomy, severity, and suitability for surgical repair in patients with mitral regurgitation. In patients with mitral prostheses, reverberation artefact overlying the left atrium limits the ability of transthoracic imaging to detect paraprosthetic regurgitation. Transoesophageal imaging provides excellent visualization of the left atrium and is particularly recommended under these circumstances. Endocarditis

Fig. 16.3.2.16  Transoesophageal echocardiography.

Characteristic vegetations or evidence of abscess formation identified by echocardiography are increasingly used as diagnostic criteria in patients with possible endocarditis. The excellent spatial resolution (10 mm) and assessing patency of the foramen ovale (Fig. 16.3.2.19). However, the clinical relevance of such atrial septal abnormalities can be questionable as the relationship to the thromboembolic event is commonly speculative. Currently, anticoagulation is the usual management following an otherwise unexplained, single, embolic event, but occasionally percutaneous or surgical correction of the defect is recommended.

Aortic disease Transthoracic imaging of the aorta is limited to the proximal aortic root and the arch in most patients. Using transoesophageal imaging, most of the ascending and the entire descending thoracic aorta can be visualized and image quality is improved. This is particularly useful in patients with suspected acute aortic dissection and, in many cases, it is the only imaging necessary before emergency surgery (see Chapter 16.14.1, Figs. 16.14.1.8 and 16.14.1.9). Large, mobile, or pedunculated aortic atheromas in the descending aorta which can be associated with ischaemic stroke may be detected by transoesophageal echocardiography (Fig. 16.3.2.18). Transoesophageal imaging of the aorta has also been recommended in suspected cases of cholesterol embolization and to assess thromboembolic risk prior to cardiac intervention or surgery. Thromboembolism In patients with thromboembolism, there has been extensive debate over the value of imaging with transoesophageal echocardiography. Clinical examination, electrocardiography, and transthoracic echocardiography provide sufficient information to determine optimal management in the majority. However, transoesophageal echocardiography is indicated when embolic events occur in anticoagulated patients with native or prosthetic valvular heart disease, especially if endocarditis is suspected, or when transthoracic images are inconclusive. In patients with unexplained or cryptogenic ischaemic

Fig. 16.3.2.19  Transoesophageal echocardiography of the interatrial septum. The flap of the patent foramen ovale can be seen where the septum primum is overlapped by the septum secundum. There is colour-​flow through it (arrowed) from the left atrium (LA) to the right atrium (RA).

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Stress echocardiography Diagnosis of reversible ischaemic myocardial dysfunction is now possible using echocardiography. Imaging can be performed either during or immediately after exercise, but more commonly an intravenous infusion of dobutamine is used to mimic the cardiac response to exercise. Development of reversible systolic regional wall motion abnormalities suggests coronary artery disease. Stress echocardiography also has an increasing role in risk stratification before general surgical procedures and in assessing myocardial viability before revascularization. The use of transpulmonary contrast agents to opacify the left ventricle and enhance endocardial definition greatly reduces the number of inconclusive scans, allowing more accurate assessment of left ventricular function and some measure of myocardial perfusion (Fig. 16.3.2.20).

Intracardiac echocardiography Miniaturization of echocardiography probes has led to the development of echocardiography from within the heart. Small, flexible catheters with ultrasound transducers (Fig. 16.3.2.21) can be manoeuvred within the heart to provide very high-​resolution images of intracardiac structures. This has been particularly useful during percutaneous closure of atrial septal defects and during radiofrequency ablation procedures (Fig. 16.3.2.22).

Fig. 16.3.2.21  Comparison of an intracardiac echocardiography probe with a standard transoesophageal echocardiography probe with a close-​up view of the tip of the probes. The intracardiac probes are for single use only; the transoesophageal probes are sterilized after each procedure.

Three-​dimensional echocardiography Real-​time, 3D image acquisitions with both transthoracic and trans­ oesophageal echocardiography are now available on most high-​end echocardiography machines. Some systems acquire a series of gated images to reconstruct the entire heart during a cardiac cycle. This image can then be manoeuvred and slices cut away to visualize the area of interest (Fig. 16.3.2.23). Regional wall tracking can also allow a 3D model of left ventricular function to be acquired and provides

Fig. 16.3.2.20  A sequence of apical two-​chamber images during a stress echo. At peak stress a wall motion abnormality in the inferior apex is evident, which persists into the recovery phase.

Fig. 16.3.2.22  Intracardiac echocardiography from the right atrium (RA). An atrial septal defect is being closed using a percutaneous approach. The disc in the left atrium (LA) has been deployed and is about to be pulled tight to the interatrial septum.

Fig. 16.3.2.23  3D transoesophageal echocardiography of the mitral valve. The images show prolapse of the central portion of the posterior leaflet with three ruptured chordae. The whole of the mitral valve is in view and oriented to mimic the view of the cardiac surgeon at the time of mitral valve repair.

16.3.2 Echocardiography

Fig. 16.3.2.24  3D transthoracic echocardiography of the left ventricle. The whole of the left ventricle is captured over four cardiac cycles and stitched together to create a single volume of data. Corrections for foreshortening can be made, the volume traced over time, and a 3D ‘model’ of the left ventricle created with each segment shaded a different colour.

an accurate assessment of left ventricular function (Fig. 16.3.2.24) as well as identifying areas of left ventricular dys-​ synchrony. Transthoracic 3D acquisition is limited by frame rate and image quality in the same way as 2D echocardiography. Transoesophageal 3D echocardiography usually produces clear 3D images, particularly of the mitral valve and is excellent for examination of prosthetic mitral valves (Fig 16.3.2.25). It is particularly helpful in displaying and communicating pathology, as views familiar to cardiac surgeons can be recreated and displayed.

Fig. 16.3.2.25  3D transthoracic echocardiography of a mechanical prosthetic mitral valve. The sutures placed by the surgeon are visible as a row of dots around the sewing ring.

Echocardiography in the emergency setting Echocardiography equipment increases in sophistication but also continues to miniaturize, and now several small portable ultrasound devices are available (Fig. 16.3.2.26). These are increasingly available in emergency and intensive care departments. A  hand-​held ‘screening ultrasound’ can be performed in a matter of seconds to exclude pericardial effusion, recognize left ventricular dysfunction

Fig. 16.3.2.26  Hand-​carried ultrasound allows rapid assessment of cardiac function and can exclude a pericardial effusion.

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or pulmonary embolism, and to diagnose most valvular abnormalities. This is proving extremely useful in the management of critically ill patients. Transducers compatible with smartphones further increase the availability of immediate ultrasound assessment; a rechargeable and fully wireless platform linked to a smartphone app by Bluetooth or Wi-​Fi has recently been released. It is important to recognize that these devices cannot perform a full echocardiogram and a more detailed study is needed if the screening scan is abnormal or inconclusive. In critically ill patients with sepsis or severe metabolic derangement, left ventricular function is often abnormal; however, this does not always imply that left ventricular dysfunction is the cause of the presentation. Repeat examination following treatment of the underlying illness often reveals that this finding is transient and is not always an indication of primary cardiac disease. The advent of portable ultrasound has prompted the development of several types of emergency ultrasound including: • FAST scan—​focused assessment with sonography for trauma • FEEL scan—​focused echocardiography in emergency life support • FICE scan—​focused intensive care echocardiography • FATE scan—​focused transthoracic echocardiography Each of these require specific training, mentoring, and accreditation to become proficient. Full training in transthoracic echocardiography typically requires 2 years and over 500 scans performed and reported.

Feigenbaum H (2004). Feigenbaum’s echocardiography. Lea & Febiger, Philadelphia, PA. Flachskampf FA, et  al. (2001). Recommendations for performing transesophageal echocardiography. Euro J Echocardiol, 2, 8. King A, et  al. (2016). Global longitudinal strain:  a useful everyday measurement? Echo Research and Practice, 3,  85–​93. Leeson P, Augustine D, Mitchell ARJ, Becher H (2012). Echocardiography, 2nd edition. Oxford University Press, Oxford. Rimington H, Chambers J (2016). Echocardiography: a practical guide for reporting and interpretation, 3rd edition. CRC Press, Florida, US. Zoghbi WA, et  al. (2003). Recommendations for evaluation of the severity of native valvular regurgitation with two-​dimensional and Doppler echocardiography. J Am Soc Echo, 16, 777.

16.3.3  Cardiac investigations: Nuclear, MRI, and CT Nikant Sabharwal, Andrew Kelion, Theodoros Karamitos, and Stefan Neubauer ESSENTIALS Myocardial perfusion scintigraphy

Limitations of echocardiography Despite the rapid and substantial advances in ultrasound technology and the widespread use of echocardiography, it is important to recognize and understand the limitations of the technique. These include reliance on acoustic windows (clear images are impossible in some patients), evaluation at rest (most echo studies are performed with the patient resting, so dynamic lesions such as outflow tract gradients of mitral regurgitation can be underestimated), subjective assessments (precise quantification of cardiac function and valve disease can be challenging and often a more subjective opinion is required, which depends critically on the operator’s experience and training), evaluation of complex structures such as the right ventricle remains a major challenge (3D techniques are showing promise but are not in mainstream use), and the fact that the scope of an ‘echo’ is broad (to measure every parameter possible would take more than 60 min). Like any other test, echocardiography is most powerful when the pretest probability has been considered and a specific question asked; for example, ‘Is there important aortic stenosis to explain symptoms and signs?’

FURTHER READING Cheitlin MD, et  al. (2003). ACC/​AHA/​ASE guideline update for the clinical application of echocardiography:  summary article. Circulation, 108, 1146. Douglas PS, et al. (2011). ACCF/​ASE/​AHA/​ASNC/​HFSA/​HRS/​SCAI/​ SCCM/​SCCT/​SCMR 2011 appropriate use criteria for echocardiography. J Am Soc Echo, 24, 229.

Myocardial perfusion scintigraphy provides physiological information about the coronary circulation, in contrast to the anatomical information provided by angiography. Three radionuclide-​labelled perfusion tracers are routinely used in single photon emission computed tomography (SPECT) imaging: thallium-​201 and the technetium-​99m-​labelled complexes sestamibi and tetrofosmin. Imaging is performed following tracer injection during stress (exercise or pharmacological) and at rest; comparison allows determination of whether regional perfusion is normal, or if there is inducible hypoperfusion or infarction/​scar. Myocardial perfusion imaging is minimally invasive, and—​in contrast to other methods of investigation—​can be performed regardless of overall exercise capacity, abnormalities of the resting electrocardiogram (ECG), pacemakers, obesity, claustrophobia, renal dysfunction, iodine allergy, or acoustic windows. In the investigation of a patient with possible coronary artery disease, a normal SPECT study is very reassuring, predicting a very low chance of cardiac death or non​fatal myocardial infarction over the following few years (10% of myocardium), transient ischaemic left ventricular dilatation, left ventricular ejection fraction (LVEF) less than 0.4 (see ‘Assessment of left ventricular volume and function’), and lung uptake (only with thallium-​201). SPECT is also able to add prognostic data when risk scores such as the Duke treadmill score are applied to exercise ECG variables (Fig. 16.3.3.2), and can stratify risk in specific populations such as patients after myocardial infarction or with diabetes mellitus, women, and patients with an abnormal ECG (e.g. left bundle branch block). More recent data have emphasized the value of MPS even in patients with proven coronary artery disease. In a large retrospective study from Cedars-​ Sinai Hospital (Los Angeles, California), patients managed conservatively had higher event rates than those managed with revascularization if they had inducible hypoperfusion that was more extensive than 10% of the left ventricular myocardium (see Fig. 16.3.3.3). The COURAGE trial failed to show any prognostic benefit of percutaneous coronary intervention (PCI) plus optimal medical therapy (OMT) over OMT alone. However, a nuclear substudy suggested that PCI was better at reducing inducible hypoperfusion than OMT alone, and that event rates were lower for patients with greater decreases in inducible hypoperfusion. Further research is ongoing to identify if MPS could be used to identify a subgroup of patients in whom, despite OMT, the prognosis could be improved by PCI. Nuclear techniques are well suited to the identification of myocardial viability, which predicts functional recovery (identified by hard events/year (%) 9 8 7 6

SPECT result normal mild-abnormal >mild abnormal

5 4 3 2 1 0 low

intermediate

high risk

Result of exercise ECG (Duke treadmill score)

Fig. 16.3.3.2  Incremental value of myocardial perfusion imaging over exercise ECG: hard event rates per year as a function of exercise SPECT in patients initially stratified by low, intermediate, and high Duke treadmill scores.

Fig. 16.3.3.3  Annualized cardiac death rate according to ischaemic burden and treatment strategy. Increasing ischaemia appears to be better treated with revascularization in this retrospective study. From Hachamovitch, R. et al. (2003). Comparison of the short-​term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation, 107, 2900–​7.

echocardiography) in approximately 80% of dysfunctional segments after revascularization. Comparative studies with low-​dose dobutamine echocardiography (see Chapter 16.3.2), positron emission tomography (PET), and cardiovascular magnetic resonance (CMR) have been performed. Each test is broadly similar in its ability to predict functional recovery. SPECT has also been used to assess success of revascularization procedures. In the acute setting, resting SPECT may be performed in patients attending the emergency department with chest pain and a non-​ diagnostic initial ECG. A normal perfusion scan is associated with a low risk of future events, lower likelihood of requiring cardiac catheterization, and lower costs owing to the shorter hospital stay and fewer subsequent investigations.

Non​perfusion uses of SPECT techniques Myocardial perfusion imaging for the investigation of suspected or known coronary disease is by far the most commonly performed nuclear cardiology investigation. However, scintigraphic imaging using other radiopharmaceuticals is increasingly performed to answer specific physiological questions in several other cardiac diseases. It has been recognized for almost 40 years that some patients with cardiac amyloidosis exhibit myocardial uptake of phosphate bone tracers. More recently, it has become apparent that this phenomenon tends to be limited to those with transthyretin-​type (ATTR) cardiac amyloidosis, as opposed to those with the light-​chain-​type (AL). Cardiac planar and SPECT imaging using bone tracers such as technetium-​99m-​3,3-​diphosphono-​1,2-​propanodicarboxylic acid (DPD—​Europe) or technetium-​99m-​pyrophosphate (PYP—​USA) can therefore be used to confirm a diagnosis of ATTR-​amyloid with very high positive predictive value, thereby obviating the need for cardiac biopsy. Iodine-​ 131-​ meta-​ iodobenzylguanidine (mIBG) is a false-​ transmitter analogue of norepinephrine and can be used to image the state of cardiac sympathetic innervation, which can become abnormal in patients with heart failure. Reduced cardiac uptake and increased washout of mIBG is associated with increased mortality, heart failure progression, and re-​admission, independent of

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left ventricular (LV) ejection fraction and brain natriuretic peptide (BNP) level. There is interest in using mIBG scintigraphy to stratify the risk of sudden arrhythmic death to help gauge the likely benefit of an implantable cardioverter-​defibrillator (ICD). The increasing use of implantable cardiac devices (pacemakers, ICDs, prosthetic valves) has led to a rise in the number of patients presenting with suspected device-​related infection. Echo imaging, even transoesophageally, is not always diagnostic, and scintigraphic imaging using the patient’s own labelled white cells may have a role. This technique is less sensitive but more specific than fluorine-​18-​fluorodeoxyglucose (FDG), and can be particularly useful within three months of valve replacement when false-​ positive FDG scans are common due to non​infective post-​surgical inflammation.

Assessment of left ventricular volumes and function using nuclear techniques Nuclear cardiology techniques have been used for the non​invasive assessment of left ventricular function since the early 1970s. Three radionuclide techniques are available for assessing left ventricular function:  first-​ pass radionuclide ventriculography, equilibrium radionuclide ventriculography, and gated myocardial perfusion SPECT. The first is rarely performed nowadays and will not be considered further. Equilibrium radionuclide ventriculography This investigation, also affectionately (but inaccurately) known as multigated acquisition (MUGA), is performed following labelling of red blood cells with technetium-​99m-​pertechnetate. This is usually performed in vivo following a preceding injection of stannous pyrophosphate. For a simple assessment of LVEF, gated planar imaging of the blood pool is performed in a LAO 45° projection to optimize separation of the left and right ventricular cavities. This method is independent of left ventricular geometry, and hence very accurate and reproducible. The wide availability of echo (with its lack of radiation exposure) has led to a substantial decrease in the number of equilibrium radionuclide ventriculography studies performed. However, the radionuclide method can still be valuable when a quick and reproducible assessment of LVEF is required, for example in the monitoring of patients undergoing chemotherapy with anthracyclines or trastuzumab. ECG-​gated myocardial perfusion SPECT SPECT acquisition during MPS can be gated at no extra inconvenience, cost, or risk to the patient. Tomographic slices are reconstructed for each of 8 or 16 frames and can be played as a cine for visual assessment. Left ventricular volumes and LVEF can be derived following endomyocardial border definition. Gated SPECT (Fig. 16.3.3.4) can be very useful in identifying attenuation artefacts (which appear as fixed perfusion defects but demonstrate normal wall motion). Indices of left ventricular function (ejection fraction and end-​systolic volume) provide independent prognostic information and are powerful predictors of cardiac death. Importantly, changes in regional and global function from post-​stress to rest imaging can help unmask multivessel ischaemia which has been underestimated by the visible regional perfusion defects.

Fig. 16.3.3.4  Gated SPECT to assess left ventricular systolic function at rest in a patient with an extensive anteroapical and septal infarct and poor left ventricular systolic function. Left column: end-​diastolic frame showing (from top to bottom) apical, mid, and basal short-​axis slices, horizontal, and vertical long-​axis slices. Right column: end-​systolic frame showing corresponding slices. Right column: calculated volumes and ejection fraction (middle panel), with time-​volume curve (bottom panel).

Positron emission tomography PET scanners employ coincidence detection of 511-​keV photons travelling 180° apart following annihilation of a positron with an electron. Cardiac PET studies are no longer confined to research centres, mainly due to the rapid increase in availability of combined PET/​CT scanners driven by developments in oncological practice. Myocardial perfusion can be assessed with nitrogen-​13-​ammonia (requiring an on-​site cyclotron) or rubidium-​82 (from a generator), but is best done with oxygen-​15-​water (though this tracer requires a cyclotron and does not permit myocardial imaging). Myocardial viability in terms of metabolic integrity is assessed with fluorine-​18-​ fluorodeoxyglucose (FDG), which has become widely commercially available with the growth of oncological PET. FDG-​PET is increasingly used to image intracardiac infection and inflammation as it is avidly taken up by metabolically active white cells. For this indication, careful patient preparation is essential to suppress myocardial FDG uptake using a carbohydrate-​restricted diet followed by fasting. FDG-​PET has a high sensitivity for identifying cardiac device-​related infection, though white cell scintigraphy is more reliable within three months of valve surgery. Its role in cardiac sarcoidosis is also well-​established, especially for disease monitoring. Sodium fluoride-​18 (NaF) PET is an interesting research tool for imaging microcalcification in coronary atheromatous plaques, which may identify those most likely to become unstable causing an acute coronary syndrome.

16.3.3  Cardiac investigations

Comparison of nuclear techniques with other imaging modalities For physiological assessment of known or suspected coronary artery disease, the alternatives to SPECT and PET are exercise electrocardiography, stress (exercise or dobutamine) echocardiography, and stress CMR (with vasodilator stress for perfusion or dobutamine for wall motion). The exercise ECG is inferior, mainly due to its dependence on exercise ability and the poor sensitivity and specificity of ECG changes. Stress echocardiography is a good alternative technique, with a slightly lower sensitivity but higher specificity in comparative studies. It is physician-​intensive and operator-​dependent, but harmonic imaging and microbubble contrast agents have greatly improved image quality. An important advantage over the radionuclide techniques is the avoidance of ionizing radiation, which makes it particularly attractive for younger patients. Cardiac MRI can assess regional and global left ventricular systolic function during a dobutamine infusion, similar to stress echocardiography. Alternatively, gadolinium can be used as a first-​pass myocardial perfusion tracer during vasodilator stress, with late-​ enhancement used to identify infarction. A large multicentre comparative study has suggested that CMR is an equivalent alternative to SPECT. In practice, the different modalities should be regarded as largely interchangeable, with local clinical expertise being more important than any marginal differences in technical performance between them. Functional imaging, however performed, is recommended in the latest National Institute for Health and Care Excellence (NICE) guidelines for the assessment of patients with chest pain of recent onset.

Cardiac MRI Introduction Cardiovascular MRI (CMR) has undergone significant advancement in terms of imaging capabilities, ease of use, and speed of acquisition over the past 20 years. A study of cardiovascular anatomy, left and right ventricular function, and viability/​fibrosis (late gadolinium enhancement) with a modern CMR scanner can be performed in less than 30 min by an experienced operator. These improvements have led to the widespread adoption of CMR in clinical practice.

How CMR works MRI is typically based on the magnetic properties of the hydrogen nucleus, though other nuclei can also be used. Hydrogen nuclei (protons), which are abundant in the human body, behave like small spinning magnets that have an alignment (magnetic moment) parallel to the direction of the external magnetic field and a rotation (precession) frequency proportional to the strength of the field. Radio waves in the form of a radiofrequency pulse transmitted into the patient cause the alignment of the protons to change, that is, the magnetic moments in that region are flipped out at an angle (flip angle) to the magnetic field (excitation). When this radiofrequency pulse is turned off, the protons in the patient’s body return to their neutral position (relaxation), emitting their own weak radio-​wave signals, which are detected by receiver coils and used to produce

an image. The contrast between tissues (e.g. heart muscle and fat) depends on the tissue density of hydrogen atoms (proton density), and on two distinct MR relaxation processes that affect the net magnetization: the longitudinal relaxation time (T1), and transverse relaxation time (T2). The differences in these parameters in distinct tissues are used to generate contrast in MR images. Image contrast can also be modified by modulating the way the radiofrequency pulses are played out (the MR sequence): for example, in so-​called T1-​weighted images, myocardial tissue is dark whereas fat is bright. On the other hand, T2-​weighted images highlight unbound water in the myocardium and are used to demonstrate myocardial oedema due to inflammation or acute ischaemia. CMR requires advanced technology, including a high-​field superconducting magnet which produces a homogeneous and stable magnetic field (1.5 or 3.0 Tesla), gradient coils within the bore of the magnet which generate the gradient fields, a radiofrequency amplifier to excite the spins with radiofrequency pulses, and a radiofrequency antenna (coil), which receives the radio signals coming from the patient. A computer and specific software are also needed to control the scanner and generate (reconstruct) the images. To prevent artefacts from cardiac motion, most CMR images are generated with ultrafast sequences gated to the R wave of the ECG. Respiratory motion, which is another factor that can produce artefacts, is eliminated by acquiring most CMR images in end-​ expiratory breath-​hold. When acquisition is long and cannot be completed within one breath-​hold, special free-​breathing sequences that track the diaphragm’s position (navigators) are used.

CMR safety MRI scan subjects and operators are not exposed to ionizing radiation and there are no proven detrimental biological side effects of MRI, if safety guidelines are followed. Ferromagnetic objects can be attracted by the scanner, becoming projectiles that could lead to significant patient or operator injury and also damage the scanner. The presence of certain medical implants and devices (e.g. most pacemakers and defibrillators, cochlear implants, cerebrovascular clips) is a contraindication for routine MR scanning, but nearly all prosthetic cardiac valves, coronary and vascular stents, and orthopaedic implants are safe in a 3-​T (or less) MR environment. MRI conditional pacemakers and defibrillators (generator and leads) are now available. Whenever there is uncertainty regarding a particular device or implant, the CMR operator should consult a more detailed source of information, such as reference manuals, dedicated websites (e.g. http://​www.mrisafety.com), or the manufacturer’s product information. Claustrophobia may be a problem for a few patients, and mild sedation usually helps to overcome this. Gadolinium contrast agents are safe for most patients (safer than iodine-​based contrast), but gadolinium-​containing contrast agents have been linked with the development of a rare systemic disorder called nephrogenic systemic fibrosis. The patients at risk for developing this disease are those with acute kidney injury or chronic kidney disease (glomerular filtration rate 60 ms in V1 RBBB pattern: qR, Rs, or Rr in V1 Axis > +90 or < −90 **Features favouring VT

QRS atypical for RBBB or LBBB*

V>A rate • Ventricular tachycardia

*Atypical features of BBB favouring VT

Yes

Atrial activity visible

No

RP > PR No

Yes

In 12-lead ECG: Fusion or capture beats Extreme axis deviation In precordial leads: Concordance (all either positive or negative) Absence of RS pattern in any chest lead Onset R to nadir of S > 100ms

Fig. 16.4.16  Algorithm for diagnosis of tachycardia from 12-​lead ECG. A, atrial rate; AF, atrial fibrillation; Afl, atrial flutter; AT, atrial tachycardia; AVNRT, atrioventricular nodal re-​entrant tachycardia; AVRT, atrioventricular re-​entrant tachycardia; BBB, bundle branch block; LBBB, left bundle branch block; PJRT, permanent junctional reciprocating tachycardia; PR, PR interval; RBBB, right bundle branch block; RP, RP interval; V, ventricular rate; VT, ventricular tachycardia. See text for details.

failings and misconceptions, the commonest being that the clinical context is not considered:

to transient AV nodal blockade with adenosine will assist diagnosis in many patients (Table 16.4.5).

• Age of the patient—​middle-​aged or older individuals presenting with a recent history of broad-​complex tachycardia, and who give a history of myocardial infarction or congestive heart failure, are more likely to have ventricular than supraventricular tachycardia. However, ventricular tachycardia can also arise in young patients. • Haemodynamic status of the patient—​it is often assumed that ventricular tachycardia should cause haemodynamic collapse, whereas patients may in fact be haemodynamically stable if the rate is not excessively fast or if underlying cardiac function is good. Conversely, supraventricular tachycardias may cause syncope, hypotension, or shock if sufficiently rapid, or if there is underlying heart disease. • Nature of the episodes of palpitation—​it is often not appreciated that ventricular tachycardia can present with a typical history of paroxysmal self-​terminating episodes, just as in the case of supraventricular tachycardia.

General principles of management

The importance of making a correct diagnosis in broad-​complex tachycardia is twofold. First, inappropriate acute therapy of the tachyarrhythmia can be avoided. In particular, the use of verapamil in ventricular tachycardia misdiagnosed as supraventricular tachycardia is associated with a high risk of haemodynamic collapse as a result of its negative inotropic effect, coupled with its lack of efficacy in terminating ventricular tachycardia. Secondly, if the original arrhythmia has been misdiagnosed, then the adverse prognostic significance of ventricular tachycardia will be overlooked. Appropriate investigation and long-​term management may not be instituted. It is therefore important that a diagnosis of SVT with aberration is made only if the ECG displays typical left or right bundle branch block with none of the features suggestive of VT listed in Fig. 16.4.16. In addition to attention to the history and 12-​lead ECG, the response

Many cardiac arrhythmias are benign and require no intervention. The main indications for treatment are to relieve symptoms, or to prevent complications such as myocardial ischaemia, cardiac failure, embolism, or arrhythmic sudden death. Precipitating factors such as myocardial ischaemia/​infarction, infection, thyrotoxicosis, alcohol, electrolyte disorders, or drug toxicity must be sought and treated if possible. The therapy indicated will commonly be influenced by the presence of underlying structural heart disease such as myocardial ischaemia/​infarction or left ventricular dysfunction and can include drug therapy, device implantation, or radiofrequency ablation. Acute management of tachycardia An algorithm for the treatment of tachyarrhythmias is shown in Fig. 16.4.17. Assessment of the patient’s cardiorespiratory status takes precedence. R-​ wave synchronized, direct current (DC) Table 16.4.5  Diagnostic use of intravenous adenosine Arrhythmia

Response

Atrial tachycardia Atrial flutter Atrial fibrillation

Transient AV block reveals atrial arrhythmia Rarely terminated

AVNRT AVRT

Terminates tachycardia by anterograde (AV) block

Ventricular tachycardia

Not terminated 1:1 VA conduction may be blocked, revealing AV dissociation

For abbreviations, see Fig. 16.4.16.

16.4  Cardiac arrhythmias

Haemodynamic compromise Yes DC cardioversion

Persistent or re-initiated

* Caution with broad complex tachycardias or known pre-excitation. Adenosine is contraindicated in pre-excited AF and asthma

No

Vagal manoeuvres IV adenosine*

** Use only one drug from list *** If clinically appropriate, e.g. frequently recurring tachycardia

Persistent or re-initiated

Terminated

QRS 1 procedure

Permanent AF

AV node

+++

Requires permanent pacing, does not cure AF

Scar-​related ventricular tachycardia

Re-​entry circuit

+

High recurrence rate

Focal ventricular tachycardia

Site of origin

++

Especially RVOT focus

AVRT, atrioventricular re-​entry tachycardia; AF, atrial fibrillation; AVNRT, atrioventricular nodal re-​entry tachycardia; LA, left atrial; CHB, complete heart block; TVA, tricuspid valve annulus; IVC, inferior vena cava; RVOT, right ventricular outflow tract.

interval, or, if sufficiently premature, complete failure of conduction (Fig. 16.4.22b). Non​conducted atrial extrasystoles must be distinguished from sinus arrest or second-​degree AV block. An atrial extrasystole will commonly reset the sinoatrial node, such that the next sinus beat occurs earlier than expected with respect to the preceding sinus beat, and the pause is less than compensatory. Atrial extrasystoles are a common finding in healthy people, particularly with increasing age, but are more frequent in the presence of increased atrial pressure or stretch such as in cardiac failure or chronic mitral valve disease. Patients should be reassured that the arrhythmia is benign, and that drug treatment is rarely necessary. If treatment is required on symptomatic grounds, β-​adrenergic blockers may be used, but class I antiarrhythmic drugs should be avoided in view of their proarrhythmic risk. Junctional extrasystoles Junctional extrasystoles are identified by the appearance of a premature, normal QRS complex in the absence of a preceding P-​wave. The atria as well as the ventricles may be activated, resulting in an inverted P-​wave simultaneous with the QRS complex, or inscribed within the ST segment. The significance and management of junctional extrasystoles are similar to those of atrial extrasystoles. (a)

Ventricular extrasystoles Ventricular extrasystoles are identified by the appearance of a bizarre, wide QRS complex not preceded by a P-​wave (Fig. 16.4.23). There is commonly ST-​segment depression and T-​wave inversion. Ventricular extrasystoles may be intermittent or occur with a fixed relationship to the preceding normal beats, that is, 1:1, 1:2 (bigeminy or trigeminy). Ventricular extrasystoles occur in otherwise normal hearts but are found particularly in the presence of structural heart disease. Benign ventricular ectopy is common and indicated by the following:  normal resting 12-​lead ECG, structurally normal heart on echo, absence of other cardiac symptoms, resolution with exercise, and the absence of a family history of early cardiac disease or sudden cardiac death. Ventricular ectopics occur commonly in the acute phase of myocardial infarction, but are also seen in the postinfarction phase, and in the presence of severe left ventricular hypertrophy or dysfunction of whatever cause. While the presence of frequent ectopy following myocardial infarction conveys an adverse prognosis, their suppression with class  I  agents (flecainide) actually increases mortality. Extrasystoles may produce symptoms that require treatment in a minority of cases. The safest option is β-​blockade.

Atrial arrhythmias Atrial fibrillation Mechanisms Studies of patients with paroxysmal atrial fibrillation suggest that the arrhythmia may be triggered by one or more rapidly discharging foci, which are commonly situated in the pulmonary veins.

(b)

Fig. 16.4.22  Atrial extrasystoles. (a) An atrial extrasystole, with an abnormal P-​wave at the end of the preceding T-​wave, occurs following a sinus beat. (b) Blocked atrial extrasystoles. In the same patient, atrial extrasystoles occur following each sinus beat. They are earlier than those in (a), and the AV node is refractory because of the proximity of the atrial extrasystoles to the preceding beat, and conduction is blocked.

Fig. 16.4.23  Ventricular extrasystole (open circle). No retrograde atrial activation occurs, and the P-​wave sequence is undisturbed (arrowed).

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In the presence of a heterogeneous substrate, it is thought that such a trigger gives rise to high frequency re-​entry in certain areas (rotors) which perpetuate fibrillatory conduction. Rapid atrial activation induces a process of electrical remodelling, which renders cardioversion and maintenance of sinus rhytshm more difficult (‘atrial fibrillation begets atrial fibrillation’). The initial mechanism of remodelling is thought to be intracellular calcium overload resulting in shortening of the atrial refractory period, although more prolonged atrial tachyarrhythmias result in downregulation of calcium entry and dedifferentiation of atrial myocytes. Structural changes, including interstitial fibrosis, also occur and further perpetuate the arrhythmia. Classification and aetiology Atrial fibrillation is a common arrhythmia affecting 1% of the population, the incidence increases with advancing age to 5–​10% in very elderly individuals. It is classified as paroxysmal (self-​terminating episodes 48 h/​no defined onset, with haemodynamic instability, and no intercurrent illness Oral digoxin loading pending urgent echocardiographic assessment, then β-​blockade if required (in the absence of cardiogenic shock or severe LV dysfunction or aortic stenosis on echo). Consider IV amiodarone and TOE-​guided cardioversion in patients failing to respond (emergency cardioversion may be required without TOE in patients in imminent danger of cardiorespiratory arrest). 4 Rapidly conducted atrial fibrillation in conjunction with intercurrent illness In the context of a prior diagnosis of well-​controlled permanent atrial fibrillation, treatment should be directed at the underlying illness and continuing the current rate of control medication. Patients with new-​onset atrial fibrillation should be treated with rate control (as aforementioned) and anticoagulation with LMWH. Where haemodynamic compromise is felt to be due to atrial fibrillation rather than the underlying illness, chemical or electrical cardioversion may be attempted depending on the duration of the arrhythmia (see earlier); however, the early recurrence rate is high. LMWH, low molecular weight heparin; LV, left ventricular; TOE, trans­ oesophageal echocardiography.

syndrome, implantation of a permanent pacemaker may be required to control bradycardia and to allow antiarrhythmic therapy for the treatment of tachycardia. Catheter ablation may be considered as first line or for those in whom pharmacological therapy has failed. The goal of catheter ablation is to achieve electrical isolation of the pulmonary veins; clinical success rates are 70–​80% from a single procedure. Persistent atrial fibrillation Persistent atrial fibrillation is not self-​terminating, usually requires electrical cardioversion to achieve sinus rhythm, and has a high recurrence rate even after successful cardioversion. The key decision is whether to employ a rhythm or rate control strategy. The AFFIRM trial showed no overall mortality benefit of a rhythm-​ control strategy in patients in whom a rhythm-​control strategy in not indicated on the basis of symptoms. In general, a rate control strategy should be employed in asymptomatic or mildly symptomatic individuals, in older people, and in those with contraindications to antiarrhythmic therapy or cardioversion. This group should be treated as having permanent atrial fibrillation. In more severely

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symptomatic or younger patients, or in those with atrial fibrillation due to a treated precipitant, a rhythm-​control strategy may be more appropriate. However, treatment choice has to be tailored to the individual and both options should be discussed with the patient. In patients with multiple comorbidities (e.g. chronic obstructive pulmonary disease, heart failure, ischaemic heart disease), the contribution of atrial fibrillation to the patient’s limitation may not be immediately clear. In such cases an attempt at restoring sinus rhythm may be worthwhile to clarify whether a rhythm-​control strategy is justified. Prophylaxis of thromboembolism should be considered in both groups. If a rhythm-​control strategy is adopted, elective cardioversion should be scheduled. Given that cardioversion may be associated with embolism, patients undergoing this procedure should be treated with warfarin or a non-​VKA oral anticoagulants (NOAC) for at least 3 weeks beforehand, and this should be continued long term if warranted according to risk stratification, and for at least 4 weeks in those at low risk of thromboembolism, otherwise long-​ term anticoagulation is indicated irrespective of the apparent success of rhythm control. There is a high risk of recurrent atrial fibrillation (up to 50% at 1  year) and antiarrhythmic prophylaxis should be considered. First-​line therapy is often a simple β-​ blocker followed by a class Ic agent if there is no structural heart disease. Amiodarone may also be considered, and treatment prior to cardioversion increases the likelihood of its success. Finally, radiofrequency ablation may be employed but this requires more extensive left atrial ablation compared to paroxysmal atrial fibrillation (Fig. 16.4.25), with a lower success rate, and often requires more than one procedure.

Permanent atrial fibrillation In permanent atrial fibrillation, restoration of sinus rhythm is not feasible or is unsuccessful and chronic management involves control of ventricular rate. Traditionally, the mainstay of treatment has been digoxin, at a dose titrated to achieve adequate slowing in the ventricular rate at rest, with therapeutic plasma concentrations. Despite adequate rate control at rest, patients commonly have an uncontrolled heart rate on exercise. Control of rate response with other AV nodal blocking drugs such as β-​blockers or verapamil is associated with improved rate control which is especially important if the duration of diastole is critical, as in mitral stenosis or ischaemic heart disease. Often a combination of AV nodal blocking drugs is required. In cases where adequate rate control cannot be achieved despite combination therapy, radiofrequency ablation of the AV node and implantation of a permanent pacemaker (or cardiac resynchronization pacemaker) is an option, although this commits the patient to lifelong pacing therapy. Prevention of thromboembolism Atrial fibrillation patients have a fivefold increased risk of stroke compared to age-​and gender-​matched peers without atrial fibrillation. However, individual stroke risk varies and is dependent upon the presence of other stroke risk factors such as increasing age, previous stroke, or transient ischaemic attack (TIA), hypertension, heart failure, diabetes mellitus, vascular disease (peripheral artery disease, myocardial infarction), and female gender; the more risk factors that are present, the greater the risk of stroke. Importantly, when stroke occurs in the presence of atrial fibrillation, the severity is greater, survival is poorer, residual neurological deficit is greater, patients are more likely to require nursing home/​residential care, and risk of recurrent stroke within 12 months is increased. Oral anticoagulation for stroke prevention.  Anticoagulant therapy significantly reduces the risk of stroke and death in atrial fibrillation patients. Accordingly, current clinical guidelines (see Table 16.4.9) recommend effective stroke prevention with oral anticoagulation, either as a vitamin K antagonist (VKA, e.g. warfarin) or one of the non-​VKA oral anticoagulants, for all atrial fibrillation patients except those patients at extremely low risk of stroke (see Table 16.4.10). These low-​risk patients are defined as men and women aged under 65 years with no stroke risk factors. It is important to formally assess each patient’s individual risk of stroke to inform appropriate treatment decisions.

Fig. 16.4.25  Virtual geometry of the left atrium using the Carto 3 system (Biosense Webster, Diamond Bar, CA, USA). The view is a posterior view. The pulmonary veins are shown and the veins are labelled (RSPV, right superior pulmonary vein; RIPV, right inferior pulmonary vein; LSPV, left superior pulmonary vein; LIPV, left inferior pulmonary vein). Lesions produced by sequential application of radiofrequency energy are shown by the red spheres, encircling the pulmonary veins to produce electrical isolation, which is confirmed using a circular mapping catheter, seen inside the RSPV.

Stroke risk assessment: CHA2DS2-​VASc.  The National Institute for Health and Care Excellence (NICE), American Heart Association/​ American College of Cardiology/​ Heart Rhythm Society, and European Society of Cardiology (ESC) guidelines advocate the use of CHA2DS2-​VASc to assess stroke risk (see Table 16.4.9). CHA2DS2-​ VASc is an acronym for the stroke risk factors which comprise it (see Table 16.4.10): congestive heart failure, hypertension, age 75 years or more, diabetes mellitus, previous stroke or TIA, vascular disease, age 65–​74 years, and female gender. The presence of each risk factor scores 1 point, except for age 75 years or over and previous stroke/​TIA, which score 2 points each; the maximum score is 9. The ACCP9 guidelines recommend assessing stroke risk using the older CHADS2 score: congestive heart failure, hypertension, age 75 years or more, diabetes mellitus (1 point for each), and previous stroke or

16.4  Cardiac arrhythmias

Table 16.4.9  Current guidelines for the antithrombotic management of atrial fibrillation Guidelines

Assessment of stroke risk

Assessment of bleeding risk

Treatment recommendations

Other recommendations

NICE (2014)

CHA2DS2-​VASc

HAS-​BLED

Offer OACa when CHA2DS2-​VASc ≥2, taking into consideration bleeding risk Consider OACa for men with CHA2DS2-​VASc ≥1, taking into consideration bleeding risk Review need for OAC at least yearly Do not offer aspirin monotherapy for stroke prevention in AF Only consider dual antiplatelet therapy if OAC contraindicated in patients with CHA2DS2-​VASc ≥2

OAC with VKA TTR ≥65% Assess TTR at each visit Correct modifiable reasons for poor INR controlc Consider alternative OAC if TTR cannot be improvedd NOACs In accordance with NICE STAs

ESC (2016)

CHA2DS2-​VASc

No formal bleeding risk tool specified. Stresses attention to modifiable bleeding risk factors

Consider patients’ treatment preferences No antithrombotic therapy if patient 3 ULN.

nonessential antiplatelets or NSAIDs, and minimizing alcohol intake (≤8 units/​week). A high HAS-​BLED score (≥3) does not indicate that OAC should be withheld, but warrants caution and should encourage more regular review and control of modifiable bleeding risks. In addition, OAC should not be withheld exclusively because of the risk of falls. Prediction of  INR control:  SAMe-​TT2R2.  Oral anticoagulation treatment options for stroke prevention in atrial fibrillation include VKAs and NOACs (see Fig. 16.4.27). The SAMe-​TT2R2 score (see Table 16.4.10), made up of routine demographic and clinical risk factors, can be used to identify upfront those newly diagnosed non-​ anticoagulated atrial fibrillation patients who are likely to have poor INR control on a VKA (SAMe-​TT2R2 score >2) and who may require more frequent INR monitoring and other interventions to help them achieve adequate time in therapeutic range (TTR) and for whom a NOAC might be a more effective option. Use of the SAMe-​TT2R2 score is recommended by an ESC Task Force on Anticoagulants in Heart Disease to aid decision-​making, rather than subjecting atrial

fibrillation patients to a ‘trial of warfarin’ which may put such patients at risk of stroke during the initial period of treatment. Patient preferences for treatment.  All of the most recent clinical guidelines advocate the importance of eliciting patients’ preferences regarding antithrombotic therapy and incorporating them into the decision-​making process. Central to informed decision-​making is patient education. The clinician’s role is to provide patients with information about their own risk of stroke, the benefits of OAC in reducing this risk, and their risk of bleeding with such treatment to allow them to make appropriate treatment decisions, and to respect their views and beliefs. Patients with better knowledge about atrial fibrillation, who understand the necessity of OAC for stroke prevention, despite having awareness and/​or concerns about the bleeding risk associated with OAC, are more likely to adhere to treatment. Use of oral anticoagulation in the United Kingdom and globally.  Despite the overwhelming evidence of the benefit of OAC for stroke prevention in atrial fibrillation, two recent sizeable observational

16.4  Cardiac arrhythmias

Patient with atrial fibrillation; eligible for oral anticoagulation

Bleeding risk assessment

Identifies ‘at-risk’ patients for more regular review and follow-up

EHR and ‘electronic alerts’ Low risk = no action High risk = patient ‘flagged up’ for review

A ‘high-risk’ bleeding risk score is not a reason or execuse to withhold oral anticoagulation

Review and address potentially reversible bleeding risk factors - Uncontrolled hypertension - Labile INRs (if receiving a VKA) - Concomitant use of aspirin or NSAIDs in anticoagulated patient - Alcohol excess

For patients with an increased risk of bleeding the benefit of oral anticoagulation usually, but not always, outweighs the bleeding risk; thus, regular review and careful monitoring of bleeding risk is important Do not withhold oral anticoagulation solely because the patient is at risk of falls

Fig. 16.4.26  Bleeding risk assessment in AF—​observations on the use and misuse of bleeding risk scores. EHR, electronic health record; INR, International Normalized Ratio; NSAID, non​steroidal anti-​inflammatory drug; VKA, vitamin K antagonist. From Lip GYH and Lane DA (2016). Bleeding risk assessment in atrial fibrillation: observations on the use and misuse of bleeding risk scores. J Thromb Haemost, 14, 1711–​4, © 2016 International Society on Thrombosis and Haemostasis, with permission from John Wiley and Sons.

Fig. 16.4.27  The approach to decision-​making in the AF patient management pathway using the CHA2DS2-​VASc, HAS-​BLED, and SAMe-​TT2R2 scores.

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studies have demonstrated that large proportions of patients at risk of stroke (CHA2DS2-​VASc score ≥2 or CHADS2 score of ≥2) still do not receive OAC. In the first cohort from the Global Anticoagulant Registry in the FIELD (GARFIELD) study, of 10 614 AF patients in 19 countries, 40.7% of patients with a CHA2DS2-​VASc score of 2 or more did not receive OAC. More than one-​half of the reasons given for withholding OAC therapy for patients at risk of stroke in the GARFIELD registry were linked to physician choice (i.e. bleeding risk, concerns over patient adherence, falls risk). Perhaps a more worrying finding from the GARFIELD registry revealed that approximately one-​quarter of patients with a CHA2DS2-​VASc score of 2 or more were receiving antiplatelet monotherapy. A  similar underuse of OAC in patients at high of stroke and overuse in those at low risk was seen in the Euro Heart Survey which was conducted a decade ago. The recent analysis in 1857 general practices in the United Kingdom, utilizing the GRASP-​AF tool (which assessed stroke risk on the basis of the CHADS2 score and recommends treatment based on the 2006 NICE guidelines), demonstrated that 34.0% of patients with a CHADS2 score of 2 or more, with no documented contraindication to OAC, were receiving OAC and the use of antiplatelet therapy rose as stroke risk increased. Use of OAC declined significantly among patients aged 80  years or over (47.4% vs. 64.5%; p 133 μmol/​l; age ≥80 years; body weight ≤60 kg

≥80 years; concomitant verapamil; HAS-​BLED score ≥3e

≥1 of the following: CrCl ml/​min 15–​50 ml/​min; body weight ≤60 kg; on ciclosporin, dronedarone, erythromycin, or ketoconazole

No dose reduction except for renal function

Drug interactions

Anticoagulants, antiplatelets, NSAIDs; ketoconazole, itraconazole, voriconazole, posaconazole, HIV protease inhibitors (ritonavir), rifampicin, St John’s wort, phenobarbital, phenytoin, carbamazepine

Anticoagulants, antiplatelets, NSAIDs; systemic ketoconazole, ciclosporin, tacrolimus, itraconazole, verapamil; quinidine, dronedarone, amiodarone, clarithromycin, rifampicin, St John’s wort, phenytoin, carbamazepine, SSRIs, SNRIs

Anticoagulants, antiplatelets, NSAIDsb Ciclosporin, dronedarone, erythromycin, or ketoconazoleb Quinidine, verapamil, amiodarone Phenytoin, carbamazepine, phenobarbital, or St John’s Wort

Anticoagulants, antiplatelets, NSAIDs; ketoconazole, fluconazole, itraconazole, voriconazole, posaconazole quinidine, HIV protease inhibitors (ritonavir), clarithromycin, erythromycin, dronedarone, rifampicin, St John’s wort, phenobarbital, phenytoin, carbamazepine

Take with/​after food

No

Yes

No

Yes

Check renal function

Divide CrCl by 10; e.g. CrCl 60 ml/​min monitor every 6 months; if decline in renal function is suspected (e.g. hypovolaemia, dehydration) or concomitant use of certain medicinal products, check renal function

a

if CrCl 15–​50 ml/​min Reduce dose to 30 mg once daily if use of concomitant use of ciclosporin, dronedarone, erythromycin, or ketoconazole. c Dose reduction if serum creatinine >133 μmol/​litre plus age ≥80 years and/​or body weight ≤60 kg. d Dabigatran not to be used if CrCl 2)

VKA with additional education and more regular follow-up, dabigatran†, rivaroxaban 20 mg once daily¶, apixaban 5 mg BID*, or edoxaban 60 mg once daily

Fig. 16.4.28  Stroke prevention in atrial fibrillation: fitting the drug to the patient profile. CrCl, creatinine clearance; TTR, time in therapeutic range; VKA, vitamin K antagonist. *Reduced to 2.5 g BID with two or three criteria from age ≥80 years, bodyweight ≤60 kg, or serum creatinine concentration ≥133 μmol/​litre. †110 mg BID for patients with a CrCl 30–​49 ml/​min (most countries, but not in the United States); in the United States only, 75 mg BID (available in the United States only) for patients with CrCl 15–​29 ml/​min (and only 150 mg BID dose available in the United States for CrCl >30 ml/​min). ‡30 mg with CrCl 15–​49 ml/​min, P-​glycoprotein inhibitors, or weight 2 Regular review/INR checks/ counselling for VKA users ... or try a NOAC

Fig. 16.4.29  The Birmingham ‘3-​step’ to streamline decision-​making for stroke prevention in patients with atrial fibrillation. Reprinted from Lip GYH (2017). Stroke prevention in atrial fibrillation. The Lancet, 38(1), 4–​5, by permission of Oxford University Press.

16.4  Cardiac arrhythmias

RA

Fig. 16.4.32  Atrial tachycardia, with variable AV conduction. Lead V1.

IVC

TVA

Fig. 16.4.30  Mechanism of atrial flutter. Typical atrial flutter results from a counterclockwise re-​entry circuit in the right atrium. The isthmus between the tricuspid valve annulus (TVA) and inferior vena cava (IVC) forms a critical part of this circuit, and linear ablation to create block can prevent recurrent atrial flutter.

a degree of AV block, although 1:1 AV conduction can occur. The ECG usually shows regular P-​waves which do not show the same ‘sawtooth’ appearance as in atrial flutter (Fig. 16.4.32). In contrast to most other forms of supraventricular tachycardia, focal atrial tachycardia usually has a long RP interval (defined as >50% of the RR interval). The rate characteristically accelerates or ‘warms up’ before reaching a rate of 125–​200/​min, and careful analysis of morphology of the P-​wave aids in localization of the source. Multifocal atrial tachycardia, in which rapid, irregular P-​waves of three or four different morphologies are seen, may occur in severely ill elderly patients, or in association with acute exacerbation of pulmonary disease. Acute management includes drug treatment or cardioversion, as for atrial fibrillation. Focal atrial tachycardia may be amenable to treatment with radiofrequency ablation with success rates approaching 80%, although recurrence rate is high.

but does not, however, alter the risk of future development of atrial fibrillation. With regards to thrombo-​prophylaxis, anticoagulation is indicated before and after cardioversion, as for atrial fibrillation. The role of longer-​term anticoagulation is less clear and is currently not mandated. However, given the close link between atrial flutter and atrial fibrillation, the presence of silent atrial fibrillation should be considered, especially in those with high CHA2DS2-​VASc scores. Finally, while it is important to note that although typical flutter accounts for more than 90% of all re-​entrant circuits occurring spontaneously in the atria (others include incisional or scar-​related re-​entry), iatrogenic left atrial flutters are increasing in frequency as a consequence of increased use of ablation to treat AF.

Although all atrial arrhythmias are (by definition) supraventricular in origin, the term supraventricular tachycardia is commonly reserved for those in whom the AV node is an obligate part of a re-​ entry circuit—​AV nodal re-​entrant tachycardia (AVNRT) or AV re-​entry tachycardia (AVRT). Correct recognition of these arrhythmias has achieved additional importance with the development of effective curative measures.

Focal atrial tachycardia

Atrioventricular nodal re-​entry tachycardia

Focal atrial tachycardia is an automatic arrhythmia, usually resulting in an atrial rate between 120 and 250/​min. There may be

Mechanism

Fig. 16.4.31  Atrial flutter with 1:1 AV conduction (top), 2:1 conduction (middle), and following adenosine administration (bottom) (6 mg intravenous injection 10 s previously).

Supraventricular tachycardia

This is the commonest cause of paroxysmal re-​entry tachycardia manifesting regular, normal QRS complexes. The basis of the arrhythmia is the presence of two functionally distinct pathways in the region of the AV node (Fig. 16.4.33). The ‘fast’ pathway conducts more rapidly but has a longer refractory period. The ‘slow’ pathway has slower conduction properties but a shorter refractory period. During sinus rhythm, AV nodal conduction occurs via the fast pathway with a normal PR interval (Fig. 16.4.33a). If a sufficiently premature atrial extrasystole arises, conduction in the fast pathway is blocked, but slow pathway conduction may continue, resulting in an abrupt increase in the AH interval as recorded in the His bundle electrogram. This corresponds to an increased PR interval on the surface ECG (Fig. 16.4.33b). If conduction down the slow pathway is sufficiently delayed to allow the fast pathway to recover excitability before activation reaches the distal end of the pathways, retrograde activation occurs via the fast pathway. The stage is then set for a re-​ entry circuit with anterograde conduction via the slow pathway and retrograde conduction via the fast pathway (‘slow/​fast AV nodal re-​ entry’; Fig. 16.4.33c). Characteristically, anterograde activation of the ventricles and retrograde activation of the atria occur virtually simultaneously, resulting in the P-​wave being ‘buried’ within the QRS complex, or producing a very small distortion of the terminal

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Fig. 16.4.35  Atypical atrioventricular nodal re-​entry tachycardia (‘long RP’). Inverted P-​waves precede the QRS complex during tachycardia (compare with preceding sinus beats).

Clinical features Atrioventricular nodal re-​entry tachycardia commonly presents in young adults, although it may appear at any age. Episodes are characterized by sudden onset and sudden offset of symptoms of regular palpitations, which are normally well tolerated unless the tachycardia is particularly rapid, prolonged, or if the patient has other heart disease. The natural history is of episodic paroxysmal tachycardia, occurring at random intervals, although there may be clustering of attacks interposed with periods of relative freedom from symptoms. Atrioventricular nodal re-​entry tachycardia has no specific association with other organic heart disease. Fig. 16.4.33  Atrioventricular nodal re-​entry tachycardia. Mechanism of initiation by atrial extrasystole. See text for details.

QRS, recognition of which requires careful comparison with the ECG during sinus rhythm (Fig. 16.4.34). A less common variant of AV nodal re-​entry tachycardia may arise where anterograde conduction during tachycardia is via the fast pathway with retrograde conduction via the slow pathway (‘fast/​ slow AV nodal re-​entry’, also termed ‘atypical AVNRT’). Under these circumstances, the atrium is activated well after the QRS complex, characteristically producing an inverted P-​wave, with the RP interval greater than the PR interval during tachycardia, termed ‘long RP tachycardia’ (Fig. 16.4.35).

Management Termination of an attack of AV nodal re-​entry tachycardia is achieved by producing transient AV nodal block. This may be achieved by vagotonic manoeuvres, by intravenous adenosine (3–​18 mg; see Fig. 16.4.34), or by intravenous verapamil (6–​18 mg). Drug prophylaxis of AV nodal re-​entry tachycardia is undertaken with β-​ blockers, a combined β-​ blocker/​ class  III agent such as sotalol, or AV nodal blocking drugs such as verapamil or digoxin, although curative treatment of AV nodal re-​entry tachycardia by radiofrequency ablation is increasingly used as a first-​line therapy. Radiofrequency energy is delivered to the ‘slow’ pathway, which lies between the compact AV node and the tricuspid annulus. Ablation at this site is normally curative in over 95% of cases but carries a small risk (0.5–​1%) of inducing complete heart block.

Atrioventricular re-​entry tachycardia Mechanism

Fig. 16.4.34  Atrioventricular nodal re-​entrant tachycardia. Rapid narrow-​ complex tachycardia with no apparent P-​waves (upper) responding to 6 mg adenosine with restoration of sinus rhythm (lower). Close inspection reveals a positive deflection of the terminal QRS during tachycardia (pseudo R′, arrowed) which is absent during sinus rhythm. This is due to retrograde atrial activity coincident with ventricular activation. Lead V1.

In contrast to AV nodal re-​entry tachycardia, the substrate for AV re-​entry is the presence of a second atrioventricular connection, separate from the AV node. This accessory pathway can lie anywhere along the mitral or tricuspid annuli. Anterograde pathway conduction produces ventricular pre-​excitation and is discussed in the ‘Pre-​excitation syndromes’ section to follow. However, some accessory pathways only conduct in the retrograde (ventriculoatrial) direction and are termed ‘concealed’, since there is no clue to their presence on the resting ECG. The anterograde limb of the re-​entrant circuit is the AV node, with retrograde atrial activation occurring over the accessory pathway (see Fig. 16.4.36). This is termed orthodromic tachycardia and normally produces a narrow-​complex QRS morphology. Retrograde atrial activation can be identified by the presence of a characteristic inverted P′-​wave early in the ST segment, an important diagnostic feature of AV re-​entry tachycardia (Fig. 16.4.37). Rarely, an accessory pathway with slow retrograde

16.4  Cardiac arrhythmias

(a)

(b)

(c)

Fig. 16.4.36  Atrioventricular re-​entry tachycardia. Mechanism of initiation by atrial extrasystole. See text for details: if the accessory pathway were concealed the ECG in sinus rhythm would not show the characteristic δ-wave.

conduction may allow a stable, incessant re-​entrant circuit with a long RP interval, referred to as permanent junctional reciprocating tachycardia. Clinical features Features are similar to AV nodal re-​entry tachycardia, although accessory pathways are the more common tachycardia substrate in children. Patients have a similar relapsing course of symptoms interspersed with periods of relative quiescence. Multiple pathways can be present within the same patient and are more common if there is coexisting structural heart disease such as Ebstein’s anomaly (see Chapter 16.12). Management As with AV nodal re-​entry tachycardia, the AV node is an obligate part of the circuit and attacks may be aborted by vagotonic manoeuvres or with intravenous adenosine. Antiarrhythmic therapy may be effective, but radiofrequency ablation offers high success rates with low incidence of complications and should be considered early in a patient’s treatment.

Pre-​excitation syndromes (Wolff–​Parkinson–​White syndrome) The term ‘pre-​excitation’ refers to the premature activation of the ventricle via one or more accessory pathways that conduct in the antegrade direction (from atrium to ventricle), bypassing the normal

AV node and His–​Purkinje system. Accessory pathways with electrophysiological properties of normal myocardium may lie at any point in the AV ring, the commonest sites being in the left free wall or the posteroseptal region (Fig. 16.4.36). The characteristic electrocardiographic appearance is due to the fusion of wavefronts progressing down the normal His–​Purkinje system and the antegradely conducting accessory pathway. Early ventricular activation through the pathway occurs more quickly than conduction through the AV node, producing a short PR interval, but thereafter intraventricular conduction is slow, resulting in slurred initiation of the QRS complex (the δ-wave; Fig. 16.4.38), before the remainder of the ventricle is excited via the normal His–​Purkinje system. QRS morphology therefore reflects fusion of AV nodal and accessory pathway conduction. As such, the degree of pre-​excitation during sinus rhythm is variable:  it may be intermittent if the refractory period of the accessory pathway is close to the sinus cycle length (Fig. 16.4.38), or inapparent if the δ-wave is obscured due to rapid AV nodal conduction. In such instances, transient slowing of AV nodal conduction (e.g. by adenosine) will enhance the proportion of the ventricle excited by the accessory pathway and reveal pre-​excitation. The ECG appearances of a δ-wave occur in approximately 1.5 per 1000 of the population, but many individuals never experience paroxysmal tachycardias. The Wolff–​Parkinson–​White syndrome describes the combination of the symptoms of palpitation and the presence of pre-​excitation on the ECG.

Fig. 16.4.37  Initiation of atrioventricular re-​entry tachycardia. The third sinus beat is followed by the onset of narrow-​complex tachycardia, initiated by an atrial extrasystole (obscured by T-​wave). Retrograde atrial activation, with inverted P-​waves in the ST segment (arrows), are seen during tachycardia.

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section 16  Cardiovascular disorders

Fig. 16.4.38  Intermittent pre-​excitation in Wolff–​Parkinson–​White syndrome. The first two beats show the characteristic short PR interval and δ-wave. The middle two beats, however, show that the pre-​excitation was intermittent. The pathway has become refractory, with normal PR interval and QRS morphology. Pathway conduction returns to cause pre-​excitation in the final two beats.

Mechanisms of orthodromic and antidromic tachycardia The mechanism for orthodromic AV re-​entry tachycardia is illustrated in Fig. 16.4.35. A premature atrial extrasystole may find the pathway refractory but be conducted through the AV node to the ventricles (Fig. 16.4.36b). If sufficient delay has occurred by the time the ventricular insertion of the accessory pathway is depolarized, the pathway may have recovered excitability and allow retrograde activation from the ventricle to atrium, with the establishment of a re-​entry circuit (Fig. 16.4.36c). Since the circuit involves activation of the ventricles via the His–​Purkinje system, the QRS morphology during re-​entry tachycardia is normal, unless a rate-​related bundle branch block develops. If a bundle branch block is seen at a lower heart rate than a documented narrow-​complex tachycardia, this is diagnostic of an accessory pathway ipsilateral to the bundle branch block (Coumel’s sign). A rare form of AV re-​entry tachycardia has anterograde conduction via the accessory pathway and retrograde conduction via the AV node (antidromic tachycardia). The QRS morphology of this tachycardia is broad and grossly abnormal, with appearances dependent upon the site of insertion of the accessory pathway. Pre-​excited atrial fibrillation The major prognostic concern in Wolff–​Parkinson–​White syndrome is pre-​excited atrial fibrillation. Conduction via an accessory pathway with a short refractory period, bypassing the normal AV nodal slowing, may result in very rapid conduction to the ventricle (Fig. 16.4.39) that can degenerate into ventricular fibrillation. The degree of pre-​excitation during atrial fibrillation varies, giving a characteristic pattern of an irregular ventricular response with QRS morphology ranging from normal to fully pre-​excited. The risk of sudden death is increased if the shortest R-​R interval is less than 250 ms during pre-​excited atrial fibrillation, and is an indication for urgent cardioversion and early radiofrequency ablation.

Management of the symptomatic patient with ventricular pre-​excitation The AV node is a part of the re-​entry circuit in both ortho-​and antidromic tachycardia, and adenosine and other AV nodal-​blocking drugs may be effective. However, adenosine may precipitate pre-​ excited atrial fibrillation and should be used with caution. In patients with known Wolff–​Parkinson–​White syndrome presenting with AV re-​entrant tachycardia, drugs which also act on the accessory pathway such as flecainide or sotalol may be preferred. In pre-​ excited atrial fibrillation, AV nodal blocking drugs such as digoxin or verapamil should be avoided, because of the risk of ventricular fibrillation; treatment should be with antiarrhythmic therapy such as flecainide or by DC cardioversion. Patients with Wolff–​Parkinson–​ White syndrome should be offered radiofrequency ablation as first-​ line therapy. This abolishes the risk of pre-​excited atrial fibrillation as well as preventing further attacks of AV re-​entry tachycardia. Careful mapping of the AV annulus using an electrode catheter is necessary to identify the site of the accessory pathway, at which the interval between the atrial and ventricular electrograms is at a minimum. Passage of the radiofrequency current causes heating of the catheter tip and results in the disappearance of accessory pathway conduction within a few seconds (Fig. 16.4.40). The success rate of I

V1

CS RF Map

0

1s

Fig. 16.4.39  Pre-​excited atrial fibrillation. Conduction via an accessory pathway results in an irregular broad-​complex tachycardia. The third and fourth beats show less pre-​excitation, with activation mainly through the normal conducting system, with more normal QRS-​complex morphology. Lead V1.

1s

2s

Fig. 16.4.40  Radiofrequency ablation of an accessory pathway. The patient had Wolff–​Parkinson–​White syndrome with evidence of ventricular pre-​excitation on the surface electrogram during sinus rhythm (short PR interval, δ-wave). One beat after switching on the radiofrequency (RF) current the QRS becomes normal, indicating successful ablation of the accessory pathway. This was a left-​sided accessory pathway, as shown by the short interval between left atrial and left ventricular activation recorded from the coronary sinus (CS). This interval is prolonged following ablation of the pathway. Surface leads I, V1, and intracardiac electrograms from CS and mapping catheter (Map) are shown.

16.4  Cardiac arrhythmias

ablation varies according to the location of the pathway, but is usually over 90%.

(a)

Approach to the asymptomatic patient with ventricular pre-​excitation Patients with Wolff–​Parkinson–​White syndrome should be evaluated carefully for the risk of pre-​excited atrial fibrillation, even in the absence of symptoms. The risk of sudden death due to rapid pre-​excited atrial fibrillation is very low among adults who have not had any symptomatic tachycardias, but is higher in symptomatic patients. If pre-​excitation is intermittent, this indicates a long refractory period of the pathway and a low risk of life-​threatening tachycardias. Abrupt disappearance of the δ-wave in response to exercise testing, or during Holter monitoring, or with the administration of a class Ia or Ic antiarrhythmic drug, also suggests a low risk. Some centres advocate diagnostic electrophysiological studies to identify a high-​risk group with short pathway refractory periods and inducible tachycardia or pre-​excited atrial fibrillation. The general tendency is for accessory pathway conduction to become slower with increasing age, and spontaneous disappearance of conduction is well documented. Other pre-​excitation syndromes Other forms of pre-​excitation include the Mahaim pathway, a direct AV, or atriofascicular connection with decremental conduction properties similar to AV nodal tissue.

Ventricular tachycardia Definitions Ventricular tachycardia is defined as the presence of three or more consecutive ventricular beats at a rate of 120/​min or greater. It is considered to be sustained if an individual salvo lasts for 30 s or more, and non​sustained if the duration is between 3 beats and 30 s.  Monomorphic ventricular tachycardia has a consistent QRS morphology, whereas polymorphic ventricular tachycardia demonstrates a constantly changing QRS morphology, often without discrete QRS complexes. Polymorphic ventricular tachycardia may degenerate into ventricular fibrillation and the ECG distinction between the two is difficult. Torsades de pointes is a polymorphic VT in association with QT interval prolongation and is discussed in more detail later in the chapter. ECG characteristics The presence of AV dissociation is a particularly important feature to seek in a broad-​complex tachycardia as it makes the diagnosis of ventricular tachycardia virtually certain (Fig. 16.4.41a). A careful search for P-​waves perturbing the QRS complex or T-​waves is necessary, ideally using multilead recordings. Occasionally, a fortuitously timed P-​wave allows the development of a capture beat of normal QRS morphology without interrupting the tachycardia. A fusion beat occurs when activation of the ventricle is partly via the normal His–​Purkinje system and partly from the tachycardia focus (Fig.  16.4.41b). Fusion and capture beats are diagnostic of ventricular tachycardia but are commonly present only if the ventricular rate is relatively slow. Although AV dissociation is diagnostic of ventricular tachycardia, it is not invariable. Retrograde ventriculoatrial conduction may occur, giving either 1:1 conduction or higher degrees of block (Fig. 16.4.41c).

(b)

(c)

Fig. 16.4.41  Sustained monomorphic ventricular tachycardia. (a) Ventricular tachycardia with atrioventricular dissociation. P-​waves (arrowed) are seen to have no relationship to the ventricular activation. Lead V1. (b) Ventricular tachycardia with fusion beat (arrow). Lead V1. (c) Ventricular tachycardia with 2:1 ventriculoatrial conduction. Lead III. P-​waves (arrows) follow every second ventricular complex.

The QRS duration in ventricular tachycardia is commonly greater than 120 ms, and values greater than 140 ms are particularly suggestive of ventricular tachycardia. Although the QRS morphology may superficially resemble left or right bundle branch block, the morphology is commonly atypical (see Fig. 16.4.16). Ventricular tachycardia arising from the right ventricular free wall has a left bundle branch block-​like pattern, whereas left ventricular free wall tachycardias show right bundle branch block morphology. The presence of concordant positive or negative QRS complexes across the chest leads is suggestive of ventricular tachycardia, as is the existence of extreme axis deviation. ECG features consistent with VT are listed in Fig. 16.4.16. Aetiology Sustained monomorphic ventricular tachycardia commonly occurs in the presence of structural heart disease, but also arises in structurally normal hearts. It rarely occurs in the acute phase of myocardial infarction, but may be seen in the subacute phase (>48 h), or may arise many years later, particularly in association with left ventricular scar or aneurysm formation. The arrhythmia also occurs in other forms of structural heart disease associated with ventricular dilatation or fibrosis such as dilated cardiomyopathy, hypertrophic cardiomyopathy, or previous ventricular surgery (e.g. following repair of Fallot’s tetralogy). Ventricular tachycardia may degenerate into ventricular fibrillation. Sustained monomorphic tachycardia can occur as a proarrhythmic response to antiarrhythmic drugs, particularly class I agents. Although ventricular tachycardia normally occurs in individuals with overt heart disease, it is also seen in young and apparently healthy subjects. In these, occult cardiac disease or cardiac genetic syndromes should be considered (see ‘Genetic syndromes’). There

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remain a few patients with documented ventricular tachycardia in whom no structural heart disease is evident on clinical, ECG, or echocardiographic examination. The tachycardia may arise from the outflow tract of the right or left ventricle, or from one of the fascicles of the left bundle branch, and is amenable to radiofrequency ablation. Acute management of ventricular tachycardia Rapid ventricular tachycardia may present with cardiac arrest, syncope, shock, anginal chest pain, or left ventricular failure, but slower tachycardias in patients with preserved cardiac function may be well tolerated. Sustained ventricular tachycardia is a medical emergency. If the patient is pulseless or unconscious, immediate DC cardioversion is necessary. If the patient is conscious but hypotensive, urgent DC cardioversion under general anaesthesia or deep sedation is used. Haemodynamically tolerated tachycardias may be terminated by drug therapy (see Fig. 16.4.17). Adenosine may be administered in the presence of haemodynamic stability to exclude the differential diagnoses of SVT with aberrancy or antidromic AVRT, but is likely to be ineffective in terminating VT (see Table 16.4.6). Amiodarone 300 mg over 20 min (ideally via a central vein) followed by 900 mg/​24 h may be effective in restoring sinus rhythm. Second-​ line drugs for the termination of ventricular tachycardia include intravenous lidocaine (lignocaine) 100 mg, sotalol, procainamide, and disopyramide, although all may be proarrhythmic. Flecainide is contraindicated in view of the risk of developing incessant tachycardia. Verapamil should be avoided as it may cause clinical deterioration. The only exception to this is in the rare instance of patients with structurally normal hearts who have ventricular tachycardia that is known to respond to verapamil (e.g. LV fascicular tachycardia). All antiarrhythmic drugs have significant negative inotropic actions that may further impair the haemodynamic status of the patient if sinus rhythm is not restored. For this reason, no more than one antiarrhythmic drug should normally be given before recourse to alternative therapy, usually DC cardioversion. Overdrive termination of ventricular tachycardia following insertion of a temporary pacing lead may be effective, particularly if the tachycardia is relatively slow. Facilities for cardioversion must be available in view of the risk of acceleration or degeneration into ventricular fibrillation. Secondary prevention Ventricular tachycardia is a potentially life-​threatening condition. Unless the acute episode was clearly precipitated by some transient or reversible factor, there is a high probability of recurrent attacks, which may result in sudden death. Prognosis is worse if the arrhythmia was poorly tolerated, or if there is severe left ventricular dysfunction. Clinical evaluation of the patient after restoration of sinus rhythm should be supported by ECG, echocardiography, cardiac magnetic resonance imaging, and/​or radionuclide ventriculography. Coronary angiography should be considered to identify the presence of significant coronary artery disease, which may act as a trigger to ventricular tachycardia. Unless there is a clear precipitating factor such as drug toxicity, electrolyte abnormality, or acute ischaemia, the risk of sudden death is high and patients should be considered for a secondary prevention ICD (see Fig. 16.4.20). A meta-​analysis of three secondary prevention trials of patients resuscitated from ventricular fibrillation or ventricular tachycardia causing haemodynamic

compromise showed defibrillators to be better than antiarrhythmic drug therapy in preventing death from any cause (Fig. 16.4.42a). Primary prevention Patients with left ventricular dysfunction of any cause are at risk of sudden death from ventricular tachycardia or fibrillation and implantable defibrillators are appropriate for a subgroup of these patients as part of a primary prevention strategy. Those with non-​ sustained ventricular tachycardia, in whom sustained tachycardia can be induced at electrophysiological testing, have a better survival with defibrillator implantation compared with drug therapy. Primary prevention trials such as the Sudden Cardiac Death in Heart Failure Trial (SCD-​HeFT) have expanded the indication to include patients with class II/​III heart failure and an ejection fraction less than 30%, even in the absence of known arrhythmia (Fig. 16.4.42b). Antiarrhythmic therapy Implantable defibrillator therapy is not affordable in all countries, and not appropriate for patients with New York Heart Association (NYHA) class  IV heart failure or other conditions causing a severely limited prognosis. Medical therapy is necessary for many patients, but is limited by a relative lack of evidence from randomized controlled trials. β-​Adrenoceptor blockers are comparable to conventional antiarrhythmic agents in the prevention of recurrent ventricular tachyarrhythmias. Since they have been shown to reduce the risk of sudden death in unselected survivors of myocardial infarction and in patients with chronic heart failure, they should be used routinely in the prophylaxis of ventricular tachycardia if tolerated. Amiodarone did not improve mortality compared to placebo in the SCD-​HeFT trial. The class I antiarrhythmics should not be used for this indication as they were associated with a higher rate of arrhythmic deaths in the Cardiac Arrhythmia Suppression Trial. Other therapies Radiofrequency ablation is used in the management of ventricular tachycardia, particularly in those with no structural heart disease. Right or left ventricular outflow tract tachycardia and fascicular tachycardia are particularly amenable to ablation. Radiofrequency ablation of critical areas of slow conduction in scar-​related ventricular tachycardias is now frequently undertaken but success rates are lower than for other types of ablation and this approach is often reserved for the treatment of recurrent tachycardia in patients with implantable defibrillators. Direct surgical management of recurrent ventricular tachycardia involves aneurysmectomy, endocardial mapping, and resection of the area containing the micro re-​entry circuit. The indications for surgery have been reduced considerably since the advent of the ICD and the emergence of catheter ablation, since the surgical mortality is up to 10–​15%. Where medically intractable ventricular tachyarrhythmias are associated with very poor left ventricular function, cardiac transplantation should be considered if catheter ablation fails. Non​sustained ventricular tachycardia The mechanism and causes of non​ sustained ventricular tachycardia (Fig. 16.4.43) are similar to those of sustained ventricular tachycardia. There is often slight variation in the R-​R interval, particularly if the salvo involves only a few beats. Short salvos of

16.4  Cardiac arrhythmias

(a) Arrhythmic death

Death 50

50

40

40

30

30 Amio ICD

20

20

Amio

10

10

0

1

2

Number at risk ICD: 934 Amio: 932

3 Years

715 664

4

467 427

0

5

273 248

ICD

159 128

104 82

1

934 932

2

715 664

3 Years 467 427

4

273 248

5

159 128

104 82

(b) Amiodarone vs. placebo ICD therapy vs. placebo

Hazard ratio (97.5% CI) 1.06 (0.86–1.30) 0.77 (0.62–0.96)

0.4

Placebo (244 deaths; 5-yr event rate, 0.361) ICD therapy (182 deaths; 5-yr event rate, 0.289)

Amiodarone (240 deaths; 5-yr event rate, 0.340)

0.3 Mortality rate

P value 0.53 0.007

0.2

0.1

0.0 0

12

24

36

48

60

484 505 501

280 304 304

Months of follow-up No. at risk Amiodarone 845 Placebo 847 ICD therapy 829

772 797 778

715 724 733

97 89 103

Fig. 16.4.42  Improved survival with the implantable cardioverter–​defibrillator (ICD). (a) Cumulative risk of fatal events for ICD or amiodarone (amio) from a meta-​analysis of trials of secondary prevention, showing reduced death with ICD (left panel), due to reduced arrhythmic death (right panel). (b) Improved survival with ICD compared to amiodarone or placebo in a study of primary prevention in patients with heart failure. (a) Reproduced from Connolly SJ, et al. (2000). Meta-​analysis of the implantable cardioverter defibrillator secondary prevention trials. Eur Heart J, 21(24), 2071–​8, by permission of Oxford University Press; (b) Bardy GH, et al. (2005), New Engl J Med, 352, 230. Copyright ©2005 Massachusetts Medical Society. All rights reserved.

Fig. 16.4.43  Non​sustained ventricular tachycardia.

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non​sustained ventricular tachycardia are often asymptomatic. Apart from the instances where non​sustained ventricular tachycardia produces troublesome symptoms, the major clinical significance of the arrhythmia is as a risk marker for sustained ventricular tachycardia or sudden cardiac death in patients with left ventricular dysfunction or hypertrophy. Patients with structural heart disease, in particular those with severe left ventricular dysfunction, with QRS duration greater than 120 ms or heart muscle disease, should be considered for an implantable defibrillator as primary prevention of sudden cardiac death. If no structural heart disease or ion channel disease is present, and the patient is asymptomatic, no treatment is indicated as long-​term follow-​up of such patients indicates a good prognosis with no excess risk of sudden death. Polymorphic ventricular tachycardia Polymorphic ventricular tachycardia is an unstable rhythm with varying QRS morphology. It is most commonly seen in the acute phase of myocardial infarction. It either undergoes spontaneous termination or degenerates into ventricular fibrillation. If episodes of polymorphic ventricular tachycardia are frequent in the early hours of myocardial infarction, they can be suppressed by β-​blockade.

Torsades de pointes and the long-​QT syndromes Torsades de pointes is a characteristic type of polymorphic ventricular tachycardia with a typical undulating variation in QRS morphology as a result of variation in axis. It occurs in association with a prolonged QT interval during sinus rhythm. Long-​QT syndromes may be acquired or congenital; the latter are discussed later in the chapter. Aetiology Although class Ia and III antiarrhythmic drugs are the best-​known causes of acquired long-​QT syndrome, a very large number of non-​ cardiac drugs inhibit the outward potassium current IKr, and may cause significant lengthening of the QT interval either singly or in combination (Table 16.4.12). Episodes of torsades de pointes are often multifactorial in origin, with prolongation of the QT interval by an IKr inhibitor in association with predisposing factors such as

Table 16.4.12  Causes or contributory factors in acquired long-​QT syndromes Drug induced

bradycardia or pauses, hypokalaemia, or hypomagnesaemia. All of these predispose to early after-​depolarizations in vitro and this mechanism appears to be the likely cause of torsades de pointes in the acquired syndromes. The prognosis of the acquired long-​QT syndromes is excellent, provided the underlying predisposing factors are identified and corrected. However, it is increasingly recognized that there is a genetic predisposition to the development of acquired long-​QT syndrome in the face of predisposing factors, leading to the concept that patients developing acquired long-​QT syndrome have reduced ‘repolarization reserve’ as a result of a forme fruste of the congenital syndrome. ECG characteristics Torsades de pointes is an atypical ventricular tachycardia characterized by a continuously varying QRS axis (‘twisting of points’; see Fig. 16.4.44). Episodes of torsades are commonly repetitive and normally self-​terminating, although they may degenerate into ventricular fibrillation. Paroxysms of torsades de pointes are associated in the preceding beats with evidence of marked QT prolongation, and frequently with morphological abnormalities of the T-​wave such as T-​U fusion, gross increases in T-​wave amplitude, or T-​wave alternans. In the acquired long-​QT syndromes a slowing of the heart rate, and in particular a postextrasystolic pause, is often associated with initiation of the arrhythmia. This produces a characteristic ‘short–​long–​short’ sequence of initiation (Fig. 16.4.44). Acute management The common clinical presentation is of recurrent dizziness or syncope, and the condition may easily be misdiagnosed as self-​ terminating polymorphic ventricular tachycardia or ventricular fibrillation unless the characteristic morphology of torsades de pointes and the associated QT interval prolongation is recognized. It is essential to discontinue predisposing drugs or other agents and to avoid empirical antiarrhythmic drug therapy, which may worsen the arrhythmia. Individual paroxysms of torsades de pointes are normally self-​limiting, but if they are persistent, cardiac arrest will occur and emergency defibrillation is necessary. Intravenous magnesium sulphate (8 mmol over 10–​15 min, repeated if necessary) is a safe and effective emergency measure for the prevention of recurrent paroxysms of tachycardia. If torsades de pointes is associated with bradycardia and pauses, the heart rate should be increased to between 90

Antiarrhythmic drugs—​classes Ia, III Macrolide antibiotics—​erythromycin Antifungals—​ketoconazole Psychotropics—​tricyclic/​tetracyclic antidepressants, antipsychotics Antihistamines—​terfenadine, astemizole Antiemetics—​domperidone, ondansetron Synthetic opioid—​methadone

Electrolyte disturbances

Hypokalaemia, hypomagnesaemia, hypocalcaemia

Metabolic

Hypothyroidism, starvation, anorexia nervosa, liquid protein diet

Bradycardia

Sinoatrial disease, AV block

Toxins

Organophosphorus insecticides, heavy metal poisoning

Fig. 16.4.44  Torsades de pointes. Note the marked QT interval prolongation in the sinus beats, and the ‘short–​long’ pattern of R-​R intervals immediately prior to initiation of the arrhythmia. Ambulatory monitoring recording is shown (continuous tracing).

16.4  Cardiac arrhythmias

and 100/​min by atrial or ventricular pacing or isoproterenol (isoprenaline) infusion. Hypokalaemia and hypomagnesaemia should be sought and corrected if necessary.

Accelerated idioventricular rhythm The term ‘accelerated idioventricular rhythm’ is used to describe a continuous ventricular rhythm with a rate less than 120/​min. Idioventricular rhythm commonly occurs in the setting of acute myocardial infarction and appears to be a marker of successful reperfusion therapy. No active treatment is necessary.

Ventricular fibrillation Ventricular fibrillation is defined as a chaotic, disorganized arrhythmia with no identifiable QRS complexes (Fig. 16.4.45). The mechanism is of multiple, unstable re-​entry circuits. The electrocardiographic pattern depends on the duration of fibrillation: recent-​ onset fibrillation is described as ‘coarse’, with a peak-​ to-​ peak amplitude of around 1 mV (1 cm). With increasing duration of cardiac arrest, the amplitude of ventricular fibrillation diminishes and such ‘fine’ ventricular fibrillation is less likely to be amenable to successful electrical defibrillation. Ventricular fibrillation may occur during acute myocardial ischaemia often initiated by an R on T extrasystole, and is the principal cause of death in the first 2 h following acute myocardial infarction (Fig. 16.4.45). Ventricular fibrillation during myocardial infarction is subdivided into primary, occurring without warning in an otherwise stable patient, and secondary, where fibrillation occurs in the context of left ventricular failure or cardiogenic shock. Ventricular fibrillation occurring in chronic heart disease is most commonly a result of degeneration of rapid ventricular tachycardia, whose causes have been described earlier. Rarer causes of fibrillation are listed in Box 16.4.4. Ventricular fibrillation is rarely self-​terminating, and normally causes cardiac arrest with the rapid onset of pulselessness, unconsciousness, and apnoea. The management of cardiac arrest due to ventricular fibrillation is discussed in Chapter 17.2. Patients who survive an episode of ventricular fibrillation should be assessed carefully to determine the risk of recurrence. If ventricular fibrillation has occurred in the first few hours of a typical ST-​elevation myocardial infarction, the risk of recurrent cardiac arrest is low, and no specific prophylactic therapy other than assessment and treatment of residual ischaemia and conventional postinfarction β-​blockade is indicated. However, in many instances ventricular fibrillation arises as a result of acute ischaemia in patients with known, extensive heart disease who have not sustained an acute infarction. These patients remain at high risk of recurrent ventricular fibrillation, and should be evaluated fully by exercise testing and coronary arteriography with a view to revascularization,

Fig. 16.4.45  Ventricular fibrillation complicating acute myocardial infarction. The arrhythmia is initiated by an ‘R on T’ ventricular extrasystole.

Box 16.4.4  Causes of ventricular fibrillation • Acute myocardial ischaemia • Acute myocardial infarction—​primary or secondary • Advanced organic heart disease with poor LV or RV function • Severe LV hypertrophy • Ventricular tachycardia/​torsades de pointes • Electrical—​electrocution, lightning, unsynchronized DC shock, competitive ventricular pacing • Pre-​excited atrial fibrillation • Profound bradycardia • Hypoxia, acidosis • Genetic syndromes (e.g. long-​QT syndrome, Brugada syndrome)

and managed with an ICD or antiarrhythmic therapy as discussed in the section on ventricular tachycardia.

Genetic syndromes Ion channel diseases Congenital long-​QT syndromes The congenital long-​QT syndromes (LQTS) are inherited conditions due to mutations in genes encoding ion channel proteins. They are mainly autosomal dominant and are subclassified according to the underlying gene defect (Table 16.4.13). Most cases are either LQT1 or LQT2, due to mutations affecting either the slow (IKs) or rapid (IKr) components of the outward potassium current. In the less common LQT3, the inward sodium current (INa) is affected. Lengthening of ventricular repolarization, and hence of the QT interval, occur as a result either of reduced outward current flow via IKr or IKs or increased duration of current flow via INa. The arrhythmia, torsades de pointes, has characteristics consistent with triggered activity. Attacks of torsades de pointes in the congenital syndromes are commonly associated with sympathetic stimulation such as exercise, waking, or fright, and are associated with increases in sinus rate. Cardiac events are particularly associated with exercise in LQT1, with auditory stimulation in LQT2, and can occur during sleep in LQT3. Paroxysms may produce syncope, which if prolonged may be complicated by convulsion, leading to misdiagnosis as epilepsy. A  family history of recurrent syncope or sudden death may be obtained. Sinus bradycardia is commonly seen in these syndromes. The diagnosis of long-​QT syndrome can be challenging and is not based on the ECG characteristics alone. The finding of a long QT interval on an ECG in patients with a history of syncope or palpitations or a routine ECG in asymptomatic patients can cause considerable anxiety among clinicians. The probability of LQTS can be assessed using the Schwartz score, with a score more than 3.5 supporting the diagnosis (Table 16.4.14). The prognosis of untreated congenital long-​QT syndrome is poor, with a high incidence of sudden death in childhood. Factors associated with high risk include personal history of aborted sudden cardiac death or syncope, and corrected QT interval greater than 500 ms. Males with LQT3 are at increased risk regardless of the degree of QT interval prolongation. LQT1 has a better prognosis than other subtypes. Episodes of torsades de pointes and T-​wave alternans on Holter monitoring also confer a higher risk.

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section 16  Cardiovascular disorders

Table 16.4.13  Genetics of congenital long-​QT syndromes Subtype

Chromosome

Gene

Product

Ion current affected

Frequency

LQT1

11

KCNQ1

KvLQT1

↓IKs

c.50%

LQT2

7

KCNH2

HERG

↓IKr

30–​40%

LQT3

3

SCN5A

Nav 1.5

↑INa

5–​10%

LQT4

4

ANKB

Ankyrin-​B

↓Multiple

Rare

LQT5

21

KCNE1

minK

↓IKs

Rare

LQT6

21

KCNE2

MiRP1

↓IKr

Rare

LQT7

17

KCNJ2

Kir2.1

↓IK1

Rare

LQT8

12

CACNA1C

Cav1.2

↑ICaL

Rare

CAV3

Caveolin 3

↑INa

Rare

Sodium channel β4

SCN4B

↑INa

Rare

AKAP9

Yotiao

↓IKs

Rare

SNTA1

↑INa

Rare

Kir3.4

↓IKr

Rare

Calmodulin 1

N/​A

Rare

Calmodulin 2

N/​A

Rare

Calmodulin 3

N/​A

Rare

LQT9

3

LQT10

11

LQT11

7

LQT12

20

Syntrophin α1

LQT13

11

KCNJ5

LQT14

14

CALM1

LQT15

2

CALM2

LQT16

19

CALM3

Table 16.4.14  Schwartz score for the diagnosis of long-​QT syndrome Clinic features

Points

ECG findingsa A

QTcb

≥480 ms

3

460–​479 ms

2

450–​459 ms (male)

1

B

QTcb 4th minute of recovery from exercise stress test ≥480 ms

1

C

Torsade de pointesc

2

D

T-​wave alternans

1

E

Notched T-​wave in three leads

F

1

d

Low heart rate for age

0.5

Clinical history A B

Syncopec Congenital deafness

With stress

2

Without stress

1 0.5

Family history A

Family members with definite LQTSe

1

B

Unexplained sudden cardiac death 85

—​

7.1 per 1000 (though not 85–​90.1 per 1000

Utrecht, Netherlands

40–​95

53% had echoes 97%-​LVSD

1640 (43)

North Glasgow, UK

25–​74

2.9% LVSD

1.4% ALVSD

15 per 1000

ECHOES

3960 (72)

West Midlands, UK

1.8% LVSD 3.5% Preserved EF

0.9% ALVSD

31 per 1000 (>45 yrs of age)

Kupari et al., 1997

Helsinki Ageing Study

501 (41)

Helsinki, Finland

75–​86

4.1 % HEFPEF 3.9 % LVSD

9% ASLVD

Mosterd et al., 1999

Rotterdam Heart Study

2267 (88)

Rotterdam, Netherlands

55–​94

3.7% LSVD

1.4% ASLVD

Morgan et al., 1999

Poole Heart Study

817 (61)

Poole, Dorset, UK

70–​84

7.5 % LVSD

3.9 % ASLVD

Authors

Name of study

Number of patients (no. of cases of heart failure)

Location

Age range

Percentage of symptomatic left ventricular systolic dysfunction (LVSD)

Parameshwar et al., 1992

Prevalence of heart failure in 3 GP practices

30 204 (117)

Northwest London, UK

5–​99

Murphy et al., 2004

National survey of heart failure

307 741 (2186)

Scotland, UK

Rutten et al., 2003

A questionnaire-​ based survey of heart failure

(202)

McDonagh et al., 1997

MONICA

Davies et al., 2001

Percentage of asymptomatic left ventricular systolic dysfunction (ASLVD)

(75–​86) –​82 per 1000 Men 7 per 1000 (55–​64) Women 6 per 1000 (55–​64)

Men 37 per 1000 (65–​74) 144 per 1000 (75–​84) 59 per 1000 (85–​94) Women 16 per 1000 (65–​74) 121 per 1000 (75–​84) 140 per 1000 (85–​94)

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Table 16.5.1.2  Studies demonstrating incident rates of heart failure within different populations Study

Name of study

McKee et al., 1971

Framingham

Erikkson et al., 1989

The men born in 1913

Cowie et al., 1999

Number of patients

Incidence of heart failure >65 yrs of age

2 per 1000 (45–​54 years)

40 per 1000 (85–​94 years)

Age range

Framingham, US

45–​94

973

Gothenburg, Sweden

67

Hillingdon Heart Study

151 000

Hillingdon, northwest London, UK

29–​95

76 years

0.02 per 1000 (25–​34 years) 0.2 per 1000 (35–​44 years) 0.2 per 1000 (45–​54 years) 1.2 per 1000 (55–​64 years)

3 per 1000 (65–​74 years) 7.4 per 1000 (75–​84 years) 11.6 per 1000 (85–​94 years)

Murphy et al., 2004

GP database, Continuous morbidity recording scheme

307 741 (2186 cases)

Scotland, UK

45–​85

—​

1.3 per 1000 (45–​64 years)

6.1 per 1000 (65–​74) 16 per 1000 (75–​84 years)

De Giuli et al., 2005

GP research database

696 884 (6478 cases)

United Kingdom

45–​101

77 years

3.4 per 1000 (55–​64 years)

25.5 per 1000 (75–​84 years)

Kalogeropoulos et al., 2009

ABC study

2934 (258)

Pittsburgh, and Memphis, Tennessee US

70–​79

73.6 years

Bibbins-​ Domingo et al.

CARDIA study

5115 (27)

Birmingham, Alabama, Chicago, Illinois, Minneapolis, Oakland, California, US

18–​30

39.1 years

Many epidemiology studies therefore focused on characterizing the incidence and prevalence of LVSD, using varying cut points of the normally distributed variable, LVEF, ranging from less than 30% to 50%. This difference in the cut points chosen affects the incidence and prevalence rates which are quoted (see Tables 16.5.1.1 and 16.5.1.2). Often studies have classified those with heart failure symptoms and signs with a normal or only mildly reduced left ventricular function to have heart failure with preserved ejection fraction (HF-​PEF). In the absence of any convincingly positive drugs trials for this end of the spectrum of heart failure, no unifying definition of HF-​PEF has emerged and been applied to community-​based studies. The latest definitions of HF-​PEF, in addition to symptoms and or signs of heart failure and a relatively preserved ejection fraction, also require evidence of structural heart disease (usually left ventricular hypertrophy, increased left atrial size/​volume and Doppler or tissue Doppler evidence of diastolic dysfunction). Rigorous population-​based studies with these more modern definitions have yet to appear.

Prevalence studies

Mean/​ Median age of diagnosis

Incidence of heart failure 5 litres) is the dominant feature. Management is principally with bed rest, loop diuretics (usually by intravenous infusion), and, where appropriate, mineralocorticoid receptor antagonists. Thiazide diuretics can be added in resistant cases. Prophylactic low molecular weight heparin should be prescribed. Careful monitoring of fluid balance with daily weights and

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daily electrolytes is essential. Angiotensin-​converting enzyme inhibitors and subsequently β-​blockade can be introduced once a satisfactory diuresis has been achieved. Management of cardiogenic shock is usually determined by the cause. Fluid status should be assessed, and an adequate left ventricular filling pressure ensured by the administration of intravenous fluids where required (particularly in the case of right ventricular infarction). Revascularization is the mainstay of therapy in acute myocardial infarction. Circulatory support with intra-​ aortic balloon counterpulsation, inotropic agents, ventricular assist devices, and extracorporeal membrane oxygenation should be considered for reversible causes (e.g. ventricular septal rupture, papillary muscle rupture, acute myocarditis, and peripartum cardiomyopathy).

Prognosis Hospital admission with acute heart failure caries a poor prognosis with an average in-​hospital mortality of 10–​15% rising to up to 60% at 30 days in cases of cardiogenic shock.

Introduction Although the term ‘acute heart failure’ often conjures up an image of a patient with acute pulmonary oedema, in extremis, struggling to breathe and producing pink, frothy sputum, such a dramatic presentation is not common. Admissions to hospital for heart failure, on the other hand, are extremely common, and most patients admitted are not breathless at rest, only becoming breathless on mild exertion. It is better to think of acute heart failure as being a worsening of symptoms and/​or signs leading the patient, carer, or primary care physician to seek urgent expert advice—​leading, in turn, to an urgent admission to hospital for investigation and/​or treatment. Many patients will be able to walk, albeit slowly, from their wheelchair to their hospital bed. Patients admitted with heart failure usually have a problem with oedema (i.e. fluid in the wrong place). The old-​fashioned term ‘anasarca’ describes a state of severe generalized oedema. It can be helpful to think of patients as being on a spectrum between pulmonary oedema at one end, in which the fluid is predominantly in the lung, and anasarca on the other, in which patients have an absolute excess of fluid, usually manifesting as peripheral oedema. This notion is similar to the classification system used for patients with chronic airways disease and emphysema: patients with pulmonary oedema can be termed ‘puffers’, and those with anasarca as ‘bloaters’ or having dropsy (Table 16.5.2.1). Patients with pulmonary oedema usually present with a short history of deterioration. There is often an obvious acute precipitating factor such as acute coronary syndrome or atrial fibrillation, particularly with a rapid ventricular response. They often have hypertension and a high peripheral vascular resistance. The patient has had no time to retain a substantial excess of body fluid. In contrast, patients with dropsy (‘bloaters’) usually have a history of deterioration over a period of weeks and no acute precipitating factors (although the development of atrial fibrillation with a slow ventricular response, anaemia, and chronic kidney disease (CKD) could be

Table 16.5.2.1  The spectrum of acute heart failure ranges from patients with acute pulmonary oedema, perhaps 15% of patients presenting to hospital with acute pulmonary oedema, to those with fluid retention. Differences between the two groups are highlighted Pulmonary oedema

Anasarca

Syndrome

Puffers

Bloaters

Acute precipitant

Yes

Usually no

Oedema

In lungs

Predominantly peripheral

Absolute fluid excess

No

Yes

Time course

Minutes to hours

Days to weeks

considered chronic precipitants). They have a low blood pressure and have had time to retain many litres (sometimes ≥20 litres) of excess fluid. The distinction is important in interpreting the results of clinical trials: an agent that is designed to improve acute breathlessness, but given to someone who is already comfortable at rest (perhaps rendered so by standard background therapy) is likely to appear ineffective, even if it is highly effective in the appropriate patient at the appropriate time. There is little evidence from randomized controlled trials in acute heart failure syndromes to guide management. Much of what follows in terms of management advice thus reflects the balance of expert opinion rather than definitive recommendations. The lack of evidence reflects a constellation of difficulties. The reasons for hospital admission may be misunderstood and patients often present at inconvenient hours of the night when it is least likely they will encounter people with the time or inclination to do research (funding nocturnal research can be expensive). Protocol procedures often cause delays which allow standard therapies to be effective before a new intervention can be started. Indeed, the effectiveness of oxygen, nitrovasodilators, and diuretics for the short-​term management of symptoms suggests that the needs for managing acute pulmonary oedema are largely satisfied. The big problems for ‘acute’ heart failure really appear 2–​3 days after admission when it is clear that diuretics alone have not solved the immediate problem. For most patients, the problem then is peripheral oedema and exertional breathlessness rather than breathlessness at rest. In the longer term, the big problems are recurrent exacerbations and death. Thankfully, the vast majority of patients who survive to discharge attain a reasonable quality of life in the intervening period. There are guidelines to help guide practice, but those relating to acute heart failure tend to focus most on the patients with acute pulmonary oedema. The European Society of Cardiology’s (ESC) guidelines of 2016 are helpful, but it is noteworthy that the only treatment to receive a class I, level A recommendation was the use of prophylaxis against thromboembolism. The National Institute for Health and Clinical Excellence clinical guideline of 2014 covered both patients with pulmonary oedema and the more common presentation with fluid retention. This placed a great deal of emphasis on the importance of organization of care and the need for patients with acute heart failure to be managed in the appropriate environment, but was notably frank regarding the absence of good trial evidence and gave a series of helpful recommendations for future research.

16.5.2  Acute cardiac failure

Cardiogenic pulmonary oedema Pathophysiology In patients with pulmonary oedema, fluid from the lung capillaries collects in the extravascular spaces of the lung. The Starling equation describes the forces acting on fluid in the pulmonary capillaries (Fig. 16.5.2.1). Hydrostatic pressure tends to force fluid out of the capillaries while the colloid osmotic pressure (largely provided by proteins) tends to maintain the fluid within the capillary. The balance between the forces varies between arteriole and venule; however, there is net filtration along the length of the capillary. Some resistance to fluid movement is provided by the alveolar–​capillary membrane and any fluid entering the interstitium is removed by the lymphatics. Problems with any of these components can lead to (or worsen) pulmonary oedema. Pulmonary lymphatic flow may increase substantially in heart failure, reducing the risk of pulmonary oedema. However, the lymphatics drain into the venous circulation and so a rise in venous pressure may inhibit lymphatic clearance. Lymphatic occlusion, as occurs in lymphangitis carcinomatosa, and disruption to the alveolar capillary membrane, as happens in adult respiratory distress syndrome, can cause pulmonary oedema. Hypoalbuminaemia causes peripheral oedema and reduces the hydrostatic pressure at which pulmonary oedema occurs. In the normal circulation, the Frank–​Starling relation describes the relation between the load on the left ventricle at the end of diastole, usually expressed as the end-​diastolic pressure, and the work subsequently performed by the ventricle during systole. The end-​ diastolic pressure is the same as the left atrial and hence pulmonary venous pressure. In patients with heart failure, the curve relating the two is shifted to the right: for any given cardiac output, the filling pressure required is greater in the failing ventricle (see Fig. 16.5.2.2). An acutely failing ventricle needs a higher and higher filling pressure to maintain cardiac output. The rising end-​diastolic pressure is reflected in a rise in left atrial, pulmonary venous, and pulmonary capillary pressure, resulting in faster rates of fluid filtration. Ultimately, fluid is filtered faster than the rate at which the lymphatics can remove it, and pulmonary oedema results. This sequence cannot be quite the full explanation: a rise in pressure (including left ventricular filling pressure) can only arise from

Fig. 16.5.2.2  The Frank–​Starling relation. As preload increases, so does cardiac output. In the failing ventricle, the relation is shifted to the right so that to deliver any given cardiac output, the ventricle requires a higher filling pressure.

an input of energy. In acute pulmonary oedema, the energy for the rise in left ventricular pressure can only come from the right heart. When the left ventricle fails, there is a fall in left ventricular stroke volume and consequent mismatch between left and right ventricular stroke volumes. The higher right ventricular stroke volume causes the increase in left ventricular filling pressure and restoration of cardiac output, but an inevitable consequence is some accumulation of fluid in the pulmonary circulation. The greater the fall in stroke volume of the left in relation to the right ventricle, the higher the left ventricular filling pressure will be and the greater the pulmonary fluid volume. Note that the total amount of fluid in the body does not increase and the effect is brought about by fluid moving to the ‘wrong’ body compartment. The fluid extravasation into the alveoli results in a reduction in blood volume during acute pulmonary oedema, which then increases back to normal levels during successful treatment. The fluid accumulation in the lungs starts with peribronchial swelling/​oedema, followed by distension of the alveolar walls; only then does fluid enter the alveoli, initially at the alveolar angles, and eventually flooding the alveoli. The accumulation starts at the lung bases as the hydrostatic pressure is greatest here.

Clinical presentation

Fig. 16.5.2.1  The forces acting on fluid in a pulmonary capillary.

Acute pulmonary oedema is a dramatic medical emergency. The typical patient presents with very severe shortness of breath that has developed abruptly over minutes or hours. He or she has to sit upright (and might indeed die if forced to lie flat) and may be unable to speak or gasp only a few words. Patients are usually very frightened and often certain that they are dying. Coughing may be prominent and will often produce blood-​tinged oedema fluid. There may be some clues in the history as to the precipitant of pulmonary oedema. Sympathetic nervous system activation usually results in a tachycardia and a rise in blood pressure; the skin is white, cold, and clammy. The patient usually exhibits central cyanosis. Heart sounds may be inaudible but a gallop rhythm is common. The lung fields

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Patient with suspected AHF

Urgent phase after first medical contact

1. Cardiogenic shock? Yes

Circulatory support • pharmacological • mechanical

No 2. Respiratory failure?

Yes

No

Ventilatory support • oxygen • noninvasive positive pressure ventilation (CPAP, BiPAP) • mechanical ventilation

Immediate stabilization and transfer to ICU/CCU

Immediate phase (initial 60–120 minutes) Identification of acute aetiology: C acute Coronary syndrome H Hypertension emergency A Arrhythmia M acute Mechanical cause’ P Pulmonary embolism No

Yes

Immediate initiation of specific treatment

Follow detailed recommendations in the specific ESC Guidelines

Diagnostic work-up to confirm AHF Clinical evaluation to select optimal management

Fig. 16.5.2.3  The treatment algorithm recommended by the European Society of Cardiology. Note that investigations and active management have to be undertaken simultaneously. From Ponikowski P, et al. (2016). 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Eur Heart J, 37(27), 2129–​200.

are usually filled with crackles and sometimes wheezes (so-​called ‘cardiac asthma’). Given how sick the patient with pulmonary oedema is, the initial investigations and management have to be carried out at speed. The ESC guidelines for the management of acute heart failure emphasize the need to investigate and treat simultaneously (Fig. 16.5.2.3). There are three strands: making the diagnosis, identifying the immediate precipitant, and initiating treatment. Identifying precipitating factors is particularly important as it will influence subsequent management (see Table 16.5.2.2).

Initial investigation A 12-​lead electrocardiogram (ECG) will often show grossly abnormal QRS complexes, including evidence of acute myocardial

infarction, or abnormal heart rhythm, including atrial fibrillation with a rapid ventricular response and ventricular tachycardia (see Fig. 16.5.2.4). A chest radiograph gives vital information. At early stages in the development of pulmonary oedema, the patient may have septal (or Kerley B) lines (Fig. 16.5.2.5), fluid in the lung fissures, and pleural effusions. There is peribronchial cuffing and upper lobe blood diversion. As oedema worsens, confluent shadows spreading out from the hila develop (Fig. 16.5.2.6). Near-​ patient testing for cardiac markers is becoming more widely available. Natriuretic peptide measurement can be helpful in making the diagnosis where there is clinical uncertainty: a patient with a normal natriuretic peptide level is extremely unlikely to have heart failure. A raised troponin suggests that there might be an acute

16.5.2  Acute cardiac failure

Table 16.5.2.2  Common precipitants of acute pulmonary oedema, helpful investigations, and possible immediate treatment options. ECG is electrocardiogram; CXR is chest X-​ray; (N)STEMI is (non) ST elevation myocardial infarction Precipitant

Examples

Investigation

Immediate management

Acute ischaemia

STEMI NSTEMI

ECG, troponina

Immediate cardiology review

Arrhythmia

Atrial fibrillation Ventricular tachycardia

ECG

DC cardioversion

Mechanical disaster

Rupture of: interventricular septum Mitral papillary muscle Sinus of Valsalva

Echocardiogram

Cardiac surgery

Hypertensive crisis

Renal artery stenosis Salt load

During recovery

Vasodilators

Intercurrent illness

Pneumonia Urinary infection Sepsis

CXR, septic screen

As appropriate

CT pulmonary angiogram

Thrombolysis, anticoagulation

History

Education

Pulmonary embolus Environment a

Lack of compliance with medication/​diet High salt intake

often elevated in acute or chronic heart failure in the absence of any other evidence of ACS. An elevated troponin in patients with heart failure is a bad prognostic sign.

coronary syndrome (ACS) in progress, but troponin is commonly raised in acute heart failure even in the absence of ACS. A full blood count, biochemical screen, and thyroid function are important investigations. Anaemia is common, often due to iron deficiency but exacerbated by plasma volume expansion. Glucose is very commonly raised due to the high sympathetic drive, and does not necessarily mean that diabetes is present. Other appropriate investigations may include CT pulmonary angiography and a septic screen. Echocardiographic assessment early in the course of admission is very useful in confirming the cause of presentation and guiding subsequent therapy.

The lowest dose of oxygen needed to restore normal oxygenation should be used. Care should be taken in patients with chronic airways disease who are at risk of developing CO2 retention (which may be exacerbated by the use of opiates). In a patient who is tiring or whose gas exchange is worsening despite treatment, positive pressure ventilation provides immediate relief. Non​invasive ventilation should be tried first: there is good evidence that both continuous positive airway pressure ventilation and bilevel positive airway pressure ventilation are safe.

Management

Medical treatment

Patients with acute pulmonary oedema should be managed in a high-​dependency unit. Whether this should be cardiac care or a unit where intubation and ventilation is available will depend upon the degree of respiratory distress.

Opiates are commonly prescribed to relieve the distress of acute pulmonary oedema, but there is no evidence that they are safe and some data suggest that their use is associated with adverse outcomes. They should be used cautiously, if at all.

Ventilatory support

Fig. 16.5.2.4  A 12-​lead electrocardiogram from a 76-​year-​old man presenting with acute pulmonary oedema. His ventricular tachycardia had been precipitated by an acute coronary syndrome.

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Vasodilators

Fig. 16.5.2.5  A plain postero-​anterior chest X-​ray in a breathless patient showing Kerley B lines–​multiple short horizontal lines visible towards the lung peripheries. There are also small pleural effusions.

Diuretics Diuretics are almost universally used in patients with acute pulmonary oedema, although trials to prove efficacy are lacking. As patients are usually not fluid overloaded, diuretics may not be the most logical therapy, although by reducing circulating volume, they do reduce filling pressure and relieve oedema. There is a firmly held view that furosemide is a vasodilator, but its haemodynamic effects coincide with the onset of diuresis.

Nitrovasodilators are a more logical approach to the treatment of pulmonary oedema. They reduce both preload and afterload, as well as helping to relieve any myocardial ischaemia. Small studies suggest that nitrates may be more helpful than diuretics, but the evidence is not definitive, and clinical surveys suggest that they are used in few patients. The National Institute for Health and Care Excellence (NICE) guideline does not recommend their routine use. Other vasodilators have been tried. Despite early promise (and, indeed, licensing in some countries), nesiritide (human recombinant B-​type natriuretic peptide) had no effect on outcome in a large trial, and no patient subset obtained a striking benefit. Serelaxin (human recombinant relaxin, a vasoactive peptide produced in pregnancy) was again promising, but a definitive trial, RELAX-​AHF-​2, was again neutral. In TRUE-​AHF, patients with acute heart failure were randomized to receive either ularitide (another natriuretic hormone) or placebo, and the results were again neutral both for longer term cardiovascular mortality and for short-​ term symptom relief. Patient selection is part of the reason for the neutral studies of vasodilators. By the time a patient has been through the processes required for study entry, several hours have typically passed since presentation and the worst may by then be over. Severely ill patients may be excluded as not being able to consent, and most studies exclude patients with many of the precipitants of acute pulmonary oedema, such as acute myocardial infarction. Indeed, it can be difficult to tell who, precisely, the criteria for the trials are targeting for inclusion. They usually appear to be trying to recruit patients with pulmonary oedema, who perhaps may have most to gain from a vasodilator, but in are in practice predominantly recruiting those with fluid retention, and if a patient is not breathless at rest, then a treatment targeting breathlessness is unlikely to be helpful. Inotropes Inotropic support is often used, particularly as a ‘last ditch’ attempt to help very sick patients, more in despair than hope. Such evidence as there is from randomized trials suggests that all positive inotropic drugs working through adrenergic pathways are associated with an adverse outcome. Investigational approaches include cardiac myosin activators and inhibitors of sarcoplasmic calcium re-​uptake. Mechanical support In selected patients, there may be a role for intra-​aortic balloon pumping to buy time, particularly when there is a potentially reversible cause for the pulmonary oedema. Similarly, a left ventricular assist device and extracorporeal membrane oxygenators may have a role when there is a potential either for recovery or for heart transplantation.

Prognosis

Fig. 16.5.2.6  More severe pulmonary oedema on supine antero-​ posterior film showing confluent shadowing spreading out from the hila. Note the relatively small heart shadow suggesting that this is an acute event in a previously normal heart.

The clinical course of acute pulmonary oedema is usually very brisk: the patient usually recovers rapidly after treatment, or deteriorates rapidly and dies. Overall, in-​hospital mortality is around 15%, but strongly age-​related; it is less than 10% in those aged less than 65  years and much higher in those aged more than 85  years, but these figures do not include those dying before reaching hospital.

16.5.2  Acute cardiac failure

The recovery from pulmonary oedema is in part an active process in which cells take up fluid and return it to the capillary or lymphatic circulation. Novel agents designed to enhance this process are being developed.

Cardiogenic anasarca Pathophysiology At the other end of the scale from pulmonary oedema are patients with fluid retention. Two processes result in oedema: the retention of sodium and water, and the transfer of fluid into the tissues. To take the second first: fluid collects in the tissues as a consequence of a rise in intravascular hydrostatic pressure or fall in osmotic pressure. As with the lungs, there is continuous filtration of fluid from the capillaries to the tissues: if extravasation exceeds lymphatic drainage, oedema develops. The effect of gravity means that the hydrostatic pressure is highest in the feet, so ankle swelling is usually the first sign of fluid retention. In a patient confined to bed, though, the fluid will collect around the sacrum. The reasons why the body retains water are less certain. Sodium and water are retained by the kidneys, presumably in response to decreased renal perfusion or deviation from the kidney’s set-​point for renal perfusion pressure (i.e. the blood pressure the kidney ‘wants’). The consequence is renin production by the juxtaglomerular apparatus leading to conversion of angiotensinogen to angiotensin I and ultimately to aldosterone production, which in turn causes salt and water retention by the kidney. In addition, antidiuretic hormone (or arginine vasopressin) is released in increased quantities, stimulating fluid retention and, importantly, thirst, and thus greater fluid intake. However, antagonists of each of these systems, even when used in combination, do not seem sufficient to prevent salt and water retention and do not obviate the need for diuretics, although they might reduce the dose required. The stimulus leading to neuroendocrine activation is not clear. A common assumption is that it is a fall in blood pressure due to the failing heart. The body responds in the same way as it would to any other cause of a fall in blood pressure, such as dehydration or haemorrhage, with avid salt and water retention to maintain blood pressure. Although some patients have a normal or high blood pressure compared to healthy people, this blood pressure may be below their individual set-​point. If the set-​point could be changed, then perhaps salt and water retention would not occur.

have had to loosen my belt’ or ‘I have increased a waist size’ in a patient with increasing breathlessness should alert the clinician to the possibility of oedema. The oedema is usually very obvious on examination. Cardiogenic oedema is pitting. The highest level of pitting oedema should be sought. The jugular venous pressure will be raised: however, when it is very high, the top of the column of the blood may not be visible in the neck, even with the patient sitting upright. There is usually a tachycardia and often hypotension. The apex beat is displaced and dyskinetic and there is almost always a third sound or gallop rhythm. Mitral regurgitation is very common. There are commonly signs of ascites and pleural effusions, with basal crackles in some patients who have pulmonary congestion.

Differential diagnosis It is important to consider the differential diagnosis of peripheral oedema (Table 16.5.2.3). Once a firm diagnosis of cardiogenic oedema is made, the next step is to consider the possible causes of the ‘right heart’ failure. Although the commonest cause is left heart failure, other cardiac conditions, particularly constrictive pericarditis, can result in severe fluid overload and be difficult to diagnose (see Table 16.5.2.4). Pulmonary hypertension leading to right ventricular dysfunction appears increasingly common in frail elderly patients with right heart failure, many of whom also have lung and left heart disease.

Initial investigations Patients presenting with anasarca should be investigated as patients presenting with chronic heart failure (see Chapter 16.5.3) with the aim of making the diagnosis, unmasking any treatable cause, and identifying any associated comorbidities. • Common ECG abnormalities include previous myocardial infarction, left bundle branch block, atrial fibrillation. • A chest radiograph will show a large heart shadow and evidence of pulmonary venous congestion. It may also exclude other causes of breathlessness. • Urinary dipstick testing will help pick up infection and gross proteinuria. • Anaemia is common in anasarca due to heart failure. Patients may benefit from an iron infusion should they have iron deficiency. • Renal dysfunction and electrolyte abnormalities are common in patients with heart failure and are major determinants of outcome. Regular testing during treatment (see next) is vital.

Clinical presentation The typical picture is of a patient with gradual weight gain, often in the context of previous coronary disease, hypertension, atrial fibrillation, and CKD. Around 5 litres of fluid (weighing 5 kg) are needed before oedema first appears. As the process is often very gradual, patients will often present only once they have retained many litres of fluid and have pitting oedema affecting the abdominal wall, and sometimes even the thoracic wall. Pleural and pericardial effusions and ascites are common in this situation. In some patients, the oedema causes obvious ballooning of the ankles. However, in many patients the oedema does not grossly distort the shape of the leg, and oedema of the trunk may develop and go unobserved by the patient or a careless doctor. Symptoms such as ‘I can’t get my shoes on’ or ‘I

Table 16.5.2.3  Differential diagnosis of peripheral oedema. Note that anasarca is easily overlooked without careful examination Oedema fluid

Cardiogenic Hypoalbuminaemia

Fluid overload

Pregnancy

Lymphatic obstruction

Idiopathic

Medicines

Dihydropyridines/​glitazones

Venous insufficiency

Varicose veins Previous DVT

Chronic stasis Fat

(Obesity)

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Table 16.5.2.4  Differential diagnosis of cardiogenic peripheral oedema Possible cause

Examples

Raised left atrial pressure (left heart failure)

Impaired left ventricular  Contraction  Ischaemic heart disease (IHD)  Dilated cardiomyopathy  Relaxation  Left ventricular hypertrophy (hypertension)  Hypertrophic cardiomyopathy  Amyloid Mitral valve disease

Raised right atrial pressure (right heart failure)

Chronic left atrial hypertension Pulmonary hypertension IHD Tricuspid valve disease (often tricuspid regurgitation due to dilated right ventricle) Right ventricular cardiomyopathy

Congenital heart disease

Left-​to-​right  shunts Right ventricle in systemic position

Pulmonary hypertension

Chronic left atrial hypertension Lung disease (cor pulmonale) Thromboembolic disease

Pericardial disease

Constrictive pericarditis

• Natriuretic peptide levels are usually grossly raised. • An echocardiogram is essential (see Fig. 16.5.2.7). The key elements to look at are: ■ Left atrial size—​mitral valve disease or chronic elevation in left ventricular filling pressure will cause left atrial dilation. It is probably the best guide to the chronic health of the left heart but may not be enlarged with severe acute-​onset disease. ■ Left ventricular size and contractility—​the left ventricle is commonly dilated with reduced systolic function but sometimes small, hypertrophied, and ‘stiff ’. Regional wall motion abnormalities suggest a possible underlying diagnosis of ischaemic heart disease. ■ Valve disease. • More sophisticated investigation may reveal pulmonary hypertension, right ventricular disease, and dilated venae cavae.

Ultrasound can also be used to identify ‘lung comets’ indicating pulmonary congestion.

Management The problem is one of an absolute excess of fluid, and initial management is directed at fluid removal. General care is important: the patient should be managed with bed rest with prophylactic low molecular weight heparin used to reduce the (high) risk of venous thrombosis. The only way to monitor progress accurately is with strict fluid balance monitoring and daily weights. The urea and electrolytes should be measured at least daily, and the patient should be reviewed daily by an experienced member of the team. Oedema is due to retention of water, not salt: in 1 litre of oedema fluid, there are 991 g of water and 9 g of salt. There is no good evidence that sodium restriction is useful, although restricting a very high intake may be useful in the occasional patient. Salt restriction may lead to hyponatraemia. Aquaresis may be greater (and hyponatraemia less likely) when moderate salt intake is allowed. Fluid intake is often restricted to around 1.5 litres per day, but the evidence for this is weak. The aim should be to try and induce a net diuresis of around 2 litres per day. Diuretic management is key. Diuretics work by preventing the reabsorption of some of the filtered sodium from the tubular lumen. • Loop diuretics block the sodium–​potassium–​chloride cotransporter in the thick ascending loop of Henle. As they reach their site of action from the lumen of the nephron, they only work if there is at least some glomerular function. Once their effects are over, the kidney goes into overdrive to restore the lost salt and water. • Thiazide diuretics work at the distal convoluted tubule. They induce a small but persistent diuresis; over a 24-​hour period loop and thiazide diuretics may have the same natriuretic effect. • Mineralocorticoid receptor antagonists block the effects of aldosterone at the sodium–​potassium exchanger in the distal convoluted tubule, resulting in potassium retention. A typical approach is to use intravenous loop diuretic. Oral absorption is very erratic in patients with cardiogenic oedema because of bowel oedema. An infusion of 10 mg per hour of furosemide is

Fig. 16.5.2.7  Echocardiogram of a patient presenting with anasarca. Long axis parasternal view. The left ventricular internal diameter is approximately 8 cm, and there is little difference between systolic and diastolic frames.

16.5.2  Acute cardiac failure

often used. Data from small studies suggests that an infusion causes a greater natriuresis than repeated boluses to the same dose, but the biggest study of infusion versus bolus dosing showed no difference between the two strategies. Particularly after chronic loop diuretic usage, the cells of the distal convoluted tubule hypertrophy and increase their capacity to reabsorb sodium. The addition of a thiazide will block the distal convoluted tubule (so-​ called ‘progressive nephron blockade’) which may lead to a profound diuresis. Metolazone is often used for this purpose although there is no convincing evidence that it is more potent than other thiazides. Combination therapy can be very helpful, but patients having the two diuretics must be monitored very closely. Potentially nephrotoxic drugs, such as non​ steroidal anti-​ inflammatory drugs (including aspirin) should be stopped. It is not certain whether pre-​existing β-​blocker (or angiotensin-​converting enzyme inhibitor or ACE) therapy should be stopped: the evidence available suggests that those patients whose pre-​existing therapy is not stopped are less likely to be discharged without these life-​saving treatments. Towards the end of intravenous therapy, ACE inhibitors and β-​blockers should be started simultaneously at low doses. If not already being used, a mineralocorticoid (aldosterone) receptor antagonist (MRA) should also be started (see Fig. 16.5.2.8). The dose of ACE inhibitor should be titrated rapidly to target with careful monitoring of blood pressure and renal function. β-​Blockers are titrated more slowly and often only after discharge. Intravenous diuretic therapy should be continued until the oedema has resolved unless an oral diuretic regimen is clearly having the desired results. It is not uncommon for renal function to improve following diuresis and diuretic therapy should not be withheld or reduced in patients with impaired renal function at the time of presentation where there is clear evidence of fluid overload. For some patients, however, complete resolution of oedema cannot be achieved due to worsening renal impairment and a balance has to be struck between some peripheral oedema and a raised creatinine. Ideally, a patient finishing intravenous therapy will be monitored for 48 h to make sure that the fluid does not re-​accumulate immediately. Some patients may fail to respond adequately to intravenous diuretics. It is important to reconsider the diagnosis: has constrictive pericarditis been missed? Is there some correctable cause of renal dysfunction, such as renal artery stenosis?

Fig. 16.5.2.8  Time course of diuresis for a patient presenting with approximately 25 litres of anasarca. Note the brisk response once the furosemide infusion was started, and the timing of introduction of long-​ term medication. ACEi is angiotensin-​converting enzyme inhibitor and βB is beta adrenoceptor antagonist.

Other therapeutic options include the use of digoxin, which has a diuretic effect, although the evidence base for its use in acute heart failure is poor. Positive inotropic drugs, particularly in hypotensive patients, are sometimes used. There is no evidence to support the practice, and no evidence that ‘renal dose dopamine’ has anything to offer. Ultrafiltration can be used to remove fluid rapidly from patients with anasarca (see Table 16.5.2.5). Veno-​venous filtration is possible in a cardiac care unit setting with small devices. There is conflicting evidence as to its value: in one study, its use was associated with a reduction in the need for subsequent emergency care, but in patients with worsening renal function, a second study suggested that ultrafiltration was associated with a higher creatinine, although this finding may simply have reflected haemoconcentration. The most recent study was terminated early by the sponsoring company: although the primary endpoint was not met, several of the secondary endpoints suggested a benefit for ultrafiltration. The role of ultrafiltration in routine practice is still uncertain, but there is no doubt that as much as 5 litres can safely be removed from a patient in 24 h, and it is useful in selected patients who are unresponsive to combined diuretic therapy or when diuresis is limited by renal dysfunction (Fig. 16.5.2.9).

Table 16.5.2.5  Diuretics commonly used in the management of anasarca. DCT is distal, and PCT, proximal, convoluted tubule. MRA is mineralocorticoid antagonist Class

Example

Route

Site of action

Comments

Loop

Furosemide, bumetanide

Intravenously

Na+/​K+/​Cl–​cotransporter in thick ascending loop of Henle

High ceiling; short duration of action

Shorter half-​life than thiazides

Thiazide

Bendroflumethiazide

By mouth

DCT

Low ceiling; longer period of action

Combined with loop may cause profound diuresis

‘Thiazide-​like’

Metolazone

By mouth

DCT (and PCT)

Combined with loop may cause profound diuresis

MRA

Spironolactone, eplerenone

By mouth

DCT–​Mineralocorticoid receptor antagonists

Essential component of long-​term management

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pulmonary capillary wedge pressure and hence confirm adequate filling. There is no evidence that using the catheter to guide further management is helpful. An ECG with right-​sided leads will help make the diagnosis of a predominantly right-​sided myocardial infarct. An echocardiogram to confirm the extent of left and right ventricular damage and to exclude a mechanical problem (free wall rupture, papillary muscle rupture, ventricular septal rupture) is a vital early investigation. Bladder catheterization will confirm that the patient is genuinely oliguric rather than confused due to retention of urine. Sepsis should be excluded.

Management

Fig. 16.5.2.9  A patient receiving ultrafiltration. There is a two-​lumen right internal jugular venous line from which blood is continuously removed, pumped through a filter (black arrow) and then returned to the body. Filtrate is seen collecting in the bag (white arrow).

Cardiogenic shock Shock occurs when there is tissue hypoperfusion despite adequate ventricular filling. There is no blood pressure level that can be used to define shock, with the consequence that the incidence and prognosis quoted varies from study to study.

Pathophysiology Cardiogenic shock most commonly arises from an acute myocardial insult which results in sufficient reduction in cardiac output that the perfusion to vital organs is insufficient to maintain organ function. By far the commonest cause is acute myocardial infarction, although patients with acute presentation of cardiomyopathy, including peripartum cardiomyopathy, may develop shock. The result is massive sympathetic nervous system activation as the body tries to restore blood pressure. The consequent increase in afterload cannot be met by the failing left ventricle. Reduced coronary artery perfusion results in worsening myocardial function, perpetuating the problem.

Clinical presentation The patient is hypotensive, usually tachycardic, pale, and sweaty. Reduced cerebral perfusion results in confusion and agitation, and the patient becomes oliguric or anuric. Except for those patients with predominant right ventricular infarction, some degree of pulmonary oedema is invariably present.

Differential diagnosis and investigations Making the correct diagnosis is fundamental: investigations should be directed at finding any reversible cause for the patient’s state. Making certain that the left ventricle is adequately filled is essential to make the diagnosis of shock:  if the left ventricle is underfilled, then fluid replacement should result in rapid resolution of symptoms. If there is doubt, then fluid challenges with rapid infusion of 100–​200 ml fluid can be helpful. In some cases, pulmonary artery catheterization is used to determine the

Dealing with any treatable cause of shock is the most important step. Revascularization in patients presenting with acute myocardial infarction may relieve shock, although if shock develops following or despite a successful procedure, the outlook is particularly poor. Patients with mechanical problems tend to have smaller and more localized infarctions than those without: although it is very high risk, early surgery may be life-​saving. For those patients with right ventricular infarction as the cause, fluid loading may improve the patient’s condition, but at a cost of high central venous pressure. Trying to sustain the circulation in patients with no readily reversible cause is rarely successful. • Positive inotropic drugs, such as catecholamines and phosphodiesterase inhibitors, may improve cardiac output and blood pressure: however, their use has not been shown to improve prognosis. Indeed, dobutamine in randomized trials is associated with a worse outcome. • Intra-​aortic balloon counterpulsation (IABP) can improve the situation, at least temporarily. Trial evidence suggests that the IABP does not improve prognosis in patients with cardiogenic shock due to acute infarction, but it can certainly help patients with acute mechanical causes such as septal rupture and mitral regurgitation. In some patients with potentially reversible causes, such as peripartum cardiomyopathy, IABP has been used successfully to sustain the circulation for many weeks. • Advanced therapies with ventricular assist devices (VADs), extracorporeal membrane oxygenation (ECMO), and even heart transplantation have been successful in selected patients. VADs and ECMO are only available in the United Kingdom in transplant centres, but there is a move to make them more widely available as a temporizing measure before patients are transferred to the centres. The prognosis of cardiogenic shock is bleak. Unless there is a readily correctable cause, the mortality rate approaches 60% at 30 days. Once treatable causes of shock have been excluded, conservative management and an easy death may be preferred rather than transfer to the intensive care unit for valiant, desperate, protracted, but ultimately futile, intervention.

FURTHER READING Chen HH, et  al. for the NHLBI Heart Failure Clinical Research Network (2013). Low-​dose dopamine or low-​dose nesiritide in acute heart failure with renal dysfunction:  the ROSE acute heart failure randomized trial. JAMA, 310, 2533–​43. Clark AL, Cleland JG (2013). Causes and treatment of oedema in patients with heart failure. Nat Rev Cardiol, 10, 156–​70.

16.5.3  Chronic heart failure

Costanzo MR, et  al. (2017). Extracorporeal ultrafiltration for fluid overload in heart failure:  current status and prospects for further research. J Am Coll Cardiol, 69, 2428–​45. Gray A, et al. 3CPO Trialists (2008). Noninvasive ventilation in acute cardiogenic pulmonary edema. N Engl J Med, 359, 142–​51. Harris P (1983). Evolution and the cardiac patient. Cardiovasc Res, 17, 313–​19, 373–​8, 437–​45. MacIver DH, Clark AL (2015). The vital role of the right ventricle in the pathogenesis of acute pulmonary edema. Am J Cardiol, 115, 992–​1000. MacIver DH, Dayer MJ, Harrison AJ (2013). A general theory of acute and chronic heart failure. Int J Cardiol, 165,  25–​34. National Institute for Health and Care Excellence (2014). Acute heart failure: diagnosis and management. Clinical guideline. https://​nice. org.uk/​guidance/​cg187 Ponikowski P, et al. (2016). 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J, 37, 2129–​200. Tharmaratnam D, Nolan J, Jain A (2013). Management of cardio­genic shock complicating acute coronary syndromes. Heart, 99, 1614–​23. Thiele H, et al. IABP-​SHOCK II Trial Investigators (2012). Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med, 367, 1287–​96.

16.5.3  Chronic heart failure: Definitions, investigation, and management John G.F. Cleland and Andrew L. Clark ESSENTIALS Heart failure is a common clinical syndrome, predominantly a disease of older people, often presenting with breathlessness, fatigue, and peripheral oedema. Its pathophysiology is complex, with a common feature being salt and water retention, possibly triggered by a relative fall in renal perfusion pressure. Common aetiologies include ischaemic heart disease, hypertension, and valvular heart disease. New treatments have improved prognosis substantially over the past two decades. Early diagnosis relies on a low threshold of suspicion and screening of people at risk. Low plasma concentrations of BNP/​NT-​ proBNP exclude most forms of heart failure, and intermediate or high concentrations should prompt referral for echocardiography to identify possible causes and determine the left ventricular ejection fraction (LVEF), leading to classification as heart failure with reduced LVEF (50%, HFnEF), or borderline LVEF (40–​50%, HFbEF). HFbEF and HFnEF are managed similarly by current guidelines. Treatable causes for heart failure (e.g. valvular disease, tachyar­ rhythmias, thyrotoxicosis, anaemia, or hypertension) should be identified and corrected. Pharmacological therapy is given to improve

symptoms and prognosis. Diuretic therapy is the mainstay for control of congestion and symptoms, but its effect on long-​term prognosis is unknown. For patients with HFrEF, either angiotensin-​converting enzyme inhibitors, angiotensin receptor blockers, or angiotensin receptor–​ neprilysin inhibitors, combined with β-​ blockers and mineralocorticoid receptor antagonists (triple therapy) provide both symptomatic and prognostic benefit. Other treatments that may be appropriate in particular cases include ivabradine, digoxin, cardiac resynchronization therapy, and implantable defibrillators. Heart transplantation or assist devices may be options for highly selected patients with end-​stage heart failure; many others may benefit from palliative care services.

Introduction Heart failure is the most common malignant disease in the United Kingdom. Heart failure in its various manifestations now causes or complicates twice as many hospital admissions (about half a million deaths and discharges each year in the United Kingdom) as do all cancers or acute coronary syndromes combined. This is likely to be a gross underestimate of total activity as the diagnosis of heart failure is often missed or ignored during admission. In the community, heart failure syndromes are almost as common as diabetes mellitus and far more deadly. For some cardiac phenotypes (e.g. left ventricular systolic dysfunction), treatment is often highly effective and may even be curative, but diagnostic awareness is low and care, when given, is often fragmented and disorganized. The reasons for the current clinical neglect of heart failure are not entirely clear but may reflect the lack of a robust definition, the difficulty and uncertainties of its clinical diagnosis, the relative complexity of its treatment, all combined with ageism and fatalism on the part of both the clinician and patient.

Definition No consensus has been reached on a simple, practical universal definition of heart failure. Indeed, it may be better to consider the diagnosis of heart failure across a spectrum of certainty based on clinical acumen supported by blood tests (particularly natriuretic peptides) and cardiac imaging. Until now, most experts and guidelines have required that the patient should have symptoms before a diagnostic label of heart failure is applied. Of course, a sedentary lifestyle and liberal use of diuretics may mask symptoms. Simply asking the patient to take a walk will often reveal how poor their effort tolerance is, and stopping diuretics will often lead to the diagnosis becoming obvious. Other specialties use biochemical definitions to define organ failure (kidney, pancreas, liver). Central to the concept of heart failure is congestion, indicating that the heart is unable to sustain a normal filling (atrial) pressure for the required cardiac output. Cardiac output is usually fairly normal at rest until the late stages of heart failure. How then should congestion be measured? Natriuretic peptides, hormones that are secreted by the stressed heart and designed to counter sodium retention, provide a simple objective method of detecting congestion, even before it becomes clinically overt (Fig. 16.5.3.1). Thus, heart failure could be considered cardiac dysfunction leading to an increase in natriuretic peptides. Natriuretic

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suggesting that the diagnosis is usually missed until the problem is bad enough to provoke severe symptoms. The onset of symptomatic heart failure may well be precipitated by an acute event, but usually on a background of chronic cardiac dysfunction. Earlier diagnosis will increase identification in the community before the onset of severe symptoms and at a time when therapy might be more effective.

Clinical physiology

Fig. 16.5.3.1  Natriuretic peptides are the earliest and most sensitive sign of congestion but do not distinguish between cardiac and renal causes. Cardiac imaging is less sensitive and accurate (i.e. abnormal cardiac function may not cause congestion) for detecting congestion but, along with tests for heart rhythm and renal function, it helps to determine the cause of congestion. Symptoms and signs are late manifestations of congestion and usually only first detected when they have deteriorated sufficiently to precipitate a hospital admission.

peptides are now an essential tool for the early detection and confirmation of a diagnosis of heart failure in any modern health service. Broadening the definition of heart failure has many consequences, the most obvious being a great increase in the number of patients. About 3% of the adult population is taking loop diuretics for no obvious reason other than symptoms or signs suggestive of heart failure. Currently, most cases of heart failure are diagnosed during a hospital admission,

Heart failure can be considered as a sequence of unfortunate events (Fig. 16.5.3.2), starting with cardiac (usually left ventricular) dysfunction leading to haemodynamic changes that are often initially subtle, including a rise in atrial pressures and a fall in blood pressure below the set-​point for renal sodium retention. This triggers activation of neuroendocrine systems such as the renin–​angiotensin–​ aldosterone and sympathetic nervous system in an attempt to restore blood pressure by vasoconstriction and blood volume expansion. This has long-​term deleterious effects on the heart. Fortunately, there is also activation of counter-​regulatory mechanisms, most notably the natriuretic peptides, which attempt to prevent sodium retention and delay the onset of symptomatic congestion. Eventually, counterregulatory systems are overwhelmed, and clinical evidence of congestion appears, manifest either as breathlessness (loosely related to left atrial pressure) or peripheral oedema (loosely related to right atrial pressure). The treatment of heart failure revolves around preventing or reversing congestion and avoiding sudden death due either to arrhythmias or vascular events, which can arise at any time.

Cardiac (imaging) phenotypes Cardiac phenotype is strongly linked to the aetiology of cardiac dysfunction and is a key determinant of management. For some cardiac phenotypes there is little evidence that treatment alters outcome.

Left ventricular dysfunction Mitral regurgitation Rise in left atrial pressure • At rest • During stress • Volume (fluid load, exercise) • Pressure (hypertension, exercise) • Pulmonary congestion • Breathlessness

• Pulmonary arteriolar hypertrophy & vasoconstriction • Pulmonary hypertension

• Right ventricular dysfunction • Tricuspid valve regurgitation • Rise in right atrial pressure • Peripheral congestion • Peripheral oedema

Fig. 16.5.3.2  Development and progression of heart failure.

16.5.3  Chronic heart failure

Table 16.5.3.1  Common cardiac phenotypes in heart failure HFrEF

HFbEF

HFpEF/​HFnEF

LVEF

50%

Ischaemic heart disease

XXX

XX

X

Hypertension

X

XX

XXX

Atrial fibrillation

XX

XX

XXX

Dilated cardiomyopathy

XXX

?

NA

Aortic stenosis

X

XX

XXX

Mitral regurgitation

XX

XX

XX

Number of crosses reflects strength of association (although not necessarily proportion affected or prevalence). HFrEF = heart failure with a reduced left ventricular ejection fraction. HFbEF = heart failure with a borderline left ventricular ejection fraction. HFpEF/​HFnEF = heart failure with a preserved or normal left ventricular ejection fraction.

Few patients have a single pure phenotype; most patients manifest several phenotypes, but usually one is dominant (Table 16.5.3.1). When heart failure is associated with a reduced left ventricular ejection fraction (LVEF) this is often termed HFrEF or left ventricular systolic dysfunction (LVSD). Patients with heart failure and a normal or preserved LVEF are termed HFnEF and HFpEF, respectively. Left ventricular diastolic dysfunction (LVDD) is a subset of HFnEF as it is possible to have HFnEF without LVDD (e.g. patients with isolated right ventricular dysfunction). Various authorities suggest different LVEF thresholds for defining HFnEF, with the cut-​off ranging from less than 40% to over 50%. Since echocardiographers usually refer to a LVEF of under 50% as LVSD the terminology is confusing, and some believe that patients with an LVEF of 40–​50% should be considered a separate group HFbEF (heart failure with a borderline LVEF), which seems a helpful concept. LVEF measured by conventional echocardiography is only accurate to within about 10%, although more advanced imaging techniques such as cardiac MRI (CMRI) may have greater precision. Each of the phenotypes is heterogeneous, particularly HFnEF (Fig. 16.5.3.3). HFrEF is the predominant cardiac phenotype in men

and patients aged less than 75 years and is often due to ischaemic heart disease. HFnEF is the predominant phenotype in older women and is often due to hypertension. In patients with HFrEF, it is important to consider to what extent contractile dysfunction is due to dysfunction of viable myocardium, which may be reversible, or to consolidated scar that is likely to be irreversible using existing technology. The relative contribution of extracellular matrix and fibrosis and impaired cardiac myocyte relaxation to HFnEF is uncertain, and the therapeutic target at the myocardial level is unclear. Heart failure due to valve disease may occur at any age, but degenerative valve disease is an increasingly common cause in older people.

Risk factors and aetiology The most important risk factor for heart failure is age. It is likely that everyone will develop heart failure if they live long enough. Biological rather than chronological age may account for the link between physical frailty and the risk of developing heart failure. Currently, one in five people is expected to develop heart failure before they die, which may be a gross underestimate given the diagnostic gap outlined earlier. The most important medical risk factors for developing heart failure are hypertension and ischaemic heart disease, and their combination may confer more than additive risk (Table 16.5.3.1). Both may go undetected and untreated for years; the onset of symptoms of heart failure may be the first time the patient seeks help. There is a wealth of evidence that hypertension, even when detected, is often poorly managed. Alarmingly, studies suggest that most myocardial infarctions, perhaps especially among older people, do not provoke symptoms sufficient for the person to seek immediate medical assistance. Good treatment of hypertension and other risk factors for coronary artery disease will undoubtedly delay the onset of disease. Poor lifestyle and inferior medical care probably account for the association between social deprivation and the onset of heart failure at an earlier age. Among patients aged under 50 years, cardiomyopathies and congenital heart disease account for a large proportion of heart failure.

Fig. 16.5.3.3  Heterogeneity of heart failure with normal left ventricular ejection fraction. Conceptually, the diagnosis of heart failure requires evidence of congestion: for example, elevated natriuretic peptides, evidence of a cardiac abnormality, and (retrospectively) an increased risk of cardiovascular events.

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Table 16.5.3.2  Some rarer causes of heart failure Causes

Comments

Phenotype and specific therapy

Amyloidosis

Due to plasma cell expansion/​myeloma (AL), transthyretin (ATTR) gene mutation or chronic infection/​inflammation (AA). TTR mutations may cause 10% of HFpEF in older people

Increased LV wall thickness, HFbEF, or HFpEF. Often atrioventricular conduction delay Poor prognosis for AL. Most patient die within a year of diagnosis. ATTR better prognosis. Specific therapies in discovery (e.g. tafamidis)

Haemochromatosis

High serum ferritin and transferrin saturation. Often diabetic. Affects c.0.05% of Northern Europeans

Haemosiderosis

Usually associated with multiple blood transfusions due to haemolytic or aplastic anaemia.

HFrEF or HFbEF. Often a restrictive picture Treat with phlebotomy and iron chelation therapy. Early detection important

Carcinoid syndrome

Caused by hepatic or more rarely pulmonary metastasis of serotonin secreting tumours

Tricuspid regurgitation and pulmonary stenosis leading to low output and peripheral congestion.

Sarcoid heart disease

Often associated with pulmonary disease

HFrEF or HFpEF. Arrhythmias and conduction defects common

Tachy-​cardiomyopathy

Ventricular rate usually persistently >150 bpm. Usually supraventricular but rarely ventricular tachycardia. Lower rates suggest that tachycardia is a consequence of heart failure

Dilated cardiomyopathy. Resolves usually within a few weeks when arrhythmia is corrected

Thyrotoxicosis

May be iodine/​amiodarone induced. Weight loss, tachycardia, and other features of thyroid hormone excess

High output

Phaeochromocytoma

Due to catecholamine secreting tumours—​usually adrenal

HFrEF. Care with the use of adrenergic antagonists. Requires surgical correction

Genetic DCM

More than a dozen genetic mutations, notably of the titin gene

HFrEF

Lamin A/​C gene mutation

Rare

HFbEF. Atrioventricular conduction defects, ventricular arrhythmias, and sudden death

Muscular dystrophy

Duchenne, Becker, and myotonic dystrophy

HFrEF often with conduction defects

Hypertrophic cardiomyopathy

May be genetic or sporadic

HFpEF or HFbEF

Left ventricular non​compaction

May be familial

HFrEF or HFbEF

Endomyocardial fibrosis

Usually a tropical disease possibly due to parasitic disease. Consider if eosinophilia

HFpEF or HFbEF. Restrictive defect

Iatrogenic

Cancer chemotherapy, radiation, calcium channel blockers, hypoglycaemic therapies

Anthracycline and radiation induced damage may be irreversible. May be HFrEF or HFpEF

Nutritional deficiency

Thiamine, iron, selenium

Rare unless severe deficiency

Peripartum Cardiomyopathy

Usually in last trimester or within a few weeks of delivery

May only be recognized when severe. Usually recovers if patient survives. May recur with further pregnancy

Myocarditis

May be viral, including HIV, or due to borrelia (Lyme disease) or trypanosomiasis (Chagas disease). Giant cell myocarditis has a particularly poor prognosis

HFrEF HIV—​often pulmonary hypertension Chagas disease—​arrhythmias Borrelia—​consider doxycycline Giant cell—​steroids?/​immunosuppression?

In patients aged over 50 years, ischaemic heart disease is the dominant cause of HFrEF and hypertension the dominant cause of HFnEF. There are many rare causes of heart failure (Table 16.5.3.2), but collectively these affect a substantial number of patients.

Diagnosis Most heart failure is first diagnosed at a late stage in the disease, subsequent to a hospital admission. This is unlikely to change until screening the population at risk with natriuretic peptides becomes routine. There are six diagnostic steps:

Step 1: Case ascertainment The first and most important step is suspecting that something might be wrong. The patient may complain of breathlessness, but this is a

late manifestation of disease in a sedentary population. By the time orthopnoea, paroxysmal nocturnal dyspnoea, or breathlessness on mild exertion have developed, the disease is far advanced. Walking with the patient at a brisk pace may well provoke symptoms but does not lend itself to the organization of conventional clinics in primary or secondary care. Ankle oedema due to rising systemic venous pressure is also a late manifestation of disease and carries low specificity. Symptoms and signs may be abolished by diuretic therapy, but there is concern that such treatment may accelerate the progression of disease by deleterious activation of neuroendocrine systems. Earlier detection of heart failure requires a provocative test of cardiac reserve (e.g. a corridor walking test) or identification of activated compensatory mechanisms (e.g. natriuretic peptides) in patients deemed at risk of heart failure by virtue of age or medical risk factors. Any patient prescribed a loop diuretic should be presumed to have heart failure until proven otherwise.

16.5.3  Chronic heart failure

Step 2: Proving that cardiac dysfunction and heart failure are present Once heart failure is suspected, objective evidence of cardiac dysfunction is required. Breathlessness and ankle swelling are not specific to heart failure. Signs of heart failure, such as jugular venous distension, are relatively specific but insensitive, often difficult to elicit, and not easily recorded in a way that convinces colleagues. Chest radiography is no longer regarded as essential. A normal chest radiograph is not uncommon in patients with heart failure, and radiographic cardiomegaly is frequently a spurious finding. The electrocardiogram (ECG) is almost universally abnormal in heart failure and if genuinely normal places the diagnosis in doubt. Until recently, echocardiography was considered the practical gold-​standard measure for cardiac dysfunction and focused almost exclusively on identifying valve disease and HFrEF. However, there is growing awareness of the limitations of echocardiography, especially when not interpreted by experts. Reproducibility of LVEF estimation is poor, and measurements of diastolic function are complex and often contradictory. Probably the best echocardiographic guide to cardiac dysfunction, at least when chronic, are atrial volumes. Natriuretic peptides provide a simple approach to diagnosis and are more closely associated with atrial volumes than many other measures of cardiac dysfunction. They are not only more sensitive than cardiac imaging but a better guide to the patient’s prognosis. Natriuretic peptides are also more specific than imaging when the question is ‘Does this patient have serious disease requiring further investigation?’ rather than ‘Does this patient have cardiac dysfunction?’ A normal plasma concentration of a natriuretic peptide in the absence of a diuretic effectively excludes heart failure with one uncommon exception—​constrictive pericarditis. Gross obesity is associated with somewhat lower plasma concentrations of natriuretic peptides and diuretics may reduce them as they improve congestion. The N-​terminal fragment of pro brain natriuretic peptide (NT-​proBNP) is stable for days in blood samples and therefore can be measured easily and inexpensively in primary or secondary care. Interpretation of results requires additional information. Atrial fibrillation and renal dysfunction are other common reasons for an increase in plasma natriuretic peptides concentrations. Clinical acumen supported by a measurement of natriuretic peptide is usually sufficient to make or refute a diagnosis of heart failure.

Step 3: Differential diagnosis If a patient has symptoms, merely excluding or diagnosing heart failure is not enough. Alternative causes of symptoms should be sought. The common differential diagnoses for breathlessness are lung disease, obesity, and being unfit, all of which may coexist with heart failure. Determining how much each is contributing to symptoms will help guide use of diuretics; dehydrating patients with lung disease is unlikely to make them better and may make them worse. Spirometry may help identify lung disease, but low values may reflect general frailty and poor technique rather than lung disease. Natriuretic peptides can help; a slim patient who is very breathless but only has moderately elevated NT-​proBNP is likely to have lung disease as the dominant pathology. Cardiopulmonary exercise

Table 16.5.3.3  Conditions masquerading as diastolic heart failure COPD/​Cor pulmonale (without RV dysfunction) Obesity-​hypoventilation syndrome Obstructive sleep apnoea Severe renal disease Anaemia Thyrotoxicosis Nephrotic syndrome Silent myocardial ischaemia Venous insufficiency Lymphatic obstruction

testing aids differential diagnosis but requires special equipment and expertise. Echocardiographic evidence of mild diastolic dysfunction is very common in elderly people and heart failure can be readily overdiagnosed. A diagnosis of HFnEF made on the isolated echocardiographic finding of diastolic dysfunction should always be regarded with caution, and only following exclusion of alternative pathology. Conditions that may masquerade as ‘diastolic heart failure’, either in isolation or in combination, are listed in Table 16.5.3.3.

Step 4: Cardiac phenotype and cause(s) of cardiac dysfunction Clinical acumen combined with natriuretic peptides may be enough to make a diagnosis of heart failure, but is a poor guide to cardiac phenotype. The workhorse of cardiac phenotyping is the echocardiogram. The echocardiogram provides an approximate guide to LVEF and therefore differentiates HFrEF from HFnEF, identifies abnormal heart valves, and quantifies atrial volumes. Of the many parameters of diastolic function, increased left atrial size is probably the simplest and most reliable, and is an important prognostic indicator regardless of baseline left ventricular function. For patients with HFrEF, the amount of myocardial scar is an important determinant of the response to treatment and is best assessed by CMRI. However, many heart failure services have little access to this investigation. Radionuclear imaging is an alternative. A diagnosis of coronary disease can usually be made based on the clinical history or, failing that, by CMRI, stress echo, or radionuclear imaging. In the absence of symptomatic angina there is no evidence that revascularization improves outcome in patients with chronic heart failure. The presence or absence of coronary disease should have little influence on the choice of pharmacological or device treatment, and there is no evidence that antiplatelet agents are safe or effective in this setting. Angiography should therefore be reserved for patients with limiting angina despite pharmacological therapy, and those presenting with heart failure in the context of an acute coronary syndrome. CT angiography can be used if it is felt necessary to exclude left main-​stem disease or that of another proximal coronary artery. There is little information to be gained from heart catheterization that cannot be obtained more pleasantly, safely and at lower cost by non​invasive methods, which may also supply information that an angiogram cannot.

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Table 16.5.3.4  Common problems (comorbidities) complicating the diagnosis and management of heart failure Problem

Comment

Obesity (and lack of fitness)

Alternative cause for breathlessness creating diagnostic uncertainty and problems with judging diuretic dose. Diuresis will not help breathlessness due to obesity. Obesity is consistently associated with a better prognosis in a broad spectrum of patients with cardiovascular disease, including heart failure.

Cachexia

Ominous sign in heart failure. Exclude cancerous malignant disease. If patient is a candidate for transplant or mechanical assist, consider urgent referral.

COPD

Alternative cause for breathlessness creating diagnostic uncertainty and problems with judging diuretic dose. Diuresis will not help breathlessness due to COPD. Patients with heart failure and COPD have a worse prognosis.

Atrial fibrillation

AF may cause heart failure and vice versa. Optimal ventricular rate control may be about 80 bpm at rest. Need for anticoagulation.

Ischaemic heart disease

Common cause of a reduced LVEF. Little evidence that revascularization improves prognosis. Coronary angiography only indicated if patient has angina. Ongoing research into revascularization of viable myocardium but randomized controlled trials neutral so far.

Hypertension

A sign that the left ventricle still has some reserve. Most treatments for heart failure reduce blood pressure, so in this context hypertension is a good sign!

Hypotension

Often limits amount of pharmacological treatment and is a poor prognostic sign. Cardiac resynchronization will increase systolic blood pressure in appropriately selected patients.

Anaemia

Often associated with iron deficiency although not always corrected by oral or even intravenous iron. Some anaemia is dilutional (plasma volume expansion) and some caused by renal dysfunction and deficient erythropoiesis. Folate and B12 deficiency are rarely important causes of anaemia in heart failure.

Diabetes mellitus

Indicates a worse prognosis, possibly because of associated renal problems. Treatment for diabetes may make heart failure worse. Optimal HbA1c in patients with heart failure being treated for diabetes may be around 7.5% (lower if ‘prediabetic’).

Chronic kidney disease

Often due to pre-​existing renal damage and exacerbated by hypotension and low renal blood flow. Often limits the doses of medication that can be given. Renal function is a powerful prognostic marker (more powerful than LVEF).

Stroke

Related mainly to pre-​existing hypertension, atherosclerosis, and atrial fibrillation.

Dementia

Age often brings deterioration in cognitive as well as cardiac function. Dementia reduces ability for self-​care and adherence to advice and medication. Worsening heart failure may impair cognitive function.

Aortic stenosis

Common in older people. Diuretics may reduce congestion and symptoms, but other medication may be of little help and may cause hypotension. Consider aortic valve surgery or transcutaneous procedure.

Mitral regurgitation

Common in all forms of heart failure. May improve with treatments that reduce ventricular volume, especially cardiac resynchronization. Patient selection for surgery often difficult. Transcutaneous repair may be considered.

Step 5: Comorbidity—​what other problems might exacerbate or complicate heart failure? Patients rarely only have heart failure. Identifying important cardiovascular and non​cardiovascular comorbidity provides additional therapeutic targets (Table 16.5.3.4).

Step 6: Diagnostic tests required to achieve therapeutic aims The therapeutic goals should first be defined. If it is palliative care, then only treatments designed to control symptoms are appropriate (this may include diuretics, ACE inhibitors, mineralocorticoid antagonists (MRA), cardiac resynchronization therapy, and possibly digoxin and intravenous iron). If the goal is to improve prognosis through ‘disease-​modifying’ interventions, then β-​blockers, ivabradine, and implantable cardiac defibrillators should be added to the list. Preventing patients with atrial fibrillation from developing the misery of a stroke might be considered appropriate regardless of other therapeutic aims. The small amount of information (10 items) routinely required to use these agents safely and effectively is shown in Table 16.5.3.5.

Prognosis The prognosis of heart failure depends on the clinical context. Incident heart failure is associated with a 30% mortality at 6 months.

The annual mortality of chronic stable patients is now probably less than 5% per annum, but admission to hospital with worsening heart failure has a mortality of about 10–​15%, with mortality in the 6 months after discharge from an admission being in the range of 15–​25%. Age is an important determinant of mortality, with the influence of treatments shown in Fig. 16.5.3.4. Readmission rates are also high; most patients with heart failure will be admitted at least once in a 3-​year period, and following a readmission, 15–​25% will have a further readmission within 30 days without expert support. Age is not such a good predictor of readmission, perhaps because older people have a higher mortality. A pragmatic prognostic scoring system for chronic heart failure can be found at http://​www.heartfailurerisk.org/​, and may be improved by some simple additional pieces of information, such as whether the patient has had a recent exacerbation of symptoms, the dose of diuretic, and plasma concentration of NT-​proBNP. Knowing prognosis can help with management, both in terms of advice to the patient and choice of therapy.

Management Modern management of patients with heart failure requires the coordinated input of a multidisciplinary team of dedicated cardiologists, specialist heart failure and rehabilitation nurses, primary care physicians, and palliative care specialists. The key to the successful

16.5.3  Chronic heart failure

management of these patients is prompt identification in the community and following admission to hospital, and access to follow-​up and management by a specialist team.

Lifestyle Patients with heart failure should be advised to lead a healthy lifestyle, avoiding smoking and excessive alcohol consumption, eating a balanced diet, and taking regular exercise (http://​www. heartfailurematters.org/​en_​GB). There is little evidence that such advice makes a difference to prognosis, but it probably improves well-​being. Attention to psychological health is important. Keeping socially active, taking holidays (with adequate health insurance; http://​www.bhf.org.uk/​heart-​health/​living-​with-​aheart-​condition/​ living-​with-​heart-​failure.aspx) and investing in hobbies and recreations are more important than pharmacological treatments for anxiety and depression that are, however, mostly safe. There is no evidence that complementary medicine can alter the course of heart failure but, provided the patient is not tempted to stop conventional therapy, it may provide them with psychological support. Patients should know what medication to take and be advised to have a system to ensure that they do so. Excessive dietary salt and fluid consumption should be avoided, but there is scant evidence that severe restriction of dietary salt is helpful and it might do harm. Fluid restriction (to 40%)

Loop diuretics

II-​IV

X

X

X

X

Symptomatic

Symptomatic

Symptomatic/​Prognostic

Symptomatic

Symptomatic/​Prognostic

?

AF

QRS

BNP

ACE/​ARB

II-​IV

X

X

X

ARNI

II-​IV

X

X

X

β-​Blocker

II-​IV

X

Prognostic

?

MRA

II-​IV

X

X

X

Symptomatic/​Prognostic (25% R wave) in at least two leads from II, III, aVF (in absence of left anterior hemiblock), V1–​V4; or I, aVL, V5–​V6

Deep S in V2 (>25 mm)

Clinical There are no clinical major criteria

Unexplained chest pain, dyspnoea, or syncope

LV, left ventricular; SAM, systolic anterior motion of the mitral valve. Reproduced from Heart, McKenna WJ, et al., 77, 130–​2. Copyright 1997 with permission from the BMJ Publishing Group Ltd.

Clinical features History Symptomatic presentation may be at any age with breathlessness on exertion, chest pain, palpitation, syncope, or sudden cardiac death. HCM is occasionally found at autopsy in a stillborn baby or presents during infancy with cardiac failure, which is usually fatal. In children and adolescents, the diagnosis is most often made during screening of siblings and offspring of affected family members. Paroxysmal symptoms or mild impairment of exercise tolerance are often present, but in the absence of a murmur, may not prompt cardiac evaluation. About 50% of adults present with symptoms; in the remainder the diagnosis is made during family screening or following the detection of an unsuspected abnormality on physical, electrocardiographic, or echocardiographic examination. Dyspnoea is common (>50%) as a consequence of elevated left atrial and pulmonary capillary wedge pressures resulting from impaired left ventricular relaxation and filling, and about 50% complain of chest pain, which is exertional, atypical, or both in similar proportions of patients. Atypical pain may have no obvious precipitant; more commonly it follows exercise-​or anxiety-​related tachycardia, when it persists for up to several hours after the stress has been removed without enzymatic evidence of myocardial damage. Syncopal episodes occur in 15 to 25%, but in only a few are there findings suggestive of an arrhythmia or evidence of overt conduction disease: in most patients, the mechanism cannot be determined. Patients rarely present with paroxysmal nocturnal dyspnoea, ascites, or peripheral oedema. Physical examination In most patients with hypertrophic cardiomyopathy the physical examination is unremarkable. There may be a rapid upstroke arterial pulse reflecting dynamic left ventricular emptying. In about one-​third, the jugular venous pulse may demonstrate a prominent ‘a’ wave, reflecting diminished right ventricular compliance secondary

to right ventricular hypertrophy. Many patients have a forceful left ventricular cardiac impulse, best appreciated on full-​held expiration in the left lateral position, when there may be a palpable atrial beat reflecting forceful atrial systolic contraction that may or may not be associated with significant forward flow of blood. The first and second heart sounds are usually normal, and—​unless the patient is in atrial fibrillation—​there is likely to be a loud fourth heart sound, reflecting increased atrial systolic flow into a non-​ compliant ventricle. However, in those patients (20–​30%) who have a resting left ventricular outflow tract gradient, the most obvious physical sign is an ejection systolic murmur. This murmur starts well after the first heart sound and ends before the second. It is best heard at the left sternal border, radiating towards the aortic and mitral areas, but not into the neck or the axilla. The intensity varies with changes in ventricular volume; it can be increased by physiological and pharmacological manoeuvres that decrease afterload or venous return (amyl nitrate, standing, Valsalva, and others), and decreased by manoeuvres that increase afterload and venous return (squatting, phenylephrine, and others). Occasionally there is an ejection sound at the onset of the systolic murmur. Most patients with a left ventricular outflow tract gradient also have mitral regurgitation. Doppler examination reveals that mitral regurgitation usually begins just before (30–​40 ms) the onset of the gradient and continues for the duration of systole. Radiation of the systolic murmur to the axilla is often the best auscultatory clue to the presence of coexistent mitral regurgitation, which may be moderate to severe, either alone or in association with a left ventricular outflow tract gradient. A mid-​diastolic rumble may sometimes result from increased transmitral flow in patients with severe mitral regurgitation. Early diastolic murmurs of aortic incompetence may develop following surgical myectomy or infective endocarditis involving the aortic valve. Although such murmurs are rare in the absence of such complications, they appear to occur more commonly than would be expected by chance and may reflect traction on the non​coronary

16.7.2  The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular

cusp of the aortic valve by the septum. An ejection systolic murmur in the pulmonary area, reflecting right ventricular outflow tract obstruction, is also rare; when present, it is usually associated with severe biventricular hypertrophy in the young or in those with coexistent Noonan’s syndrome and a dysplastic pulmonary valve (see Chapter 16.12).

Prognosis Patients with hypertrophic cardiomyopathy experience slow progression of symptoms and gradual deterioration of left ventricular function, and are at risk of sudden cardiac death throughout life. Annual mortality rates are in the range of 1–​2%, but the risk of death and other disease-​related complications varies between individuals and within individuals during the course of the disease. Severe heart failure symptoms may develop in association with progressive myocardial wall thinning caused by myocardial fibrosis and severe reduction in left ventricular systolic performance and/​ or diastolic filling. The development of systolic failure is associated with a poor prognosis, with rapid progression from onset to death or transplantation, and an overall mortality rate of up to 11% per year. Left atrial size provides important prognostic information on the risk of sudden cardiac death and atrial fibrillation/​flutter. Atrial arrhythmias are important in the clinical course, leading to a risk of acute deterioration and thromboembolic stroke. Onset of atrial fibrillation is part of the evolution of patients with diastolic dysfunction, and with appropriate management need not represent a major cause of morbidity or mortality. A few patients who experience such deterioration present with a clinical picture resembling restrictive cardiomyopathy, with grossly enlarged atria, signs of right heart failure, and relative preservation of left ventricular systolic performance. Left ventricular hypertrophy develops during childhood and adolescence, but is rarely progressive in adults. The trigger and other determinants of disease expression in late-​onset disease are uncertain.

Investigations Cardiological evaluation of patients with hypertrophic cardiomyopathy is performed to confirm the diagnosis, to guide symptomatic therapy, and to assess the risk of complications, particularly that of sudden death. Electrocardiography The 12-​lead ECG is the most sensitive diagnostic test, although occasionally normal (c.5%), particularly in the young. At the time of diagnosis, 5–​10% of patients are in atrial fibrillation. Many have an intraventricular conduction delay and 20% have left-​axis deviation, but complete right bundle or left bundle branch block is uncommon (c.5%). The latter may develop following surgery and is occasionally seen in elderly patients. ST-​segment depression and T-​wave changes are the most common abnormalities and are usually associated with voltage changes of left ventricular hypertrophy and/​or deep S waves in the anterior chest leads V1 to V3. Isolated repolarization changes or giant negative T waves are occasionally seen. Voltage criteria for left ventricular hypertrophy are rare in the absence of repolarization changes. About 20% of patients have abnormal Q waves, either inferiorly (II, III, and aVF), or less commonly in leads V1 to V3. P-​wave abnormalities of left and/​or right atrial overload are common. The distribution of the PR interval is

similar to that in the normal population, but occasionally a short PR interval may be associated with a slurred upstroke to the QRS complex. This is not usually associated with evidence of pre-​excitation, although patients with hypertrophic cardiomyopathy and accessory pathways have been described. Despite the many electrocardiographic abnormalities, there is no ECG that is typical of HCM; a useful rule is to consider the diagnosis whenever the ECG is bizarre, particularly in younger patients. The incidence of arrhythmias during 48-​h ambulatory electrocardiographic monitoring increases with age. Non​ sustained ventricular tachycardia is detected in 20–​25% of adults and, although usually asymptomatic, is associated with an increased risk of sudden cardiac death. Supraventricular arrhythmias are also common in adults and can be poorly tolerated if sustained (>30 s) unless the ventricular response is controlled. Atrial fibrillation or flutter carry an increased risk of thromboembolism. By contrast, most children and adolescents are in sinus rhythm, and arrhythmias during ambulatory electrocardiographic monitoring are uncommon. The increased incidence of supraventricular arrhythmias with age is related to increased left atrial dimensions and increased left ventricular diastolic pressure. The aetiology of ventricular arrhythmias is not known, but may relate to myocyte loss and myocardial fibrosis. Documented sustained ventricular tachycardia is uncommon, but is a recognized complication in patients with an apical aneurysm, which may develop as a consequence of midventricular obstruction. Chest radiography The chest radiograph may be normal or show evidence of left and/​or right atrial or left ventricular enlargement; if left atrial pressure has been chronically elevated, there may be evidence of redistribution of blood flow to upper lung zones. Mitral valve annular calcification is seen, particularly in elderly patients. Echocardiography Left ventricular hypertrophy may be symmetric or asymmetric and localized to the septum or the free wall, but most commonly to both the septum and free wall with relative sparing of the posterior wall (Fig. 16.7.2.2). Isolated apical hypertrophic cardiomyopathy occurs in about 10% of patients. Approximately one-​third of patients also have hypertrophy of the right ventricular free wall, the presence and severity of which is strongly related to the severity of left ventricular hypertrophy. Typically, left ventricular end-​systolic and end-​diastolic dimensions are reduced, and the left atrial dimension is increased. Indices of systolic function such as ejection fraction may be increased, but systolic function is often impaired, which may be best appreciated by measurement of long-​axis rather than short-​ axis function. Colour Doppler provides a sensitive method of detecting left ventricular outflow tract turbulence (Fig. 16.7.2.3), and when combined with continuous wave Doppler the peak velocity (Vmax) of left ventricular blood flow can be measured and left ventricular outflow tract gradients calculated. Doppler gradients (pressure gradient (mm Hg) = 4 Vmax2) are seen in 20–​30% of patients and correlate well with those measured invasively. Systolic anterior motion of the mitral valve is usually present when the calculated outflow tract gradient is more than 30 mm Hg, and early closure or fluttering of the aortic valve leaflets is often seen in association

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Cardiac catheterization

Fig. 16.7.2.2  An echocardiogram (parasternal long-​axis view) of a patient with hypertrophic obstructive cardiomyopathy demonstrating hypertrophy of the interventricular septum (IVS), enlargement of the left atrium (LA), and systolic anterior motion of the mitral valve, bringing it into contact with the septum (arrow).

Two-​dimensional echo/​Doppler evaluation has replaced invasive haemodynamic measurements and angiography as the method of assessing left ventricular structure and function in hypertrophic cardiomyopathy. Cardiac catheterization is not necessary for diagnosis and is rarely indicated unless symptoms are refractory and direct measurement of cardiac pressures is potentially informative, particularly in assessing the severity of mitral regurgitation. Coronary arteriography may be necessary to exclude coexistent coronary artery disease in older patients who have significant angina or ST-​segment changes during exercise. The left coronary arteries are usually large in calibre. The left anterior descending and septal perforator arteries may demonstrate narrowing during systole in the absence of fixed obstructive lesions, but such changes do not appear to relate to symptoms. Left ventricular angiography is rarely indicated, but recognition of the abnormally shaped ventricle, which typically ejects at least 75% of its contents in association with mild mitral regurgitation, may provide a valuable diagnostic clue when hypertrophic cardiomyopathy was not suspected before catheterization. Exercise testing

with such motion. A posteriorly directed mitral regurgitant jet is seen in association with and related to the magnitude of the outflow tract gradient (Fig. 16.7.2.3). An anterior regurgitant jet or mitral regurgitation in the absence of obstruction suggests the coexistence of structural mitral valve abnormalities. Other imaging techniques Good-​quality echocardiography suffices for diagnostic and therapeutic purposes in most patients with hypertrophic cardiomyopathy, but cardiac MRI is useful in selected cases to assess right ventricular, apical, and lateral left ventricular involvement. Gadolinium-​enhanced cardiac MRI permits detection of myocardial fibrosis, the extent of which may predict evolution to the burnt-​out  phase.

Maximal exercise testing in association with respiratory gas analysis provides useful functional and prognostic information, which can be monitored serially. Oxygen consumption at peak exercise (peak Vo2) is usually moderately reduced, even in patients who do not complain of exertional symptoms. Continuous measurement of the blood pressure during upright treadmill or bicycle exercise reveals that about one-​ third of younger patients (70% luminal narrowing) or occlusions. The choice of revascularization procedure is dependent on a range of factors and should be discussed in a multidisciplinary group that includes cardiologists and cardiac surgeons: • Coronary anatomy—​historically, PCI has been preferred for single-​vessel and two-​vessel coronary artery disease and CABG for more extensive disease. This preference, based largely on presumed prognostic benefit for CABG in patients with three-​ vessel or left main stem disease (see next), has now given way to procedure selection based on coronary scoring systems. Most widely used is the SYNTAX score designed to quantify the complexity of left main or three-​vessel disease according to simple lesion criteria readily accessible from the coronary arteriogram. If the SYNTAX score is less than 22, signifying low lesion complexity, 5-​year outcomes favour revascularization by PCI, regardless of the number of diseased vessels. If the SYNTAX score is higher CABG should also be considered, and for scores more than 33 (signifying severe lesion complexity) CABG produces unequivocally better 5-​ year outcomes than PCI. In making revascularization decisions, however, other factors are also important, and there is now clear evidence favouring CABG for patients with diabetes and multivessel disease. • Patient preference—​PCI is often preferred because it avoids surgery, requires no more than 48 h hospitalization (day-​case PCI is now feasible), and permits early return to normal activities within a few days of the procedure. In expressing a preference, however, it is important that the patient is properly informed of the relative risks and benefits of PCI and CABG in his or her particular case. • Procedural risk—​mortality is lower for PCI than CABG (0.9% vs. 2.2%). Stroke risk may also lower, but rates of non​fatal myocardial infarction are comparable. • Symptomatic benefit—​this is comparable for PCI and CABG, but recurrence of symptoms and need for repeat revascularization is higher for PCI because of coronary restenosis in the months following a successful procedure. Indeed, restenosis has been the Achilles heel of PCI, and until the introduction of coronary stents affected 30% or more of all patients. Since then stenting has become widespread, producing more effective coronary patency although reductions in rates of restenosis to less than 10% had to await the introduction of drug-​eluting stents that deliver

antiproliferative drugs (e.g. sirolimus, paclitaxel) locally within the coronary artery. The prospect of providing long-​term relief of symptoms without the need for repeat procedures has considerably enhanced the clinical value of PCI. • Prognostic benefit—​There have been no studies showing survival benefit for PCI in patients with stable angina. For CABG, the small gains in life expectancy that have been reported in patients with left main stem coronary disease and three-​vessel disease are from studies nearly 40 years ago and their contemporary relevance may have changed with advances both in surgical techniques and in medical therapy. Indeed, it is generally accepted that improvements in the prognosis of coronary artery disease in the last 25 years have little to do with revascularization, but much to do with lifestyle changes and advances in secondary prevention therapy.

Refractory angina With current management strategies patients with angina are living longer, but some (perhaps 5 to 10%) remain symptomatic on optimal medical treatment, having exhausted revascularization options. These patients commonly have extensively collateralized coronary circulations and well-​preserved left ventricular function such that prognosis is not worse than other patients with angina, but quality of life is poor because of refractory symptoms. Psychological support is important to treat anxiety and depression and improve confidence. Other options for further antianginal therapy are not evidence-​ based and are not recommended in international guidelines. These include neuromodulatory techniques (stellate ganglion block, transcutaneous electrical nerve stimulation, spinal cord stimulation) and enhanced counterpulsation therapy using pressure cuffs applied to the lower limbs that are inflated sequentially during diastole.

FURTHER READING Boden WE, et  al. (2007). Optimal medical therapy with or without PCI in stable coronary disease. N Engl J Med, 35, 1503–​16. Doris MK, Newby DE (2016). How should CT coronary angiography be integrated into the management of patients with chest pain and how does this affect outcomes? Eur Heart J Qual Care Clin Outcomes, 2,  72–​80. Fihn SD, et  al. (2012). ACCF/​AHA/​ACP/​AATS/​PCNA/​SCAI/​STS Guideline for the diagnosis and management of patients with stable ischemic heart disease:  a report of the American College of Cardiology Foundation/​ American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol, 60, e44–​e164. Head SJ, et al. (2014). The SYNTAX score and its clinical implications. Heart, 100, 169–​77. Jones DA, et  al. (2013). Novel drugs for treating angina. BMJ, 347, f4726. Jordan KP, et al. (2017). Prognosis of undiagnosed chest pain: linked electronic health record cohort study. BMJ, 357, j1194. Montalescot G, et al. (2013). 2013 ESC guidelines on the management of stable coronary artery disease:  the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J, 34, 2949–​3003.

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NICE (2011). Management of stable angina. Clinical guideline. https://​ www.nice.org.uk/​guidance/​cg126 NICE (2016). Chest pain of recent onset:  assessment and diagnosis. Clinical guideline. https://​www.nice.org.uk/​guidance/​cg95 Rapsomaniki E, et al. (2014). Prognostic models for stable coronary artery disease based on electronic health record cohort of 102,023 patients. Eur Heart J, 35, 844–​52. Sekhri N, et  al. (2007). How effective are rapid access chest pain clinics? Prognosis of incident angina and non-​cardiac chest pain in 8762 consecutive patients. Heart, 93, 458–​63. Sekhri N, et al. (2016). A 10-​year prognostic model for patients with suspected angina attending a chest pain clinic. Heart, 102, 869–​75.

16.13.4  Management of acute coronary syndrome Rajesh K. Kharbanda and Keith A.A. Fox ESSENTIALS Acute coronary syndrome (ACS) is precipitated by an abrupt change in an atheromatous plaque and/​or thrombotic occlusion. This results in increased obstruction to perfusion and ischaemia or infarction in the territory supplied by the affected vessel. The clinical consequences of plaque rupture can range from a clinically silent episode, through to unstable symptoms of ischaemia without infarction, to profound ischaemia complicated by progressive infarction, heart failure, arrhythmia, and risk of sudden death. Clinical presentation with an ACS identifies a patient at high risk of further cardiovascular events requiring a defined acute and long-​ term management strategy. The choice and timing of acute management strategy is critically dependent on the extent and severity of myocardial ischaemia, with the spectrum of ACS broken down into three elements:  (1) Unstable angina: typical ischaemic symptoms without ST elevation on ECG and without elevated biomarkers of necrosis. (2) Non-​ST-​ elevation myocardial infarction (NSTEMI): typical ischaemic symptoms without ST elevation on ECG but with biomarkers of necrosis above the diagnostic threshold. (3) ST-​elevation myocardial infarction (STEMI): typical ischaemic symptoms with ST elevation on ECG and with biomarkers of necrosis above the diagnostic threshold. An acute reperfusion strategy (primary percutaneous coronary intervention (PCI) or thrombolysis) is of proven benefit only in ST-​ segment elevation infarction (or MI with new bundle branch block). Prompt relief of pain is important, not only for humanitarian reasons, but also because pain is associated with sympathetic activation, vasoconstriction, and increased myocardial work. Effective analgesia is best achieved by the titration of intravenous opioids, with concurrent administration of an antiemetic. High-​flow oxygen is recommended for symptom relief in those patients with evidence of desaturation, particularly in those who are breathless or who have features of heart failure or shock.

The management of prehospital cardiac arrest requires special attention: at least as many lives can be saved by prompt resuscitation and defibrillation as by reperfusion. Patients may also require management of arrhythmic and haemodynamic complications, including heart failure.

Acute coronary syndromes without ST elevation (unstable angina/​non-​ST elevation MI) Risk stratification and initial management Patients without ST elevation or left bundle branch block can be triaged into low, intermediate, and high-​risk categories. (1) High-​risk—​ patients with typical clinical features of ischaemia and ST-​segment depression or transient ST-​segment elevation, or with troponin elevation and a high-​risk score (risk calculator downloadable from http://​ www.gracescore.org/​or http://​www.timi.org/​). Patients are also at high risk when ischaemia provokes arrhythmias or haemodynamic compromise. (2) Intermediate or low risk—​patients with clinical features of ACS and non​specific ECG changes (e.g. T-​wave inversion, T-​wave flattening, minor conduction abnormalities). (3) Low risk or an alternative diagnosis—​patients with a normal ECG, normal biomarkers, normal cardiac examination, and normal echo. Patients at high risk—​(1) high-​risk patients with acute ischaemia at initial presentation, or those who develop such features after hospital admission, and especially those with haemodynamic compromise, require emergency assessment for revascularization and dual antiplatelet therapy. (2) Those proceeding to emergency revascularization should receive (a) aspirin; (b) P2Y12 receptor inhibitor; (c) unfractionated or low molecular weight heparin (LMWH), or a direct thrombin inhibitor, and (d) if required for bail-​out, glycoprotein IIb/​IIIa inhibition. (3) In addition to anti-​ischaemic therapy, additional therapy may be required:  antiarrhythmic management, or haemodynamic support to reduce ischaemia and stabilize the patient for revascularization. Where the clinical features support a diagnosis of ACS, patients developing ST elevation require emergency assessment with coronary angiography and where appropriate reperfusion by primary PCI, or—​when a primary angioplasty service is not available—​by thrombolysis (see next). Patients at intermediate or low risk—​patients with non-​ST-​elevation ACS and an intermediate risk score require dual antiplatelet therapy (aspirin plus P2Y12 receptor inhibitor, e.g. ticagrelor or prasugrel; if neither available, clopidogrel) plus parenteral anticoagulation. They are candidates for an early elective revascularization strategy (within c.72 h). Clinically stable patients with minor or non​specific ECG abnormalities and a low risk score (including negative repeat troponin) are at very low risk for in-​hospital, major cardiac events. Such patients may, nevertheless, have significant underlying coronary artery disease. They require assessment of the cardiovascular risk and non-​ invasive ischaemia testing to identify the presence and extent of inducible ischaemia, ideally prior to discharge.

Specific pharmacological therapies Anti-​ischaemic therapies—​(1) nitrates—​effective in reducing ischaemia in the in-​hospital management of non-​ST-​elevation ACS, but there is no evidence that they improve mortality; (2) β-​blockers—​patients with suspected acute coronary syndromes should be initiated on β-​blocker therapy unless contraindicated; (3) dihydropyridine calcium entry blockers—​should only be employed with β-​blockers in

16.13.4  Management of acute coronary syndrome

ACS to avoid reflex tachycardia. In patients unable to tolerate β-​ blockers, a heart-​ rate-​ slowing calcium antagonist (e.g. diltiazem or verapamil) may be appropriate. Short-​acting dihydropyridines should not be used in isolation in ACS. Antiplatelet therapies—​(1) aspirin 75–​325 mg daily—​indicated in all patients with ACS unless there is good evidence of aspirin allergy or evidence of active bleeding; (2) P2Y12 receptor inhibitor—​patients with non-​ST-​elevation ACS should be given a loading dose of either ticagrelor 180 mg, prasugrel 60 mg (once anatomy is defined), or clopidogrel 300–​600 mg (if neither ticagrelor nor prasugrel are available), followed by continued treatment, in combination with aspirin. Dual antiplatelet therapy should be maintained for 12 months, unless the risks of bleeding exceed potential benefits. Certain patients may benefit from more prolonged duration of dual antiplatelet therapy. (3)  GPIIb/​IIIa inhibitors (e.g. abciximab, eptifibatide, tirofiban) can be used in patients requiring urgent percutaneous intervention for non-​ST-​segment elevation ACS and in those at intermediate to high risk. Current indications for treatment with GPIIb/​IIIa inhibitors are mainly as a bail-​out at PCI. Anticoagulation—​this is required in addition to antiplatelet therapy. Indirect thrombin inhibitors: low molecular weight heparin is better than unfractionated heparin and is most commonly used. In the absence of an urgent/​early invasive strategy, fondaparinux (a synthetic pentasaccharide that selectively binds antithrombin and causes inhibition of factor Xa) has the most favourable efficacy/​safety profile. Bilvalirudin is the only direct thrombin inhibitor currently used in ACS management.

ST-​segment-​elevation myocardial infarction Patients with clear-​cut evidence of ST-​elevation infarction (STEMI) require immediate triage to reperfusion therapy. ‘Fast-​track’ systems have been developed to minimize in-​hospital delay to reperfusion: these aim to achieve clinical assessment and electrocardiography within 15 min of arrival and rapid transfer for PCI or the institution of thrombolytic therapy within 30 min. Audit programmes and continuous training are necessary for centres to achieve this 30-​min median ‘door-​to-​needle’ time. PCI—​randomized clinical trials of primary PCI vs. thrombolysis have shown consistent findings:  primary PCI is better, providing more effective restoration of vessel patency, achieving better ventricular function, and improving important clinical outcomes with lower rates of death, reinfarction, stroke, major bleeding, and recurrent ischaemia. Particular gains are seen in haemodynamically compromised patients. In consequence, primary PCI is the preferred therapeutic option in national and international guidelines. Thrombolysis—​prehospital thrombolysis is the next best option if a primary PCI programme is not available, or if transfer times are sufficiently prolonged that reperfusion may not be achieved within 120 min of patient call. The current reference standard for the comparison of fibrinolytic agents is the accelerated infusion regimen of alteplase (tPA), or—​for simplicity—​the single-​bolus administration of tenecteplase (TNK), which does not require an infusion pump or refrigeration and hence is particularly suited for prehospital administration. Internationally, streptokinase remains the most widely used fibrinolytic agent, principally because it is relatively inexpensive. If timely primary PCI is not available, a pharmaco-​invasive strategy (thrombolysis and subsequent revascularization) may provide similar benefit to primary PCI, but requires further testing.

Antiplatelet agents and anticoagulants—​ (1) aspirin 75–​ 325 mg daily—​indicated in all patients with ACS unless there is good evidence of aspirin allergy or evidence of active bleeding. (2)  P2Y12 receptor inhibitors should be given to all patients, continuing for at least 1 month in patients managed with fibrinolysis (or as determined by the type of stents implanted). (3) Anticoagulants—​heparin or bivalirudin are indicated in patients managed with primary PCI. Patients treated with fibrinolytic therapy should receive low molecular weight heparin or fondaparinux. (4) GPIIb/​IIIa inhibitors may be used in patients managed with primary PCI (mainly for bail-​out), but not in those managed with fibrinolysis.

Secondary prevention measures in patients with ACS Patients require advice and help regarding cessation of smoking (including the avoidance of passive smoking), dietary modification, exercise, rehabilitation, and management of obesity. The following therapies have been shown to reduce the risk of subsequent cardiovascular events:  (1) antiplatelet therapy—​aspirin in a dose of 75 mg/​day, clopidogrel 75 mg/​day. Certain subgroups may benefit from prolonged dual antiplatelet therapy—​aspirin and ticagrelor 60 mg/​bd or aspirin and clopidogrel; (2)  β-​blockers in those without contraindications; (3) lipid lowering with 3-​hydroxy-​3-​ methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins); (4) angiotensin-​converting-​enzyme inhibitors/​angiotensin receptor blockers, especially in those with left ventricular dysfunction and heart failure, and benefit is also possible in other patients with vascular disease; (5) aldostrone blockade (e.g. eplerenone) in those with left ventricular ejection fraction (LVEF) less than 35% and diabetes or clinical features of heart failure.

Introduction The term ‘acute coronary syndrome’ (ACS) describes the clinical manifestations of a heterogeneous spectrum of conditions that share key pathophysiological features:  disruption or erosion of coronary atheromatous plaque, changes in vascular tone, and a variable extent of thrombotic occlusion. The clinical presentation is determined by the extent of coronary obstruction, the volume of ischaemic myocardium, and timing of the atherothrombotic disease process. ACS occurs in patients with underlying symptomatic or occult coronary artery disease, and flow-​limiting or non-​flow-​limiting atheromatous plaques in the coronary arterial wall (Fig. 16.13.4.1). The ACS is precipitated by an abrupt change in an atheromatous plaque, resulting in increased obstruction to perfusion and ischaemia or infarction in the territory supplied by the affected (culprit) vessel. For discussion of the mechanisms involved, see Chapter 16.13.1. The pattern and severity of clinical manifestations are dependent not only on the degree of obstruction to perfusion, but also on the presence or absence of collateral perfusion, the extent and distribution of fragmented microthrombi, and myocardial oxygen demand in the perfused territory. Thus, the clinical consequences of plaque rupture can range from an entirely silent episode, through to unstable symptoms of ischaemia without infarction, to profound ischaemia complicated by progressive infarction, heart failure, arrythmia, and risk of sudden death.

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Spectrum of acute coronary syndrome myocardial infarction unstable angina Marker: Tn & CK-MB undetectable

Non-ST elevation myocardial infarction

ST elevation myocardial infarction

troponin elevated +/− CK-MB

troponin elevated +/− CK-MB

Fig. 16.13.4.1  The spectrum of acute coronary syndromes.

The goals of early management of ACS are to relieve ischaemia (by reducing myocardial oxygen demand, inhibiting thrombotic occlusion, and reducing coronary obstruction), to prevent further thrombotic occlusion, and to prevent or manage complications. The choice and timing of management strategy, including pharmacological treatment and percutaneous or surgical revascularization, is critically dependent on the extent and severity of myocardial ischaemia. Despite sharing key pathophysiological mechanisms across the spectrum of ACS, ST-​segment-​elevation acute myocardial infarction (STEMI) and non-​ST-​elevation ACS (unstable angina and non-​STEMI) need to be considered separately because an acute reperfusion strategy (primary percutaneous coronary intervention (PCI) or thrombolysis) is of proven benefit in STEMI (or MI with new bundle branch block), but not in the remainder of the syndrome. Thus, although the management of STEMI differs, the remainder of the ACS should be managed as a continuous spectrum, but influenced by risk stratification.

Clinical presentation and definition of ACS The ACS may present de novo (as new-​onset angina), with typical ischaemic discomfort at rest (rest angina) or on minimal exertion. Alternatively, a previously stable pattern of angina may change,

resulting in episodes of typical rest angina or angina provoked by minor exertion (crescendo angina). New-​onset exertional angina has not previously been recognized as part of ‘acute coronary syndrome’, but the outcomes are similar—​c.7% develop non​fatal MI and 4% die, and a further 19% require revascularization within 15  months—​and such patients may fulfil the clinical and ECG/​biomarker characteristics of the syndrome (EuroHeart survey, GRACE, and CRUSADE registries). There are three components to the clinical diagnosis of ACS: the symptom description, the ECG, and biomarker evidence of myocyte necrosis. The symptoms must be distinguished from non​cardiac pain, and from stable angina. To improve the specificity of diagnosis, clinical trials use a more restricted definition, requiring at least 15 to 20 min of typical ischaemic discomfort or two 5-​min episodes at rest. The specificity is further improved when the definition requires objective evidence of ischaemia or evidence of underlying coronary artery disease. ST-​segment depression on the ECG, especially in association with typical pain, is highly predictive, whereas the less specific ECG abnormalities, including T-​wave inversion, are less strong predictors. Markers of myocardial damage (troponins or cardiac enzymes) are powerfully predictive, in the presence of a typical clinical syndrome. ST elevation or depression on the ECG and elevated biomarkers of necrosis are markers of higher risk and adverse outcome (Table 16.13.4.1). In the absence of such markers, documented

Table 16.13.4.1  Prognostic value of admission ECG for early risk stratification in 12 142 patients with an acute coronary syndrome Outcome

ST elevation + ST depression (n = 15)

ST elevation (n = 28)

ST depression (n = 35)

T-​wave inversion (n = 23)

p

Acute infarction on admission (%)

87

81

47

31

0.5  mm in thrombolysis in mycocardial infarction (TIMI) score); isolated T-​wave inversion carries a lower risk. The number of leads demonstrating ST deviation also yields prognostic information:  among those with ST deviation in the anterior leads a rate of death or MI of 12.4% was seen at 1 year—​ higher than seen with similar changes in other locations (TIMI III trial). Patients with a left main and three-​vessel coronary

artery disease may show a combination of ST-​segment elevation and depression. Ambulatory ST-​segment recording can identify patients with unstable angina and either silent or symptomatic myocardial ischaemia with an increased risk for major subsequent cardiac events. However, conventional ambulatory monitoring usually requires offline analysis and is not suitable for the prediction of imminent events. Computer-​ assisted, continuous, multilead, ECG monitoring techniques have become available for real-​time ECG and ST-​segment monitoring. The occurrence and extent of ischaemic territory identified by such continuous recordings can provide additional prognostic information over and above the admission ECG. The information can be combined with biomarkers and, together, they provide additional prognostic information (FRISC study).

Biochemical markers and outcome Markers of myocardial damage Biomarkers of necrosis are gradually released into the systemic circulation following complete or transient occlusion of the coronary artery, or fragmentation of a thrombus and embolization. Following total occlusion of the vessel, troponins and creatine kinase (or more specifically CK-​MB) are released and are detectable at clearly abnormal levels about 6 to 8 h after the event unless there is extensive collateral perfusion. The cardiac isoforms of troponin I and troponin T are exclusively expressed in cardiac myocytes and provide specific evidence of myocardial damage. Following infarction, troponins are released from the cytosolic pool and first appear in the circulation in detectable concentrations between 3 and 4 h after the ischaemic event, reaching diagnostic concentrations at 6 to 8 h. Troponin release is evidence of myocardial injury and carries prognostic significance: the greater the troponin release, the greater the risk of subsequent MI and death. High-​sensitivity or ultrasensitive assays have a 10-​to 100-​fold lower limit of detection than current assays, allowing detection of MI more frequently and earlier (within 1 hour), but it is important to recognize that other causes of myocyte necrosis can give rise to detectable troponin concentrations in the circulation, hence the diagnosis of ACS requires an appropriate clinical context. A clinical assessment of the reasons for troponin detection in the circulation is vital for determination of the correct diagnosis (Fig. 16.13.4.3 and Table 16.13.4.4). When should the cardiac enzymes be measured? The time course of the release of troponins (or enzymes) from myocardium is such that diagnostic concentrations may not be achieved until some time after an ischaemic event, depending on

Table 16.13.4.3  Classification of unstable angina (Braunwald) Class

A: Secondary unstable angina (e.g. anaemia, hypoxia)

B: Primary unstable angina

C: Postinfarction (48 h since last pain)

IIA

IIB

IIC

III

Acute rest angina (99th centile

1

No

Significant change in troponin concentration

No significant change in troponin concentration

CLINICAL ASSESSMENT

CLINICAL ASSESSMENT

Oxygen supply-demand imbalance? eg sustained hypotension, tachycardia, hypoxaemia

Known structural heart disease or clear alternative pathology*

Known CAD

Consider invasive coronary angiography

Consider no further investigation

Yes

Yes

No

No known CAD

Consider invasive or CT coronary angiography

No further cardiac investigation

Consider echocardiography or cardiac MRI scan

INVESTIGATION RESULTS Coronary artery disease with plaque rupture

Obstructive coronary artery disease

1

No coronary artery disease

2

ACUTE

CHRONIC

Injury

Injury

Fig. 16.13.4.3  Algorithm for the investigation of patients with elevated cardiac troponin concentration on serial measurements is used to identify patients with acute and chronic myocardial injury. The definition of significant change in cardiac troponin will be dependent on the particular assay used and should be consistent with the local pathway for the assessment of patients with an isolated presentation with acute coronary syndrome. CAD, coronary artery disease. * alternative pathologies that can lead to troponin elevation are shown in Table 16.13.4.4. Adapted from Chapman AR, Adamson PD, Mills NL (2017). Assessment and classification of patients with myocardial injury and infarction in clinical practice. Heart, 103, 10–​18.

the assays employed. Thus, a normal value for a patient on arrival within a short duration of time after the event does not exclude infarction or unstable angina, but an elevated value is highly predictive of subsequent infarction. Troponins should be measured Table 16.13.4.4  Causes of elevation of serum troponins Cause

Example

Cardiac

Cardiac contusion Cardiac failure Cardiac interventions/​surgery Cardiac toxins, e.g. cocaine, anthracyclines Cardiac tumour Cardiomyopathies Cardioversion Myocardial infarction Myocarditis (Myo)pericarditis

Cardiovascular

Aortic dissection Pulmonary embolism

Neurological

Stroke Subarachnoid haemorrhage

Other

Acute kidney injury Sepsis Chronic kidney disease

on arrival depending upon the clinical presentation, and may require a second sample. The timing of the second sample depends upon the troponin assay. The latest generation of high-​sensitive troponin assays increase diagnostic performance and improve the early diagnosis of MI regardless of the time of chest-​pain onset, and re-test within 3 hours maybe feasible. Implementation of a sensitive troponin assay, and lowering the diagnostic threshold for MI, reduces recurrent MI and death in patients with suspected ACS. Among those with persistently negative troponins and without significant ECG changes, there is a very low risk of subsequent infarction and death (provided that severe underlying coronary artery disease is excluded). Such patients should undergo predischarge risk assessment and stress testing. The best tests are myocardial perfusion scanning or stress echocardiography, but treadmill ECGs on exercise are more widely available. Rule-​in and rule-​out pathways The specific pathway depends upon the biomarker and assay system used. With the use of high-​sensitivity troponins a 0 h/​3 h pathway is suggested, although future refinements may endorse a 0 h/​1 h pathway. Current guidelines advocate a pathway as illustrated in Fig. 16.13.4.4.

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Fig. 16.13.4.4  0 h/​3 h rule-​out algorithm of non-​ST elevation coronary syndromes using high-​sensitivity cardiac troponin assays. From Roffi M, et al. (2016). 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-​segment elevation. Eur Heart J, 37, 267–​315, by permission of Oxford University Press.

Markers of left ventricular wall stress and inflammation Natriuretic peptides such as brain natriuretic peptide (BNP) or its N-​ terminal prohormone fragment (NT-​ proBNP) are associated with left ventricular dysfunction and elevated levels are associated with adverse prognosis; however, current management protocols are not determined by BNP levels. Inflammatory changes in the vessel wall promote plaque fissuring or erosion, and inflammatory changes also follow episodes of minor myocardial damage. In ACS there is evidence that inflammatory markers, such as C-​reactive protein (CRP) and interleukins IL-​6 and IL-​1, are independently associated with adverse outcome. After the acute phase, continuing inflammation (e.g. with elevated CRP) occurs in one-​half of those whose levels are acutely elevated and identifies a category of patients at increased risk. However, although inflammatory mechanisms are implicated in plaque growth and plaque destabilization, specific anti-​ inflammatory therapies have not yet been demonstrated to improve outcome, and measurement of CRP or other inflammatory markers is not part of routine clinical practice.

Non​invasive imaging and outcome Transthoracic echocardiography is useful to identify regional wall motion abnormality and assess LV function, in addition to detecting other important pathology associated with chest pain such as aortic dissection, pericardial effusion, valve disease, or right ventricular strain suggestive of pulmonary embolism for example. Non​invasive assessment of ischaemia can be performed in low risk patients using stress echo, cardiac magnetic resonance, or nuclear perfusion techniques. Multidetector computed tomography (MDCT) allows for visualization of the coronary arteries. It may be applied to assess certain ACS patients but requires a high level of expertise and is not yet routinely available.

Risk characterization in ACS The timing and the nature of key management decisions in ACS are dependent upon risk estimation. For example, the choice of reperfusion therapy in ST elevation may be influenced by the presence of comorbidity, bleeding risk, and time delay from symptom onset. Similarly, in non-​STEMI ACS, ongoing ischaemia with ST depression or the presence of hypotension or a high-​risk score may initiate very early revascularization. Specific pharmacological (e.g. glycoprotein IIb/​IIIa inhibitors) or interventional therapies (PCI) have demonstrated benefit in high-​or moderate-​risk patients but not in low-​risk patients (5-​year outcome: RITA 3, FRISC-​II). In patients with ACS, risk can be separated into two components: ‘prior risk’ and ‘acute ischaemic risk’. Prior risk is determined by patient characteristics (age and gender), prior ischaemic heart disease (MI, heart failure, prior angina), and systemic factors that influence risk (hypertension, diabetes, renal dysfunction, and other life-​threatening systemic disorders). These can be considered as the background level of risk that the patients bring with them to the point of presentation. Although several of the individual risk components may not be modifiable, the combined impact of prior risk influences the balance between benefit and risk for each of the therapeutic strategies in ACS. Thus, prior risk sets the baseline for risk–​ benefit decisions. By contrast, ‘acute ischaemic risk’ is potentially modifiable and determined by the severity of coronary obstruction and the extent of the territory affected. Collateral perfusion, embolization, myocardial oxygen demand, and cytoprotection mechanisms all influence the extent of ischaemia. Patients with similar clinical features may have experienced transient complete occlusion, or severe subtotal occlusion complicated by distal embolization of fragments of a platelet-​rich thrombus, and altered vascular tone in the distal territory. Clinical markers of acute ischaemic risk include ECG changes,

16.13.4  Management of acute coronary syndrome

Box 16.13.4.2  Practical steps to assess risk (in addition to clinical symptoms) • 12-​lead ECG—​obtained directly after first medical contact, repeated after recurrent symptoms • Troponin estimation (cTnT or cTnI)—​ repeated if the initial test is negative • Apply a risk score (such as GRACE, TIMI—​see Table 16.13.4.2 and http://www.outcomes.org/grace) • An echocardiogram may be required to rule in/​out alternative diagnoses and assess left ventricular function • In patients with no recurrence of pain, normal ECG, and no troponin ­elevation, a non​invasive stress test or coronary imaging may be required

release of biomarkers of necrosis into the systemic circulation, and mechanical and arrhythmic complications of the ischaemic episode. Simplistically, prior risk can be regarded as the ‘baggage’ that the patient carries with them, and acute ischaemic risk as an ‘acquired hazard’ arising from the new ischaemic event. The distinction is important because management strategies for prior risk aim to treat heart failure, underlying coronary and systemic disease, and risk factors. The management of acute ischaemic risk aims to reverse the impact of acute coronary obstruction and thrombosis and is the first priority in the management of patients with ACS. Assessment of the extent and impact of underlying coronary artery disease (e.g. with stress testing) and assessment of left ventricular function can take place later in the management of these patients (Box 16.13.4.2), and are important determinants of the longer-​term outcomes. In summary: (1) A diagnosis of ACS is a clinical diagnosis based on the suspicion that coronary ischaemia due to atherothrombosis is responsible for the patient’s presentation; (2) clinical examination and ECG provide early and rapid assessment tools; (3) patients with STEMI require consideration of emergency reperfusion therapy, and those without require further risk assessment to guide the ongoing management (Table 16.13.4.5).

Management of ACS without ST elevation (unstable angina/​non-​STEMI) Anti-​ischaemic therapy Anti-​ischaemic therapy can decrease myocardial oxygen consumption by reducing heart rate, lowering blood pressure, or depressing left ventricular contractility, and may also act by inducing vasodilatation. In consequence, anti-​ischaemic therapy can limit the progression of occlusion and improve perfusion and improve the supply–​demand imbalance. Mechanical revascularization (PCI and coronary bypass surgery) also aims to relieve obstruction and reduce a patient’s susceptibility to ischaemia and its complications—​ these interventions will be considered separately (see later section of this chapter and Chapter 16.13.5). Nitrates Nitrates act by venodilatation and—​ in higher dose—​ by arteriolar dilatation, and hence reduce preload and afterload, thereby decreasing oxygen demand. In addition, nitrates can also induce coronary vasodilatation. They are effective in relieving symptoms of ischaemia. In the acute phase of the syndrome, where dose titration is required, they are most conveniently administered intravenously. Once dose titration is no longer required, oral administration is feasible. However, continuous nitrate administration can induce tolerance, hence oral nitrates should be prescribed with appropriate nitrate-​free intervals when symptoms are controlled. An alternative is to use drugs with nitrate-​like properties but with­ out the same problems of tolerance, such as a potassium channel activator (see ‘Potassium channel activators and other antianginals’). Large outcome trials have been conducted with nitrates in acute STEMI but not in other ACS. However, patients without ST-​segment elevation or bundle branch block were randomized within the ISIS-​ 4 trial: their mortality was 5.3% for nitrate treatment and 5.5% for placebo treatment, a non​significant difference. Nitrates are effective

Table 16.13.4.5  Recommendations for diagnosis and risk stratification in patients with suspected non-​ST-​segment elevation acute coronary syndromes Recommendations

Class of recommendation

Level of evidence

It is recommended to base diagnosis and initial short-​term ischaemic and bleeding risk stratification on a combination of clinical history, symptoms, vital signs, other physical findings, ECG, and laboratory results.

I

A

It is recommended to obtain a 12-​lead ECG within 10 min after first medical contact and to have it immediately interpreted by an experienced physician. It is recommended to obtain an additional 12-​lead ECG in case of recurrent symptoms or diagnostic uncertainty.

I

B

Additional ECG leads (V3R, V4R, V7–​V9) are recommended if ongoing ischaemia is suspected when standard leads are inconclusive.

I

C

It is recommended to measure cardiac troponins with sensitive or high-​sensitivity assays and obtain results within 60 min.

I

A

A rapid rule-​out protocol at 0 h and 3 h is recommended if high-​sensitivity cardiac troponin tests are available.

I

B

A rapid rule-​out and rule-​in protocol at 0 h and 1 h is recommended if a high-​sensitivity cardiac troponin test with a validated 0 h/​1 h algorithm is available. Additional testing after 3–​6 h is indicated if the first two troponin measurements are not conclusive and the clinical condition is still suggestive of ACS.

I

B

It is recommended to use established risk scores for prognosis estimation.

I

B

Diagnosis and risk stratification

Modified from Roffi M, et al. (2016). 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-​segment elevation. Eur Heart J, 37, 267–​315, by permission of Oxford University Press.

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in reducing ischaemia in the in-​hospital management of non-​ST-​ elevation ACS, but there is no evidence that they improve mortality. β-​Blockers

Box 16.13.4.3  Recommendations for anti-​ischaemic therapy • Anti-​ischaemic therapy should be administered in conjunction with antithrombotic and interventional therapy (see next), with the overall strategy guided by risk evaluation of the patient (see risk stratification) • Patients with suspected ACS should be initiated on nitrate and β-​blocker therapy, unless there are contraindications to the use of β-​blockers • In patients with contraindications to β-​blockers, heart-​rate slowing calcium antagonists should be employed • The combination of a calcium antagonist and β-​blocker is superior to either agent alone • Angiography and revascularization should be considered in patients with recurrent or persistent ischaemia, or patients with troponin elevation (including non-​STEMI). The timing of angiography should be guided by the risk status of the patient

β-​Adrenoceptor antagonists reduce heart rate and blood pressure and myocardial contractility and hence decrease myocardial oxygen consumption. They are primarily employed to reduce ischaemia in ACS. Large-​scale trials have not been conducted in patients with non-​ ST-​elevation ACS. However, in the context of acute STEMI treated by thrombolysis, β-​blockers reduce mortality by approximately 10 to 15% (ISIS-​1 study). They may act by reducing ventricular arrhythmias, reinfarction, and myocardial rupture. However, this trial was conducted before the widespread use of reperfusion therapy and the findings may not be relevant to contemporary practice. More recently the large COMMIT/​CCS study demonstrated that immediate intravenous (metoprolol 5–​15 mg) followed by oral metoprolol 200 mg daily had no effect on mortality, with reductions in recurrent MI and cardiac arrest offset by increased cardiogenic shock. A meta-​ analysis of 27 trials showed a 13% relative risk reduction of mortality in the first week after MI. Patients with significantly impaired atrioventricular conduction or asthma or acute left ventricular dysfunction should not receive β-​blockers. Although β-​blockers may exacerbate acute heart failure, extensive trials have produced strong evidence of a benefit for the gradual introduction of β-​blockers in ambulant patients with heart failure (see Chapter 16.5.3). In the absence of bradycardia or hypotension, patients with suspected ACS should be initiated on β-​blocker therapy unless contraindicated.

been shown to be better than placebo in relieving the symptoms of angina. A randomized trial of nicorandil (a combined nitrate-​like and potassium channel activator) suggested benefit on a composite clinical endpoint (IONA study), and this drug may be considered as an alternative to nitrate administration. Ivabradine selectively inhibits the primary pacemaker current in the sinus node and maybe used in selective patients with contraindications to β-​blockers. Ranolazine inhibits the late sodium current, and can reduce recurrent ischaemia in non-​ST-​elevation ACS. The recommendations in Box 16.13.4.3 are based on current clinical and trial evidence.

Calcium entry blockers

Antiplatelet therapy

These agents inhibit the slow inward current induced by the entry of extracellular calcium through the cell membrane, especially in cardiac and arteriolar smooth muscle. They act by lowering myocardial oxygen demand, reducing arterial pressure, and reducing contractility. Calcium channel blockers can provide symptom relief in patients already receiving nitrates and β-​blockers, and may be useful in patients with contraindications to β-​blockade. Some agents induce a reflex tachycardia (e.g. nifedipine, nicardipine, amlodipine) and are best administered in combination with a β-​adrenoceptor antagonist. By contrast, diltiazem and verapamil are suitable for patients who cannot tolerate a β-​blocker because they inhibit conduction through the atrioventricular node and tend to cause bradycardia. All calcium antagonists reduce myocardial contractility and may aggravate heart failure. Calcium entry blockers have been demonstrated to reduce the frequency of angina in patients with variant angina. A meta-​analysis of calcium entry blockers in ACS indicates a non-​ significant trend towards a higher mortality in treated vs. control patients (5.9% vs. 5.2%, in 7551 patients). In individual trials, diltiazem has been compared with propranolol, and both agents produced a similar reduction in anginal episodes. Dihydropyridine calcium entry blockers should be employed with β-​blockers in ACS to avoid reflex tachycardia. In patients unable to tolerate β-​blockers, a heart-​ rate-​slowing calcium antagonist may be appropriate. Short-​acting dihydropyridines should not be used in isolation in ACS. Potassium channel activators and other antianginals These agents (e.g. nicorandil) have arterial and venous dilating properties, but do not exhibit the tolerance seen with nitrates. They have

Aspirin Exposure of the contents of atheromatous plaque to circulating blood triggers platelet activation by several different pathways. Aspirin is a potent and irreversible inhibitor of platelet cyclooxygenase, blocking the formation of thromboxane A2 and inhibiting platelet aggregation. Although the effects of aspirin can be overcome in the presence of potent thrombogenic stimuli, nevertheless the benefits of aspirin treatment in unstable angina are clearly defined and substantial. The Antiplatelet Trialists Collaboration demonstrated a reduction of 36% in death or MI with antiplatelet treatment (predominantly aspirin) vs. placebo in unstable angina trials. Aspirin treatment significantly reduces subsequent MI, stroke, and vascular death, with the largest reductions seen among patients at highest risk. In patients with unstable angina, four key studies have demonstrated that aspirin significantly reduces the risk of cardiac death or non​fatal MI by approximately 50%. The efficacy of lower-​dose aspirin (75 mg/​day) therapy has been demonstrated in several studies, including those of Wallentin and colleagues where long-​term effects were evaluated in men under 70 years of age with unstable coronary artery disease. After 6 and 12 months of aspirin treatment, the risk of MI or death was reduced by 54% and 48%, respectively (risk ratio 0.52 with 95% confidence intervals 0.37–​0.72). The strength of evidence and magnitude of benefit demonstrated with aspirin treatment in non-​ST-​segment elevation ACS is such that aspirin is indicated in all patients with ACS, unless there is a clear contraindication. Nevertheless, patients with ACS remain at significant risk despite aspirin therapy. In prospective registry studies of unstable angina/​non-​STEMI, and

16.13.4  Management of acute coronary syndrome

in spite of aspirin treatment in more than 80% of patients, the risk of death or MI is approximately 10% at 6 months and the risk of death/​MI or refractory angina is approximately 22 to 33% over the same period (OASIS registry, PRAIS registry). Aspirin treatment (75–​325 mg daily) is indicated in all patients with ACS unless there is good evidence of aspirin allergy or evidence of active bleeding. P2Y12 receptor inhibitors Ticlopidine and clopidogrel are ADP receptor antagonists, and they block the ADP-​induced pathway of platelet activation by inhibiting the P2Y12 ADP receptor. Clopidogrel replaced ticlopidine on account of a superior safety profile and has been tested in a large-​scale trial of patients with unstable angina/​non-​STEMI (n = 12 562, CURE trial). The agent was used on top of existing therapy, and in addition to aspirin. It reduced death, non​fatal MI, and stroke from 11.4 to 9.3% (95% confidence interval 0.72–​0.90, p 140 Intermediate-​risk criteria • Diabetes mellitus • Renal insufficiency (eGFR 65 years for aortic valve replacement in European guidelines)

Class IIaC

Guidelines favouring mechanical valves

ECS/EACTS 2017 guidelines

Informed patient preference

Class IC

Accelerated risk of structural valve deterioration (age 10 years) and high risk for future repeat valve replacement

Class IIaC

A mechanical prosthesis is reasonable for those aged 30

1.5

1.5

ABPI, ankle–​brachial pressure index. Most peripheral arterial disease, both stenosing and dilating, is asymptomatic. The data have been derived from several studies and geographical variation may occur.

For aortic aneurysms, strong familial clustering has been observed, and genome wide association studies have identified associations with several genes not associated with coronary artery disease, including those modifying the protease MMP-9. White and northern European populations appear to be at higher risk of aneurysmal disease than black populations. Stenosing and aneurysmal disease are associated with degenerative changes of the artery wall, the prevalence of both diseases increasing sharply with age (Table 16.14.2.1). Epidemiological studies also indicate a difference between stenosing and aneurysmal disease, with death from aneurysmal disease (aortic aneurysm) being more common among those of higher social classes and in affluent geographical areas.

Leg ischaemia Clinical features The terms acute and chronic relate purely to the length of time that symptoms have been present and must not be confused with terms related to severity, such as critical limb ischaemia. Critical leg ischaemia Critical leg ischaemia is defined as gangrenous change, ulceration, tissue loss, or rest pain lasting for 2 weeks, with an absolute ankle pressure of less than 50 mm Hg, although patients with diabetes are difficult to include in this classification because ankle pressures in such patients may be unreliable due to arterial calcification. Acute leg ischaemia The incidence of acute leg ischaemia, which presents as a painful, pale, and pulseless limb, is 1 in 12 000 patients per year. It can be due either to an embolic event or to thrombosis of an atherosclerotic stenosis. The commonest cause of a peripheral embolus used to be rheumatic heart disease in a patient with atrial fibrillation, but this is now uncommon, and other sources of emboli, such as an aortic aneurysm, must be considered. The development of a thrombosis at the site of an atherosclerotic stenosis, in either the superficial femoral artery or the popliteal artery, is undoubtedly now the commonest cause of acute leg ischaemia. However, it should be stressed that, whatever the cause, there is no difference on clinical examination of the acutely ischaemic limb.

Arterial trauma due to road traffic accidents and knife or gunshot wounds is becoming commoner, as is iatrogenic trauma following the insertion of intra-​arterial catheters for diagnosis or therapy. A  rare but dramatic cause of acute leg ischaemia is phlegmasia cerulea dolens, in which massive thrombosis of all the major veins of the limb occurs with gross swelling that obstructs the arterial supply. Patients with a thrombosis of a popliteal aneurysm may present with classic symptoms of pain, paralysis, loss of power, paraesthesia, pallor, lack of pulse, and perishing cold. If the blood supply is not restored, fixed blue staining of the skin is a further sign of irreversible ischaemia, as is a tense calf with plantar flexion. However, most patients presenting with acute ischaemia have symptoms that are less severe. Chronic leg ischaemia Chronic leg ischaemia is much more common than acute ischaemia (Table 16.14.2.1), and its main cause is atherosclerosis. In the young patient, one should also consider cystic adventitial disease, entrapment of the popliteal artery, and occasionally fibromuscular hyperplasia of the iliac arteries, particularly in women. Symptoms are pain on walking, claudication affecting the calf and thigh, rest pain, ulceration, and gangrenous change. Less commonly, patients may present with buttock claudication and impotence (Leriche’s syndrome). Although the differential diagnoses of the acutely ischaemic limb are few, in the chronically ischaemic limb pain may be due to spinal stenosis or nerve-​root compression (spinal claudication) or arthritis of the hip or knee. Classically the patient with claudication will complain of cramp-​like pain in the calf, appearing after walking a particular distance, relieved by a few minute’s rest, and recurring again at the same distance if the patient resumes walking. Failure of the pain to disappear on resting, or its reappearance after a shorter distance after each rest, suggests a possible musculoskeletal cause, particularly if distal pulses are present on examination. However, it should also be remembered that distal pulses may be felt at rest in the limbs of patients with claudication due to peripheral vascular disease, but disappear on exercise to the point of pain.

Investigations The main diagnostic method used to confirm the diagnosis of peripheral arterial disease is Doppler ultrasonography (duplex scanning),

16.14.2  Peripheral arterial disease

Management Critical and acute leg ischaemia

Fig. 16.14.2.1  Occlusion of the superficial femoral artery demonstrated by colour-​coded duplex ultrasonography. On the left, the common femoral artery (CFA) lies outside the colour box. In the colour box antegrade flow through the profunda femoris artery (PFA) is shown in blue. The red flash represents rebound flow against the occluded origin of the superficial femoral artery (SFA).

an example of which is shown in Fig. 16.14.2.1. The ratio of systolic blood pressure at the ankle and in the arm, the ankle–​brachial pressure index (ABPI), provides a physiological measure of blood flow at the level of the ankle. At rest, in a normal leg, the ABPI lies between 1.0 and 1.4. As the blood flow in the leg is compromised, the ABPI falls sharply, and values below 0.9 are considered abnormal and likely to confirm the diagnosis of peripheral vascular disease. To emphasize the important overlap between this condition and coronary artery disease, a reduction in ABPI nearly always signals the presence of coronary artery disease, which is the cause of death in most patients with peripheral arterial disease. Exercise testing provides an objective method of assessing walking distance and helps with the identification of disease processes, such as angina, that may be limiting. It only needs to be used in those people who have a history of claudication but have normal resting ABPI, and can be used as a way of eliminating or suggesting other diagnoses. In addition to establishing the diagnosis of peripheral arterial disease, duplex ultrasonography is able to determine the site of disease and indicate the degree of stenosis or length of an occlusion and hence aid in the planning of interventional treatment. Other imaging modalities such as CT scanning and magnetic resonance angiography can provide three-​dimensional reconstructions of the diseased vessels and may be used for planning surgical treatment. Angiography is only required as an adjuvant to endovascular treatment, for surgical planning in some circumstances, or in the management of the acutely ischaemic limb. Attention to risk factors, in particular smoking, blood pressure, and exercise, are important issues.

Critical limb ischaemia requires administration of analgesia and rapid surgical intervention. The severity of ischaemia will determine the treatment options considered. However, all patients with a severely ischaemic limb should be given adequate analgesia and 5000 units of heparin intravenously. Many will be old and frail, with significant medical comorbidities. These issues must be considered in deciding whether or not surgical intervention is appropriate for any individual case, with action taken to improve those aspects of the patient’s medical condition that can be improved before surgery, or as part of continuing medical management. For a patient with irreversible ischaemia (fixed skin staining and tense muscles), the main decision is whether a primary amputation or palliative care should be offered. If severe but potentially reversible ischaemia is present (white leg), surgery is usually the treatment of choice. Delay while thrombolytic therapy is tried is not advisable in this group. For patients with moderate limb ischaemia, where there is no paralysis and only mild sensory loss, arteriography with consideration of the potential use of thrombolysis should be performed. However, it should be remembered that thrombolysis is associated with numerous potential complications, most notably gastrointestinal haemorrhage and stroke, and is contraindicated in the early postoperative period. If the limb is salvageable, it may be possible to offer the patient an endovascular procedure, such as an angioplasty (with or without stenting). Surgical treatment can involve simple embolectomy, but may require a bypass procedure or endarterectomy, and in the severely ischaemic limb fasciotomies may be needed to treat or prevent a compartment syndrome. For at least 10% of patients, it will not be possible to offer revascularization: a few of these may benefit from the use of a prostacyclin analogue (iloprost), which might diminish amputation rates and alleviate pain. Any benefits of gene therapy on avoidance of amputation, with vascular endothelial growth factor, fibroblast growth factor, or other molecular mediators, are far from established and the only large randomized trial was disappointing. Limb salvage rates for patients presenting with critical limb ischaemia are variable, probably 50–​60% at 2 years, dependent on the severity of disease. In a patient presenting with acute leg ischaemia the outlook is poor, with only about 60% leaving hospital with an intact limb. The 30-​day mortality for this group of patients can be as high as 30%, the main cause of death being cardiac disease. The strategy for management is described in Fig. 16.14.2.2. Controversial areas in the treatment of acute leg ischaemia include the role of arteriography, which technique of thrombolysis is the safest and most cost-​effective, and whether initial treatment with thrombolysis is beneficial or harmful as compared to surgery. A recently updated Cochrane review, which included five randomized trials comparing thrombolysis and surgery for the initial treatment of acute limb ischaemia, found no overall difference in outcomes (limb salvage or death) at 1  year. Initial thrombolysis was associated with higher risk of major haemorrhage, stroke, and distal embolization, but also less severe degree of intervention overall. In the patient who has had an embolic event, long-​ term anticoagulation should not be forgotten, and nor should a search for the source of embolus. If the patient is not in atrial fibrillation, and has normal cardiac enzymes and 12-​lead electrocardiogram (ECG),

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• Pain relief • Intravenous heparin (5000 IU) • Assessment of patient prognosis and limb salvage with vascular surgical consultation

Irreversible Fixed skin staining Tense muscles

Severe White leg

Amputation or palliative care

Surgery

Moderate Dusky leg Mild sensory loss Duplex or arteriogram to evaluate treatment modaility

Fig. 16.14.2.2  Management of the patient with an acutely ischaemic leg.

then they should have an echocardiogram to exclude any valvular lesion, a 24-​h electrocardiogram (ECG) to look for arrhythmia, an ultrasound scan to exclude abdominal aortic aneurysm, and a screen for thrombophilia. In many centres a CT scan of the thoracic and abdominal aorta will be performed. Chronic leg ischaemia In chronic limb ischaemia, management depends upon the severity of the disease. Most patients present with claudication, which is relatively benign: symptoms of intermittent claudication will progress to critical limb ischaemia in less than one in five patients and only about 5% will go on to lose a limb. However, claudication identifies patients with a threefold increased risk of death from either heart disease or cerebrovascular disease compared with age-​and sex-​ matched controls. It is important when planning treatment that all the potential risk factors are covered. In the past surgical intervention was usually considered unnecessary: at least one-​third will have improvement of symptoms with simple medical treatment and exercise. However recent trials have suggested that either angioplasty with adjunct and stents or coated balloons or angioplasty combined with exercise therapy may offer early benefits (to 2 years) and longer-​ term results are awaited eagerly. The current treatment of patients with chronic lower leg pain is shown in Fig. 16.14.2.3. ABPI ≥ 0.9

ABPI Ppv

Zone II Ppa>Palv>Ppv Zone III Ppa>Ppv>Palv Blood flow

Fig. 16.15.1.3  The three-​zone model of pulmonary blood flow distribution.

encompassed in the three-​zone model of pulmonary circulation (Fig. 16.15.1.3). This model relies on the assumption that the site of major flow resistance is in the small vessels whose extravascular pressure is the alveolar pressure (Palv). There is no flow in zone I because Palv is greater than Ppa. Flow increases down zone II because the driving pressure increases by 1 cm of H2O for each 1 cm distance down the lung. Flow increases with distance down zone III, although ΔP (Ppa − Ppv) remains constant, because local PVR decreases due to capillary distension and recruitment. The driving pressure for blood flow is determined by the relationship between Palv, Ppa, and pulmonary venous pressure (Ppv) down the upright lung. A further zone (zone IV) is found at the lung base: in this zone, blood flow is observed to decrease with distance down the lung due to increased perivascular pressure in extra-​alveolar vessels.

Gravity-​independent  flow The branching pattern of pulmonary arteries imposes changes in perfusion that are independent of gravity. Within any given horizontal level of the upright lung, there is a decrease in blood flow in peripheral lung regions compared to central hilar regions. This is thought to be due to the reduction in Ppa in small acinar arteries with increasing distance from the hilum. This pattern is also seen at the level of the secondary lobule (the group of acini supplied by one terminal bronchiole), with a decreasing gradient of blood flow from the centre to the periphery.

Regulation of pulmonary vasomotor tone The pulmonary circulation differs from the systemic in that it is under minimal resting tone and is almost fully dilated under normal conditions. Circulating and local production of vasodilators and vasoconstrictors contribute to the resting tone, with the balance tipped in favour of vasodilators. Nitric oxide, produced locally by endothelial cells, and the arachidonic acid metabolite prostacyclin are important vasodilators that contribute to this low pulmonary vascular tone. The autonomic nervous system interacts with humoral mediators and haemodynamic forces in the control of pulmonary vascular tone, autonomic innervation of the lung being via parasympathetic (cholinergic:  predominantly vasodilator) and

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sympathetic (adrenergic:  predominantly vasoconstrictor) nerves in the periarterial plexus.

Hypoxic pulmonary vasoconstriction The pulmonary circulation responds to a reduction in the partial pressure of alveolar oxygen by vasoconstriction. This is opposite to the response to hypoxia in the systemic circulation, where tissue hypoxia leads to vasodilatation, hence improving tissue oxygen delivery. Hypoxic pulmonary vasoconstriction (HPV) probably plays little role in the normal distribution of pulmonary blood flow or regulation of ventilation–​perfusion relationships in humans. However, in diseases characterized by airway obstruction, such as acute asthma or chronic obstructive lung disease, HPV can divert blood flow away from poorly ventilated lung regions, reducing venous admixture (shunt through poorly ventilated lung regions) and preserving arterial oxygenation. The magnitude of the response varies widely between individuals and is, at best, 50% efficient. It is noteworthy that populations indigenous to high-​altitude regions (e.g. Tibetans), lack HPV with no obviously detrimental effect. At high altitude, with low atmospheric partial pressures of oxygen, HPV would lead to generalized vasoconstriction and pulmonary hypertension, which is presumably more detrimental than the lack of HPV.

Ventilation–​perfusion relationships In the normal lung, it is remarkable that pulmonary blood flow and ventilation are, in general, well matched given the heterogeneity of blood flow described earlier. Of course, regional ventilation is also under similar constraints and forces as the blood flow. In terms of the structure and function of the airways and alveoli in brief, the airways run with the arteries in the bronchovascular bundle and the branching patterns are similar. Regional ventilation is under the influence of gravity: the lung sits in the thorax under its own weight, which leads to a gradient of intrapleural pressure, with more negative pressures at the top of the lung than at the bottom in the upright position. This means that the lung is more expanded at the apex than at the base at the end of a normal breath (functional residual capacity). Thus, the upper and lower parts of the lung are operating on different portions of their pressure–​volume curves. The result is that, during normal breathing, greater ventilation is delivered to the bottom than to the top of the lung. This gradient of regional ventilation down the lung is reminiscent of the gradient of blood flow just described. In fact, with increasing distance up the lung, the rate of change of ventilation per unit of alveolar volume is somewhat less than the rate of change of perfusion (about one-​third). This leads to large regional differences in the ventilation–​perfusion ratio up the lung (Fig. 16.15.1.4):  alveoli at the bottom of the lung are relatively overperfused, leading to a low ventilation–​perfusion ratio (c.0.6); by contrast, alveoli at the apex of the lung are relatively underperfused, leading to ventilation–​perfusion ratios over 3.0. Nevertheless, the overall ventilation–​perfusion ratio for the whole lung is approximately 0.85. The regional ventilation–​perfusion ratio will determine the partial pressures of oxygen and CO2 found in the alveoli at a given level of the lung, and this will be reflected in the gas tensions found in pulmonary venous blood draining those alveoli. The result is that the Po2 is higher, and the Pco2 lower, in blood draining from the top of the lung, compared

Fig. 16.15.1.4  (a) O2–​CO2 diagram showing how the change in ventilation–​perfusion ratio up the lung determines the regional composition of alveolar gas. Dashed lines show the composition of mixed venous (pulmonary arterial) blood and inspired (tracheal) gas. (b) Effects of change in ventilation–​perfusion ratio up the lung on the regional composition of alveolar gas, with volumes of lung slices, ventilations, and blood flows also shown.

with the bottom. The matching of ventilation and perfusion in the normal lung ensures that the overall ventilation–​perfusion ratio remains fairly constant with changes in posture or exercise.

Acknowledgement Much of the chapter written for the third edition of the Oxford Textbook of Medicine by the late J. S. Prichard has been retained here.

16.15.2  Pulmonary hypertension

FURTHER READING De Mello DE, Reid LM (1997). Arteries and veins. In:  Crystal RG, et al. (eds) The lung: scientific foundations, 2nd edition, pp. 1117–​27. Lippincott-​Raven, Philadelphia, PA. Hughes JMB (1997). Distribution of pulmonary blood flow. In: Crystal RG, et  al. (eds) The lung:  scientific foundations, 2nd edition, pp. 1523–​36. Lippincott-​Raven, Philadelphia, PA. Hughes JMB, Morrell NW (2001). Pulmonary circulation: from basic mechanisms to clinical practice. Imperial College Press, London. Singhal S, et  al. (1973). Morphometry of the human pulmonary arterial tree. Circ Res, 33,  190–​7. West JB, Dollery CT, Naimark A (1964). Distribution of blood flow in isolated lung: relation to vascular and alveolar pressures. J Appl Physiol, 19, 713–​24. West JB (1985). Ventilation/​blood flow and gas exchange, 4th edition. Blackwell Scientific Publications, Oxford.

16.15.2  Pulmonary hypertension Nicholas W. Morrell ESSENTIALS Symptoms of unexplained exertional breathlessness or symptoms out of proportion to coexistent heart or lung disease should alert the clinician to the possibility of pulmonary hypertension, and the condition should be actively sought in patients with known associated conditions, such as scleroderma, hypoxic lung disease, liver disease, or congenital heart disease. Heterozygous germ-​line mutations in the gene encoding the bone morphogenetic protein type II receptor (BMPR2) are found in over 70% of families with pulmonary arterial hypertension. Pulmonary hypertension is defined as a mean pulmonary arterial pressure greater than 25 mm Hg at rest, and may be due to increased pulmonary vascular resistance (e.g. pulmonary arterial hypertension), increased transpulmonary blood flow (e.g. congenital heart disease), or increased pulmonary venous pressures (e.g. mitral stenosis). Exercise tolerance and survival in pulmonary hypertension is ultimately related to indices of right heart function, such as cardiac output. Investigation—​echocardiography is a good screening tool for the presence of pulmonary hypertension, but right heart catheterization is needed to confirm the diagnosis and guide treatment. CT pulmonary angiography and high-​resolution CT are important to exclude underlying chronic thomboembolic pulmonary hypertension and parenchymal lung disease. In idiopathic pulmonary arterial hypertension a vasodilator study should be undertaken at the time of right heart catheterization to detect the few (5–​10%) patients who will have good long-​term survival on calcium channel blockers. Management—​ treatments for pulmonary arterial hypertension include prostanoids, endothelin receptor antagonists, phosphodiesterase inhibitors, and direct activators of soluble guanylyl cyclase, which improve symptoms of breathlessness, exercise tolerance, quality of life, and probably survival. Chronic thromboembolic

pulmonary hypertension is an important diagnosis to make because selected patients with predominantly proximal disease can be cured by pulmonary endarterectomy.

Introduction The normal pulmonary circulation, as described in Chapter 16.15.1, is a low-​pressure, high-​flow system that delivers the output of the right ventricle to the alveolar capillary network during each cardiac cycle for the purposes of gas exchange. Pulmonary hypertension is defined as a sustained elevation of mean pulmonary arterial pressure to more than 25 mm Hg at rest. Many diseases can lead to an elevation of pulmonary arterial pressure. Therefore, the term ‘pulmonary hypertension’ is not a final diagnosis, but a starting point for further investigation. In general terms, the main causes of pulmonary hypertension are (1) a narrowing or obstruction of the precapillary pulmonary arteries, (2) an increase in pulmonary venous pressure, (3) a persistent elevation of pulmonary blood flow, (4) chronic thromboembolic disease, or (5) miscellaneous causes. This simplified approach is worth keeping in mind during the assessment of patients found to have pulmonary hypertension, because it has major consequences for prognosis and management.

Classification of pulmonary hypertension Table 16.15.2.1 shows the 5th World Symposium on Pulmonary Hypertension (2013) classification of pulmonary hypertension as determined by an international panel of experts. The grouping of causes in this classification takes into account similarities in aetiology, pathology, and haemodynamic assessment at right heart catheterization. The classification helps to understand the underlying cause of pulmonary hypertension in a given patient and to plan management, hence it is a useful framework to consider the various causes of pulmonary hypertension, described in more detail next.

Pulmonary arterial hypertension The term pulmonary ‘arterial’ hypertension (PAH) refers to conditions characterized predominantly by a precapillary obstruction to blood flow through the pulmonary vascular bed, characterized hemodynamically by a mean pulmonary arterial pressure of greater than 25 mm Hg, an end-​expiratory pulmonary artery wedge pressure (PAWP) 15 mm Hg or less, and a pulmonary vascular resistance more than 3 Wood units. This elevation of pulmonary vascular resistance increases the driving pressure required to maintain blood flow through the lungs: pulmonary arterial pressure rises to maintain adequate left ventricular filling. The normal mean pulmonary arterial pressure (c.17  mm Hg) is about one-​fifth of the systemic mean blood pressure. In PAH, mean pulmonary arterial pressure may approach systemic levels. The normally thin-​walled right ventricle struggles to cope with the increasing pressure. At first it undergoes a degree of hypertrophy, which increases its ability to generate higher pressures, but ultimately it begins to fail and cardiac output

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Table 16.15.2.1  Clinical classification of pulmonary hypertension (NICE 2013) 1 Pulmonary arterial hypertension 1.1 Idiopathic PAH 1.2 Heritable PAH 1.2.1 BMPR2

Increasing PVR Preclinical

Symptomatic / stable

Cardiac output at peak exercise

Progressive / declining Pulmonary pressure

1.2.2 ALK-​1, ENG, SMAD9, KCNK3 1.2.3 Unknown 1.3 Drug and toxin induced 1.4 Associated with:

Cardiac output at rest

1.4.1 Connective tissue disease 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart diseases 1.4.5 Schistosomiasis 1′ Pulmonary veno-​occlusive disease and/​or pulmonary capillary haemangiomatosis 1″ Persistent pulmonary hypertension of the newborn (PPHN) 2 Pulmonary hypertension due to left heart disease

Fig. 16.15.2.1  Relationship between pulmonary hypertension, right ventricular function, and symptoms in pulmonary hypertension. Pulmonary arterial hypertension (PAH) is characterized by progressively increasing pulmonary vascular resistance. In the early stages, the disease is asymptomatic and only manifests during exercise or during unusually demanding activities, but over time there is a progressive reduction in cardiac output and increasing pulmonary vascular resistance (PVR), eventually progressing to cardiac failure and death.

2.1 Left ventricular systolic dysfunction 2.2 Left ventricular diastolic dysfunction

Epidemiology and aetiology

2.3 Valvular disease

PAH is broadly divided into idiopathic PAH (previously known as primary pulmonary hypertension), and PAH found with other known associated conditions or triggers. Idiopathic PAH is further divided into familial or sporadic disease, with about 10% of patients with idiopathic PAH having an affected relative. Idiopathic PAH is a rare disorder with an estimated incidence of 1 to 2 per million per year. It is more common in women (female:male sex ratio = 2.3:1), can occur at any age, but most commonly occurs between the ages of 40 and 50 years. PAH that is pathologically indistinguishable from the idiopathic form can occur in a range of associated conditions (Table 16.15.2.1). Of the autoimmune rheumatic diseases, the most common association is with systemic sclerosis, where PAH can complicate the clinical course in 15–​20% of patients in the absence of interstitial lung disease. Other associated conditions include mixed connective tissue disease and systemic lupus erythematosus, and more rarely rheumatoid arthritis, dermatopolymyositis, and primary Sjögren’s syndrome. There is a well-​recognized association of PAH with congenital heart disease leading to left-​to-​right shunts. Overall, the prevalence of PAH is 15–​30%, but varies depending on the nature of the underlying cardiac defect. Portal hypertension, usually associated with cirrhosis, is associated with PAH in less than 5% of patients. There is an unusually high prevalence of PAH (c.0.5%) in patients with HIV infection. Epidemiological studies have confirmed the association of PAH with amphetamine-​like diet pills: in the 1970s, increased numbers of patients with PAH were found to have been exposed to Aminorex, and in the 1990s further studies confirmed an association of PAH with appetite-​ suppressant drugs of the fenfluramine and dexfenfluramine group. An epidemic of PAH also occurred in Spain in the 1980s, following the ingestion of contaminated rapeseed oil. Other more rarely associated conditions are listed in Table 16.15.2.1.

2.4 Congenital/​acquired left heart inflow/​outflow tract obstruction and congenital cardiomyopathies 3 Pulmonary hypertension due to lung diseases and/​or hypoxia 3.1 Chronic obstructive pulmonary disease 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-​disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental lung diseases 4 Chronic thromboembolic pulmonary hypertension (CTEPH) 5 Pulmonary hypertension with unclear multifactorial mechanisms 5.1 Haematologic disorders: chronic haemolytic anaemia, myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: tumoural obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH Main modifications to the previous Dana Point classification are in bold. BMPR2, bone morphogenic protein receptor type II; ENG, endoglin; PAH, pulmonary arterial hypertension. Reprinted from J Am Coll Cardiol, vol. 62 (25 Suppl), Simonneau G, et al., Updated Clinical Classification of Pulmonary Hypertension, pp. D34–​41, Copyright 2013, with permission from the American College of Cardiology Foundation.

declines. It is the reduction in cardiac output that generates most of the clinical symptoms in patients, with dyspnoea and fatigue being the most common (Fig. 16.15.2.1). The function of the right heart is the main determinant of prognosis in patients with PAH.

16.15.2  Pulmonary hypertension

The classification of PAH includes another rare pulmonary vascular disease, pulmonary veno-​occlusive disease (PVOD) and pulmonary capillary haemangiomatosis (PCH), which are the same entity. PVOD/​PCH is rarer than idiopathic PAH, but its true prevalence is unknown. Persistent pulmonary hypertension of the newborn is a disorder characterized by a failure of vascular transition from fetal to a neonatal circulation and estimated to affect 0.2% of liveborn term infants.

Genetics Familial or heritable PAH is a rare autosomal dominant condition, with reduced penetrance. It is indistinguishable on clinical or pathological grounds from idiopathic PAH. Linkage studies localized the gene to the long arm of chromosome 2 (2q33). In 2000, heterozygous germ-​line mutations were identified in the BMPR2 gene encoding the bone morphogenetic protein type II receptor, which is a constitutively active serine-​threonine kinase that acts as a receptor for bone morphogenetic proteins (BMPs), these being members of the transforming growth factor β (TGFβ) superfamily. Mutations in BMPR-​II have now been identified in over 70% of cases of familial PAH, and similar mutations are also found in 15–​26% of patients thought to have sporadic or idiopathic disease. Many of these are unexpected examples of familial disease with low penetrance, although de novo mutations have also been reported. BMPR-​II mutations have been identified in most of the 13 exons of the BMPR2 gene, most (c.70%) being nonsense or frameshift mutations predicted to cause haploinsufficiency due to nonsense-​ mediated mRNA decay of the mutant transcript: only the wild-​type allele is expressed in these cases, reducing the amount of BMPR-​ II protein to about 50% of normal. About 30% of the mutations are mis-​sense mutations, which cause retention of mutant protein within the endoplasmic reticulum or affect important functional domains of the receptor, such as the ligand-​binding domain or the kinase domain. Mutations in BMPR-​II have also been found in a small proportion (c.10%) of patients with PAH associated with appetite suppressants, and in children with complicated PAH associated with congenital heart disease. Mutations in another TGFβ receptor, ALK-​1, have also been reported in association with PAH. These are usually found in families with hereditary haemorrhagic telangiectasia, but occasionally some family members develop severe PAH. These findings have highlighted the central role of the TGFβ signalling pathway in the pathogenesis of PAH. The BMPR-​II/​ALK-​1 receptor complex on endothelial cells has been found to be the major signalling complex for BMPs 9 and 10, providing major mechanistic insights into the pathobiology of PAH. Mutations in other TGFβ-​related genes have also been identified in rare cases of heritable PAH, including endoglin, Smad1, Smad9, and BMP9. In addition, mutations in the potassium channel KCNK3 have been reported in rare cases of heritable PAH. Mutations in the eukaryotic translation initiation factor 2-α kinase 4 (EIF2AK4) were recently identified in families with autosomal recessive PVOD/​PCH, accounting for all familial cases and up to 25% of sporadic cases.

Pathology Typical morphological appearances include increased musculari­ zation of small ( vasodilators

Minimal resting tone

Increased tone Vascular remodelling

Fig. 16.15.2.4  An imbalance of pulmonary vascular vasodilators and vasoconstrictors contributes to the vascular constriction and remodelling in pulmonary hypertension. ANP, atrial natriuretic peptide; NO, nitric oxide; PGI2, prostacyclin.

important vasodilator pathways also exert antiproliferative effects on smooth muscle cells and fibroblasts via production of the cyclic nucleotides cAMP and cGMP. Deficiency of these key vasodilator pathways has provided the rationale for many of the new therapies that have emerged over the past two decades (see ‘Newer agents’). Another important pathway involved in the process of pulmonary vascular remodelling includes loss of potassium channel (Kv1.5 and Kv2.1) expression and function, promoting smooth muscle cell contraction and survival. Activation of vascular elastases within the vessel media and disruption of the elastic laminae is also a key step in disease pathogenesis. Inflammatory cells may also contribute, especially in PAH associated with autoimmune conditions, accompanied by increased expression of inflammatory cytokines and chemokines in small pulmonary arteries. Pathological studies have identified the presence of thrombosis in small pulmonary arteries of patients with PAH. It is not clear whether this represents in situ thrombosis as a consequence of the reduced blood flow, or embolic phenomena. Platelet dysfunction has also been recognized in PAH, and an increased frequency of antiphospholipid antibodies associated with an increased thrombotic risk. The identification of mutations in the BMPR-​II receptor has highlighted the important role of the TGFβ superfamily in the pathogenesis of familial PAH. Most mutations lead to a reduction in a critical signalling pathway, the Smad pathway, downstream of BMP receptors. This, in turn, leads to the failure of BMPs to activate transcription of important target genes. In smooth muscle cells, BMPR-​ II mutation leads to a failure of the normal growth suppressive and proapoptotic effects of bone morphogenetic proteins, favouring excessive pulmonary artery smooth muscle cell proliferation and survival (Fig. 16.15.2.5). In endothelial cells, by contrast, BMPR-​ II mutation promotes endothelial dysfunction and endothelial cell apoptosis. The combination of endothelial cell dysfunction and smooth muscle cell proliferation within the pulmonary circulation favours the development of vascular obliterative lesions and pulmonary hypertension. Clonal expansion of apoptosis-​resistant endothelial cells may contribute to the formation of plexiform lesions. However, this simple model does not explain all of the features of heritable PAH. In particular, it does not explain why disease is

confined to the lung circulation, although BMPR-​II is most highly expressed in the lung vasculature. In addition, it does not explain why the presence of the mutation is not sufficient on its own to cause disease, with gene penetrance as low as 20% in some families. These observations indicate that additional environmental and/​or genetic factors are necessary for disease manifestation. This putative ‘second hit’ may further impact on BMP signalling pathways, leading to a critical reduction in bone morphogenetic signalling via Smad proteins and initiation of the process of pulmonary vascular remodelling. Although mutations in BMPR-​II are not generally found in most secondary forms of PAH, it is now becoming clear that dysfunction of the BMPR-​II pathway is involved in their pathogenesis. Further research is likely to reveal further clues to the involvement of this important pathway in vascular disease.

Clinical features Symptoms The three main presenting symptoms are dyspnoea, chest pain, and syncope. The severity of symptoms is related to prognosis. A modified New York Heart Association (NYHA) score is a useful way to assess symptom severity and follow response to treatment (Box 16.15.2.1). Unexplained breathlessness on exertion should always raise the possibility of PAH, particularly in the setting of conditions known to be associated with pulmonary hypertension (Table 16.15.2.1). The condition may have an insidious onset: frequently, there is a delay of years between the onset of first symptoms and diagnosis. Syncope is an ominous sign, usually reflecting severe right ventricular dysfunction. Other symptoms include lassitude, abdominal swelling from ascites, and ankle swelling. Small haemoptyses may occur at later stages. Clinical signs Tachypnoea may be present, even at rest. Peripheral cyanosis is common due to a low cardiac output. Central cyanosis occurs later as pulmonary gas exchange deteriorates or right-​to-​left shunting occurs through a patent foramen ovale. The jugular venous pulse may be elevated with a prominent ‘a’ wave, reflecting the increased force

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MUTANT

cell proliferation clonal expansion

R-smad BMPR-II Co-smad

BMP–2, –4, –7

Primary pulmonary hypertension

GDF–5, –6 Type 1 receptor P

heterodimeric complex WILD TYPE

P DNA binding partner

P

growth inhibition cell differentiation gene transcription

P

Normal pulmonary artery

R - smad cell membrane

Fig. 16.15.2.5  The potential role of mutations in the bone morphogenetic protein type II receptor (BMPR-​II) in familial PAH. The wild-​type receptor signals in response to ligands by activating receptor-​regulated Smad proteins (R-​Smads), which dimerize with common partner Smads (Co-​Smads) to regulate gene expression in the vascular cell. Mutation in BMPR-​II disrupts Smad signalling and leads to abnormal vascular cell proliferation. BMP, bone morphogenetic protein; GDF, growth differentiation factors. By Hughes, J. B. M. From Pulmonary circulation: Basic mechanisms to clinical practice (2001). With permission of Imperial College Press.

of atrial contraction, or—​if tricuspid regurgitation is present—​there may be a large ‘V’ wave. There may be a right ventricular heave and a pulsatile liver. On auscultation, forceful closure of the pulmonary valve leads to an accentuated pulmonary arterial component of the second heart sound. There are often a third and fourth right heart sound. The murmurs of tricuspid regurgitation (systolic) or pulmonary regurgitation (diastolic) may be heard. Jaundice, ascites, and peripheral oedema may be present at advanced stages of the disease.

Differential diagnosis If the symptoms and clinical signs suggest pulmonary hypertension, the differential diagnosis should be considered with reference to the Box 16.15.2.1  Modified New York Heart Association functional classification of pulmonary hypertension • Class I—​pulmonary hypertension without resultant limitation of physical activity. Ordinary physical activity does not cause undue dyspnoea or fatigue, chest pain, or near syncope • Class II—​pulmonary hypertension resulting in slight limitation of physical activity. The patient is comfortable at rest. Ordinary physical activity causes undue dyspnoea or fatigue, chest pain, or near syncope • Class  III—​pulmonary hypertension resulting in marked limitation of physical activity. The patient is comfortable at rest. Less than ordinary activity causes undue dyspnoea or fatigue, chest pain, or near syncope • Class  IV—​ Pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnoea and/​or fatigue may be present at rest. Discomfort is increased by any physical activity

classification in Table 16.15.2.1. Most importantly, the presence of left heart disease, parenchymal lung disease, or congenital heart disease should be excluded. Pulmonary hypertension due to chronic thromboembolic disease is important to detect because specific surgical treatment is available. Idiopathic PAH remains a diagnosis of exclusion.

Clinical investigation The investigation of a patient with suspected pulmonary hypertension involves (1)  the exclusion of other underlying causes and (2) an assessment of severity of pulmonary hypertension and right heart failure for prognosis and treatment. The investigations that are useful in identifying the aetiology of newly diagnosed, unexplained pulmonary hypertension are listed in Box 16.15.2.2. Blood tests A thrombophilia screen, including antithrombin III, proteins C and S, factor V Leiden, anticardiolipin antibodies, and lupus anticoagulant should be performed, and may reveal clotting abnormalities predisposing to chronic thromboembolic pulmonary hypertension (CTEPH). Thyroid function should be checked since both hypo-​and especially hyperthyroidism are commonly reported associations. An autoantibody screen should be performed to exclude underlying autoimmune rheumatic or vasculitic disease:  positive antinuclear antibodies (ANA) can be found in 30–​40% of patients with idiopathic PAH, but a positive test for antineutrophil cytoplasmic antibodies (ANCA) would be uncommon. Since there is an increased incidence of unexplained pulmonary hypertension in HIV-​positive patients, this diagnosis should always be considered.

16.15.2  Pulmonary hypertension

Box 16.15.2.2  Investigation of the patient with suspected idiopathic pulmonary hypertension Blood tests • Full blood count/​film/​differential • Hb electrophoresis • Urea and electrolytes • Liver function including γ-GT • Thyroid function • Thrombophilia screen: − Antithrombin III − Protein C − Protein S − Factor V Leiden − Anticardiolipin antibody − Lupus anticoagulant • CMV DEAFF • Autoantibodies: − RhF − ANA − ENAs − Anti-​dsDNA − Anticardiolipin IgG and IgM − Anti-​sm/​anti-​SCL/​anti-​SS − Complement C3, C4, CH50 − ANCA • Serum angiotensin converting enzyme • Hepatitis screen • HIV test Imaging • Chest radiograph • Ventilation–​perfusion lung scan • High-​resolution and spiral CT • Pulmonary artery angiography

Fig. 16.15.2.6  Chest radiograph demonstrating cardiomegaly with dilated right heart chambers and dilatation of the proximal pulmonary arteries in a patient with PAH secondary to an atrial septal defect. Courtesy of Dr Nick Screaton, Addenbrooke’s Hospital.

only sign in predominantly distal disease (Fig. 16.15.2.8). A high-​ resolution CT scan will pick up unsuspected parenchymal abnormalities, such as fibrosis. CT scanning is also useful to indicate more uncommon forms of PAH, such as PVOD, when there may be a degree of mediastinal lymphadenopathy and septal lines in the lung periphery, presumably indicating lymphatic and venous obstruction (Fig. 16.15.2.9). On ventilation–​perfusion lung scanning, the pattern of ventilation is usually normal in idiopathic PAH, and uneven ventilation

Lung function • Pulmonary function tests • Exercise tests with saturation monitoring • Arterial blood gases on air Cardiac function • ECG • Echocardiogram • Diagnostic cardiac catheterization Miscellaneous • Urine microscopy • Abdominal ultrasound—​cirrhosis

Imaging The plain chest radiograph shows enlargement of the proximal pulmonary arteries, which may be dramatic, with peripheral pruning of the pulmonary vascular pattern, giving rise to increased peripheral radiolucency. If heart failure is present the heart may be enlarged, with particular enlargement of the right atrium (Fig. 16.15.2.6). The chest radiograph may also give clues to underlying diagnoses such as interstitial lung disease. Spiral contrast-​enhanced CT will detect proximal pulmonary arterial obstruction suggestive of acute or chronic thromboembolic disease (Fig. 16.15.2.7). A pattern of mosaic perfusion of the lung parenchyma is also a feature of CTEPH, and may be the

Fig. 16.15.2.7  Image from a CT pulmonary angiogram at the level of the right main pulmonary artery demonstrating dilatation of the main pulmonary artery (PA) with laminated thrombus in the distal right pulmonary artery (arrow) in keeping with proximal CTEPH. Courtesy of Dr Nick Screaton, Addenbrooke’s Hospital.

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Pulmonary artery angiography is really only required if the diagnosis is likely to be CTEPH, in which situation angiography will provide precise anatomical information regarding the location of vascular obstruction, indicated by abrupt cut-​off of vessels or intravascular webs, that may be of great use if surgical endarterectomy is being contemplated. However, CT pulmonary angiography or MR angiography may be employed in place of conventional angiography. The main contribution of MRI is in the assessment of patients with suspected intracardiac shunts or with anomalous vascular anatomy (e.g. if a shunt is suspected on the basis of right heart catheterization but cannot be demonstrated by echocardiography). MRI can also provide further pulmonary angiographic images. Pulmonary function tests

Fig. 16.15.2.8  Coronal multiplanar reconstruction demonstrating extensive mosaic perfusion in both lungs in a patient with CTEPH. Courtesy of Dr Nick Screaton, Addenbrooke’s Hospital.

should suggest underlying lung disease. The pattern of perfusion is also virtually normal, although small patchy perfusion defects may be present. This is in contrast to the appearance in CTEPH when segmental or larger perfusion defects persist, often indistinguishable from the pattern of acute pulmonary embolism (Fig. 16.15.2.10).

The typical pattern for standard pulmonary function test for disease confined to the pulmonary circulation is to find normal lung volumes; normal forced expiratory volume in 1 s (FEV1)/​vital capacity (VC) ratio (>0.75), indicating no airflow obstruction; and low transfer factor (diffusing capacity, TLco), and low transfer coefficient (Kco). The low diffusing capacity probably results from a combination of a reduced cardiac output and disease affecting the small arterioles, thereby reducing local perfusion. If the Kco is less than 50% predicted with normal spirometry, a diagnosis of PVOD/​ PCH should be suspected. Additional findings in the pulmonary function tests—​such as marked airflow obstruction (e.g. severe chronic obstructive pulmonary disease) or a restrictive defect (e.g. pulmonary fibrosis)—​would indicate the presence of an underlying cause for the pulmonary hypertension. However, subtle changes in lung volumes and mild airflow obstruction have been reported in a few patients with PAH. In some groups of patients at high risk of developing PAH (e.g. in scleroderma), the low transfer coefficient can be monitored at intervals, with breathlessness accompanied by a fall in the low transfer coefficient sometimes being the first sign of this complication. Exercise testing

Fig. 16.15.2.9  Transverse CT image through the lower zones demonstrating heterogeneous attenuation of the lung parenchyma, centrilobular ground-​glass opacities, and smooth thickening of the interlobular septa in a patient with pathologically proven veno-​ occlusive disease. Courtesy of Dr Nick Screaton, Addenbrooke’s Hospital.

Significant PAH is always associated with a reduced exercise capacity, one of the most useful tests of this being the 6 min walk test, with monitoring of heart rate and oxygen saturation. This can readily be repeated to assess patients over time and as a measure of response to treatment. A normal distance is more than 500 m, with a low 6 min walk predictive of a poor survival. Full cardiopulmonary exercise testing is technically more demanding to perform and is only recommended if the diagnosis is in doubt (e.g. if there was a need to document cardiovascular limitation on exercise). Peak oxygen uptake on exercise is low and the anaerobic threshold is reduced to about 40% of normal. There is excessive ventilation for a given degree of oxygen consumption or CO2 output, even at rest. There is no ventilatory impairment when underlying lung disease is absent. There is often a pronounced tachycardia at submaximal exercise, and usually arterial oxygen desaturation. ECG In symptomatic PAH, the ECG is abnormal in 80 to 90% of cases, but it has inadequate sensitivity (55%) and specificity (70%) as a

16.15.2  Pulmonary hypertension

Perfusion

Ventilation

Fig. 16.15.2.10  Perfusion scintigram demonstrates multiple perfusion defects in a patient with CTEPH. Courtesy of Dr Nick Screaton, Addenbrooke’s Hospital.

screening tool for detecting pulmonary hypertension. The typical appearances are right-​axis deviation (more than + 120°) in the limb leads, and a dominant R wave and T wave inversion in the right precordial leads, accompanied by a dominant S wave in the left precordial leads, suggesting right ventricular hypertrophy (Fig. 16.15.2.11). Tall, peaked P waves in the right precordial and inferior leads denote right atrial enlargement. Right bundle branch block is common.

where RAP is right atrial pressure, which can be estimated clinically from the height of the jugular venous pressure. In the absence of pulmonary valve stenosis, the right ventricular systolic pressure is equal to the pulmonary artery systolic pressure (PASP). There is a reasonable correlation between Doppler estimates of PASP and catheter measurements. Newer echocardiographic techniques such as three-​ dimensional echo and tissue Doppler are being evaluated.

Echocardiography

Right heart catheterization

Echocardiography remains the best screening test for significant pulmonary hypertension. It detects the presence, and direction, of intracardiac shunts. Usually this is possible using conventional transthoracic techniques, but if visualization is poor or a small shunt is still suspected, then transoesophageal echocardiography may be necessary. In addition, the left ventricle can be assessed to determine whether there is a contribution from left ventricular systolic or diastolic dysfunction to elevated pulmonary arterial pressure. The function of the right side of the heart can also be assessed qualitatively and quantitatively. Atrial and ventricular dimensions and wall thickness can be measured, and paradoxical bowing of the intraventricular septum into the left ventricular cavity may be seen during systole as a consequence of greatly elevated right-​ sided pressures. Continuous-​wave Doppler echocardiography is used to measure high-​flow velocities across cardiac valves, one of the most commonly derived indices in the right heart being the pulmonary artery systolic pressure estimated by Doppler echocardiography from measurement of the velocity of the tricuspid regurgitant jet (c.80% of patients with PAH and 60% of normal subjects, have measurable tricuspid regurgitation). The maximum flow velocity (v) of the regurgitant jet is measured and inserted into the modified Bernoulli equation for convective acceleration pressure change, giving an estimate of right ventricular systolic pressure (RVSP):

Right heart catheterization remains the best technique for confirming the diagnosis of pulmonary hypertension and for providing important prognostic information. An elevated mean pulmonary arterial pressure of greater than 25 mm Hg at rest is the accepted definition. In patients with idiopathic PAH the mean pulmonary arterial pressure may exceed 60 mm Hg. The pulmonary capillary wedge pressure (PCWP) can also be determined at catheterization, which is an approximation of left atrial pressure. An elevated PCWP (>15 mm Hg) generally indicates left heart disease. Measurement of PCWP is often unreliable in the presence of CTEPH. Sampling of venous blood oxygen saturation as the catheter passes down from the right atrium to right ventricle may detect a sudden ‘step-​up’ in oxygenation, which would indicate the presence of a left-​to-​right shunt. Cardiac output can be determined by thermodilution or the Fick method. Indicators of right heart failure, and hence poorer prognosis, include (1) an elevated right atrial pressure (>10 mm Hg); (2) an elevated right ventricular end-​diastolic pressure (>10 mm Hg); (3) a reduced mixed venous oxygen saturation (Svo2 101.3°F)

7

1

Cardiac examination (any abnormality) Increased P2

21 23

Third heart sound

3

Fourth heart sound

24

Right ventricular lift

4

Jugular venous distension

Wheezes

29 51

18

5

2

Rhonchi

2

Decreased breath sounds Pleural friction rub

4 14

Lung examination (any abnormality) Rales (crackles)

15

17 3

0

11

47a

DVT Calf or thigh Calf only

32

Calf and thigh

14

Thigh only Homans’ sign

2 4

P2, pulmonary component of second sound. a Number of patients with PE who had one or more signs of DVT: oedema, 55; erythema, 5; tenderness, 32; palpable cord, 2. Data from Stein PD, et al. (1991). Clinical, laboratory, roentgenographic and electrocardiographic findings in patients with acute pulmonary embolism and no pre-​existing cardiac or pulmonary disease. Chest, 100, 598–​603 and Stein PD, et al. (2007). Clinical characteristics of patient with acute pulmonary embolism: data from PIOPED II. Am J Med, 120, 871–​9.

of atelectasis or a parenchymal abnormality was present in 98%. The remaining patients usually had either DVT or an unexplained low Pao2. PE was rarely diagnosed in the absence of dyspnoea or tachypnoea or pleuritic pain. Dyspnoea or tachypnoea occurred in 92% of all patients with PE (irrespective of pre-​existing cardiopulmonary disease) in whom the pulmonary emboli were in main or lobar pulmonary arteries, but in only 65% of patients in whom the largest PE was in segmental pulmonary arteries. Dyspnoea or tachypnoea or pleuritic pain occurred in 97% of patients with proximal PE and 77% of patients with pulmonary emboli in only segmental pulmonary arteries. Accuracy of clinical assessment To emphasize the point that the diagnosis of PE is difficult to make, senior staff physicians and postgraduate fellows taking part in the PIOPED study were uncertain of the diagnosis in most patients. Using individual judgement without any specific predetermined

Table 16.16.1.12  A model to determine the clinical probability of pulmonary embolism according to Wells and associates Clinical feature

Score (points)

Clinical signs and symptoms of DVT (objectively measured leg swelling and pain with palpation in the deep vein system)

3.0

Heart rate>100/​min

1.5

Immobilization ≥3 consecutive days (bed rest except to access bathroom) or surgery in previous 4 weeks

1.5

Previous objectively diagnosed PE or DVT

1.5

Haemoptysis

1.0

Malignancy (cancer patients receiving treatment within 6 months or receiving palliative treatment)

1.0

PE as likely or more likely than alternative diagnosis (based on history, physical examination, chest radiograph, ECG, and blood tests)

3.0

Score: 4, likely probability; >6.0, high probability. Data from Wells PS, et al. (2000). Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-​dimer. Thromb Haemost, 83, 416–​20 and from Wells PS, et al. (2001). Excluding PE at the bedside without diagnostic imaging: management of patients with suspected PE presenting to the emergency department by using a simple clinical model and D-​dimer. Ann Intern Med, 135, 98–​107.

criteria, senior staff were correct in the diagnosis in 88% of cases when their clinical assessment indicated a high probability of PE. When their clinical assessment indicated a low probability of PE, senior staff correctly excluded PE in 86%. Postgraduate fellows, on the basis of clinical assessment, were more accurate in excluding PE than they were in making the diagnosis. Objective scoring systems for the probability of acute PE give probability assessments similar to those of experienced physicians and do not require experience or clinical judgement. An example of a scoring system that is mostly objective is shown in Table 16.16.1.12.

Differential diagnosis The commonest presentation of acute PE is with dyspnoea and/​or pleuritic chest pain. There are several other possible causes of these symptoms, the commonest being musculoskeletal pain and pneumonia. Musculoskeletal chest pain can be very similar to that caused by pleurisy, and splinting of the chest can lead to a perception of breathlessness that may be exacerbated by anxiety. If there is an obvious history of local trauma to the chest, then the patient will rarely present to the physician, but it is worthwhile to ask specifically whether there has been any trauma or unaccustomed physical activity, whether the pain can be brought on by particular movements, and to examine carefully for local tenderness of the ribs, muscles, or costal margins. However, tenderness can sometimes be found in cases of pleurisy, and chest pain was reproduced by palpation in 20% of patients with PE. Appropriate history often supports a diagnosis of musculoskeletal pain. Pneumonia complicated by pleurisy can cause dyspnoea and chest pain. Important features to look for in the history include preceding systemic upset (flu-​like symptoms), high fever, and rigors, and on examination, high fever, ‘toxic appearance’, and chest signs of pneumonic consolidation. If a positive diagnosis of another cause of dyspnoea and/​or pleuritic chest pain cannot be made, then the default position should be to assume that the patient has PE until proven otherwise.

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Investigation Detection of evidence of thrombus within the circulation: D-​dimer As when considering the diagnosis of DVT, a ‘negative’ D-​dimer test is useful for excluding PE in patients who are clinically thought to be at low risk, but a ‘positive’ result does not establish the diagnosis. Hence, when used in the appropriate clinical context, D-​dimer testing is useful in defining a group of patients with suspected PE who do not require further investigation. In ranking the D-​dimer assays according to their sensitivity values and likelihood of increasing certainty for ruling out PE, the ELISA and quantitative rapid ELISA assays are significantly superior to the semiquantitative latex and whole-​blood agglutination assays. The quantitative rapid ELISA assay is more convenient than the conventional ELISA and provides a high level of certainty for a negative diagnosis of PE as well as DVT. A  particle-​enhanced immunoturbidometric assay (quantitative latex agglutination) gives results comparable to the rapid ELISA. The 3-​month risk of PE in untreated patients with a negative rapid ELISA D-​dimer measurement and low or intermediate clinical probability Geneva score was 0% (0 of 220). With a negative D-​dimer by rapid ELISA or quantitative latex agglutination assay and an unlikely (≤4) Wells score, PE occurred in 0.4% (4 of 1028), and with an unlikely (≤10) revised Geneva score in 1 of 320 (0.3%). Detection of the physical presence of thrombus in the pulmonary circulation Ventilation–​perfusion lung scans By 2001 in the United States of America the use of CT pulmonary angiography surpassed the use of ventilation–​perfusion lung scans for the diagnosis of acute PE, the use of ventilation–​perfusion lung scans having fallen into disfavour after the PIOPED trial because in most patients they led to an indeterminate result. Now, two decades since PIOPED was published, advances have been made in imaging equipment, improved methods of interpretation, and new radiopharmaceuticals. With such advances, and recognizing the risk of radiation with CT angiography, radionuclear imaging is receiving renewed interest. Based on the results of PIOPED, a high-​ probability lung ventilation–​perfusion scan (Fig. 16.16.1.2) indicates PE in 87%

of patients (Table 16.16.1.13) and a normal scan excludes PE. In the absence of any other information an intermediate probability scan indicates a 30% chance of PE and a low-​probability scan of 14%. A low-​probability ventilation–​perfusion scan by the criteria used in PIOPED does not therefore exclude PE. Intermediate and low-​probability interpretations may be grouped as ‘non​diagnostic’, which was frequently the case in PIOPED. Prior clinical assessment in combination with interpretation of the ventilation–​ perfusion scan improves diagnostic validity (Table 16.16.1.13). If the ventilation–​perfusion scan is interpreted as high probability for PE, and if the clinical impression is concordantly high, then the positive predictive value for PE is 96%. If the ventilation–​perfusion scan is low probability and the clinical suspicion is concordantly low, then PE is excluded in 96% of patients. The probability of PE can be determined based on the number of mismatched defects. Since PIOPED, criteria for the interpretation of very low probability lung scans (positive predictive value 6) n/​N (%)

Intermediate clinical probability (Wells score 2–​6) n/​N (%)

Low clinical probabilitya (Wells score 28 Days

Segmental

Fig. 16.16.1.5  Resolution of pulmonary emboli in main or lobar (▲) pulmonary arteries (PA) or segmental branches (●) according to number of days after initial CT angiogram. Bars = 95% confidence interval. Rate of resolution was slower in segmental branches. Data from Stein PD, et al. (2010). Resolution of pulmonary embolism on CT pulmonary angiography. AJR Am J Roentgenol, 194, 1263–​8.

16.16.1  Deep venous thrombosis and pulmonary embolism

support are indications for intervention. Analysis of data from 72 230 unstable (in shock or requiring ventilatory support) patients with PE throughout the United States of America from 1999 to 2008 showed that in-​hospital mortality with thrombolytic therapy was 15% compared with 47% in those who did not receive thrombolytic therapy. Mortality was further reduced to 7.6% if a vena cava filter was used in addition to thrombolytic therapy compared with 33% mortality in those who received a vena cava filter, but no thrombolytic therapy. All-​cause mortality in unstable patients was lower with thrombolytic therapy in every age group, including older people, irrespective of comorbid conditions. Right ventricular dysfunction on the echocardiogram of normotensive patients with PE may indicate impending haemodynamic instability. For this group meta-​analysis showed mortality was 1.4% with thrombolytics versus 2.9% with anticoagulants, but this benefit was offset by major bleeding in 7.7% with thrombolytics, versus 2.3% with anticoagulants. A more rapid lysis of pulmonary thromboemboli occurs with thrombolytic agents than occurs spontaneously in patients treated only with anticoagulants, but pulmonary reperfusion as demonstrated on perfusion lung scans is similar after 2 weeks in patients treated with thrombolytic agents and patients treated with anticoagulants. In 1973 the Urokinase Pulmonary Embolism Trial showed no improvement of mortality and no difference of the rate of recurrence of PE among stable patients treated with thrombolytic therapy and patients treated with anticoagulants. There have been no subsequent prospective randomized trials to contradict these results, although a trend suggesting a lower rate of recurrent PE has been shown among patients with right ventricular dysfunction who were treated with tissue plasminogen activator. Thrombolysis has risks. Based on pooled data the frequency of major bleeding from tissue plasminogen activator among patients with PE in randomized trials was 14.7%. This occurred despite the fact that all studies excluded patients at a high risk of bleeding, such those with recent surgery, recent biopsy, peptic ulcer disease, blood dyscrasia, or severe hepatic or renal disease. The risk of intracranial haemorrhage with tissue plasminogen activator (2%) was higher among patients with PE than among patients who received tissue plasminogen activator for myocardial infarction. Even though there are risks of thrombolysis, mortality is lower in unstable patients (in shock or requiring ventilatory support) who receive thrombolysis than those who do not receive it. Regimens of thrombolytic therapy When thrombolytic therapy is appropriate, current evidence supports a short (2-hour) infusion through a peripheral vein. The most widely used regimen In the United States is recombinant tissue plasminogen activator (rt-PA)(altelplase) 100 mg IV over 2 hours. In the United States, it is recommended that IV unfractionated heparin should be discontinued during the infusion of rt-PA. • In Europe, rt-​PA is administrated using a 10-​mg bolus, followed by a 90-​mg continuous IV infusion with concomitant unfractionated heparin. Inferior vena cava filters Recommendations for use of inferior vena cava filters are shown in Table 16.16.1.8.

The Prévention du Risque d’Embolie Pulmonaire par Interruption Cave (PREPIC) study, a randomized controlled trial of permanent filters plus anticoagulants (n  =  200) compared with anticoagulants alone (n = 200) was performed in patients with proximal DVT, with or without symptomatic PE. Fewer patients in the filter group showed symptomatic PE at 1  year (1.1% versus 5.0%) and at 8  years 6.2% versus 15.1%) after recruitment. Recurrent DVT, however, was more frequent in the filter group and there was no difference in mortality. The Prévention du Risque d’Embolie Pulmonaire par Interrup­tion Cave 2 (PREPIC2) trial was a randomized controlled trial of retrievable filters in stable patients with acute pulmonary embolism. This trial showed no reduction of mortality in 200 stable patients with filters compared with 199 who did not receive a filter. Subgroups that might benefit from filters could not be assessed. Such subgroups are 1) haemodynamically unstable patients (in shock or on ventilatory support) 2) require thrombolytic therapy and are stable, 3) undergo pulmonary embolectomy, 4) have solid malignant tumors (except liver gall bladder, bile ducts and ovary) and are >60 years old, 5) have chronic obstructive pulmonary disease and are >50 years old, 6) very elderly (>80 years) even though stable, and 7) patients who suffer recurrent PE during the first 3 months (while on anticoagulants). These subgroups were shown to reduce in–hospital mortality based on administrative data from retrospective cohort studies of huge United States government or commercial databases. These results have not been assessed by randomized controlled trials and are not endorsed by authoritative guidelines. Routine insertion of an inferior vena cava filter is not indicated solely on the basis of a continuing predisposition for DVT, although in special circumstances this may be the best approach (e.g. in high-​ risk patients with DVT, severe pulmonary hypertension, and minimal cardiopulmonary reserve). Several vena cava filters have been designed for percutaneous insertion and many are retrievable. They differ in outer diameter of the delivery system, maximal caval diameter into which they can be inserted, hook design, retrievability, biocompatibility, and filtering efficiency. They may be effective alone in preventing PE, but anticoagulant therapy after insertion of a filter is recommended for the duration of treatment that would be required without a filter. Thereafter, anticoagulant therapy can be discontinued even though the filter remains in place. Complications of permanent vena cava filters include improper anatomical placement, filter deformation, filter fracture, insufficient opening of the filter, and filter migration; also perforation, thrombosis, and stenosis of the cava wall. Symptomatic occlusion of the inferior vena cava is the most frequent complication, occurring in about 9% of patients. Complications at the site of insertion of the catheter do not differ from complications observed locally with other catheter techniques. DVT at the puncture site generally has been reported in 8% to 25%. Retrievable vena cava filters typically are successfully removed after 1 to 3 months, but some have been successfully removed after 1 year. PE after insertion of an inferior vena cava filter is uncommon (1%), and fatal embolism is rare. Possible mechanisms that can explain PE after filter insertion are: (1) ineffective filtration, especially with tilting of the filter; (2) growth of trapped thrombi through the filter; (3) thrombosis on the proximal side of the filter; (4) filter migration; (5)  filter retraction from the caval wall; (6)  embolization through collaterals; (7) embolization from sites other than the inferior vena cava; and (8) incorrect position of the filter. Over the last two decades, the use of inferior vena cava filters in the United States

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of America has increased markedly in patients with PE, patients with DVT alone, and patients at risk who had neither PE nor DVT. The use for primary prevention in patients who do not have DVT or PE has accelerated. Extensive use of permanent and retrievable vena cava filters indicates a liberalization of indications, but despite the benefits of retrievability, retrieval has been attempted in only a minority of patients. For patients with retrievable IVC filters in whom the transient risk of PE has passed, the benefit/risk profile begins to favor filter removal between 29 and 54 days after insertion. Catheter interventions Catheter-​tip devices for the extraction or the fragmentation of PE have the potential of producing immediate relief from massive PE. Such interventions may be particularly useful in patients in whom there is a contraindication to thrombolytic therapy. A  suction-​tip device for extraction of PE has been used in some patients, and thrombus fragmentation with a guide wire, angiographic catheter, balloon catheter, or specially designed devices has been reported in small case series or case reports. The release of fragmented thromboemboli into the distal pulmonary arterial branches is not a problem. A registry of management strategies used by hospitals throughout Germany showed use of catheter fragmentation in 1.3–​ 6.8% of patients with PE, depending on severity. Although originally it was thought that catheter embolectomy or fragmentation could substitute for thrombolytic therapy, it now appears to be an adjunct to thrombolysis, allowing a larger surface area of the fragmented emboli to be exposed to thrombolytic agent. Among patients who undergo fragmentation with standard angiographic catheters, the rate of successful clinical outcome with a local infusion of thrombolytic agents in combination with fragmentation is higher than with a systemic infusion. Pulmonary embolectomy Thrombolytic therapy is likely to give better results than embolectomy, although the latter may have life-​saving potential in some instances. The average operative mortality in the United States of America among 620 unstable patients operated from 2004 to 2008 was 40%, and among 1550 stable patients, mortality was 23%. These data reflect average results. Advanced centres with expertise might show a lower mortality. A candidate for pulmonary embolectomy should meet the following criteria:  (1) massive PE, angiographically documented if possible; (2) haemodynamic instability (shock) despite heparin therapy and resuscitative efforts; and (3) failure of thrombolytic therapy or a contraindication to its use.

Chronic pulmonary thromboembolic hypertension The vast majority of PE resolve because of natural thrombolytic processes. Residual emboli, if any, undergo fibrovascular organization causing chronic obstruction to pulmonary arterial blood flow. It is estimated that 2.8% of patients with PE develop chronic thromboembolic pulmonary hypertension, usually within 3 years after the acute PE. The predominant symptom of chronic thromboembolic pulmonary hypertension is unexplained dyspnoea on exertion, often following an asymptomatic period of several months or years after the acute PE. The reference standard for the diagnosis is combined right heart catheterization to quantify the haemodynamic impairment, and conventional pulmonary angiography to determine the extent and proximal location of the chronic thromboembolic obstruction. CT pulmonary angiography is essential to exclude rare

conditions that may present with similar signs and symptoms such as fibrous mediastinitis, mediastinal carcinoma, and pulmonary artery sarcoma. Pulmonary thromboendarterectomy in an experienced centre is the treatment of choice in symptomatic patients with surgically accessible thromboemboli. Early diagnosis is important because the surgical mortality in patients who have progressed to dyspnoea at rest is substantially greater than among those with less severe symptoms. Neither anticoagulants nor vasodilators are effective, with the haemodynamic and symptomatic benefits of medical therapy being modest in comparison to those resulting from successful pulmonary thromboendarterectomy. See Chapter 16.15.2 for further discussion.

FURTHER READING Agnelli G, Becattini C (2010). Acute pulmonary embolism. N Engl J Med, 363, 266–​74. Agnelli G, et al. (2013). AMPLIFY Investigators: oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med, 369, 799–​808. Chatterjee S, et  al. (2014). Thrombolysis for pulmonary embolism and risk of all-​cause mortality, major bleeding, and intracranial hemorrhage: a meta-​analysis. JAMA, 311, 2414–​21. Collaborative Study by the PIOPED Investigators (1990). Value of the ventilation/​perfusion scan in acute pulmonary embolism—​results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). JAMA, 263, 2753–​59. Fedullo P, et al. (2011). Chronic thromboembolic pulmonary hypertension. Am J Resp Crit Care Med, 183, 1605–​13. Goldhaber SZ (2016). Requiem for liberalizing indications for vena caval filters? Circulation, 133, 1992–​4. Guyatt GH, et  al. (2012). Antithrombotic therapy and prevention of thrombosis, 9th ed. American College of Chest Physicians Evidence-​ Based Clinical Practice Guidelines. Chest, 141(suppl), 7S–​47S. Kearon C, et  al. (2012). Antithrombotic therapy for VTE disease. Antithrombotic therapy and prevention of thrombosis, 9th ed. American College of Chest Physicians Evidence-​Based Clinical Practice Guidelines. Chest, 141(suppl), e419S–​94S. Kearon C, et al. (2016). Antithrombotic therapy for VTE disease: chest guideline and expert panel report. Chest, 149, 315–​52. Mismetti P, et al. (2015). PREPIC2 Study Group. Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial. JAMA, 313, 1627–​35. Morales JP, et al. (2013). Decision analysis of retrievable inferior vena cava filters in patients without pulmonary embolism. J Vasc Surg Venous Lymphat Disord, 1, 376–84. PREPIC Study Group (2005). Eight-​year follow-​up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC (Prevention du Risque d’Embolie Pulmonaire par Interruption Cave) randomized study. Circulation, 112, 416–​22. Schulman S, et al.; RE-​COVER II Trial Investigators (2014). Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation, 18, 129, 764–​72. Sostman, HD et al. (2008). Sensitivity and specificity of perfusion scintigraphy combined with chest radiography for acute pulmonary embolism in PIOPED II. J Nucl Med, 49, 1741–​8. Stein PD, et  al. (1991). Clinical, laboratory, roentgenographic and electrocardiographic findings in patients with acute pulmonary embolism and no pre-​existing cardiac or pulmonary disease. Chest, 100, 598–​603.

16.16.2  Therapeutic anticoagulation

Stein PD, et  al. (2004). D-​dimer for the exclusion of deep venous thrombosis and acute pulmonary embolism:  a systematic review. Ann Intern Med, 140, 589–​602. Stein PD, et al. (2006). Diagnostic pathways in acute pulmonary embolism:  recommendations of the PIOPED II investigators. Am J Med, 119, 1048–​55. Stein PD, et al. (2006). Multidetector computed tomography for acute pulmonary embolism. N Engl J Med, 354, 2317–​27. Stein PD, et al. (2007). Clinical characteristics of patients with acute pulmonary embolism: data from PIOPED II. Am J Med, 120,  871–​9. Stein PD, et al. (2010). Early discharge of patients with venous thromboembolism: implications regarding therapy. Clin Appl Thromb Hemost, 16,  141–​5. Stein PD, et  al. (2010). Outcome in stable patients with acute pulmonary embolism who had right ventricular enlargement and/​or elevated levels of troponin I. Am J Cardiol, 106, 558–​63. Stein PD, et al. (2010). Silent pulmonary embolism in patients with deep venous thrombosis: a systematic review. Am J Med, 123, 426–​31. Stein PD, et al. (2011). Elevated cardiac biomarkers with normal right ventricular size indicate an unlikely diagnosis of acute pulmonary embolism in stable patients. Clin Appl Thromb Hemost, 17, E153–​7. Stein PD, et  al. (2011). Prognosis based on cardiac biomarkers and right ventricular size in stable patients with acute pulmonary embolism. Am J Cardiol, 107,  774–​7. Stein PD, et  al. (2012). Diagnosis and management of isolated subsegmental pulmonary embolism: review and assessment of the options. Clin Appl Thromb Hemost, 18,  20–​6. Stein PD, et al. (2012). Impact of vena cava filters on in-​hospital case fatality rates from pulmonary embolism. Am J Med, 125, 478–​84. Stein PD, et al. (2012). Trends in case fatality rates in patients with pulmonary embolism according to stability and treatment. Thrombosis Research, 130, 841–​46. Stein PD, Matta F (2012). Pulmonary embolectomy for acute pulmonary embolism. Am J Med, 125,  471–​7. Stein PD, Matta F (2012). Thrombolytic therapy in unstable patients with acute pulmonary embolism:  save lives but underused. Am J Med, 125, 465–​70. Stein PD, Matta F (2013). Treatment of unstable pulmonary embolism in elderly and those with comorbid conditions. Am J Med, 126, 304–​10. Stein PD, et  al. (2014). A critical review of SPECT imaging in pulmonary embolism. Clin Transl Imaging, 2, 379–​90. Stein PD (2016). Pulmonary embolism, 3rd edition. Wiley Blackwell, Oxford. Stein PD, et al. (2019). Optimal therapy for unstable pulmonary embolism. Am J Med, 132, 168–71. Stein PD, et al. (2019). Usefulness of inferior vena cava filters in stable patients with acute pulmonary embolism. Am J Cardiol, 123, 1874–77. Tapson VF (2008). Acute pulmonary embolism. N Engl J Med, 358, 1037–​52. van Belle A, et  al. (2006). Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-​dimer testing, and computed tomography. JAMA, 295,  172–​9. Wells PS, et  al. (1997). Value of assessment of pretest probability of deep-​vein thrombosis in clinical management. Lancet, 350, 1795–​8. Wells PS, et al. (2000). Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-​dimer. Thromb Haemost, 83, 416–​20. Wells PS, et al. (2001). Excluding PE at the bedside without diagnostic imaging: management of patients with suspected PE presenting to the emergency department by using a simple clinical model and D-​dimer. Ann Intern Med, 135, 98–​107.

16.16.2  Therapeutic anticoagulation David Keeling ESSENTIALS Low-​molecular-​weight heparins have largely replaced unfractionated heparin. Their much more predictable anticoagulant response combined with high bioavailability after subcutaneous injection means that the dose can be calculated by body weight and given subcutaneously without any monitoring or dose adjustment. Their widespread use resulted in most patients with deep vein thrombosis being managed as outpatients, and this is also increasingly the case for uncomplicated pulmonary embolism. Oral vitamin K antagonists (most commonly warfarin) have historically been the mainstay of long-term anticoagulant therapy, but direct acting oral anticoagulants (DOACs) that specifically target thrombin or factor Xa are increasingly used to treat acute venous thromboembolism and for stroke prevention in atrial fibrillation. Particular issues—​(1) in patients with cancer and venous thromboembolism, giving low-​molecular-​weight heparins for the first 6 months of long-​term anticoagulant therapy has been shown to be superior to vitamin K antagonist; (2) high-​dose loading regimens of warfarin are unnecessary and may increase the risk of over-​anticoagulation and bleeding; (3) warfarin for venous thromboembolism and atrial fibrillation should be given with a target INR of 2.5 (range 2.0–​3.0); for patients with prosthetic heart valves the target INR is usually greater; (4) indefinite anticoagulation is required for patients with atrial fibrillation or a mechanical heart valve; for venous thromboembolism a careful clinical decision is required regarding duration of treatment; (5)  for patients with atrial fibrillation anticoagulation is much more effective than aspirin in preventing stroke; (6) if warfarin needs to be stopped for surgery, full-​dose heparin does not have to be given perioperatively unless the risk of thromboembolism is high, and warfarin can be continued in patients having dental extractions.

Introduction The main indications for therapeutic anticoagulation are venous thromboembolism (VTE), deep vein thrombosis (DVT), and pulmonary embolism (PE) (see Chapter 16.16.1), and the prevention of stroke in patients with atrial fibrillation or mechanical heart valves. Oral vitamin K antagonists (in the United Kingdom, mostly warfarin) have been the mainstay of treatment, but oral direct inhibitors of thrombin or factor Xa (direct acting oral anticoagulants, DOACs) are being increasingly used to treat VTE and to prevent stroke in atrial fibrillation. When warfarin is used in acute venous thromboembolism, initial anticoagulation with heparin is required because warfarin takes time to become effective.

Therapeutic anticoagulation for venous thromboembolism DVT and PE are aspects of the same disease—​VTE. Forty per cent (40%) of patients with DVT without clinical evidence of PE have

3729

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section 16  Cardiovascular disorders

evidence of emboli on lung scanning. The principles of therapeutic anticoagulation are the same for both. In proximal DVT and PE this has historically involved immediate anticoagulation with heparin, followed by a period of anticoagulation with warfarin (or other oral vitamin K antagonists). Distal DVT can be managed in the same way, but an alternative strategy is to use serial non​invasive testing (e.g. ultrasonography), which only reliably detects proximal thrombosis, to ensure that suspected distal thrombosis does not extend above the knee, withholding treatment if it does not. There is clear evidence that an immediately acting anticoagulant is needed in the initial phase and that anticoagulation with oral vitamin K antagonists alone is inadequate. Warfarin can be commenced on the first day and heparin is continued for 5 days or until the international normalized ratio (INR) is greater than 2.0 for two consecutive days, whichever is the longer. Extending the period of heparinization from 5 to 10 days is not more effective and increases the risk of heparin-​induced thrombocytopenia. The DOACs act immediately and rivaroxaban and apixaban have been used to treat acute VTE without initial heparin. Dabigatran and edoxaban have also been used for acute VTE, but with initial heparin.

Heparin Heparin, a glycosaminoglycan, is composed of alternating uronic acid and glucosamine saccharides that are sulphated to a varying degree. Its mode of action is to potentiate the activity of the serine protease inhibitor (serpin) antithrombin, whose main mode of action is to inhibit thrombin, but which also inhibits several other coagulant proteases such as factor Xa. A specific pentasaccharide sequence (see ‘Fondaparinux’) determined by the sulphation pattern along the heparin chain binds to antithrombin and causes a conformational change, giving it full activation against factor Xa but only partial activation against thrombin. Heparins of 18 saccharides (molecular weight (MW) 5400)  or more can extend across the intermolecular gap and also bind to thrombin giving full antithrombin activity, which is lost if the chains are shorter. Unfractionated or standard heparins are a mixture of chains of different lengths (MW 5000–​35 000, mean 13 000) and low-​molecular-​ weight heparins (LMWH, MW 2000–​8000, mean 5000) are derived from them by enzymatic or physicochemical cleavage. LMWH have, with good reason, largely replaced unfractionated heparin for the treatment of venous thromboembolism, but the use of the latter is discussed first. Anticoagulation with unfractionated heparin Unfractionated heparin has most often been given by continuous intravenous infusion, the rate of which has to be adjusted, usually by measuring the activated partial thromboplastin time (APTT). An inadequate APTT response in the first 24 h may increase the risk of recurrence of thromboembolism, although this does not seem to be critical if the starting infusion rate is at least 1250 IU/​h. A validated regimen is to give a bolus dose of 80 IU/​kg and to start the infusion at 18 IU/​kg/​h, performing the first APTT estimate after 6 h. The dose is then usually adjusted to maintain the APTT between 1.5 to 2.5 times the average laboratory control value. With older APTT reagents, this corresponded to a therapeutic heparin level of 0.3–​0.7 IU/​ml by anti-​Xa assay. However, many current APTT reagents show an increased sensitivity to unfractionated

heparin and, with these, higher ratios should be aimed for. The local laboratory should advise on the appropriate therapeutic range with its reagent. When the dose is therapeutic, the APTT should be checked daily. An alternative is to give unfractionated heparin subcutaneously once every 12 h, and a meta-​analysis suggested that this might be more effective and at least as safe as continuous intravenous infusion. A reasonable starting dose is 250 IU/​kg, adjusting the dose according to the mid-​interval APTT. Anticoagulation with LMWH The key clinical property of LMWHs is that they produce a much more predictable anticoagulant response than unfractionated heparin. This, combined with the fact that they have very high bioavailability after subcutaneous injection, means that the dose can be calculated by body weight and be given subcutaneously without any monitoring or dose adjustment. The actual dosage used differs slightly with the different LMWH and the manufacturers’ recommendations should be followed, but a typical dose is 200 IU/​ kg once a day. They are at least as effective and at least as safe as unfractionated heparin. Their widespread use resulted in most patients with DVT being managed as outpatients, and this is increasingly the case for low-​risk PE. LMWH is renally excreted and so the dose needs to be reduced in patients with renal failure, with monitoring and (if necessary) adjustment of the dose based on anti-​Xa levels. In patients with cancer, giving LMWH for the first 6 months of long-​term anticoagulant therapy has been shown to be superior to switching to a vitamin K antagonist. Complications of heparin treatment If a patient on intravenous unfractionated heparin is excessively anticoagulated, it is usually sufficient simply to stop the infusion, the half-​life being 1 to 2 h. If bleeding is severe, the heparin can be neutralized with protamine sulphate, giving 1 mg for every 100 IU that has been infused over the previous hour. The reversal of LMWH is more problematic. Although protamine sulphate may not neutralize the smaller chains, it is often clinically effective, though estimating an appropriate dose is more difficult (the maximum dose is 50 mg, so this is often given if the subcutaneous injection was recent). Heparin-​induced thrombocytopenia is a feared complication, but much less common now that short courses of LMWH are used. It is due to the development of an antibody to the heparin–​platelet factor 4 complex and can be associated with serious venous and arterial thrombosis. Heparin must be stopped if heparin-​induced thrombocytopenia is likely and an alternative immediately acting non​heparin anticoagulant substituted. Fondaparinux The specific pentasaccharide sequence of heparin which binds to antithrombin has been chemically synthesized and is marketed as the drug fondaparinux. Like LMWH it is given by subcutaneous injection with no monitoring. It is equivalent to heparin in the treatment of venous thromboembolism, and is superior to heparin in the treatment of unstable angina and non-​ST elevation myocardial infarction. It carries virtually no risk of heparin-​induced thrombocytopenia.

16.16.2  Therapeutic anticoagulation

Warfarin The oral vitamin K antagonists have historically been the mainstay of long-​term anticoagulant therapy. Warfarin is the commonest vitamin K antagonist given; acenocoumarol (which has a shorter half-​life) and phenindione (which has a higher incidence of skin rashes) are seldom used in the United Kingdom. The procoagulant factors II, VII, IX, and X (and the anticoagulants protein C and protein S) need vitamin K for the γ-​carboxylation of the glutamic acid residues that form their gla domains. Without this post-​translational modification they cannot bind calcium, and as a consequence cannot bind to anionic phospholipid surfaces such that assembly of the key coagulation complexes is disrupted. Warfarin takes several days to become effective, so heparin is given initially if immediate anticoagulation is needed. When warfarin is started, the vitamin K-​dependent factors fall according to their half-​lives. Factor VII and protein C have the shortest half-​lives, so that despite a prolongation of the INR due to factor VII deficiency, warfarin may initially be procoagulant. This is the mechanism for the rare problem of warfarin-​induced skin necrosis, most often described in those with protein C deficiency. Initiation and monitoring of anticoagulation with warfarin Monitoring of warfarin treatment is by the INR. This is a manipulation of the prothrombin time (PT) to allow for the different sensitivities of various laboratory reagents to the warfarin-​induced coagulopathy. The INR equals (PT/​MNPT)ISI where MNPT is the (mean normal) control PT and ISI is the international sensitivity index of the thromboplastin used in the assay. For the treatment of DVT and PE, the target INR should be 2.5 (target range 2.0–​3.0). If the initial coagulation tests are not prolonged, it has been customary to give 10 mg of warfarin on the first evening and check the INR the following morning, adjusting the dose according to the daily INR results until the patient is stable. With such regimens, most patients received 10 mg of warfarin on the first 2 days. There is, however, no evidence to suggest a 10 mg loading dose is superior to 5 mg, and regimens that start with 5 mg doses, or a single 10 mg dose followed by 5 mg doses, may be preferable to regimens that start with repeated 10 mg doses. This is the case in patients with an increased risk of bleeding (e.g. people >60 years old, and those with liver disease or cardiac failure). The dosing algorithm used in Oxford is shown in Table 16.16.2.1. Table 16.16.2.1  A warfarin induction regimen Days 1 and 2

Give 5 mg each evening if baseline INR 3 months ago, bi-​leaflet aortic valve with no other risk factors, AF without recent stroke

Nil or prophylactic LMWH

Prophylactic LMWH

AF, atrial fibrillation; IV, intravenous; LMWH, low-​molecular-​weight heparin; SC, subcutaneous; UFH, unfractionated heparin; VTE, venous thromboembolism. a Stop full-​dose IV UFH 6 h before surgery and check APTT before operation begins, omit full-​dose SC LMWH on day of surgery. b Therapeutic dose heparin must not be given for at least 48 h after high bleeding risk surgery.

Various national and international recommendations are made regarding the target INR in patients with mechanical heart valves, with 3.5 traditionally being advised. This is reasonable for caged-​ball valves, but for tilting-​discs and bileaflet valves the target INR can possibly be lower, for example, 2.5 (range 2.0–​3.0) for aortic valves and 3.0 (range 2.5–​3.5) for mitral valves. When a new valve is inserted, it is recommended that unfractionated heparin or LMWH be given until the INR is stable and at a therapeutic level for two consecutive days.

Perioperative management of therapeutic anticoagulation Warfarin does not need to be stopped for dentistry, nor for some minor surgery. For many operations, however, warfarin will need to be temporarily discontinued. It can generally be stopped 5 days before surgery and the INR be checked on the day of surgery (checking the day before obviates the risk of cancellation as a small dose of oral vitamin K can be given if necessary). The main clinical decision is whether to give bridging therapy with treatment-​dose heparin perioperatively when the INR is less than 2.0. This depends on balancing the risk of bleeding with the risk of thromboembolism. Treatment-​dose heparin is usually given for those at high risk of thromboembolism, such as patients with a mechanical mitral valve, but must not be (re-​)started for at least 48 h after high bleeding risk surgery (Table 16.16.2.4). The DOACs have short half-​lives and so bridging is not required. They can normally be stopped 1 or 2 days preoperatively, although

renal function needs to be taken into consideration, particularly for dabigatran. They must not be given for at least 48 h after surgery with a high bleeding risk.

FURTHER READING Burnett AE, et al. (2016). Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis, 41, 206–​32. Connolly SJ, et al. (2009). Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med, 361, 1139–​51. Dager WE, Roberts AJ, Nishijima DK (2019). Effect of low and moderate dose FEIBA to reverse major bleeding in patients on direct oral anticoagulants. Thromb Res, 173, 71–6. Giugliano RP, et al. (2013). Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med, 369, 2093–​104. Granger CB, et al. (2011). Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med, 365, 981–​92. Kearon C, et  al. (2016). Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest, 149, 315–​52. Keeling D, et  al. (2011). Guidelines on oral anticoagulation with warfarin—​fourth edition. Br J Haematol, 154, 311–​24. Keeling D, et al. (2016). Peri-​operative management of anticoagulation and antiplatelet therapy. Br J Haematol, 175, 602–​13. Patel MR, et  al. (2011). Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med, 365, 883–​91.

16.17

Hypertension

CONTENTS 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

16.17.1  Essential hypertension: Definition, epidemiology, and pathophysiology Bryan Williams and John D. Firth

typically used for both daytime ambulatory blood pressure and home measurements. Isolated diastolic hypertension (systolic blood pressure (SBP) 90  mm Hg) is more common in younger people, and isolated systolic hypertension (SBP >140 mm Hg, DBP 140

and

90 mm Hg) bridging the two extremes of age (Fig. 16.17.1.1). Although traditionally DBP was considered to carry the greatest prognostic significance, it is now clear that this is not the case. Most people with hypertension are over the age of 50 years, and in them SBP is by far the most important contributor to the burden of cardiovascular disease attributable to hypertension. The different patterns of blood pressure and the relative importance of DBP and SBP with regard to prognosis reflect progression of the underlying pathology. The pathogenesis of hypertension in younger people is characterized by an increased peripheral vascular resistance. This results in an increased diastolic pressure, with any associated rise in systolic pressure ‘cushioned’ by a compliant aorta, hence the commonly observed IDH. With ageing there is progressive stiffening of the aorta, a consequent reduction in large-​artery compliance, and a reduced capacity to sustain diastolic pressure and to cushion systolic pressure. The result is an age-​related widening of pulse pressure as diastolic pressure falls alongside a progressive rise in SBP, hence the emergence of ISH (Fig. 16.17.1.2).

80

70

Diastolic blood pressure

0 18–29 30–39 40–49 50–59 60–69 70–79 ≥80 Age, y

Systolic blood pressure

Non-Hispanic black Non-Hispanic white Mexican American

80

70

Diastolic blood pressure

0 18–29 30–39 40–49 50–59 60–69 70–79 ≥80 Age, y

Fig. 16.17.1.2  Data from the United States of America NHANES III population survey (1988–​91) showing the progressive rise in SBP with age and the rise in DBP up until age c.50 years, after which DBP falls and pulse pressure widens. This pattern is typical of Westernized countries and explains the high prevalence of isolated systolic hypertension in older people in these countries. Reproduced from Burt VL, et al. (1995). Prevalence of hypertension in the US adult population. Hypertension, 23, 305–​13.

3737

section 16  Cardiovascular disorders

2000

Men Women

50 37.4 37.2

40

35.3

34.8 22.0 23.7

20.6 20.9

20

Rate of hypertension (%)

40.7

39.1

30

26.9

22.6

19.7

17.0

28.3

14.5

10 0 2025 50

41.6 42.5

40

45.9

44.5

39.1

30

40.2 24.0

22.9 23.6

27.0

27.7

27.0 28.2

27.0 18.8 17.1

20 10

er As i isl a an an d ds Su bSa h Af aran ric a

in a

th

Ch

t e in A Ca m rib er be ica an M id dl e e cr ast es em ce nt

In di a

th

O

La

m

an

d

ar

ke

E t e sta co bli no sh m ed ie Fo s rm er ec so on ci om alis ie t s

0

Fig. 16.17.1.3  Frequency of hypertension in people aged 20 years and older by world region and gender in 2000 (upper panel) and projected to 2025 (lower panel). Reprinted from The Lancet, Vol. 365, Kearney PM, et al., Global burden of hypertension: analysis of world-​wide data, pp. 217–​23. Copyright (2005), with permission from Elsevier.

adult population and affecting 1.6 billion people (Fig. 16.17.1.3). Most of this increase in the worldwide burden of hypertension is expected to result from an increase in the number of people with hypertension in economically developing regions, hence almost 75% of the world’s hypertensive populations will be in economically developing regions by 2025. The prevalence of hypertension in almost all regions of the world increases with age and more steeply in women. By the age of 60, more than one-​half of adults in most regions of the world will be

(a) 100

Risk of hypertension, %

3738

hypertensive. India and Asia have and will most likely continue to have the lowest rates of hypertension, whereas the highest rates are likely to remain in Latin America, the Caribbean, former Soviet republics, and sub-​Saharan Africa. Consequently, hypertension is set to remain the single most important preventable cause of premature death worldwide over the next two decades, with the World Health Organization (WHO) estimating that about 7.1 million deaths per year may be attributable to hypertension, and that suboptimal blood pressure (SBP ≥115 mm Hg by their definition) is responsible for

(b) 100

Women aged 65 years

80

80

60

60

40

40

20

0

1976–1998 1952–1975 0

2

4

6

8 10 12 Years of follow-up

14

16

18

20

Men aged 65 years

20

0

0

2

4

6

8 10 12 Years of follow-up

14

16

18

Fig. 16.17.1.4  Lifetime risk of hypertension in women and men aged 65 years. Reprinted from Vasan RS, et al. (2002). Residual lifetime risk for developing hypertension in middle-​aged women and men, the Framingham Heart Study. JAMA, 287, 1003–​10. Copyright © 2002, American Medical Association.

20

16.17.1  Essential hypertension

62% of cerebrovascular disease and 49% of ischaemic heart disease worldwide, with little variation by sex.

men and women who were not hypertensive at 55 or 65 years old and survived to age 80 to 85 (Fig. 16.17.1.4).

Lifetime risk

Cardiovascular morbidity and mortality associated with hypertension

IHD mortality (floating absolute risk and 95% CI)

(a)

Systolic blood pressure 256

Age at risk: 80–89 years

128

70–79 years

64

60–69 years

32

50–59 years

16

40–49 years

8 4 2

Elevated blood pressure increases the risk of cardiovascular morbidity and mortality. Data from observational studies of over 1 million people has indicated a continuous relationship between blood pressure and cardiovascular risk from blood pressure values as low as 115/​75 mm Hg (Fig. 16.17.1.5). The relationship is steeper

(b)

Diastolic blood pressure 80–89 years

128

70–79 years 60–69 years

64 32

50–59 years

16

40–49 years

8 4 2 1

1 120 140 160 180 Usual systolic blood pressure (mm Hg) (a)

Age at risk:

256 IHD mortality (floating absolute risk and 95% CI)

The prevalence of hypertension increases with age, affecting over one-​half of those aged 60–​69 years and over three-​quarters of those aged over 70 years in the United States of America and most developed countries. As indicated earlier, almost all of the age-​related rise in the prevalence of hypertension is due to a progressive rise in SBP. The lifetime probability of developing hypertension is about 90% for

70

(b)

Systolic blood pressure

Diastolic blood pressure

256

80–89 years

256

128

70–79 years

128

60–69 years

32

50–59 years

16 8 4 2

Stroke mortality (floating absolute risk and 95% CI)

Stroke mortality (floating absolute risk and 95% CI)

Age at risk:

64

80 90 100 110 Usual diastolic blood pressure (mm Hg)

Age at risk: 80–89 years 70–79 years

64

60–69 years

32

50–59 years

16 8 4 2 1

1

120 140 160 180 Usual systolic blood pressure (mm Hg)

70

80 90 100 110 Usual diastolic blood pressure (mm Hg)

Fig. 16.17.1.5  Relationship between usual blood pressure at the start of a decade and the risk of ischaemic heart disease (IHD, top panel) and stroke (bottom panel) mortality rates in that decade, for each decade for each decade of life. Reprinted from The Lancet, Vol. 360, Lewington S, et al., Age-​specific relevance of usual blood pressure to vascular mortality: a meta-​analysis of individual data for one million adults in 61 prospective studies, pp. 1903–​13. Copyright (2002), with permission from Elsevier.

3739

section 16  Cardiovascular disorders

Women

(a)

(b)

Men

14 High normal

8 6 4

Normal

2 0

Optimal

Cumulative incidence (%)

10 Cumulative incidence (%)

No. at risk Optimal 1875 Normal 1126 High normal 891

2

4 1867 1115 874

6 8 Time (yr) 1851 1097 859

1839 1084 840

10 1821 1061 812

12 1734 974 722

10

Normal

8 6

Optimal

4 2

14 887 649 520

High normal

12

0 0

0

No. at risk Optimal 1005 Normal 1059 High normal 903

2

4 995 1039 879

6 8 Time (yr) 973 1012 857

962 982 795

10 934 952 795

12 892 892 726

14 454 520 441

Fig. 16.17.1.6  High normal blood pressure and the risk of cardiovascular disease. Cumulative incidence of cardiovascular events in women (a) and men (b) without hypertension, according to blood pressure category at the baseline examination. For this analysis, optimal blood pressure was defined as SBP less than 120 mm Hg and DBP less than 80 mm Hg, normal blood pressure as SBP 120–​129 mm Hg and/​or DBP 80–​84 mm Hg, and high normal blood pressure as SBP 130–​139 mm Hg and/​or DBP 85–​89 mm Hg (95% confidence intervals are shown). Reprinted from Vasan RS, et al. (2001). Impact of high-​normal blood pressure on the risk of cardiovascular disease. N Engl J Med, 345, 1291–​7. Copyright © 2001, Massachusetts Medical Society.

for stroke than it is for coronary heart disease and is magnified by age. For every 20/​10 mm Hg increase in blood pressure, there is a doubling in risk of stroke and ischaemic heart disease mortality. Hypertension also increases the risk of congestive cardiac failure, end-​stage renal disease, and dementia. Moreover, data from the Framingham Heart Study also indicates that there is a doubling of risk of cardiovascular complications in patients with blood pressure levels above normal but not yet classified as having overt hypertension (Fig. 16.17.1.6). This was the basis for the American guidelines introducing the term ‘prehypertension’ (SBP 120–​139 mm Hg and/​or DBP 80–​89 mm Hg) to emphasize that this level of blood pressure (1) is not benign, (2) is associated with an elevated cardiovascular disease risk, and (3)  predicts with a high degree of certainty that blood pressure is on an upward trajectory and that affected people are almost certain to develop more severe hypertension, unless there is intervention with effective lifestyle changes and/​or drug therapy.

What method of blood pressure measurement best predicts cardiovascular outcome? It has been known for many years that ambulatory blood pressure measurement (ABPM) provides better prediction of mortality than clinic measurements (Fig. 16.17.1.8). The US Preventive Services Task Force (2015) conducted a thorough review of the literature looking at studies comparing ABPM vs. office blood pressure measurement (OBPM), and home blood pressure measurement (HBPM) vs. OBPM. Eleven studies reported that daytime, night-​time, and 24-​hour ABPM predicted stroke and other fatal and non​fatal CV events independently of OBPM (Fig. 16.17.1.9). Five studies suggested similar results for HBPM, but there was insufficient data to allow firm conclusions. Only a single study compared HBPM with ABPM, which was insufficient to allow conclusions to be drawn. OBPM added no significant predictive capacity independently of ABPM (Fig. 16.17.1.10). In healthcare systems where they are readily available, ABPM or HBPM should be used as the basis for diagnosing (and therefore treating) hypertension.

Systolic blood pressure as the main risk factor For many years DBP was considered the main denominator for defining the threshold and treatment targets for hypertension. This is no longer the case. As indicated earlier, there is a progressive rise in DBP up to about the age of 50 years and thereafter it usually falls. By contrast, SBP begins to rise relentlessly from the age of around 40 years (Figs. 16.17.1.1 and 16.17.1.2). Thus, at the age of peak prevalence of hypertension (i.e. older than 60 years), SBP is the major contributor to the diagnosis of the condition and its associated risk. Below the age of 50 years, DBP is also important. Fig. 16.17.1.7 illustrates the shift in the major risk burden attributable to hypertension, from DBP to SBP, at about the age of 50 years. However, because most hypertension (>75%) occurs over the age of 50 years, SBP rather than DBP is by far the most important contributor to the huge global cardiovascular risk burden attributable to hypertension. SBP is also the most difficult to treat, which has led some to argue that for patients over the age of 50 years the attention of doctors should be focused solely on the SBP.

1.0 0.5 β(SBP) - β(DBP)

3740

0.0 −0.5 P = 0.008

−1.0 −1.5 25

35

45

55

65

75

Age (years)

Fig. 16.17.1.7  The impact of DBP and SBP on the risk of coronary heart disease as a function of age. A β-​coefficient level less than 0.0 indicates a stronger effect of DBP on coronary heart disease (CHD) risk, a β-​coefficient level greater than 0.0 indicates a greater importance of SBP. The ‘switch’ from DBP to SBP occurs at around age 50 years. Reprinted from Franklin SS, et al. (2001). Does the relation of blood pressure to coronary heart disease risk change with aging? Circulation, 103, 1245. (http://​circ. ahajournals.org/​cgi/​content/​abstract/​103/​9/​1245).

16.17.1  Essential hypertension

5-Year risk of cardiovascular death (%)

3.5

Nighttime

3.0 24-hour 2.5 Daytime

2.0 1.5

2.2

Nighttime

1.9

24-hour

1.6

Daytime

1.3

Clinic

Clinic 1.0

1.0

0.7

0.5 90

110 130 150 170 190 210 230

50

60

Systolic BP (mm Hg)

70

90 100 110 120 130

80

Diastolic BP (mm Hg)

Fig. 16.17.1.8  Adjusted five-​year risk of cardiovascular death in 5292 patients. Curves are for average night-​time, 24-​hour, and daytime ambulatory readings, and for clinic readings. Reprinted from Dolan E, et al. (2005). Superiority of ambulatory over clinic blood pressure measurement in predicting mortality: the Dublin outcome study. Hypertension, 46, 156–​61.

Study

Outcome

HR (95% Cl)

Cardiac events or mortality Staessen, 1999 Dolan, 2005

Systolic: Cardiac end points, fatal and nonfatal Systolic: Cardiac mortality (fatal HF, MI, sudden death)

1.11 (0.91, 1.35) 1.06 (1.01, 1.10)

CV events or mortality Systolic: CV mortality Dolan, 2005

1.06 (1.02, 1.10)

Systolic: CV mortality Systolic: CV mortality Systolic: CV mortality

1.10 (0.94, 1.29) 1.25 (1.10, 1.42) 1.32 (1.03, 1.68)

Systolic: MI or stroke, fatal and monfatal Systolic: Major CV events (CV death, MI or stroke)

1.10 (0.98, 1.25) 1.30 (1.19, 1.42)

Dolan, 2005 Clement, 2003

Systolic: Stroke, fatal

1.07 (1.00, 1.15)

Systolic: Stroke, fatal or nonfatal

1.21 (1.04, 1.42)

Staessen, 1999

Systolic: Stroke, fatal or nonfatal

1.29 (0.98, 1.71)

Gasowski, 2008 Hansen, 2005 Staessen, 1999 Clement, 2003 Hemida, 2011 Stroke

All cuase mortality Systolic: All-cause mortality Clement, 2003 Systolic: All-cause mortality Dolan, 2005 Systolic: All-cause mortality Hansen, 2005 Systolic: All-cause mortality Staessen, 1999

1.17 (1.05, 1.32) 1.02 (0.99, 1.05) 1.05 (0.96, 1.14) 1.24 (1.03, 1.49)

Note: Weights are from random effects analysis

.5

1

2

Abbreviations: CI = confidence interval; CV = cardiovascular; HF = heart failure; HR = hazard ratio; MI = myocardial infarction.

Fig. 16.17.1.9  Risk for cardiovascular and mortality outcomes: systolic 24 hr ABPM, adjusted for OBPM. Each 10 mm Hg increase in systolic 24 hr ABPM, adjusted for OBPM, was consistently associated with an increased risk for fatal or non​fatal stroke or cardiovascular events. From Piper MA, et al. (2014). Screening for high blood pressure in adults: A systematic evidence review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 121. AHRQ Publication No. 13-​05194-​EF-​1. Rockville, MD: Agency for Healthcare Research and Quality.

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section 16  Cardiovascular disorders

Study

HR (95% Cl)

Outcome

Any stroke Ohkubo, 2005

Systolic: Stroke, fatal or nonfatal

1.04 (0.94, 1.15)

CV mortality Gasowski, 2008

Systolic: CV mortality

0.96 (0.79, 1.16)

Ohkubo, 2005

Systolic: CV mortality

1.04 (0.91, 1.19)

Note: Weights are from random effects analysis .5

1

2

Abbreviations: CI = confidence interval; CV = cardiovascular; HF = heart failure; HR = hazard ratio; MI = myocardial infarction.

Fig. 16.17.1.10  Risk for cardiovascular and mortality outcomes: systolic OBPM, adjusted for systolic 24 hr ABPM. Systolic OBPM adds no significant predictive capacity for cardiovascular and mortality outcomes when systolic 24 hr ABPM data is available. From Piper MA, et al. (2014). Screening for high blood pressure in adults: A systematic evidence review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 121. AHRQ Publication No. 13-​05194-​EF-​1. Rockville, MD: Agency for Healthcare Research and Quality.

Pathogenesis and pathophysiology of hypertension The pathogenesis of essential hypertension has remained something of an enigma, in part reflecting the fact that the basis for the diagnosis (i.e. an elevated blood pressure), has so many potential causes. From a physiological perspective, the pressure in the circulation is the product of the cardiac output (CO) and impedance to flow, that is, peripheral resistance (PR): blood pressure = CO × PR. Both cardiac output and peripheral resistance can be influenced by several control mechanisms, including activity of the renin–​ angiotensin–​ aldosterone system, activity of the sympathetic nervous system, and other factors influencing salt and water homeostasis. In addition, vascular structural changes associated with hypertension play a role in accentuating its severity and conferring resistance to treatment. These structural changes include small-​artery remodelling that results in a reduced media/​lumen ratio (which increases peripheral resistance) and large-​artery stiffening (which changes pulse wave characteristics and reduces the compliance of the circulation). Recent reports suggest that a reduced diameter of the proximal aorta may also be a factor contributing to the development of hypertension. Whether structural changes precede and predispose to the onset of hypertension, or follow it, or both, remains a subject of considerable debate. In some cases (probably 10%

If younger than 40 years

Offer antihypertensive drug treatment

Consider specialist referral

Offer lifestyle interventions Offer to check blood pressure at least every 5 years, more often if blood pressure is close to 140/90 mm Hg

1 Signs of papilloedema or retinal haemorrhage 2 Labile or postural hypotension, headache,

palpitations, pallor and diaphoresis

3 Ambulatory blood pressure monitoring 4 Home blood pressure monitoring

Offer patient education and interventions to support adherence to treatment

Offer annual review of care to monitor blood pressure, provide support and discuss lifestyle, symptoms and medication

Fig. 16.17.2.6  Thresholds and appropriate inventions depending on blood pressure. Note: if ABPM or HBPM are not available, then proceed as advised in Table 16.17.2.3. From National Clinical Guideline Centre (2011). Hypertension—​the clinical management of primary hypertension in adults. Clinical Guideline 127, with modification from National Clinical Guideline Centre (2019) Hypertension in adults: diagnosis and management. Clinical Guideline 136.

American guidelines suggest treating to a goal of less than 150/​ 90 mm Hg for patients over 60 years of age; the British guideline recommends the same higher target for those over 80  years of age; and the 2018 European guideline suggests a systolic target of 130–​139 mm Hg in patients over 80 years of age ‘if tolerated’.

The reason that the 2018 European guidelines recommend a lower treatment threshold than most other guidelines is worthy of some comment. The SPRINT trial, published in 2015, found that patients at high risk of cardiovascular events but without diabetes (excluded because of the findings of the ACCORD trial) had lower rates of fatal

16.17.2  Essential hypertension: Diagnosis, assessment, and treatment

Table 16.17.2.3  Typical observation periods for different grades of hypertension and associated cardiovascular disease, diabetes, and/​or target organ damage Grade of hypertension

Typical observation period

Accelerated (malignant) hypertension (papilloedema and/​or fundal haemorrhages and exudates, or with acute cardiovascular complications e.g. aortic dissection)

Immediate treatment—​usually requiring acute hospital admission (see Chapter 16.17.5)

BP ≥220/​120 mm Hg

Treat immediately—​hospital admission not usually required

Grade III hypertension BP >180–​219/​110–​119 mm Hg

Confirm by repeated measurements over 1–​2 weeks, then treat

Grade II hypertension BP 160–​179/​100–​109 mm Hg

In the presence of cardiovascular disease, diabetes, or target organ damage: confirm over 3–​4 weeks, then treat No cardiovascular disease, diabetes, or target organ damage: lifestyle measures, re-​measure weekly initially, and treat if BP persists at these levels over 4–​12 weeks

Grade I hypertension: BP 140–​159/​90–​99 mm Hg

Cardiovascular disease, diabetes, or target organ damage: either confirm or refute diagnosis by (a) ABPM) or HBPM, or (b) repeat clinic measurement within weeks, then treat if diagnosis confirmed No clinical cardiovascular disease, diabetes or target organ damage: lifestyle advice and either confirm or refute diagnosis by (a) ABPM or HBPM, or (b) re-​measure clinic BP at monthly intervals for 3–​6 months. If mild hypertension persists, estimate 10-​year cardiovascular diseases risk and treat if this is ≥20% (if 100 mg/​24 h or protein:creatinine ratio >100 mg/​ mmol) • Haematuria (>10 dysmorphic red blood cells per high power field) • Casts of red and white blood cells

Histopathology Various glomerular patterns of immune complex-​mediated injury are seen on biopsy and classification of lupus nephritis is based primarily on the location (mesangial, endothelial, and epithelial) and nature of lesions seen (active, chronic, focal, or diffuse) (Figs. 21.10.3.1–​21.10.3.3 and Table 21.10.3.1). Immunofluorescence microscopy of biopsies with lupus nephritis can show florid deposition (the classical ‘full-​ house’ picture) of immunoglobulins, IgG, IgA, and IgM, as well as complement proteins, C3, C4, and C1q (Fig. 21.10.3.4). The 2003 International Society of Nephrology/​Renal Pathology Society (ISN/RPS) classification of

Fig. 21.10.3.3  Lupus nephritis. The glomerulus has marked swelling of the glomerular basement membrane (membranous lesions; ISN/RPS class V). Reproduced with permission from Condon M, Dodd P, Lightstone L. The patient with systemic lupus erythematosus: clinical features, investigations, and diagnosis. In: Turner N, Lameire N, Goldsmith DJ, Winearls CG, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Copyright © 2015 Oxford University Press.

21.10.3  The kidney in rheumatological disorders

Table 21.10.3.1  Active and chronic glomerular lesions Active

Chronic

Endocapillary hypercellularity

Glomerular sclerosis (segmental or global)

Crescents—​cellular or fibrocellular

Fibrous crescents

Karyorrhexis

Fibrous adhesions

Fibrinoid necrosis Rupture of glomerular basement membrane Wire loops Hyaline thrombi

lupus nephritis (Table 21.10.3.2 and Fig. 21.10.3.5) was developed to enable a more uniform description of histopathological lesions, promoting standardization of patient care and enabling improved comparison of outcomes between multinational centres. Inclusion of renal vascular lesions in the 2003 ISN/RPS classification system improves the prediction of renal outcomes.

Treatment of lupus nephritis Decisions regarding treatment of patients with lupus nephritis are primarily dependent on histological lesions seen, but also reflect

Fig. 21.10.3.4  Lupus nephritis. IgG deposition within the glomerulus. Reproduced with permission from Condon M, Dodd P, Lightstone L. The patient with systemic lupus erythematosus: clinical features, investigations, and diagnosis. In: Turner N, Lameire N, Goldsmith DJ, Winearls CG, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Copyright © 2015 Oxford University Press.

Table 21.10.3.2  The 2003 International Society of Nephrology/​Renal Pathology Society classification of lupus nephritis (which is a modification of the 1995 WHO classification) Class I

Minimal mesangial lupus nephritis Normal glomeruli by light microscopy, but mesangial immune deposits by immunofluorescence

Class II

Mesangial proliferative lupus nephritis Purely mesangial hypercellularity of any degree or mesangial matrix expansion by light microscopy with mesangial immune deposits May be a few isolated subepithelial or subendothelial deposits visible by immunofluorescence or electron microscopy, but not by light microscopy (Fig. 21.10.3.1)

Class III

Focal lupus nephritis Active or inactive focal, segmental or global endo-​or extracapillary glomerulonephritis involving 90% global sclerosis without activity

YES

NO

YES

Class I

50% or more of involved glomeruli have segmental lesions?

Class II

Class V

Class III (A or A/C or C)

Class IV-G

Class IV-S

Fig. 21.10.3.5  Algorithm showing how the class of lupus nephritis is determined. In Class III or IV, A = active lesions only, A/C = active and chronic lesions, C = chronic lesions only, and if >50% glomeruli have >50% capillary walls with membranous change = Class III + V, or Class IV + V. See Table 21.10.3.1 for further explanation.

the severity of clinical presentation (the degree of associated proteinuria, hypertension, and/​or extrarenal manifestations of SLE). Proliferative disease (class III and class IV lupus nephritis) is more aggressive than nonproliferative lupus nephritis and requires intensive immunosuppressive treatment to induce remission and prevent lasting kidney damage. Management of nonproliferative lupus nephritis Class I and class II ISN/RPS class  I  and class  II lesions are associated with a better prognosis and consequently renal-​specific therapy is not indicated. Patients with class I lupus nephritis and class II with proteinuria less than 1 g/​day should have treatment dictated by the extrarenal manifestations of SLE. For those patients with class II lupus nephritis and proteinuria greater than 3 g/​day, treatment with corticosteroids or calcineurin inhibitors can be useful if proteinuria cannot be controlled by renin–​angiotensin system blockade alone. Class VI From a renal perspective, immunosuppression is not indicated in class  VI lupus nephritis, which reflects chronic insult without active immune-​mediated injury. However, many patients with class VI lupus nephritis exhibit extrarenal manifestations of SLE necessitating immunosuppressive treatment. Class V (membranous nephropathy) Class V lupus nephritis, while generally regarded as a less aggressive form of lupus nephritis compared to types III and IV, is still

associated with the development of chronic kidney disease and ESRD, particularly if there is marked proteinuria (even with normal baseline renal function). Given the adverse effects of subnephrotic proteinuria on kidneys, most nephrologists would treat these patients with antiproteinuric and antihypertensive medications. Sustained heavy proteinuria (and associated hypercoagulable state) is associated with adverse cardiovascular effects, but there is only a limited evidence base looking at treatment of class V lupus nephritis. Steroids, ciclosporin, and cyclophosphamide treatment have been used, along with other immunosuppressive agents including mycophenolate mofetil (MMF), azathioprine, and tacrolimus. Appropriately sized randomized controlled trials would need to be undertaken before these immunosuppressive therapies can be unequivocally recommended, and such trials are unlikely to be done. In a post hoc review of the outcomes of patients with ‘pure’ class V lupus nephritis in two trials, the combination of MMF and steroids was as effective as high-​dose cyclophosphamide and steroids. Management of proliferative lupus nephritis (class III and class IV) Proliferative lupus nephritis is the most common renal manifestation of SLE. Prior to the advent of immunotherapy regimens, kidney survival and overall patient survival in diffuse proliferative lupus nephritis was only 20 to 25%. While patient and kidney survival in class III and class IV lupus nephritis has markedly improved through intensive immunosuppression (current reviews suggest c.90% survival over 10 years, in those who achieve remission), the response to treatment is often slow, and the risk of relapse remains high.

21.10.3  The kidney in rheumatological disorders

The goal of treatment for active proliferative lupus nephritis is to induce a remission with intensive immunotherapy aimed at switching off the renal inflammation. Once this has been attained, maintenance therapy is commenced with the aim of continuing disease remission, with minimal treatment side effects and ideally prevention of relapse. Induction regimens Traditionally, the mainstay of induction therapy in lupus nephritis has been corticosteroids plus cytotoxic agents. If disease is more severe, pulses of intravenous methylprednisolone are used prior to commencing oral corticosteroids. Since the early 1980s, cyclophosphamide has dominated as the cytotoxic of choice, but concerns about the side effect profile, specifically risks of bladder toxicity, ovarian failure, leucopenia, and alopecia, have led to trials examining reduced doses of cyclophosphamide and the introduction of MMF as an alternative immunosuppressant. The ‘Euro-​Lupus’ regimen compared a lower-​dose of cyclophosphamide (500 mg intravenously every 2 weeks for 3 months) to the original ‘National Institutes of Health (NIH) regimen’ (0.5–​1 g/​m2 given monthly for 6 months). The trial demonstrated that the lower-​ dose regimen was as effective at inducing remission as the higher dose, but patients suffered fewer severe infections. The original study was in an exclusively northern European Caucasian population, but a more recent trial (the Abatacept and Cyclophosphamide Combination Therapy for Lupus Nephritis (ACCESS) study) used Euro-​Lupus as the standard of care to which abatacept or placebo was added. There was no significant improvement gained by the addition of abatacept, but the trial demonstrated well that the Euro-​ Lupus regimen was effective in African American and Hispanic patients. The Aspreva Lupus Management Study (ALMS) was an international trial designed to compare MMF to intravenous cyclophosphamide (NIH regimen, plus standard glucocorticoid tapering) as induction therapy. The study was designed as a superiority study, with the aim of demonstrating that MMF would be superior at inducing complete remission at 6 months. It was not, but the rates were very similar for cyclophosphamide and MMF, with a similar incidence of adverse effects, serious infections, and deaths in both the MMF and cyclophosphamide arms. Post hoc analysis of the study suggested MMF was as efficacious as cyclophosphamide in the small group of patients with an estimated glomerular filtration rate of less than 30 ml/​min per 1.73 m2 at the outset and in those with class V lupus nephritis. All the recent guidelines on therapy suggest that induction for class  III or IV lupus nephritis can be with cyclophosphamide-​or MMF-​based regimens. They have suggested that in severe class III/​ IV lupus nephritis ‘a cyclophosphamide-​containing protocol for initial therapy may be preferred’, but it is worth noting that MMF may be more effective than cyclophosphamide in patients of African descent and Hispanic patients. A Cochrane review in 2012 systematically analysed nine studies, concluding that MMF is as effective as cyclophosphamide, but with reduced side effects. A  key factor in deciding which induction regimen to use is the importance of preserving fertility. Cyclophosphamide causes infertility in a dose-​ and age-​related manner that may be offset to a degree by the concomitant use of ovarian protection regimens. By contrast, MMF does not cause infertility so may be preferable as a first-​line agent,

although patients must be warned to avoid pregnancy while taking it as it is teratogenic. Regardless of initial therapy used, response needs to be assessed at 6 months to guide further management. There have been several analyses of very long-​term outcomes of the Euro-​Lupus trial and ALMS trial patients. These have clearly demonstrated that early reduction in proteinuria predicts long-​term renal survival and that proteinuria of less than between 500 and 800 mg/​day at 1  year is associated with good long-​term outcomes. Maintenance therapy Following initial therapy to induce remission, the goal of treatment of lupus nephritis is to prevent systemic and lupus nephritis flares, and to preserve renal function while minimizing potential side effects of long-​term therapy. Prolonged maintenance therapy after initial treatment is usually required as patients who receive only a short-​term (6 month) course of therapy have been shown to have an increased frequency of lupus nephritis relapse. Current options for maintenance therapy include azathioprine, MMF, cyclophosphamide, and ciclosporin. When determining long-​term maintenance therapy options, patient-​specific factors, for example, tolerability of side effects, and desire for pregnancy should be considered. Initial studies in maintenance therapy for lupus nephritis compared cyclophosphamide pulses with maintenance azathioprine or MMF and demonstrated that patients treated with MMF or azathioprine were significantly less likely to develop chronic kidney disease. Mortality was similarly reduced compared to the cyclophosphamide group at 72 months. This has led to preferential use of MMF and azathioprine over cyclophosphamide. Trials to determine MMF or azathioprine superiority have yielded mixed results. Two key studies to date have been the ALMS trial extension phase and the Mycophenolate Mofetil Versus Azathioprine for Maintenance Therapy of Lupus Nephritis Trial (MAINTAIN Nephritis Trial). In a Caucasian population, azathioprine appears to be equivalent to MMF, whereas MMF is the treatment of choice in a multiethnic population. Differences between the two drugs as maintenance therapy are small, and so if one drug is not tolerated, then the other should be tried. Similarly, patient circumstances may dictate the use of one drug over another: MMF is contraindicated in pregnancy, and azathioprine will be the preferred option in regions where cost or drug availability is an issue. The optimal time to remain on maintenance therapy has not been determined but in general is at least 2 to 3 years after remission induction. Novel therapies Some patients fail to respond to available treatment, and for others treatment-​associated side effects, particularly from corticosteroid therapy, limit patient adherence and subsequent treatment efficacy. Consequently, there is an urgent need to identify and develop new immunotherapies, enabling steroid-​sparing treatment regimens and to better manage refractory cases. Current lupus nephritis immunosuppressive therapies are anti-​ inflammatory, anti-complement and anti-cytokine in a relatively nonspecific manner. In recent years there has been an increased focus on targeting critical pathways in SLE pathogenesis with the aim of disrupting autoimmune mechanisms leading to kidney inflammation and acute and chronic kidney injury (B-​and T-​cell activity, costimulatory molecules, and antibody production). Sadly, all

5005

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section 21  Disorders of the kidney and urinary tract

trials of new agents to date, all of which have been evaluated as ‘add-​ on’ therapies to standard of care, have not shown significant superiority. The list of negative studies in lupus nephritis includes the use of rituximab, CTLA4-​Ig, and ocrelizumab. In each case, the trial has failed not necessarily due to lack of efficacy of the drug, but because the study was too small, or because of a finding of increased rates of infection (often attributable to higher doses of steroids). However, there remains optimism that better designed trials may translate into improvements in outcomes. Anti CD20 (rituximab) therapy Rituximab is a chimeric anti-​ CD20 human/​ mouse monoclonal antibody that has been used extensively in the treatment of non-​ Hodgkin’s lymphoma and has an excellent safety profile. Binding of rituximab to CD20+ cells results in both complement and FcγR-​ mediated cell killing, and clinically rituximab is an effective B-​cell depleter. B-​cell depletion ultimately might not only lead to reduction in autoantibodies (though note rituximab does not deplete plasma cells) but may also disrupt antigen presentation to T cells, critical for maintaining the autoimmune response, and markedly reduce cytokine production. A small subgroup of patients appear not to respond to rituximab, failing to deplete their B cells. The degree and duration of B-​cell depletion usually correlates with improvements in disease activity and scores. Prospective open-​label studies have reported widely on the efficacy of rituximab in both renal and non renal lupus, and rituximab has been found to be generally safe and well tolerated. However, the LUNAR study (Lupus Nephritis Assessment with Rituximab) and EXPLORER trial (Exploratory Phase II/​III SLE Evaluation of Rituximab)—​ two large, prospective, placebo-​ controlled trials—​both failed to find a benefit of rituximab in renal or non renal lupus when added to standard-​of-​care treatment. Trial design has been implicated in the failure of these studies to meet their primary endpoints. In both studies participants were given high-​ dose corticosteroids in addition to immunosuppressives such as MMF, which may have obscured the ability to discriminate between the rituximab and placebo arms. Efforts continue to try to find regimens using rituximab and MMF (and other agents) that would allow omission of oral steroids without compromising efficacy.

monoclonal), a novel calcineurin inhibitor (voclosporin), as well as studies of small-​molecule inhibitors. It is a crowded area and the trials need to be smart to overcome the limitations of previous negative studies. Refractory lupus nephritis Up to 22% of patients with proliferative lupus nephritis are refractory to therapy with cyclophosphamide or MMF. If induction therapy fails, the general consensus is to switch and use the alternative (MMF or intravenous cyclophosphamide). Rituximab is often added at this stage: although trial evidence is generally lacking, there have been reports of some promising results, for example, Jonsdottir and colleagues demonstrated that the addition of rituximab results in clinical and histological improvements in patients with refractory lupus nephritis. The RING trial (ClinicalTrials.gov identifier: NCT01673295) was formally assessing whether the addition of rituximab in refractory lupus nephritis improved responses. Relapse of lupus nephritis Some patients have persistent relapses of lupus nephritis despite repeated treatment. It is important to recognize and treat relapses quickly, as with each relapse further renal damage is sustained. This is associated with both the development of chronic kidney disease and ESRD. Relapse is diagnosed clinically:  increasing proteinuria, rising serum creatinine level, and changes in urinary sediment should all alert clinicians. A  reduction in serum complement levels and increase in anti-​double stranded DNA antibody titres may be seen prior to clinical relapse, and while these do not justify treatment per se, it is wise to see the patient more frequently in order to detect relapse early. If a renal relapse is suspected, then a renal biopsy may well be indicated to confirm the diagnosis and identify the class of lupus nephritis, which may transform spontaneously from one histological class to another and such changes cannot be predicted clinically with certainty. The most common transformations seen are from class III to class IV, or from a proliferative to nonproliferative class. Importantly, the development of increased proteinuria may represent chronic damage rather than acute inflammation, or a podocytopathy rather than proliferative or class V lupus nephritis. A definitive diagnosis requires a renal biopsy.

Other targets in lupus nephritis

Prognosis

As B cells are depleted in response to rituximab, levels of the B-​ lymphocyte-​stimulating factor (BlyS, also known as BAFF) increase, which may increase the generation of new autoreactive B cells. To counteract this potentially detrimental rise in BAFF, an anti-​BlyS monoclonal antibody, belimumab, has been trialled. A post hoc analysis of phase III belimumab studies in non renal SLE patients examined renal outcomes and demonstrated a reduction in the number of renal flares in belimumab-​treated patients. This is now being evaluated in an ongoing trial in lupus nephritis comparing belimumab and placebo in addition to the standard of care (ClinicalTrials.gov identifier: NCT01639339). Tacrolimus (FK506), a calcineurin inhibitor, has demonstrated similar efficacy to mycophenolate mofetil as induction therapy, and other studies include trials of an interferon-​α receptor blocker, an anti-​CD40, another anti-CD20 (obinutuzumab, a humanised

While the overall prognosis of patients with SLE and a proliferative glomerulonephritis has improved significantly with the judicious use of immunosuppressants, 5 to 10% of patients will have died after 10 years of treatment, and a further 5 to 15% will have developed ESRD. The prognosis is poorer in African and Hispanic people (the reasons are unclear), and this needs to be remembered when interpreting results of randomized control trials. Proliferative glomerulonephritis (class  III and IV) is associated with a worse outcome, along with the presence of chronic histological changes on renal biopsy. Many patients with lupus nephritis (30–​50%) do not achieve complete remission and this is associated with a significantly increased risk of having further renal relapses, of developing ESRD and of dying. In patients who do achieve complete remission, relapses develop in 20–​40% over a follow-​up of about 10 years, and these are also associated with an increased risk

21.10.3  The kidney in rheumatological disorders

of developing ESRD. Significant reduction in proteinuria at 3 and 6 months, and persistent reduction in proteinuria at 1 year, predicts better long-​term renal outcomes.

Antiphospholipid antibody nephropathy in SLE Antiphospholipid antibodies are associated with a syndrome (antiphospholipid syndrome) characterized by arterial and venous thromboses and repeated miscarriages. These antibodies have reactivity against cardiolipin and the lupus anticoagulant and are found in 15 to 30% of patients with SLE. Antiphospholipid syndrome can be primary or associated with SLE. Renal manifestations of antiphospholipid syndrome include thrombotic microangiopathy and chronic vascular lesions, superimposed on those of lupus nephritis. If there is evidence of extrarenal thrombosis, oral anticoagulants should be commenced. Patients with lupus nephritis and antiphospholipid antibodies have a worse renal prognosis, presumably because of the superimposed renal vasculopathy. See Chapter 14.14 for further discussion.

Long-​term outcome The main causes of death in lupus nephritis are treatment-​related sepsis (early) and cardiovascular causes (late). Renal failure can be treated with transplantation and dialysis; generally the activity of lupus nephritis reduces once dialysis is initiated. Overall survival on dialysis is approximately 75% at 10 years. Graft survival in patients with SLE after kidney transplantation is similar to patients with other diseases, and recurrence of lupus nephritis is rare.

Systemic sclerosis/​scleroderma Systemic sclerosis (SSc) is a multiorgan connective tissue disease of uncertain aetiology that is characterized by progressive interstitial and vascular fibrosis in the skin and other organs. There are three subtypes of SSc:  limited cutaneous SSc (lcSSc) where cutaneous involvement is limited to the hands, forearms, face, and feet; diffuse cutaneous SSc (dcSSc) with proximal extension above the elbows or knees; and scleroderma sine scleroderma where skin involvement is absent and patients present only when end-​organ damage has occurred (see Chapter  19.11.3). Renal involvement in SSc can be acute or chronic and most renal manifestations are clinically silent, with autopsy studies detecting occult renal pathology in 60 to 80% of patients. By contrast, scleroderma renal crisis demonstrates the acute effects of microvasculopathy in SSc.

Pathogenesis The pathogenesis of renal involvement in SSc is not fully understood. Acute vascular injury activates the coagulation and other inflammatory pathways, culminating in proliferative fibrovasculo­ pathy and thrombotic microangiopathy. Decreased renal perfusion from arterial constriction leads to hyperplasia of the juxtaglomerular apparatus and hyperreninaemia, resulting in a hypertensive crisis and rapidly progressive renal injury.

Pathology The smaller arcuate and interlobular arteries are predominantly involved in scleroderma renal crisis, showing intimal hyperplasia with concentric mucoid intimal degeneration, but the internal and external elastic laminae remain intact. The adventitia of interlobular arteries shows an abnormal degree of fibrosis. There is fibrinoid necrosis of afferent arterioles and glomeruli, and also glomerular thrombosis. Ischaemia of the glomerular tuft leads to wrinkling and thickening of the glomerular basement membrane and glomerular sclerosis (Fig. 21.10.3.6). These lesions resemble those seen in accelerated hypertension or the haemolytic uraemic syndrome, although the vessels involved tend to be larger and adventitial fibrosis is not seen in accelerated hypertension.

Clinical presentation Mild proteinuria without loss of renal function is the most common presentation of SSc renal disease. An isolated reduction in glomerular filtration rate is also in seen in patients with SSc and often follows a benign, non progressive course. By contrast, scleroderma renal crisis is characterized by new-​onset accelerated-​phase hypertension and a decrease in renal function of at least 30%. It is often associated with systemic symptoms including headache, visual disturbances, seizures, or encephalopathy. Flash pulmonary oedema can occur, and arrhythmias, myocarditis, and pericarditis are all associated with poorer prognosis.

Scleroderma renal crisis Scleroderma renal crisis predominantly affects patients with dcSSC, occurring in 10 to 15% of patients with this disease. Mortality in scleroderma renal crisis remains high, particularly in patients who develop ESRD. Patients with early dcSSc are at greatest risk, and rapidly progressive skin disease or tendon friction rubs are independent risk factors. Other studies have suggested that recent high-​dose corticosteroid use, the presence of anti-​RNA polymerase III antibodies, anaemia, and new-​onset cardiac failure are also risk factors for the development of scleroderma renal crisis.

Fig. 21.10.3.6  Scleroderma kidney. A small artery has concentric mucoid intimal thickening, an arteriole has thrombosis and fibrinoid necrosis, and tubules and a glomerulus have ischaemic damage (periodic acid–​methenamine silver staining, magnification ×25). By courtesy of Professor A.J. Howie.

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Scleroderma renal crisis can (rarely) develop in individuals with a normal blood pressure. They are more likely to have a micro­ angiopathic haemolytic anaemia (90 vs 30%), thrombocytopenia (83 vs 21%), and pulmonary haemorrhage than patients with a hypertensive scleroderma renal crisis.

Investigations/​assessment Autoantibodies (antinuclear antibodies (ANA)) are detectable in virtually all patients with SSc. A speckled ANA pattern is also seen in approximately 60% of patients with scleroderma renal crisis. Other autoantibodies associated with renal disease in SSc include anti-RNA polymerase III antibodies (ARA) and anti-fibrillarin antibodies (AFA, also known as anti-U3 RNP antibodies). In contrast, SSc patients with anti-centromere or anti-topoisomerase 1 antibodies are less likely to develop renal disease. Renal function should be monitored and blood pressure checked at least monthly, with daily self-​monitoring introduced if hypertension develops. Urinalysis may reveal the presence of proteinuria (non-​nephrotic range) and nonvisible haematuria, with casts visible on direct microscopy. Anaemia can be an early feature of scleroderma renal crisis. Thrombocytopenia and anaemia occur in up to 50 and 60% of cases respectively. Elevated levels of lactate dehydrogenase, low haptoglobin, and schistocytes in the peripheral blood smear may also be seen. Occasionally, disseminated intravascular coagulation can develop. Many clinical features of a scleroderma renal crisis are similar to those seen in thrombotic thrombocytopenic purpura. It is important to differentiate the two because management varies markedly. Assays for plasma ADAMTS13 enzyme can be useful to exclude thrombotic thrombocytopenic purpura.

Treatment Control of hypertension is fundamental in preventing irreversible vascular injury. A  gradual decrease in blood pressure should be targeted because a rapid reduction can reduce renal perfusion and increase the risk of acute tubular necrosis. Angiotensin-​converting enzyme inhibitors are first-​line therapy and lead to regression of skin manifestations in some patients:  they should be titrated up to maximum doses. In an acute crisis, continuous intravenous iloprost infusion can help reverse microvascular changes and control blood pressure; if substantial thrombotic microangiopathy is present, plasma exchange can be used.

Prognosis Approximately 25% of patients with scleroderma renal crisis require dialysis at presentation, and 40 to 66% of these may not recover. Assessment of prognosis may be guided by renal biopsy, but clinical predictors of poor outcome include dcSSc, high skin scores (>20), older age, and evidence of cardiac involvement. Long-​term survival following scleroderma renal crisis is poor, especially for patients who do not recover renal function. Increased mortality is seen in males, those with normal blood pressure at presentation, and older patients. Scleroderma renal crisis is one of the few conditions where late recovery of renal function is sometimes seen as the inflammatory process resolves and blood pressure is tightly controlled.

Box 21.10.3.1  Renal disease in rheumatoid arthritis Consequences of rheumatoid arthritis • Amyloid A amyloidosis • Vasculitic glomerulonephritis • Mesangiocapillary glomerulonephritis • Mesangial IgA proliferative glomerulonephritis Drug nephrotoxicity Nonsteroidal anti-​inflammatory drugs • Reversible haemodynamically mediated renal impairment • Acute tubular necrosis • Acute interstitial nephritis with or without a nephrotic syndrome Gold and penicillamine • Proteinuria • Nephrotic syndrome • Membranous nephropathy • Rare reports of a crescentic glomerulonephritis

Rheumatoid arthritis Historically, the main causes of renal disease in rheumatoid arthritis have been secondary (amyloid A) amyloidosis and nephrotoxicity from drugs used in treatment (Box 21.10.3.1) (see Chapter  19.5). Renal vasculitis and glomerulonephritis are also described. However, the pattern of renal disease in rheumatoid arthritis is changing. Gold and penicillamine are now infrequently used, hence nephrotoxicity from these causes has become rare, and the incidences of amyloid A amyloidosis and rheumatoid vasculitis have declined, probably as a result of early use of disease-​ modifying agents.

Secondary amyloidosis Secondary amyloidosis results from deposition of fibrils containing amyloid A  protein that is antigenically related to the acute-​phase reactant serum amyloid A (see Chapter 12.12.3). Rheumatoid arthritis is the commonest disease producing secondary amyloidosis in developed countries. Prevalence rates of 8 to 17% are reported in autopsy series and 5 to 10% in biopsy series, but the incidence has dropped dramatically due to much more aggressive therapy of rheumatoid disease, with fewer patients being left with a persistently active acute-​phase response. Cases of crescentic glomerulonephritis superimposed on renal amyloidosis in patients with rheumatoid arthritis have been described. Clinical features and diagnosis The presentation of renal amyloid is with proteinuria that is often severe enough to cause a nephrotic syndrome. Renal vein thrombosis is particularly common. Diagnosis is established by renal biopsy (Fig. 21.10.3.7), where histological Congo red staining, which is birefringent in polarized light, is characteristic of amyloid. This staining is abolished by potassium permanganate in reactive amyloidosis but not in primary amyloidosis. Monoclonal and polyclonal antibodies that specifically bind amyloid A are available and of use for histological diagnosis. The diagnosis of amyloid is also aided by the availability of scans using radiolabelled serum amyloid P (SAP)

21.10.3  The kidney in rheumatological disorders

tubulointerstitial inflammation. Penicillamine may lead to the development of a rapidly progressive glomerulonephritis with crescents and pulmonary haemorrhage, resembling Goodpasture’s syndrome but without anti-glomerular basement membrane antibodies. Treatment and prognosis In general, gold and penicillamine should be discontinued when significant proteinuria develops (>0.5 g/​24 h). After cessation of the drug, proteinuria peaks at around 1  month then gradually disappears, and most patients will have clear urine by 1 year and almost all will achieve this by 2 years. Renal function does not deteriorate in uncomplicated cases.

Glomerulonephritis Fig. 21.10.3.7  Amyloidosis in rheumatoid arthritis. Arterioles and glomeruli contain acellular masses of amyloid (periodic acid–​ methenamine silver staining, magnification ×40). By courtesy of Professor A.J. Howie.

The most commonly described glomerulonephritis in rheumatoid arthritis that is not related to drug use is a mesangiocapillary glomerulonephritis, which in many cases is accompanied by IgA deposits (IgA nephropathy). Membranous nephropathy is also described.

Renal vasculitis protein, utilizing the strong calcium-​dependent affinity of SAP for amyloid fibrils of any protein type. Treatment and prognosis There is no specific therapy for amyloid A amyloidosis, the general principle being suppression of the underlying chronic inflammation. Uncontrolled evidence suggests that aggressive treatment of rheumatoid arthritis may be effective in delaying the deterioration of renal function in patients with renal amyloid, and treatment with prednisolone and cyclophosphamide or methotrexate can induce remission of the nephrotic syndrome due to amyloid in patients with this condition. Treatment with antitumour necrosis factor-​α antibodies is also reported to lead to remission of renal disease due to amyloidosis. Renal amyloid leads to progressive renal failure; 50% of patients develop ESRD after 5 years, rising to 90% at 10 years, treatment of which is by dialysis and renal transplantation.

The clinical spectrum of rheumatoid arthritis includes a systemic necrotizing vasculitis with involvement of blood vessels ranging in size from capillaries to small and medium-​sized arteries. With more aggressive treatment of rheumatoid arthritis, vasculitis from this cause is now uncommon. The clinical presentation includes nail-​fold infarcts, a leucocytoclastic vasculitis, a peripheral neuropathy, pericarditis, gastrointestinal infarcts, and renal vasculitis. Renal abnormalities are found in about 25% of patients with rheumatoid vasculitis, usually nonvisible haematuria, proteinuria, and renal impairment. Renal histology shows a large-​vessel renal arteritis and a segmental necrotizing glomerulonephritis with crescent formation (vasculitic glomerulonephritis) (Fig. 21.10.3.8).

Gold and penicillamine nephropathy Clinical features and diagnosis The most frequent presenting feature is proteinuria, which occurs in approximately 10% of patients receiving gold and up to 30% of those taking penicillamine. This progresses to the nephrotic syndrome in 30 and 16%, respectively. Haematuria is uncommon, although it is seen more frequently with penicillamine, and still requires the exclusion of other causes when occurring in the context of therapy with these drugs. Renal function is usually normal. Gold and penicillamine are no longer widely used to treat patients with rheumatoid arthritis and nephrotoxicity from these agents is correspondingly uncommon. About 55 to 80% of patients who present with penicillamine-​ or gold-​induced proteinuria will have a membranous glomerulonephritis. Minimal-​ change nephropathy is the next most frequently encountered histological lesion. Other less common renal lesions include mesangiocapillary glomerulonephritis and

Fig. 21.10.3.8  Vasculitic glomerulonephritis in rheumatoid arthritis. Two glomeruli have sharply defined segmental lesions where there has been disruption of the tuft and partial obliteration of Bowman’s space (periodic acid–​methenamine silver staining, magnification ×32). By courtesy of Professor A.J. Howie.

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Treatment is with prednisolone and cyclophosphamide, usually leading to improvement of renal function.

with steroid-​sparing agents. Glomerular involvement will generally be treated in a similar manner to lupus nephritis, depending on the histology.

Renal disease in juvenile chronic arthritis Renal involvement in juvenile chronic arthritis is infrequent, but its presence is associated with a poor outcome. Proteinuria is found in 3 to 12% of patients and nonvisible haematuria in 3 to 8%. The renal lesions reported are usually complications of the underlying rheumatic disease, such as amyloidosis, or those arising as side effects of the drugs used. Cases of necrotizing crescentic glomerulonephritis, focal segmental glomerulosclerosis, and mesangial glomerulonephritis have all been described in children with the condition. Renal amyloid is found in 1.2 to 6.7% of patients with juvenile chronic arthritis, and affects patients with chronic and active disease, with a predilection for systemic-​onset disease. It typically presents with nephrotic-​range proteinuria. Aggressive treatment with chlorambucil has been shown to improve survival in patients with juvenile chronic arthritis and amyloid A amyloidosis.

Sjögren’s syndrome Sjögren’s syndrome is an autoimmune condition in which there is inflammatory cellular infiltration of the exocrine glands (particularly the salivary and lacrimal glands) (see Chapter 19.11.4). The condition can occur in isolation (primary Sjögren’s syndrome) or in conjunction with other autoimmune diseases, usually lupus or mixed connective tissue disease (secondary Sjögren’s syndrome).

Clinical features Dry mouth (xerostomia) and dry eyes (keratoconjunctivitis) are characteristic of Sjögren’s syndrome. Renal involvement is usually mild and often subclinical. Some patients present with distal tubular acidosis, impairment of urinary concentration, hypokalaemia, or rarely with Fanconi’s syndrome. Clinical manifestations of these renal tubular disorders include sterile pyuria, the development of renal calculi, polyuria, and (very rarely) the development of hypokalaemic periodic paralysis. Up to a quarter of patients can develop acute or chronic kidney disease.

Investigation/​assessment Urine dip might reveal occasional leucocytes and moderate proteinuria. The most common histological abnormality is tubulointerstitial nephritis with predominantly T-​lymphocyte infiltrate, but various types of glomerulonephritis are also described. Glomerular abnormalities are rare.

Drug nephrotoxicity following treatment for rheumatic disorders Nonsteroidal anti-​inflammatory drugs The widespread use of nonsteroidal anti-​ inflammatory drugs (NSAIDs) for the relief of pain and inflammation has meant that, although in any individual patient the risk of renal adverse events is small, renal complications are frequently seen. Non selective NSAIDs inhibit both constitutive cyclooxygenase (COX)-​1 and inducible COX-​2 enzymes involved in the prostaglandin and thromboxane A2 pathways responsible for the regulation of pain, renin release, and vascular tone. Since both COX-​1 and COX-​2 are expressed in the kidney, adverse effects are associated with both non selective and COX-​2 selective NSAIDs. Clinical syndromes associated with NSAID use reflect either predictable abnormalities arising from their mode of action, especially in volume-​depleted individuals, or those with vascular impairment or idiosyncratic allergic responses. The clinical syndromes seen include a​ cute tubular necrosis, acute tubulointerstitial nephritis, nephrotic syndrome (minimal-​change disease or membranous nephropathy), and renal papillary necrosis. In addition, NSAID therapy may induce salt and water retention, hypertension, hyperkalaemia, and chronic kidney disease. In patients with chronic kidney disease or a functioning renal transplant, NSAIDs should not be used without careful consideration of the balance of benefit versus risk. Great care must be taken when prescribing NSAIDs to patients with volume depletion, and when using concomitant nephrotoxins.

Chronic analgesic nephropathy Chronic analgesic nephropathy is characterized by renal papillary necrosis and chronic interstitial nephritis caused by prolonged and excessive consumption of analgesic mixtures. Compound analgesic mixtures are associated with the development of analgesic nephropathy, and classic radiographic findings (bilateral small kidneys, irregular contour, and renal papillar calcifications) are easily seen on CT. The course of the disease is dependent on severity of chronic damage at presentation, and unless analgesic consumption ceases, renal dysfunction will progress. If analgesics are discontinued, renal function stabilizes or improves slightly in most patients, but there is an association with the later development of urinary tract malignancies in these patients.

Renal toxicity of anti-rheumatic drugs

Mixed connective tissue disease Mixed connective tissue disease is a rheumatological overlap syndrome associated with anti-​U1-​RNP antibodies and clinical signs including synovitis, myositis, Raynaud’s phenomenon, acrocyanosis, and hand oedema. Renal involvement occurs in up to one-​third of cases. Treatment has generally been with steroid therapy along

Many conventional antirheumatic drugs are nephrotoxic, even in the absence of chronic kidney disease. Calcineurin inhibitors (ciclosporin and tacrolimus) are associated with significant renal toxicity. Acute renal impairment and hypertension are usually dose dependent and improve with dose reduction. Chronic renal dysfunction is associated with characteristic histological changes (vascular hyalinosis, interstitial fibrosis, tubular atrophy, and glomerular

21.10.3  The kidney in rheumatological disorders

sclerosis), is often progressive, and irreversible unless calcineurin inhibitors are stopped. The commonest manifestation of drug toxicity in the kidney is tubulointerstitial nephritis, often with an eosinophilic infiltrate. The presentation may be acute with systemic symptoms such as a drug rash and fever, and may be associated with systemic eosinophilia and hypocomplementaemia as well as acute kidney injury that can be severe. Patients usually have sterile pyuria, may have haematuria and can have nephrotic range proteinuria, though more commonly much lower levels of urinary protein loss. Some patients have a slower more insidious renal limited progression and the major finding will be unexplained chronic kidney disease and sterile pyuria. Unless biopsied, the inflammation will be missed and these patients will present with irreversible advanced tubulointerstitial scarring. Nowadays the commonest drugs associated with tubulointerstitial nephritis are penicillins, NSAIDs, proton pump inhibitors, furosemide, and sulphasalazine (which can also cause crystalluria and urinary stone formation)—​all used frequently in patients with rheumatic diseases. Treatment involves stopping the causative drug, if known, plus a course of oral steroids. Although there are no trials, a large retrospective study strongly suggested that those treated with steroids had better preservation of renal function than those who were not. In patients with pre-​existing chronic kidney disease, leflunomide is contraindicated (the active ingredient is renally excreted) and other medications including methotrexate, azathioprine, chlorambucil, and cyclophosphamide require reduced doses. Hydroxychloroquine is not reported to cause renal toxicity, but increased retinal monitoring should be undertaken in the presence of renal impairment. At present, there has been no reported incidence of renal toxicity in clinical trials of new biological therapies, but their use in patients with severe renal impairment has not been fully evaluated. Also of interest is the pharmacokinetics of these drugs in the face of severe nephrotic syndrome: are larger and/​or more frequent doses needed?

FURTHER READING Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group (2012). KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Int Suppl, 2, 139–​274. Rovin BH, et  al. (2019). Management and treatment of glomerular diseases (part 2): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int, 95, 281–95.

Lupus nephritis Almaani S, Meara A, Rovin BH (2017). Update on lupus nephritis. CJASN, 12, 825–35. Appel GB, et al. (2009). Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol, 20, 1103–​12. Austin HA, et al. (1986). Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Eng J Med, 314, 614–​19. Austin HA, et al. (2009). Randomised controlled trial of prednisone, cyclophosphamide and cyclosporine in lupus membranous nephropathy. J Am Soc Nephrol, 20, 901–​11.

Boumpas DT, et al. (1992). Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet, 340,  741–​5. Condon M, et al. (2013). Prospective observational single-​centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. Ann Rheum Dis, 72, 1280–​6. Dooley MA, et al. (2011). Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med, 365, 1886–​95. Dooley M, et al. (2013). Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE. Lupus, 22,  63–​72. Gordon C, et al. (2018). The British Society for Rheumatology guideline for the management of systemic lupus erythematosus in adults. Rheumatology, 57, e1–e45. Henderson L, et  al. (2012). Treatment for lupus nephritis. Cochrane Database Syst Rev, 12, CD002922. Houssiau FA, et al. (2002). Immunosuppressive therapy in lupus nephritis:  the Euro-​Lupus Trial, a randomised trial of low-​dose versus high dose intravenous cyclophosphamide. Arthritis Rheum, 46, 2121–​31. Houssiau FA, et al. (2010). Azathioprine versus mycophenolate mofetil for long term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. Ann Rheum Dis, 69, 2083–​9. Houssiau FA, et  al. (2010). The 10-​year follow-​up data of the Euro-​ Lupus Nephritis Trial comparing low-​dose and high-​dose intravenous cyclophosphamide. Ann Rheum Dis, 69,  61–​4. Jónsdóttir T, et  al. (2013). Long-​term follow-​up in lupus nephritis patients treated with rituximab—​clinical and histopathological response. Rheumatology (Oxford), 52, 847–​55. Korbet S, et al. (2000). Factors predictive of outcome in severe lupus nephritis. Lupus Nephritis Collaboration Study Group. Am J Kidney Dis, 35, 904–​14. Merrill J, et  al. (2010). Efficacy and safety of rituximab in subjects with moderately to severely active systemic lupus erythematosus (SLE): results from the randomised, double blind phase II/​III study EXPLORER. Arthritis Rheum, 58, 4029–​30. Mok C, et al. (2016). Tacrolimus versus mycophenolate mofetil for induction therapy of LN: a randomised controlled trial and long-​term follow-​up. Ann Rheum Dis, 75,  30–​6. Rovin B, et al. (2012). Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum, 64, 2515–​26. Rovin BH, et al. (2019). A randomized, controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus nephritis. Kidney Int, 95, 219–31. Ruiz-​Irastorza G, Hunt B, Kahmashta M (2007). A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies. Arthritis Rheum, 57, 1487–​95. Sloan RP, et  al. (1996). Long-​ term outcome in systemic lupus erythematosus membranous glomerulonephritis. Lupus Nephritis Collaborative Study Group. J Am Soc Nephrol, 7, 299–​305. Weening JJ, et al. (2004). The classification of glomerulonephritis in systemic lupus erythematosus revisited J Am Soc Nephrol, 15, 241–​50. Wu L-H, et al. (2013). Inclusion of renal vascular lesions in the 2003 ISN/RPS system for classifying lupus nephritis improves renal outcome predictions. Kidney Int, 83, 715–23. Yo JH, Barbour TD, Nicholls K (2019). Management of refractory lupus nephritis: challenges and solutions. Open Access Rheumatol, 11, 179–88.

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Systemic sclerosis DeMarco PJ, et  al. (2002). Predictors and outcome of scleroderma renal crisis: the high-​dose versus low-​dose D-​penicillamine in early diffuse systemic sclerosis trial. Arthritis Rheum, 46, 2983–​9. Denton C, et al. (2009). Renal complications and scleroderma renal crisis. Rheumatology (Oxford), 48, iii32–​5. Kowal-​Bielecka O, et al. (2009). EULAR recommendations for the treatment of systemic sclerosis:  a report from the EULAR Scleroderma trials and research group (EUSTAR). Ann Rheum Dis, 68,  620–​8. Nagaraja V (2019). Management of scleroderma renal crisis. Curr Opin Rheumatol, 31, 223–30. Penn H, et al. (2007). Scleroderma renal crisis: patient characteristics and long-​term outcomes. Q J Med, 100, 485–​94. Steen VD (1994). Renal involvement in systemic sclerosis. Clin Dermatol, 12,  253–​8. Steen VD (2001). Treatment of systemic sclerosis. Am J Clin Dermatol, 2, 315–​25. Teixeira L, et al. (2008). Mortality and risk factors of scleroderma renal crisis: a French retrospective study in 50 patients. Ann Rheum Dis, 67, 110–​16.

Rheumatoid arthritis Adu D, et al. (1993). Glomerulonephritis in rheumatoid arthritis. Br J Rheumatol, 32, 1008–​11. Boers M (1990). Renal disorders in rheumatoid arthritis. Semin Arthritis Rheum, 20,  57–​68. Esteve V, et al. (2006). Renal involvement in amyloidosis. Clinical outcomes, evolution and survival. Nefrologia, 26, 212–​17. Hall CL, et al. (1987). The natural course of gold nephropathy: long term study of 21 patients. BMJ, 295, 745–​84. Hall CL, et al. (1988). Natural course of penicillamine nephropathy: a long term study of 33 patients. BMJ, 296, 1085–​6. Harper L, et al. (1997). Focal segmental necrotizing glomerulonephritis in rheumatoid arthritis. QJM, 90, 125–​32. Honkanen E, et al. (1987). Membranous glomerulonephritis in rheumatoid arthritis not related to gold or D-​penicillamine therapy: a report of four cases and review of the literature. Clin Nephrol, 27,  87–​93. Kuznetsky KA, et  al. (1986). Necrotizing glomerulonephritis in rheumatoid arthritis. Clin Nephrol, 26, 257–​64. Stokes MB, et al. (2005). Development of glomerulonephritis during anti-​ TNF-​ alpha therapy for rheumatoid arthritis. Nephrol Dial Transplant, 20, 1400–​6. Uda H, et al. (2006). Two distinct clinical courses of renal involvement in rheumatoid patients with AA amyloidosis. J Rheumatol, 33, 1482–​7.

Sjögren’s syndrome Goules A, et al. (2019). Renal involvement in primary Sjogren’s syndrome: natural history and treatment outcome. Clin Exp Rheumatol, 37 Suppl 118(3), 123–32. Shioji R, et al. (1970). Sjogrens syndrome and renal tubular acidosis. Am J Med, 48, 456–​63. Tu W, et al. (1968). Interstitial nephritis in Sjogren’s syndrome. Ann Intern Med, 69, 1163–​70.

Mixed connective tissue disease Kitridou R, et al. (1986). Renal involvement in mixed connective tissue disease:  a longitudinal clinicopathologic study. Semin Arthritis Rheum, 16, 135–​45. Sharp G, et al. (1972). Mixed connective tissue disease-​an apparently distinct rheumatic disease syndrome associated with a

specific antibody to an extractable nuclear antigen (ENA). Am J Med, 52, 148–​59.

Drug nephrotoxicity Clive D, Stoff J (1984). Renal syndromes associated with anti-​ inflammatory drugs. N Engl J Med, 310, 563–​72. De Broe M, Elseviers M. (2009). Over the counter analgesic use. J Am Soc Nephrol, 20, 2098–​103. Elseviers M, et  al. (1995). High diagnostic performance of CT scan for analgesic nephropathy in patients with incipient to severe renal failure. Kidney Int, 48, 1316–​23. Joint Formulary Committee. British national formulary (online). BMJ Group and Pharmaceutical Press, London. https://​ www. medicinescomplete.com/​mc/​bnf/​current/​ Pusey C, Saltissi D, Bloodworm L (1983). Drug associated acute interstitial nephritis: clinical and pathological features and the response to high dose steroid therapy. Q J Med, 52, 194–​211. Sandler D, Burr F, Weinberg C (1991). Nonsteroidal anti-​ inflammatory drugs and risks for chronic renal disease. Ann Int Med, 115, 165–​72. Savill J, Chia Y, Pusey C (1988). Minimal change nephropathy and pemphigus vulgaris associated with penicillamine treatment of rheumatoid arthritis. Clin Nephrol, 29, 267–​70.

21.10.4  The kidney in sarcoidosis Ingeborg Hilderson and Jan Donck ESSENTIALS Sarcoidosis is associated with a broad spectrum of renal manifestations, but clinically important disease occurs in few patients. The most common cause of renal dysfunction is abnormal calcium metabolism:  untreated chronic hypercalcaemia and hypercalciuria causes progressive tubulointerstitial inflammation with associated calcium deposits, leading to nephrocalcinosis, which is the leading cause of chronic kidney disease. Interstitial granulomatous nephritis is the most typical histological finding, but development of renal insufficiency is unusual. A range of glomerulopathies can be associated with sarcoidosis. When treatment is required, steroids are the first line, with various steroid-​sparing agents used in cases that are refractory.

Introduction Sarcoidosis is a multisystem inflammatory disease characterized by the presence of noncaseating epithelioid granulomas. These granulomas can resolve without sequelae or result in the development of fibrosis. The disease has a benign course with spontaneous resolution in up to two-​third of cases. However, in one-​third a chronic disorder develops, leading to significant organ impairment. Sarcoidosis most frequently involves the lungs, but may affect any organ system. The most common sites of extrapulmonary disease include skin, eyes, liver, spleen, peripheral lymph nodes,

21.10.4  The kidney in sarcoidosis

central nervous system, and heart. The incidence of renal involvement remains unclear. There is a great difference in reported prevalence due to the heterogeneity of renal manifestations and the often insidious nature of the disease.

Clinical presentations Sarcoidosis is associated with a broad spectrum of renal manifestations, but clinically important disease occurs in only a few patients. The most prevalent cause of renal dysfunction is a disordered calcium metabolism. Interstitial granulomatous nephritis is the most typical histological finding, but development of renal insufficiency is unusual. Finally, there is a wide range of glomerulopathies associated with sarcoidosis. Different types of renal sarcoidosis can coexist.

Calcium metabolism Epidemiology Hypercalcaemia occurs in approximately 10 to 20% of patients with sarcoidosis and hypercalciuria is found in up to 50% of patients. Pathogenesis In sarcoidosis and other granulomatous diseases there is an increased activity of 1-​ α-​ hydroxylase, which is synthetized by granulomas and activated macrophages. This enzyme activity is responsible for the increase in 1,25-​dihydroxy vitamin D (calcitriol) and is resistant to negative feedback mechanisms. Calcitriol augments the gastrointestinal calcium absorption, stimulates the osteoclast activity and bony reabsorption, and increases renal tubular calcium reabsorption. The net result is hypercalcaemia, which is known to cause renal dysfunction by several different mechanisms (Box 21.10.4.1). The rise in calcitriol suppresses the production of the parathyroid hormone. Along with an increased renal calcium load, this results in hypercalciuria. Untreated, chronic hypercalcaemia and hypercalciuria causes a progressive tubulointerstitial inflammation with associated calcium deposits, leading to nephrocalcinosis, which is the leading cause of chronic kidney disease in sarcoidosis. Furthermore, hypercalciuria predisposes to nephrolithiasis and obstructive uropathy.

Interstitial nephritis with granuloma formation

autopsy studies of patients with sarcoidosis, a granulomatous infiltrate is found in the kidneys in 7 to 23%. Clinical course Granulomatous interstitial nephritis is usually present when the initial diagnosis of systemic sarcoidosis is made and rarely develops in patients who have longstanding sarcoidosis. Most often there is diffuse active sarcoidosis, although isolated renal disease is an accepted entity. Interstitial nephritis has an insidious nature and is asymptomatic until late in the course of the disease when severe kidney dysfunction develops as a result of progressive fibrosis. It has a highly variable course with a tendency to wax and wane, either spontaneously or under treatment. Relapses are frequent. Diagnosis Screening for renal disease is important. Renal function tests, measurement of serum calcium, and urine analysis should be performed systematically both during initial evaluation and the follow-​ up of patients with sarcoidosis. Whenever granulomatous interstitial nephritis is suspected, a histopathological confirmation should be attempted. Noncaseating granulomas are the hallmark of the disease, but they are nonspecific (Fig. 21.10.4.1).

(a)

(b)

(c)

Epidemiology Granulomatous interstitial nephritis is the most common renal lesion seen on biopsy, but in only a few patients does this cause clinically significant disease. The true incidence is unknown, but in

Box 21.10.4.1  Mechanisms of renal dysfunction caused by hypercalcaemia • Vasoconstriction of the afferent arteriole, causing a decrease in glomerular filtration • Inhibition of Na+/​K+-​ATPase leading to urinary sodium wasting with polyuria and dehydration • Decreased sensitivity to antidiuretic hormone • Acute tubular necrosis

Fig. 21.10.4.1  Granulomatous interstitial nephritis. (a) On the left there is a localized inflammation of the renal parenchyma, which is not present on the right (haematoxylin and eosin stain, original magnification ×100). (b) Further magnification of the inflammation. There is a granulomatous infiltration with central collections of histiocytes surrounded by lymphocytes (haematoxylin and eosin stain, original magnification ×200). (c) Confirmation of the histiocytic character of the inflammation by an immunohistochemical staining with antibodies directed against CD68 (anti-​CD68 stain, original magnification ×200). Courtesy of Prof. Dr. E. Lerut, University of Leuven, Belgium.

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Table 21.10.4.1  Differential diagnosis of granulomatous nephritis Diagnosis

Example

Drug reaction

β-​lactam antibiotics, nonsteroidal anti-​inflammatory drugs

Infections

Tuberculosis, chronic fungal infection

Autoimmune disorders

Sarcoidosis, granulomatosis with polyangiitis

Neoplasia

Lymphoma

Foreign body reaction

Heroin

Table 21.10.4.2  Treatment of hypercalcaemia and hypercalciuria in sarcoidosis Standard of care: glucocorticoids Starting dose: 0.3–​0.5 mg/​kg per day Maintenance dose: 5–​10  mg/​day Total duration of treatment: at least 12 months Alternatives Chloroquine Hydroxychloroquine Dose: 250–​500 mg/​day Dose: 200–​400 mg/​day

Ketoconazole Dose: 600–​800 mg/​day

Preventive measures

Especially in case of isolated renal disease, other reasons of granulomatous infiltration should be excluded (Table 21.10.4.1). The absence of kidney biopsy findings does not exclude the diagnosis as renal sarcoidosis can be focal in nature and the typical lesions can easily be missed in biopsy. The urinary manifestations are also nonspecific: there is often mild proteinuria, or less frequently aseptic pyuria or nonvisible haematuria. In some cases, the urine sediment is bland.

Glomerular disease Membranous nephropathy is the most common glomerular manifestation of sarcoidosis, although its incidence is very low. Some case reports suggest an association between sarcoidosis and focal segmental sclerosis, mesangioproliferative glomerulonephritis, IgA nephropathy, and crescentic glomerulonephritis, but a definitive causal relationship to these conditions has not been proven.

Tubular dysfunction Tubular dysfunction is frequently associated with hypercalcaemia and granulomatous interstitial nephritis. It may present as isolated proximal or distal tubular acidosis, Fanconi’s syndrome, urinary concentration deficits, or metabolic alkalosis.

Obstructive and vascular uropathy Obstructive uropathy usually results from nephrolithiasis, but in patients with sarcoidosis, obstruction may also be due to retroperitoneal fibrosis or lymphadenopathy. Renal artery stenosis caused by granulomatous angiitis is an extremely rare complication of sarcoidosis, often accompanied by arterial hypertension.

Treatment Treatment is always required for renal disease, as it is for cardiac, ocular, and neurological manifestations of sarcoidosis, given the substantial risk of end-​organ damage. However, there is no standard of care and little is known about the optimal dose and duration of treatment.

Hypercalcaemia and hypercalciuria Glucocorticoids are the mainstay of treatment (Table 21.10.4.2) as they block the 1-​α-​hydroxylase activity and diminish the intestinal calcium absorption and bony resorption. Most often, a

Limit sunlight exposure Low dietary intake of calcium, vitamin D, and oxalate Adequate oral hydration Avoid thiazide use

starting dose of prednisolone of 0.3 to 0.5 mg/​kg once daily is recommended, followed by a taper to a maintenance dose of 5–​10 mg once daily. The total duration of treatment should be at least 12 months. Chloroquine is an alternative treatment. The optimal dose is unknown, but a daily dosage of 250 to 500 mg is most often used. Retinal toxicity is the major concern. Hydroxychloroquine (recommended daily dosing is 200–​4 00 mg) is slightly less effective, but carries a lesser risk of retinopathy. Ketoconazole in a daily dose of 600–​800 mg can also be used. Hepatic toxicity is the major limiting side effect. The effect of these alternative forms of treatment is less predictable and slower than treatment with corticoids. Preventive measures such as ensuring adequate oral hydration, a low dietary intake of calcium, vitamin D, and oxalate, as well as the limitation of sunlight exposure play additional supportive roles. Thiazide use should be avoided given the substantial risk of aggravating hypercalcaemia.

Interstitial nephritis with granuloma formation Glucocorticoids Glucocorticoids are the cornerstone of treatment (Table 21.10.4.3). Most authors recommend a starting dose of 0.5 to 1 mg per kg prednisone once daily, depending on the severity of the disease. The initial dose should be maintained for 4 weeks to allow improvement and/​or stabilization of renal function. Most patients respond rapidly to treatment but a full recovery of renal function is rare. Patients with a poor response after 1 month tend to have a worse renal outcome and are more susceptible to relapse. After 4 weeks of treatment, the dose can be tapered by 5 mg each week until a daily dose of 5 to 10 mg is reached. There is an increased risk of relapse if corticosteroids are tapered too quickly. In this eventuality, the dose should be augmented to the last dose that was effective, with an increase to the initial dose if there is no improvement after 4 weeks. Subsequent tapering should be more gradual. However, in some patients it is impossible to taper the glucocorticoids adequately. Given the many side effects of a prolonged treatment with high-​dose glucocorticoids,

21.10.4  The kidney in sarcoidosis

Table 21.10.4.3  Treatment of granulomatous interstitial nephritis in sarcoidosis

it should be pointed out that the evidence in support of these second-​ line agents is very limited.

Step 1: glucocorticoids

Tumour necrosis factor-​α inhibitors

Starting dose: • Major organ impairment: —  Oral prednisone 1 mg/​kg per day Or — Intravenous pulse methylprednisolone (3 days), followed by oral prednisone 1 mg/​kg per day • Milder disease: oral prednisone 0.5 mg/​kg per day

Tumour necrosis factor (TNF) is thought to be a major player in sarcoidosis through its role in the maintenance of granuloma formation. TNFα inhibitors have therefore been suggested as appropriate treatment in cases of steroid-​resistant sarcoidosis. They should only be used when at least one other immunosuppressive agent has been tried, or in patients who have developed severe steroid toxicity. Evidence is scarce. Infliximab is usually given in a dosage of 3 to 5 mg per kg at weeks 0, 2, and 6, followed by 3 to 5 mg per kg every 6 to 8 weeks thereafter. Adalimumab could be an interesting option for patients intolerant of infliximab, but more research is needed before its use can be advocated. Etanercept seems to have no beneficial effect in patients with sarcoidosis, as in other granulomatous diseases.

Keep initial dose for 4 weeks, if renal function does not stabilize/​improve continue to step 2 After 4 weeks of treatment, reduce dose by 5 mg a week Maintenance dose: 5–​10 mg daily Relapse: • Augment prednisone to the last dose that was effective and continue for 4 weeks • No improvement after 4 weeks: augment corticoids to the starting dose and continue for 4 weeks • Subsequent tapering: more gradual Total duration of treatment: 18–​24 months Step 2: add another immunosuppressive agent Failure of corticosteroids Relative contraindication to corticosteroids Impossibility to taper the corticosteroids Azathioprine Dose: 2 mg/​kg per day

Mycophenolate mofetil Dose: 1 g, twice a day

Subsequently reduce the corticosteroids by 5 mg a week until a daily dose of 5–​10 mg is reached Step 3: add a TNFα inhibitor—​infliximab Steroid-​resistant sarcoidosis when at least one other immunosuppressive agent has been tried Severe steroid toxicity Dose: 2–​5 mg/​kg at weeks 0, 2, and 6 and every 6 to 8 weeks thereafter Experimental therapy Thalidomide, pentoxifylline, rituximab, etc.

a steroid-​sparing agent (azathioprine or mycophenolate mofetil) can be added, with the intention of subsequently reducing the glucocorticoid dose. The ideal duration of maintenance therapy is unknown. A total duration of treatment of 18 to 24 months seems necessary to be effective and to prevent relapse. For the few patients who suffer frequent relapses, lifelong treatment with low-​dose glucocorticoids may be required. There are, however, important side effects from long-​term steroid use which need to be balanced against the risk of progression to endstage renal disease. Azathioprine and mycophenolate mofetil Azathioprine and mycophenolate mofetil can be used as steroid-​ sparing agents or in patients with failure of or a strong contraindication to continued corticosteroids. Treatment with these drugs should only be started after at least 1 month of treatment with corticosteroids, since this duration is needed to allow improvement or stabilization of renal function. The daily dose of azathioprine is 2 mg per kg, mycophenolate mofetil is dosed at 1 g, twice a day. However,

Kidney transplantation Endstage renal disease secondary to sarcoidosis is very uncommon. One concluded that renal transplantation can be carried out safely with excellent graft and patient survival, although there was a relatively high rate of renal recurrence (17%). A short delay between the last episode of sarcoidosis and renal transplantation was a risk factor for recurrence. Experimental therapy With recognition of the role of cytokines in the pathogenesis of sarcoidosis, other immunosuppressive drugs including thalidomide, pentoxifylline, and rituximab have been proposed as steroid-​sparing agents, but more data are needed before their use can be advocated.

Conclusion Sarcoidosis may affect any organ, including the kidney. Disordered calcium metabolism is the most common cause of renal failure. Granulomatous interstitial nephritis is the most typical histological finding, but development of renal insufficiency is rare. The lack of large, randomized controlled treatment trials limits therapeutic options. Corticosteroids remain the cornerstone of treatment. The role of corticosteroid-​sparing medications continues to evolve.

FURTHER READING Berliner AR, Haas M, Choi MJ (2006). Sarcoidosis: the nephrologist’s perspective. Am J Kidney Dis, 48, 856–​70. Hilderson I, et  al. (2014). Treatment of renal sarcoidosis:  is there a guideline? Overview of the different treatment options. Nephrol Dial Transplant, 29, 1841–​7. Mahévas M, et  al. (2009). Renal sarcoidosis:  clinical, laboratory, and histologic presentation and outcome in 47 patients. Medicine (Baltimore), 88, 98–​106. Rajakariar R, et al. (2006). Sarcoid tubulo-​interstitial nephritis: long-​ term outcome and response to corticosteroid therapy. Kidney Int, 70,  165–​9.

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21.10.5  Renal involvement in plasma cell dyscrasias, immunoglobulin-​based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias Pierre Ronco, Frank Bridoux, and Arnaud Jaccard ESSENTIALS Plasma cell disorders are characterized by uncontrolled proliferation of a single clone of B cells which is responsible for the secretion of a monoclonal immunoglobulin (Ig) or Ig subunit that can deposit in tissues. They can cause a wide range of renal diseases. Light-​chain amyloidosis—​renal presentation is usually with proteinuria, often progressing to nephrotic syndrome. A progressive decline in renal function may occur, leading finally to endstage renal failure. Diagnosis is made by the detection of monoclonal gammopathy and free light-​chain excess in the serum (90% of cases), in combination with biopsy evidence of amyloid-​forming light-​chain deposits. Treatment is based on chemotherapy with oral melphalan plus dexamethasone, or bortezomib-​based regimens in patients with heart involvement. High dose melphalan followed by autologous stem cell transplantation can be considered in highly selected patients. Treatment efficacy should be evaluated by estimation of light-​chain response. Myeloma—​renal failure is found at presentation in 20% of patients, occurs in 50% at some time, and is most commonly caused by cast nephropathy, diagnosis of which relies on the detection of proteinuria mostly composed of monoclonal light chains, with renal biopsy typically showing ‘fractured’ casts. Chemotherapy should be introduced promptly (e.g. high-​dose dexamethasone, combined with bortezomib, and/​or alkylating agents, and/​or thalidomide or another immunomodulatory agent). Light-​ chain, light-​and heavy-​ chain, and heavy-​ chain deposition disease—​collectively known as monoclonal Ig deposition diseases, present with proteinuria and renal failure. Diagnosis is by renal biopsy which reveals nodular glomerulosclerosis, monotypic light-​and/​or heavy-​chain deposits along glomerular and tubular basement membranes (by immunofluorescence), and nonfibrillar linear electron-​dense deposits (by electron microscopy). Treatment strategy is based on chemotherapy (bortezomib-​based regimens) followed by autologous stem cell transplantation in selected cases. Fibrillary glomerulonephritis and immunotactoid glomerulopathy— ​usual presentation is with nephrotic syndrome, microscopic haematuria, and hypertension. Diagnosis is by renal biopsy when electron microscopy reveals (respectively) fibrils (solid, diameter 12–​22 nm, randomly arranged) or microtubules (hollow, diameter 10–​60 nm, in parallel arrays). Immunotactoid glomerulopathy, often associated with chronic lymphocytic leukaemia or lymphoma, usually responds to chemotherapy. Cryoglobulinaemia—​type II (‘essential mixed’), which involves a monoclonal IgM with rheumatoid factor activity and a polyclonal IgG, may present with proteinuria, haematuria, hypertension, and

gradually declining renal function, or with an acute nephritic picture. It should be suspected in the presence of an IgM rheumatoid factor and low complement C4, and confirmed by the finding of a cryoglobulin. It is often associated with hepatitis C. Renal biopsy typically reveals membranoproliferative glomerulonephritis with massive subendothelial deposits. Treatment involves antiviral agents and/​or immunosuppression. Tumour lysis syndrome—​a life-​threatening metabolic emergency that occurs in patients with haemopathies with high cell turnover (e.g. Burkitt’s lymphoma and acute leukaemia), mostly at the onset of chemotherapy. Prevention is by vigorous hydration with 0.9% saline before treatment with the addition of allopurinol (in low-​risk cases) or the recombinant modified urate oxidase rasburicase (in high-​risk cases). Treatment is based on saline diuresis (if possible), rasburicase, and haemodialysis (if required).

Introduction Plasma cell disorders are characterized by uncontrolled proliferation of a single clone of B cells, usually with plasma cell differentiation, which is responsible for the secretion of a monoclonal immunoglobulin (Ig) or Ig subunit that can deposit in tissues. The range of renal diseases secondary to deposition or precipitation of Ig-​related material has expanded dramatically in recent years. These conditions can be classified into two categories on the basis of their ultrastructural appearances (Table 21.10.5.1). Those with organized deposits include diseases with crystal formation, mainly Fanconi’s syndrome and myeloma cast nephropathy; diseases with fibril formation, mainly light-​chain amyloidosis; and diseases with microtubule formation, including cryoglobulinaemia kidney and immunotactoid/​ microtubular glomerulonephritis (also called glomerulonephritis with organized microtubular monoclonal Ig deposits (GOMMID)). A second category of diseases is characterized by the presence of nonorganized granular electron-​dense deposits made of light and/​or heavy chains along the basement membranes of many tissues, most importantly the kidney. First described by Randall and associates, these are referred to as monoclonal Ig deposition diseases (MIDD). More recently, glomerular diseases with amorphous monoclonal Ig deposits distinct from Randall-​ type MIDD and referred to as proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) have been described. It is now established that the spectrum of plasma cell dyscrasia-​related renal complications is due to intrinsic properties of the monoclonal component. Except for myeloma cast nephropathy, diagnosis relies on careful analysis of a biopsy specimen taken from the kidney, which should systematically include immunohistochemical studies with specific antibodies and also electron microscopy in all ambiguous cases. Since most of these patients will develop renal failure, it is essential to identify the underlying plasma cell clone because appropriate treatment may halt the extension of visceral deposits, and even induce their regression. Except in patients with myeloma cast nephropathy, who usually present with a high-​mass myeloma, most renal disorders related to monoclonal Ig deposition occur in the context of an indolent B-​cell disorder that manifests as isolated monoclonal

21.10.5  Renal involvement in plasma cell dyscrasias

Table 21.10.5.1  Pathological classification of diseases with tissue deposition or precipitation of monoclonal Ig-​related material Organized

Nonorganized (granular)

Crystals

Fibrillar

Microtubular

MIDD (Randall-​type)

Other

Myeloma cast nephropathy

Light-​chain amyloidosis

Cryoglobulinaemia kidney

LCDD

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID)

Fanconi’s syndrome

Nonamyloid fibrillary GN

Immunotactoid GN/​GOMMID

LHCDD

Waldenström’s macroglobulinaemia

Other

HCDD

GN, glomerulonephritis; GOMMID, glomerulonephritis with organized microtubular monoclonal Ig deposits; LCDD, LHCDD, HCDD, light-​chain, light-​and heavy-​chain, heavy-​chain deposition disease; MIDD, monoclonal immunoglobulin deposition disease.

gammopathy. To individualize this condition, the term monoclonal gammopathy of renal significance (MGRS) was recently introduced to highlight the association of a small B-​cell clone and renal disease related to the nephrotoxic property of the secreted monoclonal Ig, and the importance of chemotherapy to prevent consequences of renal and sometimes widespread organ deposition.

Renal involvement in Ig light-​chain amyloidosis

tubular dysfunction may be the presenting problem. Hypertension is uncommon but may develop concomitantly with renal failure. The kidneys may be of normal size or large, even when renal function is impaired. Systemic organ involvement is common, particularly cardiac disease, diagnosed in 60% of patients and strongly impacting survival. Deposits commonly also affect the liver, peripheral nervous system, carpal tunnel, gastrointestinal tract, skin, and tongue. Purpuric macules in the periorbital region are very typical of AL amyloidosis.

Definition and epidemiology

Diagnosis

Amyloidosis is a general term for a family of diseases defined by morphological criteria and characterized by deposition in extracellular spaces of a proteinaceous material that stains with Congo red and is metachromatic. Amyloid deposits are composed of a felt-​like array of 10-​nm-​wide, rigid, linear aggregated fibrils of indefinite length with a β-​pleated sheet configuration. They occur in a variety of conditions including Alzheimer’s disease and other neurodegenerative disorders, tumoural and inflammatory diseases, and plasma cell disorders. The various types of amyloidosis differ essentially by the nature of the precursor protein that yields the main component of fibrils, and are classified accordingly (see Chapter 12.12.3 for further discussion). Light-​chain (AL) amyloidosis is the most frequent form of systemic amyloidosis with renal involvement in Western countries. AL amyloidosis most commonly occurs in patients with isolated monoclonal gammopathy or smouldering myeloma, with only 20% of patients having evidence of a symptomatic plasma cell or B-​cell disorder at diagnosis.

AL amyloidosis should be suspected when the clinical manifestations previously described are associated with a monoclonal component in the serum or urine. AL amyloidosis is always the result of the proliferation of a small plasma cell clone: most patients have an increased number of plasma cells in the bone marrow, but only 15% have true myeloma. By immunofixation, a monoclonal Ig is found in the serum and/​or the urine in nearly 80% of patients. The recent development of a sensitive nephelometric immunoassay for circulating free Ig light chains has been an important advance in the management of AL amyloidosis, allowing detection of abnormal serum free light-​chain levels in 98% of patients, the λ isotype being involved twice as frequent as the κ isotype, with an over-​representation of the Vλ6 subgroup found in AL amyloidosis with renal involvement. Monitoring of serum free light chains at diagnosis and throughout follow-​up is mandatory to evaluate the response to chemotherapy. It is important to recognize that detection of monoclonal gammopathy is insufficient for the diagnosis of AL amyloidosis, which should be established in all cases by taking a biopsy specimen from a superficial organ (salivary glands), or by aspiration biopsy of abdominal fat. These biopsies should be performed before biopsies of rectal mucosa and/​or of kidney, because of the risk of bleeding complications due to factor X deficiency, fibrinolysis, or amyloid infiltration of vascular walls. After Congo red staining, amyloid deposits appear faintly red and show characteristic apple-​green birefringence under polarized light. Congo red staining may be falsely negative if tissue sections are less than 5 µm in thickness. In the kidney, the earliest lesions are located in the mesangium, along the glomerular basement membrane, and in the blood vessels (Fig. 21.10.5.1). Because there are specific diagnostic and therapeutic strategies depending on the type of protein deposited within tissues, immunofluorescence with specific antisera including anti-​κ and anti-​λ light chains should be performed routinely. When pathological confirmation of AL type cannot be obtained, genetic studies should be performed to exclude systemic hereditary amyloidosis caused by mutations in the genes encoding leucocyte chemotactic factor 2, fibrinogen A  α-​chain,

Clinical presentation Systemic AL amyloidosis can infiltrate almost any organ and thus be responsible for a wide variety of clinical manifestations. The main presenting symptoms are fatigue and dyspnoea. Renal disease is the most common manifestation of systemic AL amyloidosis. Proteinuria, composed mainly of albumin, is the usual symptom, detected in approximately 70% of patients at presentation and often progressing to a severe nephrotic syndrome, which can be complicated by renal vein thrombosis. Haematuria is uncommon, and when present should prompt examination for a bleeding lesion of the urinary tract. Progressive decline in renal function leading finally to endstage renal failure may occur, particularly in patients with baseline proteinuria greater than 5 g/​24 h and an estimated glomerular filtration rate less than 50 ml/​min per 1.73 m2. In those rare patients in whom renal tubulointerstitial deposits predominate, renal failure may progress without a nephrotic stage, and renal

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(a)

(b)

Table 21.10.5.2  Diagnostic and response criteria in AL amyloidosis Definition of renal involvement

24-​h urine protein ≥0.5 g/​day, predominantly albumin

Mayo Clinic staging for heart involvement

Stage 1: hs-​cTnTa ≤77 ng/​litre and NT-​proBNP ≤332 ng/​ litre Stage 2: hs-​cTnT >77 ng/​litre or NT-​proBNP >332 ng/​litre Stage 3: hs-​cTnT >77 ng/​litre and NT-​proBNP >332 ng/​ litre

Definition of renal response

2005 criteria: 50% decrease (at least 0.5 g/​day) of 24-​h urine protein (urine protein must be >0.5 g/​day pretreatment) in the absence of a reduction in eGFR ≥25% or an increase in serum creatinine ≥0.5  mg/​dl 2014 revised criteria: ≥30% decrease in proteinuria or drop of proteinuria below 0.5 g/​24 h in the absence of renal progression (as defined by ≥25% decrease in eGFR)

Definition of haematological response

CR: negative serum and urine IFE, normal kappa/​ lambda ratio VGPR: dFLC 30 nm), at times arranged in parallel arrays (Fig. 21.10.5.3). When immunotactoid/​microtubular glomerulopathy occurs in the setting of chronic lymphocytic leukaemia or related B-​cell lymphoma, inclusions showing the same microtubular organization and containing the same IgG subclass and light-​chain type as the renal deposits are often detected in the cytoplasm of leukaemic lymphocytes in the blood. Mesangial proliferation and membranoproliferative glomerulonephritis are the commonest lesions observed in nonamyloid fibrillary glomerulonephritis. Immunofluorescence studies show predominant polyclonal IgG4, usually associated with IgG1 deposits. DNAJB9 was recently found as sensitive and specific biomarker for fibrillary glomerulonephritis. Positive glomerular staining for DNAJB9 by immunohistochemistry is a strong indicator of the diagnosis. Electron microscopy shows the fibrils, devoid of a central lumen, to be randomly arranged with a diameter varying between 12 and 22 nm. In almost all cases there is no evidence of associated lymphoproliferative disorder or monoclonal gammopathy.

(c)

Fig. 21.10.5.3  Immunotactoid/​microtubular glomerulopathy in a patient with chronic lymphocytic leukaemia. Atypical membranous glomerulonephritis showing exclusive staining of the deposits with (a) anti-​ γ (b) and anti-​κ antibodies (immunohistochemistry, alkaline phosphatase, magnification × 312). (c) Electron micrograph of glomerular basement membrane, showing the microtubular structure of the subepithelial deposits (uranyl acetate and lead citrate, magnification × 12 000). From Béatrice Mougenot’s personal collection.

Infection with hepatitis C virus has sometimes been reported in patients with nonamyloid fibrillary glomerulonephritis and immunotactoid glomerulopathy.

21.10.5  Renal involvement in plasma cell dyscrasias

Treatment In patients with GOMMID, especially in those with chronic lymphocytic leukaemia, chemotherapy is associated with partial or complete remission of the nephrotic syndrome, parallel with improvement of the haematological condition. More variable results are obtained with cytotoxic treatments in patients with fibrillary glomerulonephritis, although rituximab produced improvement in renal parameters in few patients. Recurrence of these diseases has been reported in patients receiving a renal allograft.

Renal involvement in cryoglobulinaemia Definition and epidemiology Cryoglobulinaemia is a pathological condition in which the blood contains Igs that precipitate on cooling (4°C) and resolubilize on warming (37°C). According to Brouet’s classification, there are three types of cryoglobulinaemia defined by their composition. Renal involvement is observed mainly in patients with mixed type II cryoglobulinaemia involving a monoclonal IgM (most often including a κ light chain) with rheumatoid factor activity and a polyclonal IgG. Type II cryoglobulinaemia can be associated with overt lymphoproliferative disorders of the B-​cell lineage, although in many cases no underlying haematological disorder is found such that this type of cryoglobulinaemia has long been referred to as essential mixed cryoglobulinaemia. Glomerular disease may also occur in type I  cryoglobulinaemia, composed of a single monoclonal Ig (mostly IgM or IgG), usually in the context of underlying lymphoproliferative or plasma cell disorder (see later). Viral infections may trigger the formation of cryoglobulin. Whereas hepatitis B and Epstein–​Barr virus infections have been implicated in the past, the role of hepatitis C virus infection is now recognized to be an important factor in the pathogenesis of type II cryoglobulinaemia. Antibodies to hepatitis C virus and hepatitis C virus RNA are found in the sera of most patients with type II cryoglobulinaemia, probably explaining the uneven geographical distribution of mixed cryoglobulinaemias, which predominate in southern Europe where hepatitis C infection is more prevalent. The condition is commonest in adults in the fifth and the sixth decades of life, with a slight female predominance.

Clinical presentation Renal disease most often occurs in patients with a long history of cryoglobulinaemia-​related vasculitic symptoms, including palpable purpura (70%), arthralgias (50%), fatigue, Raynaud’s phenomenon, peripheral neuropathy (22%), and hepatic involvement. The renal disease may present as an acute nephritic syndrome (in 20 to 30% of patients) with gross haematuria, heavy proteinuria, hypertension, and renal failure of sudden onset, sometimes with oliguria (5% of patients). The pathological finding in these patients is membranoproliferative glomerulonephritis with the presence of numerous intraluminal thrombi and/​or necrotic vasculitic lesions. Remission may occur spontaneously or during therapy, with relapses following in up to 20% of cases. Most patients with mixed cryoglobulinaemia (55%) have an indolent and protracted renal course, presenting with proteinuria, haematuria, and hypertension. The usual renal lesion in this context

is membranoproliferative glomerulonephritis, with some of the peculiarities described earlier. Nephrotic syndrome affects another 20% of patients. Arterial hypertension is observed in more than 80% of patients at the time of onset of renal disease. Endstage renal disease develops in fewer than 10% of patients. It should be stressed that the overall risk of non-​Hodgkin B-​cell lymphomas is 35 times higher in patients with hepatitis C virus-​related cryoglobulinaemia compared to the general population.

Diagnosis Mixed type II cryoglobulinaemia should be suspected in patients with the clinical picture described previously, an IgM rheumatoid factor, and a very low serum C4 fraction and total haemolytic activity of complement. In this context, a careful search for the presence of cryoglobulin must be made, requiring that a blood sample from a fasting patient should be placed in warm water and taken promptly to the laboratory, which needs to be forewarned that such a sample will arrive. Cryoglobulinaemia-​related membranoproliferative glomerulonephritis usually shows several distinctive histological features, including massive subendothelial deposits filling the capillary lumen and forming so-​called thrombi, and dramatic infiltration by leucocytes, mainly monocytes (Fig. 21.10.5.4). The thrombi are brightly stained with anti-​ μ and anti-​κ antibodies and present a microtubular crystalline structure similar to that of the cryoprecipitate. These glomerular changes may be associated with acute vasculitis of the small and medium-​sized arteries (33%) and lymphocytic infiltrates in the interstitium. Crescentic extracapillary proliferation is rare and always limited.

Treatment The best treatment of mixed cryoglobulinaemia is not firmly established because the course of the disease is unpredictable and acute exacerbations may remit spontaneously. In patients with moderate renal and extrarenal manifestations, immunosuppressive agents are not indicated. In those with hepatitis C virus infection, sustained viral response is generally associated with improvement in clinical manifestations of cryoglobulinaemia. Combined pegylated interferon and ribavirin for at least 1 year was until recently the treatment of choice. The use of novel direct-acting antihepatitis C agents is more efficient in eradicating hepatitis C virus, and with less side effects, will likely result in improved outcomes in type II cryoglobulinaemia. In more severe cases, particularly those with signs of systemic vasculitis, high-​dose steroids, plasma exchange, and cytotoxic drugs are indicated. Among these, the monoclonal anti-​CD20 antibody (rituximab), which is usually well tolerated, is recommended, as it also appears to be as efficient as cyclophosphamide. Hypertension needs to be carefully controlled because cardiovascular complications are the major causes of death. In patients with severe symptomatic type I  or type II cryoglobulinaemia secondary to B-​cell proliferative disorder, treatment relies on chemotherapy adapted to the nature of the underlying clone.

Renal involvement in Waldenström’s macroglobulinaemia A glomerulonephritis with intracapillary thrombi of monoclonal IgM is rare, but is almost specific for Waldenström’s macroglobulinaemia. It is characterized by periodic acid–​Schiff-​positive, noncongophilic

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(a)

(b)

endomembranous deposits in capillary loops, which sometimes occlude the capillary lumen either partially or completely, thus forming thrombi. These lesions, which occurred in patients with advanced disease and high serum IgM levels, usually with hyperviscosity syndrome and detectable cryoglobulinaemia, have decreased over time. AL amyloidosis currently represents the most frequent glomerular disease, but other types have been described, including membranoproliferative glomerulonephritis with nonorganized monoclonal IgM deposits, type I  and type II cryoglobulinaemic glomerulonephritis, and Randall-​type MIDD. Neoplastic infiltration of the renal interstitium by malignant B cells is common and may be observed alone or associated with glomerular or tubular disorders. Tubular lesions, secondary to monoclonal light chain precipitation, are less frequent, but cases of Fanconi’s syndrome and cast nephropathy have been reported. Management relies on chemotherapy (see Chapter 22.4.6) with rituximab-​based regimens. Plasmapheresis should be considered in patients with acute kidney injury and symptoms of hyperviscosity.

C3 glomerulopathy and monoclonal gammopathy

(c)

Isolated glomerular deposition of C3 is a rare condition in adults that results from dysregulation of the complement alternative pathway. It manifests histologically with mesangial proliferative or membranoproliferative glomerulonephritis, with diffuse, bright deposition of C3 in the mesangium and capillary walls by immunofluorescence, and no significant immunoglobulin deposit. Ultrastructurally, two different patterns may be observed: dense deposit disease characterized by diffuse intramembranous electron-​dense deposits with a typical ‘sausage-​like’ appearance, and C3 glomerulonephritis with less intense granular mesangial, subendothelial, or subepithelial deposits. A high prevalence of monoclonal gammopathy (>60%) was recently identified in patients with C3 glomerulopathy aged over 50  years. Clinical presentation is with hypertension, chronic renal failure, nonvisible haematuria, and proteinuria, with nephrotic syndrome in half of cases. Most patients have an indolent plasma cell proliferation, consistent with MGRS, and one-​third have decreased C3 levels at diagnosis. Control of the underlying plasma cell clone with appropriate chemotherapy may result in significant improvement in renal parameters, before severe renal impairment develops. Although the pathophysiology remains unclear, local or systemic activation of the complement alternative pathway by the monoclonal immunoglobulin is likely to be involved, through autoantibody activity of the monoclonal Ig against a complement alternative pathway regulator protein, or other mechanisms, including direct activation of the complement alternative pathway by the monoclonal immunoglobulin itself. See Chapter 21.8.6 for further discussion.

Renal involvement in lymphomas and leukaemias Fig. 21.10.5.4  Cryoglobulinaemic glomerulonephritis. (a) The glomerulus shows a marked endocapillary hypercellularity with massive infiltration of mononuclear leucocytes (Masson’s trichrome stain, magnification × 500). (b) Frequent double-​contour aspect and intraluminal thrombi (periodic acid–​Schiff stain, magnification × 312). (c) Thrombi and segments of glomerular basement membrane are brightly stained with anti-​IgM antibody (immunofluorescence, magnification × 312). From Béatrice Mougenot’s personal collection.

Renal complications of lymphomas and leukaemias are summarized in Box 21.10.5.1. All patients with unexplained renal failure should undergo ultrasound examination of the kidney, which should be arranged as a matter of urgency, to identify either enlarged kidneys due to tumour infiltration or hydronephrosis. The presence of heavy albuminuria in this setting is suggestive of paraneoplastic glomerulopathy.

21.10.5  Renal involvement in plasma cell dyscrasias

Box 21.10.5.1  Renal complications of lymphomas and leukaemias Mechanical complications: • —​  Infiltration of renal parenchyma —​ Obstructive uropathy (retroperitoneal fibrosis) —​ Compression of renal artery or vein • Electrolyte disturbances and disseminated intravascular coagulation • Glomerulopathies (including amyloidosis) • Treatment-​induced complications: —​ Tumour lysis syndrome —​ Lithiasis and urate nephropathy —​ Radiation nephropathy —​ Drug-​induced toxic nephropathy —​ Thrombotic microangiopathy and mesangiolysis

Hodgkin’s disease and non-​Hodgkin’s lymphoma Glomerulonephritis is a rare complication of lymphoma, most often described in patients with Hodgkin’s disease, of whom 0.4% have minimal-​change disease and 0.1% have amyloid A amyloidosis. This low incidence of amyloidosis in patients with Hodgkin’s disease is most likely attributable to modern treatment protocols that induce rapid remission. Hodgkin’s lymphoma-​related minimal-​change disease shows features of a paraneoplastic glomerulopathy. The nephrotic syndrome usually appears early, revealing the haemopathy in about one-​half of the cases; it rapidly disappears after effective treatment of the underlying condition; and it usually relapses simultaneously with the haemopathy. Cases of crescentic glomerulonephritis with rapidly progressive renal failure due to antiglomerular basement antibodies have also been reported. Glomerulonephritis may also occur in patients with non-​Hodgkin’s lymphoma, including both T-​and B-​cell proliferations. In these conditions, unlike in Hodgkin’s lymphoma, minimal-​change disease is uncommon, and membranoproliferative glomerulonephritis and necrotizing crescentic glomerulonephritis with or without vasculitis are the most frequent lesions. Some cases are associated with type I  cryoglobulinaemia or GOMMID. In other cases, the association between non-​Hodgkin’s lymphoma and renal disease may be coincidental. Presenting renal symptoms are nephrotic syndrome and/​or renal impairment. Full remission of these symptoms can be achieved in some patients by aggressive therapy of the lymphoma.

Chronic lymphocytic leukaemia and low-​grade B-​cell lymphoma These haemopathies, particularly chronic lymphocytic leukaemia, have been reported in association with glomerular disease in about 50 cases. Most commonly, the nephropathy, usually manifesting as nephrotic syndrome with impaired renal function, and the leukaemia are detected simultaneously. The most frequent glomerular disease is membranoproliferative glomerulonephritis with or without cryoglobulinaemia (mostly type I). In type I cryoglobulinaemic glomerulonephritis, glomerular monoclonal Ig deposits often display an ultrastructural organization into microtubules, and less frequently into crystals. In the absence of cryoglobulinaemia, a molecular link can be established between the haemopathy and the glomerulopathy when monotypic Ig deposits are found in the glomerulus, which can occur even in the absence of detectable circulating M component. As discussed previously, some of these patients present with typical immunotactoid/​ microtubular glomerulopathy or MIDD. Improvement of the nephropathy after chemotherapy for the leukaemia is well described.

Acute leukaemias Disseminated intravascular coagulation has been associated with acute progranulocytic leukaemia. Other renal complications are commonly due to treatment, most particularly the tumour lysis syndrome (see ‘Tumour lysis syndrome’).

POEMS syndrome POEMS syndrome is a rare condition defined by the presence of peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder (IgA, IgG, IgM, or LC only the LC being almost always of the lambda isotype), and skin changes. The association of POEMS syndrome with osteosclerotic myeloma or Castleman’s disease is common. Although the pathophysiology of the disease is unknown, POEMS syndrome is characterized by a very high serum level of vascular endothelial growth factor, which seems to be responsible for most symptoms present in this disease. Renal disease may occur, which usually manifests as proteinuria, haematuria, and renal failure that may progress to endstage renal failure. Kidney biopsy reveals lesions resembling thrombotic microangiopathy, with glomerular enlargement, cellular proliferation, and mesangiolysis with marked swelling of endothelial and mesangial cells, associated with endarteritis-​like lesions in the small renal arteries. The monoclonal component is usually not deposited in kidney.

Tumour lysis syndrome Tumour lysis syndrome is a life-​threatening metabolic emergency. It occurs in patients with haemopathies involving a high cell turnover, such as Burkitt’s lymphoma or acute leukaemia, mostly at the onset of chemotherapy and/​or on radiation therapy. The ensuing massive cytolysis generates high levels of uric acid, phosphate, potassium, and xanthine (especially in patients treated with allopurinol), with a concomitant decrease in serum calcium concentration. Oliguric or anuric acute kidney injury may occur, especially in those who are dehydrated or have pre-​existing impairment of kidney function. This acute kidney injury is mostly the consequence of acute precipitation of urate crystals in the tubular lumen, but in those with a moderate increase in uric acid concentration, the role of severe hyperphosphataemia causing precipitation of calcium/​phosphate complexes in renal interstitium and the tubular system has been assumed. Prevention is better than cure, and intensive monitoring is mandatory to prevent the development and the consequences of this syndrome. Patients at risk of the tumour lysis syndrome should be vigorously hydrated with 0.9% saline (assuming normal or near-​ normal baseline renal function, and with care taken to avoid inducing pulmonary oedema) before receiving chemotherapy or radiotherapy. Urinary alkalinization should be used with caution because it may induce phosphate precipitation. Reduction of urate production with allopurinol, which increases the risk of formation of xanthine nephropathy/​stones due to accumulation of xanthine, should be reserved for patients at low risk for developing tumour lysis syndrome. In high-​ risk patients (high tumour burden, aggressive chemotherapy, hypovolaemia) with hyperuricaemia, recombinant modified urate oxidase (rasburicase) should be preferred, which rapidly reduces the uric acid pool, prevents accumulation of xanthine and hypoxanthine, and does

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not require alkalinization for effect. Rasburicase is also indicated in the treatment of established tumour lysis syndrome, associated with vigorous hydration with 0.9% saline to encourage urinary output in patients passing urine, with close clinical monitoring to prevent iatrogenic fluid overload. Patients with severe acute kidney injury should be treated with haemodialysis, which allows recovery of renal function following the reduction of serum phosphate and serum uric acid concentrations.

FURTHER READING Bridoux F, et  al. (2015). Diagnosis of monoclonal gammopathy of renal significance. Kidney Int, 87, 698–​711. Leung N, et  al. (2012). Monoclonal gammopathy of renal significance:  when MGUS is no longer undetermined or insignificant. Blood, 120, 4292–​5. Leung N, et al. (2019). The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group. Nat Rev Nephrol, 15, 45–59.

Renal involvement in Ig light-​chain amyloidosis Dispenzieri A, et al. (2004). Serum cardiac troponins and N-​terminal pro-​brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol, 22, 3751–​7. Gertz MA, Merlini G (2010). Definition of organ involvement and response to treatment in AL amyloidosis:  an updated consensus opinion. Amyloid, 17 Suppl 1, 48–​9. Jaccard A, et al. (2007). High-​dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med, 357, 1083–​93. Kyle RA, Gertz MA (1995). Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol, 32,  45–​59. Palladini G, et al. (2010). The combination of high-​sensitivity cardiac troponin T (hs-​cTnT) at presentation and changes in N-​terminal natriuretic peptide type B (NT-​proBNP) after chemotherapy best predicts survival in AL amyloidosis. Blood, 116, 3426–​30. Palladini G, et al. (2014). A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis. Blood, 124, 2325–​32. Ronco PM, Aucouturier P, Moulin B (eds) (2010). Renal amyloidosis and glomerular diseases with monoclonal immunoglobulin deposition. In: Floege J, Johnson RJ, Feehally J (eds) Comprehensive clinical nephrology, 4th edition, pp. 322–​34. Saunders Elsevier, London. Vrana JA, et  al. (2009). Classification of amyloidosis by laser microdissection and mass spectrometry-​based proteomic analysis in clinical biopsy specimens. Blood, 114, 4957–​9. Wechalekar AD, et al. (2015). Guidelines on the management of AL amyloidosis. Br J Haematol, 168, 186–​206.

Renal involvement in myeloma Bridoux F, et al. (2017). Effect of high-cutoff hemodialysis vs conventional hemodialysis on hemodialysis independence among patients with myeloma cast nephropathy: a randomized clinical trial. JAMA, 318, 2099–110. Dimopoulos MA, et al. (2010). Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol, 28, 4976–​84. Ecotière L, et al. (2016). Prognostic value of kidney biopsy in myeloma cast nephropathy: a retrospective study of 70 patients. Nephrol Dial Transplant, 31,  64–​72.

Hutchison CA, et al. (2007). Efficient removal of immunoglobulin free light chains by hemodialysis for multiple myeloma: in vitro and in vivo studies. J Am Soc Nephrol, 18, 886–​95. Hutchison CA, et al. (2019). High cutoff versus high-flux haemodialysis for myeloma cast nephropathy in patients receiving bortezomibbased chemotherapy (EuLITE): a phase 2 randomised controlled trial. Lancet Haematol, 6, e217–e228. Leung N, Behrens J (2012). Current approach to diagnosis and management of acute renal failure in myeloma patients. Adv Chronic Kidney Dis, 19, 297–​302.

Light-​chain, light-​and heavy-​chain, and heavy-​chain deposition disease Cohen C, et  al. (2015). Bortezomib produces high haematological response rates with prolonged survival in monoclonal immunoglobulin deposition disease. Kidney Int, 88, 1135–​43. Joly F, et al. (2019). Randall-type monoclonal immunoglobulin deposition disease: novel insights from a nationwide cohort study. Blood, 133, 576–87. Ronco PM, Aucouturier P, Moulin B (2010). Renal amyloidosis and glomerular diseases with monoclonal immunoglobulin deposition. In: Floege J, Johnson RJ, Feehally J (eds) Comprehensive clinical nephrology, 4th edition, pp. 322–​34. Saunders Elsevier, London. Royer B, et al. (2004). High dose chemotherapy in light chain or light and heavy chain deposition disease. Kidney Int, 65,  642–​8.

Non-​Randall-​type  MIDD Gumber R, et al. (2018). A clone-directed approach may improve diagnosis and treatment of proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Kidney Int, 94, 199–205. Nasr SH, et  al. (2009). Proliferative glomerulonephritis with monoclonal IgG deposits. J Am Soc Nephrol, 20, 2055–​64. Touchard G (2003). Ultrastructural pattern and classification of renal monoclonal immunoglobulin deposits. In: Touchard G, et al. (eds) Monoclonal gammopathies and the kidney, pp. 95–​117. Kluwer, Dordrecht.

Nonamyloid fibrillary and immunotactoid glomerulopathies Bridoux F, et al. (2002). Fibrillary glomerulonephritis and immunotactoid (microtubular) glomerulopathy are associated with distinct immunologic features. Kidney Int, 62, 1764–​75. Javaugue V, et al. (2013). Long-​term kidney disease outcomes in fibrillary glomerulonephritis: a case series of 27 patients. Am J Kidney Dis, 62, 679–​90. Nasr SH, et al. (2011). Fibrillary glomerulonephritis: a report of 66 cases from a single institution. Clin J Am Soc Nephrol, 6, 775–​84. Nasr SH, et al. (2017). DNAJB9 is a specific immunohistochemical marker for fibrillary glomerulonephritis. Kidney Int Rep, 3, 56–64. Rosenstock JL, et al. (2003). Fibrillary and immunotactoid glomerulonephritis: distinct entities with different clinical and pathologic features. Kidney Int, 63, 1450–​61.

Renal involvement in cryoglobulinaemia Brouet JC, et  al. (1974). Biologic and clinical significance of cryoglobulins. A report of 86 cases. Am J Med, 57, 775–​88. Cacoub P, Terrier B, Saadoun D (2014). Hepatitis C virus-​induced vasculitis: therapeutic options. Ann Rheum Dis, 73,  24–​30.

21.10.6  Haemolytic uraemic syndrome

D’Amico G (1998). Renal involvement in hepatitis C infection: cryoglobulinemic glomerulonephritis. Kidney Int, 54, 650–​71. De Vita S, et  al. (2012). A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis Rheum, 64, 843–​53. Saadoun D, et  al. (2006). Antiviral therapy for hepatitis C virus-​ associated mixed cryoglobulinemia vasculitis. Arthritis Rheum, 54, 3696–​706. Saadoun D, et al. (2017). Efficacy and Safety of Sofosbuvir Plus Daclatasvir for Treatment of HCV-Associated Cryoglobulinemia Vasculitis. Gastroenterology, 153, 49–52.e5. Terrier B, et  al. (2012). Management of non infectious mixed cryoglobulinaemia vasculitis: data from 242 cases included in the CryoVas survey. Blood, 119, 5996–​6004.

Renal involvement in Waldenström’s macroglobulinaemia Audard V, et al. (2008). Renal lesions associated with IgM-​secreting monoclonal proliferations:  revisiting the disease spectrum. Clin J Am Soc Nephrol, 3, 1339–​49. Chauvet S, et al. (2015). Kidney disorders associated with monoclonal IgM-​secreting B-​cell lymphoproliferative disorders: a case series of 35 patients. Am J Kidney Dis, 66, 756–​67.

21.10.6  Haemolytic uraemic syndrome Edwin K.S. Wong and David Kavanagh ESSENTIALS Haemolytic uraemic syndrome (HUS) is a thrombotic microangiopathy characterized by the triad of thrombocytopenia, microangiopathic haemolytic anaemia, and acute kidney injury. It is most often caused by Shiga toxin-​producing Escherichia coli (STEC-​HUS), and any HUS not caused by this is often termed atypical HUS (aHUS). aHUS may be caused by an underlying complement system abnormality (primary aHUS) or by a range of precipitating events, such as infections or drugs (secondary aHUS). Management of STEC-​HUS is supportive. In aHUS, plasma exchange is the initial treatment of choice until ADAMTS13 activity is available to exclude thrombotic thrombocytopenic purpura as a diagnosis. Once this has been done, eculizumab should be instigated as soon as possible.

C3 glomerulopathy and monoclonal gammopathy Bridoux F, et al. (2011). Glomerulonephritis with isolated C3 deposits and monoclonal gammopathy: a fortuitous association? Clin J Am Soc Nephrol, 6, 2165–​74. Chauvet S, et al. (2017). Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy-associated C3 glomerulopathy. Blood, 129, 1437–447. Chauvet S, et al. (2018). Both monoclonal and polyclonal immunoglobulin contingents mediate complement activation in monoclonal gammopathy associated-C3 glomerulopathy. Front Immunol, 9, 2260. Ravindran A, et al. (2018). C3 glomerulopathy associated with monoclonal Ig is a distinct subtype. Kidney Int, 94, 178–86. Zand L, et al. (2013). C3 glomerulonephritis associated with monoclonal gammopathy: a case series. Am J Kidney Dis, 62, 506–​14.

Renal involvement in lymphomas and leukaemias Moulin B, et al. (1992). Glomerulonephritis in chronic lymphocytic leukemia and related B-​cell lymphomas. Kidney Int, 42, 127–​35. Ronco PM (1999). Paraneoplastic glomerulopathies: new insights into an old entity. Kidney Int, 56, 355–​77.

Renal involvement in POEMS syndrome Nakamoto Y, et al. (1999). A spectrum of clinicopathological features of nephropathy associated with POEMS syndrome. Nephrol Dial Transplant, 14, 2370–​8.

Tumour lysis syndrome Coiffier B, et al. (2008). Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-​based review. J Clin Oncol, 26, 2667–​78. Cairo MS, et  al. (2010). Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol, 149, 578–​86. Rampello E, et al. (2006). The management of tumor lysis syndrome. Nat Clin Pract Oncol, 3, 438–​47.

Introduction Haemolytic uraemic syndrome (HUS) is a thrombotic microangiopathy characterized by the triad of thrombocytopenia, microangiopathic haemolytic anaemia, and acute kidney injury. HUS is broadly classified according to aetiology. The most common form of HUS is secondary to Shiga toxin-​producing Escherichia coli (STEC), STEC-​HUS. The term, atypical HUS (aHUS) has been used to classify any HUS not caused by Shiga toxin. With the discovery of the role of complement gene mutations in aHUS, primary aHUS has been used to refer to those cases with documented complement dysregulation. Many precipitating events, including infections, drugs, autoimmune conditions, transplants, pregnancy, and metabolic conditions have been associated with aHUS. These have frequently been called secondary aHUS. It is increasingly recognized that patients with an underlying complement system abnormality often require a secondary trigger for aHUS to manifest. Classifications describing both the genetic background and aetiological trigger are beginning to be introduced.

Epidemiology The incidence of STEC-​HUS is approximately 20 per million population per year, but it is more common in children. An exception to this was in the 2011 E. coli 0104:H4 outbreak in Northern Europe where more than 800 cases of STEC-​HUS were reported, predominantly adults. The best estimate of aHUS incidence is 0.42 per million population per year in a British population.

Pathology In the acute phase of disease, glomerular capillary wall thickening is seen as a result of endothelial cell swelling and accumulation of

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Atypical HUS Complement-​mediated aHUS A series of groundbreaking studies in the late 1990s established the role of complement overactivation in the pathogenesis of aHUS (Fig. 21.10.6.2). In patients with aHUS, loss-​of-​function mutations in complement regulators, activating mutations in complement components, and autoantibodies to complement regulatory components have been reported (Table 21.10.6.1). Loss-​of-​function mutations

Fig. 21.10.6.1  A glomerulus from a patient with HUS showing severe acute changes of congestion, intraluminal thrombi, red cell fragmentation, and endothelial cell swelling (haematoxylin and eosin, magnification ×400).

flocculent material between the endothelium and the underlying basement membrane (Fig. 21.10.6.1). Double contouring can be seen on silver staining. Collapsed capillary loops containing fragmented red blood cells, fibrin, and platelet thrombi give the classical bloodless glomerular appearance. Fibrinoid necrosis of the afferent arteriole associated with thrombosis is also present. Mesangiolysis and development of aneurysmal dilatation of the capillaries may be seen. Subsequently, there is mucoid intimal hyperplasia with narrowing of the vessel lumen. With time, sclerotic and membranoproliferative changes may develop. Immunofluorescence demonstrates fibrin or fibrinogen in the glomeruli and vessel walls and nonspecific deposition of immunoglobulin and complement may be seen. There are no pathognomonic features to allow discrimination of STEC-​HUS from aHUS on histological grounds.

Pathogenesis STEC-​HUS E.  coli O157:H7 is the most common strain causing STEC-​ HUS. Other serotypes of E. coli can also produce toxin, and the largest recorded outbreak of STEC-​H US occurred in Northern Europe in 2011 due to infection with serotype O104:H4. In developing countries, Shigella dysenteriae type 1 is a common cause of HUS. STEC strains adhere to the gut and Shiga toxin is translocated through the intestinal epithelium. It has been suggested that Shiga toxin is then taken up by circulating leucocytes and transported to the kidney. Globotriaosylceramide (Gb3) is the receptor for Shiga toxin and mediates internalization, following which it is transported to the endoplasmic reticulum. The Shiga toxin complex is then cleaved to release the enzymatically active component that inactivates the ribosome, leading to inhibition of protein synthesis and cell death. It can also activate signalling pathways, inducing an inflammatory response in affected cells

Mutations in the complement factor H gene (CFH) are the most common genetic predisposition to disease, accounting for around 25% of aHUS. The factor H protein (FH) is the major regulator of complement in the fluid phase. It functions by competing with factor B (FB) for C3b binding, decaying the complement component 3 (C3) convertase, and by acting as a cofactor for factor I (FI)-​ mediated C3b proteolysis. There is also a recognition domain at the C-​terminal end of FH that binds to C3b and glycosaminoglycans allowing FH to bind to and regulate complement on the glomerular endothelial surface. In aHUS, many of the mutations alter this region and thus impair cell surface complement regulation. FI is a serum serine protease that cleaves C3b and C4b in the presence of its cofactors (FH and CD46). Mutations in the complement factor I gene (CFI) are found in around 5 to 10% of aHUS, and defective regulation of complement has been demonstrated in functional analyses. CD46 is a cell surface-​bound complement regulator that acts as a cofactor for FI. Mutations in the CD46 gene account for approximately 10% of aHUS cases, with most mutations resulting in a quantitative deficiency. Activating mutations Activating mutations have been described in the genes encoding complement factor B (CFB) and C3 (C3). These are the complement components from which the amplifying C3 convertase is comprised. C3 mutations are found in around 2 to 10% of aHUS cases, whereas CFB mutations are rare. Mutations in both result in increased C3 convertase activity and consequently greater complement-​mediated damage to glomerular endothelium. Inhibitory autoantibodies Autoantibodies against FH have been identified in aHUS. These are usually shown to block the ability of FH to bind to C3b or glycosaminoglycans and, therefore, inhibit complement regulation at the glomerular endothelium. Penetrance of disease Penetrance of disease is age related and has been reported to be as high as 64% by the age of 70 for individuals carrying a single genetic mutation. This suggests that additional disease risk modifiers are important. Around 3% of patients have one or more mutations, with increased penetrance per extra mutation. Together, these still do not explain why some patients develop disease until later in life. This is best explained by the need for an environmental trigger such as infection, drugs, or pregnancy (Box 21.10.6.1).

21.10.6  Haemolytic uraemic syndrome

Activation Classical Pathway

Alternative Pathway

Lectin Pathway

C3b

Amplification Loop

B

C3

Regulation —

FH

Ba

C3b

C3 convertase

FI Bb

C5 convertase

Terminal Pathway

C3b

CD46

C3b Bb C5a

— C5

C5b

MAC

Eculizumab

Fig. 21.10.6.2  Complement cascade. Activation of the complement system occurs via one of three pathways, classical, alternative, or lectin, resulting in the cleavage of C3 into C3b. C3b then forms C3bBb, the C3 convertase of the alternative pathway, which in turn generates more C3b as part of a positive amplification loop. This then leads to the formation of C3bC3bBb, the C5 convertase, and activation of terminal pathway by cleaving C5 into C5a and C5b. C5a is an anaphylatoxin while C5b allows formation of membrane attack complex (MAC) generation and cell lysis. The regulatory proteins (FH, FI, and CD46) protect the host from complement overactivation by preventing persistent amplification of complement. Eculizumab prevents terminal pathway activation by inhibition of the cleavage of C5.

Other forms of aHUS Genetic Autosomal recessive defects in methylmalonic aciduria and homocystinuria, cobalamin C (cblC) type (MMACHC) and diacylglycerol kinase-​ε (DGKE) have been shown to cause aHUS (Table 21.10.6.1). Combined methylmalonic aciduria and homocystinuria (cblC) is a disorder of cobalamin (vitamin B12) metabolism characterized by

neurological, metabolic, and developmental symptoms. It is a heterogeneous disorder and only some patients develop aHUS. The pathophysiological mechanism of HUS in the cblC defect is unclear, but the endothelial abnormalities on kidney biopsies are striking and suggest that endothelial cell dysfunction may be the precipitating event. Long-​term management of cblC disease is with cobalamin, folinic acid, and betaine. Mutations in DGKE have been reported to cause aHUS in the first year of life. DGK-​ε is part of an intracellular signalling cascade and

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Table 21.10.6.1  Genetic causes of atypical HUS

Box 21.10.6.2  Extrarenal manifestations of HUS

Gene name

Gene symbol

OMIM number

Inheritance

Complement factor H

CFH

235400

AD/​AR

Complement factor I

CFI

612923

AD

CD46

CD46

612922

AD/​AR

Complement component 3

C3

612925

AD

Complement factor B

CFB

612924

AD

Diacylglycerol kinase-​ε

DGKE

615008

AR

Methylmalonic aciduria and homocystinuria, cobalamin C type

MMACHC

277400

AR

AD, autosomal dominant; AR, autosomal recessive.

although its role in the pathogenesis of aHUS has yet to be fully elucidated, it is not thought to participate in the complement system. In keeping with this, several individuals with mutations in DGKE have failed to respond to eculizumab. Noninherited Infection with neuraminidase-​producing Streptococcus pneumoniae accounts for approximately 5% of childhood HUS. The incidence is greatest in children younger than 2 years, most commonly in patients with parapneumonic empyema. Neuraminidase cleaves sialic acid residues from the glycoproteins on the cell membrane of erythrocytes, platelets, and endothelium, exposing the normally hidden Thomsen–​Friedenreich antigen (T antigen). This then reacts with anti-​T IgM antibodies that are normally present in plasma. It has been hypothesized that binding of anti-​T IgM to platelets and glomerular endothelium causes thrombotic microangiopathy by platelet aggregation and direct endothelial cell damage. Treatment is supportive with eradication of streptococcal infection. Many drugs have been reported to cause aHUS and this occurs by two main mechanisms:  immune-​mediated damage and direct toxicity. For example, quinine induces the development of autoantibodies reactive with either platelet glycoprotein Ib/​IX or IIb/​IIIa complexes, or both. In contrast, mitomycin C, an alkylating agent used to treat a variety of malignancies, is thought to cause aHUS by a direct toxic effect on endothelium. Box 21.10.6.1  Triggers of atypical HUS Pregnancy • • Respiratory infections: Bordetella pertussis, Streptococcus pneumoniae, Haemophilus influenza • Parasites: Plasmodium falciparum • Non-​STEC diarrhoeal illnesses:  norovirus, Campylobacter upsaliensis, Clostridium difficile • Drugs:  alemtuzumab, cisplatin, gemcitabine, mitomycin, clopidogrel, quinine, interferon-​α, -​β, anti-​VEGF, ciclosporin, tacrolimus, ciprofloxacin, oral contraceptives, illicit drugs • Autoimmune:  anticardiolipin, C3 nephritic factor, systemic lupus erythematosus • Vaccination • Bone marrow transplantation • Malignancy: gastric, breast, prostate, lung, colon, ovarian, pancreatic, lymphoma

Neurological involvement • • Cerebral artery thrombosis/​stenosis • Digital gangrene • Extracerebral artery stenosis • Cardiac involvement/​myocardial infarction • Ocular involvement • Pulmonary involvement • Pancreatic involvement

Pregnancy was historically cited as a cause of aHUS, but recent studies have suggested that over 80% of patients have a complement gene mutation and that pregnancy acts by unmasking complement-​mediated  aHUS.

Clinical features The diagnostic triad of acute kidney injury, microangiopathic haemolytic anaemia, and thrombocytopenia is common to both STEC-​HUS and aHUS. In cases of STEC-​HUS there is usually a prodromal phase. Around 3  days after ingestion of contaminated food, abdominal pain and bloody diarrhoea usually, although not invariably, occur. HUS develops in about 10% of patients after 3 to 4 days. In complement-​mediated aHUS, a triggering event is typically noted prior to presentation. Upper respiratory tract infections, fevers, pregnancy, and drugs have been suggested as potential triggers. Additionally, non-​STEC diarrhoea is a not uncommon trigger and clinicians should not assume diarrhoea equates to STEC-​HUS (Box 21.10.6.1). In pneumococcal-​associated aHUS, pneumonia or meningitis is usually present. Extrarenal manifestations, predominantly neurological, are reported in all types of HUS (Box 21.10.6.2).

Laboratory investigations Once routine biochemical and haematological analyses have demonstrated a thrombotic microangiopathy, investigations are aimed at determining the underlying aetiology and excluding other differential diagnoses (Fig. 21.10.6.3). The most urgent test is an ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) assay, deficiency of which is characteristic of thrombotic thrombocytopenic purpura.

Diagnosis of STEC-​HUS To confirm the diagnosis of STEC-​HUS, stool samples should be sent for STEC culture in tellurite-​enriched sorbitol–​MacConkey agar. Samples may be negative, especially if sampling is late in the course of disease. Even following cessation of diarrhoea, rectal swabs or a faecal culture should be taken. Enzyme-​linked immunosorbent assay identification of Shiga toxins should be attempted from stool and stool cultures, as should polymerase chain reaction testing of stool for Shiga toxin genes. Serology identifying IgM against the commonly occurring STEC strains should also be performed.

21.10.6  Haemolytic uraemic syndrome

In contrast, a nonrandomized assessment from the 2011 E. coli O104:H4 outbreak suggested antibiotics reduced seizures and death. Unlike the O157:H7 strain, treatment of E. coli O104:H4 with antibiotics did not increase quantities of Shiga toxin. Antibiotic treatment of S. dysenteriae does not increase the risk of HUS. There is no conclusive evidence to suggest plasma exchange is beneficial in STEC-​HUS and it is not routinely administered. The complement inhibitor eculizumab did not show any benefit when retrospective analysis of the Northern European STEC-​ HUS O104:H4 outbreak was performed. As STEC-​HUS is a self-​ limiting illness, only a randomized controlled trial will delineate any benefit.

TMA ↓Hb ↓Plts

↑LDH ↓Haptoglobin

TTP HUS

ADAMTS13 activity 80% patients)

Early signs of renal damage (30–​60% of patients)

Markers of progressive disease (10–​20% patients)

Increased glomerular filtration rate

Microalbuminuria

Nonselective proteinuria

Hyposthenuria

Haematuria

Falling glomerular filtration rate (>5 ml/​min per 1.73 m2 per year)

Nocturia/​enuresis

Tendency to hyperkalaemia

Falling steady state haemoglobin concentrationa

Due to falling endogenous erythropoietin production as renal function declines.

sickle haemoglobinopathies. This is highly aggressive, can occur in children as young as 2 years of age, and, so far, has proved to be universally fatal within 2 years of presentation.

Albuminuria and proteinuria The appearance of abnormal levels of albumin in the urine is an early manifestation of SCN. It is present in some teenage children but its prevalence increases with age, reaching approximately 60% in adults over 45  years. For many, the degree of albuminuria appears not to progress, but in others, nonselective proteinuria develops rapidly, and these are the patients most at risk of future renal impairment. Rarely, patients can develop full-​blown nephrotic syndrome, though this should always be investigated to rule out a second pathology. In particular, nephrotic syndrome has been reported in a number of patients following infection with human parvovirus B19, in which case renal biopsy demonstrates the collapsing form of focal segmental glomerulosclerosis and (if taken early in the disease course) occasionally positive staining for the HPV B19 virus. In such cases the nephrotic syndrome is usually self-​limiting, although a gradual decline in renal function often occurs in the months and years following the acute event.

health in those who respond well to this therapy in other respects. Haematopoietic cell transplantation is the only curative treatment currently available for SCD and is usually reserved for children with major complications such as stroke. Although it is probable that recipients of such transplants who have a good outcome are protected from developing SCN in future, most published studies exclude those with established renal disease from receiving this treatment and so its role in treating kidney dysfunction has not yet been studied.

Treatment of endstage kidney disease Despite optimal treatment, some patients with SCD will develop progressive kidney failure that will eventually necessitate the need for renal replacement therapy. The prognosis for patients with SCD on dialysis is poor and the average lifespan after a diagnosis of endstage kidney disease is only 4 years. Kidney transplantation offers a better outcome and can increase life expectancy to 10 to 15 years in those who have a well-​functioning graft. Recurrent SCN can complicate the outcome following transplantation, although this can be mitigated by placing the patient on an exchange transfusion programme.

FURTHER READING Alvarez O, et al. (2012). Effect of hydroxyurea treatment on renal function parameters:  results from the multi-​center placebo-​controlled BABY HUG clinical trial for infants with sickle cell anemia. Pediatr Blood Cancer, 59, 668–​74. Derebail VK, et al. (2019). Progressive Decline in Estimated GFR in Patients With Sickle Cell Disease: An Observational Cohort Study. Am J Kidney Dis, pii: S0272-6386(19)30007-1. doi: 10.1053/j. ajkd.2018.12.027. Nath KA, Hebbel RP (2015). Sickle cell disease: renal manifestations and mechanisms. Nat Rev Nephrol, 3, 161–​71. Sharpe CC, Thein SL (2014). How I treat renal complications in sickle cell disease. Blood, 24, 3720–​6. Thompson J, et al. (2007). Albuminuria and renal function in homozygous sickle cell disease:  observations from a cohort study. Arch Intern Med, 167,  701–​8.

Treatment options Therapies to prevent progression of chronic kidney disease Treatment of patients with proteinuria with inhibitors of the renin–​ angiotensin system to reduce glomerular pressure and proteinuria has become accepted as standard practice in those who can tolerate it from a blood pressure and serum potassium perspective. Intermittent or regular blood transfusion is often used to manage the acute complications of SCD or for primary or secondary prevention of stroke, but there is little evidence for its use in the prevention or treatment of SCN. However, using blood transfusion to reduce the percentage of sickle haemoglobin in patients prior to surgery does have proven benefits and this is likely to be particularly important in those undergoing renal transplantation. Hydroxycarbamide (hydroxyurea) therapy has clear clinical benefits for many patients with SCD, including a reduction in hospitalization episodes and painful crises. Although studies have failed to demonstrate any clear benefit of this treatment in the short term, it is likely that it helps maintain kidney

21.10.8  Infection-​associated nephropathies A. Neil Turner ESSENTIALS Infection may be a primary cause of renal disease (e.g. postinfectious glomerulonephritis) or affect the kidneys on a background of debilitating illnesses and previous medical interventions. Renal disease may arise as a consequence of immune responses to a pathogen, direct invasion by the microorganism, or the effects of infection on the systemic or local circulations.

21.10.8  Infection-associated nephropathies

Glomerulonephritis—​associated with chronic and acute bacterial infections. Shunt nephritis follows colonization of a ventriculoatrial shunt, most commonly with Staphylococcus epidermidis, leading to constitutional symptoms, an acute inflammatory response, and (most characteristically) a type 1 mesangiocapillary glomerulonephritis. Infective endocarditis and other deep-​seated bacterial infections may produce a similar renal picture, but they can also mimic vasculitic syndromes and outcome is dependent on the response of the infection to treatment. Acute postinfectious glomerulonephritis—​see Chapter 21.8.5. Interstitial nephritis—​bacteria that can cause this include leptospira (Weil’s disease), Rickettsia rickettsii (Rocky Mountain spotted fever), legionella, and mycobacteria. Viral infections include hantaviruses (haemorrhagic fever with renal syndrome and nephropathia epidemica) and, almost exclusively following renal transplantation, cytomegalovirus and polyomavirus hominis type 1 (BK) virus. HIV-​associated renal disorders—​these include HIV nephropathy, which is a focal segmental glomerulosclerosis of ‘collapsing’ form, occurring almost exclusively in black patients. Other morphologies are more common in other races, but interstitial disease is also common as a manifestation of infection or of drug toxicity. Hepatitis B virus—​chronic infection is strongly associated with membranous nephropathy; affected individuals are HBeAg and HBsAg positive, usually with coexistent hepatitis; seroconversion from HBeAg positive to HBeAb positive (naturally or induced by treatment) is associated with remission of the renal lesion. Hepatitis C virus—​chronic infection is the commonest cause of mixed essential (type II) cryoglobulinaemia in most populations; it is associated with membranoproliferative glomerulonephritis (MPGN, also described as MCGN), and reduction of viral replication has been associated with disease remission.

Introduction Almost all renal lesions, particularly glomerular lesions, may be associated with infections. In the developed world, infection-​associated nephritis was once predominantly recognized during acute infections occurring in apparently healthy individuals, and this is still the pattern in many countries. However, improvements in living conditions and health care reduce the numbers of healthy people succumbing to complications of infection. Instead, infections occurring on a background of debilitating illnesses and previous medical interventions become more common precipitants of renal disease. In this chapter, glomerular diseases and interstitial diseases associated with infection are considered in turn. Particular attention is given to those glomerulopathies associated with bacterial endocarditis and other chronic bacterial infections, and three viral infections of worldwide importance, HIV, hepatitis B, and hepatitis C.

Pathogenesis Infection-​ associated glomerular disease is usually attributed to trapping of circulating antigen–​antibody complexes in the glomerulus, or to immune responses to pathogen-​derived antigens that become ‘planted’ in the glomerulus. The evidence for deposition

of circulating immune complexes is strong for cryoglobulinaemia, and highly plausible for infections occurring within the vascular system such as bacterial endocarditis. In most other infections the evidence is less clear, and this is probably not a common mechanism of glomerular disease. A direct cytopathic effect on glomerular cells seems likely for some pathogens such as HIV and parvovirus, both of which infect glomerular podocytes and have been associated with ‘collapsing’ focal segmental glomerulosclerosis (FSGS). Interstitial renal disease is often blamed on direct invasion by the microorganism, and for some there is evidence that this is true. The pathogen may cause injury directly, or indirectly by causing cells to express foreign antigens which generate an immune response. More speculatively, an immune response generated to an organism may cross-​react with a remote self-​antigen, triggering autoimmunity through molecular mimicry, but there are no unequivocal examples of this. Infection may also involve the kidney by interfering with the circulation either generally (septic shock) or locally (e.g. by causing thrombotic microangiopathy, as for Escherichia coli O157 or Capnocytophaga canimorsus (previously DF-​ 2)). Occasionally, toxins may be released that harm the kidney directly (e.g. haemoglobin in malaria). Medically administered toxins include antimicrobial agents that impair renal function by crystallization (e.g. aciclovir, indinavir) or by predictable toxicity (e.g. aminoglycosides, amphotericin, and tenofovir), or by idiosyncratic reactions such as acute interstitial nephritis (e.g. penicillins).

Glomerulonephritis associated with chronic and acute bacterial infections Classic acute postinfectious glomerulonephritis is considered in Chapter  21.8.5. This account considers subacute or chronic diseases, although other causes of a ‘classic’ picture are mentioned. Shunt nephritis was first recognized in the 1960s, and it remains the archetype of an immune complex nephritis. The glomerulonephritis occurring in association with infective endocarditis is very similar. Both are caused by subacute infection within the bloodstream, with constant shedding of antigen and formation of antigen–​antibody complexes. Other bacterial infections may cause similar pictures.

Shunt nephritis and similar syndromes of intravascular infection In shunt nephritis, a ventriculoatrial shunt implanted for hydrocephalus becomes colonized by bacteria, usually of low pathogenicity. More common modern equivalents are infected long-​term central venous catheters and other intravascular devices. The syndrome does not occur with ventriculoperitoneal shunts, which are therefore now the preferred neurosurgical option, making shunts now a rare cause of the syndrome. Although Staphylococcus epidermidis has been most commonly implicated in these infections, Propionibacterium acnes or other organisms are sometimes involved. Typically the diagnosis is only appreciated after weeks to months of symptoms of mild to moderate pyrexia and malaise associated with haematuria and proteinuria and progressive renal impairment. Fevers have often been attributed to urinary infection in patients with neurogenic bladders. There may be moderate splenomegaly. Investigations show complement consumption and

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section 21  Disorders of the kidney and urinary tract

an acute-​phase response with normochromic normocytic anaemia, and variable renal impairment. The renal lesion is characteristically a type 1 membranoproliferative (mesangiocapillary) glomerulonephritis with deposition of multiple immunoglobulins and complement components beneath the endothelium, the classic appearance of a circulating immune complex nephritis. Sometimes the picture is more severe, showing a diffuse proliferative lesion, occasionally with crescents. In other cases, the histological appearances are less pronounced with focal proliferative changes. Antibiotic treatment alone is almost never adequate to cure these infections, which require removal of the intravascular device, followed by its replacement after an interval if it is still required. Delayed diagnosis and delayed removal may lead to more severe and irreversible renal damage, and sometimes to endstage renal failure, but some degree of recovery can follow successful treatment.

Infective endocarditis A similar syndrome can occur in infective endocarditis, as part of which minor degrees of glomerular disease are probably extremely common. In truly subacute endocarditis, symptoms and signs are as seen in shunt nephritis. Typical streptococcal infections are well represented in case reports, but there have been multiple reports involving ‘slow’ infections such as Q fever (Coxiella burnetii), and more unusual causes including chlamydia and fungi. Typical patients in developed countries have shifted from being young patients with rheumatic heart disease, to being elderly with comorbid conditions, long-​ term vascular access devices, pacemakers, etc. Infection of prosthetic or native heart valves may be implicated. Right-​sided endocarditis occurring in intravenous drug abusers may be particularly likely to present as nephritis, because the diagnosis is often delayed. Depletion of serum complement is again diagnostically useful, but, as for shunt nephritis, most other serological and haematological changes are nonspecific. Partial treatment with antibiotics makes diagnosis and management more difficult, as positive blood cultures are usually a key part of proving the diagnosis and selecting appropriate therapy. The pathological lesion is typically similar to that of shunt nephritis, but forms of endocarditis that are acute, rather than subacute (e.g. that associated with Staphylococcus aureus), are more likely to cause glomerulonephritis in a diffuse proliferative pattern, sometimes with crescent formation. Focal changes that are indistinguishable from antineutrophil cytoplasmic antibody (ANCA)-​associated vasculitis have been reported in the literature, and ANCA are detected in some patients. There may be a florid purpuric cutaneous vasculitis (as in Fig. 21.10.8.1), but there may be few or no other signs of vasculitis elsewhere. However, immune deposits are usually present in glomeruli, in contrast to the primary small-​vessel vasculitides. In most cases, the outcome is dependent on the response of the endocarditis to treatment, but renal involvement is a poor prognostic factor for survival, which may be simply because it reflects long-​lasting infection, although recovery from dialysis dependence may occur. Patients with endocarditis are also prone to two other renal lesions: interstitial nephritis related to antibiotics and, in those with disease on the left side of the heart or with right–​left shunts, renal emboli, although glomerulonephritis is a more common cause of urinary abnormalities.

Fig. 21.10.8.1  Cutaneous vasculitis in a patient with Staphylococcus aureus endocarditis.

Deep-​seated bacterial infections Amyloidosis is a well-​recognized consequence of very chronic bacterial (including mycobacterial) and other infections, and is described in Chapters 12.12.3 and 21.10.5. As in reactive amyloidosis of other aetiologies, progression of the renal lesion may be prevented or even partially reversed by treatment of the cause. Deep-​seated infections, particularly abscesses, may also be associated with glomerulonephritis. Although the mechanisms involved are presumably similar to those of shunt nephritis and nephritis associated with endocarditis, blood cultures have often been negative in reported cases. Staphylococcus aureus is the most frequently implicated organism. A wide variety of renal lesions have been described, usually inflammatory/​proliferative and with immunoglobulin deposition. Unsuspected abscesses or other deep-​seated infections are occasionally found only after the renal biopsy appearances trigger a search. Such hidden abscesses are more likely in obese or older people, and in those on corticosteroids or who are immunosuppressed by other means or by disease.

Acute glomerulonephritis and other infections Acute glomerulonephritis resembling poststreptococcal nephritis has been reported in association with a large number of other organisms, including current (as opposed to recent) infection with staphylococci, streptococci, and other bacteria, and with acute viral infections that are usually self-​limiting. These include Epstein–​Barr virus, cytomegalovirus, varicella, measles, mumps, parvovirus, and coxsackieviruses. Some may cause a clinical syndrome that is very similar to poststreptococcal nephritis, while others typically cause a less florid ‘nephritic’ or mixed ‘nephritic/​ nephrotic’ picture. Staphylococcus aureus is particularly associated with a variant of postinfectious glomerulonephritis with prominent nephrotic features and dominant IgA deposition in glomeruli.

Diagnostic difficulties in bacterial infection-​related glomerulonephritis Infection-​related nephritis may present in a very similar manner to nephritis associated with other systemic diseases, notably microscopic polyangiitis and other small-​vessel vasculitides (see

21.10.8  Infection-associated nephropathies

Chapter 21.10.2). As both types of disease process may be associated with fever, a systemic illness, and an acute-​phase response, it is important to consider the possibility of infection in all patients thought to have systemic vasculitis. Blood cultures should be routine. ANCA assays are extremely useful, but it is important to note that ANCA positivity has been recorded in many infections, both by fluorescence and by solid-​phase assays: ANCA are not diagnostic of small-​vessel vasculitides. Renal biopsy is often the most discriminating investigation. Infection-​associated glomerulonephritis is usually (but not invariably) associated with plentiful immunoglobulin deposition, whereas small-​vessel vasculitis is characteristically pauci-​immune. Nonglomerular causes of renal impairment (interstitial nephritis, acute tubular necrosis) are also distinguished by renal biopsy.

Interstitial nephritis associated with infections Bacterial infections Acute bacterial pyelonephritis is usually a florid and painful disorder associated with symptoms of urinary tract infection, as described in Chapter 21.13. Substantial renal impairment is usual only if a single functioning kidney is affected. Occasionally, however, the diagnosis is masked by immunosuppression (e.g. in a transplanted kidney), age, or other factors, and the diagnosis is made by the renal biopsy appearances of neutrophils in the interstitium and in tubules, which are rarely found in any other renal lesions. Acute interstitial nephritis is a key feature of Weil’s disease, a severe form of leptospirosis (see Chapter 8.6.35). Jaundice and renal failure follow a febrile illness caused by infection with Leptospira interrogans. The renal lesion comprises interstitial oedema with predominantly mononuclear infiltrates and foci of tubular necrosis. Renal failure is usually oliguric but may be polyuric. Dialysis may be required for days to weeks, and renal recovery may sometimes be incomplete. Other bacterial infections that may cause a similar pathological picture include Rocky Mountain spotted fever (Rickettsia rickettsii), in which there may be an interstitial nephritis with foci of haemorrhage, and acute Yersinia pseudotuberculosis infection, in which an acute lymphocytic interstitial nephritis has been described in several patients. Legionnaires’ disease (Legionella pneumophila) has been reported to be associated with renal impairment, also with an interstitial nephritis, but in some instances may show a picture of acute tubular necrosis. The same is probably true of other severe pneumonias. Mycobacteria can cause a chronic granulomatous interstitial nephritis (discussed in ‘Mycobacteria’).

Viral infections Hantaviruses Hantaviruses are carried by small rodents, and have been associated with a range of human syndromes that involve the kidneys with varying severity. ‘Haemorrhagic fever with renal syndrome’ (HFRS) is characterized by oliguric renal failure, associated histologically with lymphocytic interstitial nephritis that may be haemorrhagic in severe cases, reflecting the systemic bleeding diathesis. Some patients have been reported to have persistent renal impairment after recovery.

HFRS was originally associated with Hantaan strains of hantavirus in Korea, while milder disease, with less frequent and usually less severe renal impairment and without haemorrhagic diathesis, was associated with the Seoul strain. Milder disease (nephropathia epidemica) recognized in northern Europe and subsequently more widely was associated with the Puumula strain. However, it has become apparent that there are many more subtypes of hantavirus, and the association of a serotype with a particular clinical picture is not rigid. Severe disease with shock, variable haemorrhage, and sometimes pulmonary impairment has been encountered in the Balkans and Greece. Disease with predominantly pulmonary manifestations and shock has been recognized, particularly in North America, although these geographical variations in clinical picture are no more rigid than the strain variations. Ribavirin is active against hantaviruses in vitro, and therapy with ribavirin was found to be effective in HFRS caused by the classic Hantaan strain in China and confirmed in Korea, but there are likely to be strain differences as no benefit could be demonstrated in trials in the pulmonary syndrome in North America, and evidence for value more widely seems weak. Cytomegalovirus, polyomaviruses, and other viruses Cytomegalovirus (CMV) may lie dormant in renal tubular cells, and during new or reactivated infection causes characteristic inclusion bodies. This rarely has a significant impact on renal function outside the setting of renal transplantation, where CMV infection commonly occurs concurrently with acute rejection. Although there is evidence that CMV infection may precipitate rejection, it is also clear that the risk of CMV infection is greatly increased by most types of antirejection therapy. CMV may also rarely cause a florid glomerular lesion characterized by gross endothelial cell damage and swelling, resembling pre-​eclampsia. This has again been recognized almost exclusively in renal transplants, where some believe that the appearances are due to, or complicated by, vascular rejection. Human polyomaviruses (BK and JC) were previously believed to be benign passenger viruses which replicated without causing damage during immunosuppression. However, BK virus has been increasingly recognized as a cause of impaired renal transplant function, usually many months after transplantation. The histological changes of tubulitis closely resemble acute cellular rejection, but further immunosuppression favours further infective damage. Observation of typical inclusion bodies and immunohistochemical studies prove the true cause of the tubulitis, and renal function may improve after reduction of immunosuppressive agents, although renal outcome is often poor despite this. Polymerase chain reaction-​based screening has been introduced in many centres in attempts to make an earlier diagnosis, but there is still no proven antiviral therapy and reduction of immunosuppression is not without risk. A  strategy of combining leflunomide (as a replacement for azathioprine or mycophenolate mofetil), intravenous immunoglobulin, and ciprofloxacin has been tried, but shown no benefit. Polyomavirus renal disease seems to be less common in patients immunosuppressed for reasons other than renal transplantation, but it is being increasingly recognized. A wide range of other viruses and microorganisms have been less regularly associated with interstitial lesions. HIV (considered in the following section) may cause an interstitial nephritis. Another

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condition that is likely to be infective in origin, Kawasaki’s disease, is associated with interstitial nephritis, although glomerular lesions have also been described occasionally.

HIV and renal disease Renal impairment is commonly encountered at some stage of HIV infection. The largest single cause of serious renal disease in this group is the distinct entity of HIV nephropathy. However, this generalization is misleading as this specific diagnosis is largely restricted to black patients, and there are many other causes of renal disease in patients with HIV infection.

FSGS associated with HIV infection (HIV nephropathy) HIV nephropathy is characterized by heavy proteinuria and renal impairment. It is an important cause of endstage renal failure in Africa, but also significant in black adults of working age in the United States of America. Although it has often been described as an initial manifestation of HIV infection, in these circumstances the infection is advanced, with high viral loads and low CD4 counts. Histologically, the appearances are of FSGS of the ‘collapsing’ form, with injury and hypertrophy of glomerular epithelial cells accompanied by variable interstitial inflammation with oedema and microtubular dilatation (Fig 21.10.8.2). The racial (black African) restriction of susceptibility to HIV nephropathy and increased risk of other types of FSGS is due to variants in the APOL1 gene which convey resistance to trypanosomiasis. How they produce their disadvantageous renal effects is not yet known. Without therapy the condition progresses to endstage renal failure rapidly, over weeks to months. Perhaps because it is associated with low CD4 counts, the medium-​term prognosis in the past was poor despite renal replacement therapy, but effective antiviral therapy can alter this.

Non-​FSGS nephropathies in HIV infection FSGS accounts for a minority of HIV-​associated renal disease in most populations. An HIV immune complex glomerulonephritis (HIVICK) has been described, but so have other specific types of renal disease, encompassing almost all types of glomerular lesion, interstitial nephritis, cryoglobulinaemia, and thrombotic microangiopathy. IgA nephropathy has been frequently recorded. Some of these lesions may be directly caused by HIV infection, while others are related to concurrent infections with other microorganisms, and some may be related to therapy. The occurrence of autoimmune phenomena in HIV infection may also be accompanied by an increase in immune-​mediated primary renal diseases of many types. Interstitial nephritis is often but not always related to anti-​HIV drugs. Tenofovir in particular may cause tubular injury with renal impairment and sometimes Fanconi’s syndrome. Aciclovir and indinavir have replaced sulphonamides as common causes of crystal nephropathy. Adjusting the doses of these and other drugs in the setting of renal impairment is problematic. Patients with HIV infection receive many other drugs with predictable nephrotoxicity, and polypharmacy also puts them at risk of allergic reactions.

Highly active antiretroviral therapy and other therapies Highly active antiretroviral therapy (HAART), when instituted early, may arrest the progression of FSGS as well as lowering the mortality of patients with endstage renal failure. Severity of chronic damage on biopsy may be a better prediction of prognosis than serum creatinine. Its effect on non-​FSGS nephropathies may also be beneficial. Patients with any diseases associated with proteinuria should be treated with angiotensin-​converting enzyme inhibitors. Treatment with corticosteroids should probably be considered in patients with HIV-​FSGS who progress despite effective HAART and intensive renoprotective therapy with angiotensin-​converting enzyme inhibitors and blood pressure control. Patients with good control of HIV do well on renal replacement therapies, and several national guidelines now allow and recommend transplantation for patients whose prognosis is of many years. In high-​incidence regions, transplantation of kidneys from HIV-​ positive donors improves organ supply.

Nephropathy associated with hepatitis B virus

Fig. 21.10.8.2  Histology of HIV-​associated nephropathy showing glomerular collapse with a focal sclerosing lesion, microcystic tubular dilatation, and interstitial inflammation (magnification ×200). Reproduced with permission from Naicker S, Paget G. HIV and renal disease. In: Turner N, Lameire N, Goldsmith DJ, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Courtesy of Prof Stewart Goetsch, University of the Witwatersrand.

Chronic infection with hepatitis B virus (HBV) (see Chapter 8.5.21) is strongly associated with membranous nephropathy, and it is an important secondary cause of the lesion. A  less clear relationship holds with membranoproliferative glomerulonephritis (MPGN, also known as MCGN), while for hepatitis C virus (HCV) the converse is true. Chronic HBV infection is much more common in some regions and racial groups, and the distribution of HBV-​related nephropathy closely follows this distribution. The clinical picture may be complicated by the concurrence of HBV infection by infection with HCV, HIV, or with other organisms, or by the coincidence of significant renal and hepatic disease. HBV membranous nephropathy has a

21.10.8  Infection-associated nephropathies

close relationship with virus multiplication, so affected individuals are usually HBeAg and HBsAg positive, with evidence of hepatitis, although this may be minor. Membranous nephropathy is a more common complication of HBV infection in children, but it is also more benign in this group. The lesion may be static, or in some cases (particularly in adults) associated with progressive deterioration to endstage renal failure. Histopathology is typical of membranous nephropathy, and HBV antigens may be detectable in glomerular deposits. Idiopathic membranous nephropathy is caused by autoantibodies to podocyte surface proteins, usually to the phospholipase A2 (PLA2) receptor, but these are not typically identified in patients with secondary membranous nephropathy, including that associated with HBV. The target in these circumstances may be viral, but it has not been identified. Seroconversion from HBeAg positive to HBeAb positive is associated with remission of the renal lesion, whether the conversion occurs naturally or is induced by treatment. Spontaneous remission of the renal lesion is more likely in children. Antiviral treatment is the appropriate therapy when required, as immunosuppression may increase viral burden. Recently acquired (within months) HBV infection has been associated with classic polyarteritis nodosa (PAN) in some populations, such as in France and North America, but even in these areas HBV-​ PAN is uncommon and apparently decreasing. Furthermore, the association of the two diseases is rare in some countries with low (e.g. the United Kingdom) and with high (e.g. Thailand) rates of HBV carriage, suggesting the involvement of a cofactor. Clinically, the disease is typical of PAN, affecting medium and somewhat smaller vessels but not capillaries, and therefore not usually associated with focal necrotizing or crescentic nephritis. ANCA are not usually detected. Treatment is difficult to balance as immunosuppression (usually with corticosteroids alone) is often indicated, but favours viral replication and exacerbation of liver disease, while remission

(a)

(b)

is associated with seroconversion from HBeAg positivity to HBeAb positivity.

Nephropathy associated with hepatitis C virus Chronic HCV (see Chapter 8.5.22) infection is the commonest cause of mixed essential (type II) cryoglobulinaemia in most populations, and an important cause of MPGN without overt cryoglobulinaemia. The clinical picture includes cutaneous vasculitis, glomerular pathology (mesangiocapillary glomerulonephritis, MCGN), and other manifestations. Cryoglobulins contain quantities of HCV antigens and bound antibody, in addition to monoclonal IgM rheumatoid factors. HCV may also be associated with MCGN in the absence of detectable cryoglobulins. A relationship with membranous nephropathy is also possible, but not proven. As for HBV, reduction of viral replication has been associated with disease remission. Immunosuppression with corticosteroids and sometimes other agents may be required to control disease manifestations caused by vasculitis. B-​cell depletion with anti-​CD20 monoclonal antibodies may help to control the disease if antiviral therapy does not.

Renal sequelae of other chronic infections Amyloidosis Amyloidosis (see Chapter 12.12.3) may be a consequence of all sorts of chronic infection, but of the ‘tropical’ infections is most frequently associated with schistosomiasis, filariasis, or leishmaniasis.

Mycobacteria Mycobacterial infections (see Chapter 8.6.26) cause a chronic granulomatous interstitial nephritis that is characteristically associated with inflammatory and fibrotic abnormalities in the ureters and lower

(c)

Fig. 21.10.8.3  Radiological appearances in urinary schistosomiasis. (a) Plain radiograph showing linear bladder calcification. (b) Retrograde urogram showing contracted bladder with reflux into extremely dilated ureter, and hydronephrosis. (c) Cystogram showing large irregular filling defect in the bladder caused by a tumour. Reproduced with permission from Barsoum RS. Schistosomiasis. In: Turner N, Lameire N, Goldsmith DJ, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Copyright © 2015 Oxford University Press.

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urinary tract. Symptoms often relate to lower tract involvement, but the disease may be asymptomatic, and in the earliest stages involvement is presumed to be restricted to the kidneys, with subsequent spread to the lower tract. Sterile pyuria is the rule, and impaired renal function is common at presentation. Imaging by intravenous urography or other techniques will show blunting of calyces, progressing to changes typical of pyelonephritis or papillary necrosis, along with lower tract abnormalities such as ureteric strictures and scarring and contraction of the bladder. Amyloidosis is a well-​recognized secondary complication of mycobacterial infections. Idiosyncratic reactions to antituberculous drugs are another common cause of late renal dysfunction.

Syphilis Congenital syphilis (see Chapter 8.6.37) may cause severe nephrotic syndrome with the histological pattern of membranous nephropathy. This is also the usual pattern when secondary syphilis rarely causes nephrotic syndrome. Both respond to antispirochaetal treatment.

Malaria Plasmodium falciparum infections (see Chapter  8.8.2) are an extremely important cause of acute kidney injury worldwide. This occurs in 1 to 5% of infected patients native to a malarial area, but a higher proportion of nonimmune visitors, and is associated with high mortality (15–​45%). Series from Africa have cast doubt on the existence of a specific chronic malarial nephropathy that was described in earlier literature. Biopsy studies have shown a high incidence of infection-​related glomerulonephritis and of FSGS, but have found little evidence of a distinct malarial disease.

Schistosomiasis Schistosomiasis (Fig. 21.8.10.3; see Chapter  8.11.1) is best recognized for causing disease of the lower urinary tract, but chronic infections associated with hepatosplenomegaly may be associated with glomerular disease after many years. In Schistosoma haematobium infection this is often due to secondary infections with Salmonella spp. rather than directly associated with schistosomal infection. In Schistosoma mansoni infection the relationship is probably usually directly causal, typically causing MPGN.

Filariasis Longstanding filariasis (see Chapter 8.9.2) may also be associated with glomerular lesions. An acute syndrome with tubulointerstitial nephritis has also been described in association with the presence of microfilariae in renal capillaries.

FURTHER READING Arendse CG, et al. (2010). The acute, the chronic and the news of HIV-​ related renal disease in Africa. Kidney Int, 78, 239–​45. Bigé N, et al. (2012). Presentation of HIV-​associated nephropathy and outcome in HAART-​treated patients. Nephrol Dial Transplant, 27, 1114–​21. Bonarek H, et al. (1999). Reversal of c-​ANCA positive mesangiocapillary glomerulonephritis after removal of an infected cysto-​atrial shunt. Nephrol Dial Transplant, 14, 1771–​3. Clementi A, et al. (2011). Renal involvement in leishmaniasis: a review of the literature. Nephrol Dial Transplant Plus, 4, 147–​52.

Conlon PJ, et al. (1998). Predictors of prognosis and risk of acute renal failure in bacterial endocarditis. Clin Nephrol, 49, 96–​101. Daugas E, Rougier JP, Hill G (2005). HAART-​related nephropathies in HIV-​infected patients. Kidney Int, 67, 393–​403. De Vita S, et  al. (2012). A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis Rheum, 64, 843–​53. Doe JY, et al. (2006). Nephrotic syndrome in African children: lack of evidence for ‘tropical nephrotic syndrome’? Nephrol Dial Transplant, 21,  672–​6. Elsheikha HM, Sheashaa HA (2007). Epidemiology, pathophysiology, management and outcome of renal dysfunction associated with plasmodium infection. Parasitol Res, 101, 1183–​90. Fabian J, et al. (2013). The clinical and histological response of HIV-​ associated kidney disease to antiretroviral therapy in South Africans. Nephrol Dial Transplant, 28, 1543–​54. Genovese G, et al. (2010). Association of trypanolytic ApoL1 variants with kidney disease in African-​Americans. Science, 329,  841–​5. Haffner D, et  al. (1997). The clinical spectrum of shunt nephritis. Nephrol Dial Transplant, 12, 1143–​8. Krautkrämer E, Zeier M, Plyusnin A (2013). Hantavirus infection:  an emerging infectious disease causing acute renal failure. Kidney Int, 83,  23–​7. Lai AS, Lai KN (2006). Viral nephropathy. Nat Clin Pract Nephrol, 2, 254–​62. Majumdar A, et  al. (2000). Renal pathological findings in infective endocarditis. Nephrol Dial Transplant, 15, 1782–​7. Montseny JJ, et al. (1995). The current spectrum of infectious glomerulonephritis: experience with 76 patients and review of the literature. Medicine (Baltimore), 74,  63–​73. Moudgil A, et al. (2001). Association of parvovirus B19 infection with idiopathic collapsing glomerulopathy. Kidney Int, 59, 2126–​33. Muller E, Kahn D, Mendelson M (2010). Renal transplantation between HIV-​positive donors and recipients. N Engl J Med, 362, 2336–​7. Naqvi R, et al. (2003). Outcome in severe acute renal failure associated with malaria. Nephrol Dial Transplant, 18, 1820–​3. Nasr SH, et al. (2008). Acute postinfectious glomerulonephritis in the modern era: experience with 86 adults and review of the literature. Medicine (Baltimore) 87,  21–​32 Neugarten J, Baldwin DS (1984). Glomerulonephritis in bacterial endocarditis. Am J Med, 77, 297–​304. Nickeleit V, Mihatsch MJ (2006). Polyomavirus nephropathy in native kidneys and renal allografts: an update on an escalating threat. Transpl Int, 19, 960–​73. Perico N, et al. (2009). Hepatitis C infection and chronic renal diseases. Clin J Am Soc Nephrol, 4, 207–​20. Peters CJ, Simpson GL, Levy H (1999). Spectrum of hantavirus infection: hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Ann Rev Med, 50, 531–​45. Post FA, et al. (2008). Predictors of outcome in HIV-​associated nephropathy. Clin Infect Dis, 15, 1282–​9. Sneller M, Hu Z, Langford C (2012). A randomized controlled trial of rituximab following failure of antiviral therapy for hepatitis C virus-​ associated cryoglobulinemic vasculitis. Arthritis Rheum, 64, 835–​42. Turner AN, et al. (eds) (2015). Oxford textbook of clinical nephrology, 4th edition. Chapters 183–​198 and 284. Oxford University Press, Oxford. Watts RA, Scott DG, Mukhtyar C (2015). Secondary vasculitis. In: Vasculitis in clinical practice, pp. 173–​84. Springer International Publishing AG, Cham. Wearne N, et  al. (2012). The spectrum of renal histologies seen in HIV with outcomes, prognostic indicators and clinical correlations. Nephrol Dial Transplant, 27, 4109–​18.

21.10.9  Malignancy-associated renal disease

21.10.9  Malignancy-​associated renal disease A. Neil Turner

Table 21.10.9.1  How malignant disease affects the kidney and urinary tract Mode of involvement

Examples

Direct

Tumours of the renal substance Lymphoma, leukaemia deposits Remote metastases from solid tumours Tumours of the urinary tract, prostate gland, etc.

ESSENTIALS Malignancies can affect the kidneys by direct invasion, metabolic and remote effects of tumour products, deposition of tumour products, triggering of immune reactions, and effects of treatment. Particular malignancy-​ associated renal diseases include the following: Thrombotic microangiopathy—​particularly reported for malignancies of the stomach, pancreas, and prostate, and also with certain chemotherapeutic agents. Minimal-​change nephrotic syndrome—​rarely caused by lymphoma. Membranous nephropathy—​associated with malignancy, usually of solid organs, in 5 to 11% of cases. Malignant disease is typically advanced and obvious when nephrotic syndrome or heavy proteinuria is recognized. Very few treatable and otherwise subclinical tumours are uncovered by investigation in routine clinical practice. Focal necrotizing and crescentic nephritis—​may rarely be associated with malignancy, when they are usually antineutrophil cytoplasmic antibody negative. Proteinuria—​may be caused by agents that modulate interferons or vascular endothelial growth factors.

Introduction Malignant disease may affect the kidney and urinary tract by five broad mechanisms (see Table 21.10.9.1). Acute kidney injury is common in patients with malignancy: in many instances the cause is not specifically related to the malignancy, but it can be, and in many instances several factors combine (Fig. 21.10.9.1).

Direct involvement of the urinary tract Solitary kidney tumours in adults are usually caused by renal cell carcinoma (hypernephroma). Bilateral tumours may occur, but multicentric tumours or bilateral tumours in young patients should lead to suspicion of an inherited disorder, particularly von Hippel–​ Lindau syndrome (see Chapter 21.12; cystic and solid lesions, some malignant) or tuberous sclerosis (see Chapter 21.12; benign lesions), both having autosomal dominant inheritance. Lymphoma and leukaemia may occasionally invade the renal substance on a sufficient scale to cause renal impairment, but it is rare for other tumours to do so. A rare and aggressive renal medullary tumour has been described in young patients with sickle cell trait or disease. These are easily confused with tumours of the collecting system and carry a poor prognosis. The collecting system and lower urinary tract may be affected by transitional cell tumours or by malignancies that may invade the

Local invasion (cervix, colon) Metabolic and remote effects

Hypercalcaemia Hypokalaemia Hyperuricaemia Thrombotic microangiopathy (tumour-​associated thrombotic thrombocytopenic purpura)

Deposition of tumour products

Myeloma kidney (precipitation in tubules)

Immune reaction

Minimal-​change disease (particularly with lymphomas)

Immunoglobulin deposition diseases

Membranous nephropathy (particularly with solid tumours) Rapidly progressive glomerulonephritis and small-​vessel vasculitis Effect of treatment

Tumour lysis syndrome Direct toxicity of drugs Idiosyncratic (e.g. immune) response

tract bilaterally or below the bladder. Transitional cell tumours affecting the bladder are common, and sometimes cause renal manifestations if extensive. Lesions in the ureters and collecting system are less common. They occur multifocally in association with analgesic nephropathy and two conditions caused by aristolochic acid(‘Chinese herb’) nephropathy and Balkan endemic nephropathy (see Chapter 21.9.2).

Metabolic effects of malignancies on the kidney Hypercalcaemia is a feature of many malignancies, both with and without metastasis. Its renal effects are discussed in Chapter 21.14. Hypokalaemia may be a consequence of acute leukaemias or rectal tumours, and may occasionally be severe enough to cause renal dysfunction (see Chapter 21.2.2). Severe hyperuricaemia (>900 µmol/​litre) is characteristically associated with massive cell death occurring following chemotherapy of haematological or solid tumours (tumour lysis syndrome), when it is usually accompanied by marked hyperphosphataemia and often by hypocalcaemia. High serum lactate dehydrogenase levels may also be diagnostically useful. Similar gross hyperuricaemia may be seen following radiotherapy of radiosensitive tumours, or may occur without therapy in malignancies with a very high rate of cell turnover, particularly acute lymphocytic or acute myeloid leukaemia, or poorly differentiated solid tumours. Uric acid levels this high can lead to precipitation within renal tubules and acute kidney injury. Prevention and treatment of tumour lysis syndrome is discussed in Chapter 21.10.5.

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Causes of AKI in a patient with Malignancies Vein

Artery

Prerenal Causes

Renal Vein Thrombosis Renal Arterial Occlusion

• NSAIDS • Contrast • Sepsis • Hypotension • Diarrhea • N/V • Capillary Leak Syndrome

Kidney

lntrarenal Causes

lgM Thrombi, (Waldenstrom's Cryoglobulinaemia), Light Chain Deposition Disease

Artery Stenosis Ureter

ATI from Tubulotoxins

Amyloidosis Drug Crystals

Post-renal Causes

• Lymphadenopathy • Blood Clots • Tumor infiltration & Encasement, Fibrosis

Cast Nephrophathy

Bladder Infiltration in plasma cell leukaemia or lymphoma Nephron

Urethra

Fig. 21.10.9.1  Summary of causes of acute kidney injury (AKI) in patients with cancer. ATI, acute tubular injury; NSAIDs, nonsteroidal anti-​ inflammatory drugs; N/​V, nausea and vomiting. Reproduced with permission from Moeckel GW, Manjunath V, and Perazella MA. Acute kidney injury in the cancer patient. In: Turner N, Lameire N, Goldsmith DJ, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Copyright © 2015 Oxford University Press.

Remote effects of malignant tumours on the kidney Thrombotic microangiopathy Thrombotic microangiopathy occurring in association with malignant disease (also known as malignancy-​associated thrombotic thrombocytopenic purpura; see Chapters 22.7.3 and 22.7.5) is often attributed to chemotherapy. It is particularly associated with certain agents (e.g. bleomycin, mitomycin), although isolated reports implicate others. However, in some instances the classic presentation with thrombocytopenia, microangiopathic haemolytic anaemia, and renal failure occurs in association with primary tumours. This has been particularly reported for malignancies of the stomach, pancreas, and prostate. The syndrome is occasionally the presenting sign of malignancy but often occurs in a patient known to have a tumour. In the absence of specific evidence, tumour-​related thrombotic microangiopathy is usually treated in the same way as thrombotic microangiopathy of other types, by plasma exchange for fresh frozen plasma. If the tumour itself is responsive to treatment, microangiopathy generally subsides too. Renal function may be recoverable if the process is halted rapidly, an outcome that is most likely in prostatic carcinoma.

Deposition of tumour products The protean effects of monoclonal overproduction of immunoglobulins, or their component parts, are considered elsewhere (see Chapter 21.10.5). The tubulotoxic effects of freely filtered immunoglobulin light chains may be amplified by hypercalcaemia in myeloma, or by concurrent administration of other nephrotoxins, notably intravenous radiological contrast media or possibly loop diuretics. AL amyloidosis (see Chapters 12.12.3 and 21.10.5) is another possible consequence of monoclonal proliferation of B cells, devastating enough on its own, but it may be associated with myeloma or progress to overt myeloma. A variety of other renal consequences may occur in B-​cell disorders with overproduction of immunoglobulin fragments, notably the light-​ chain (and rarer heavy-​chain) deposition disorders.

Immune reactions Malignant diseases are common, hence on occasions cancer will be associated with nephropathies by chance. There are many case reports in the literature, but some associations have been reported

21.10.9  Malignancy-associated renal disease

consistently and are beyond doubt. The best-​supported linkages between malignancies and intrinsic renal diseases are for minimal-​ change disease and membranous nephropathy, glomerular conditions that are (membranous) or are believed to be (minimal-​change) immunologically mediated. There is also a frequently reported association of malignancy with various types of vasculitis, particularly small-​ vessel vasculitis, which—​ as with glomerulonephritis—​ is usually believed to be immunologically mediated, both because of the typical contexts in which it occurs and because of its usual response to immunosuppressive agents. By contrast, there is little evidence for association of malignancies with primary interstitial renal diseases. Some malignancies are particularly likely to be associated with renal disease. Chronic lymphocytic leukaemia and similar low-​ grade B-​cell tumours are associated with a variety of types of glomerulopathy. Thymomas have frequently been associated with glomerular lesions, usually causing nephrotic syndrome with various histological patterns reported. Minimal-​change nephrotic syndrome Lymphomas, usually Hodgkin’s disease, are rarely associated with minimal-​change nephropathy. The renal lesion is typical in pathological characteristics, and usually also in response to corticosteroid treatment. In exceptional cases, this is the presenting sign of the lymphoma, and it may also herald relapse. More so than with other renal lesions that are putatively associated with malignancy, there is often a close temporal relationship between the occurrence of nephrotic syndrome and the presentation of the tumour. However, there is no way of proving the association in an individual patient, or of suspecting an underlying lymphoma in patients who present with nephrotic syndrome without systemic symptoms. As the association is very rare in comparison to the number of young patients with minimal-​change disease, screening other than by clinical examination and simple investigations is not justified. Less commonly, minimal-​change disease has been associated with solid tumours, and particularly with malignant and benign thymomas. Membranous nephropathy Membranous nephropathy is caused by antibody (autoantibody) formation to any of several molecules on the surface of the podocyte. It has often been associated with malignancies, but membranous nephropathy is not rare and occurs in older patients who are at relatively high risk of malignancy simply on account of their age. Series have shown rates of malignancy from 5 to 11%, although the risk is greater in older patients. However, variation in reporting practice makes published figures difficult to interpret, for example, if tumours that are recognized long after the renal diagnosis are included. Most reported tumours are of solid organs, including almost all types, but haematological malignancies are also implicated. Very often the disease is advanced and obvious when nephrotic syndrome or heavy proteinuria is recognized. In some cases, the nephrotic syndrome or proteinuria lessens after effective treatment of the malignancy. The use of alkylating agents or corticosteroids as treatment for the membranous nephropathy is not recommended in this setting, unless this would be appropriate for treatment of the malignancy itself.

There is controversy about the value of screening for malignancy in patients presenting with membranous nephropathy when malignancy is not apparent from initial investigations. Aside from routine haematological and biochemical investigations, chest radiography, and renal ultrasonography that are needed in all cases of nephrotic syndrome, in older patients it is appropriate to perform careful breast and rectal examination, faecal occult blood screening, and possibly mammography and sigmoidoscopy or colonoscopy. However, in clinical practice, the number of treatable and otherwise subclinical tumours uncovered in this way is low. Systemic vasculitis Focal necrotizing and crescentic nephritis, with or without evidence of small-​vessel vasculitis affecting other organs, may occur in association with malignancy. Some cases may be chance associations of malignancy with typical small-​vessel vasculitis that is not uncommon in older people, but there are sufficient reports of unusual associations to strongly suggest that there is sometimes a causal relationship. As well as true vasculitis, cancer-​related thrombotic microangiopathy and thrombotic events complicating disseminated intravascular coagulation in association with cancer may resemble systemic vasculitis and lead to diagnostic confusion. The most common type of vasculitis to be associated with malignancy is small-​vessel cutaneous vasculitis. In other cases, bowel and other organs including the kidney have been involved by a small-​to medium-​vessel systemic vasculitis, which is usually antineutrophil cytoplasmic antibody (ANCA) negative. However, more typical ANCA-​associated vasculitis has also been associated with malignancy, and there may be a particular relationship between granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis) and renal cell carcinoma. Usually the kidney is not involved in cancer-​associated systemic vasculitis, but when it is, the appearances are indistinguishable from those of small-​vessel vasculitis of other aetiologies. Immune deposits in glomeruli are not usual (pauci-​immune). Atrial myomas have been associated with lesions of larger and smaller vessels, and it appears that embolization is not always the explanation for this.

Effects of treatment for malignancy These include the tumour lysis syndrome (discussed earlier and in Chapter 21.10.5), as well as idiosyncratic or predictable reactions to therapeutic agents. On occasions, minimal-​ change disease or other proteinuria-​ causing lesions have been associated with treatment with interferons and with drugs that target vascular endothelial growth factor (VEGF) or its signalling. Anti-​VEGF therapy may also cause thrombotic microangiopathy. The bisphosphonate pamidronate has caused proteinuria and focal segmental glomerulosclerosis, usually when given at high doses in myeloma. Cisplatin may cause tubular damage, predominantly to proximal tubules, and is characteristically associated with features of a renal Fanconi syndrome (see Chapter 21.16), although there can also be significant loss of glomerular filtration rate when severe. Ifosfamide,

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but not cyclophosphamide, is also prone to cause permanent tubular damage. High-​ dose methotrexate and pemetrexed may cause tubular damage. Radiation nephropathy develops slowly and is termed acute if it occurs within 6  months of exposure. Hypertension is usually a prominent feature, and there may be accompanying thrombotic microangiopathy. Chronic radiation nephropathy appears from 1 to 20 years after exposure and typically presents indolently with chronic kidney disease, with imaging revealing small kidneys.

FURTHER READING Bacchetta J, et al. (2008). Paraneoplastic glomerular diseases and malignancies. Crit Rev Oncol Haematol, 70,  39–​58. Biava CG, et al. (1984). Crescentic glomerulonephritis associated with nonrenal malignancies. Am J Nephrol, 4, 208–​14. Dabbs DJ, et al. (1986). Glomerular lesions in lymphomas and leukemias. Am J Med, 80,  63–​70. Goel A, et  al. Renal medullary carcinoma. Radiopaedia. http://​ radiopaedia.org/​articles/​renal-​medullary-​carcinoma Gordon LI, et al. (1999). Thrombotic microangiopathy manifesting as thrombotic thrombocytopenic purpura/​ hemolytic uremic syndrome in the cancer patient. Semin Thromb Hemost, 25, 217–​21. Gupta R, Billis A, Shah RB (2012). Carcinoma of the collecting ducts of Bellini and renal medullary carcinoma: clinicopathologic analysis of 52 cases of rare aggressive subtypes of renal cell carcinoma with a focus on their interrelationship. Am J Surg Pathol, 36, 1265–​78. Gurevich F, Perazella MA (2009). Renal effects of anti-​angiogenesis therapy: update for the internist. Am J Med, 122,  322–​8. Izzedine H, et al. (2006). Drug-​induced glomerulopathies. Exp Opin Drug Saf, 5, 95–​106. Izzedine H, et al. (2010). VEGF signalling inhibition-​induced proteinuria: mechanisms, significance and management. Eur J Cancer, 46, 439–​48. Kurzrock R, Cohen PR, Markowitz A (1994). Clinical manifestations of vasculitis in patients with solid tumors. A case report and review of the literature. Arch Intern Med, 154, 334–​40. Maher ER (2011). Genetics of familial renal cancers. Nephron Exp Nephrol, 118,  e21–​6. Markowitz GS, et  al. (2001). Collapsing focal segmental glomerulosclerosis following treatment with high-​ dose pamidronate. J Am Soc Nephrol, 12, 1164–​72. Markowitz GS, Bomback AS, Perazella MA (2015). Drug-​induced glomerular disease: direct cellular injury. Clin J Am Soc Nephrol, 10, 1291–​9. O’Callaghan CA, et  al. (2002). Characteristics and outcome of membranous nephropathy in older patients. Int Urol Nephrol, 33, 157–​65. Pabla N, Dong Z (2008). Cisplatin nephrotoxicity:  mechanisms and renoprotective strategies. Kidney Int, 73, 994–​1007. Ronco PM (1999). Paraneoplastic glomerulopathies: new insights into an old entity. Kidney Int, 56, 355–​77. Turner AN, et al. (eds) (2015). Oxford textbook of clinical nephrology, 4th edition. Oxford University Press, Oxford. Watts RA, Scott DG, Mukhtyar C (2015). Secondary vasculitis. In: Vasculitis in clinical practice, pp. 173–​84. Springer International Publishing AG, Cham.

21.10.10 Atherosclerotic renovascular disease Philip A. Kalra and Diana Vassallo ESSENTIALS Atherosclerotic renovascular disease (ARVD) refers to atheromatous narrowing of one or both renal arteries and frequently coexists with atherosclerotic disease in other vascular beds. Patients with this condition are at high risk of adverse cardiovascular events, with mortality around 8% per year. Many patients with ARVD have chronic kidney disease, but only a minority progress to endstage kidney disease, suggesting that pre-​existing hypertensive and/​or ischaemic renal parenchymal injury is the usual cause of renal dysfunction. Many patients with ARVD are asymptomatic, but there can be important complications such as uncontrolled hypertension, rapid decline in kidney function, and recurrent acute heart failure (flash pulmonary oedema). Management—​patients with ARVD should receive medical vascular protective therapy just like other patients with atheromatous disease. This involves antiplatelet agents such as aspirin, statins, antihypertensive agents (angiotensin-​ converting enzyme inhibitors or angiotensin receptor blockers are the drugs of choice), optimization of glycaemic control in diabetic patients, and advice/​help to stop smoking. On the basis of randomized controlled trial data, the majority of patients should not be offered revascularization by angioplasty/​stenting for the purpose of improving blood pressure control or stabilizing/​improving renal function. However, there is evidence that a subgroup of patients with specific complications of ARVD (as previously mentioned) may benefit from revascularization.

Introduction Atheromatous disease is common, indeed almost universal in elderly individuals, and it is a multiorgan disease process. Atherosclerotic renovascular disease (ARVD) refers to atheromatous narrowing or occlusion of one or both renal arteries and as expected, occurs more frequently with increasing age and in the presence of cardiovascular risk factors such as diabetes, smoking, and hypertension. Although ARVD is very often asymptomatic and usually discovered incidentally during investigation for extrarenal atherosclerotic disease, haemodynamically significant stenosis in certain patients can lead to important complications such as uncontrolled hypertension, progressive decline in kidney function, and recurrent episodes of acute heart failure (flash pulmonary oedema). The heterogeneous nature of ARVD poses a significant diagnostic and management dilemma to the physician. Despite significant progress in imaging techniques, accurate determination of the haemodynamic significance of a stenosis remains difficult. In addition, percutaneous revascularization carries a risk of complications and does not guarantee improved outcomes. This is probably due to irreversible renal parenchymal damage in the poststenotic kidney, a product of both local (e.g. oxidative stress) and systemic

21.10.10  Atherosclerotic renovascular disease

(e.g. longstanding hypertension, diabetes) insults. This would explain the neutral results of recent large prospective trials in ARVD, which have shown that revascularization does not confer any added benefit to optimal medical therapy in unselected populations. However, there is evidence that subgroups of patients with a ‘high-​ risk’ phenotype, for example, patients with recurrent flash pulmonary oedema, or refractory hypertension in conjunction with rapidly declining renal function, do benefit from revascularization. Identifying these patients in a timely manner remains a considerable challenge. The issue of investigation and treatment of renal artery stenosis (RAS) in the context of the patient presenting with hypertension is discussed in Chapter 16.17.3. This brief chapter focuses more on patients with impairment of renal excretory function (chronic kidney disease) with reduced (and falling) estimated glomerular filtration rate (eGFR) in association with ARVD. The underlying aetiology, genetics, pathogenesis, and histopathology of the major macrovascular RAS lesions in ARVD are broadly as for atherosclerotic disease in general (see Chapter  16.13.1). However, as already mentioned, histopathological changes in the kidneys of patients with chronic kidney disease associated with ARVD can include hypertensive and ischaemic injury, as well as atheroembolic disease. The latter is a recognized cause of acute kidney injury occurring after revascularization.

Epidemiology It is difficult to state the true incidence and prevalence of ARVD because of variability in both the definition and in the enthusiasm with which the diagnosis is pursued. There is no uniform agreement about the precise degree of RAS which constitutes a haemodynamically significant lesion. However, in the context of the patient with gradually failing renal function, in which the causal mechanism might be ‘ischaemic renovascular disease’ (ischaemic nephropathy), many consider that the presence of significant high-​grade RAS (>70% narrowing of both renal arteries, or of the artery to a single functioning kidney) is necessary to make the diagnosis. Most ARVD epidemiological studies have been performed in populations with known atherosclerosis or cardiovascular risk factors, hence leading to selection bias. A  study of administrative claims data from the United States Medicare population over 67  years of age gave an incidence of 3.7/​1000 patient years. The overall prevalence in such patients is around 0.5%. Another study in which healthy individuals over 65 years of age living in the United States of America were screened for ARVD by means of a doppler ultrasound scan reported an incidence of 6.8%. However, the prevalence of ARVD in populations with significant comorbidities is much higher—​unsuspected ARVD has been found in around 25% of patients with peripheral vascular disease and in up to 50% of patients with congestive heart failure. In various studies RAS has been demonstrated in 5 to 22% of patients with endstage renal disease aged over 50 years, but the presence of ARVD here does not always imply causality of the renal dysfunction. Conversely, patients with ARVD usually have evidence of other macrovascular disease such as coronary (67%), peripheral arterial (56%), and cerebrovascular (37%) atherosclerotic disease.

Some atherosclerotic RAS lesions become worse with time, but this is not inevitable, especially since the advent of modern, multitargeted medical management of atherosclerosis, which includes statins and tight risk factor control. Serial imaging studies performed in the pre-​statin era reported a rate of progression to occlusion of up to about 40% over 12 months’ follow-​up, leading to loss of renal function and renal atrophy. However, nowadays, progression to total occlusion occurs much less commonly, and later studies have reported a rate of occlusion of 3% over 3 years.

Clinical features The diagnosis of ARVD should be suspected in any patient with other manifestations of atherosclerosis who presents with stable chronic kidney disease or progressive impairment of renal function, especially in the presence of hypertension that is particularly severe or difficult to control. Other clinical pointers are the presence of abdominal or iliofemoral bruits, significant deterioration in renal function after initiation of treatment with an angiotensin-​ converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB), and asymmetry of renal size on imaging (>1.5 cm difference in length of the two kidneys). Flash pulmonary oedema is a well-​described and ‘classic’ manifestation of ARVD, but pulmonary oedema in a patient with ARVD is more usually attributable to concurrent ischaemic cardiac disease. ARVD is now increasingly recognized in association with congestive cardiac failure.

Clinical investigations ARVD can only be confirmed by some form of imaging and the main techniques used include duplex Doppler ultrasonography (very operator dependent) (Figs. 21.10.10.1 and 21.10.10.2), magnetic resonance angiography (either contrast free or with gadolinium, although the latter is contraindicated in patients with an eGFR 50 mg/​mmol), but is bland, without red cells or casts.

Management All patients with ARVD should receive interventions appropriate for any patient with known atherosclerotic disease, including encouragement of and assistance with smoking cessation, aspirin

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Fig 21.10.10.1  Normal right renal artery as assessed by colour Doppler ultrasound. Spectral analysis (bottom of image) shows low resistance waveform in the artery. From https://​www.med-​ed.virginia.edu/​courses/​rad/​gu/​anatomy/​kidneys.html.

(or other antiplatelet agents), statin therapy, blood pressure control, and in patients with diabetes, optimization of glycaemic control. Early studies discouraged the use of ACE inhibitors or ARBs in patients with RAS as they were thought to decrease perfusion pressure across a stenosis and exacerbate renal injury, but subsequent studies confirmed that renin–​angiotensin blockade can both mitigate the intrarenal parenchymal injury that leads to chronic kidney disease in ARVD and improve overall survival by optimizing cardiac (a)

status. In view of this, ACE inhibitors and ARBs are now considered the antihypertensive agents of choice in patients with ARVD. Nonetheless, a minority of patients with bilateral RAS or severe RAS affecting a solitary functioning kidney are at risk of acute kidney injury with such therapy, hence close monitoring of kidney function after initiation of an ACE inhibitor or ARB is essential. Blood pressure and renal chemistry should be checked within 2 weeks of starting renin–​angiotensin blockade in any patient, and especially in those with RAS. Renal function should then be rechecked on a 6-​monthly basis once the patient is receiving a stable maintenance dose, and more frequent monitoring may be required in patients who are on concurrent diuretic therapy or aldosterone antagonists. If, following initiation of an ACE inhibitor or ARB, serum creatinine concentration increases by more than 30% or eGFR declines by more than 25%, and there is no other apparent precipitating cause of acute kidney injury such as dehydration or concurrent nephrotoxic medication (e.g. nonsteroidal anti-​ inflammatory agents), the dose of the ACE inhibitor or ARB may need to be reduced to a previously tolerated level or stopped altogether. Hypotension may cause an acute decline in GFR due to impaired autoregulation in patients with chronic kidney disease or in those with critical RAS receiving an ACE inhibitor or ARB. In the event of an intercurrent illness which can cause hypotension, such as diarrhoea, vomiting, or sepsis, it should be recommended that the ACE inhibitor or ARB are temporarily stopped until the patient has recovered. Such advice is now part of ‘Sick Day rules’ programmes for prevention of acute kidney injury. A key management question concerns whether renal revasculari­ zation with renal artery angioplasty/​stenting is warranted. While there is no doubt that such interventional procedures can produce ‘anatomical cure’ of RAS (Fig. 21.10.10.3), there is a small chance (approximately 3%) of major debilitating complications including groin haematoma, acute kidney injury, cholesterol embolization, arterial dissection, and renal infarction.

(b)

Fig 21.10.10.2  Panel (a) shows a CT angiogram with the red arrow indicating significant stenosis in the right renal artery. Panel (b) shows the colour Doppler ultrasound appearance compatible with the angiographic findings. An elevated peak systolic velocity of 246.6 cm/​s is noted at the area of stenosis. (a) From http://​www.radblazer.com/​renal-​artery-​stenosis-​angiogram/​. (b) From https://​iame.com/​online/​duplex_​and_​color_​doppler_​of_​the_​kidney/​content.php.

21.10.10  Atherosclerotic renovascular disease

(a)

(b)

(c)

Fig 21.10.10.3  An intra-​arterial digital subtraction angiography series showing left renal angioplasty and stent placement. (a) Flush aortogram showing severe (>95%) left renal artery stenosis (arrow); the more distal circulation beyond the stenosis is just visible. (b) The angioplasty catheter (arrow) has traversed the renal artery stenosis. (c) A stent has been deployed (arrow). Courtesy of Professor J. Moss, Gartnavel Hospital, Glasgow.

A number of studies have been carried out over the past two decades to determine whether anatomical improvement translates into clinically useful outcomes for patients, and to assess how revascularization compares with modern multitargeted medical management. Results from small randomized controlled trials showed no clear evidence of benefit for revascularization over conservative medical management. The largest and most recent randomized controlled trials, the Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) and Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) studies, provide the most robust data regarding the role of revascularization in the management of patients with ARVD. The United Kingdom-​ based ASTRAL trial randomized 806 patients with ARVD to either medical therapy alone or medical therapy with revascularization. The primary endpoint was change in renal function from baseline and after a median follow-​up of 34 months. Results showed that revascularization had no impact on decline in renal function or on blood pressure control, incidence of cardiovascular events, or mortality (secondary endpoints), and there was a significant complication rate of 7% associated with the procedure. The CORAL study was based in the United States of America (although around 50% of patients were from the rest of the world), and is the largest study in ARVD to date; 947 patients were randomized to stenting and best medical therapy or best medical therapy alone. The primary endpoint was a composite of major cardiovascular events, progressive deterioration in renal function, and death from cardiovascular or renal causes. Again, after a median follow-​up of 43 months, revascularization did not confer any clinical benefit over medical therapy on its own. However, a major criticism of these ARVD trials is the fact that these results may not be entirely generalizable as patients with ‘high-​ risk’ features (e.g. uncontrolled hypertension, rapidly deteriorating renal function, or unstable cardiac status) were specifically excluded. A  recent single-​centre retrospective study looked at 237 patients with at least 50% RAS and one or more ‘high-​risk’ features. Around one-​quarter (24%) of these patients underwent revascularization and their outcomes were compared with those of patients who were treated exclusively medically. Revascularization led to improved clinical outcomes in patients with either flash pulmonary oedema or a combination of rapidly declining kidney function and uncontrolled hypertension. Our recommendation is that there is no benefit in screening asymptomatic patients with chronic kidney disease and/​or hypertension for ARVD, and that most patients found to have ARVD should generally not be referred for revascularization for the purpose of improving blood pressure control or stabilizing/​ improving renal function. There is, however, some evidence that revascularization may play a role in the management of an important subset of patients with certain ‘high-​risk’ features who have not been well-​represented in clinical trials. These include patients with severe RAS and with otherwise unexplained rapid decline in renal function, those with recurrent episodes of flash pulmonary oedema (not explained by cardiac disease), and perhaps those with severe hypertension not adequately controlled by multiple drug treatments (or in whom reduction in arterial pressure leads to significant decline in eGFR). Another subgroup who

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section 21  Disorders of the kidney and urinary tract

could justifiably be treated with revascularization are those who require ACE inhibitors or ARBs because of concomitant heart disease and/​or renal parenchymal injury, but show intolerance of these drugs as manifest by acute kidney injury.

Prognosis Patients with ARVD are at a higher risk of cardiovascular events and death than the general population due to their significant atherosclerotic burden. However, renal function tends to remain stable and only rarely do patients with ARVD require renal replacement therapy due to ARVD progression. Indeed, in the Medicare population in the United States of America, the risk of mortality during follow-​up was almost six times that of requiring renal replacement therapy. Recent trials in ARVD have shed light on the heterogeneous nature of this condition and how prognosis may be quite variable. This is illustrated by the different baseline characteristics of patients enrolled into the ASTRAL and CORAL trials and their slightly divergent outcomes; the average eGFR for ASTRAL was 40 ml/​min per 1.73 m2 whereas that for CORAL was higher, approximately 58 ml/​min per 1.73 m2. As a result, mortality was around 8% per year for ASTRAL, compared to around 4% per year for CORAL, whereas the incidence of endstage kidney disease was 2% per year for ASTRAL and 0.5% per year for CORAL. Nonetheless, the results of both of these trials highlight the steady improvement in the prognosis of ARVD that has occurred over the past few decades, a testament to the reno-​and cardioprotective effects of modern medical therapy.

Future developments Timely identification of individuals who may gain benefit from revascularization remains a very important challenge to clinicians, and recent progress in imaging and diagnostic technology may help address this issue. Novel functional magnetic resonance imaging (MRI) techniques such as blood oxygen level-​dependent (BOLD)-​ MRI may estimate the degree of intrarenal hypoxia and thus help identify critically ischaemic kidneys. MRI has also been used to measure single-​kidney GFR and other perfusion parameters that may correspond to the functional status of the kidney. Indeed, a high single-​kidney GFR-​to-​parenchymal volume ratio has been shown to identify kidneys that may be salvaged by revascularization because they retain viable or ‘hibernating parenchyma’. Progress in biomarker technology over the past decade has stimulated interest in the identification of serum or urine biomarkers, such as neutrophil gelatinase-​associated lipocalin (NGAL), tubular kidney injury molecule-​1 (KIM-​1), or brain natriuretic peptide (BNP), which can

help predict outcomes post revascularization. However, these novel techniques have only been studied under experimental conditions and more research is required to determine whether they can be applied to clinical practice. Increased understanding of the complex pathogenesis of renal parenchymal injury in ARVD has paved the way for novel therapeutic strategies. Cell-​ based therapies have been proposed to counteract the inflammatory milieu and oxidative stress typically found in the poststenotic kidney. These might prevent irreversible loss of renal microvascular architecture and help improve clinical outcomes.

FURTHER READING Bax L, et al. (2009). Stent placement in patients with atherosclerotic renal artery stenosis and impaired renal function:  a randomized trial. Ann Intern Med, 150,  840–​8. Cheung CM, et al. (2006). MR-​derived renal morphology and renal function in patients with atherosclerotic renovascular disease. Kidney Int, 69, 715–​22. Cooper CJ, et al. (2014). Stenting and medical therapy for atherosclerotic renal-​artery stenosis. N Engl J Med, 370,  13–​22. Chrysochou C, et  al. (2012). BOLD imaging:  a potential predictive biomarker of renal functional outcome following revascularization in atheromatous renovascular disease. Nephrol Dial Transplant, 27, 1013–​19. Eirin A, Textor SC, Lerman LO (2019). Novel therapeutic strategies for renovascular disease. Curr Opin Nephrol Hypertens, 28, 383–9. Herrmann SMS, Saad A, Textor SC (2014). Management of atherosclerotic renovascular disease after Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL). Nephrol Dial Transplant, 30, 366–​75. Kalra PA, et al. (2005). Atherosclerotic renovascular disease in United States patients aged 67 years or older: risk factors, revascularization, and prognosis. Kidney Int, 68, 293–​301. National Institute for Health and Care Excellence (2013). Acute kidney injury:  prevention, detection and management. Clinical guideline [CG169]. National Institute for Health and Care Excellence, London. National Institute for Health and Care Excellence (2014). Chronic kidney disease: in adults: assessment and management. Clinical guideline [CG182]. National Institute for Health and Care Excellence, London. Ritchie J, et al. (2014). High-​risk clinical presentations in atherosclerotic renovascular disease:  prognosis and response to renal artery revascularization. Am J Kidney Dis, 63, 186–​97. Saad A, et  al. (2013). Stent revascularization restores cortical blood flow and reverses tissue hypoxia in atherosclerotic renal artery stenosis but fails to reverse inflammatory pathways or glomerular filtration rate. Circ Cardiovasc Interv, 6, 428–​35. The ASTRAL Investigators (2009). Revascularisation versus medical therapy for renal-​artery stenosis. N Engl J Med, 361, 1953–​62.

21.11

Renal diseases in the tropics Vivekanand Jha

ESSENTIALS Kidney diseases encountered in tropical areas are a mix of conditions that have a worldwide distribution and those that are secondary to factors unique to the tropics, for example, climatic conditions, infectious agents, nephrotoxic plants, envenomations, and chemical toxins. Cultural factors, illiteracy, superstitions, living conditions, level of access to health care, and nutritional status also affect the nature and course of disease. Knowledge of such conditions and issues is important for medical professionals in all parts of the globe, as ease of travel means that individuals and practices are exported with increasing frequency. Glomerular diseases—​there is a high prevalence of infection-​related glomerulonephritis throughout the tropics, with the pattern of injury dependent upon the nature of the prevalent endemic infection in that region. Important infection-​related glomerulopathies include quartan malarial, schistosomal, and filarial nephropathies. Once established, the course of disease is rarely modified by treatment of underlying infection. Acute kidney injury (AKI)—​ there is a higher prevalence of community-​acquired AKI in the tropics than elsewhere. Medical causes predominate, with diarrhoeal diseases, intravascular haemolysis due to glucose-​6-​phosphate dehydrogenase deficiency, ingestion of toxic plants, snake bites, insect stings, and locally prevalent infections being responsible for most cases, although obstetric causes remain common in some tropical countries. Falciparum malaria and leptospirosis are the most important infectious aetiologies. Use of indigenous herbs and chemicals by traditional healers (‘witch doctors’) are the most important toxic causes of AKI in sub-​Saharan Africa. Chronic kidney disease (CKD)—​although the contributions of diabetes and hypertension are growing, many cases are secondary to glomerular diseases, likely infection related, or have CKD of undetermined aetiology. Many of the latter are agriculture or farm workers presenting with chronic tubulointerstitial nephritis of unknown cause.

Introduction Approximately 40% of the world’s population live in the tropics, geographically defined as the area between the latitudes 23° north

to 23° south. Kidney diseases in tropical areas are a variable mix of globally encountered conditions and those specific to the geopolitical characteristics of the region. Tropical ecobiology strongly influences the pattern and presentation of kidney diseases encountered. Tropics are characterized by high ambient temperature; some regions receive heavy rains, while other areas are arid, with little precipitation. Extreme heat and humidity can lead to unrecognized fluid losses, especially among those engaged in manual labour. Studies have demonstrated that people can lose up to 5 kg of weight during the course of a day and show features of subclinical rhabdomyolysis, both of which can lead to kidney injury. Rains force leaching of minerals and organic compounds from the fragile tropical soil into flowing water, which can leading to waterlogging and contamination of fields with potentially toxic metals. The combination of high temperatures, wet weather, and salinity support growth of a variety of flora and fauna, including potentially nephrotoxic plants, pathogenic microorganisms, and animals that can serve as disease vectors and intermediate hosts. The end result is a high prevalence of water­borne and infectious diseases, many of which are associated with kidney injury. Rains cause a spike in the incidence of nephrotoxic snake bites, since flooding of snake burrows forces their inhabitants to come to the surface. Population migration over millennia has led to accumulation of certain genetic traits that increase kidney disease risk in the tropics. These include glucose-​6-​phosphate dehydrogenase (G6PD) deficiency giving rise to intravascular haemolysis and pigment-​ induced acute kidney injury (AKI); progressive kidney disease in haemoglobinopathies such as sickle cell anaemia and thalassaemias; MYH9 and APOL1 alleles predisposing to HIV-​associated kidney disease; and hypokalaemia, hypercalcaemia, hypocitraturia, and renal tubular acidosis due to inherited defects in tubular transport. Compared to countries in temperate regions, tropical countries are disadvantaged in socioeconomic terms. Except for two small countries (Singapore and Hong Kong), all tropical countries are classified in low-​or middle-​income categories. Poorly developed healthcare systems reduce access of large populations to medical services. Traditional health systems that rely on unproven and potentially harmful therapies flourish in the tropics, some of which are associated with practices that increase kidney disease risk.

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section 21  Disorders of the kidney and urinary tract

Cultural factors, illiteracy, superstitions, poor living conditions, and nutritional status also affect the nature, presentation, and course of kidney disease. Delayed diagnosis leads to extreme presentations that have been (almost) eliminated in the developed world. For example, it is not uncommon for children with distal renal tubular acidosis to present with marked skeletal deformities and severe growth retardation, or those with posterior urethral valves to go undiagnosed until they are several years old. Acute renal cortical necrosis following septic abortion and placental abruption continues to be seen regularly. Malnutrition exaggerates the impact of kidney disease; a lower degree of protein loss leads to more severe peripheral oedema and serous effusions. Delayed and suboptimal treatment leads to loss of opportunities to implement preventive and/​ or curative therapies, thereby increasing morbidity and mortality. Economic considerations also prevent the implementation of more refined technological solutions. For example, continuous renal replacement therapy is eschewed in favour of cheaper and less complex peritoneal dialysis. In an era of easy transcontinental movement of people, organisms, and materials, all physicians and nephrologists need, more than ever before, to be aware of tropical renal diseases. People who have migrated from the tropics may continue to engage in habits that predispose to kidney disease, even in their new location. Slowly progressive diseases due to past exposures in the tropics may produce delayed clinical manifestations. This chapter highlights the important differences between different syndromes of kidney disease in the tropics and the rest of the world, and discusses some specific renal diseases unique to the tropical regions.

Types of renal disease Glomerular diseases The overall prevalence of glomerulonephritis is reported to be higher in tropical countries than in temperate regions. Surveys from hospitals in sub-​Saharan Africa show that nephrotic syndrome accounts for 0.2 to 4% of all admissions. Primary glomerular diseases account for the majority, but secondary causes are responsible in 40 to 55% of patients in Zimbabwe and Jamaica. There is variation in the epidemiology, aetiology, clinical presentation, and natural history of glomerulonephritis between different tropical countries (Figs. 21.11.1 and 21.11.2). In general, there is a high prevalence of infection-​related glomerulonephritis throughout the tropics, with the pattern of injury dependent upon the nature of the prevalent endemic infection in that region. Minimal-​change disease is as frequent in Asia and North Africa as in the developed world, but is less common in the rest of Africa. In a study from South Africa, minimal-​change disease was responsible for nephrotic syndrome in 75% of children of Indian ancestry, whereas only 13.5% of black children showed this lesion. A  high frequency of proliferative glomerulopathies and steroid resistance is described in paediatric patients from the Democratic Republic of Congo, Zimbabwe, Malawi, Nigeria, Kenya, and Uganda. Membranous nephropathy is seen with a high frequency among children with nephrotic syndrome in countries with a high hepatitis B virus (HBV) carrier rate, and in some areas HBV-​related disease accounts for up to 15% of all membranous nephropathy cases. By

Jamaica Ghana Sudan South Africa Pakistan Papua New Guinea Singapore North India Europe 0%

20%

40%

60%

80%

100%

Minimal change

Membranous

Mesangioproliferative

Diffuse proliferative

Mesangiocapillary

FSGS

Others

Fig. 21.11.1  Prevalence of different types of glomerular lesions in adults with nephrotic syndrome in different parts of the world. FSGS, focal segmental glomerulosclerosis.

contrast, mesangial proliferative forms with IgA deposits seem to be more common in adults with HBV infection. A strong (and likely causal) association has been described between chronic hepatitis C virus (HCV) infection and several chronic glomerular diseases. An autopsy study revealed glomerular lesions in 55% of HCV-​infected individuals, including mesangial proliferative glomerulonephritis (17.6%), membranoproliferative glomerulonephritis (11.2%), and membranous nephropathy (2.7%). Recent population-​based studies have shown a link between the prevalence of HCV infection and proteinuria. The introduction of new treatments for HCV is likely to reduce the prevalence of HCV-​related glomerulonephritis. Postinfectious glomerulonephritis continues to be encountered in high frequency throughout the tropics. In studies from north Africa and the Middle-​East, about 15 to 20% of all paediatric biopsies show diffuse proliferative glomerulonephritis, likely postinfectious. The prevalence of poststreptococcal glomerulonephritis in the Goajiro

United Kingdom South India North India Papua New Guinea Zimbabwe Nigeria South Africa (Blacks) South Africa (Indians) 0%

20%

40%

60%

80%

100%

Minimal change

Membranous

Mesangioproliferative

Diffuse proliferative

Mesangiocapillary

FSGS

Others

Fig. 21.11.2  Prevalence of different types of glomerular lesions in children with nephrotic syndrome in different parts of the world. FSGS, focal segmental glomerulosclerosis.

21.11  Renal diseases in the tropics

Fig. 21.11.3  Map showing areas with a high prevalence of community-​acquired AKI. Areas with a high prevalence of malaria-​associated AKI are shown in maroon, and with intermediate prevalence in yellow; orange indicates areas with a high prevalence of both leptospiral and malarial AKI; textured fill in countries of sub-​Saharan Africa indicates a high prevalence of malarial and herbal remedy-​induced AKI; green indicates AKI of other causes.

Indian community of Venezuela was twice that seen in other parts of the Goajira state.

Acute kidney injury Community-​acquired AKI is the commonest nephrological emergency encountered in the tropics, and referral patterns to dialysis units suggest a higher prevalence of community-​acquired AKI in the tropics than elsewhere. In a large referral hospital in North India, 1.5% of all hospital admissions were referred to the nephrology service for management of moderate to severe AKI. Medical causes predominate, with diarrhoeal diseases, intravascular haemolysis due to G6PD deficiency,

ingestion of toxic plants, snake bites, insect stings, and locally prevalent infections being responsible for most cases, although obstetric causes remain common in some tropical countries (Figs. 21.11.3 and 21.11.4). In a recent global study conducted by the International Society of Nephrology, AKI patients in low-​and low–​middle-​income countries of the tropics were younger than those from rest of the world, although the extent to which this is explained by ascertainment bias remains uncertain. In a study from India, the average age of patients dialysed for AKI was 34.3 years. Dehydration was the most common cause of AKI, followed by infections, pregnancy-​related AKI, and animal envenomation.

100% 90% 80% 70% 60% 50% 40% 30% 20% 10%

a Ar

ge n

tin

a an

Obstetric

Gh

Surgical

S

Af

ric

a

ia ig

Medical

N

Th

ai

la

er

nd

ka an iL Sr

In h ut So

N or

th

In

di

di

a

a

0%

Fig. 21.11.4  Causes of AKI in different tropical countries. Modified from Chugh, Satprija and Jha, Oxford Textbook of Clinical Nephrology, Oxford University Press, Oxford 2005.

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section 21  Disorders of the kidney and urinary tract

Fig. 21.11.5  Tropical countries from where hot spots of chronic kidney disease of undetermined aetiology have been reported (red: definite; yellow: probable).

In contrast to patients with hospital-​acquired AKI seen in temperate countries, the kidney is the sole affected organ in more than 50% of cases at diagnosis. However, when tropical AKI is seen as part of an undifferentiated illness that includes AKI, liver failure, respiratory failure, neurological dysfunction, disseminated intravascular coagulation, and metabolic acidosis, then establishing the cause can be impossible in the absence of specialized facilities. Lack of resources forces a significant proportion of patients with AKI in tropical low-​income countries to go untreated, but the proportion of those receiving treatment who recover is greater than in the developed world, reflecting the relatively young age and absence of any pre-​existing disease in the affected individuals. Saving Young Lives, a collaborative project between the International Society of Nephrology, International Paediatric Nephrology Association, International Society for Peritoneal Dialysis, and Sustainable Kidney Care Foundation, is developing a sustainable programme to treat AKI using peritoneal dialysis in several countries of sub-​Saharan Africa and Southeast Asia.

‘Mini-​epidemics’ of such cases has been reported from several tropical regions in central America (Costa Rica, Guatemala, Nicaragua, El-​ Salvador, Mexico), north America (California), South and Southeast Asia (India, Sri Lanka, Thailand), Middle-​East (Saudi Arabia, Qatar), and Africa (Egypt, Sudan) (Fig. 21.11.5). Dubbed variously CKD of uncertain aetiology (CKDu), chronic interstitial nephritis in agricultural communities (CINAC) and other terms (e.g. mesoamerican nephropathy), the aetiology of this condition has been a subject of intense speculation. The currently favoured postulations include recurrent heat stress with episodes of dehydration and/or rhabdomyolysis, and exposure to agrochemicals, particularly pesticides. Other hypotheses are heavy metals (contaminating drinking water, rice and edible fish), fluoride, tropical infections, dietary peculiarities, consumption of herbal medicines, and abuse of over-​the-​counter medications. See Chapter 21.9.2 for further discussion. Obstructive nephropathy due to urolithiasis is common in Pakistan, Thailand, and parts of India known as ‘stone belts’.

Chronic kidney disease

Kidney diseases specific to the tropics

There are several notable differences in the pattern of chronic kidney disease (CKD) in topical populations compared to those in temperate zones. Tropical patients with endstage renal disease are significantly younger. Although the contribution of diabetes and hypertension to the overall CKD burden in the tropics is growing, a significant proportion develop CKD secondary to glomerular diseases, likely infection related, or have CKD of undetermined aetiology. Many patients come to medical attention for the first time with advanced renal failure and few prior symptoms. Most often, these are individuals from poor socioeconomic background and are agriculture or farm workers who work long hours in hot and humid environments. Investigations reveal minimal proteinuria, bland urinary sediment, and smooth contracted kidneys. Kidney biopsies in a few cases have shown bland tubulointerstitial nephritis.

In addition to nephropathies that have a worldwide distribution, some renal lesions have been described solely in residents of tropical countries. These can be broadly grouped under infectious and toxic categories. Causal relationships are suggested by epidemiological studies, demonstration of a temporal relationship between the inciting event (infection, environmental insult, or toxin exposure) and the development of renal manifestations, and by resolution following treatment of the infection or withdrawal of the insult. Improved diagnostic techniques and appropriately designed experimental studies have provided concrete evidence of a cause-​and-​effect relationship in some instances. Examples include establishment of aristolochic acid as the cause of Balkan endemic nephropathy, and identification of specific infections (e.g. scrub typhus, dengue, and leptospirosis) as the cause of undifferentiated febrile syndromes with

21.11  Renal diseases in the tropics

AKI. Confirmation has been obtained by the demonstration of either the organism or microbial antigens in the renal lesions, and elution of specific antibodies in the case of infections, and toxic compounds in the case of plant and animal toxins. In some cases, animal models have provided insight into the genesis of the lesions.

Infectious causes of renal disease in the tropics Table 21.11.1 shows the various tropical infections that can cause kidney injury.

Malarial renal diseases Malaria, caused by members of the protozoan Plasmodium genus, is endemic in the Indian subcontinent, Middle East, East Asia, Table 21.11.1  Tropical infections associated with kidney injury Class

Organism

Nature of renal lesion

Protozoal

Plasmodium malariae

Glomerulonephritis

Plasmodium falciparum

AKI, TMA

Plasmodium vivax and knowlesi

AKI

Schistosoma mansoni

Glomerulonephritis

Wuchereria bancrofti

Glomerulonephritis

Loa loa

Glomerulonephritis

Onchocerca volvulus

Glomerulonephritis

Mycobacterium leprae

Glomerulonephritis, amyloidosis

Mycobacterium tuberculosis

Glomerulonephritis, interstitial nephritis, destructive inflammation, amyloidosis

Salmonella typhi and paratyphi

Glomerulonephritis

Shigella dystenteriae

AKI, TMA

Brucella abortus

AKI

Burkholderia pseudomallei

AKI

Vibrio cholera and vulnificus

AKI

Orient tsutsugamushi

AKI

Campylobacter jejuni

AKI

Dengue haemorrhagic fever

Glomerulonephritis, AKI

Hantaan virus

AKI

Rift valley fever

AKI

Yellow fever

Glomerulonephritis, AKI

Spotted fever

AKI

HIV

Glomerulonephritis, AKI, TMA

Hepatitis B and C

Glomerulonephritis

Bacterial

Viral

sub-​Saharan Africa, and Central America. Of the five species pathogenic to humans, renal lesions have been described following infections with Plasmodium falciparum, P.  vivax, P.  knowlesi, and P. malariae, but not after P. ovale. Glomerulonephritis is the chief complication of P. malariae infection, whereas the others primarily present with AKI. Malarial AKI Less than 1% of all patients with P. falciparum and P. knowlesi infection develop AKI, but the prevalence increases to 60% in those with severe infection. Nonimmune visitors to an endemic area are more likely to develop severe infection than local residents. Malarial AKI has been reported from the Indian subcontinent, Thailand, Malaysia, and Africa. In recent years, AKI has been encountered in association with P. vivax infection, in particular from the Indian subcontinent. Molecular methods have permitted identification of human infection with P. knowlesi, earlier thought to be limited to macaques in Malaysia, Thailand, Vietnam, Myanmar, and Philippines. Clinical features The initial symptoms are nonspecific and consist of malaise, headache, fatigue, muscle aches, fever, and chills. Nausea, vomiting, and hypotension are frequent in nonimmune individuals. Encephalopathy, acute respiratory distress syndrome, and disseminated intravascular coagulation indicate severe infection. AKI is usually seen by the end of the first week and is nonoliguric in 50 to 75% of cases. Haemolytic anaemia and cholestatic jaundice are frequent accompaniments. The so-​called blackwater fever has seen a resurgence among nonimmune European expatriates, probably due to the reintroduction of quinine and mefloquine into the treatment regimen. Individuals with G6PD deficiency can develop severe haemolysis. Renal failure lasts from a few days to several weeks, with an average of 2 weeks. Investigations show azotaemia, hyponatraemia, hyperkalaemia, and lactic acidosis. Diagnosis requires the demonstration of asexual forms of the parasite in peripheral blood smears stained with Giemsa stain or acridine orange. Morphological features of P.  knowlesi infection resemble those of P. falciparum in the early and P. malariae in the late stages, and accurate identification requires the use of molecular techniques. Test kits for rapid diagnosis of malaria on finger-​prick blood samples are commercially available. These depend upon immunochromatographic detection of malaria antigens such as histidine-​rich protein 2 (PfHRP2), lactate dehydrogenase (pLDH) or aldolase (pAldo). Useful in the field, these tests are relatively insensitive at low levels of parasitaemia and for nonimmune populations. Other problems include false positivity and cross-​reactivity between Plasmodium species. Pathology Acute tubular necrosis, characterized by cloudy swelling and degeneration of tubular cells and casts loaded with malarial pigment, is the most prominent finding. Tubular cells contain haemosiderin granules. Varying degrees of interstitial oedema and mononuclear cell infiltrate are also seen.

Rotavirus, Norwalk agent

AKI

Spirochete

Leptospira icterohaemorrhagica

AKI, AIN, CKD

Pathogenesis

Fungus

Zygomycetes spp.

AKI, renal infarction

Kidney injury is attributed to haemorheological changes induced by the parasite that lead to renal ischaemia. P. falciparum merozoites consume and degrade erythrocyte proteins and alter the red cell

AIN, acute interstitial nephritis; AKI, acute kidney injury; CKD, chronic kidney disease; TMA, thrombotic microangiopathy.

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section 21  Disorders of the kidney and urinary tract

membrane, making the erythrocytes more spherical and less deformable. Cup-​shaped, electron-​dense structures that overlie accretions of histidine-​rich P. falciparum erythrocyte membrane protein and extrude an adhesive protein of high molecular weight are expressed on the erythrocyte membrane and mediate attachment to endothelial cells, causing a phenomenon called ‘cytoadherence’. Infected erythrocytes adhere to uninfected red cells, platelets, monocytes, and lymphocytes. P.  falciparum can also activate the alternate complement pathway and intrinsic coagulation cascade. Increased production of endothelin-​1, increased plasma viscosity secondary to an increase in plasma fibrinogen, and rhabdomyolysis also contribute to the AKI. Contributory factors include volume depletion secondary to capillary leak and haemolysis. Studies from Thailand indicate that prior infestation with helminths protects against malarial AKI. Management Severe falciparum malaria requires supportive care in combination with specific antimalarial treatment (see Chapter  8.8.2). Combination therapies, including artemisinin derivatives, are the norm. Careful fluid management is needed in patients with pulmonary oedema. Prognosis The mortality of malarial AKI is 10 to 40%. Late referral, high parasitaemia, multiorgan involvement, and infection in previously unimmunized subjects portend a poor prognosis. Malarial glomerulopathy Before 1980, nephrotic syndrome was encountered during periods of intense transmission of P.  malariae infection among children in western Nigeria, Uganda, Kenya, Côte d’Ivoire, Sumatra, New Guinea, and Yemen, with plasmodium positivity in 40 to 75% of cases. The prevalence of such quartan malarial nephropathy (the term quartan is used because the fever tends to return at 3-​day intervals) has shown a sharp decline with the eradication of malaria, and the entity does not find a mention in recent reports. Clinical features The nephrotic syndrome develops several weeks after the onset of fever. Nonvisible haematuria is noted in about one-​third of cases. Hypertension develops along with decline in renal function. Hypoalbuminaemia is profound, with values commonly less than 1 g/​dl. The serum cholesterol level tends to be normal or low, reflecting low dietary intake. Serum creatinine is usually normal at presentation. Glomerulonephritis in other malaria infections is usually clinically silent, but nonselective proteinuria, nonvisible haematuria, and casts are noted in 20 to 50% of cases with falciparum malaria. Glomerular lesions are seen at autopsy in about 18% of cases who die with P. falciparum and P. knowlesi infections. Pathology and pathogenesis The morphological appearance of quartan malarial nephropathy is of a mesangiocapillary pattern. Demonstration of malarial antigen in the deposits and binding of specific antibody to circulating malarial antigens suggest an immunological basis for the condition. Experimental studies also support this hypothesis. Environmental

factors such as malnutrition or coinfection with Epstein–​Barr virus may be permissive. The liver may act as a source of continuous antigen supply. Mild endocapillary glomerulonephritis has been described in falciparum malaria. Management Once established, quartan malarial nephropathy follows an inexorably progressive course, culminating in renal failure within 2 to 4 years. Antimalarials and steroids have proved ineffective in arresting progression of kidney disease. Remission has been reported occasionally with cyclophosphamide, but there is no improvement in survival. By contrast, glomerulonephritis associated with falciparum malaria resolves within a few weeks of eradication of infection.

Renal disease in schistosomal infections Schistosomiasis is a chronic infection caused by trematodes (blood flukes) and affects over 300 million people in Asia, Africa, and South America. Of the seven species pathogenic to humans, the most prevalent are Schistosoma haematobium (Africa and the Middle East), S.  mansoni (South America and Africa), and S.  japonicum (China and the Far East). S.  haematobium primarily involves the lower urinary tract, whereas S.  mansoni involves the gastrointestinal tract and portal system, leading to hepatic fibrosis and portal hypertension. Schistosomal glomerulopathy Glomerulonephritis has been described in association with hepatosplenic schistosomiasis produced by S.  mansoni. Reports from autopsy series in Brazil during the 1960s were followed by clinical observations from endemic areas of Africa, Saudi Arabia, and Yemen. Proteinuria has been reported in 1 to 22% of patients infected with S. mansoni and 2 to 5% with S. haematobium infection. Subclinical glomerular lesions were found in about 40% of patients with hepatosplenic schistosomiasis. Clinical features Though described at all ages, glomerulonephritis is most frequent in young adults with overt hepatosplenic disease. Males are affected twice as frequently as females. Peripheral oedema and ascites are the hallmarks; hypertension is seen in 50% of cases, appearing late in the disease. Proteinuria is poorly selective and haematuria uncommon. Complement levels are usually low. Nonspecific antibody production is demonstrated by false-​positive rheumatoid factor or the VDRL (Venereal Disease Research Laboratory) tests. It is important to exclude other causes of nephrotic syndrome before attributing the lesions to schistosomiasis. Diagnosis is confirmed by demonstrating viable eggs in the stool or egg-​containing granulomas in rectal or liver biopsies. Pathology Five patterns of glomerular pathology have been described (Table 21.11.2). The class I lesion is the earliest and most frequent, and is the principal lesion in renal allografts with recurrent schistosomal nephropathy. Class  II lesions are more frequent in patients with concomitant salmonella infection. The frequency of class  III lesions varies from 20% in asymptomatic patients to over 80% in those with overt renal disease. The class IV lesion, seen in 15 to 40% of cases, cannot be distinguished from idiopathic focal segmental

21.11  Renal diseases in the tropics Table 21.11.2  Clinicopathological classification of schistosomal glomerulopathy Class

I

II

Light microscopic pattern

Mesangioproliferative Exudative

III A

IIIB

IV

V

Mesangiocapillary type I

Mesangiocapillary type II

Focal and segmental glomerulosclerosis

Amyloidosis

(a) ‘Minimal lesion’ (b) Focal proliferative (c) Diffuse proliferative Immunofluorescence

Mesangial IgM and C3. Schistosomal gut antigens

Endocapillary C3 Schistosomal antigens

Mesangial IgG, IgA, and C3, schistosomal gut antigen

Mesangial and subepithelial IgG and C3, schistosomal gut antigen (early), IgA (late)

Mesangial IgG, IgM, and IgA

Mesangial IgG

Asymptomatic proteinuria

+++

–​

+

+

+

+

Nephrotic syndrome

+

+++

++

+++

+++

+++

Hypertension

±

–​

++

+

+++

±

Progression to endstage renal disease

±

±

++

++

+++

+++

Response to treatment

±

+++

–​

–​

–​

–​

Modified with permission from Barsoum R, Kidney Int 1993.

glomerulosclerosis on the basis of light microscopy, but immunofluorescence reveals IgA deposition. Class  III and IV lesions are seen in patients with fibrotic livers and associated with severe hypocomplementaemia. Class V prevalence varies from 15 to 40%, with a higher frequency in African patients. This form is not usually affected by hepatic fibrosis. Pathogenesis The glomerulopathy is caused by the immunological reaction to specific schistosomal antigens. Antigens have been demonstrated in the glomeruli of baboons infected with S.  mansoni, and circulating immune complexes have been documented in experimental animals and humans with hepatosplenic disease. Circulating complexes localize in mesangial and subendothelial locations, whereas the extramembranous deposits form in situ. Portocaval shunting prevents hepatic processing of worm antigen and delivers it directly into the systemic circulation. IgM antibodies are seen in most patients with hepatosplenic schistosomiasis alone, but circulating mononuclear IgA-​bearing cells and IgA antibodies predominate in those with glomerular involvement. An isotope switch from IgM-​to IgA-​producing B cells is believed to be responsible for this alteration. An aberrant Th2 cytokine response contributes to organ damage. Genetic factors are thought to play a role; polymorphisms in IL13 and STAT6 genes have been associated with disease severity. The immune reaction may be modified by concomitant infection with salmonella, hepatitis viruses, staphylococci, and mycobacteria. Epidemiological studies have shown clearance of urinary abnormalities following therapy for salmonella alone, suggesting a permissive role of this infection. Management Treatment of schistosomal glomerulopathy is disappointing. Antischistosomal drugs (see Chapter 8.11.1) do not alter the clinical course, which is one of inexorable progression to renal failure.

Steroids or cytotoxic agents are similarly ineffective. Salmonella infection should be looked for and treated in all patients. Schistosomiasis involving the lower urinary tract The adult S. hematobium worm resides and lays eggs in the perivesical venous plexus, where they get trapped in the urinary tract mucosa and incite granuloma formation. Clinical manifestations appear when they coalesce into larger granulomata or polyps that ulcerate and bleed. Over time, fibrosis and calcification set in. The presenting feature is painful haematuria, and characteristic ova with terminal spikes may be seen on urinary examination. Later stages are characterized by symptoms related to reduced bladder volume, obstruction to urine flow at the level of bladder outlet or ureterovesical junction, vesicoureteric reflux, or urinary tract infection. Plain radiology may reveal linear or irregular calcification in the bladder wall, ureter, or seminal vesicles (Fig. 21.11.6). Bladder cancer is a complication of chronic schistosomal cystitis, and develops two to three decades after the initial infection in about 5% of all infected individuals. In Egypt, schistosomal eggs are demonstrated in over 85% of resected bladder cancer specimens. Long-​standing obstruction leads to progressive loss of kidney function; 7 to 20% of the endstage renal disease population in Egypt is secondary to lower tract schistosomiasis.

Renal disease in filarial infection Filarial worms are nematodes transmitted to humans through arthropod bites. Clinical manifestations depend upon the location of microfilariae and adult worms in the tissues. Of the eight filarial species that infect humans, Loa loa, Onchocerca volvulus, Wuchereria bacrofti, and Brugia malayi are associated with kidney disease. Loiasis is prevalent in West and Central Africa and manifests with localized allergic inflammation and swelling. Onchocerciasis (river blindness) is characterized by subcutaneous nodules, a pruritic skin rash, sclerosing lymphadenitis, and ocular lesions. Bancroftian and

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Fig. 21.11.6  Plain radiograph of a patient with S. haematobium infection showing calcification of bladder wall. Courtesy of Professor R. Barsoum.

brugia infections cause febrile episodes associated with acute lymphangitis and lymphadenitis, leading to lymphoedema manifesting as hydrocele and elephantiasis. This form of filariasis is endemic in Africa and South and South-​East Asia. Filarial nephropathy Clinical features

Fig. 21.11.7  Photomicrograph of a kidney biopsy showing microfilariae with parallel-​arranged nuclei throughout their length and covered by a sheath on their external aspect in the glomerular capillary lumen in a patient with lymphatic filariasis (arrows) (periodic acid–​Schiff stain, magnification ×100).

developed after selective catheterization and infusion of D. immitis into one renal artery; the contralateral kidney either remained uninvolved or showed minor lesions, suggesting in situ immune complex formation. Diethylcarbamazine treatment, by killing the parasite, may lead to antigen release into the circulation, thus exacerbating the immune process. A temporal relationship between the administration of this agent and the development of proteinuria has been noted.

Urinary abnormalities have been described in 11 to 25% of cases of loiasis and onchocerciasis, with nephrotic syndrome in 3 to 5%. In a survey in an endemic area, proteinuria was detected in over 50% of patients with lymphatic filariasis, with 25% showing a glomerular pattern of protein loss. The frequencies of proteinuria, nonvisible haematuria, and hypertension are significantly higher in patients with chronic sclerosing filariasis than in those with an acute febrile illness or microfilaraemia. False-​positive rheumatoid factor and anti-​DNA and antiphospholipid antibodies have been described.

Good response to antifilarial therapy with diethylcarbamazine is observed in patients with non-​nephrotic proteinuria and/​or haematuria. The response is inconsistent in those with nephrotic syndrome, when deterioration of renal function may continue despite clearance of microfilariae.

Pathology

Chyluria

Light microscopy reveals a gamut of lesions, including minimal-​ change disease and focal segmental glomerulosclerosis, and mesangial proliferative, mesangiocapillary, and chronic sclerosing glomerulonephritis. Diffuse basement membrane thickening with endocapillary proliferation is the commonest finding. Mononuclear interstitial infiltration and microinfarcts around blood vessels have been demonstrated in patients with loiasis. Microfilariae may be found in the glomerular capillary lumina (Fig. 21.11.7), tubules, and interstitium. Electron microscopy shows widely spaced subepithelial, subendothelial, and intramembranous deposits and spikes. O. volvulus and B. malayi antigens, along with IgM, IgG, and C3 have been demonstrated.

Lymphatic filariasis secondary to W. bancrofti or B. malayi infections leads to fibrosis of lymph glands and dilatation of draining lacteals. Under pressure, the dilated retroperitoneal lacteals rupture into the low-​pressure urinary system, leading to leakage of lymph in urine. The presentation is characterized by passage of milky white urine (Fig. 21.11.8), with or without haematuria. Patients complain of backache, probably caused by distended vessels. Formation of chylous clots may result in acute urinary retention. Prolonged chyluria results in the loss of protein, fat, and lymphocytes in the urine, leading to hypoproteinaemia and lymphopenia. Urinalysis shows proteinuria, and—​if the history of change in urine colour is not elicited—​an erroneous diagnosis of nephrotic syndrome might be made, prompting an unnecessary kidney biopsy. About 80% of cases respond to treatment with diethylcarbamazine and dietary modification. Sclerotherapy using local instillation of povidone iodine, hypertonic dextrose, or silver nitrate is required for resistant cases (or less commonly surgery).

Pathogenesis Glomerulonephritis is likely immune complex mediated. The levels of circulating immune complexes correlate with the adult worm burden. Dogs infected with Dirofilaria immitis develop glomerular lesions similar to human filariasis: glomerular lesions

Management

21.11  Renal diseases in the tropics

(a)

(b)

Fig. 21.11.8  Panel (a) shows milky white urine in a patient with chyluria secondary to lymphatic filariasis and panel (b) shows filling up of ruptured lacteals on retrograde pyelogram.

Renal disease in leprosy Leprosy is a chronic granulomatous disorder caused by the acid-​fast bacillus Mycobacterium leprae. Nephritis was an important cause of death until the 1950s, but is now rare. The main renal lesions encountered are glomerulonephritis, secondary amyloidosis, and tubulointerstitial nephritis. Glomerulonephritis The incidence of glomerulonephritis in leprosy is now less than 2%, but old autopsy series showed lesions in over 50% of cases. Most cases are seen in patients with multibacillary disease and during episodes of erythema nodosum leprosum. Clinical presentation may be as nephrotic syndrome, acute nephritic syndrome, or rapidly progressive renal failure. Hypocomplementaemia is common, and circulating cryoglobulins may be present. Mesangial proliferative and diffuse proliferative glomerulonephritis are the commonest histological lesions. Electron microscopy reveals electron-​dense deposits in the mesangial and subendothelial regions, focal foot-​process widening, glomerular capillary basement membrane reduplication with mesangial interposition, and endothelial cytoplasmic vacuolation. Immunofluorescence reveals granular IgG and C3 deposits in the mesangium and along capillary walls. Circulating immune complexes can be detected in 30 to 75% of patients, and can be of mycobacterial origin or dapsone:antidapsone antibodies. Alternate pathway complement activation by cryoprecipitates can also contribute. Steroids or antileprosy drugs have no effect on the course of glomerular disease. Prednisolone may hasten the recovery of renal function in patients with renal failure during episodes of erythema nodosum leprosum. Amyloidosis Amyloid was documented in 55% of cases in older autopsy and biopsy studies in leprosy cases from the United States of America, 31% from Brazil, and less than 10% from Mexico, Africa, and India. The amyloid is of AA type and is far more frequent in lepromatous than nonlepromatous leprosy. Erythema nodosum leprosum further increases the risk as each episode is associated with a marked elevation

of serum amyloid A protein. Patients with tuberculoid leprosy who have long-​standing and infected trophic ulcers can also develop this complication.

Renal disease in tuberculosis Tuberculosis is endemic throughout the tropics. Concerted efforts to contain the disease have been thwarted by the HIV epidemic and treatment default, leading to a rise in drug-​resistant disease. Seen in less than 10% of all cases with tuberculosis, urinary tract involvement is a relatively late manifestation of disease. Common presenting features are irritative lower urinary symptoms suggestive of infection as a result of ureteric and bladder involvement secondary to seeding of M. tuberculosis into the urine. Urinalysis shows pus cells, but cultures are repeatedly sterile. The presence of sterile pyuria or failure of symptoms to respond to conventional antibacterial treatment should raise the possibility of urinary tract tuberculosis. Systemic symptoms like fever, night sweats, and weight loss are helpful diagnostic clues when present. Only about one-​third of patients show simultaneous pulmonary involvement. Involvement of renal parenchyma takes the form of granulomatous interstitial nephritis and caseous destruction, culminating in small nonfunctioning and often calcified kidneys. An association with glomerulonephritis was postulated in the pre-​antibiotic era, but only occasional recent reports have described immune complex glomerulonephritis and dense-​deposit disease in tuberculosis. A well-​known complication, however, is amyloidosis, which is still seen in a significant proportion of patients in poor countries where the disease remains untreated for long periods. Once established, the course of amyloidosis is unaffected by treatment of the underlying tuberculosis. Imaging (Fig. 21.11.9) provides important diagnostic clues, with about 30% showing dystrophic calcification of the urinary tract (bladder and ureteric walls, or—​ less commonly—​ renal parenchyma). Involvement of the excretory system is delineated better by intravenous urography, CT, or magnetic resonance imaging which shows thickening, irregularity or narrowing of involved segments, and cavities or mass effects secondary to necrosis. Fibrosis and

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of the second week, and may last longer than that associated with other causes of AKI. Recent studies suggest that leptospiral infection can persist in humans and may have long-​term adverse effects on kidney function. Molecular techniques have shown asymptomatic urinary shedding of leptospira in areas of high disease transmission, including in those without serological evidence of recent infection. In a recent population-​based study, individuals with previous leptospira exposure had a higher prevalence of CKD stages 3 to 5. Further, those with a higher antibody titre showed a greater decline in estimated glomerular filtration rate on follow-​up. Diagnosis

Fig. 21.11.9  Intravenous pyelogram in a patient with renal tuberculosis. The left kidney is hydronephrotic and the right kidney is nonfunctioning and shows punctuate calcification of the dilated pelvicalyceal system. Courtesy of Professor John Eastwood.

contraction of the bladder gives rise to reduction in capacity—​the classical ‘thimble bladder’. Extrarenal spread can also be identified on imaging. Patients with advanced and bilateral disease have a reduced glomerular filtration rate due to generalized destruction of the parenchyma, but a more common cause for renal failure is urinary tract obstruction due to scarring of the lower tract. Management requires institution of antitubercular therapy according to local guidelines. Obstructive lesions that fail to respond to therapy require surgical correction, including urinary diversion and bladder augmentation surgery.

Renal disease caused by leptospirosis Leptospirosis, the most widespread zoonosis in the world, is an occupational hazard in fishermen, coal miners, and sewage, abattoir, and farm workers throughout the tropics. The pathogenic Leptospira interrogates complex has 30 serogroups and 240 serotypes. Leptospira are shed in the urine by the animal hosts (rats, mice, gerbils, hedgehogs, foxes, dogs, cattle, sheep, pigs, and rabbits) and survive for several weeks in a moist environment. Human infection occurs upon exposure of abraded skin and exposed mucosae to contaminated water, soil, or vegetation. Clinical features Leptospirosis occurs in both sexes and in all age groups. The incidence peaks during or soon after the rainy season, especially following floods. The disease starts with fever, chills, headache, severe muscle aches and tenderness, and dry cough, which terminate with defervescence after 4 to 10 days. Organ involvement is seen in the second phase and takes the form of AKI, cholestatic jaundice, and haemorrhagic manifestations (Weil’s syndrome). AKI occurs in 20 to 85% of cases and is oliguric in 40 to 60%. It is typically mild and nonoliguric in anicteric patients. Renal magnesium and phosphate wasting is common. Diuresis ensues by the end

Diagnosis is based on culture or serology. The organisms can be grown on Fletcher’s or Stuart’s semisolid media from blood during the first phase, and later from urine. Antileptospiral antibodies are detectable in the second phase. A single titre of greater than 1:400 or a fourfold increase is taken as significant. A macroscopic agglutination test or a slide test can be used to screen patients, but these are not specific. The gold standard is the complex microscopic agglutination test that requires maintenance of live leptospira cultures. Other tests include an IgM-​specific dot enzyme-​linked immunosorbent assay (ELISA), complement fixation, serum and salivary ELISA, rapid IgM dipstick ELISA, and gold immunoblot tests. Lately, nucleic acid-​based testing has allowed identification of greater number of cases. Pathology Grossly, the kidneys are swollen and bile stained. The main light-​ microscopic lesion is a tubulointerstitial nephritis, with mononuclear cells and eosinophilic infiltration. Mild and transient mesangial proliferative glomerulonephritis with C3 and IgM deposition is occasionally noted. Pathogenesis Renal involvement results from direct invasion of the renal tissue by the organism and liberation of bacterial enzymes, metabolites, and endotoxins. Addition of leptospira endotoxin to human macrophages induces release of tumour necrosis factor-​α (TNFα). Proximal convoluted tubules show a decrease in expression of sodium/​hydrogen exchanger isoform 3, aquaporin 1, and α-​Na+,K+-​ ATPase. The glycoprotein component of the endotoxin inhibits the renal Na+,K+-​ATPase and apical Na+–​K+–​Cl− cotransporter, leading to potassium wasting. Leptospiral outer membrane proteins have been localized to the proximal tubules and interstitium of infected animals. Recent studies have suggested the involvement of Toll-​like receptor, leading to activation of NF-​κB and mitogen-​activated protein kinases, and enhanced message for inducible nitric oxide synthase, monocyte chemoattractant protein-​1 and TNFα. Leptospiral outer membrane proteins may also induce activation of the transforming growth factor-​ β/​SMAD-​associated fibrosis pathway, leading to accumulation of extracellular matrix. Management Leptospirosis is a self-​limiting disease, and mild cases recover spontaneously. The emphasis is on symptomatic measures, together with correction of hypotension and fluid and electrolyte imbalance. Antibiotic therapy can shorten the duration of fever and hasten amelioration of leptospiruria. Adverse prognostic factors include

21.11  Renal diseases in the tropics

advanced age, pulmonary complications, hyperbilirubinaemia, diarrhoea, hyperkalaemia, and the presence of other infections.

Kidney injury in scrub typhus Scrub typhus, caused by Orientia tsutsugamushi, a Gram-​negative α-​proteobacterium of family Rickettsiaceae, is endemic in Asia, with an estimated 1 million cases occurring annually. The infection is maintained in nature by transovarian transmission in trombiculid mites. Human involvement occurs when people get bitten by infected larvae, leading to inoculation of organisms into the skin. The World Health Organization identifies scrub typhus as a re-​ emerging disease in South-​East Asia and the South-​Western Pacific region, with a fatality rate of 30% in untreated cases. Until recently, renal involvement due to scrub typhus had not received much attention, and a recent systematic review could only find a few case reports specifically describing AKI. However, recent studies from India have shown renal abnormalities in 70 to 80% of cases, and about 50% exhibit AKI, which is an independent predictor of mortality. Vascular endothelial cell injury is thought to be the predominant mechanism. Renal biopsies have shown mild mesangial hyperplasia, acute tubular necrosis, or tubulointerstitial nephritis.

abscesses. Characteristic broad, aseptate hyphae can be demonstrated in material obtained by needle aspiration or biopsy. The only definitive treatment is extensive debridement of affected tissue, which may include bilateral nephrectomy and systemic amphotericin B therapy. This condition carries an extremely poor prognosis. HIV infection Most individuals affected with HIV infection live in the tropical countries of Africa and South Asia. The frequency of renal involvement varies widely in different geographic areas and races, with less than 5% in Asia and Latin America and 25 to 50% in Africa. Renal lesions can be as a direct result of the HIV infection, or indirectly secondary to treatment or associated conditions (Table 21.11.3 and Fig. 21.11.11).

Table 21.11.3  Renal manifestations in of HIV infection Direct renal effects associated with HIV infection Acute kidney injury

• Volume loss (e.g. gastroenteritis, pancreatitis)

Other infective causes of renal disease

• Infections

Zygomycosis

• Myocardial dysfunction (e.g. cardiomyopathy)

Zygomycosis (syn. mucormycosis) is an opportunistic infection caused by the saprophytic fungi of the order Mucorales and genera Rhizopus, Absidia, and Rhizomucor. The spores gain entry into the body through inhalation or cutaneous breach. The fungus primarily spreads through vascular route, leading to thrombosis of large and small arteries and infarction and necrosis of the affected organ. Primary renal zygomycosis has been described from several tropical countries. Patients present with high fever, lumbar pain, pyuria, and oliguric AKI. The initial route of entry of the organism is often uncertain. Diagnosis requires a high index of suspicion and use of imaging. Ultrasonography reveals enlarged kidneys. CT scan appearance is often diagnostic and shows large kidneys with perinephric stranding, large nonenhancing areas indicating infarction (Fig. 21.11.10), along with perirenal and/​or intrarenal

• Liver failure (HIV cholangiopathy or

coinfection with hepatitis B and/​or C); hepatorenal syndrome

Chronic kidney disease

• HIV-​associated nephropathy (HIVAN) • HIV immune complex glomerulonephritis

Electrolyte and acid–​base disorders

• Hyponatraemia (related to SIADH, volume depletion, and adrenal insufficiency)

• Hypernatraemia (related to dehydration) • Hyperkalaemia (related to renal dysfunction, trimethoprim, or IVI pentamidine use and adrenal insufficiency)

• Hypokalaemia (related to diarrhoea and amphotericin B therapy)

• Metabolic acidosis (lactic acidosis secondary

to tissue hypoperfusion, stavudine use or liver disease or kidney failure)

Indirect renal involvement Acute kidney injury

• Toxins, especially traditional herbal medications

• Analgesics, especially nonsteroidal anti-​inflammatory drugs

• Antiretroviral agents, especially tenofovir

(tubular toxicity), ritonavir (exacerbates tenofovir nephrotoxicity), indinavir (crystal formation and obstruction), and stavudine (lactic acidosis and/​or pancreatitis)

Chronic kidney disease

• Metabolic syndrome associated with antiretroviral drug use

• Other chronic kidney disease with incidental HIV infection

Fig. 21.11.10  Contrast-​enhanced CT of the abdomen showing almost complete nonenhancement of the left and minimal patchy contrast enhancement of the right renal parenchyma (suggesting infarction), along with bilateral perinephric stranding (arrows) in a patient with AKI due to bilateral mucormycosis.

IVI, intravenous infusion; SIADH, syndrome of inappropriate antidiuretic hormone secretion. Reproduced with permission from Naicker S, Paget G. HIV and renal disease. In: Turner N, Lameire N, Goldsmith DJ, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Copyright © 2015 Oxford University Press.

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Fig. 21.11.11  Photomicrograph of a patient with HIV-​associated nephropathy showing glomerular collapse, focal sclerosis, and microcytic dilatation of tubules. Reproduced with permission from Naicker S, Paget G. HIV and renal disease. In: Turner N, Lameire N, Goldsmith DJ, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Courtesy of Prof Stewart Goetsch, University of the Witwatersrand.

The presentation of renal disease in HIV infection is the result of a complex interplay between the pheno-​and/​or genotypic variants of the virus, the genetic make-​up of the host, and environmental factors. The viral genes nef and var increase podocyte proliferation and dedifferentiation, and alter podocyte protein expression. HIV-​1 infection induces tubular injury by triggering an apoptotic pathway involving caspase activation and FAS up-​ regulation. Release of a variety of cytokines also affects podocytes and tubular cells. HIV-​associated nephropathy also shows a strong genetic predilection:  people of African ancestry exhibit a 20-​fold increase in relative risk compared with individuals of Caucasian descent. The differential risk has been traced to the presence of pathogenic variants of MYH9 and APOL1 gene variants in this population. A number of studies have shown a direct link between the viral load and development as well as progression of kidney disease. Use of highly active retroviral therapy has had a favourable effect on disease course.

Toxic causes of renal disease in the tropics

Fig. 21.11.12  Contrast-​enhanced CT of the abdomen in a patient with AKI following an Echis carinatus bite showing acute cortical necrosis. The nonenhancing zone of necrotic cortex is limited by the enhancing subcortical rim on the outside (arrows) and the medulla on the inside (arrowheads).

Clinical features The initial symptoms are pain and swelling of the bitten part, followed by blister formation and ecchymosis. Bleeding—​as ooze from fang marks, haematemesis, melaena, or haematuria—​is seen in 65% of cases. Sea-​snake bites cause myonecrosis, which manifests as muscle pains and weakness. Renal failure sets in from within a few hours to as late as 4 days after the bite, and is usually oliguric. A history of passage of ‘Coca-​ Cola’-​ coloured urine, indicating intravascular haemolysis, is obtained in about one-​half of cases, and over 90% show oliguria. Life-​threatening hyperkalaemia may develop in patients with haemolysis or myonecrosis. With effective management, oliguria resolves in 5 to 21 days; persistence indicates the likelihood of renal cortical necrosis (Fig. 21.11.12). Pathology Grossly, the kidney are swollen and exhibit petechial haemorrhages. Light microscopy shows acute tubular necrosis in 70 to 80% of cases. Interstitial oedema, inflammatory cell infiltration, and scattered haemorrhages may be seen. Electron microscopy reveals dense intracytoplasmic bodies in the proximal tubules representing degenerated organelles. Other lesions include acute interstitial nephritis, thrombotic microangiopathy, necrotizing arteritis, and crescentic glomerulonephritis. Acute cortical necrosis is seen in 20 to 25% of cases.

Snake venoms

Pathogenesis

Most of the 450 venomous snake species are found in the tropical and subtropical regions. Renal lesions have been reported following bites by snakes belonging to classes Viperidae (Russell’s viper, saw-​ scaled viper, puff adder, pit viper, and rattlesnakes), Colubridae (boomslang, Bothrops jararaca, gwardar, dugite, and Cryptophis nigrescens), and Hydrophidae (sea snakes). AKI is the most frequent and clinically important effect of envenomation on the kidneys, with most cases seen following viper and sea snake bites. In India, about 13 to 32% of those bitten by Echis carinatus (Russell’s viper) develop AKI. The reported incidence from other countries varies between 1 and 27%.

Renal damage is a cumulative effect of direct nephrotoxicity of venom, hypovolaemia, haemolysis, myoglobinuria, and disseminated intravascular coagulation. Injection of snake venom leads to increased excretion of tubular enzymes in rats. Administration of Russell’s viper venom led to a dose-​dependent decrease in inulin clearance in isolated perfused rat kidney. Destruction of the glomerular filter, lysis of vessel walls, mesangiolysis, and tubular injury have been shown in experimental models. A vasculotoxic factor has been isolated from the venoms of several snakes. Similarities have been noted between the structure of the potent vasoconstrictor endothelin-​1 and the venom of the Israeli burrowing asp.

21.11  Renal diseases in the tropics

Hypotension and circulatory collapse can result from blood loss, release of kinins, or depression of the medullary vasomotor centre or myocardium. Kininogenases are present in crotalid venom. Viper palastinae venom produces depression of the medullary vasomotor centre, whereas Bitis arietans venom causes myocardial depression, arteriolar dilatation, and increased vascular permeability. Phospholipase A  and a basic protein called ‘direct lytic factor’ present in Russell’s viper and E.  carinatus venoms cause intravascular haemolysis and disseminated intravascular coagulation. Microangiopathic haemolytic anaemia can develop following A. rhodostoma, Russell’s viper, E. carinatus, puff adder, and guarder bites. Viper venom activates the coagulation cascade at several levels, leading to rapid thrombin formation.

Other conditions AKI has been reported following stings by scorpion, jellyfish, and giant centipede. Scorpion stings result in disseminated intravascular coagulation and internal bleeding, and these can give rise to intravascular haemolysis.

Plant toxins

The mainstay of management is prompt antivenom administration to cases with evidence of systemic envenomation or local inflammation involving more than 50% of the limb circumference. There is no agreement on the exact dose needed, or duration of therapy. A rule of thumb is to continue administration until the effects of systemic envenoming disappear as shown by normalization of the whole-​blood clotting time. Concomitant measures include replacement of lost blood, maintenance of electrolyte balance, administration of tetanus immunoglobulin, and adequate treatment of pyogenic infection. Maintenance of a high urinary output, as well as alkalinizing the urine, may attenuate renal damage in those with haemolysis.

Tropical communities consume products derived from locally grown plants, either as food or as medicines, and many of these contain nephrotoxic substances. Exposure may be accidental, when a toxic plant is mistaken for an edible one. The insult can be identified quickly when the presentation is acute, but the cause–​effect relationship may be harder to establish in the case of slowly progressive kidney disease. Traditional medicines constitute a special class of nephrotoxins among poor populations in tropical Africa and Asia. In African hospitals, more than 75% of all deaths from acute poisoning and 25 to 60% of all AKI from medical causes are due to traditional medicines. These agents are obtained from traditional healers (‘witch-​doctors’), who wield considerable power. Administration is either by the oral route or as enemas, the latter consisting of mixtures of herbs, barks, roots, leaves, and bulbs, administered through a truncated cow’s horn or hollow reed. Increasing urbanization and industrialization have introduced potent chemicals (e.g. paint thinners, turpentine, chloroxylenol, ginger, pepper, soap, vinegar, copper sulphate, and potassium permanganate) into their armamentarium. AKI has been reported following the use of such enemas: detailed studies are not available, but histology usually shows acute tubular necrosis.

Other animal toxins

Callilepis laureola (impila) poisoning

Bee, wasp, and hornet stings

C. laureola, a herb with a tuberous rootstock, grows in several countries in sub-​Saharan Africa. An extract of the tubers is taken orally or as an enema as a traditional remedy, and is a common cause of AKI in the black South African population. Symptoms appear within 24 h in 40% and within 4 days in 70% of patients. Children and older people show earlier and more severe abnormalities. Abdominal pain and vomiting are followed by hypoglycaemia, convulsions, and jaundice. Histology shows acute tubular necrosis and/​or interstitial infiltration. Atractyloside, an alkaloid in the tuber of the plant, inhibits ATP synthesis and is believed to have nephrotoxic and hypoglycaemic effects. Gastrointestinal fluid loss contributes to the renal dysfunction. Treatment is supportive and includes correction of hypoglycaemia and volume and electrolyte replacement. The mortality rate is over 50%.

Management

Stinging insects belonging to the order Hymenoptera, such as honeybees, yellow jackets, hornets, and paper wasps, are found in most tropical countries. Systemic symptoms develop when an individual is attacked by a swarm of insects and receives a large dose of venom. Manifestations include vomiting, diarrhoea, hypotension, and loss of consciousness. AKI is secondary to haemolysis, rhabdomyolysis, or both. Haemolysis results from the action of a basic protein fraction, melittin, and phospholipase A.  Rhabdomyolysis has been attributed to polypeptides, histamine, serotonin, and acetylcholine. Experimental studies have suggested a direct nephrotoxic role of venom components. Renal biopsy invariably reveals acute tubular necrosis. Carp and sheep bile Acute hepatic and renal failure have been reported following consumption of the raw gallbladder or bile of freshwater and grass carps (Ctenophryngodon idellus, Cyprus cardio, Hypophythalmichthys molitrixn, Mylopharyngodon pisces, and Aristichthys nobles) in Taiwan, South China, Hong Kong, Japan, India, and South Korea, and sheep bile in the Middle East. Initial symptoms include abdominal pain, nausea, vomiting, and watery diarrhoea. Hepatocellular jaundice and AKI occur 48 h after ingestion. Haematuria is noted in 75% of cases. The duration of renal failure ranges from 2 to 3 weeks. Manifestations vary depending upon the varieties of carp and amount of bile ingested. Histology reveals acute tubular necrosis and interstitial oedema.

Djenkol bean poisoning Djenkol beans (Pithecolobium lobatum and P.  jiringa, family Mimosaceae) are considered a delicacy in Indonesia, Malaysia, southern Thailand, and Myanmar (Burma). AKI can occur when raw beans are consumed in large amounts with low fluid intake, and nephrotoxicity has been reported most commonly in the rainy season from Malaysia and Indonesia. Symptoms include dysuria, lumbar pain, hypertension, haematuria, and oligoanuria. The breath and urine emit a characteristic sulphuric odour. Urinalysis shows needle-​like crystals of djenkolic acid, a sulphur-​rich cysteine thioacetal of formaldehyde that forms in the concentrated acidic urine of the distal tubules. Individual susceptibility to the toxic

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effects is variable, possibly related to hydration status or variability in activity of metabolizing enzymes. High fluid intake and urinary alkalinization helps in dissolving the crystals. Most victims recover within a few days. Chronic ingestion can lead to development of djenkolic acid stones. Mushroom poisoning Less than 1% of all mushrooms are toxic. AKI has been observed following the ingestion of mushrooms of the genera Amanita, Galleria, Cortinarius, and Inocybe. Amanita phalloides (death cap) and A. virus (destroying angel) grow commonly in lawns, pastures, on living trees, in basements, plasterboard walls, and flower pots, and may be picked and ingested by inexperienced collectors and children. Initial symptoms are related to the gastrointestinal tract and may result in dehydration and hypotension. The toxic compounds (phallotoxin, amatoxin) inhibit RNA polymerase. Hepatic and renal failure develops after a couple of days. Renal histology shows acute tubular necrosis. Management is supportive; charcoal haemoperfusion is effective in clearing α-​amanitin from circulation and may improve outcome. Overall mortality is over 50%, and exceeds 70% in children. Long-​term ingestion of cortinarius mushrooms has been implicated in chronic renal failure. Details of other toxic plants that have been associated with development of kidney diseases are described in Table 21.11.4.

Chemical nephrotoxins Increasing industrialization has facilitated the access of the poor and poorly educated populations of tropical countries to a variety of chemicals. Poisonings have been reported after accidental ingestion or following attempted suicide or homicide. AKI is a manifestation of toxicity of many of these agents, such as copper sulphate, ethylene glycol, paraphenylenediamine (PPD), paraquat, ethylene dibromide, and hexavalent chromium compounds. Ethylene glycol Ethylene glycol is used as an organic solvent, antifreeze, preservative, and glycerine substitute. It is metabolized in the liver to glyoxylic acid and oxalate, which combines with calcium and gets deposited in the acid milieu of renal tubules as calcium oxalate crystals, leading to AKI. Epidemics of ethylene glycol poisoning in children as a result of substitution of nontoxic propylene glycol with toxic di-​and polyethylene glycols as a vehicle in paediatric syrup preparations have been reported from tropical countries including India, Bangladesh, Nigeria, South Africa, and Haiti. The mortality is high due to underlying diseases and delayed diagnosis:  236 deaths were recorded among 339 children with AKI in Bangladesh during one such epidemic. Paraphenylenediamine PPD is a widely used chemical in Africa, Middle East, and Indian subcontinent as a textile, fur, or hair dye, to colour cosmetics, for temporary tattoos, photographic development, and in gasoline. It is a well-​known skin irritant and may be absorbed from the skin. Being cheap and widely available, it is also used for suicidal purposes. Clinical manifestations include cervicofacial oedema,

chocolate brown-​coloured urine, oliguria, muscular oedema, and shock. The most common renal presentation is as oliguric AKI, perhaps secondary to direct toxicity, rhabdomyolysis, and hypovolaemia, and PPD toxicity is a common cause of AKI in parts of the Indian subcontinent and Africa. Treatment is mostly supportive. Antihistamines and steroids are used in the management of airway oedema. Alkaline diuresis is tried in those with myoglobinuria. PPD is not dialysable. Copper sulphate Copper sulphate is commonly used as a pesticide, in the leather industry, and in making home-​made glue. Its blue colour makes it attractive to children, with risk of inadvertent poisoning, and it is used for suicidal purposes in the Indian subcontinent. Initial symptoms of copper sulphate poisoning consist of a metallic taste, increased salivation, burning retrosternal pain, nausea, vomiting, diarrhoea, haematemesis, and melaena. Jaundice, hypotension, convulsions, and coma indicate severe poisoning. Acute pancreatitis, myoglobinuria, and methaemoglobinaemia have also been reported. Oliguric AKI develops in 20 to 25% of cases and is frequently associated with passage of dark (Coca-​C ola)-​coloured urine, indicating intravascular haemolysis, the risk of which is increased in genetic G6PD deficiency. Renal histology shows acute tubular necrosis with abundant pigmented haemoglobin casts indicating haemoglobinuria. Acute cortical necrosis occurs rarely. Dialysis may be required for renal failure, but is ineffective in clearing copper from the body.

Future challenges In the coming years, tropical societies will face major impacts of climate change and water scarcity on kidney health. Changes in air and ocean temperature will make their impact felt in the tropics during the course of next 10 years, long before changes are noted in the temperate regions. Temperatures in excess of 50°C are already being recorded regularly in the tropics. The number of tropical cyclones is rising year on year. According to the United Kingdom-​based risk analysis firm Maplecroft, the top 10 countries at ‘extreme risk’ from climate change are all tropical countries. The kidneys are particularly vulnerable to the effects of climate change. Dehydration secondary to heat stress will increase the risk of acute as well as chronic kidney injury. Unpredictable rainfall, as seen in the Indian state of Tamil Nadu in 2015, is likely to lead to the re-​emergence of water-​borne and vector-​borne infectious diseases, nullifying the past gains made in infection control. Changes in climate and biodiversity have been linked to increases in zoonotic and vector-​borne disease outbreaks. Changes in vector ecology and water quality will increase the risk of the re-​emergence of previously contained infections or of the emergence of new infections in the tropics. Potential changes in the virulence of organisms is also a possibility, as shown by the emergence of kidney injury in vivax malaria, once considered benign, and of kidney injury in scrub typhus. Degradation of the ecosystem, with air and water pollution, will increase the risk of exposure to environmental toxins.

21.11  Renal diseases in the tropics Table 21.11.4  Plant nephrotoxins in the tropics Plant

Reported from

Active molecule

Renal manifestations

Other manifestations

Averrhoa bilimbi (irumban puli)

South India

Oxalic acid

Intratubular obstruction

Averrhoa carambola (star fruit)

Hong Kong, Taiwan

Oxalate

Intratubular precipitation of oxalate crystals

Vomiting

Callilepis laureola (impila)

Sub-​Saharan Africa

Atractyloside

ATN

Abdominal pain, diarrhoea, vomiting, jaundice, seizures, and coma

Catha edulis (khat leaf)

East Africa, Arab peninsula

S-​cathione, ephedrine

ATN

Hepatotoxicity

Cleistanthus collinus (oduvan)

India

Cleistanthin A and B, collinusin, diphylline

AKI

Hypotension, hypokalaemia, arrhythmia

Colchicum autumnale (meadow saffron)

Turkey

Colchicine

ATN

Haemorrhagic gastroenteritis, muscle paralysis, respiratory failure

Crotalaria laburnifolia (bird flower)

Zimbabwe, Sri Lanka

Pyrrolizidine alkaloids

ATN, HRS

Hepatic veno-​occlusive disease, pulmonary injury, thrombocytopenia

Cupressus funebris Endl (mourning cypress)

Taiwan

Flavonoid

ATN, AIN

AHF, haemolytic anaemia, thrombocytopenia

Dioscorea quartiniana and D. quinqueloba (yam)

Africa, Asia

Dioscorine, dioscin

ATN

Convulsions, encephalopathy

Dodonaea angustifolia (sand olive)

South Africa

Unknown

AIN

Pulmonary embolism

Euphorbia metabelensis, E. paralias (spurge)

Zimbabwe

Irritant chemicals in plant latex

ATN

Thrombocytopenia

Glycyrrhiza glabrata (liquorice)

Several countries

Glycyrrhizic acid

ATN

Rhabdomyolysis, hypokalaemia, hypertension, cardiac arrhythmia

Larrea tridentate (chaparral)

Chile, South Africa

Nordihydroguaiaretic acid, s-​quinone

Renal cysts, renal cell carcinoma

Hepatic failure

Lawsonia alba (henna)

Middle east, North Africa, Pakistan

2-​hydroxy-​1,4-​ naphthoquinone

ATN

Haemolysis

Pithecolobium lobatum and Pithecolobium jiringa (djenkol) beans

South East Asia

Djenkolic acid

Intratubular obstruction and ATN

Lumbar and lower abdominal pain, hypertension

Propolis

Brazil, Taiwan

Unknown

AIN

Contact dermatitis

Rhizoma rhei

Hong Kong

Anthraquinones (emodin, aloe-​emodin)

AIN

None

Securidacea longepedunculata (violet tree, wild wisteria)

Congo, Zambia, Zimbabwe

Methylsalicylate, securinine, ATN saponins

Vomiting, diarrhoea

Sutherlandia frufesces (cancer brush), Dodonaea angustifolia

South Africa

Unknown

AIN

Pulmonary embolism

Takeout roumia

Morocco, Sudan

Paraphenylenediamine

ATN

Rhabdomyolysis

Taxus celebia (Chinese yew)

Asia

Flavonoid

ATN, AIN

Hepatitis, haemolysis, DIC

Thevetia peruviana (yellow oleander)

India, Sri Lanka

Cardiac glycosides

ATN, mesangiolysis

Liver failure, cardiac arrhythmias

Tribulus terrestris

USA, Iran

Unknown

ATN, AIN

Liver failure, encephalopathy

Tripterygium wilfordii Hook F (thunder god vine)

Taiwan

Triptolide

ATN

Diarrhoea, shock

Uncara tomentosa (cat’s claw)

Peru

Alkaloids, flavonols

AIN

Diarrhoea, hypotension, bruising, bleeding gums

AHF, acute hepatic failure; AIN, acute interstitial nephritis, AKI, acute kidney injury; ATN, acute tubular necrosis, DIC, disseminated intravascular coagulation; GI, gastrointestinal; HRS, hepatorenal syndrome.

A decreased ability to excrete, secondary to dehydration, will lead to higher concentrations of such toxins in the kidney, with adverse consequences on kidney health. Combating these challenges will require concerted action on medical as well as societal and political fronts. Anticipating the upcoming challenges and fortifying the health system to address these in a timely manner is a challenge that needs to be tacked urgently.

FURTHER READING Araujo ER, et  al. (2010). Acute kidney injury in human leptospirosis: an immunohistochemical study with pathophysiological correlation. Virchow Arch, 456, 367–​75. Barber BE, et al. (2013). A prospective comparative study of knowlesi, falciparum, and vivid malaria in Sabah, Malaysia: high proportion with severe disease from Plasmodium knowlesi and Plasmodium

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vivid but no mortality with early referral and artesunate therapy. Cain Infect Dis, 56, 383–​97. Barsoum R (2000). Malarial acute renal failure. J Am Soc Nephrol, 11, 2147–​54. Barsoum R (2004). The changing face of schistosomal glomerulopathy. Kidney Int, 66, 2472–​84. Chugh KS, et al. (1994). Acute renal cortical necrosis—​a study of 113 patients. Ten Fail, 16,  37–​47. Cruz LS, et  al. (2009). Snakebite envenomation and death in the developing world. Ethn Dis, 19 Suppl 1, S42–​6. Correa-​Rotter R, et  al. (2014). CKD of unknown origin in Central America: the case for a Mesoamerican nephropathy. Am J Kidney Dis, 63, 506–​20. Daher EF, et al. (2010). Clinical presentation of leptospirosis: a retrospective study of 201 patients in a metropolitan city of Brazil. Bras J Infect Dis, 14,  3–​10. Das BS (2008). Renal failure in malaria. J Vector Borne Dis, 45,  83–​97. Da Silva Junior GB, et al. (2006). Renal involvement in leprosy: retrospective analysis of 461 cases in Brazil. Bras J Infect Dis, 10, 107–​12. Eastwood J, et  al. (2015). Mycobacterial infections:  tuberculosis. In: Turner N, et al. (eds) Oxford textbook of clinical nephrology, 4th edition, pp. 1620–​4. Oxford University Press, Oxford. Isnard A, et al. (2008). Recent advances in the characterisation of genetic factors involved in human susceptibility to infection by schistosomiasis. Cure Genomics, 9, 290–​300. Jayakumar M, et  al. (2006). Epidemiological trend changes in acute renal failure—​a tertiary centre experience from South India. Ten Fail, 28, 405–​10. Jha V (2015). ESRD burden in South Asia: the challenges we are facing. Clin Nephrol, 83,  7–​10. Jha V, Chugh KS (2008). Acute kidney injury in Asia. Semi Nephron, 28, 330–​47. Jha V, Parameswaran S (2013). Community acquired acute kidney injury in the tropics. Nat Rev Nephrol, 9, 278–​90. Jha V, Prasad N (2016). CKD and infectious diseases in Asia Pacific: challenges and opportunities. Am J Kidney Dis, 68, 148–​60. Jha V, Rathi M (2008). Acute kidney injury due to natural medicines. Semim Nephrol, 28, 416–​28. Jha V, et al. (1992). Spectrum of hospital-​acquired acute renal failure in the developing countries—​Chandigarh study. Q J Med, 83, 497–​505. Liyanage T, et al. (2015). Worldwide access to treatment for end stage kidney disease: a systematic review. Lancet, 385, 1975–​82.

Mehta RL, et al. (2015). International Society of Nephrology’s 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology. Lancet, 385, 2616–​43. Mendley SR, et al. (2019). Chronic kidney disease in agricultural communities: report from a workshop. Kidney Int, pii: S00852538(19)30781-1. doi: 10.1016/j.kint.2019.06.024. Minho FM, Zanetti DM, Burdman EA (2005). Acute renal failure after Crotalus duress’s snakebite:  a prospective survey on 100 patients. Kidney Int, 67, 659–​67. Morand S, et  al. (2014). Infectious diseases and their outbreaks in Asia-​Pacific: biodiversity and its regulation loss matter. PLoS One, 9, e90032. Murray KO, et  al. (2015). Mesoamerican nephropathy:  a neglected tropical disease with an infectious ethology? Microbes Infect, 17,  671–​5. Naicker S, Paget G (2015). HIV and renal disease. In: Turner N, et al. (eds) Oxford textbook of clinical nephrology, 4th edition, pp. 1667–​ 75. Oxford University Press, Oxford. Nguansangiam S, et al. (2007). A quantitative ultrastructural study of renal pathology in fatal Plasmodium falciparum malaria. Trop Med Int Health, 12, 1037–​50. Olowu WA, et  al. (2010). Quartan malaria-​ associated childhood nephrotic syndrome: now a rare clinical entity in malaria endemic Nigeria. Nephrol Dial Transplant, 25, 794–​801. Prakash J, et al. (2006). Acute renal failure in pregnancy in a developing country: twenty years of experience. Ren Fail, 28, 309–​13. Rodrigues VL, et al. (2010). Glomerulonephritis in schistosomiasis mansion: a time to reappraise. Rev Soc Bras Med Trop, 43, 638–​42. Rosenberg AZ, et al. (2015). HIV-​associated nephropathies: epidemiology, pathology, mechanisms and treatment. Nat Rev Nephrol, 11, 150–​60. Shalaby SA, et al. (2010). Clinical profile of acute paraphenylenediamine intoxication in Egypt. Toxic Ind Health, 26,  81–​7. Singh SK, et  al. (2008). Milky urine. Chyluria. Kidney Int, 74, 1100–​1. Utah IA, et al. (2005). Factors contributing to maternal mortality in north-​central Nigeria: a seventeen-​year review. Afr J Reprod Health, 9,  27–​40. Wang X, et al. (2014). A two-​fold increase of carbon cycle sensitivity to tropical temperature variations. Nature, 506, 212–​15. Yang HY, et  al. (2015). Overlooked risk for chronic kidney disease after leptospiral infection: a population-​based survey and epidemiological cohort evidence. PLoS Negl Trop Dis, 9, e0004105.

21.12

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

ESSENTIALS There are more than 200 inherited disorders in which the kidney is affected. Many are single gene diseases that affect children, but cases are not restricted to paediatrics and diagnosis is often made in adults. They display a wide range of renal features: cystic, glomerular, tubulointerstitial, vascular, malformative, tumoural, and urolithiasis. Autosomal dominant polycystic kidney disease—​affects about 1/​1000 individuals and accounts for 7% of cases of endstage renal failure in Western countries. Inheritance is autosomal dominant, with mutations in polycystin 1 responsible for 75% of cases and mutations in polycystin 2 accounting for most of the remainder. May present with renal pain, haematuria, urinary tract infection, or hypertension, or be discovered incidentally on physical examination or abdominal imaging, or by family screening, or after routine measurement of renal function. Commonly progresses to endstage renal failure between 40 and 80  years of age. Main extrarenal manifestations are intracranial aneurysms, liver cysts, and mitral valve prolapse. Alport’s syndrome—​ X-​ linked dominant inheritance in 85% of kindreds, with molecular defects involving the gene encoding the α-​5 chain of the type IV collagen molecule. Males typically present with visible haematuria in childhood, followed by permanent nonvisible haematuria, and later by proteinuria and renal failure. Extrarenal manifestations include perceptive deafness of variable severity and ocular abnormalities (bilateral anterior lenticonus is pathognomonic). Carrier women often have slight or intermittent urinary abnormalities, but may develop mild impairment of renal function late in life, and a few develop endstage renal disease. In the autosomal recessive form of Alport’s syndrome, renal disease progresses to endstage before 20 to 30 years of age at a similar rate in both affected men and women. Hereditary tubulointerstitial nephritis—​ nephronophthisis is the most common genetic cause of endstage renal disease in children and young adults, and is a group of autosomal recessive tubulointerstitial nephropathies with multiple, small medullary cysts that appear late in the course of the disease. Eighty per cent of cases are caused by homozygous deletions of the NPH1 gene, which codes for nephrocystin. It presents with polyuria, polydipsia, and growth retardation in early childhood, progressing to endstage renal disease at a mean age of 14 years. In adults, autosomal dominant

tubulointerstitial nephritis, sometimes with gout and medullary cysts, is related to mutations in various genes (UMOD, MUC1, REN, TCF2). Hereditary tumours—​in von Hippel–​Lindau disease, due to mutations in the tumour suppressor gene VHL, renal cysts and bilateral multifocal renal cell carcinomas are found in 70% of cases. Carcinomas are often asymptomatic, should be screened for regularly, and occur at a mean age of 45 years. In tuberous sclerosis, due to mutations in genes encoding hamartin (TSC1) or tuberin (TSC2), multiple and bilateral renal angiomyolipomas may bleed, or induce progressive renal impairment.

Autosomal dominant polycystic kidney disease and other cystic diseases of the kidneys An overview of the most frequent causes of cystic kidney diseases, genetic and nongenetic, is shown in Table 21.12.1.

Autosomal dominant polycystic kidney disease Autosomal dominant polycystic kidney disease (ADPKD) is by far the most frequent inherited kidney disorder, accounting for approximately 7% of cases of endstage renal failure in Western countries. It is one of the most frequent human inherited monogenic diseases (c.1 in 1000 individuals). Diagnosis The diagnosis of ADPKD is mainly based on renal imaging. Ultrasonography, inexpensive and safe, remains the imaging modality of choice to make the diagnosis. One must take into account the presence or absence of a family history of ADPKD, the patient’s age, the number of observed cysts, and their localization and morphology. If unsure, a genetic diagnosis is sometimes offered and differential diagnoses must be explored. Positive diagnosis in a subject at risk of ADPKD This follows screening, usually of asymptomatic children and/​or siblings of an affected individual who have a 50% risk of having inherited ADPKD. Paediatric complications of ADPKD are exceptional and there is no proven benefit to screen for ADPKD in

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Table 21.12.1  Conditions causing cystic kidney diseases Condition

Characteristics

Autosomal dominant diseases Autosomal dominant polycystic kidney disease

Large kidneys (often), numerous diffuse renal cysts, hepatic cysts

Von Hippel–​Lindau (VHL) disease Large kidneys (often), cysts, solid lesions Tuberous sclerosis

Large kidneys (often), cysts, angiomyolipomas

TCF2 mutation (renal cysts and diabetes syndrome)

Medullary cysts; cystic dysplasia ± urinary malformations ± diabetes (MODY type 5)

UMOD, REN, MUC1 mutations

Medullary cysts ± gout

Table 21.12.2  Diagnostic tests for ADPKD Test

Age (years)

To affirm ADPKD

To exclude ADPKD

Renal ultrasonography

15–​39

≥3 cysts (total)

Impossible

40–​59

≥2 cysts in each kidney

0 or 1 cyst in each kidney

Renal MRI

>16

≥10 cysts (total)

75 years in PKD2 disease). PKD1 disease progresses more slowly in women than in men. Control of hypertension may slightly reduce the rate of progression. Extrarenal manifestations Liver cysts develop in 70% of patients, usually later in life than renal cysts. They are more frequent and more diffuse in women than in men. They are usually asymptomatic but may be clinically palpable, and are typically detected by ultrasonography. Liver function tests are usually normal. Liver cyst infection may occur, particularly in patients on dialysis or in transplant recipients. Massive liver involvement can cause severe discomfort in some cases, mostly in women. Cardiovascular abnormalities include intracranial aneurysms and mitral valve prolapse. Subarachnoid haemorrhage or intracerebral bleeding due to rupture of intracranial aneurysm are among the most severe complications of ADPKD and occur in approximately 1 to 2% of patients. Rapid diagnosis and urgent neurosurgical opinion are required. Diagnosis should be suspected early, before complete rupture, in patients with ADPKD with recent and severe headache, or with any transient focal neurological deficit. In cross-​sectional studies performed using noninvasive screening methods such as high-​resolution CT or magnetic resonance angiography, intracranial aneurysms have been found in 7 to 8% of asymptomatic middle-​aged patients with ADPKD. The prevalence is higher in those with a family history of intracranial aneurysm. The risk of rupture is largely dependent on aneurysm size. Routine screening by noninvasive methods is not indicated for all asymptomatic patients with ADPKD, but it seems reasonable in certain subgroups, in particular those with a family history of intracranial aneurysm or subarachnoid haemorrhage, those who have already bled from an aneurysm (since recurrent aneurysm is possible), and possibly those who are to undergo major elective surgery. In high-​ risk groups, screening should be repeated every 5 to 10 years since the cerebral vascular disease is progressive.

Mitral valve prolapse is discovered in 20% of patients with ADPKD by echocardiography, whereas it is found in only 2 to 3% of the general population. Other cardiac valve abnormalities and occasionally artery dissection or aneurysm may also be detected. Other extrarenal abnormalities observed in ADPKD include pes excavatum, colonic diverticula, and abdominal hernias. Pathogenesis Cysts develop only in a few nephrons and only focally, whereas all nephron cells carry the mutated gene. This has been explained by a two-​hit phenomenon which postulates that renal tubular (or liver biliary) cells that are at the origin of cysts bear first the germinal PKD gene mutation, and then acquire a somatic PKD gene mutation involving the other allele, this event occurring at random in a limited number of cells. This explanation does not exclude other mechanisms. The link between the genetic event(s) and cystic fluid accumulation is not known. The disease has an autosomal dominant mode of inheritance, so that the risk of any child of an affected parent carrying the abnormal gene is one in two, new mutations being rare. Mutations affecting polycystin 1 (from the PKD1 gene on the short arm of chromosome 16) are responsible for 75% of cases in the most recent series, with mutations affecting polycystin 2 (from the PKD2 gene on the long arm of chromosome 4) accounting for most of the remainder. Polycystin 1 and polycystin 2 are transmembrane proteins that are able to interact, function together as a nonselective cation channel, and also induce several distinct transduction pathways. The ‘polycystin complex’ may have three different subcellular localizations and associated putative functions: at lateral membranes of the cells (with a role in cell–​cell interaction), at the basal pole of the cell (with a role in cell–​ extracellular matrix interaction), and at the apical primary cilia of the cells (with a role in mechanotransduction of the urinary flux). Treatment—​general and symptomatic High fluid intake and regular follow-​up of blood pressure and renal function are indicated in all patients with ADPKD. The control of hypertension is an essential part of management, achieved with standard antihypertensive agents. Haematuria should be managed conservatively if possible, although bleeding may sometimes be prolonged over several days and even weeks. The relief of pain or abdominal discomfort can be difficult. In addition to symptomatic treatment, surgical renal cyst decompression should be restricted to very selected cases. Surgery is rarely needed in the management of renal stones. Liver cyst aspirations by needle under CT guidance, fenestration, or resection may be needed when massive involvement gives rise to pain; and in very rare cases such patients have come to liver transplantation. Kidney infection requires administration of antimicrobials appropriate for upper urinary tract infection (see Chapter 21.13). In some cases, control of infection is not obtained, most probably because agents penetrate some infected cyst fluids poorly and do not achieve adequate concentration. Lipophilic drugs such as trimethoprim–​ sulphamethoxazole and fluoroquinolones have the best penetration into cyst fluid. Liver cyst infection also requires antimicrobials and drainage if infection is not controlled. Standard medical management of chronic renal failure is indicated, as are renal replacement therapy and kidney transplantation when the patient reaches endstage, the results being similar to those obtained in other renal diseases.

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Treatment—​specific Identification of polycystins and their downstream intracellular dysregulated signalling pathways has provided clues to how the disease develops and thereby to the possibility of specific interventions. Among various molecules, V2 receptor antagonists (tolvaptan), somatostatin analogues (octreotide), and mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus) have been tested and shown promise in animal models. A  randomized trial of tolvaptan in patients aged 18 to 50 years, with an estimated glomerular filtration rate greater than 60 ml/​min and total kidney volume greater than 750 mL, demonstrated a reduced rate of annual increase in total kidney volume (2.8% vs 5.5%), a reduced annual rate of decline of renal function (−3.0 µmol/​L vs −4.3 µmol/​L), and reduced rate of reaching a composite endpoint comprising measures of clinical progression and rate of kidney function decline (44 vs 50 events per 100 patient-​years of follow-​ up). Patients who took tolvaptan had a higher rate of adverse events related to aquaresis, but a lower frequency of adverse events related to ADPKD. Elevation of serum alanine aminotransferase to more than 2.5 times normal occurred in 4.9% of patients taking tolvaptan (vs 1.2% controls), and the United States Food and Drug Administration has subsequently issued a safety warning about the possibility of irreversible liver injury associated with the use of the drug. In the United Kingdom the National Institute for Health Care and Excellence have recommended Tolvapatan as an option to slow progression of cyst development and renal failure in patients with CKD stages 2 or 3 who have evidence of rapidly progressing disease, subject to the medication being provided at an agreed discount. Clinical trials of octreotide have shown a tendency for reduction in increase in renal size and decline in glomerular filtration rate, but without the reductions reaching statistical significance and with a suggestion that beneficial effects may be attenuated after 2  years. Clinical trials of everolimus and sirolimus have not shown significant clinical benefit, and these agents have a formidable side effect profile. Genetic counselling The pattern of inheritance of ADPKD means that the offspring of an affected subject each have a 50% risk of having the disease. The disease has a highly variable clinical course, even within a given family. Prenatal diagnosis by gene linkage studies using material derived from chorionic villus sampling has been performed and can be considered if required and if adequate family information is available, but the demand for such prenatal diagnosis has been very low in Western countries. This is explained by the late onset and the variable clinical course of the disease, often relatively benign, which cannot yet be predicted by DNA analysis. Ultrasonography may occasionally show renal cysts in the fetus, but late in pregnancy. Obviously, due to the slow and late development of macrocysts, negative ultrasonography in the fetus (as well as in a child) does not rule out the disease.

Autosomal recessive polycystic kidney disease Autosomal recessive polycystic kidney disease (ARPKD) is a rare inherited disease (c.1 in 40  000 individuals), the first manifestations of which appear early in childhood. Mutations at a single locus, polycystic kidney and hepatic disease 1 (PKHD1, located on

chromosome 6), are responsible for all typical forms of ARPKD. The PKDH1 gene product, fibrocystin, is a transmembrane protein localized to the cell primary cilia. Three clinical features characterize this disease: • Its recessive nature:  both heterozygous parents are unaffected, with normal renal ultrasonography; parental consanguinity is found in some families. • Renal cysts derive from the collecting ducts, accounting for the striations in the dilated collecting system seen on MRI. • The renal disease is in most cases associated with congenital hepatic fibrosis: this may be responsible for portal hypertension due to presinusoidal block, or for bacterial angiocholitis due to intrahepatic bile duct dilatation. In children, ARPKD should be differentiated from ADPKD, which can be detected in childhood, even in neonates. Family history and renal ultrasonography in parents are decisive for correct diagnosis. In very rare families with PKD1 disease, renal involvement may be revealed in neonates and may progress to endstage within the first year of life. The diagnosis of ARPKD may be made before birth by antenatal ultrasonography, showing renal enlargement and increased echogenicity (as well as oligohydramnios). However, prenatal diagnosis may be uncertain and, since cystic changes occur in well-​ developed collecting ducts, these are detected only in the second half of pregnancy. When there is huge renal enlargement, pulmonary hypoplasia and respiratory distress may lead to death within hours after birth. With prolonged survival, liver and renal involvement becomes prominent. Gastrointestinal bleeding due to portal hypertension may be life-​threatening and necessitate surgical portocaval shunt. Systemic hypertension is a frequent finding in the first year of life but, surprisingly, it may regress in subsequent years. Urinary tract infection is common. The rate of progression of renal failure is variable:  of those who survive the neonatal period, about 50% reach endstage in childhood, whilst this occurs in adulthood in the remainder.

TCF2 mutation; renal cysts and diabetes syndrome (RCAD) Heterozygous mutations in the TCF2 gene encoding hepatocyte nuclear factor (HNF)-​1β, a DNA transcription factor, were initially described as one of the main molecular causes of maturity-​onset diabetes of the young (MODY) type 5. It now appears that renal anomalies are the key feature of HNF1β mutation phenotype and often precede the onset of diabetes. Renal cysts and progressive renal failure are frequent; glomerulocystic kidney disease and renal hypoplasia have been reported. Abnormal liver function tests, hyperuricaemia, hypomagnesaemia, pancreatic hypoplasia, and urogenital malformations have also been related to HNF1β mutations.

Other hereditary cystic kidney diseases Renal cysts may be found in other autosomal dominant diseases, such as von Hippel–​Lindau disease, tuberous sclerosis, as well as in three recently identified major causes of familial tubulointerstitial nephritis (UMOD, REN, and MUC1 gene mutations) with frequent medullary cysts. Most of these rare condition progress to endstage renal failure. Renal medullary cysts are also found in juvenile nephronophthisis, but not early in the course.

21.12  Renal involvement in genetic disease

Genetic glomerular diseases Glomerular structural diseases In glomerular structural diseases, proteins of podocytes or basement membrane are mutated (Table 21.12.3). X-​linked Alport’s syndrome Basement membranes of glomeruli may be altered by type IV collagen mutations. Six α chains of type IV collagen have been identified so far, with each molecule of type IV collagen being made up of three of these chains, differently associated in various basement membranes. In X-​linked Alport’s syndrome, mutations have been identified in the gene encoding the α-​5 chain that maps to the long arm of the X chromosome. X-​linked Alport’s syndrome is characterized by the association of progressive haematuric hereditary nephritis and bilateral sensorineural hearing loss. Its prevalence is approximately 1 in 5000 individuals. The first renal manifestation is typically visible haematuria, occurring sometimes in the first year of life, recurring during childhood, and followed by permanent nonvisible haematuria. Proteinuria appears later. A nephrotic syndrome, usually moderate, develops in 30 to 40% of patients. In other cases, moderate proteinuria and nonvisible haematuria are the presenting symptoms in adulthood. By electron microscopy, the basement membrane can be abnormally thickened with splitting of the lamina densa, thinned with focal thickening, or diffusely thin. The disease is progressive, leading to renal failure in all affected males, but the rate of progression is heterogeneous from one family to another, although usually homogeneous within a given family. In some, endstage is reached at or before 30 years of age, sometimes in childhood; in others, renal failure progresses to endstage between the ages of 30 and 60 years. Carrier females of X-​linked Alport’s syndrome often have slight or intermittent urinary abnormalities. Some may develop impairment of renal function late in life.

The hearing defect may lead to severe perceptive deafness, but it is often moderate or slight, only detected by audiometric testing. The hearing loss labels a given family, but is not found in all patients with renal disease. Eye abnormalities are detected in 30 to 40% of cases. These include bilateral anterior lenticonus detected by slit-​lamp examination—​a pathognomonic abnormality—​and perimacular or macular retinal flecks that are seen by fundoscopic examination and do not alter visual acuity. Recurrent corneal erosions occur in some patients. Genetic counselling first requires the correct identification of the mode of inheritance. If X-​linked dominant inheritance is documented, affected men will not transmit the disease to their sons, whereas all their daughters will carry the mutant gene; affected women will transmit the mutant gene to 50% of either sons or daughters. DNA analysis may be helpful for genetic counselling in these families. Treatment of hypertension and supportive management of renal failure are indicated in patients with progressive disease. The results of kidney transplantation are similar to those obtained in other renal diseases, but in rare cases antiglomerular basement membrane crescentic glomerulonephritis develops in the graft. It is assumed that this complication is related to alloimmunization to the ‘missing antigen’ introduced by the transplant. Autosomal Alport’s syndromes In the autosomal recessive form, renal disease progresses to endstage before 20 to 30 years of age at a similar rate in both affected men and women. The genes encoding α-​3 or α-​4 chains are mutated. Affected subjects are homozygotes in consanguineous families, or compound heterozygotes in other cases. In families with leiomyomatosis, α-​5 and α-​6 genes, located contiguously on the X chromosome, are both involved in a large deletion. In some families, macrothrombocytopenia is associated with nephritis and hearing defects: mutations involve the MYH9 gene, encoding the nonmuscle myosin heavy chain IIA.

Table 21.12.3  Genetic glomerular structural diseases Disease

Gene (OMIM)

Inheritance

Renal phenotype

Extrarenal phenotype

X linked Alport’s syndrome

COL4A5 (301050)

XL

Nonvisible haematuria (constant) ± episodes of visible haematuria; increasing proteinuria ± nephrotic range, progressive renal failure. Early endstage renal disease (ESRD) in most males

Sensorineural hearing loss; anterior lenticonus and other eye anomalies

Myosin heavy chain 9 (MYH9)

MYH9

AD

Nonvisible haematuria, proteinuria, progressive renal failure

Macrothrombocytopenia Leucocyte inclusions Sensorineural hearing loss Cataract

Nail patella syndrome (osteo-​onychodysplasia)

LMX1B (161200)

AD

Focal and segmental glomerulosclerosis with specific ultrastructural changes of the glomerular basement membrane, in 30% of patients, may progress to ESRD in some

Inconstant. Absence, dysplasia, or hypoplasia of the nails and patella; elbow dysplasia; bilateral iliac horns arising from the anterosuperior iliac crest; eye disease and sensorineural hearing loss possible

Congenital nephrotic syndrome of the Finnish type

Nephrin

AR

Massive proteinuria occurs in utero and persists in infancy. Intense therapy needed: nutritional support to compensate for protein loss; prevention of infection and thrombosis; bilateral nephrectomy; continuous peritoneal dialysis, and finally kidney transplantation

None

Familial focal segmental glomerulosclerosis

Various (see text)

AR or AD

Progressive proteinuria, sometimes nephrotic. May progress to ESRD

None

AD, autosomal dominant; AR, autosomal recessive; XR, X-​linked.

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Benign familial haematuria

Metabolic diseases with glomerular involvement

This condition is characterized by isolated nonvisible haematuria, without proteinuria or progression to renal failure, in both men and women. Renal biopsy usually shows a thin glomerular basement membrane (hence the alternative name thin basement membrane nephropathy) and immunofluorescence studies are negative. The mode of transmission is compatible with autosomal dominant inheritance of mutations involving the α-​3 or α-​4 chain gene.

In metabolic diseases with glomerular involvement, a defect in an enzyme or its cofactor leads to accumulation or deficiency of a specific metabolite. Fabry disease’s, mitochondrial cytopathy, lecithin-​cholesterol acyl transferase (LCAT) deficiency, hepatorenal glycogenosis (glucose-​ 6-​ phosphatase deficiency), and glycogen storage disease type I are the most important diseases in this group (Table 21.12.4).

Familial focal segmental glomerulosclerosis

Fabry’s disease, a rare X-​linked lysosomal storage disease, results from α-​galactosidase A  deficiency. Glycosphingolipid deposition mainly occurs in the cardiovascular and renal system. Hemizygotes males are more severely affected than heterozygote females. The first manifestations are painful acroparaesthesias, appearing in childhood and often prevented by administration of carbamazepine or phenytoin. Angiokeratomas, anhidrosis, and corneal deposits develop subsequently. Ischaemic cerebrovascular complications, cardiac valve abnormalities, myocardial deposition of glycolipids, and coronary events are the most severe manifestations, along with renal involvement. In the kidney, glycolipid deposition involves glomerular epithelial cells, tubular cells, and endothelial and smooth muscle cells of intrarenal arteries. The latter changes are responsible for progressive renal ischaemia. Renal disease is revealed by proteinuria at around 20 years, and then progresses to endstage between 40 and 60 years of age, necessitating regular dialysis and/​or kidney transplantation. Glycolipid deposition does not recur in the renal graft that contains normal α-​galactosidase activity. Diagnosis is based on symptoms, familial history, measurement of α galactosidase activity in leucocytes, demonstration of typical inclusions on a tissue biopsy, and genetic analysis. Two different recombinant enzyme treatments (agalsidase α and agalsidase β) have been available since 2001. Enzyme replacement therapy promotes

Familial focal segmental glomerulosclerosis with either autosomal dominant or autosomal recessive inheritance has been well characterized. Mutation of the NPHS2 gene, which encodes podocin, and mutations of PLCE may cause recessive steroid-​resistant nephrotic syndrome in some families, which can be of early or late onset. Mutations in ACTN4, which encodes α-​actinin-​4, mutations of TRPC6, and mutations of INF2 (which encodes formin) may cause autosomal dominant focal segmental glomerulosclerosis. All these proteins are synthesized and secreted by the podocytes, and interact and regulate plasticity and slit diaphragm permselectivity with other podocyte proteins. Mutations (especially podocin mutations) may be detected in some cases of sporadic steroid-​resistant nephrotic syndrome. Nephrin is localized at the slit diaphragm between podocyte foot processes (which are both absent in affected subjects), and plays a key role in the normal glomerular filtration barrier. Mutations of nephrin are responsible for autosomal recessive congenital nephrotic syndrome. Familial IgA nephropathy For most types of other primary glomerulonephritis, familial cases have been anecdotally reported. The most frequent form, albeit rare, is probably familial IgA nephropathy, either primary (Berger’s disease) or associated with Henoch–​Schönlein purpura.

Fabry’s disease

Table 21.12.4  Genetic glomerular metabolic diseases Disease

Gene (OMIM)

Inheritance

Renal phenotype

Extrarenal phenotype

Fabry’s disease

GLA (301500)

XL

Mostly in men: proteinuria, progressive kidney failure; sometimes tubular dysfunction (polyuria, Fanconi’s syndrome) and renal parapyelic cysts. Glycolipids accumulation observed on light and electron microscopy

Pain (acromelalgia), skin (angiokeratomas, anhidrosis), eye (cornea verticillata), heart (left ventricular hypertrophy, conduction anomalies, valve anomalies, angina), strokes (hearing loss, ataxia, vascular dementia)

Mitochondrial cytopathy, MIDD type

MT-​TL1 (520000)

Mitochondrial

Proteinuria, progressive renal failure (focal segmental glomerular sclerosis, tubulointerstitial nephritis)

Sensorineural hearing loss and diabetes in adults (seek for maternal inheritance); pigmentary retinopathy, ptosis, cardiomyopathy, myopathy, neuropsychiatric symptoms

Lecithin-​cholesterol acyl transferase (LCAT) deficiency

LCAT (245900)

AR

Lipid accumulation occurs in glomerular mesangial cells and progresses to endstage renal disease. Lipid deposition recurs slowly in kidney transplants

Lipid accumulation occurs in the eyes (causing corneal deposits), erythrocyte membranes (leading to low-​grade haemolytic anaemia), arterial walls (contributing to premature atherosclerosis)

Hepatorenal glycogenosis (glucose-​6-​ phosphatase deficiency; glycogen storage disease type I; von Gierke)

G6PC (type a 232200) SLC37A4 (type b 232220)

AR

Early enlarged kidneys Late glomerular hyperfiltration proteinuria, progressive renal failure

Early hypoglycaemia, intolerance to fasting, hepatomegaly, growth retardation, osteopenia, round face, platelet ± neutrophil dysfunction, enteropathy Late hepatic adenomas and carcinomas

AR, autosomal recessive; XR, X-​linked.

21.12  Renal involvement in genetic disease

cell clearance of substrate and improves some clinical parameters (heart, kidney damage, pain, quality of life). However, there is no proven efficacy to date on central nervous system lesions, on cardiac morbidity and mortality, nor on renal damage beyond a certain stage (proteinuria >1 g/​day and/​or estimated glomerular filtration rate 4.4 mmol/​day) may be seen in patients with calcium stones, often caused by a diet high in protein. Hyperuricosuria decreases the solubility of calcium oxalate, and promotes stones. Allopurinol was successful in decreasing stone recurrence in such patients (Table 21.14.3), and a decrease in protein intake would be helpful as well. Calcium phosphate stones Calcium phosphate stones form when supersaturation for calcium phosphate (brushite) in the urine is exceeded. The major determinant of this type of supersaturation is alkaline urine pH (>6.3), coupled with hypercalciuria. These stones are associated with a more destructive renal pathology, and often require more procedures for removal. The cause of the elevated urine pH in these patients is often unclear; few have true distal renal tubular acidosis. Treatment with thiazide to lower urine calcium can prevent recurrent stones. The use of potassium citrate as a treatment for stones requires careful follow-​up to assure that supersaturation with respect to calcium phosphate is not rising, as formation of calcium phosphate stones may worsen.

Nephrocalcinosis Nephrocalcinosis is defined as precipitation of calcium salts in the renal tubules or interstitium. As noted previously, all calcium stones are accompanied by at least some tissue precipitation of calcium phosphate, but the amount is not large, and not yet detectable by current radiological methods. Larger amounts of precipitation may be seen in certain disease states (Table 21.14.2), and particularly in diseases such as distal renal tubular acidosis and primary hyperoxaluria, where deposition of large amounts of mineral in medullary (and occasionally cortical) tissue may lead to renal failure.

Uric acid stones Aetiology and pathogenesis Uric acid stones occur when urine pH is abnormally low. The solubility of undissociated uric acid is only 0.54 mmol/​litre (90 mg/​litre), and at a pH below 5.35 (the pKa) over half the uric acid present is in the undissociated form. Normal daily excretion of uric acid is 3 to 4.8 mmol/​day (500–​800 mg/​day), depending on protein intake, so it is easy to see that acid urine will be supersaturated with respect to uric acid in most cases. Low urinary volume and high uric acid excretion will exacerbate the tendency to uric acid precipitation. Patients with diarrhoea, especially with ileostomy, excrete concentrated, acid urine because of loss of water and bicarbonate in stool; uric acid stones are a common complication of this condition. Low urinary pH and uric acid stones also occur in patients with insulin resistance, as in diabetes or the metabolic syndrome, because insulin resistance is associated with a decreased ability to synthesize ammonia, leading to a lower urinary pH because of the lack of this proton buffer. Increasing body weight is also associated with a low urinary pH, perhaps because of insulin resistance. In diabetic stone formers, as many as 35 to 45% of stones will be composed of uric acid, which is much higher than the 5 to 10% prevalence seen in the general population of stone formers. Patients with gout are frequently obese or diabetic; however, some forms of gout are associated with acid urine pH without the established need for insulin resistance. Certain forms of renal disease result in reduced ammonia production and low pH; chronic lead nephropathy is a well-​known example (saturnine gout). Although a low pH is common in most forms of progressive renal failure, uric acid stones are not.

Diagnosis and treatment Uric acid stones are poorly visualized on standard plain radiographs, although they are easily seen on CT. On intravenous pyelograms they may be seen as filling defects. Alkali treatment to raise urinary pH above 6.2 will solubilize uric acid and can prevent stones. Use of potassium alkali (citrate or bicarbonate) is preferred, as sodium alkali (sodium citrate or sodium bicarbonate) will raise urinary calcium, and possibly blood pressure. Urine pH needs monitoring because excessive elevation may cause calcium phosphate stones, and serum potassium also needs to be monitored to avoid hyperkalaemia, especially in diabetics. Giving doses of 10 to 20 mmol of alkali two to three times a day is usually sufficient to keep the urinary pH at 6 to 6.5. Dietary intake of purine should be moderated if uric acid excretion is elevated, increased fluids are a standard part of stone management, and xanthine oxidase inhibitors play a role in those with hyperuricaemia.

Cystine stones Aetiology and pathogenesis Cystine stones form in patients with inherited defects of dibasic amino acid transport in the proximal tubule, which lead to increased excretion of cysteine, ornithine, lysine, and arginine in the urine (Table 21.14.2). The only clinical outcome of this defect is cystine

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stones, because of the tendency of cysteine molecules to disulphide bond, forming cystine which is significantly less soluble than free amino acids, thus the defect has been termed cystinuria. Cystine stones are found in only 1 to 2% of stone formers, but they are often recurrent, and may become very large, leading to the need for many stone removal procedures. Cystine stones are poorly fragmented by extracorporeal shock-​wave lithotripsy, hence alternative means of stone removal may be needed. Renal function is often reduced, perhaps as the result of the effects of stones and surgery. Stones are not well visualized using plain abdominal radiographs, although they are seen well with CT. Cystinuria has traditionally been regarded as an autosomal recessive disorder, which may be caused by defects in either of two genes, SLC3A1 or SLC7A9, although cystine stone formation has now been reported in some heterozygotes. The proteins encoded by these genes form a heterodimer, which is responsible for cysteine transport in the apical membrane of the proximal tubule, and in the small intestine. Defects in these two genes appear to explain most cases of cystinuria, and they are clinically indistinguishable with respect to age of stone onset, frequency of recurrence, or cystine excretion. Papillary biopsies show crystal deposits that contain cystine and also calcium phosphate in collecting ducts. The degree of interstitial fibrosis and tubular cell injury is quite marked, and accords with reduction of renal function that is more severe than in almost any other stone disease. Cystine stones may begin in childhood, or even in infancy, although presentation may be delayed to adulthood. In a large cohort study, the median age of first stone was 12 years; males appear to be more severely affected than females for reasons that are unclear. Cystinuria should always be looked for when stones present in childhood or adolescence. Preventive therapy should be started as soon as stones are diagnosed, and continued lifelong because of high recurrence rates and severe kidney injury.

Diagnosis and treatment Cystinuria may be diagnosed by stone analysis showing cystine, and the finding of characteristic hexagonal crystals in urine is pathognomonic. All stone formers should have at least one urine sample screened for cystine. Cystine excretion may be transiently elevated in infancy, and diagnosis in this age group is more difficult. Lowering supersaturation of the urine with respect to cystine is the goal of treatment. Cystine solubility is pH dependent, and is higher at alkaline pH, but not very accurately predicted from nomograms. At a pH of 7 to 7.5, solubility can vary from 0.7 to 1.47 mmol/​ litre. A  reasonable goal is to keep urinary cystine concentration below 1 mmol/​litre and urine pH about 7 to 7.5. Management begins with measurement of daily cystine excretion and urinary pH. High fluid intake is a cornerstone of treatment, and the amount needed to achieve a concentration of less than 1 mmol/​ litre can be calculated and prescribed, with fluid intake distributed throughout the day, and in the evening as well. Some patients will require potassium alkali, as potassium citrate or bicarbonate, in divided doses, to improve solubility. Potassium salts are preferred, as sodium intake can raise cystine excretion. Low sodium (100 mmol/​ day) and protein (0.8–​1 g/​kg per day) intake can reduce cystine excretion modestly. If stones recur despite adequate hydration and increase of pH, a cysteine-​binding drug should be added to fluids and alkali to

decrease the concentration of cystine further. Cystine is formed by the linkage of two cysteine molecules by a disulphide bond. Cysteine binding drugs have sulphydryl groups that form mixed disulphides with cysteine, which are more soluble than the homodimer, cystine. d-​Penicillamine (1–​2 g/​day, in three or four divided doses) is one such drug, the penicillamine–​cysteine disulphide being 50 times more soluble than cystine. A second agent, α-​mercaptopropionylglycine (tiopronin, 400–​1200 mg/​day in divided doses), is also effective. Both drugs have side effects, including fever, rash, impaired taste, arthralgias, leucopenia, and proteinuria, but tiopronin is better tolerated, with a lesser incidence and severity of adverse reactions. Captopril has a free sulphydryl group and is thus the antihypertensive of choice in patients with cystinuria. Recurrent stones should be analysed, as patients may form stones containing calcium phosphate due to the alkaline urine pH, which require different treatment.

Struvite stones Struvite (magnesium ammonium phosphate) stones may present with vague flank pain and gradual deterioration of renal function, rather than colic. They form when the kidney is infected with organisms that possess the enzyme urease, such as proteus, providentia, klebsiella, pseudomonas, and enterobacter species. Urease hydrolyses urea to ammonia and CO2, with the ammonia raising the pH of the urine and leading to production of carbonate in the urine. Calcium carbonate coprecipitates with struvite, forming large, branched stones within the kidney. Bacteria adhere to the stone, where they are poorly reached by antibiotics, making urine sterilization impossible when stones are present, hence adequate treatment requires removal of all stone material in addition to appropriate antibiotics. Struvite stones are more common in settings with chronic urological instrumentation, or in patients with neurogenic bladders. In cases where removal of all stone material is not possible, acetohydroxamic acid, a urease inhibitor, has been used to prevent stone recurrence and growth, but its use is limited by serious side effects, including headache, gastrointestinal upset, and thrombophlebitis.

FURTHER READING Abate N, et  al. (2004). The metabolic syndrome and uric acid nephrolithiasis: novel features of renal manifestation of insulin resistance. Kidney Int, 65, 386–​92. Asplin JR, et  al. (1999). Reduced crystallization inhibition by urine from men with nephrolithiasis. Kidney Int, 56, 1505–​16. Auge BK, Preminger GM (2002). Surgical management of urolithiasis. Endocrinol Metabol Clin North Am, 31, 1065–​82. Barcelo P, et al. (1993). Randomized double-​blind study of potassium citrate in idiopathic hypocitraturic calcium nephrolithiasis. J Urol, 150, 1761–​4. Belostotsky R et al. (2010). Mutations in DHDPSL are responsible for primary hyperoxaluria type III. Am J Hum Genet, 87,  392–​9. Borghi L, et al. (1993). Randomized prospective study of a nonthiazide diuretic, indapamide, in preventing calcium stone recurrences. J Cardiovasc Pharmacol, 22 Suppl 6, S78–​86.

21.14  Disorders of renal calcium handling, urinary stones, and nephrocalcinosis

Borghi L, et al. (1996). Urinary volume, water and recurrences of idiopathic calcium nephrolithiasis:  a 5-​year randomized prospective study. J Urol, 155, 839–​43. Borghi L, et  al. (2002). Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med, 346,  77–​84. Coe FL, Evan A, Worcester E (2005). Kidney stone disease. J Clin Invest, 115, 2598–​608. Curhan GC, et  al. (2001). Twenty-​four-​hour urine chemistries and the risk of kidney stones among women and men. Kidney Int, 59, 2290–​8. Ettinger B, et  al. (1986). Randomized trial of allopurinol in the prevention of calcium oxalate calculi. N Engl J Med, 315, 1386–​9. Ettinger B, et al. (1988). Chlorthalidone reduces calcium oxalate calculous recurrence but magnesium hydroxide does not. J Urol, 139, 679–​84. Ettinger B, et al. (1997). Potassium-​magnesium citrate is an effective prophylaxis against recurrent calcium oxalate nephrolithiasis. J Urol, 158, 2069–​73. Evan AP, et al. (2003). Randall’s plaque of patients with nephrolithiasis begins in basement membranes of thin loops of Henle. J Clin Invest, 111, 607–​16. Evan AP, et al. (2005). Crystal-​associated nephropathy in patients with brushite nephrolithiasis. Kidney Int, 67, 576–​91. Gambaro G, et  al. (2004). Genetics of hypercalciuria and calcium nephrolithiasis: from the rare monogenic to the common polygenic forms. Am J Kidney Dis, 44, 963–​86. Hofbauer J, et al. (1994). Alkali citrate prophylaxis in idiopathic recurrent calcium oxalate urolithiasis—​a prospective randomized study. Br J Urol, 73,  362–​5. Laerum E, Larsen S (1984). Thiazide prophylaxis of urolithiasis:  a double-​blind study in general practice. Acta Med Scand, 215,  383–​9.

Lieske JC, et al. (2005). International registry for primary hyperoxaluria. Am J Nephrol, 25,  290–​6. Moe OW (2006). Kidney stones: pathophysiology and medical management. Lancet, 367, 333–​44. Paisson R, et al. (2019). Genetics of common complex kidney stone disease: insights from genome-wide association studies. Urolithiasis, 47, 11–21. Pak CY, et  al. (1986). Management of cystine nephrolithiasis with alpha-​mercaptopropionylglycine. J Urol, 136, 1003–​8. Parks JH, Coe FL (2009). Evidence for durable kidney stone prevention over several decades. BJU Int, 103, 1238–​46. Parks JH, et  al. (2004). Clinical implications of abundant calcium phosphate in routinely analyzed kidney stones. Kidney Int, 66, 777–​85. Ryall RL (2004). Macromolecules and urolithiasis: parallels and paradoxes. Nephron Physiol, 98,  37–​42. Sakhaee K, Moe OW (2016). Urolithiasis. In: Skorecki K, et al. (eds) Brenner & Rector’s The kidney (10th edn), pp. 1322–​67. Elsevier, Philadelphia. Sayer JA (2017). Progress in understanding the genetics of calciumcontaining nephrolithiasis. J Am Soc Nephrol, 28, 748–59. Stamatelou KK, et  al. (2003). Time trends in reported prevalence of kidney stones in the United States: 1976–​1994. Kidney Int, 63, 1817–​23. Taylor EN, Stampfer MJ, Curhan GC (2004). Dietary factors and the risk of incident kidney stones in men: new insights after 14 years of follow-​up. J Am Soc Nephrol, 15, 3225–​32. Worcester EM (2002). Stones from bowel disease. Endocrinol Metab Clin North Am, 31, 979–​99. Worcester EM, Coe FL (2010). Clinical practice. Calcium kidney stones. N Engl J Med, 363, 954–​63. Worcester EM, et al. (2006). Reduced renal function and benefits of treatment in cystinuria vs other forms of nephrolithiasis. Br J Urol Int, 97, 1285–​90.

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21.15

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

ESSENTIALS Renal tubular acidosis (RTA) arises when the kidneys either fail to excrete sufficient acid, or are unable to conserve bicarbonate, with both circumstances leading to metabolic acidosis of varying severity with altered serum potassium. Proximal and distal types of RTA can be differentiated according to which nephron segment is malfunctioning. The condition may be secondary (e.g. associated with drugs, autoimmune disease, or diabetes mellitus) or inherited, and there may be renal tract calcification and—​in chronic cases—​metabolic bone disease.

Proximal RTA Aetiology and diagnosis—​the condition may be (1) secondary to generalized proximal tubular dysfunction (part of the renal Fanconi’s syndrome), or rarely (2) due to an inherited mutation of a single transporter (NBC1) located at the basolateral surface of the proximal tubular epithelium. The combination of normal anion gap acidosis with other features of proximal tubular dysfunction such as renal phosphate wasting (and hypophosphataemia), renal glycosuria, hypouricaemia (due to uricosuria), aminoaciduria, microalbuminuria, and other low molecular weight proteinuria suggests the diagnosis. Management—​this requires large quantities (up to 10–​15 mEq/​kg per day) of oral alkali (as bicarbonate or citrate), with (in most cases) potassium supplements to prevent severe hypokalaemia. Associated phosphate and vitamin D deficiencies may also require treatment. Precipitating drugs should be stopped if possible.

Distal RTA Aetiology—​two main classes are differentiated by whether (1)  the acid-​handling cells (α-​intercalated cells) in the collecting ducts are themselves functioning inadequately, in which case there is associated hypokalaemia (this is ‘classic’ distal RTA); or (2)  the main abnormality is of the salt-​handling principal cells in the same nephron segment, in which case hyperkalaemia occurs and the acidosis is a secondary phenomenon. This is hyperkalaemic distal RTA, which is most often secondary to hyporeninaemic hypoaldosteronism (e.g. in diabetes mellitus or critical illness) but may also be reversibly precipitated by drugs such as trimethoprim or ciclosporin.

Diagnosis—​the combination of normal anion gap acidosis with a urine pH higher than 5.5 suggests classic distal RTA, especially if renal tract calcification is present or there is coexistent autoimmune disease. Diagnosis may require an oral urine acidification test if the metabolic abnormalities are partially masked by compensatory mechanisms, when inability to achieve a urine pH less than 5.5 clinches the diagnosis of classic distal RTA. By contrast, urine acidification capacity is normal in hyperkalaemic distal RTA. Management—​ (1) classic distal RTA—​ 1 to 3 mg/​ kg per day of oral alkali (additional supplements should not be required); (2) hyperkalaemic distal RTA—​treatment is with sodium bicarbonate, but fludrocortisone and/​or potassium-​lowering measures may also be necessary. Precipitating drugs should be stopped.

Introduction The kidney plays a key role in the regulation of acid–​base balance and the term ‘renal tubular acidosis’ (RTA) refers to systemic acidosis arising from a tubular ion transport abnormality. On a mixed omnivorous diet, humans produce a net acid load of about 1 mmol/​ kg per day, which must be excreted. Through activity at two main sites in the nephron, the proximal convoluted tubule and the collecting duct, the kidney is able to vary bicarbonate reclamation and net acid excretion such that urine pH can range from about 4.5 to over 8, enabling systemic pH to be closely maintained between 7.35 and 7.45. Failure of these tubular functions can cause very severe acidosis with pH less than 7. The traditional classification of the RTAs is an historical one, based on the order in which the defects were described, but in thinking about the different mechanisms involved it is least confusing to use a tubular location to classify them: • Proximal (former type 2) • Distal, subdivided into ‘classic’ (type 1)  and ‘hyperkalaemic’ (type 4) • Mixed, which usually refers to carbonic anhydrase deficiency (type 3)

21.15  The renal tubular acidoses

Note that RTA excludes the acidosis of chronic kidney disease (which would be a raised anion gap metabolic acidosis), also that within each class of RTA there is then a division into primary (inherited) and secondary types. Primary RTA is directly due to inadequate function of a proton or bicarbonate transporter, and molecular genetic studies have identified a variety of these (as discussed later). In general, disorders associated with RTA that are inherited dominantly are clinically milder and give rise to overactivity or gain of abnormal function of a channel or transporter, whereas those that are recessively inherited are clinically more severe and due to loss-​of-​function genetic defects. Although all the recessive diseases described in this chapter are rare, they are encountered more commonly in areas of the world where parental consanguinity is prevalent, and the investigation of kindreds where affected children are the offspring of such unions of unaffected parents has allowed us to investigate the genetic causes of such disorders, and to understand better the molecular pathophysiology involved. In adult clinical practice, secondary causes of RTA are much commoner than primary, in particular hyperkalaemic distal RTA (dRTA) in association with diabetes mellitus, and classic dRTA in association with autoimmune diseases. Secondary RTA also describes metabolic acidosis arising from other renal ion transporter dysfunctions: the kidney does not carry out any of its myriad homeostatic functions in isolation, and interactions with these other systems form an important part of the overall picture. This is perhaps most marked in the context of salt homeostasis, where the endocrine system—​ particularly the mineralocorticoid axis—​is closely involved, and defects in these pathways can cause hyperkalaemic RTA.

Physiology of renal acid–​base homeostasis To understand the pathophysiology of the different types of RTA, it is helpful to consider normal renal acid–​base balance, again in terms of tubular location. Broadly, this consists of the combination of bicarbonate reabsorption (proximal tubule), proton secretion and bicarbonate generation (collecting duct), and ammonium generation and secretion (proximal tubule and medulla).

Proximal tubule Since the total load of sodium and bicarbonate reaching the glomeruli is freely filtered, the proximal tubule has a considerable reabsorption task to perform, reclaiming 90% (3–​4 mol) of bicarbonate daily from the tubular fluid, with Na+, H+, and HCO3–​ transport linked, as shown in Fig. 21.15.1. Citrate is also reabsorbed by the proximal tubule, which yields additional bicarbonate. Proximal tubular cells are also capable of generating ‘extra’ bicarbonate through the deamination of glutamine to glutamate, then forming α-​ketoglutarate and eventually glucose (Fig. 21.15.1). This produces bicarbonate and ammonium—​the former is reabsorbed and the latter secreted into the tubular lumen. This process is up-​regulated in states of chronic acidosis of nonrenal origin.

Collecting duct Two cell types with distinctly different functions are present in the collecting duct (Fig. 21.15.2). These are principal cells (responsible for salt handling) and intercalated cells (ICs, responsible for maintenance of acid–​base). Within the IC population, many studies—​mostly

Filtrate

H2O + CO2 CA4

H2O + CO2 CA2

HCO3− + H+

H+ + HCO3−

NHE3

Na+

HCO3−

Na+ −

H2PO4

NBC1

Na+

Glutamine

NH4+

NH4+, glucose, HCO3−

lumen

blood

Fig. 21.15.1  Schema of proximal tubular acid–​base movement. H+/​ HCO3–​ movement pathways are shown in red, Na+/​Cl–​ in blue, and ammonium in green. Na+ is absorbed in direct exchange for H+ by the sodium–​proton exchanger NHE3 (encoded by SLC9A3). In the lumen, the H+ and HCO3–​ rapidly form H2O and CO2 under the catalytic influence of membrane-​bound carbonic anhydrase (CA4, encoded by CA4). Having diffused into the cell, CO2 undergoes a reverse reaction (via intracellular CA2, encoded by CA2) to reform bicarbonate, which is then available for Na+/​HCO3–​ reabsorption into the interstitial fluid (and from there into the blood) via the sodium bicarbonate transporter NBC1 (encoded by SLC4A4). Any excess luminal H+ is buffered by filtered phosphate (HPO42–​). Proximal tubular cells also generate ‘extra’ HCO3–​ and ammonium through the deamination of glutamine as shown, the former being reabsorbed and the latter secreted into the tubular lumen. Dopamine antagonizes NHE3 and acetazolamide is a carbonic anhydrase inhibitor.

in rodents—​have described at least two subtypes, α-​ and β-​ICs. α-​ ICs are responsible for coupled apical secretion of protons into the urine and reclamation of bicarbonate across the basolateral surface (Fig. 21.15.2). On the apical surface, the multisubunit proton pump (H+-​ATPase) transfers H+ into the urine. It is of the same type as the H+-​ATPases found ubiquitously in intracellular organelles such as lysosomes, which require a low pH for efficient function. H+-​ATPases are composed of at least 13 different subunits, organized into a membrane-​anchored V0 (‘stalk’) domain (subunits a–​e), through which protons are moved, and a V1 ‘head’ that hydrolyses ATP (subunits A–​H). Apical and intracellular proton pumps can be differentiated by their subunit composition: the α-​IC’s apical renal pumps contain B1 and a4 subunits. In α-​ICs, apical H+-​ATPase function is coupled to basolateral bicarbonate exit (in exchange for chloride) via the anion exchanger AE1 (Fig. 21.15.2), which is structurally similar to the isoform present in the erythrocyte membrane, except that it is a little shorter at the N-​terminal end. Chloride/​bicarbonate exchange is 1:1. β-​ICs essentially reverse the processes of α-​ICs, so they secrete bicarbonate into the urine. It remains unclear whether α-​ and β-​ICs are molecular mirror images of each other or are separate cell types. Two other potential Cl–​/​HCO3–​ exchangers, pendrin (SLC26A4) and AE4, which may reside apically in β-​IC, have been reported in animals. Defects in pendrin cause Pendred’s syndrome of deafness and goitre, but alkalosis is not a feature in either Pendred’s patients or pendrin knockout mice. In any event, the acid load provided by an omnivorous human diet dictates that the great majority of ICs will be α-​ICs.

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A B1 A B1 G3 A E C2

α-intercalated cell

B1

H a4 e2 H+ATPase

D F

d2

ATP ADP

H+

AE1 Cl−

H− + HCO3− CA2

c" c

HCO3−

H2O + CO2

H+

K+ Cl−

K+ principal cell ENaC

MR

Na+ K+

K+ ATP ADP lumen

Na+ blood

Fig. 21.15.2  Collecting duct acid–​base regulation. Intercalated cells are responsible for coupled apical secretion of protons into the urine and reclamation of bicarbonate across the basolateral surface. On the apical surface, the multisubunit proton pump (H+ATPase) transfers H+ into the urine. The various subunits of this pump are shown on the left of the figure: mutations in B1 (ATP6V1B1) and a4 (ATP6V0A4) cause recessive dRTA. Basolateral bicarbonate exit (in exchange for chloride) occurs via the anion exchanger AE1 (SLC4A1). A cartoon of this exchanger is shown on the right of the figure, with R589—​a mutational hotspot for dominant dRTA—​marked with a red dot. There is a second, less structurally complex, P-​type ATPase present on the apical surface and exit routes for K and Cl that are not yet well characterized in humans. The adjacent principal cells (responsible for salt handling) are depicted: electrogenic sodium reabsorption via the epithelial sodium channel ENaC (SCNN1A, -​B, and -​G) takes place in exchange for K+ secretion; this is under the control of aldosterone, acting via the basolateral mineralocorticoid receptor (MR).

There is a second, less structurally complex, P-​type ATPase present apically in α-​ICs, which exchanges protons for K+. In humans, however, the overall contribution of H+/​K+-​ATPase to α-​IC function is not clear.

Clinical presentation RTA can range from being asymptomatic and undetectable without specialized biochemical tests, to presenting with a severe syndrome of failure to thrive in infancy. A  list of causes of RTA is given in Table 21.15.1. The following patients should all be suspected of having RTA: • Recurrent calcium-​ containing (especially calcium phosphate) stone formers, especially if there is a family history of renal stone disease • Individuals with osteomalacia (rickets in children) without other clear explanation • Patients with autoimmune disease, especially Sjögren’s syndrome (see Chapter 19.11.4) and an unexplained low serum potassium and/​or bicarbonate • Infants with osteopetrosis • Unexplained metabolic acidosis

Biochemically, overt RTA is characterized by the presence of a normal anion gap (hyperchloraemic) metabolic acidosis in the setting of either reduced renal net acid secretion (dRTAs) or bicarbonate wasting (proximal RTA), but otherwise normal or near normal renal excretory function (preserved estimated glomerular filtration rate). In dRTA, similar molecular defects can cause mild or severe acidosis, the reasons for which are not well understood. The clinical features of the various types of RTA are summarized in Table 21.15.2.

Proximal RTA Clinical and biochemical features The hallmark of proximal RTA is bicarbonate wasting into the urine. The consequent metabolic acidosis is often less severe than in other types of RTA because as serum bicarbonate falls, a larger proportion of filtered bicarbonate can be reabsorbed more distally, such that an equilibrium is reached at a venous bicarbonate level of around 15 mmol/​litre. The urinary bicarbonate loss from the proximal tubule is usually accompanied by other features of proximal tubular dysfunction (i.e. the renal Fanconi’s syndrome), such as renal phosphate wasting (and hypophosphataemia), renal glycosuria, hypouricaemia (due to uricosuria), aminoaciduria, microalbuminuria, and other

21.15  The renal tubular acidoses

Table 21.15.1  Causes of RTA

Acquired

Proximal RTA

Classic distal RTA

Hyperkalaemic distal RTA

Intrinsic renal disease

Hypokalaemic nephropathy Renal transplant rejection (acute and chronic)

Medullary sponge kidney Nephrocalcinosis

Diabetic nephropathy Interstitial nephritis

Haematological disease

Myeloma

Myeloma

Drugs

Gentamicin Cisplatin Ifosfamide Sodium valproate Zidovudine Tenofovir

Amphotericin Lithium Ifosfamide

Heavy metals/​toxins

Lead Cadmium Mercury Toluene (glue sniffing)

Vanadate

Hormonal

Primary hyperparathyroidism

Pregnancy

Nutritional

Kwashiorkor (protein-​energy malnutrition)

Autoimmune Inherited

Trimethoprim Ciclosporin/​tacrolimus K+-​sparing diuretics (spironolactone and eplerenone) Angiotensin-​converting enzyme inhibitors/​angiotensin receptor blockers Renin inhibitors Heparin

Sjögren’s syndrome

Inherited renal disease

Autosomal dominant Fanconi’s syndrome Autosomal recessive proximal RTA X-​linked (Dent’s disease 1 and 2, but acidosis usually mild and may be absent)

Autosomal dominant dRTA Autosomal recessive dRTA

Inherited syndromes

Cystinosis Tyrosinaemia type 1 Galactosaemia Oculocerebrorenal syndrome (Lowe’s syndrome) Wilson’s disease Hereditary fructose intolerance

Sickle cell anaemia

Pseudohypoaldosteronism type 1 Gordon’s syndrome

Table 21.15.2  Clinical and biochemical features of RTA Proximal RTA

Distal RTA—​dominant/​ sporadic

Distal RTA—​recessive

Mixed RTA

Hyperkalaemic RTA

Usual age of presentation

Childhood (primary) Adult (acquired)

Older/​child/​adult

Infancy/​early childhood

Infancy/​early childhood

Adult

Symptoms/​ signs

Variable including intellectual disability Rarely glaucoma/​ cataracts

Sometimes none Nephrolithiasis Nephrocalcinosis Sometimes rickets/​ osteomalacia

Vomiting/​dehydration Poor growth Early nephrocalcinosis Rickets Sensorineural deafness (early or late onset) Cystic kidneys

Fractures Poor growth Intellectual disability Blindness Osteopetrosis/​fractures Conductive deafness Dental malocclusion

Related to underlying disorder, e.g. diabetes complications

Biochemistry

Mild/​moderate acidosis Normal/​low K+ (if Na+ given)

Mild or compensated acidosis Low/​normal K+

Severe acidosis Low K+

Severe acidosis Low K+

Mild/​moderate acidosis High K+

Minimum urine pH

5.5

>5.5

>5.5

90% at 5  years). In these patients, the issue is of risk of relapse and subsequent progression. This risk increases with a number of factors including depth of invasion (Ta 3 cm

5% risk of malignancy Requires regular imaging follow-​up

III

Indeterminate mass Thick, enhancing wall or septa

50% risk of malignancy Resect

IV

Malignant cystic mass Thick, enhancing wall or septa with enhancing soft tissue component

Malignant Resect

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Patient operable? Met. completely resectable?

Symptomatic Or “Must Act”?

No

Observe

Yes

Yes

MDT Feasible to observe?

Yes

No

Palliate

No Surgery

RT/ablate

Systemic Rx

Observe for 3–6 months

Fig. 21.18.4  Algorithm for management of patients with metastatic renal cancer. MDT, multidisciplinary team; Met., metastasis; RT, radiotherapy; Rx, prescribed treatment.

The patient with distant disease Metastatic renal cancer can behave in a very variable manner: many patients will remain well without any active treatment for long periods, while others will progress quickly and require aggressive intervention. Factors that point to an aggressive tumour include systemic symptoms of weight loss, night sweats, and hypercalcaemia. The most commonly used risk scoring system for advanced disease is the MSKCC score for metastatic renal cell cancer (also available online). This predicts survival based on yes/​no answers to the following questions: (1) time from diagnosis to systemic treatment less than 1 year, (2) haemoglobin less than lower limit of normal, (3) calcium greater than 2.5 mmol/​litre, (4) lactate dehydrogenase (LDH) concentration greater than 1.5 times the upper limit of normal, and (5) performance status less than 80% (Karnofsky). The algorithm will have to be revalidated with the arrival of T-​cell checkpoint inhibitors. A patient with metastatic disease who has a painful and bleed­ing primary lesion may benefit from a palliative nephrectomy. Embolization may be performed to palliate symptoms for patients with advanced symptomatic RCC who are not operable. Surgery also has a role in selected patients with oligometastatic disease (metastatic disease present at just one or two sites). Factors which select patients for a good outcome include a disease-​free interval longer than 12 months, a solitary

site of disease, and age less than 60 years. An algorithm for management of patients with metastatic renal cancer is shown in Fig. 21.18.4. Systemic treatment options have been investigated in a number of first-​, second-​, and third-​line settings. The treatment grid in Table 21.18.5 shows where phase III data have supported various treatment options. Antiangiogenic tyrosine kinase inhibitors targeting vascular endothelial growth factor receptor signalling have an approximately 75% chance of causing tumour shrinkage or reduction, and an approximately 35% chance of causing a partial response by agreed criteria (Response Evaluation Criteria In Solid Tumours, RECIST). Each results in 10 to 14 months of progression-​free survival in the first-​line setting. The combination of the vascular endothelial growth factor antibody bevacizumab with interferon similarly doubles progression-​free survival compared to interferon alone. The toxicities of tyrosine kinase inhibitors need to be considered carefully as these are used in the maintenance setting:  these include hypertension, skin rash, fatigue, stomatitis, and a variety of less common toxicities. The key features of toxicity management are early intervention and use of prophylactic measures. The mammalian target of rapamycin (mTOR) inhibitors temsirolimus and everolimus are of modest benefit and have a

Table 21.18.5  Phase III data of treatment options in metastatic renal cancer Good risk

Intermediate risk

Poor risk

First line

Pembrolizumab + Axitinib Sunitinib Pazopanib Tivozanib Bevacizumab + IFN

Pembrolizumab + Axitinib Nivolumab + Ipilimumab Cabozantinib Sunitinib Pazopanib Tivozanib Bevacizumab + IFN

Pembrolizumab + Axitinib Nivolumab + Ipilimumab Cabozantinib Sunitinib Pazopanib Temsirolimus

Second and third line options

Nivolumab Cabozantinib Axitinib Everolimus Lenvatinib + everolimus

Nivolumab (if no prior immunotherapy) Cabozantinib Axitinib Everolimus Lenvatinib + everolimus

Nivolumab (if no prior immunotherapy) Cabozantinib Axitinib Everolimus Lenvatinib + everolimus

21.18  Malignant diseases of the urinary tract

diminishing role in treatment. The role of immunotherapy is undergoing a renaissance. There is intensive research in the use of novel immunotherapies such as autologous tumour vaccines, and T-​ cell checkpoint inhibitors such as antibodies to PD-​1, PD-​L1, and CTLA4, which relieve the control of autoimmunity and may induce host-​versus-​tumour immune reactions. The PD-​1-​directed antibody, nivolumab, has recently been established as a standard second-​line agent. The most notable feature of treatment is that the 20% of patients whose disease remains under control for at least a year have an excellent chance of prolonged benefit. Combinations of checkpoint inhibitors look particularly effective, albeit with toxicity. In the past year, combinations of immune checkpoint inhibitors with tyrosine kinase inhibitors have shown significant survival benefits and are likely to become the first line standard of care in the near future.

Prostate cancer Epidemiology Prostate cancer is the second most common cause of male cancer deaths in the Western world. It represented 13% of all cancer cases diagnosed in the United Kingdom in 2013, with 47 300 new cases and 10 837 men who died from the disease in 2012. In the United States of America alone, it is estimated that 220 800 men were diagnosed in 2015, with 27 540 men dying of the disease. Age, race, and family history are strong risk factors for developing the disease, with a known higher incidence in African American men.

Aetiology and pathogenesis Prostate cancer is a heterogeneous malignancy, with much genomic diversity. Multiple genome-​wide association studies have reported 77 single nucleotide polymorphisms (SNPs) associated with the condition. Further studies are required to identify whether targeted screening could be performed based on the genetic information obtained from these SNPs. In addition to the familial risk in first-​degree relatives of men with prostate cancer, who have a two-​to threefold higher risk, rare highly penetrant germline mutations are linked to genetic predisposition, such as HOXB13 and BRCA2 in families with a high incidence of breast and ovarian cancer. The genomic diversity of prostate cancer is further confirmed by high-​throughput new-​generation sequencing studies of multi-​focal disease, including the presence of genomic aberration in phenotypically benign prostate tissue, and lethal clonality of metastatic disease associated with phenotypically low-​risk primary cancers. This represents one of the biggest challenges in the management of this common cancer.

Clinical features Most cases of prostate cancer are asymptomatic at presentation, being detected following measurement of serum prostate-​specific antigen (PSA) or after digital rectal examination and subsequent biopsy. Lower urinary tract symptoms are common, but usually attributable to coexisting benign prostatic hypertrophy. Haematuria and haematospermia are uncommon, and more likely to be due to benign prostatic disease. Men with metastatic prostate cancer may present with bone pain, but in healthcare systems where awareness of the disease and screening are prevalent, this presentation has become uncommon.

Screening and diagnosis Screening for prostate cancer remains one of the most controversial public health issues. At present, prostate cancer screening continues to fall short of the World Health Organization criteria described by Wilson and Jungner, with its natural history poorly understood. PSA is a serum protease that is secreted by prostatic epithelium. It is not a specific marker for cancer as there are many nonmalignant processes that also elevate PSA, such as benign prostatic hyperplasia, urinary tract infection, urinary tract instrumentation, ejaculation, and traumatic catheterization. A total PSA cut off value of 3.0 ng/​ml is widely accepted in order to trigger further investigation, as best balancing the risk of missing clinically important cancers with the hazard of subjecting men to unnecessary prostate biopsies to reveal clinically insignificant disease. How men with a borderline elevation of PSA should best be advised is a matter of much debate. One study found that 44% of men with an isolated elevation of PSA had a normal PSA at one or more subsequent annual tests, hence standard advice is that a borderline result should be retested a few weeks later. Age-​adjusted norms for PSA improve the sensitivity and specificity of the measurement in clinical practice. PSA kinetics may be more valuable in making treatment decisions than a single value: a rapidly rising PSA with a short doubling time (even if starting at a very low number) indicates that a man is likely to have high-​risk prostate cancer. More recently, however, it has been shown that a single PSA value of 1 ng/​ml or higher from the age of 45 years may determine the necessity for further and frequent testing. The diagnosis of prostate cancer, suspected following measurement of serum PSA, is established by transrectal ultrasound-​guided biopsy, which in itself can carry morbidity and complications. There is increasing enthusiasm for the use of prebiopsy multiparametric magnetic resonance imaging (mpMRI) in order to identify or exclude ‘significant’ lesions, and facilitate MRI-​transrectal ultrasound fusion biopsies. At present, the use of prebiopsy mpMRI is not widespread in most countries, but is likely to evolve following completion of ongoing clinical trials. Protocols incorporating imaging into screening programmes will need to be evaluated prospectively. Most cases of prostate cancer detectable through PSA-​ based screening are of low-​or intermediate-​risk of progression. Most of these screen-​detected cases may never become lethal during an individual’s lifetime, and it is becoming increasingly apparent that our definition of ‘significant’ versus ‘insignificant’ prostate cancer is inadequate. However, there is compelling evidence from the European Randomised study of Screening for Prostate Cancer (ERSPC) that PSA-​based screening for prostate cancer can yield a significant survival benefit, as well as a reduction in the burden of metastatic disease, albeit at the cost of exposing unacceptably large numbers of men to radical treatment for each life saved. The fact that the ERSPC clearly demonstrated that prostate cancer screening can reduce the future development of advanced metastatic disease can be used as a powerful argument for the introduction of screening. However, it is likely that the screening process could be further refined by the risk stratification of men at the introduction of the screening process, taking into consideration factors such as family history, race, life expectancy, and baseline PSA level, with the subsequent screening protocol modified for individuals based on these risk factors. The frequency with which men may need to be screened may also be influenced by their initial PSA test result within a screening programme protocol. Other developments in the prostate cancer diagnosis pathway, such as

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the use of additional kallikrein markers, targeted screening, and the introduction of mpMRI, may improve the performance of a screening protocol such that the benefits could be increased and the risks reduced. These and other future developments are likely to influence the ratio of risks to benefits in favour of the introduction of screening in due course. In the meantime, men who request PSA testing should only receive the test after careful professional counselling about the potential benefits and harms caused by screening for prostate cancer.

Management and prognosis Clinically localized disease Effective treatments to cure clinically localized prostate cancer are widely available, including different forms of radiotherapy and minimally invasive surgery such as robot-​assisted laparoscopic radical prostatectomy, with excellent outcomes. Since Walsh and Donker first described the anatomy of the prostatic apex, ligaments and nerves that enabled development of nerve-​sparing radical prostatectomy in 1982, morbidity associated with radical surgery has decreased substantially, with reduced rates of postoperative impairment of continence and erectile function. The advent of laparoscopic and robot-​assisted radical prostatectomy brings better visualization and potential improved outcomes, with reduced blood loss and length of hospital stay already reported. The Scandinavian prospective randomized controlled trial (RCT) SPCG-​ 4 comparing radical prostatectomy with watchful waiting demonstrated improved disease-​specific, overall survival and a reduction in disease progression in men receiving surgery. In parallel, the PIVOT (Prostate Intervention Versus Observational Treatment) study in the United States of America showed no benefit of surgery over watchful waiting in men with low-​risk disease and in those above the age of 65 years compared with watchful waiting. Over the last decade, there have been significant developments in the use of radiotherapy to manage localized prostate cancer. Biochemical relapse and survival rates appear similar to surgery and side effects have been reduced, enhanced by sophisticated three-​dimensional conformal or intensity-​modulated systems. The use of brachytherapy has also increased, either as monotherapy or in conjunction with external beam radiotherapy. The addition of neoadjuvant androgen deprivation therapy prior to external beam radiotherapy has also demonstrated improved outcomes in a number of RCTs, and this has become now standard practice globally. Paradoxically, many patients detected to have clinically localized prostate cancer following PSA screening do not require treatment, as their disease is unlikely to cause them harm in the long term, and they are best managed by active surveillance or monitoring, with delayed intervention if necessary. For low-​risk, low-​volume prostate cancer, universal recommendations are that they are suitable for active surveillance, with regular monitoring using PSA measurements, imaging, and repeat biopsies, although there is no consensus about the optimal protocol to maintain patients in a window of curability should their disease progress in due course, and some of these patients can progress while monitored. Other therapeutic options have developed, including the use of partial ablation of the prostate using different forms of energy delivery such as high-​intensity focused ultrasonography, cryotherapy, and vascular targeted photodynamic therapy. The potential advantages are the reduced functional adverse events with equivalent oncological outcomes compared with

conventional radical treatment options. These newer technologies are enhanced by considerable improvement in the reliability of imaging techniques. In the United Kingdom, the NIHR HTA ProtecT (Prostate Testing for Cancer and Treatment) trial is the world’s largest RCT comparing the three major treatment options in screen-​detected prostate cancer—​ surgery, radiotherapy, and active monitoring. Following screening of 82 429 men, 2664 received a diagnosis of localized prostate cancer, and 1643 were randomized. Prostate cancer-​specific mortality was low at 10 years irrespective of treatment (1.5 deaths/​1000 patient-​years in the active monitoring group vs 0.9 surgery vs 0.7 radiotherapy), but surgery and radiotherapy were associated with lower incidences of disease progression (22.9 events/​1000 patient-​years in the active monitoring group vs 8.9 surgery vs 9.0 radiotherapy) and metastases (6.3 events/​1000 patient-​years in the active monitoring group vs 2.4 surgery vs 3.0 radiotherapy). Locally advanced disease When prostate cancer infiltrates tissues into and beyond the prostatic capsule, it is likely to develop into progressive and metastatic disease and requires intervention. While approximately one-​third of men who receive radical treatment for clinically localized disease demonstrate pathological evidence of extracapsular extension, many of these will not require additional treatment, but residual disease after surgery will benefit from salvage external beam radiotherapy. Large RCTs have demonstrated the benefit of androgen deprivation therapy for up to 3 years as an adjunct to radiotherapy in men with clinically locally advanced disease, compared with radiotherapy or androgen deprivation therapy alone. Metastatic disease Aggressive prostate cancer tends to spread to locoregional and distant lymph nodes, and particularly to the axial skeleton. There is a particular affinity between primary prostate cancer epithelial cells and the bone microenvironment, leading to a mixed picture of osteolytic and osteoblastic skeletal lesions. These lead to weakening of the skeletal architecture, deranged bone remodelling, and sequelae such as skeletal pain, pathological fractures, and cord compression. The mainstay of treatment in metastatic prostate cancer is the administration of androgen deprivation therapy to reduce levels of circulating testosterone. This causes apoptosis in prostate cells and remissions in most patients lasting 3 years or longer, after which castration-​resistant disease becomes likely with morbidities leading to death from prostate cancer in due course. Androgen deprivation therapy treatment relies on the interface between prostate cancer cell growth and the androgen receptor axis. The androgen receptor is an intracellular steroid receptor normally present in the cytoplasm when in an inactive state. It is maintained by chaperone binding in an inactive conformation; upon binding to dihydrotestosterone, the androgen receptor changes into its active conformation and is separated from its chaperones. Once in the active conformation, the nuclear localization signal is exposed, leading to the translocation of androgen receptor into the nucleus, where it binds to the androgen response element motifs in the promoter regions of its target genes. In prostate cancer cells, this transactivates the expression of a number of genes responsible for cell proliferation.

21.18  Malignant diseases of the urinary tract

Typically, men with metastatic prostate cancer will receive oral antiandrogens followed by a luteinizing hormone-​releasing hormone agonist, or antagonist without preliminary antiandrogens. Symptomatic relief, particularly of pain, and objective remission in measurable metastatic lesions can be achieved with side effects related to loss of libido and sexual function, and metabolic changes as well as effects on cognitive function. More recently, androgen deprivation therapy has also been associated with an increased risk in cardiovascular events. Once castration-​resistant prostate cancer is established, second-​ line hormone treatment with newer agents such as abiraterone (an androgen synthesis inhibitor) and enzalutamide (a synthetic nonsteroidal antiandrogen) can be used in conjunction with prednisolone, also with cytotoxics such as docetaxel and cabazitaxel, all of which have been shown to improve survival through large-​ scale RCTs. Skeletal-​related events can be delayed and reduced in incidence by modulating osteoclast activity through agents such as bisphosphonates and RANK-​ligand inhibition. Intravenous administration of the bone-​seeking radioisotope radium-​223 has been shown to improve survival and reduce skeletal related events. There is currently one form of immunotherapy approved for the treatment of castration-​resistant prostate cancer: Sipuleucel-​T, generated from the patient’s peripheral blood mononuclear cells. The vaccine relies on the ex vivo activation of antigen-​presenting cells with recombinant PSA. Improved survival was demonstrated of the same order as that obtained by cytotoxic chemotherapy. Other prostate cancer vaccines are undergoing intensive investigation at present, aimed at modulating the immune system to treat this lethal form of the disease.

Likely developments in the near future The management of prostate cancer remains one of the most controversial public health problems. While screening is currently not recommended as a public health policy in any country worldwide, opportunistic PSA testing continues to result in overdetection and overtreatment of indolent cancers, and paradoxically undertreatment in men with unrecognized lethal forms of the disease. Targeted screening in men at high risk of harbouring aggressive prostate cancer, accurate stratification of patients at risk of developing the metastatic and lethal phenotype, and providing precision treatment to individual patients tailored to their specific cancer signatures through novel biomarkers and risk factors all remain challenging tasks for researchers worldwide.

Testicular cancer Introduction Testicular tumours affect predominantly young adult men in whom they are the most common malignant tumours. Most (95%) are germ cell tumours; less commonly they are of stromal cell origin (Sertoli and Leydig cell tumours), lymphomas, or metastases, and tumours may also rarely occur in the rete testis. Testicular germ cell tumours are commonest in the Caucasian population, especially in Northern Europe. There is strong familial predisposition and an increased risk in patients with prior testicular maldescent, testicular atrophy, and other urogenital abnormalities.

Patients with inherited syndromes, including Klinfelter’s and Down’s syndromes, are also at increased risk of testicular cancer. Prevalence has increased markedly over the last 100  years and testicular tumours now affect approximately 1 in 400 European men.

Aetiology, pathogenesis, and pathology The pathogenesis of testicular cancer is thought to involve a noninvasive precursor stage, termed intratubular germ cell neoplasia or carcinoma in situ. Although the natural history of this condition is not completely defined, it would appear that most men with it eventually progress to invasive testicular cancer. The pathology of testicular germ cell tumours is complex. Approximately 50% of patients present with a pure classical seminoma. Seminomas resemble primordial germ cells and are often associated with lymphocytic infiltrate. The remainder are generally classed as nonseminoma germ cell tumours (NSGCTs) and consist of tumours either of tissues of embryonic or extra-​embryonic origin, including yolk sac and placental tissue (choriocarcinoma). The most undifferentiated form of this tumour is termed ‘embryonal carcinoma’. Tumours may be of one subtype or, more frequently, consist of mixed subtypes. Mixtures of nonseminoma and seminoma tumours can also be found (termed combined tumours). The presence of any nonseminomatous element defines a tumour as nonseminoma, and leads to treatment as for nonseminoma.

Clinical features About 90% of testicular germ cell tumours present in men as a lump in the testis, which is usually painless but may less commonly be associated with an ache or episodic pain. About 10% present with symptoms of advanced disease such as back pain (retroperitoneal nodal disease), cough, haemoptysis or shortness of breath (lung metastases), bone pain (skeletal metastases), neck mass (supraclavicular lymph node metastasis), unilateral or bilateral leg swelling (iliac or caval venous thrombosis or obstruction), upper gastrointestinal symptoms (retroperitoneal upper abdominal metastases), or gynaecomastia (raised human chorionic gonadotropin (HCG)).

Assessment Initial investigations consist of a testicular ultrasound examination, where the characteristic appearance of a hypoechoic lesion is usually sufficient to confirm diagnosis (Fig. 21.18.5). Many tumours secrete onco-​ fetal proteins/​ tumour markers (α-​fetoprotein) or β-​HCG (Table 21.18.6). These should be measured when a testicular germ cell tumour is suspected as they have a role in diagnosis, prognostication, and monitoring of disease, although they are not universally present. α-​Fetoprotein is not elevated in seminomas. Once the diagnosis is confirmed, disease extent is assessed by a CT examination of the chest, abdomen, and pelvis. Patients with extensive lung metastases or high HCG levels should receive brain imaging (CT or MRI). PET imaging does not have a routine role, but is occasionally useful for problem-​solving in case of equivocal findings.

Staging Until recently, patients have been staged according to the Royal Marsden system, but this has been supplanted by the TNM staging system (Table 21.18.7). The key division is between stage 1 disease

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Fig. 21.18.5  Ultrasound scan of testis showing lesion of heterogeneous echogenicity replacing most of testis. Courtesy of Addenbrooke’s Hospital, Urology and Radiology departments.

and other stages when metastases are present. For those with metastatic disease, management is defined by the International Germ Cell Collaboration Group (IGCCG) prognostic factor index (Table 21.18.8). Patients with persistently elevated markers and no imaging abnormality are labelled as ‘stage 1M’ and treated as for metastatic disease. Seminomas are divided into good or intermediate classification depending on the presence or absence of nonpulmonary visceral metastases.

Management and prognosis For most patients, initial management consists of an inguinal orchidectomy. The inguinal approach avoids scrotal contamination of tumour and better access for securing the inguinal blood vessels. Patients with an equivocal lesion or an absent testis or atrophic testicular atrophy should be referred for a specialist opinion and consideration be given for undertaking excisional biopsy/​partial orchidectomy. Patients presenting with extensive disease, particularly with lung metastasis in the presence of markedly raised HCG, should be discussed with a specialist oncology service. In this situation, disease can be rapidly progressive and immediate chemotherapy is usually indicated. Stage 1 disease Most patients present with stage 1 disease (seminoma 80–​85%, nonseminoma 70–​75%) and have an expected cure rate of 98 to 99%.

However, despite a normal staging scan on follow-​up, some patients will develop relapse. The key issue in management is whether to follow patients (surveillance with salvage treatment at relapse) or to offer immediate adjuvant therapy. Both approaches achieve similar long-​term survival. The decision is a complex one and depends on the assessment of risk of relapse, and long-​term risks of adjuvant versus more intensive salvage treatment. Considerations are patient preference, ability to comply with surveillance, psychological issues, and (in some healthcare systems) personal financial issues. Surveillance involves regular marker estimations and chest imaging, with intermittent cross-​sectional imaging (Table 21.18.9). Clinical examination is usually performed, but its value is questioned. There is concern about the radiation dose of repeat CT imaging, and to limit such exposure it may be possible to restrict imaging to the retroperitoneal lymph nodal areas, either by CT scan or (increasingly) by MRI. An Medical Research Council trial has shown that imaging at 3 and 12 months may be sufficient for stage 1 NSGCT. If adjuvant treatment is required for seminoma, a single dose of carboplatin AUC7 reduces the risk of recurrence to less than 5%. Radiotherapy was formerly widely used, but is not now recommended because of concern with regard to the long-​term risk of a second malignancy. In NSGCT, two cycles of the ‘BEP’ schedule (see following ‘Metastatic disease’ section) have been shown to reduce the risk of recurrence in high-​risk stage 1 patients to less than 2%, and recent data suggests that one cycle of BEP may be sufficient, with

Table 21.18.6  Testicular tumour markers Marker

Seminoma

Nonseminoma

Other causes of raised marker

α-​Fetoprotein

Never raised

40%

Hepatocellular cancer, gastric cancer, alcohol, other liver disease, hereditary

β-​HCG

15–​20%

40%

Neuroendocrine, bladder, kidney, lung, and rarely other cancers. marijuana, hypogonadism

LDH

40–​60%

40–​60%

Infection, inflammation

21.18  Malignant diseases of the urinary tract

Table 21.18.7  Royal Marsden Hospital (RMH) and TNM staging systems compared Stage group

RMH system

TNM system

I

Testis only

T1–​T4 N0 M0

II

Infra-​diaphragmatic lymph node involvement

T1–​T4 N1–​3 M0

III

Infra-​diaphragmatic lymph node involvement

Any T, any N M1a (nonregional lymph nodes)

IV

Extranodal metastases

Any T, any N M1a (pulmonary metastases) or M1b (nonpulmonary visceral metastases)

In the RMH system, each stage is subcategorized according to the size of abdominal mass that maps onto N1–​3 in the TNM system, i.e. A (N1) 5 cm.

several studies showing a risk of relapse of less than 5%, hence one cycle of BEP is increasingly recommended as the optimal adjuvant treatment. Metastatic disease The mainstay of management of metastatic germ cell tumours has been the BEP schedule (bleomycin 30  000 IU days 1, 8, and 15; etoposide 100 mg/​m2 days 1–​5; cisplatin 20 mg/​m2 days 1–​5; on a 21-​day cycle) This is a highly successful treatment, but should be given without dose reduction or delays to optimize outcomes. Use of supportive treatments (antiemetics, growth factors) is recommended to achieve this, but it does have a significant burden of toxicities, both acute and late (Table 21.18.10). For good prognosis disease, a randomized trial has defined three cycles as the appropriate treatment, and potentially the chemotherapy can be given over 3 days. The exception to this is in stage 2a/​b seminoma, where radiotherapy to the para-​aortic nodes with or without carboplatin is equally effective and may be better tolerated. In intermediate or poor prognosis disease, four cycles of 5-​day BEP is recommended. The outcomes, particularly in poor prognosis disease, remain less than satisfactory. A number of approaches have been tried to improve results, as summarized in Table 21.18.11. To date, however, none have been shown to improve overall survival, but some may improve progression-​free survival. The GETUG study investigated if slow marker decline could be utilized to select patients for dose intensification. In this study, patients with a ‘good’ marker decline (c.20%) who had a better prognosis received BEP chemotherapy and those with a poor marker decline were randomized to dose intensification versus BEP. The dose intensified patients had better progression-​ free survival, lower use of salvage high-​dose chemotherapy, and showed a trend to improved survival.

Residual masses commonly remain following chemotherapy. In NSGCTs, it is recommended that these are completely resected (if >1 cm) as they may harbour residual malignancy (in which case surgery may be curative) or be teratoma differentiated. Though the latter histology is generally regarded as being benign, teratoma differentiated can gradually enlarge and become unresectable, transform to more active germ cell tumour, develop into somatic malignancies, and may be responsible for the phenomenon of late relapse. Seminomas should not develop teratoma differentiated, and routine treatment to residual masses has not been shown to improve outcome. A significant proportion of large (>3 cm) residual masses may, however, harbour residual active seminoma. An FDG-​PET scan taken more than 6 weeks after chemotherapy has shown a high sensitivity for residual disease and is recommended to define subsequent treatments. Salvage treatment About 10% of good prognosis, 20% of intermediate prognosis, and 40 to 50% of poor prognosis patients will go on to develop relapse. Management of these cases is challenging, but usually involves chemotherapy along with aggressive local therapy and/​or high-​ dose chemotherapy. A number of salvage regimens have been described, the most common of which is probably the TIP schedule (paclitaxel 250 mg m2 over 24 h; ifosfamide 1.5 g/​m2 daily, days 2–​5; cisplatin 25 mg/​m2, days 2–​5) given for a total of four cycles. The success of this treatment has been shown to depend on pretreatment prognostic factors (Table 21.18.12), but overall 30% of patients are cured by this approach. The main debate is whether treatment should be consolidated, or replaced in second line by use of high-​dose chemotherapy. An international retrospective study suggested some improvement with immediate high-​dose chemotherapy, but the one European randomized trial of this approach showed no significant advantage. A further trial of cyclical high-​dose chemotherapy (TIGER trial) was launched in 2016. Consolidation of salvage chemotherapy should utilize aggressive surgery and/​or radiotherapy wherever possible. Some patients develop what is termed a late relapse, defined as a relapse more than 2 years after initial treatment. These tumours often secrete α-​fetoprotein and tend to be relatively drug resistant. Surgical excision is the optimal approach. Prognosis Overall, the cure rate of testicular germ cell is favourable, with a 5-​ year survival in the United Kingdom of over 97% rising to over 99% in patients with stage 1 disease. For most patients, the key issues as highlighted are maintaining cures but minimizing long-​term

Table 21.18.8  International Germ Cell Collaboration Group prognostic classification for nonseminomas Category

Criteria

HCG level IU/​litre

α-​Fetoprotein level IU/​litre

LDH × normal

NPVM

Mediastinal primary

Predicted PFS

Good

All of

10

Yes

Yes

41%

Intermediate Poor

Any of

HCG, human chorionic gonadotropin; LDH, lactate dehydrogenase; NPVM, nonpulmonary visceral metastases; PFS, progression-​free survival. a I or marker category plus no nonpulmonary visceral metastases or mediastinal mass.

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Table 21.18.9  Surveillance schedules for stage 1 germ cell tumours Nonseminoma

Seminoma

Year 1

1 months

3 months

Year 2

3 months

3 months

Year 3

4 months

4 months

Year 4

6 months

6 months

Year 5

6 months

6 months

Imaging

3 months, 12 months

6, 12, 18, 24, 36, 48, and 60 months

Table 21.18.12  International Germ Cell Consensus Classification Group-​2 prognostic classification for germ cell tumours undergoing salvage treatment Variable

Markers and clinical review are performed at each visit, and chest radiograph at alternate visits in year 1. Imaging is by CT or MRI, and may be restricted to abdomen in most patients. Source data from Van As et al. Evidence-​based pragmatic guidelines for the follow-​up of testicular cancer: optimising the detection of relapse, Br J Cancer. 2008 Jun 17; 98(12): 1894–​1902.

Histology

Seminoma 1, nonseminoma 0

Primary site

Gonadal 0, retroperitoneal 1, mediastinum 3

Response first line

CR/​PRM− 0, PRM + 1, PD 2

Progression free interval

>3 months 0, 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

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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.

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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

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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.

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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)

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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

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(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

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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

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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.

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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)

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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),

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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,

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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.

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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

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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

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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

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(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.

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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

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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.

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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

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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,

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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

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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

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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

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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.

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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

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• 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).

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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.

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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

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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

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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,

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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.

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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

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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)

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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.

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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.

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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

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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.

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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

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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).

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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

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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.

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(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

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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.

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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

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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